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Sample records for acute streptococcal sepsis

  1. Streptococcal acute pharyngitis.

    PubMed

    Anjos, Lais Martins Moreira; Marcondes, Mariana Barros; Lima, Mariana Ferreira; Mondelli, Alessandro Lia; Okoshi, Marina Politi

    2014-07-01

    Acute pharyngitis/tonsillitis, which is characterized by inflammation of the posterior pharynx and tonsils, is a common disease. Several viruses and bacteria can cause acute pharyngitis; however, Streptococcus pyogenes (also known as Lancefield group A β-hemolytic streptococci) is the only agent that requires an etiologic diagnosis and specific treatment. S. pyogenes is of major clinical importance because it can trigger post-infection systemic complications, acute rheumatic fever, and post-streptococcal glomerulonephritis. Symptom onset in streptococcal infection is usually abrupt and includes intense sore throat, fever, chills, malaise, headache, tender enlarged anterior cervical lymph nodes, and pharyngeal or tonsillar exudate. Cough, coryza, conjunctivitis, and diarrhea are uncommon, and their presence suggests a viral cause. A diagnosis of pharyngitis is supported by the patient's history and by the physical examination. Throat culture is the gold standard for diagnosing streptococcus pharyngitis. However, it has been underused in public health services because of its low availability and because of the 1- to 2-day delay in obtaining results. Rapid antigen detection tests have been used to detect S. pyogenes directly from throat swabs within minutes. Clinical scoring systems have been developed to predict the risk of S. pyogenes infection. The most commonly used scoring system is the modified Centor score. Acute S. pyogenes pharyngitis is often a self-limiting disease. Penicillins are the first-choice treatment. For patients with penicillin allergy, cephalosporins can be an acceptable alternative, although primary hypersensitivity to cephalosporins can occur. Another drug option is the macrolides. Future perspectives to prevent streptococcal pharyngitis and post-infection systemic complications include the development of an anti-Streptococcus pyogenes vaccine. PMID:25229278

  2. The contribution of group A streptococcal virulence determinants to the pathogenesis of sepsis.

    PubMed

    Reglinski, Mark; Sriskandan, Shiranee

    2014-01-01

    Streptococcus pyogenes (group A streptococcus, GAS) is responsible for a wide range of pathologies ranging from mild pharyngitis and impetigo to severe invasive soft tissue infections. Despite the continuing susceptibility of the bacterium to β-lactam antibiotics there has been an unexplained resurgence in the prevalence of invasive GAS infection over the past 30 years. Of particular importance was the emergence of a GAS-associated sepsis syndrome that is analogous to the systemic toxicosis associated with TSST-1 producing strains of Staphylococcus aureus. Despite being recognized for over 20 years, the etiology of GAS associated sepsis and the streptococcal toxic shock syndrome remains poorly understood. Here we review the virulence factors that contribute to the etiology of GAS associated sepsis with a particular focus on coagulation system interactions and the role of the superantigens in the development of streptococcal toxic shock syndrome. PMID:24157731

  3. The contribution of group A streptococcal virulence determinants to the pathogenesis of sepsis

    PubMed Central

    Reglinski, Mark; Sriskandan, Shiranee

    2014-01-01

    Streptococcus pyogenes (group A streptococcus, GAS) is responsible for a wide range of pathologies ranging from mild pharyngitis and impetigo to severe invasive soft tissue infections. Despite the continuing susceptibility of the bacterium to β-lactam antibiotics there has been an unexplained resurgence in the prevalence of invasive GAS infection over the past 30 years. Of particular importance was the emergence of a GAS-associated sepsis syndrome that is analogous to the systemic toxicosis associated with TSST-1 producing strains of Staphylococcus aureus. Despite being recognized for over 20 years, the etiology of GAS associated sepsis and the streptococcal toxic shock syndrome remains poorly understood. Here we review the virulence factors that contribute to the etiology of GAS associated sepsis with a particular focus on coagulation system interactions and the role of the superantigens in the development of streptococcal toxic shock syndrome. PMID:24157731

  4. Delayed onset of right congenital diaphragmatic hernia associated with Group B streptococcal sepsis in a neonate.

    PubMed

    Parida, Lalit

    2016-01-01

    A full-term male neonate was initially managed for respiratory distress which developed few hours after birth. His initial chest radiograph was normal, and blood culture revealed Group B streptococcal (GBS) sepsis. He subsequently developed progressive right chest opacification that did not improve with medical management. Imaging done few days later revealed right-sided diaphragmatic hernia. The 12-day-old neonate underwent primary repair of the diaphragmatic defect and had an uneventful recovery. This case report intends to highlight this unique association between early onset GBS sepsis and delayed onset of the right congenital diaphragmatic hernia. PMID:27046983

  5. An Unbiased Systems Genetics Approach to Mapping Genetic Loci Modulating Susceptibility to Severe Streptococcal Sepsis

    PubMed Central

    Abdeltawab, Nourtan F.; Aziz, Ramy K.; Kansal, Rita; Rowe, Sarah L.; Su, Yin; Gardner, Lidia; Brannen, Charity; Nooh, Mohammed M.; Attia, Ramy R.; Abdelsamed, Hossam A.; Taylor, William L.; Lu, Lu; Williams, Robert W.; Kotb, Malak

    2008-01-01

    Striking individual differences in severity of group A streptococcal (GAS) sepsis have been noted, even among patients infected with the same bacterial strain. We had provided evidence that HLA class II allelic variation contributes significantly to differences in systemic disease severity by modulating host responses to streptococcal superantigens. Inasmuch as the bacteria produce additional virulence factors that participate in the pathogenesis of this complex disease, we sought to identify additional gene networks modulating GAS sepsis. Accordingly, we applied a systems genetics approach using a panel of advanced recombinant inbred mice. By analyzing disease phenotypes in the context of mice genotypes we identified a highly significant quantitative trait locus (QTL) on Chromosome 2 between 22 and 34 Mb that strongly predicts disease severity, accounting for 25%–30% of variance. This QTL harbors several polymorphic genes known to regulate immune responses to bacterial infections. We evaluated candidate genes within this QTL using multiple parameters that included linkage, gene ontology, variation in gene expression, cocitation networks, and biological relevance, and identified interleukin1 alpha and prostaglandin E synthases pathways as key networks involved in modulating GAS sepsis severity. The association of GAS sepsis with multiple pathways underscores the complexity of traits modulating GAS sepsis and provides a powerful approach for analyzing interactive traits affecting outcomes of other infectious diseases. PMID:18421376

  6. The Coagulopathy of Acute Sepsis

    PubMed Central

    Simmons, Jeff; Pittet, Jean-Francois

    2015-01-01

    Purpose of Review Sepsis, defined by the presence of infection and host inflammation, is a lethal clinical syndrome with an increasing mortality rate worldwide. In severe disease, the coagulation system becomes diffusely activated, with consumption of multiple clotting factors resulting in Disseminated Intravascular Coagulation (DIC). When present, DIC portends a higher mortality rate. Understanding the mechanisms that tie inflammation and diffuse thrombosis will allow therapeutic interventions to be developed. The Coagulopathy of Acute Sepsis is a dynamic process that is time and disease burden specific. Whole blood testing of coagulation may provide more clinically useful information than classical tests. Natural anticoagulants that regulate thrombosis are down regulated in sepsis. Patients may benefit from modulation of the coagulation system when systemic inflammation and hypercoagulopathy exist. Proper timing of anticoagulant therapy may ultimately lead to decreased incidence of multisystem organ dysfunction (MODS). Recent Findings The pathogenesis of coagulopathy in sepsis is driven by an up-regulation of procoagulant mechanisms and simultaneous down-regulation of natural anticoagulants. Inflammation caused by the invading organism is a natural host defense than cannot be eliminated during treatment. Successful strategies to prevent MODS center on stratifying patients at high risk for DIC and restoring the balance of inflammation and coagulation. Summary The prevention of DIC in septic patients is a key therapeutic target in preventing death from multisystem organ failure. Stratifying patients for therapy using thromboelastometry, specific markers for DIC, and composite scoring systems is an area of growing research. PMID:25590467

  7. Acute Placental Villitis as Evidence of Fetal Sepsis: An Autopsy Case Report.

    PubMed

    Bae, Go Eun; Yoon, Nara; Choi, Misun; Hwang, Soohyun; Hwang, Hyewon; Kim, Jung-Sun

    2016-01-01

    Acute placental villitis is very rare and believed to reflect overwhelming fetal sepsis in utero, commonly caused by Escherichia coli or group B streptococci. We present a case of intrauterine fetal death associated with acute placental villitis and acute necrotizing chorioamnionitis by early-onset group B streptococcal infection. A 36-year-old woman presented with decreased fetal movement and fever at 21 weeks of gestation. Ultrasound demonstrated intrauterine fetal death. After delivery, the placenta revealed multifocal neutrophilic infiltration in chorionic villi, most prominently beneath the trophoblast basement membrane, which was also accompanied by acute necrotizing chorioamnionitis. Gram-positive microorganisms were detected in villous vessels as well as in the major organs of the fetus, which was consistent with Streptococcus agalactiae (group B) cultured from maternal blood. Acute placental villitis should be recognized as evidence of fetal sepsis that often has lethal clinical outcome, as compared to intra-amniotic infection associated with acute chorioamnionitis alone. PMID:26457860

  8. Pathogenic mechanism of acute post-streptococcal glomerulonephritis.

    PubMed

    Nordstrand, A; Norgren, M; Holm, S E

    1999-01-01

    Considerable knowledge has been accumulated regarding the characteristics of acute post-streptococcal glomerulonephritis (APSGN), and many attempts have been made to identify a streptococcal factor or factors responsible for triggering this disease. However, the pathogenic mechanism behind APSGN remains largely unknown. As glomerular deposition of C3 is generally demonstrated before that of IgG in the disease process, it is likely that the inflammatory response is initiated by renal deposition of a streptococcal product, rather than by deposition of antibodies or pre-formed immune complexes. During recent years, a number of streptococcal products have been suggested to be involved in the pathogenic process. In this review, possible roles of these factors are discussed in the context of the clinical and renal findings most often demonstrated in patients with APSGN. Streptokinase was observed to be required in order to induce signs of APSGN in mice, and a number of findings suggest that the initiation of the disease may occur as a result of renal binding by certain nephritis-associated variants of this protein. However, additional factors may be required for the development of the disease. PMID:10680980

  9. Post–Acute Care Use and Hospital Readmission after Sepsis

    PubMed Central

    Jones, Tiffanie K.; Fuchs, Barry D.; Small, Dylan S.; Halpern, Scott D.; Hanish, Asaf; Umscheid, Craig A.; Baillie, Charles A.; Kerlin, Meeta Prasad; Gaieski, David F.

    2015-01-01

    Rationale: The epidemiology of post–acute care use and hospital readmission after sepsis remains largely unknown. Objectives: To examine the rate of post–acute care use and hospital readmission after sepsis and to examine risk factors and outcomes for hospital readmissions after sepsis. Methods: In an observational cohort study conducted in an academic health care system (2010–2012), we compared post–acute care use at discharge and hospital readmission after 3,620 sepsis hospitalizations with 108,958 nonsepsis hospitalizations. We used three validated, claims-based approaches to identify sepsis and severe sepsis. Measurements and Main Results: Post–acute care use at discharge was more likely after sepsis, driven by skilled care facility placement (35.4% after sepsis vs. 15.8%; P < 0.001), with the highest rate observed after severe sepsis. Readmission rates at 7, 30, and 90 days were higher postsepsis (P < 0.001). Compared with nonsepsis hospitalizations (15.6% readmitted within 30 d), the increased readmission risk was present regardless of sepsis severity (27.3% after sepsis and 26.0–26.2% after severe sepsis). After controlling for presepsis characteristics, the readmission risk was found to be 1.51 times greater (95% CI, 1.38–1.66) than nonsepsis hospitalizations. Readmissions after sepsis were more likely to result in death or transition to hospice care (6.1% vs. 13.3% after sepsis; P < 0.001). Independent risk factors associated with 30-day readmissions after sepsis hospitalizations included age, malignancy diagnosis, hospitalizations in the year prior to the index hospitalization, nonelective index admission type, one or more procedures during the index hospitalization, and low hemoglobin and high red cell distribution width at discharge. Conclusions: Post–acute care use and hospital readmissions were common after sepsis. The increased readmission risk after sepsis was observed regardless of sepsis severity and was associated with

  10. Sepsis-Associated Acute Kidney Injury

    PubMed Central

    Alobaidi, Rashid; Basu, Rajit K.; Goldstein, Stuart L.; Bagshaw, Sean M.

    2015-01-01

    Summary Acute kidney injury (AKI) is an epidemic problem. Sepsis has long been recognized as a foremost precipitant of AKI. Sepsis-associated AKI (SA-AKI) portends a high burden of morbidity and mortality in both children and adults with critical illness. Although our understanding of its pathophysiology is incomplete, SA-AKI likely represents a distinct subset of AKI contributed to by a unique constellation of hemodynamic, inflammatory, and immune mechanisms. SA-AKI poses significant clinical challenges for clinicians. To date, no singular effective therapy has been developed to alter the natural history of SA-AKI. Rather, current strategies to alleviate poor outcomes focus on clinical risk identification, early detection of injury, modifying clinician behavior to avoid harm, early appropriate antimicrobial therapy, and surveillance among survivors for the longer-term sequelae of kidney damage. Recent evidence has confirmed that patients no longer die with AKI, but from AKI. To improve the care and outcomes for sufferers of SA-AKI, clinicians need a robust appreciation for its epidemiology and current best-evidence strategies for prevention and treatment. PMID:25795495

  11. Sepsis and Acute Respiratory Distress Syndrome: Recent Update

    PubMed Central

    Kim, Won-Young

    2016-01-01

    Severe sepsis or septic shock is characterized by an excessive inflammatory response to infectious pathogens. Acute respiratory distress syndrome (ARDS) is a devastating complication of severe sepsis, from which patients have high mortality. Advances in treatment modalities including lung protective ventilation, prone positioning, use of neuromuscular blockade, and extracorporeal membrane oxygenation, have improved the outcome over recent decades, nevertheless, the mortality rate still remains high. Timely treatment of underlying sepsis and early identification of patients at risk of ARDS can help to decrease its development. In addition, further studies are needed regarding pathogenesis and novel therapies in order to show promising future treatments of sepsis-induced ARDS. PMID:27066082

  12. Acute nonrheumatic streptococcal myocarditis resembling ST-elevation acute myocardial infarction in a young patient

    PubMed Central

    Jurado, Margarita; Porres-Aguilar, Mateo; Olivas-Chacon, Cristina; Porres-Muñoz, Mateo; Mukherjee, Debabrata; Taveras, Juan

    2015-01-01

    Acute myocarditis can be induced by various concomitant disease processes including infections. Most of these cases are viral in origin; however, bacterial infections are also implicated to a lesser degree. Group A streptococcus is a frequent culprit in bacterial-induced myocarditis. Its diagnosis is suspected by the presence of signs and symptoms of rheumatic fever as established by the Jones criteria. The development and refinement of current diagnostic tools has improved our ability to identify specific pathogens. It has been found that group A streptococcus may be responsible for more cases of infection-induced acute myocarditis than previously thought, and often without the clinical features of rheumatic fever. We present the case of a 43-year-old man hospitalized with chest pain that was initially diagnosed as an acute ST-elevation myocardial infarction. Further evaluation confirmed that his chief complaint was due to acute nonrheumatic streptococcal myocarditis. PMID:25829649

  13. Vaccine based on a ubiquitous cysteinyl protease and streptococcal pyrogenic exotoxin A protects against Streptococcus pyogenes sepsis and toxic shock

    PubMed Central

    Ulrich, Robert G

    2008-01-01

    Background The gram-positive bacterium Streptococcus pyogenes is a common pathogen of humans that causes invasive infections, toxic-shock syndrome, rheumatic fever, necrotizing fasciitis and other diseases. Detection of antibiotic resistance in clinical isolates has renewed interest in development of new vaccine approaches for control S. pyogenes sepsis. In the study presented, a novel protein vaccine was examined. The vaccine was based on a recombinant protein fusion between streptococcal pyrogenic exotoxin B (SpeB), a cysteinyl protease expressed by all clinical isolates, and streptococcal pyrogenic exotoxin A (SpeA), a superantigen produced by a large subset of isolates. Results A novel protein was produced by mutating the catalytic site of SpeB and the receptor binding surface of SpeA in a fusion of the two polypeptides. Vaccination of HLA-DQ8 transgenic mice with the SpeA-SpeB fusion protein protected against a challenge with the wild-type SpeA that was lethal to naïve controls, and vaccinated mice were protected from an otherwise lethal S. pyogenes infection. Conclusion These results suggest that the genetically attenuated SpeA-SpeB fusion protein may be useful for controlling S. pyogenes infections. Vaccination with the SpeA-SpeB fusion protein described in this study may potentially result in protective immunity against multiple isolates of S. pyogenes due to the extensive antibody cross-reactivity previously observed among all sequence variants of SpeB and the high frequency of SpeA-producing strains. PMID:18976486

  14. Improving Sepsis Management in the Acute Admissions Unit

    PubMed Central

    Adcroft, Laura

    2014-01-01

    Sepsis is a common condition with a major impact on healthcare resources and expenditure. We therefore wanted to investigate and improve how the acute admission unit (AAU) at the Great Western Hospital (GWH) is managing patients who present directly to the unit with sepsis. In order to obtain this information, an audit was undertaken against the College of Emergency Medicine standards used by the emergency department within GWH and across the UK. Data was retrospectively collected for 30 patients with a diagnosis of severe sepsis or septic shock. The notes were scrutinized with regard to the implementation of College of Emergency Medicine standards for the management of sepsis. This meant that performance in the AAU was compared against the emergency department at GWH and national figures. The data collected shows performance is below national standards with regard to documentation of high flow oxygen use (AAU: 24%, ED 100%; national median: 50%; CEM standard 95%), crystalloid fluid boluses (AAU: 52%; ED: 90%; national median: 83%; CEM standard 100%), lactate measurements (AAU: 66%, ED: 93%; national median: 80%; CEM standard 95%), and obtainment of blood cultures (AAU: 52%; ED 73%; national median: 77%; CEM standard: 95%). Only 3% of patients received all six parts of the sepsis bundle. Since auditing in 2012/2013 we have introduced a sepsis proforma based on a current proforma being used within Severn Deanery. This proforma uses the ‘Sepsis Six’ bundle appropriate to ward based care. We have raised awareness of sepsis implications and management through the creation of a ‘sepsis working group’ to educate both junior doctors and nurses. In turn, this has led to education through the use of posters, pocket reference cards, and teaching sessions. Re-audit shows significant improvement in administering all parts of the Sepsis Six bundle and an 8% improvement in patients receiving all six of the bundle. PMID:26734269

  15. Evidence of streptococcal origin of acute non-necrotising cellulitis: a serological study.

    PubMed

    Karppelin, M; Siljander, T; Haapala, A-M; Aittoniemi, J; Huttunen, R; Kere, J; Vuopio, J; Syrjänen, J

    2015-04-01

    Bacteriological diagnosis is rarely achieved in acute cellulitis. Beta-haemolytic streptococci and Staphylococcus aureus are considered the main pathogens. The role of the latter is, however, unclear in cases of non-suppurative cellulitis. We conducted a serological study to investigate the bacterial aetiology of acute non-necrotising cellulitis. Anti-streptolysin O (ASO), anti-deoxyribonuclease B (ADN) and anti-staphylolysin (ASTA) titres were measured from acute and convalescent phase sera of 77 patients hospitalised because of acute bacterial non-necrotising cellulitis and from the serum samples of 89 control subjects matched for age and sex. Antibiotic treatment decisions were also reviewed. Streptococcal serology was positive in 53 (69%) of the 77 cases. Furthermore, ten cases without serological evidence of streptococcal infection were successfully treated with penicillin. Positive ASO and ADN titres were detected in ten (11%) and three (3%) of the 89 controls, respectively, and ASTA was elevated in three patients and 11 controls. Our findings suggest that acute non-necrotising cellulitis without pus formation is mostly of streptococcal origin and that penicillin can be used as the first-line therapy for most patients. PMID:25403372

  16. Improving management of severe sepsis and uptake of sepsis resuscitation bundle in an acute setting

    PubMed Central

    Kafle, Sumitra; Nath, Navdeep

    2014-01-01

    Severe sepsis still remains a major cause of morbidity and mortality, claiming between 36,000 to 64,000 lives annually in the UK, with a mortality rate of 35%.[1,2] The project aims to measure the management of severely septic patients in acute medical unit (AMU) in a district general hospital against best practice guidelines, before and after a set of interventions aiming to optimise patient management and outcomes. All new admissions who met the criteria for sepsis in AMU over a two week period were evaluated. Those who met the criteria for severe sepsis were further analysed. The criteria evaluated were time to first administration of oxygen, intravenous fluids, antibiotics, the taking of blood cultures, other relevant bloods tests (including lactate) and urine output monitoring. A re-audit was completed after the introduction of a set of interventions which included a “sepsis box.” A total of 32 patients (19 Males, 13 Females) were identified in the pre-intervention group. Twenty-two of these patients met the criteria for severe sepsis. Only 15 out of 32 (47%) had their lactate measured. Ten out of 22 (45%) received fluids within an hour. Twelve out of 22 (55%) had their blood culture sample taken after administration of antibiotics and only 12 out of 22 (55%) had antibiotics administrated within an hour of medical assessment. Post-intervention the results however improved dramatically. A total of 30 patients were identified in the post-intervention group (12 Males, 18 Females). Antibiotics administration within an hour went up by 22%. Lactate was performed in 26/30 (87%) patients presented with sepsis compared to 47% in the pre-intervention group. Similarly, identification of severe sepsis, and administration of intravenous fluids also showed improvement ultimately improving patient safety. Following the initial success, the trial was repeated over three months period, which showed sustainable improvement. PMID:26734299

  17. A Pediatric Case of Acute Generalized Pustular Eruption without Streptococcal Infection

    PubMed Central

    Tabata, Nobuko; Yoshizawa, Hideka

    2016-01-01

    Generalized pustular lesions characterized by acute onset with fever occur in pustulosis acuta generalisata, acute generalized exanthematous pustulosis, and generalized pustular psoriasis. In the present report, we describe a pediatric case of generalized pustular eruption that was not completely consistent with clinical features. Our patient had no evidence of a post-streptococcal infection. We observed scattered symmetric eruption of discrete pustules with an inflammatory halo on normal skin. The eruption was absent on her palms and soles of the feet. To the best of our knowledge, there are no reports in the English literature of cases with clinical features similar to those of our patient. PMID:27462226

  18. Sepsis

    MedlinePlus

    ... the episode 3 , 4 . What is the economic cost of sepsis? Treatment for sepsis often involves a ... care unit and complex therapies, which incur high costs. The Agency for Healthcare Research and Quality lists ...

  19. Sepsis

    MedlinePlus

    Sepsis is an illness in which the body has a severe response to bacteria or other germs. ... The symptoms of sepsis are not caused by the germs themselves. Instead, chemicals the body releases cause the response. A bacterial infection anywhere ...

  20. Sepsis

    MedlinePlus

    ... Symptoms In sepsis, blood pressure drops, resulting in shock . Major organs and body systems, including the kidneys, ... RS, Suffredini AF. Spesis, severe sepsis, and septic shock. In: Bennett JE, Dolin R, Mandell GL, eds. ...

  1. Sepsis

    MedlinePlus

    ... pressure drops and the heart weakens, leading to septic shock. Anyone can get sepsis, but the risk is higher in People with ... severe burn or physical trauma Common symptoms of sepsis are fever, chills, rapid breathing and heart rate, ...

  2. Post-streptococcal reactive arthritis in children: a distinct entity from acute rheumatic fever

    PubMed Central

    2011-01-01

    There is a debate whether post-streptococcal reactive arthritis (PSRA) is a separate entity or a condition on the spectrum of acute rheumatic fever (ARF). We believe that PSRA is a distinct entity and in this paper we review the substantial differences between PSRA and ARF. We show how the demographic, clinical, genetic and treatment characteristics of PSRA differ from ARF. We review diagnostic criteria and regression formulas that attempt to classify patients with PSRA as opposed to ARF. The important implication of these findings may relate to the issue of prophylactic antibiotics after PSRA. However, future trials will be necessary to conclusively answer that question. PMID:22013970

  3. CLOCK modulates survival and acute lung injury in mice with polymicrobial sepsis.

    PubMed

    Wang, Chao-Yung; Hsieh, Ming-Jer; Hsieh, I-Chang; Shie, Shian-Sen; Ho, Ming-Yun; Yeh, Jih-Kai; Tsai, Ming-Lung; Yang, Chia-Hung; Hung, Kuo-Chun; Wang, Chun-Chieh; Wen, Ming-Shien

    2016-09-16

    Polymicrobial sepsis is a potentially fatal condition and a significant burden on health care systems. Acute lung injury is the most common complication of sepsis and results in high mortality. However, there has been no recent significant progress in the treatment of sepsis or acute lung injury induced by sepsis. Here we show that mice deficient in the circadian protein CLOCK had better survival than wild-type mice after induction of polymicrobial sepsis by cecal ligation and puncture. Inflammatory cytokine production was attenuated and bacterial clearance was improved in CLOCK-deficient mice. Moreover, acute lung injury after induction of sepsis was significantly decreased in CLOCK-deficient mice. Genome-wide profiling analysis showed that inhibin signaling was reduced in CLOCK-deficient mice. These data establish the importance of circadian CLOCK-inhibin signaling in sepsis, which may have potential therapeutic implications. PMID:27520377

  4. Sepsis.

    PubMed

    Dean, Erin

    2016-07-20

    Essential facts Sepsis is a clinical syndrome caused by the body's immune and coagulation systems being switched on by an infection and is thought to cause 44,000 deaths a year. If not recognised early, sepsis can lead to shock, multiple organ failure and death. Sepsis is a leading cause of avoidable death that kills more people than breast, bowel and prostate cancer combined. PMID:27440336

  5. Sepsis.

    PubMed

    Dean, Erin

    2016-09-01

    Essential facts [Figure: see text] Sepsis, a clinical syndrome caused by the body's immune and coagulation systems being switched on by an infection, is believed to cause about 44,000 deaths a year. If not recognised early and treated promptly, sepsis can lead to shock, multiple organ failure and death. Major reports (UK parliamentary and health service ombudsman enquiry in 2013 and the UK National Confidential Enquiry into Patient Outcome and Death in 2015) have highlighted sepsis as being a leading cause of avoidable death that kills more people than breast, bowel and prostate cancer combined. PMID:27615338

  6. Sepsis.

    PubMed

    Dean, Erin

    2016-09-01

    Essential facts Sepsis, a clinical syndrome caused by the body's immune and coagulation systems being switched on by an infection, is believed to cause about 44,000 deaths a year. If not recognised early and treated promptly, sepsis can lead to shock, multiple organ failure and death. Major reports (UK parliamentary and health service ombudsman enquiry in 2013 and the UK National Confidential Enquiry into Patient Outcome and Death in 2015) have highlighted sepsis as being a leading cause of avoidable death that kills more people than breast, bowel and prostate cancer combined. PMID:27581906

  7. Knockdown of Burton's tyrosine kinase confers potent protection against sepsis-induced acute lung injury.

    PubMed

    Zhou, Panyu; Ma, Bing; Xu, Shuogui; Zhang, Shijie; Tang, Hongtai; Zhu, Shihui; Xiao, Shichu; Ben, Daofeng; Xia, Zhaofan

    2014-11-01

    Sepsis is a common and critical complication in surgical patients that often leads to multiple organ failure syndrome (MOFS), including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Despite intensive supportive care and treatment modalities, the mortality of these patients remains high. In this study, we investigated the role of Burton's tyrosine kinase (BTK), a member of the Btk/Tec family of cytoplasmic tyrosine kinases, in the pathogenesis of sepsis, and evaluated the protective effect of in vivo Btk RNA interference in a mouse model of cecal ligation and puncture (CLP)-induced sepsis. After intratracheal injection of Btk siRNA, the mice were then subjected to CLP to induce sepsis. The results demonstrated that this approach conferred potent protection against sepsis-induced ALI, as evidenced by a significant reduction in pathological scores, epithelial cell apoptosis, pulmonary edema, vascular permeability, and the expression of inflammatory cytokines and neutrophil infiltration in the lung tissues of septic mice. In addition, RNA interference of Btk significantly suppressed p-38 and iNOS signaling pathways in transduced alveolar macrophages in vitro. These results identify a novel role for BTK in lethal sepsis and provide a potential new therapeutic approach to sepsis and ALI. PMID:24906236

  8. Aspirin as a potential treatment in sepsis or acute respiratory distress syndrome.

    PubMed

    Toner, Philip; McAuley, Danny Francis; Shyamsundar, Murali

    2015-01-01

    Sepsis is a common condition that is associated with significant morbidity, mortality and health-care cost. Pulmonary and non-pulmonary sepsis are common causes of the acute respiratory distress syndrome (ARDS). The mortality from ARDS remains high despite protective lung ventilation, and currently there are no specific pharmacotherapies to treat sepsis or ARDS. Sepsis and ARDS are characterised by activation of the inflammatory cascade. Although there is much focus on the study of the dysregulated inflammation and its suppression, the associated activation of the haemostatic system has been largely ignored until recently. There has been extensive interest in the role that platelet activation can have in the inflammatory response through induction, aggregation and activation of leucocytes and other platelets. Aspirin can modulate multiple pathogenic mechanisms implicated in the development of multiple organ dysfunction in sepsis and ARDS. This review will discuss the role of the platelet, the mechanisms of action of aspirin in sepsis and ARDS, and aspirin as a potential therapy in treating sepsis and ARDS. PMID:26494395

  9. Glycyrrhizic Acid Prevents Sepsis-Induced Acute Lung Injury and Mortality in Rats.

    PubMed

    Zhao, Hongyu; Zhao, Min; Wang, Yu; Li, Fengchun; Zhang, Zhigang

    2016-02-01

    Glycyrrhizic acid (GA), an active ingredient in licorice, has multiple pharmacological activities. However, the effects of GA on sepsis-induced acute lung injury (ALI) have not been determined. Tthe aim of this study was to investigate the molecular mechanism involved in the effects of GA against sepsis-induced ALI in rats. We found that GA alleviated sepsis-induced ALI through improvements in various pathological changes, as well as decreases in the lung wet/dry weight ratio and total protein content in bronchoalveolar lavage fluid, and a significant increase in the survival rate of treated rats. Additionally, GA markedly inhibited sepsis-induced pulmonary inflammatory responses. Moreover, we found that treatment with GA inhibited oxidative stress damage and apoptosis in lung tissue induced by ALI. Finally, GA treatment significantly inhibited NF-κ B, JNK and P38 MAPK activation. Our data indicate that GA has a protective effect against sepsis-induced ALI by inhibiting the inflammatory response, damage from oxidative stress, and apoptosis via inactivation of NF-κB and MAPK signaling pathways, providing a molecular basis for a new medical treatment for sepsis-induced ALI. PMID:26385569

  10. Early diverting colostomy for perianal sepsis in children with acute leukemia.

    PubMed

    Pini Prato, Alessio; Castagnola, Elio; Micalizzi, Concetta; Dufour, Carlo; Avanzini, Stefano; Pio, Luca; Guida, Edoardo; Mattioli, Girolamo; Jasonni, Vincenzo; Disma, Nicola; Mameli, Leila; Montobbio, Giovanni; Buffa, Piero

    2012-10-01

    Perineal sepsis is a life-threatening complication of acute leukemia. Although conservative management (antibiotics, incision, and drainage, alone or in combination) is considered the criterion standard, it provides an outcome that is not fully satisfactory, with an overall mortality of roughly 30%. This report presents a case series of 4 children who underwent early defunctioning colostomy for the treatment of perineal sepsis during leukemia. This management proved to be successful and allowed prompt reestablishment of chemotherapy, thus improving overall results. Routine application of this "aggressive" management in these cases will presumably increase overall survival of children with leukemia. PMID:23084226

  11. Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid.

    PubMed

    Fisher, Bernard J; Kraskauskas, Donatas; Martin, Erika J; Farkas, Daniela; Wegelin, Jacob A; Brophy, Donald; Ward, Kevin R; Voelkel, Norbert F; Fowler, Alpha A; Natarajan, Ramesh

    2012-07-01

    Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Abdominal peritonitis often results in acute lung injury (ALI). Recent reports demonstrate a potential benefit of parenteral vitamin C [ascorbic acid (AscA)] in the pathogenesis of sepsis. Therefore we examined the mechanisms of vitamin C supplementation in the setting of abdominal peritonitis-mediated ALI. We hypothesized that vitamin C supplementation would protect lungs by restoring alveolar epithelial barrier integrity and preventing sepsis-associated coagulopathy. Male C57BL/6 mice were intraperitoneally injected with a fecal stem solution to induce abdominal peritonitis (FIP) 30 min prior to receiving either AscA (200 mg/kg) or dehydroascorbic acid (200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers (myeloperoxidase, chemokines), bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression (aquaporin 5, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and Na(+)-K(+)-ATPase), tight junction protein expression (claudins, occludins, zona occludens), cytoskeletal rearrangements (F-actin polymerization), and coagulation parameters (thromboelastography, pro- and anticoagulants, fibrinolysis mediators) of septic blood. FIP-mediated ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, coagulation abnormalities, and increased mortality. Parenteral vitamin C infusion protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the proinflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities. Parenteral vitamin C may potentially have a role in the management of sepsis and ALI associated with sepsis. PMID

  12. Acute Lung Injury and Fibrosis in a Baboon Model of Escherichia coli Sepsis

    PubMed Central

    Keshari, Ravi S.; Silasi-Mansat, Robert; Zhu, Hua; Popescu, Narcis I.; Peer, Glenn; Chaaban, Hala; Lambris, John D.; Polf, Holly; Lupu, Cristina; Kinasewitz, Gary

    2014-01-01

    Sepsis-induced inflammation of the lung leads to acute respiratory distress syndrome (ARDS), which may trigger persistent fibrosis. The pathology of ARDS is complex and poorly understood, and the therapeutic approaches are limited. We used a baboon model of Escherichia coli sepsis that mimics the complexity of human disease to study the pathophysiology of ARDS. We performed extensive biochemical, histological, and functional analyses to characterize the disease progression and the long-term effects of sepsis on the lung structure and function. Similar to humans, sepsis-induced ARDS in baboons displays an early inflammatory exudative phase, with extensive necrosis. This is followed by a regenerative phase dominated by proliferation of type 2 epithelial cells, expression of epithelial-to-mesenchymal transition markers, myofibroblast migration and proliferation, and collagen synthesis. Baboons that survived sepsis showed persistent inflammation and collagen deposition 6–27 months after the acute episodes. Long-term survivors had almost double the amount of collagen in the lung as compared with age-matched control animals. Immunostaining for procollagens showed persistent active collagen synthesis within the fibroblastic foci and interalveolar septa. Fibroblasts expressed markers of transforming growth factor-β and platelet-derived growth factor signaling, suggesting their potential role as mediators of myofibroblast migration and proliferation, and collagen deposition. In parallel, up-regulation of the inhibitors of extracellular proteases supports a deregulated matrix remodeling that may contribute to fibrosis. The primate model of sepsis-induced ARDS mimics the disease progression in humans, including chronic inflammation and long-lasting fibrosis. This model helps our understanding of the pathophysiology of fibrosis and the testing of new therapies. PMID:24066737

  13. PRImary care Streptococcal Management (PRISM) study: identifying clinical variables associated with Lancefield group A β-haemolytic streptococci and Lancefield non-Group A streptococcal throat infections from two cohorts of patients presenting with an acute sore throat

    PubMed Central

    Little, Paul; Moore, Michael; Hobbs, F D R; Mant, David; McNulty, Cliodna; Williamson, Ian; Cheng, Edith; Stuart, Beth; Kelly, Joanne; Barnett, Jane; Mullee, Mark

    2013-01-01

    Objective To assess the association between features of acute sore throat and the growth of streptococci from culturing a throat swab. Design Diagnostic cohort. Setting UK general practices. Participants Patients aged 5 or over presenting with an acute sore throat. Patients were recruited for a second cohort (cohort 2, n=517) consecutively after the first (cohort 1, n=606) from similar practices. Main outcome Predictors of the presence of Lancefield A/C/G streptococci. Results The clinical score developed from cohort 1 had poor discrimination in cohort 2 (bootstrapped estimate of area under the receiver operator characteristic (ROC) curve (0.65), due to the poor validity of the individual items in the second data set. Variables significant in multivariate analysis in both cohorts were rapid attendance (prior duration 3 days or less; multivariate adjusted OR 1.92 cohort, 1.67 cohort 2); fever in the last 24 h (1.69, 2.40); and doctor assessment of severity (severely inflamed pharynx/tonsils (2.28, 2.29)). The absence of coryza or cough and purulent tonsils were significant in univariate analysis in both cohorts and in multivariate analysis in one cohort. A five-item score based on Fever, Purulence, Attend rapidly (3 days or less), severely Inflamed tonsils and No cough or coryza (FeverPAIN) had moderate predictive value (bootstrapped area under the ROC curve 0.73 cohort 1, 0.71 cohort 2) and identified a substantial number of participants at low risk of streptococcal infection (38% in cohort 1, 36% in cohort 2 scored ≤1, associated with a streptococcal percentage of 13% and 18%, respectively). A Centor score of ≤1 identified 23% and 26% of participants with streptococcal percentages of 10% and 28%, respectively. Conclusions Items widely used to help identify streptococcal sore throat may not be the most consistent. A modified clinical scoring system (FeverPAIN) which requires further validation may be clinically helpful in identifying individuals who are

  14. Streptococcal superantigens: categorization and clinical associations.

    PubMed

    Commons, Robert J; Smeesters, Pierre R; Proft, Thomas; Fraser, John D; Robins-Browne, Roy; Curtis, Nigel

    2014-01-01

    Superantigens are key virulence factors in the immunopathogenesis of invasive disease caused by group A streptococcus. These protein exotoxins have also been associated with severe group C and group G streptococcal infections. A number of novel streptococcal superantigens have recently been described with some resulting confusion in their classification. In addition to clarifying the nomenclature of streptococcal superantigens and proposing guidelines for their categorization, this review summarizes the evidence supporting their involvement in various clinical diseases including acute rheumatic fever. PMID:24210845

  15. Chitinase-like Proteins are Candidate Biomarkers for Sepsis-induced Acute Kidney Injury*

    PubMed Central

    Maddens, B.; Ghesquière, B.; Vanholder, R.; Demon, D.; Vanmassenhove, J.; Gevaert, K.; Meyer, E.

    2012-01-01

    Sepsis-induced acute kidney injury (AKI) is a frequent complication of critically ill patients and leads to high mortality rates. The specificity of currently available urinary biomarkers for AKI in the context of sepsis is questioned. This study aimed to discover urinary biomarkers for septic AKI by contemporary shotgun proteomics in a mouse model for sepsis and to validate these in individual urine samples of mice and human septic patients with and without AKI. At 48 h after uterine ligation and inoculation of Escherichia coli, aged mice (48 weeks) became septic. A subgroup developed AKI, defined by serum creatinine, blood urea nitrogen, and renal histology. Separate pools of urine from septic mice with and without AKI mice were collected during 12 h before and between 36–48 h after infection, and their proteome compositions were quantitatively compared. Candidate biomarkers were validated by Western blot analysis of urine, plasma, and renal tissue homogenates from individual mice, and a limited number of urine samples from human septic patients with and without AKI. Urinary neutrophil gelatinase-associated lipocalin, thioredoxin, gelsolin, chitinase 3-like protein 1 and -3 (CHI3L3) and acidic mammalian chitinase were the most distinctive candidate biomarkers selected for septic AKI. Both neutrophil gelatinase-associated lipocalin and thioredoxin were detected in urine of septic mice and increased with severity of AKI. Acidic mammalian chitinase was only present in urine of septic mice with AKI. Both urinary chitinase 3-like protein 1 and -3 were only detected in septic mice with severe AKI. The human homologue chitinase 3-like protein 1 was found to be more excreted in urine from septic patients with AKI than without. In summary, urinary chitinase 3-like protein 1 and -3 and acidic mammalian chitinase discriminated sepsis from sepsis-induced AKI in mice. Further studies of human chitinase proteins are likely to lead to additional insights in septic AKI. PMID

  16. Urgent endoscopic ultrasound-guided choledochoduodenostomy for acute obstructive suppurative cholangitis-induced sepsis.

    PubMed

    Minaga, Kosuke; Kitano, Masayuki; Imai, Hajime; Yamao, Kentaro; Kamata, Ken; Miyata, Takeshi; Omoto, Shunsuke; Kadosaka, Kumpei; Yoshikawa, Tomoe; Kudo, Masatoshi

    2016-04-28

    Acute obstructive suppurative cholangitis (AOSC) due to biliary lithiasis is a life-threatening condition that requires urgent biliary decompression. Although endoscopic retrograde cholangiopancreatography (ERCP) with stent placement is the current gold standard for biliary decompression, it can sometimes be difficult because of failed biliary cannulation. In this retrospective case series, we describe three cases of successful biliary drainage with recovery from septic shock after urgent endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) was performed for AOSC due to biliary lithiasis. In all three cases, technical success in inserting the stents was achieved and the patients completely recovered from AOSC with sepsis in a few days after EUS-CDS. There were no procedure-related complications. When initial ERCP fails, EUS-CDS can be an effective life-saving endoscopic biliary decompression procedure that shortens the procedure time and prevents post-ERCP pancreatitis, particularly in patients with AOSC-induced sepsis. PMID:27122677

  17. Urgent endoscopic ultrasound-guided choledochoduodenostomy for acute obstructive suppurative cholangitis-induced sepsis

    PubMed Central

    Minaga, Kosuke; Kitano, Masayuki; Imai, Hajime; Yamao, Kentaro; Kamata, Ken; Miyata, Takeshi; Omoto, Shunsuke; Kadosaka, Kumpei; Yoshikawa, Tomoe; Kudo, Masatoshi

    2016-01-01

    Acute obstructive suppurative cholangitis (AOSC) due to biliary lithiasis is a life-threatening condition that requires urgent biliary decompression. Although endoscopic retrograde cholangiopancreatography (ERCP) with stent placement is the current gold standard for biliary decompression, it can sometimes be difficult because of failed biliary cannulation. In this retrospective case series, we describe three cases of successful biliary drainage with recovery from septic shock after urgent endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) was performed for AOSC due to biliary lithiasis. In all three cases, technical success in inserting the stents was achieved and the patients completely recovered from AOSC with sepsis in a few days after EUS-CDS. There were no procedure-related complications. When initial ERCP fails, EUS-CDS can be an effective life-saving endoscopic biliary decompression procedure that shortens the procedure time and prevents post-ERCP pancreatitis, particularly in patients with AOSC-induced sepsis. PMID:27122677

  18. [Bacillus cereus sepsis and subarachnoid hemorrhage following consolidation chemotherapy for acute myelogenous leukemia].

    PubMed

    Kawatani, Eri; Kishikawa, Yuki; Sankoda, Chikahiro; Kuwahara, Nobuo; Mori, Daisuke; Osoegawa, Kouichi; Matsuishi, Eijo; Gondo, Hisashi

    2009-04-01

    A 64-year-old man with acute myelogenous leukemia (FAB classification, M7) in remission received consolidation chemotherapy with mitoxantrone/cytosine arabinoside. WBC counts decreased to 0/microl on day 14, and fever (39.3 degrees C) and epigastralgia developed on day 15. Cefozopran was instituted for febrile neutropenia; however, on day 16, he was found to be in cardiac arrest. CT scan on day 16 revealed subarachnoid hemorrhage. Gram-positive rods were isolated from blood cultures on day 15, and were later identified as B.cereus. He recovered transiently, but eventually died on day 19. Postmortem examination demonstrated many colonies of B. cereus in the cerebrum, cerebellum, lung, and liver. Hepatocyte necrosis was also observed in the liver. Bacterial aneurysms or septic emboli were not identified in the arachnoid vessels, but necrosis of cerebral vessels was prominent, which was considered to be the cause of subarachnoid hemorrhage. Fatal subarachnoid hemorrhage has been reported to be associated with B. cereus sepsis, which developed at nadir following chemotherapy for leukemia patients. Because of the aggressive clinical course of B. cereus sepsis, including the risk for subarachnoid hemorrhage, early treatment with effective antibiotics for B. cereus sepsis would be important in the management of leukemia patients after chemotherapy. PMID:19404024

  19. Exogenous Carbon Monoxide Decreases Sepsis-Induced Acute Kidney Injury and Inhibits NLRP3 Inflammasome Activation in Rats.

    PubMed

    Wang, Peng; Huang, Jian; Li, Yi; Chang, Ruiming; Wu, Haidong; Lin, Jiali; Huang, Zitong

    2015-01-01

    Carbon monoxide (CO) has shown various physiological effects including anti-inflammatory activity in several diseases, whereas the therapeutic efficacy of CO on sepsis-induced acute kidney injury (AKI) has not been reported as of yet. The purpose of the present study was to explore the effects of exogenous CO on sepsis-induced AKI and nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in rats. Male rats were subjected to cecal ligation and puncture (CLP) to induce sepsis and AKI. Exogenous CO delivered from CO-releasing molecule 2 (CORM-2) was used intraperitoneally as intervention after CLP surgery. Therapeutic effects of CORM-2 on sepsis-induced AKI were assessed by measuring serum creatinine (Scr) and blood urea nitrogen (BUN), kidney histology scores, apoptotic cell scores, oxidative stress, levels of cytokines TNF-α and IL-1β, and NLRP3 inflammasome expression. CORM-2 treatment protected against the sepsis-induced AKI as evidenced by reducing serum Scr/BUN levels, apoptotic cells scores, increasing survival rates, and decreasing renal histology scores. Furthermore, treatment with CORM-2 significantly reduced TNF-α and IL-1β levels and oxidative stress. Moreover, CORM-2 treatment significantly decreased NLRP3 inflammasome protein expressions. Our study provided evidence that CORM-2 treatment protected against sepsis-induced AKI and inhibited NLRP3 inflammasome activation, and suggested that CORM-2 could be a potential therapeutic candidate for treating sepsis-induced AKI. PMID:26334271

  20. Exogenous Carbon Monoxide Decreases Sepsis-Induced Acute Kidney Injury and Inhibits NLRP3 Inflammasome Activation in Rats

    PubMed Central

    Wang, Peng; Huang, Jian; Li, Yi; Chang, Ruiming; Wu, Haidong; Lin, Jiali; Huang, Zitong

    2015-01-01

    Carbon monoxide (CO) has shown various physiological effects including anti-inflammatory activity in several diseases, whereas the therapeutic efficacy of CO on sepsis-induced acute kidney injury (AKI) has not been reported as of yet. The purpose of the present study was to explore the effects of exogenous CO on sepsis-induced AKI and nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in rats. Male rats were subjected to cecal ligation and puncture (CLP) to induce sepsis and AKI. Exogenous CO delivered from CO-releasing molecule 2 (CORM-2) was used intraperitoneally as intervention after CLP surgery. Therapeutic effects of CORM-2 on sepsis-induced AKI were assessed by measuring serum creatinine (Scr) and blood urea nitrogen (BUN), kidney histology scores, apoptotic cell scores, oxidative stress, levels of cytokines TNF-α and IL-1β, and NLRP3 inflammasome expression. CORM-2 treatment protected against the sepsis-induced AKI as evidenced by reducing serum Scr/BUN levels, apoptotic cells scores, increasing survival rates, and decreasing renal histology scores. Furthermore, treatment with CORM-2 significantly reduced TNF-α and IL-1β levels and oxidative stress. Moreover, CORM-2 treatment significantly decreased NLRP3 inflammasome protein expressions. Our study provided evidence that CORM-2 treatment protected against sepsis-induced AKI and inhibited NLRP3 inflammasome activation, and suggested that CORM-2 could be a potential therapeutic candidate for treating sepsis-induced AKI. PMID:26334271

  1. Accelerated Cellular Uptake and Metabolism of L-Thyroxine during Acute Salmonella typhimurium Sepsis

    PubMed Central

    DeRubertis, Frederick R.; Woeber, Kenneth A.

    1973-01-01

    The effects of acute Salmonella typhimurium sepsis on the kinetics of peripheral L-thyroxine (T4) distribution and metabolism and on serum total and free T4 concentrations were studied in rhesus monkeys inoculated i.v. with either heat-killed or viable organisms. The rate of disappearance of labeled T4 from serum was increased within 8 h after inoculation of monkeys with either heat-killed or viable Salmonella. The effects of the heat-killed organisms were transient and no longer evident by 16 h postinoculation. The monkeys inoculated with the viable Salmonella experienced a 2-3 day febrile, septic illness that was accompanied by an increase in the absolute rate of T4 disposal. In the infected monkeys, serum total T4 and endogenously labeled protein-bound iodine concentrations fell significantly during the period of acute sepsis and then rose during convalescence to values that exceeded the preinoculation values, suggesting that thyroidal secretion of hormone had increased in response to a primary depletion of the peripheral hormonal pool. Total cellular and hepatic uptakes of T4 were enhanced by 4 h after inoculation of monkeys with either heat-killed or viable Salmonella, but the increase in total cellular uptake persisted for 24 h only in the monkeys inoculated with the viable organisms. These alterations in T4 kinetics could neither be correlated with changes in the binding of T4 in plasma nor attributed to an increase in vascular permeability. Moreover, they could not be ascribed to an in vitro product of bacterial growth, suggesting that the presence of the organisms themselves was required. An acceleration of T4 disappearance was also observed during Escherichia coli and Diplococcus pucumoniae bacteremias. Our findings are consistent with a primary increase in the cellular uptake and metabolism of T4 during bacterial sepsis, possibly related to phagocytic cell function in the host. PMID:4629910

  2. Time profile of oxidative stress and neutrophil activation in ovine acute lung injury and sepsis.

    PubMed

    Lange, Matthias; Szabo, Csaba; Traber, Daniel L; Horvath, Eszter; Hamahata, Atsumori; Nakano, Yoshimitsu; Traber, Lillian D; Cox, Robert A; Schmalstieg, Frank C; Herndon, David N; Enkhbaatar, Perenlei

    2012-05-01

    The formation of oxidative stress in the lung and activation of neutrophils are major determinants in the development of respiratory failure after acute lung injury and sepsis. However, the time changes of these pathogenic factors have not been sufficiently described. Twenty-four chronically instrumented sheep were subjected to cotton smoke inhalation injury and instillation of live Pseudomonas aeruginosa into both lungs. The sheep were euthanized at 4, 8, 12, 18, and 24 h after injury. Additional sheep received sham injury and were euthanized after 24 h. Pulmonary function was assessed by determination of oxygenation index and pulmonary shunt fraction. In addition, lung tissue was harvested at the respective time points for the measurement of malondialdehyde, interleukin 6, poly(ADP ribose), myeloperoxidase, and alveolar polymorphonuclear neutrophil score. The injury induced severe respiratory failure that was associated with an early increase in lipid peroxidation and interleukin 6 expression. The injury further led to an increase in poly(ADP ribose) activity that reached its peak at 12 h after injury and declined afterward. In addition, progressive increases in markers of neutrophil accumulation in the lung were observed. The peak of neutrophil accumulation in the lung was associated with a severe depletion of circulating neutrophils. The results from our model may enhance the understanding of the pathophysiological alterations after acute lung injury and sepsis and thus be useful in exploring therapeutic interventions directed at modifying the expression or activation of inflammatory mediators. PMID:22266977

  3. Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis

    PubMed Central

    Lin, Wei-Chieh; Chen, Chang-Wen; Huang, Yu-Wen; Chao, Lee; Chao, Julie; Lin, Yee-Shin; Lin, Chiou-Feng

    2015-01-01

    Kallistatin, an endogenous plasma protein, exhibits pleiotropic properties in inhibiting inflammation, oxidative stress and apoptosis, as evidenced in various animal models and cultured cells. Here, we demonstrate that kallistatin levels were positively correlated with the concentration of total protein in bronchoalveolar lavage fluids (BALF) from patients with sepsis-related acute respiratory distress syndrome (ARDS), indicating a compensatory mechanism. Lower ratio of kallistatin to total protein in BALF showed a significant trend toward elevated neutrophil counts (P = 0.002) in BALF and increased mortality (P = 0.046). In lipopolysaccharide (LPS)-treated mice, expression of human kallistatin in lung by gene transfer with human kallistatin-encoding plasmid ameliorated acute lung injury (ALI) and reduced cytokine/chemokine levels in BALF. These mice exhibited attenuated lung epithelial apoptosis and decreased Fas/FasL expression compared to the control mice. Mouse survival was improved by kallistatin gene transfer or recombinant human kallistatin treatment after LPS challenge. In LPS-stimulated A549 human lung epithelial cells, kallistatin attenuated apoptosis, down-regulated Fas/FasL signaling, suppressed intracellular reactive oxygen species (ROS) and inhibited ROS-mediated NF-κB activation and inflammation. Furthermore, LPS-induced apoptosis was blocked by antioxidant N-acetylcysteine or NF-κB inhibitor via down-regulating Fas expression. These findings suggest the therapeutic potential of kallistatin for sepsis-related ALI/ARDS. PMID:26198099

  4. Rest energy expenditure is decreased during the acute as compared to the recovery phase of sepsis in newborns

    PubMed Central

    2010-01-01

    Background Little is known with respect to the metabolic response and the requirements of infected newborns. Moreover, the nutritional needs and particularly the energy metabolism of newborns with sepsis are controversial matter. In this investigation we aimed to evaluate the rest energy expenditure (REE) of newborns with bacterial sepsis during the acute and the recovery phases. Methods We studied nineteen neonates (27.3 ± 17.2 days old) with bacterial sepsis during the acute phase and recovery of their illness. REE was determined by indirect calorimetry and VO2 and VCO2 measured by gas chromatography. Results REE significantly increased from 49.4 ± 13.1 kcal/kg/day during the acute to 68.3 ± 10.9 kcal/kg/day during recovery phase of sepsis (P < 0.01). Similarly, VO2 (7.4 ± 1.9 vs 10 ± 1.5 ml/kg/min) and VCO2 (5.1 ± 1.7 vs 7.4 ± 1.5 ml/kg/min) were also increased during the course of the disease (P < 0.01). Conclusion REE was increased during recovery compared to the sepsis phase. REE of septic newborns should be calculated on individualized basis, bearing in mind their metabolic capabilities. PMID:20653967

  5. Ketamine attenuates sepsis-induced acute lung injury via regulation of HMGB1-RAGE pathways.

    PubMed

    Li, Kehan; Yang, Jianxue; Han, Xuechang

    2016-05-01

    High mobility group box protein 1 (HMGB1) and receptor for the advanced glycation end product (RAGE) play important roles in the development of sepsis-induced acute lung injury (ALI). Ketamine is considered to confer protective effects on ALI during sepsis. In this study, we investigated the effects of ketamine on HMGB1-RAGE activation in a rat model of sepsis-induced ALI. ALI was induced in wild type (WT) and RAGE deficient (RAGE(-/-)) rats by cecal ligation and puncture (CLP) or HMGB1 to mimic sepsis-induced ALI. Rats were randomly divided to six groups: sham-operation+normal saline (NS, 10mL/kg), sham-operation+ketamine (10mg/kg), CLP/HMGB1+NS (10mL/kg), CLP/HMGB1+ketamine (5mg/kg), CLP/HMGB1+ketamine (7.5mg/kg), and CLP/HMGB1+ketamine (10mg/kg) groups. NS and ketamine were administered at 3 and 12h after CLP/HMGB1 via intraperitoneal injection. Pathological changes of lung, inflammatory cell counts, expression of HMGB1and RAGE, and concentrations of various inflammatory mediators in bronchoalveolar lavage fluids (BALF) and lung tissue were then assessed. Nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways in the lung were also evaluated. CLP/HMGB1 increased the wet to dry weight ratio and myeloperoxidase activity in lung, the number of total cells, neutrophils, and macrophages in the BALF, and inflammatory mediators in the BALF and lung tissues. Moreover, expression of HMGB1and RAGE in lung tissues was increased after CLP. Ketamine inhibited all the above effects. It also inhibited the activation of IκB-α, NF-κB p65, and MAPK. Ketamine protects rats against HMGB1-RAGE activation in a rat model of sepsis-induced ALI. These effects may partially result from reductions in NF-κB and MAPK. PMID:26945830

  6. Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis.

    PubMed

    Weber, Georg F; Chousterman, Benjamin G; He, Shun; Fenn, Ashley M; Nairz, Manfred; Anzai, Atsushi; Brenner, Thorsten; Uhle, Florian; Iwamoto, Yoshiko; Robbins, Clinton S; Noiret, Lorette; Maier, Sarah L; Zönnchen, Tina; Rahbari, Nuh N; Schölch, Sebastian; Klotzsche-von Ameln, Anne; Chavakis, Triantafyllos; Weitz, Jürgen; Hofer, Stefan; Weigand, Markus A; Nahrendorf, Matthias; Weissleder, Ralph; Swirski, Filip K

    2015-03-13

    Sepsis is a frequently fatal condition characterized by an uncontrolled and harmful host reaction to microbial infection. Despite the prevalence and severity of sepsis, we lack a fundamental grasp of its pathophysiology. Here we report that the cytokine interleukin-3 (IL-3) potentiates inflammation in sepsis. Using a mouse model of abdominal sepsis, we showed that innate response activator B cells produce IL-3, which induces myelopoiesis of Ly-6C(high) monocytes and neutrophils and fuels a cytokine storm. IL-3 deficiency protects mice against sepsis. In humans with sepsis, high plasma IL-3 levels are associated with high mortality even after adjusting for prognostic indicators. This study deepens our understanding of immune activation, identifies IL-3 as an orchestrator of emergency myelopoiesis, and reveals a new therapeutic target for treating sepsis. PMID:25766237

  7. Glycyrrhizic Acid Attenuates Sepsis-Induced Acute Kidney Injury by Inhibiting NF-κB Signaling Pathway

    PubMed Central

    Zhao, Hongyu; Zhao, Min; Wang, Yu; Li, Fengchun; Zhang, Zhigang

    2016-01-01

    Glycyrrhizic acid (GA) is a major active ingredient in licorice. In our study, the effects of GA on acute kidney injury (AKI) in rats and its underlying molecular mechanisms were investigated. The sepsis model was produced by caecal ligation and puncture (CLP) in rats. The molecular and histological experiments were performed in the kidney tissues and serum samples of rats. According to the results obtained, GA alleviated sepsis-induced AKI by improving the pathological changes, decreasing the levels of blood urea nitrogen (BUN), creatinine (Cre), and increasing the survival rate of rats with AKI significantly. The production of inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, was markedly inhibited by GA. Moreover, treatment with GA inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2) and expression levels of induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in kidney tissues. Furtherly, the apoptosis in kidney tissue induced by AKI was suppressed by GA. Finally, GA could inhibit the activation of NF-κB signaling pathway. Our study suggests that GA alleviates sepsis-induced AKI by inhibiting the NF-κB signaling pathway, which provides a strong evidence for a new approach for treating sepsis-induced AKI. PMID:26904148

  8. Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury.

    PubMed

    Zhao, Wen-Yu; Zhang, Lei; Sui, Ming-Xing; Zhu, You-Hua; Zeng, Li

    2016-01-01

    Acute kidney injury (AKI) is a rapid loss of kidney function characterized by damage to renal tubular cells driven by mitochondrial dysregulation and oxidative stress. Here, we used a murine caecal ligation and puncture (CLP) model of sepsis-induced AKI to study the role of sirtuin 3 (SIRT3), a NAD(+) dependent deacetylase critical for the maintenance of mitochondrial viability, in AKI-related renal tubular cell damage and explored the underlying mechanisms. CLP induced alterations in kidney function and morphology were associated with SIRT3 downregulation, and SIRT3 deletion exacerbated CLP-induced kidney dysfunction, renal tubular cell injury and apoptosis, mitochondrial alterations, and ROS production in a knockout mouse model. SIRT3 deletion increased the CLP-induced upregulation of the NLRP3 inflammasome and apoptosis-associated speck-like protein, resulting in the activation of oxidative stress, increased production of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and the enhancement of apoptosis, and these effects were reversed by antioxidant NAC. Our results suggest that SIRT3 plays a protective role against mitochondrial damage in the kidney by attenuating ROS production, inhibiting the NRLP3 inflammasome, attenuating oxidative stress, and downregulating IL-1β and IL-18. PMID:27620507

  9. Lung Transcriptomics during Protective Ventilatory Support in Sepsis-Induced Acute Lung Injury

    PubMed Central

    Acosta-Herrera, Marialbert; Lorenzo-Diaz, Fabian; Pino-Yanes, Maria; Corrales, Almudena; Valladares, Francisco; Klassert, Tilman E.; Valladares, Basilio; Slevogt, Hortense; Ma, Shwu-Fan

    2015-01-01

    Acute lung injury (ALI) is a severe inflammatory process of the lung. The only proven life-saving support is mechanical ventilation (MV) using low tidal volumes (LVT) plus moderate to high levels of positive end-expiratory pressure (PEEP). However, it is currently unknown how they exert the protective effects. To identify the molecular mechanisms modulated by protective MV, this study reports transcriptomic analyses based on microarray and microRNA sequencing in lung tissues from a clinically relevant animal model of sepsis-induced ALI. Sepsis was induced by cecal ligation and puncture (CLP) in male Sprague-Dawley rats. At 24 hours post-CLP, septic animals were randomized to three ventilatory strategies: spontaneous breathing, LVT (6 ml/kg) plus 10 cmH2O PEEP and high tidal volume (HVT, 20 ml/kg) plus 2 cmH2O PEEP. Healthy, non-septic, non-ventilated animals served as controls. After 4 hours of ventilation, lung samples were obtained for histological examination and gene expression analysis using microarray and microRNA sequencing. Validations were assessed using parallel analyses on existing publicly available genome-wide association study findings and transcriptomic human data. The catalogue of deregulated processes differed among experimental groups. The ‘response to microorganisms’ was the most prominent biological process in septic, non-ventilated and in HVT animals. Unexpectedly, the ‘neuron projection morphogenesis’ process was one of the most significantly deregulated in LVT. Further support for the key role of the latter process was obtained by microRNA studies, as four species targeting many of its genes (Mir-27a, Mir-103, Mir-17-5p and Mir-130a) were found deregulated. Additional analyses revealed 'VEGF signaling' as a central underlying response mechanism to all the septic groups (spontaneously breathing or mechanically ventilated). Based on this data, we conclude that a co-deregulation of 'VEGF signaling' along with 'neuron projection

  10. The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults.

    PubMed

    McGill, F; Heyderman, R S; Michael, B D; Defres, S; Beeching, N J; Borrow, R; Glennie, L; Gaillemin, O; Wyncoll, D; Kaczmarski, E; Nadel, S; Thwaites, G; Cohen, J; Davies, N W S; Miller, A; Rhodes, A; Read, R C; Solomon, T

    2016-04-01

    Bacterial meningitis and meningococcal sepsis are rare conditions with high case fatality rates. Early recognition and prompt treatment saves lives. In 1999 the British Infection Society produced a consensus statement for the management of immunocompetent adults with meningitis and meningococcal sepsis. Since 1999 there have been many changes. We therefore set out to produce revised guidelines which provide a standardised evidence-based approach to the management of acute community acquired meningitis and meningococcal sepsis in adults. A working party consisting of infectious diseases physicians, neurologists, acute physicians, intensivists, microbiologists, public health experts and patient group representatives was formed. Key questions were identified and the literature reviewed. All recommendations were graded and agreed upon by the working party. The guidelines, which for the first time include viral meningitis, are written in accordance with the AGREE 2 tool and recommendations graded according to the GRADE system. Main changes from the original statement include the indications for pre-hospital antibiotics, timing of the lumbar puncture and the indications for neuroimaging. The list of investigations has been updated and more emphasis is placed on molecular diagnosis. Approaches to both antibiotic and steroid therapy have been revised. Several recommendations have been given regarding the follow-up of patients. PMID:26845731

  11. Blocking Cyclic Adenosine Diphosphate Ribose-mediated Calcium Overload Attenuates Sepsis-induced Acute Lung Injury in Rats

    PubMed Central

    Peng, Qian-Yi; Zou, Yu; Zhang, Li-Na; Ai, Mei-Lin; Liu, Wei; Ai, Yu-Hang

    2016-01-01

    Background: Acute lung injury (ALI) is a common complication of sepsis that is associated with high mortality. Intracellular Ca2+ overload plays an important role in the pathophysiology of sepsis-induced ALI, and cyclic adenosine diphosphate ribose (cADPR) is an important regulator of intracellular Ca2+ mobilization. The cluster of differentiation 38 (CD38)/cADPR pathway has been found to play roles in multiple inflammatory processes but its role in sepsis-induced ALI is still unknown. This study aimed to investigate whether the CD38/cADPR signaling pathway is activated in sepsis-induced ALI and whether blocking cADPR-mediated calcium overload attenuates ALI. Methods: Septic rat models were established by cecal ligation and puncture (CLP). Rats were divided into the sham group, the CLP group, and the CLP+ 8-bromo-cyclic adenosine diphosphate ribose (8-Br-cADPR) group. Nicotinamide adenine dinucleotide (NAD+), cADPR, CD38, and intracellular Ca2+ levels in the lung tissues were measured at 6, 12, 24, and 48 h after CLP surgery. Lung histologic injury, tumor necrosis factor (TNF)-α, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activities were measured. Results: NAD+, cADPR, CD38, and intracellular Ca2+ levels in the lungs of septic rats increased significantly at 24 h after CLP surgery. Treatment with 8-Br-cADPR, a specific inhibitor of cADPR, significantly reduced intracellular Ca2+ levels (P = 0.007), attenuated lung histological injury (P = 0.023), reduced TNF-α and MDA levels (P < 0.001 and P = 0.002, respectively) and recovered SOD activity (P = 0.031) in the lungs of septic rats. Conclusions: The CD38/cADPR pathway is activated in the lungs of septic rats, and blocking cADPR-mediated calcium overload with 8-Br-cADPR protects against sepsis-induced ALI. PMID:27411462

  12. Hemodynamic changes in the kidney in a pediatric rat model of sepsis-induced acute kidney injury.

    PubMed

    Seely, Kathryn A; Holthoff, Joseph H; Burns, Samuel T; Wang, Zhen; Thakali, Keshari M; Gokden, Neriman; Rhee, Sung W; Mayeux, Philip R

    2011-07-01

    Sepsis is a leading cause of acute kidney injury (AKI) and mortality in children. Understanding the development of pediatric sepsis and its effects on the kidney are critical in uncovering new therapies. The goal of this study was to characterize the development of sepsis-induced AKI in the clinically relevant cecal ligation and puncture (CLP) model of peritonitis in rat pups 17-18 days old. CLP produced severe sepsis demonstrated by time-dependent increase in serum cytokines, NO, markers of multiorgan injury, and renal microcirculatory hypoperfusion. Although blood pressure and heart rate remained unchanged after CLP, renal blood flow (RBF) was decreased 61% by 6 h. Renal microcirculatory analysis showed the number of continuously flowing cortical capillaries decreased significantly from 69 to 48% by 6 h with a 66% decrease in red blood cell velocity and a 57% decline in volumetric flow. The progression of renal microcirculatory hypoperfusion was associated with peritubular capillary leakage and reactive nitrogen species generation. Sham adults had higher mean arterial pressure (118 vs. 69 mmHg), RBF (4.2 vs. 1.1 ml·min(-1)·g(-1)), and peritubular capillary velocity (78% continuous flowing capillaries vs. 69%) compared with pups. CLP produced a greater decrease in renal microcirculation in pups, supporting the notion that adult models may not be the most appropriate for studying pediatric sepsis-induced AKI. Lower RBF and reduced peritubular capillary perfusion in the pup suggest the pediatric kidney may be more susceptible to AKI than would be predicted using adults models. PMID:21511700

  13. N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation.

    PubMed

    Campos, Renata; Shimizu, Maria Heloísa Massola; Volpini, Rildo Aparecido; de Bragança, Ana Carolina; Andrade, Lucia; Lopes, Fernanda Degobbi Tenório Quirino Dos Santos; Olivo, Clarice; Canale, Daniele; Seguro, Antonio Carlos

    2012-04-01

    Sepsis is a common cause of acute kidney injury (AKI) and acute lung injury. Oxidative stress plays as important role in such injury. The aim of this study was to evaluate the effects that the potent antioxidant N-acetylcysteine (NAC) has on renal and pulmonary function in rats with sepsis. Rats, treated or not with NAC (4.8 g/l in drinking water), underwent cecal ligation and puncture (CLP) 2 days after the initiation of NAC treatment, which was maintained throughout the study. At 24 h post-CLP, renal and pulmonary function were studied in four groups: control, control + NAC, CLP, and CLP + NAC. All animals were submitted to low-tidal-volume mechanical ventilation. We evaluated respiratory mechanics, the sodium cotransporters Na-K-2Cl (NKCC1) and the α-subunit of the epithelial sodium channel (α-ENaC), polymorphonuclear neutrophils, the edema index, oxidative stress (plasma thiobarbituric acid reactive substances and lung tissue 8-isoprostane), and glomerular filtration rate. The CLP rats developed AKI, which was ameliorated in the CLP + NAC rats. Sepsis-induced alterations in respiratory mechanics were also ameliorated by NAC. Edema indexes were lower in the CLP + NAC group, as was the wet-to-dry lung weight ratio. In CLP + NAC rats, α-ENaC expression was upregulated, whereas that of NKCC1 was downregulated, although the difference was not significant. In the CLP + NAC group, oxidative stress was significantly lower and survival rates were significantly higher than in the CLP group. The protective effects of NAC (against kidney and lung injury) are likely attributable to the decrease in oxidative stress, suggesting that NAC can be useful in the treatment of sepsis. PMID:22268121

  14. Anti-inflammatory mechanisms of apolipoprotein A-I mimetic peptide in acute respiratory distress syndrome secondary to sepsis.

    PubMed

    Sharifov, Oleg F; Xu, Xin; Gaggar, Amit; Grizzle, William E; Mishra, Vinod K; Honavar, Jaideep; Litovsky, Silvio H; Palgunachari, Mayakonda N; White, C Roger; Anantharamaiah, G M; Gupta, Himanshu

    2013-01-01

    Acute respiratory distress syndrome (ARDS) due to sepsis has a high mortality rate with limited treatment options. High density lipoprotein (HDL) exerts innate protective effects in systemic inflammation. However, its role in ARDS has not been well studied. Peptides such as L-4F mimic the secondary structural features and functions of apolipoprotein (apo)A-I, the major protein component of HDL. We set out to measure changes in HDL in sepsis-mediated ARDS patients, and to study the potential of L-4F to prevent sepsis-mediated ARDS in a rodent model of lipopolysaccharide (LPS)-mediated acute lung injury, and a combination of primary human leukocytes and human ARDS serum. We also analyzed serum from non-lung disease intubated patients (controls) and sepsis-mediated ARDS patients. Compared to controls, ARDS demonstrates increased serum endotoxin and IL-6 levels, and decreased HDL, apoA-I and activity of anti-oxidant HDL-associated paraoxanase-1. L-4F inhibits the activation of isolated human leukocytes and neutrophils by ARDS serum and LPS in vitro. Further, L-4F decreased endotoxin activity and preserved anti-oxidant properties of HDL both in vitro and in vivo. In a rat model of severe endotoxemia, L-4F significantly decreased mortality and reduces lung and liver injury, even when administered 1 hour post LPS. Our study suggests the protective role of the apoA-I mimetic peptide L-4F in ARDS and gram-negative endotoxemia and warrant further clinical evaluation. The main protective mechanisms of L-4F are due to direct inhibition of endotoxin activity and preservation of HDL anti-oxidant activity. PMID:23691230

  15. Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design.

    PubMed

    Prescott, Hallie C; Calfee, Carolyn S; Thompson, B Taylor; Angus, Derek C; Liu, Vincent X

    2016-07-15

    Both quality improvement and clinical research efforts over the past few decades have focused on consensus definition of sepsis and acute respiratory distress syndrome (ARDS). Although clinical definitions based on readily available clinical data have advanced recognition and timely use of broad supportive treatments, they likely hinder the identification of more targeted therapies that manipulate select biological mechanisms underlying critical illness. Sepsis and ARDS are by definition heterogeneous, and patients vary in both their underlying biology and their severity of illness. We have long been able to identify subtypes of sepsis and ARDS that confer different prognoses. The key is that we are now on the verge of identifying subtypes that may confer different response to therapy. In this perspective, inspired by a 2015 American Thoracic Society International Conference Symposium entitled "Lumpers and Splitters: Phenotyping in Critical Illness," we highlight promising approaches to uncovering patient subtypes that may predict treatment responsiveness and not just differences in prognosis. We then discuss how this information can be leveraged to improve the success and translatability of clinical trials by using predictive enrichment and other design strategies. Last, we discuss the challenges and limitations to identifying biomarkers and endotypes and incorporating them into routine clinical practice. PMID:27244481

  16. Glycyrrhizic acid pretreatment prevents sepsis-induced acute kidney injury via suppressing inflammation, apoptosis and oxidative stress.

    PubMed

    Zhao, Hongyu; Liu, Zhenning; Shen, Haitao; Jin, Shuai; Zhang, Shun

    2016-06-15

    Glycyrrhizic acid (GA), an active ingredient in licorice, has multiple pharmacological activities. The aim of our study was to investigate the molecular mechanism involved in the protective effects of GA in lipopolysaccharide (LPS) stimulated rat mesangial cells (HBZY-1) and septic rats. Sepsis model was established by injection of 5mg/kg LPS in rats or incubation with 1μg/ml LPS for 24h in HBZY-1 cells. A variety of molecular biological experiments were carried out to assess the effects of GA on inflammation, apoptosis, and oxidative stress. First we found that GA alleviated sepsis-induced kidney injury in vivo. Furthermore, GA suppressed inflammatory response in vivo and in vitro. Additionally, GA inhibited cell apoptosis and the changes in expressions of apoptosis related proteins induced by LPS. Moreover, GA markedly inhibited oxidative stress induced by LPS via activation of ERK signaling pathway. Finally GA could inhibit the activation of NF-κ B induced by LPS. Our present study indicates that GA has a protective effect against sepsis-induced inflammatory response, apoptosis, and oxidative stress damage, which provides a molecular basis for a new medical treatment of septic acute kidney injury. PMID:27063444

  17. Serum Neutrophil Gelatinase-Associated Lipocalin in Infants and Children with Sepsis-Related Conditions with or without Acute Renal Dysfunction

    PubMed Central

    Afify, Mohammed Farouk M.; Maher, Sheren Esam; Ibrahim, Nora Mohamed; El-Hamied, Waleed Mahamoud Abd

    2016-01-01

    PURPOSE To validate serum neutrophil gelatinase-associated lipocalin (NGAL) as an early biomarker for acute kidney injury (AKI) in sepsis-related conditions and its predictive and prognostic values. PATIENTS AND METHODS This study included 65 patients, who were clinically evaluated for sepsis, severe sepsis, or septic shock, and 20 apparently healthy served as controls. Patients were divided into two groups: Group I (AKI-sepsis): 65 newly admitted patients diagnosed as sepsis, who were further divided into three subgroups according to the severity: systemic inflammatory response syndrome, severe sepsis, and septic shock, and Group II (control group): 20 apparently healthy subjects matched for age and sex, serum creatinine and serum NGAL concentrations were estimated initially within 24 hours of admission and after 72 hours of admission in all patients and control groups. RESULTS Serum NGAL increased significantly with increasing severity of renal impairment. Receiver-operating characteristic analysis suggested that serum NGAL cutoff value of 40 ng/mL within the first 24 hours of admission is highly specific and sensitive for predicting AKI, with sensitivity of 90.9% and specificity of 75.8%. CONCLUSION We concluded that early measurement of serum NGAL level in sepsis can serve as a clinically useful marker for early prediction of AKI and for grading of its severity. PMID:27547045

  18. Curcumin protects against sepsis-induced acute lung injury in rats.

    PubMed

    Xiao, Xuefei; Yang, Mingshi; Sun, Dao; Sun, Shenghua

    2012-07-01

    The present study aimed to investigate the effect of curcumin on sepsis-induced acute lung injury (ALI) in rats, and explore its possible mechanisms. Male Sprague-Dawley rats were randomly divided into the following five experimental groups (n = 20 per group): animals undergoing a sham cecal ligature puncture (CLP) (sham group); animals undergoing CLP (control group); or animals undergoing CLP and treated with vehicle (vehicle group), curcumin at 50 mg/kg (low-dose curcumin [L-Cur] group), or curcumin at 200 mg/kg (high-dose curcumin [H-Cur] group).At 6, 12, 24 h after CLP, blood, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level, and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathologic changes in lungs. Myeloperoxidase (MPO) activity, malondialdehyde (MDA) content, as well as superoxidase dismutase (SOD) activity were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), interluekin-8 (IL-8), and macrophage migration inhibitory factor (MIF) were determined in the BALF. Survival rates were recorded at 72 h in the five groups in another experiment. Treatment with curcumin significantly attenuated the CLP-induced pulmonary edema and inflammation, as it significantly decreased lung W/D ratio, protein concentration, and the accumulation of the inflammatory cells in the BALF, as well as pulmonary MPO activity. This was supported by the histopathologic examination, which revealed marked attenuation of CLP-induced ALI in curcumin treated rats. In addition, curcumin significantly increased SOD activity with significant decrease in MDA content in the lung. Also, curcumin caused down-regulation of the inflammatory cytokines TNF-α, IL-8, and MIF levels in the lung. Importantly, curcumin improved the survival rate of rats by 40%-50% with CLP-induced ALI. Taken together, these results

  19. Ghrelin attenuates sepsis-associated acute lung injury oxidative stress in rats.

    PubMed

    Zeng, Mian; He, Wanmei; Li, Lijun; Li, Bin; Luo, Liang; Huang, Xubin; Guan, Kaipan; Chen, Weiling

    2015-04-01

    This study investigated the effect of ghrelin on oxidative stress in septic rat lung tissue. Male Sprague-Dawley rats were divided into sham-operation, sepsis, and ghrelin groups. Sepsis was induced by cecal ligation and puncture. Ghrelin was administered intraperitoneally at 3 and 15 h post-operation. Bronchoalveolar lavage was performed to collect alveolar macrophages (AMs). Inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) expression in alveolar macrophages and iNOS protein levels were measured by reverse transcription PCR (RT-PCR) and Western blot. Pulmonary pathology was analyzed and nitrotyrosine expression was examined by immunohistochemistry. Plasma superoxide dismutase (SOD) and lung wet/dry weight were measured. In the sepsis group, iNOS mRNA expression in AMs was 1.33 ± 0.05, 1.44 ± 0.08, and 1.57 ± 0.11 at 6, 12, and 20 h post-surgery, respectively, and were higher compared with the sham-operation group (p<0.05). No increase was observed at longer time points. iNOS mRNA expression in the sepsis group was lower compared with the ghrelin group (2.27 ± 0.37) (p<0.05) at 20 h post-surgery. iNOS protein levels in the ghrelin group (0.87 ± 0.03, p<0.05) were lower than in the sepsis group at 20 h. Ghrelin group pathological scores were lower than in the sepsis group (p<0.05). Plasma SOD was slightly non-significantly decreased in the ghrelin group. No difference was observed in lung wet/dry weight ratios between sepsis and ghrelin groups. iNOS mRNA expression in AMs was elevated between 6 and 20 h after cecal ligation and puncture (CLP), but did not progress. Ghrelin attenuated pulmonary iNOS protein expression and tended to increase plasma SOD activity. Ghrelin suppressed pulmonary nitrosative stress in septic rats, but did not improve lung wet/dry weight ratios. PMID:25037094

  20. [Sepsis in Emergency Medicine].

    PubMed

    Christ, Michael; Geier, Felicitas; Bertsch, Thomas; Singler, Katrin

    2016-07-01

    Sepsis is defined as "life-threatening organ dysfunction caused by a dysregulated host-response to infection". Presence of organ dysfunction is associated with a mortality of 10% and higher in hospitalized sepsis patients.Introduction of standards in diagnosis and treatment of sepsis in intensive care units has not considerably reduced sepsis mortality. About 80% of patients with sepsis are transferred to intensive care units from usual care wards and emergency departments. Thus, it is tempting to speculate whether opportunities for further improvement of sepsis management exist outside of intensive care units. Performing a "quick sequential organ assessment" (qSOFA; two of following criteria have to be present: respiratory rate >22/min; sytolic blood pressure <100mmHg; altered mental status) supports to identify patients with suspicion of an infection and an increased risk of death within the hospital. Subsequent treatment according to current guidelines on sepsis management will reduce in-hospital mortality of sepsis patients. Indeed, we were able to show a substantial decrease of in-hospital mortality of about 20% in patients presenting with community acquired pneumonia to the emergency department.In summary, decision of further management of sepsis patients has to be done outside intensive care units at the time of initial presentation to professional care givers. Sepsis management in acute care settings should include a structured and standardized protocol to further improve survival in affected patients with even mild organ dysfunction. PMID:27464279

  1. TNF-mediated damage to glomerular endothelium is an important determinant of acute kidney injury in sepsis.

    PubMed

    Xu, Chang; Chang, Anthony; Hack, Bradley K; Eadon, Michael T; Alper, Seth L; Cunningham, Patrick N

    2014-01-01

    Severe sepsis is often accompanied by acute kidney injury (AKI) and albuminuria. Here we studied whether the AKI and albuminuria associated with lipopolysaccharide (LPS) treatment in mice reflects impairment of the glomerular endothelium with its associated endothelial surface layer. LPS treatment decreased the abundance of endothelial surface layer heparan sulfate proteoglycans and sialic acid, and led to albuminuria likely reflecting altered glomerular filtration permselectivity. LPS treatment decreased the glomerular filtration rate (GFR), while also causing significant ultrastructural alterations in the glomerular endothelium. The density of glomerular endothelial cell fenestrae was 5-fold lower, whereas the average fenestrae diameter was 3-fold higher in LPS-treated than in control mice. The effects of LPS on the glomerular endothelial surface layer, endothelial cell fenestrae, GFR, and albuminuria were diminished in TNF receptor 1 (TNFR1) knockout mice, suggesting that these LPS effects are mediated by TNF-α activation of TNFR1. Indeed, intravenous administration of TNF decreased GFR and led to loss of glomerular endothelial cell fenestrae, increased fenestrae diameter, and damage to the glomerular endothelial surface layer. LPS treatment decreased kidney expression of vascular endothelial growth factor (VEGF). Thus, our findings confirm the important role of glomerular endothelial injury, possibly by a decreased VEGF level, in the development and progression of AKI and albuminuria in the LPS model of sepsis in the mouse. PMID:23903370

  2. Hypervolemia induces and potentiates lung damage after recruitment maneuver in a model of sepsis-induced acute lung injury

    PubMed Central

    2010-01-01

    Introduction Recruitment maneuvers (RMs) seem to be more effective in extrapulmonary acute lung injury (ALI), caused mainly by sepsis, than in pulmonary ALI. Nevertheless, the maintenance of adequate volemic status is particularly challenging in sepsis. Since the interaction between volemic status and RMs is not well established, we investigated the effects of RMs on lung and distal organs in the presence of hypovolemia, normovolemia, and hypervolemia in a model of extrapulmonary lung injury induced by sepsis. Methods ALI was induced by cecal ligation and puncture surgery in 66 Wistar rats. After 48 h, animals were anesthetized, mechanically ventilated and randomly assigned to 3 volemic status (n = 22/group): 1) hypovolemia induced by blood drainage at mean arterial pressure (MAP)≈70 mmHg; 2) normovolemia (MAP≈100 mmHg), and 3) hypervolemia with colloid administration to achieve a MAP≈130 mmHg. In each group, animals were further randomized to be recruited (CPAP = 40 cm H2O for 40 s) or not (NR) (n = 11/group), followed by 1 h of protective mechanical ventilation. Echocardiography, arterial blood gases, static lung elastance (Est,L), histology (light and electron microscopy), lung wet-to-dry (W/D) ratio, interleukin (IL)-6, IL-1β, caspase-3, type III procollagen (PCIII), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) mRNA expressions in lung tissue, as well as lung and distal organ epithelial cell apoptosis were analyzed. Results We observed that: 1) hypervolemia increased lung W/D ratio with impairment of oxygenation and Est,L, and was associated with alveolar and endothelial cell damage and increased IL-6, VCAM-1, and ICAM-1 mRNA expressions; and 2) RM reduced alveolar collapse independent of volemic status. In hypervolemic animals, RM improved oxygenation above the levels observed with the use of positive-end expiratory pressure (PEEP), but increased lung injury and led to higher inflammatory and fibrogenetic

  3. Severe sepsis in cirrhosis.

    PubMed

    Gustot, Thierry; Durand, François; Lebrec, Didier; Vincent, Jean-Louis; Moreau, Richard

    2009-12-01

    Sepsis is physiologically viewed as a proinflammatory and procoagulant response to invading pathogens. There are three recognized stages in the inflammatory response with progressively increased risk of end-organ failure and death: sepsis, severe sepsis, and septic shock. Patients with cirrhosis are prone to develop sepsis, sepsis-induced organ failure, and death. There is evidence that in cirrhosis, sepsis is accompanied by a markedly imbalanced cytokine response ("cytokine storm"), which converts responses that are normally beneficial for fighting infections into excessive, damaging inflammation. Molecular mechanisms for this excessive proinflammatory response are poorly understood. In patients with cirrhosis and severe sepsis, high production of proinflammatory cytokines seems to play a role in the worsening of liver function and the development of organ/system failures such as shock, renal failure, acute lung injury or acute respiratory distress syndrome, coagulopathy, or hepatic encephalopathy. In addition, these patients may have sepsis-induced hyperglycemia, defective arginine-vasopressin secretion, adrenal insufficiency, or compartmental syndrome. In patients with cirrhosis and spontaneous bacterial peritonitis (SBP), early use of antibiotics and intravenous albumin administration decreases the risk for developing renal failure and improves survival. There are no randomized studies that have been specifically performed in patients with cirrhosis and severe sepsis to evaluate treatments that have been shown to improve outcome in patients without cirrhosis who have severe sepsis or septic shock. These treatments include recombinant human activated C protein and protective-ventilation strategy for respiratory failure. Other treatments should be evaluated in the cirrhotic population with severe sepsis including the early use of antibiotics in "non-SBP" infections, vasopressor therapy, hydrocortisone, renal-replacement therapy and liver support systems, and

  4. Predictors of Acute Hemodynamic Decompensation in Early Sepsis: An Observational Study

    PubMed Central

    Lee, Young Im; Smith, Robert L.; Gartshteyn, Yevgeniya; Kwon, Sophia; Caraher, Erin J.; Nolan, Anna

    2016-01-01

    Background The study of sepsis is hindered by its heterogeneous time course and evolution. A subgroup of patients with severe sepsis develops shock soon after the initiation of treatment while others present hypotensive. We sought to determine the incidence of hypotension after the initiation of treatment for sepsis, and characterize their clinical features and course. Methods A retrospective review of electronic medical record of all septic patients (n = 542) that met the definition of septic shock within 24 hours of admission (2011 - 2012) at an urban Veteran Affairs Hospital was performed. Subjects either had 1) initial normotension (INT) with hypotension developing within 24 hours or 2) initial hypotension (IH). Logistic regression was used to model associated factors of INT/IH. Results INT occurred in 62 patients (11%) with average initial blood pressure of 120/71 mm Hg and developed hypotension to 79/48 mm Hg. IH was identified in 52 patients (10%) with average presenting blood pressure of 81/46 mm Hg. INT showed evidence of increased sympathetic tone with significantly higher heart rate, blood pressure and temperature. INT patients were younger, more frequently on alpha-blockers, and more likely septic from pneumonia compared to IH patients. INT and IH patients had similar timing of antibiotic initiation, amount of 24-hour fluid resuscitation, vasopressor use, organ dysfunction and mortality at 28 days. Using alpha-blockers, being Caucasian, and having higher temperatures were independent predictors of INT. Conclusion INT is a distinctive presentation of septic shock characterized by rapid deterioration during early treatment. By further studying this subgroup, mediators of septic shock may be identified that clarify pathophysiology and provide timely targeted treatment. PMID:27429677

  5. Melatonin augments apoptotic adipose-derived mesenchymal stem cell treatment against sepsis-induced acute lung injury

    PubMed Central

    Chen, Hong-Hwa; Chang, Chia-Lo; Lin, Kun-Chen; Sung, Pei-Hsun; Chai, Han-Tan; Zhen, Yen-Yi; Chen, Yi-Ching; Wu, Ying-Chung; Leu, Steve; Tsai, Tzu-Hsien; Chen, Chih-Hung; Chang, Hsueh-Wen; Yip, Hon-Kan

    2014-01-01

    This study investigated whether combining melatonin and apoptotic adipose-derived mesenchymal stem cells (A-ADMSC) was superior to ADMSC alone in ameliorating sepsis-induced acute lung injury. Adult male Sprague-Dawley rats (n=50) were randomized equally into five groups: sham controls (SC), sepsis induced by cecal-ligation and puncture (CLP), CLP-melatonin, CLP-A-ADMSC, and CLP-melatonin-A-ADMSC. Circulating interleukin (IL)-6 at 6, 18, and 72 hrs, were highest in CLP and lowest in SC groups, higher in CLP-melatonin than CLP-A-ADMSC and CLP-melatonin-A-ADMSC groups, higher in CLP-A-ADMSC than CLP-melatonin-A-ADMSC groups (all p<0.001). Immune reactivity (indicated by circulating cytotoxic-, and regulatory-T cells) and WBC count at 72 h exhibited the same pattern as that of circulating IL-6 (all p<0.001). Changes in histological scoring of lung parenchyma and the number of CD68+ and CD14+ cells showed a similar pattern compared to that of IL-6 level in all groups (all p<0.001). Changes in protein expressions of inflammatory (oxidative stress, RANTES, TNF-α, NF-κB, MMP-9, MIP-1, IL-1β), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), fibrotic (Smad3, TGF-β) markers and those of reactive-oxygen-species (NOX-1, NOX-2) displayed an identical pattern compared to that of circulating IL-6 in all groups (all p<0.001). Anti-oxidative capacities (GR+, GPx+, HO-1, NQO-1+) and angiogenesis marker (CXCR4+ cells) were lowest in SC group but highest in CLP-melatonin-A-ADMSC group, lower in CLP than CLP-melatonin and CLP-A-ADMSC groups, and lower in CLP-melatonin than CLP-A-ADMSC groups (all p<0.001). In conclusion, combined melatonin and A-ADMSC were superior to A-ADMSC alone in protecting the lung from sepsis-induced injury. PMID:25360211

  6. Post-streptococcal reactive arthritis: where are we now.

    PubMed

    Pathak, Himanshu; Marshall, Tarnya

    2016-01-01

    A 35-year-old man presented with polyarthritis and constitutional symptoms, and a recent history of multiple tick bites and skin rash on trekking holiday. He did not respond to oral doxycycline and cephalexine for presumed Lyme's disease. Further investigation confirmed strongly positive streptococcal serology. There was absence of clinical or echocardiography evidence of heart involvement and immunological screening for inflammatory arthritis was negative. In the absence of other major Jones criteria for acute rheumatic fever, besides polyarthritis and the serological evidence of a recent streptococcal infection, a diagnosis of post-streptococcal reactive arthritis (PSRA) was also made. He responded well to penicillin therapy and has been started on oral penicillin prophylaxis as per available guidance. As streptococcal infections in the adult population are increasingly reported, it is a timely opportunity to revisit PSRA, and develop comprehensive treatment and antibiotic prophylaxis guidelines. PMID:27520996

  7. Post-streptococcal reactive arthritis: where are we now

    PubMed Central

    Pathak, Himanshu; Marshall, Tarnya

    2016-01-01

    A 35-year-old man presented with polyarthritis and constitutional symptoms, and a recent history of multiple tick bites and skin rash on trekking holiday. He did not respond to oral doxycycline and cephalexine for presumed Lyme's disease. Further investigation confirmed strongly positive streptococcal serology. There was absence of clinical or echocardiography evidence of heart involvement and immunological screening for inflammatory arthritis was negative. In the absence of other major Jones criteria for acute rheumatic fever, besides polyarthritis and the serological evidence of a recent streptococcal infection, a diagnosis of post-streptococcal reactive arthritis (PSRA) was also made. He responded well to penicillin therapy and has been started on oral penicillin prophylaxis as per available guidance. As streptococcal infections in the adult population are increasingly reported, it is a timely opportunity to revisit PSRA, and develop comprehensive treatment and antibiotic prophylaxis guidelines. PMID:27520996

  8. Serum Neutrophil Gelatinase Associated Lipocalin (NGAL) Outperforms Serum Creatinine in Detecting Sepsis-Induced Acute Kidney Injury, Experiments on Bilateral Nephrectomy and Bilateral Ureter Obstruction Mouse Models.

    PubMed

    Leelahavanichkul, Asada; Somparn, Poorichaya; Issara-Amphorn, Jiraphorn; Eiam-Ong, Somchai; Avihingsanon, Yingyos; Hirankarn, Nattiya; Srisawat, Nattachai

    2016-05-01

    Serum neutrophil gelatinase associated lipocalin (sNGAL), a promising acute kidney injury (AKI) biomarker produced by renal and non-renal tissues, might be affected by sepsis. We evaluated sNGAL in zero glomerular filtration rate models [bilateral ureter obstruction (BUO) and bilateral nephrectomy (BiNx)] with subsequent cecal ligation and puncture (CLP)-induced sepsis in 6 to 8-week-old ICR mice. We found that sNGAL increased earlier than serum creatinine (Scr) in BiNx/BUO with and without CLP. The earliest time-point of increased sNGAL in BiNx+CLP was 1 h after surgery. Scr, but not sNGAL, was lower at 18 h after BiNx/BUO+CLP compared with BiNx/BUO alone. Compared with BUO, BiNx had higher, and equal sNGAL at 1 to 18 h and 36 h, respectively. Additionally, similar NGAL expression in internal organs (heart, lung, liver, and spleen) and survival rates indicated the comparable severity of BiNx and BUO. Serum interleukin (IL)-6 was increased and correlated with sNGAL in BiNx/BUO with and without sepsis. In summary, we demonstrated: sNGAL is an early AKI biomarker, which is not affected by sepsis; sNGAL is mainly produced by extrarenal sources as demonstrated by the comparable sNGAL in BiNx and BUO; the saturation of renal NGAL re-absorption in BUO is demonstrated by lower sNGAL in BUO at 1 to 18 h, but not at 36 h when compared with BiNx; and a correlation of sNGAL and IL-6 implied sNGAL is a good sepsis prognostic biomarker. Therefore, sNGAL is a more beneficial sepsis-AKI biomarker than Scr. PMID:26863120

  9. Neonatal sepsis

    MedlinePlus

    ... and some strains of streptococcus. Group B streptococcus (GBS) has been a major cause of neonatal sepsis. ... an infant's risk of early-onset bacterial sepsis: GBS colonization during pregnancy Preterm delivery Water breaking (rupture ...

  10. Determinants of hepcidin levels in sepsis-associated acute kidney injury: Impact on pAKT/PTEN pathways?

    PubMed

    Schaalan, Mona F; Mohamed, Walid A

    2016-09-01

    The antimicrobial β-defensin-like role of hepcidin (HEPC) has been increasingly investigated for its potential role in acute kidney injury (AKI). In sepsis-induced AKI, there is a complex interplay between positive and negative regulation of HEPC, with consequently altered distributions of iron caused by changes in HEPC levels. The aim of the current research was to assess serum HEPC levels in a cohort of septic patients with AKI and investigate the regulatory impact of hypoxia-inducing factor (HIF)-1α, erythropoietin (EPO) and inflammation on HEPC levels and related signal cascades in these patients. Baseline, higher levels of SCr (2.3-fold), blood urea nitrogen (BUN) (1.8-fold), uric acid (2.3-fold) and white blood cell (2.3-fold) were noted in septic AKI patients, along with decreased levels of albumin (15.7%), creatinine (44.7%) and BUN/creatinine ratios (23.8%), compared to in normal subjects. These hosts also had increased serum levels of TNFα (4.4-times) and TGFβ1 (3.2-times) compared to controls (p < 0.05). Further, HEPC and HIF-1α levels were also increased (8.8- and 3.6-times control levels), while EPO levels were decreased (77.8%) from control levels. After 12 weeks of antibiotic therapy, all septic AKI patients showed significant improvement of the altered markers of kidney dysfunction. In line with significant reductions in serum TNFα and TGFβ1 (25.5% and 26.2%, respectively), HEPC and HIF-1α levels were significantly decreased (31.6% and 19.3%), and EPO levels increased (1.9-fold) compared to pretreatment values. There was a significant positive correlation between HEPC levels and kidney function markers (SCr and BUN), inflammatory TNFα and TGFβ1 and serum HIF-1α and pAKT in septic AKI patients before and after treatment. Based on the results here, we conclude that HEPC, EPO and HIF-1α are involved in the pathogenesis of sepsis-induced AKI and confirm the dominating effects of inflammatory determinants over hypoxia

  11. Functional Characterization of Streptococcal Pyrogenic Exotoxin J, a Novel Superantigen

    PubMed Central

    McCormick, John K.; Pragman, Alexa A.; Stolpa, John C.; Leung, Donald Y. M.; Schlievert, Patrick M.

    2001-01-01

    Streptococcal toxic shock syndrome (STSS) is a highly lethal, acute-onset illness that is a subset of invasive streptococcal disease. The majority of clinical STSS cases have been associated with the pyrogenic toxin superantigens (PTSAgs) streptococcal pyrogenic exotoxin A or C (SPE A or C), although cases have been reported that are not associated with either of these exotoxins. Recent genome sequencing projects have revealed a number of open reading frames that potentially encode proteins with similarity to SPEs A and C and to other PTSAgs. Here, we describe the cloning, expression, purification, and functional characterization of a novel exotoxin termed streptococcal pyrogenic exotoxin J (SPE J). Purified recombinant SPE J (rSPE J) expressed from Escherichia coli stimulated the expansion of both rabbit splenocytes and human peripheral blood lymphocytes, preferentially expanded human T cells displaying Vβ2, -3, -12, -14, and -17 on their T-cell receptors, and was active at concentrations as low as 5 × 10−6 μg/ml. Furthermore, rSPE J induced fevers in rabbits and was lethal in two models of STSS. Biochemically, SPE J had a predicted molecular weight of 24,444 and an isoelectric point of 7.7 and lacked the ability to form the cystine loop structure characteristic of many PTSAgs. SPE J shared 19.6, 47.1, 38.8, 18.1, 19.6, and 24.4% identity with SPEs A, C, G, and H, streptococcal superantigen, and streptococcal mitogenic exotoxin Z-2, respectively, and was immunologically cross-reactive with SPE C. The characterization of a seventh functional streptococcal PTSAg raises important questions relating to the evolution of the streptococcal superantigens. PMID:11179302

  12. Ulinastatin is a novel candidate drug for sepsis and secondary acute lung injury, evidence from an optimized CLP rat model.

    PubMed

    Wang, Ning; Liu, Xin; Zheng, Xinchuan; Cao, Hongwei; Wei, Guo; Zhu, Yuanfeng; Fan, Shijun; Zhou, Hong; Zheng, Jiang

    2013-11-01

    Ulinastatin is a potent multivalent serine protease inhibitor, which was recently found with therapeutic potentials in treating sepsis, and the most life-threatening complication of critically ill population. However, the pharmacological features and possible mechanisms need to be further elucidated in reliable and clinical relevant sepsis models. As known, sepsis induced by surgery of cecal ligation and puncture (CLP) is widely accepted as the gold standard animal model, but the inconsistency of outcomes is the most obvious problem. In the present experiments, we reported an improved rat CLP model with much more consistent outcomes using self-made three edged puncture needles in our lab. Results from this optimized model revealed that ulinastatin improved survivals of CLP rats, attenuated proinflammatory response and prevented systemic disorder and organ dysfunction. Ulinastatin was also found to be effective in ameliorating sepsis-related ALI, a syndrome most frequent and fatal in sepsis. The molecular mechanism investigation showed that ulinastatin's protection against ALI was probably related to the down-regulation of NF-κB activity and inhibition of TNF-α, IL-6 and elastase expressions in the lung tissue. In conclusion, based on a successful establishment of optimized rat CLP model ulinastatin is proved to be an effective candidate for sepsis treatment, due to its anti-inflammation and anti-protease activities that ameliorate systemic disorders, prevent organ injuries and thus improve the survival outcomes of sepsis in animals. PMID:24075864

  13. Gadolinium chloride attenuates sepsis-induced pulmonary apoptosis and acute lung injury.

    PubMed

    Kishta, Osama A; Goldberg, Peter; Husain, Sabah N A

    2012-01-01

    Gadolinium chloride (GdCl3), a Kupffer cells inhibitor, attenuates acute lung injury; however, the mechanisms behind this effect are not completely elucidated. We tested the hypothesis that GdCl3 acts through the inhibition of lung parenchymal cellular apoptosis. Two groups of rats were injected intraperitoneally with saline or E. coli lipopolysaccharide. In two additional groups, rats were injected with GdCl3 24 hrs prior to saline or LPS administration. At 12 hrs, lung injury, inflammation, and apoptosis were studied. Lung water content, myeloperoxidase activity, pulmonary apoptosis and mRNA levels of interleukin-1 β , -2, -5, -6, -10 and TNF- α rose significantly in LPS-injected animals. Pretreatment with GdCl3 significantly reduced LPS-induced elevation of pulmonary water content, myeloperoxidase activity, cleaved caspase-3 intensity, and attenuated pulmonary TUNEL-positive cells. GdCl3 pre-treatment upregulated IL-1 β , -2 and -10 pulmonary gene expression without significantly affecting the others. These results suggest that GdCl3 attenuates acute lung injury through its effects on pulmonary parenchymal apoptosis. PMID:24049647

  14. Induction of hepatocyte lipopolysaccharide binding protein in models of sepsis and the acute-phase response.

    PubMed

    Geller, D A; Kispert, P H; Su, G L; Wang, S C; Di Silvio, M; Tweardy, D J; Billiar, T R; Simmons, R L

    1993-01-01

    Lipopolysaccharide binding protein (LBP) is a serum glycoprotein that complexes with lipopolysaccharide (LPS) to facilitate macrophage response to endotoxin. To determine the conditions that stimulate LBP production in vivo, we measured the induction of LBP in models of inflammation produced by LPS, Corynebacterium parvum, and turpentine injection. Plasma aspartate aminotransferase and alanine aminotransferase concentrations and hepatocyte fibrinogen synthesis were elevated in all models. Northern blot analysis revealed 17-, 14-, and 20-fold upregulation of hepatocyte LBP mRNA following treatment with LPS, C parvum, and turpentine, respectively. Peritoneal macrophage interleukin 6 and tumor necrosis factor production following endotoxin stimulation was augmented by cultured hepatocyte supernatants, suggesting increased LBP synthesis in these groups. The results show that LBP mRNA is induced during hepatic inflammation and suggest that LBP is an acute-phase protein important in regulating the in vivo response to endotoxin. PMID:8418776

  15. OPTICAL IMAGING OF LIPOPOLYSACCHARIDE-INDUCED OXIDATIVE STRESS IN ACUTE LUNG INJURY FROM HYPEROXIA AND SEPSIS

    PubMed Central

    SEPEHR, REYHANEH; AUDI, SAID H.; MALEKI, SEPIDEH; STANISZEWSKI, KEVIN; EIS, ANNIE L.; KONDURI, GIRIJA G.; RANJI, MAHSA

    2014-01-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of many acute and chronic pulmonary disorders such as acute lung injury (ALI) in adults and bronchopulmonary dysplasia (BPD) in premature infants. Bacterial infection and oxygen toxicity, which result in pulmonary vascular endothelial injury, contribute to impaired vascular growth and alveolar simplification seen in the lungs of premature infants with BPD. Hyperoxia induces ALI, reduces cell proliferation, causes DNA damage and promotes cell death by causing mitochondrial dysfunction. The objective of this study was to use an optical imaging technique to evaluate the variations in fluorescence intensities of the auto-fluorescent mitochondrial metabolic coenzymes, NADH and FAD in four different groups of rats. The ratio of these fluorescence signals (NADH/FAD), referred to as NADH redox ratio (NADH RR) has been used as an indicator of tissue metabolism in injuries. Here, we investigated whether the changes in metabolic state can be used as a marker of oxidative stress caused by hyperoxia and bacterial lipopolysaccharide (LPS) exposure in neonatal rat lungs. We examined the tissue redox states of lungs from four groups of rat pups: normoxic (21% O2) pups, hyperoxic (90% O2) pups, pups treated with LPS (normoxic + LPS), and pups treated with LPS and hyperoxia (hyperoxic + LPS). Our results show that hyperoxia oxidized the respiratory chain as reflected by a ~31% decrease in lung tissue NADH RR as compared to that for normoxic lungs. LPS treatment alone or with hyperoxia had no significant effect on lung tissue NADH RR as compared to that for normoxic or hyperoxic lungs, respectively. Thus, NADH RR serves as a quantitative marker of oxidative stress level in lung injury caused by two clinically important conditions: hyperoxia and LPS exposure. PMID:24672581

  16. OPTICAL IMAGING OF LIPOPOLYSACCHARIDE-INDUCED OXIDATIVE STRESS IN ACUTE LUNG INJURY FROM HYPEROXIA AND SEPSIS.

    PubMed

    Sepehr, Reyhaneh; Audi, Said H; Maleki, Sepideh; Staniszewski, Kevin; Eis, Annie L; Konduri, Girija G; Ranji, Mahsa

    2013-07-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of many acute and chronic pulmonary disorders such as acute lung injury (ALI) in adults and bronchopulmonary dysplasia (BPD) in premature infants. Bacterial infection and oxygen toxicity, which result in pulmonary vascular endothelial injury, contribute to impaired vascular growth and alveolar simplification seen in the lungs of premature infants with BPD. Hyperoxia induces ALI, reduces cell proliferation, causes DNA damage and promotes cell death by causing mitochondrial dysfunction. The objective of this study was to use an optical imaging technique to evaluate the variations in fluorescence intensities of the auto-fluorescent mitochondrial metabolic coenzymes, NADH and FAD in four different groups of rats. The ratio of these fluorescence signals (NADH/FAD), referred to as NADH redox ratio (NADH RR) has been used as an indicator of tissue metabolism in injuries. Here, we investigated whether the changes in metabolic state can be used as a marker of oxidative stress caused by hyperoxia and bacterial lipopolysaccharide (LPS) exposure in neonatal rat lungs. We examined the tissue redox states of lungs from four groups of rat pups: normoxic (21% O2) pups, hyperoxic (90% O2) pups, pups treated with LPS (normoxic + LPS), and pups treated with LPS and hyperoxia (hyperoxic + LPS). Our results show that hyperoxia oxidized the respiratory chain as reflected by a ~31% decrease in lung tissue NADH RR as compared to that for normoxic lungs. LPS treatment alone or with hyperoxia had no significant effect on lung tissue NADH RR as compared to that for normoxic or hyperoxic lungs, respectively. Thus, NADH RR serves as a quantitative marker of oxidative stress level in lung injury caused by two clinically important conditions: hyperoxia and LPS exposure. PMID:24672581

  17. Requisite Role of the Cholinergic α7 Nicotinic Acetylcholine Receptor Pathway in Suppressing Gram-Negative Sepsis-Induced Acute Lung Inflammatory Injury

    PubMed Central

    Su, Xiao; Matthay, Michael A.; Malik, Asrar B.

    2010-01-01

    Although activation of the α7 nicotinic acetylcholine receptor (α7 nAChR) modulates the response to sepsis, the role of this pathway in the development of sepsis-induced acute lung injury (ALI) is not known. In this study, we addressed the contribution of α7 nAChR in mediating endotoxin- and live Escherichia coli–induced ALI in mice. Because we found that α7 nAChR+ alveolar macrophages and neutrophils were present in bronchoalveolar lavage and injured lungs of mice, we tested whether acetylcholine released by lung vagal innervation stimulated these effector cells and thereby down-regulated proinflammatory chemokine/cytokine generation. Administration of α7 nAChR agonists reduced bronchoalveolar lavage MIP-2 production and transalveolar neutrophil migration and reduced mortality in E. coli pneumonia mice, whereas vagal denervation increased MIP-2 production and airway neutrophil accumulation and increased mortality. In addition, α7 nAChR−/− mice developed severe lung injury and had higher mortality compared with α7 nAChR+/+ mice. The immunomodulatory cholinergic α7 nAChR pathway of alveolar macrophages and neutrophils blocked LPS- and E. coli–induced ALI by reducing chemokine production and transalveolar neutrophil migration, suggesting that activation of α7 nAChR may be a promising strategy for treatment of sepsis-induced ALI. PMID:19949071

  18. Group A Streptococcal Infection in Pregnancy and the Puerperium.

    PubMed

    Sosa, Mary Ellen Burke

    2016-01-01

    There has been an increasing incidence worldwide of invasive group A streptococcal disease in pregnancy and the puerperal period over the past 30 years. Group A Streptococcus (GAS) was identified as the major cause of maternal morbidity and mortality from sepsis before the identification that hand washing techniques could prevent the transmission of the bacteria. Hand washing remains the cornerstone of prevention as transmission can occur directly from an asymptomatic colonized healthcare provider, other patients, or a community-acquired source. Pregnancy and the puerperal period are associated with significant maternal physiologic changes that must be identified and clarified to identify signs and symptoms of GAS so that treatment can be initiated at the earliest moment. Treatment of group A streptococcal sepsis follows the guidelines developed under the Surviving Sepsis Campaign model. Maternal outcomes are improved by identifying risk factors and working with the perinatal team to implement rapid intervention. Even with prompt treatment of invasive group A Streptococcus, it remains the most common cause of infection that results in severe maternal morbidity and death in the world. PMID:27104603

  19. Effects of Fluid Resuscitation With 0.9% Saline Versus a Balanced Electrolyte Solution on Acute Kidney Injury in a Rat Model of Sepsis*

    PubMed Central

    Zhou, Feihu; Peng, Zhi-Yong; Bishop, Jeffery V.; Cove, Matthew E.; Singbartl, Kai; Kellum, John A.

    2014-01-01

    Objective To compare the acute effects of 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis. Design Controlled laboratory experiment. Setting University laboratory. Subjects Sixty adult, male Sprague-Dawley rats. Interventions We induced sepsis by cecal ligation and puncture and randomized animals to receive fluid resuscitation with either 0.9% saline or Plasma-Lyte solution for 4 hours after 18 hours of cecal ligation and puncture (10 mL/kg in the first hour and 5 mL/kg in the next 3 hr). Blood and urine specimens were obtained from baseline, 18 hours after cecal ligation and puncture, immediately after 4 hours fluid resuscitation, and 24 hours later. We measured blood gas, plasma electrolytes, creatinine, interleukin-6, cystatin C, and neutrophil gelatinase-associated lipocalin concentrations. We also analyzed urine for cystatin C and neutrophil gelatinase-associated lipocalin. We used Risk, Injury, Failure, Loss and End-stage criteria for creatinine to assess severity of acute kidney injury. We observed all animals for survival up to 1 day after resuscitation. Surviving animals were killed for kidney histology. Finally, we carried out an identical study in 12 healthy animals. Measurements and Main Results Compared with Plasma-Lyte, 0.9% saline resuscitation resulted in significantly greater blood chloride concentrations (p < 0.05) and significantly decreased pH and base excess. Acute kidney injury severity measured by RIFLE criteria was increased with 0.9% saline compared with Plasma-Lyte resuscitation (p < 0.05), and these results were consistent with kidney histology and biomarkers of acute kidney injury. Twenty-four-hour survival favored Plasma-Lyte resuscitation (76.6% vs 53.3%; p = 0.03). Finally, in healthy animals, we found no differences between fluids and no evidence of acute kidney injury. Conclusion Volume resuscitation with Plasma-Lyte resulted in less acidosis and less kidney injury and improved short

  20. Removal of regulatory T cells prevents secondary chronic infection but increases the mortality of subsequent sub-acute infection in sepsis mice

    PubMed Central

    Wang, Xiaoya; Zhao, Yong; Wang, Yi; Zhao, Xiaomin; Chang, Lingling; Liu, Shan-lu; Tong, Dewen; Zhang, Hai; Huang, Yong

    2016-01-01

    The immunosuppression following initial septic insult impairs resistance to secondary infection. Modulation of lymphocytes population may help to develop an effective therapeutic strategy. In this study, lipopolysaccharide (LPS)-induced endotoxemia was employed as the initial septic insult. 24 hours later, mice underwent cecal ligation and puncture to induce chronic or sub-acute peritonitis. Potential usefulness of T regs deletion antibody (anti-CD25) in improving LPS-induced immunosuppression and the survival of subsequent different infections were evaluated. LPS injection induced lymphocyte loss and led to decreased IL-6, TNF-α and IFN-γ, and weakened bacteria clearance upon chronic peritonitis at 24 h post-LPS, whereas reconstitution with lymphocytes reversed these changes. LPS-induced T regs expansion contributed to T and NK cells decrease in number and activity during sepsis. Depletion of T regs using anti-CD25 antibodies partly prevented lymphocyte loss and increased the responses of T and NK cells to subsequent stimulation, resulting in significantly increased bacterial clearance and survival in a 2-hit model of chronic peritonitis, but which significantly increased early mortality upon subsequently sub-acute infection. Yet, using lower dosage of anti-CD25 antibodies to moderate down-regulate T regs levels could partly improve bacterial clearance and survival in either chronic or sub-acute infection. These results demonstrate that using anti-CD25 antibodies to deplete T regs can ameliorate immunosuppression through increasing T cells and NK cells responses in sepsis, which is beneficial for preventing subsequently chronic infection, but will probably bring some deleterious effects for subsequent sub-acute infection. PMID:26918357

  1. Atorvastatin along with imipenem attenuates acute lung injury in sepsis through decrease in inflammatory mediators and bacterial load.

    PubMed

    Choudhury, Soumen; Kandasamy, Kannan; Maruti, Bhojane Somnath; Addison, M Pule; Kasa, Jaya Kiran; Darzi, Sazad A; Singh, Thakur Uttam; Parida, Subhashree; Dash, Jeevan Ranjan; Singh, Vishakha; Mishra, Santosh Kumar

    2015-10-15

    Lung is one of the vital organs which is affected during the sequential development of multi-organ dysfunction in sepsis. The purpose of the present study was to examine whether combined treatment with atorvastatin and imipenem could attenuate sepsis-induced lung injury in mice. Sepsis was induced by caecal ligation and puncture. Lung injury was assessed by the presence of lung edema, increased vascular permeability, increased inflammatory cell infiltration and cytokine levels in broncho-alveolar lavage fluid (BALF). Treatment with atorvastatin along with imipenem reduced the lung bacterial load and pro-inflammatory cytokines (IL-1β and TNFα) level in BALF. The markers of pulmonary edema such as microvascular leakage and wet-dry weight ratio were also attenuated. This was further confirmed by the reduced activity of MPO and ICAM-1 mRNA expression, indicating the lesser infiltration and adhesion of inflammatory cells to the lungs. Again, expression of mRNA and protein level of iNOS in lungs was also reduced in the combined treatment group. Based on the above findings it can be concluded that, combined treatment with atorvastatin and imipenem dampened the inflammatory response and reduced the bacterial load, thus seems to have promising therapeutic potential in sepsis-induced lung injury in mice. PMID:26375251

  2. Management of streptococcal pharyngitis reconsidered.

    PubMed

    Gerber, M A; Markowitz, M

    1985-01-01

    Adequate treatment of GABHS pharyngitis with penicillin shortens the course of illness, reduces the spread of streptococci and prevents suppurative complications. It has also been a major factor in the markedly accelerated decline in the incidence of acute rheumatic fever in this country. Difficulties in the clinical diagnosis of GABHS pharyngitis make bacteriologic confirmation highly desirable. Currently a properly performed throat culture is the best way to obtain this bacteriologic confirmation. However, it is possible that rapid antigen detection tests will replace the throat culture in the future. These diagnostic tools should be used more selectively and only in conjunction with clinical and epidemiologic data. Greater selectivity will help control costs and will increase the chances of identifying patients who are truly infected and are not merely streptococcal carriers. Penicillin is still the drug of choice and an oral preparation given twice daily is as effective as more frequent doses. Patients at risk for noncompliance should be treated with a single injection of benzathine penicillin combined with procaine penicillin to lessen the local discomfort. Routine follow-up cultures of asymptomatic patients should be abandoned. Persistence of GABHS following a course of treatment may no longer be an important risk factor for the development of rheumatic fever. However, there are exceptional cases, as noted in the text, in which eradication of GABHS carriage with a short course of rifampicin may be desirable. PMID:3931060

  3. Neuronal antibody biomarkers for Sydenham's chorea identify a new group of children with chronic recurrent episodic acute exacerbations of tic and obsessive compulsive symptoms following a streptococcal infection.

    PubMed

    Singer, Harvey S; Mascaro-Blanco, Adda; Alvarez, Kathy; Morris-Berry, Christina; Kawikova, Ivana; Ben-Pazi, Hilla; Thompson, Carol B; Ali, Syed F; Kaplan, Edward L; Cunningham, Madeleine W

    2015-01-01

    Several autoantibodies (anti-dopamine 1 (D1R) and 2 (D2R) receptors, anti-tubulin, anti-lysoganglioside-GM1) and antibody-mediated activation of calcium calmodulin dependent protein kinase II (CaMKII) signaling activity are elevated in children with Sydenham's chorea (SC). Recognizing proposed clinical and autoimmune similarities between SC and PANDAS (pediatric autoimmune neuropsychiatric disorder associated with a streptococcal infection), we sought to identify serial biomarker changes in a slightly different population. Antineuronal antibodies were measured in eight children (mean 11.3 years) with chronic, dramatic, recurrent tics and obsessive-compulsive disorder (OCD) associated with a group A β-hemolytic streptococcal (GABHS) respiratory tract infection, but differing because they lacked choreiform movements. Longitudinal serum samples in most subjects included two pre-exacerbation samples, Exac), one midst Exac (abrupt recurrence of tic/OCD; temporally association with a GABHS infection in six of eight subjects), and two post-Exac. Controls included four groups of unaffected children (n = 70; mean 10.8 years) obtained at four different institutions and published controls. Clinical exacerbations were not associated with a significant rise in antineuronal antibody titers. CaMKII activation was increased at the GABHS exacerbation point in 5/6 subjects, exceeded combined and published control's 95th percentile at least once in 7/8 subjects, and median values were elevated at each time point. Anti-tubulin and anti-D2R titers did not differ from published or combined control group's 95th percentile or median values. Differences in anti-lysoganglioside-GM1 and anti-D1R titers were dependent on the selected control. Variances in antibody titers and CaMKII activation were identified among the institutional control groups. Based on comparisons to published studies, results identify two groups of PANDAS: 1) a cohort, represented by this study, which lacks choreiform

  4. Streptococcal Infection-related Nephritis (SIRN) Manifesting Membranoproliferative Glomerulonephritis Type I.

    PubMed

    Iseri, Ken; Iyoda, Masayuki; Yamamoto, Yasutaka; Kobayashi, Naoto; Oda, Takashi; Yamaguchi, Yutaka; Shibata, Takanori

    2016-01-01

    We herein report the case of an 18-year-old boy who developed nephrotic syndrome and hypertension after upper airway inflammation. Post-streptococcal acute glomerulonephritis was diagnosed on the basis of a high antistreptolysin O titer, hypocomplementemia, proteinuria, and microscopic hematuria. A renal biopsy was performed due to persistent proteinuria, and the pathological diagnosis was membranoproliferative glomerulonephritis (MPGN) type I. Glomeruli showed positive staining for nephritis-associated plasmin receptor (NAPlr), a nephritogenic group A streptococcal antigen, and plasmin activity was found in a similar distribution as NAPlr deposition. This rare case of streptococcal infection-related nephritis (SIRN) manifesting MPGN type I supports the histological diversity of SIRN. PMID:26984084

  5. Pediatric sepsis

    PubMed Central

    Randolph, Adrienne G; McCulloh, Russell J

    2014-01-01

    Sepsis is the leading cause of death in children worldwide. Although the diagnosis and management of sepsis in infants and children is largely influenced by studies done in adults, there are important considerations relevant for pediatrics. This article highlights pediatric-specific issues related to the definition of sepsis and its epidemiology and management. We review how the capacity of the immune system to respond to infection develops over early life. We also bring attention to primary immune deficiencies that should be considered in children recurrently infected with specific types of organisms. The management of pediatric sepsis must be tailored to the child’s age and immune capacity, and to the site, severity, and source of the infection. It is important for clinicians to be aware of infection-related syndromes that primarily affect children. Although children in developed countries are more likely to survive severe infections than adults, many survivors have chronic health impairments. PMID:24225404

  6. Genetic variation in the TNF receptor-associated factor 6 gene is associated with susceptibility to sepsis-induced acute lung injury

    PubMed Central

    2012-01-01

    Background Recent studies showed that overwhelming inflammatory response mediated by the toll-like receptor (TLR)-related pathway was important in the development of acute lung injury (ALI). The aim of this study was to determine whether common genetic variation in four genes of the TLR signaling pathway were associated with sepsis-induced ALI susceptibility and risk of death in Chinese Han population. Methods Fourteen tag single nucleotide polymorphisms (tagSNPs) in MyD88, IRAK1, IRAK4 and TRAF6 were genotyped in samples of sepsis-induced ALI (n = 272) and sepsis alone patients (n = 276), and tested for association in this case-control collection. Then, we investigated correlation between the associated SNP and the mRNA expression level of the corresponding gene. And we also investigated correlation between the associated SNP and tumor necrosis factor alpha (TNF-α) as well as interleukin-6 (IL-6) concentrations in peripheral blood mononuclear cells (PBMCs) exposed to lipopolysaccharides (LPS) ex vivo. The mRNA expression level was determined using real-time quantitative Polymerase Chain Reaction (PCR) assays, and concentrations of TNF-α and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). Results The association analysis revealed that rs4755453, an intronic SNP of TRAF6, was significantly associated with susceptibility to sepsis-induced ALI. The C allele frequency of rs4755453 in the sepsis alone group was significantly higher than that in the sepsis-induced ALI group (P = 0.00026, odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.37–0.74). These associations remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. TRAF6 mRNA expression levels in PBMCs from homozygotes of the rs4755453G allele were significantly higher than that in heterozygotes and homozygotes of the rs4755453C allele at baseline (P = 0.012 and P = 0.003, respectively) as well as after

  7. Hemodynamic variables and progression of acute kidney injury in critically ill patients with severe sepsis: data from the prospective observational FINNAKI study

    PubMed Central

    2013-01-01

    Introduction Knowledge of the association of hemodynamics with progression of septic acute kidney injury (AKI) is limited. However, some recent data suggest that mean arterial pressure (MAP) exceeding current guidelines (60–65 mmHg) may be needed to prevent AKI. We hypothesized that higher MAP during the first 24 hours in the intensive care unit (ICU), would be associated with a lower risk of progression of AKI in patients with severe sepsis. Methods We identified 423 patients with severe sepsis and electronically recorded continuous hemodynamic data in the prospective observational FINNAKI study. The primary endpoint was progression of AKI within the first 5 days of ICU admission defined as new onset or worsening of AKI by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We evaluated the association of hemodynamic variables with this endpoint. We included 53724 10-minute medians of MAP in the analysis. We analysed the ability of time-adjusted MAP to predict progression of AKI by receiver operating characteristic (ROC) analysis. Results Of 423 patients, 153 (36.2%) had progression of AKI. Patients with progression of AKI had significantly lower time-adjusted MAP, 74.4 mmHg [68.3-80.8], than those without progression, 78.6 mmHg [72.9-85.4], P < 0.001. A cut-off value of 73 mmHg for time-adjusted MAP best predicted the progression of AKI. Chronic kidney disease, higher lactate, higher dose of furosemide, use of dobutamine and time-adjusted MAP below 73 mmHg were independent predictors of progression of AKI. Conclusions The findings of this large prospective multicenter observational study suggest that hypotensive episodes (MAP under 73 mmHg) are associated with progression of AKI in critically ill patients with severe sepsis. PMID:24330815

  8. Pathogenesis of Group A Streptococcal Infections

    PubMed Central

    Cunningham, Madeleine W.

    2000-01-01

    Group A streptococci are model extracellular gram-positive pathogens responsible for pharyngitis, impetigo, rheumatic fever, and acute glomerulonephritis. A resurgence of invasive streptococcal diseases and rheumatic fever has appeared in outbreaks over the past 10 years, with a predominant M1 serotype as well as others identified with the outbreaks. emm (M protein) gene sequencing has changed serotyping, and new virulence genes and new virulence regulatory networks have been defined. The emm gene superfamily has expanded to include antiphagocytic molecules and immunoglobulin-binding proteins with common structural features. At least nine superantigens have been characterized, all of which may contribute to toxic streptococcal syndrome. An emerging theme is the dichotomy between skin and throat strains in their epidemiology and genetic makeup. Eleven adhesins have been reported, and surface plasmin-binding proteins have been defined. The strong resistance of the group A streptococcus to phagocytosis is related to factor H and fibrinogen binding by M protein and to disarming complement component C5a by the C5a peptidase. Molecular mimicry appears to play a role in autoimmune mechanisms involved in rheumatic fever, while nephritis strain-associated proteins may lead to immune-mediated acute glomerulonephritis. Vaccine strategies have focused on recombinant M protein and C5a peptidase vaccines, and mucosal vaccine delivery systems are under investigation. PMID:10885988

  9. Coagulation abnormalities in sepsis.

    PubMed

    Tsao, Cheng-Ming; Ho, Shung-Tai; Wu, Chin-Chen

    2015-03-01

    Although the pathophysiology of sepsis has been elucidated with the passage of time, sepsis may be regarded as an uncontrolled inflammatory and procoagulant response to infection. The hemostatic changes in sepsis range from subclinical activation of blood coagulation to acute disseminated intravascular coagulation (DIC). DIC is characterized by widespread microvascular thrombosis, which contributes to multiple organ dysfunction/failure, and subsequent consumption of platelets and coagulation factors, eventually causing bleeding manifestations. The diagnosis of DIC can be made using routinely available laboratory tests, scoring algorithms, and thromboelastography. In this cascade of events, the inhibition of coagulation activation and platelet function is conjectured as a useful tool for attenuating inflammatory response and improving outcomes in sepsis. A number of clinical trials of anticoagulants were performed, but none of them have been recognized as a standard therapy because recombinant activated protein C was withdrawn from the market owing to its insufficient efficacy in a randomized controlled trial. However, these subgroup analyses of activated protein C, antithrombin, and thrombomodulin trials show that overt coagulation activation is strongly associated with the best therapeutic effect of the inhibitor. In addition, antiplatelet drugs, including acetylsalicylic acid, P2Y12 inhibitors, and glycoprotein IIb/IIIa antagonists, may reduce organ failure and mortality in the experimental model of sepsis without a concomitant increased bleeding risk, which should be supported by solid clinical data. For a state-of-the-art treatment of sepsis, the efficacy of anticoagulant and antiplatelet agents needs to be proved in further large-scale prospective, interventional, randomized validation trials. PMID:25544351

  10. Urinary output and fractional excretion of sodium and urea as indicators of transient versus intrinsic acute kidney injury during early sepsis

    PubMed Central

    2013-01-01

    Introduction The pathophysiology of acute kidney injury (AKI) in sepsis is ill defined. We investigated parameters associated with low glomerular filtration, and their predictive value to discriminate transient from intrinsic septic AKI. Methods In 107 sepsis patients, AKI was defined by the Risk, Injury, Failure, Loss of Kidney Function, End-stage renal disease (RIFLE) urinary output or serum creatinine criterion, or both. Transient AKI (TAKI) versus intrinsic AKI was defined as RIFLE R, I, or F on the first day evolving to no AKI or not, respectively, over the following 5 days. Fractional excretion of sodium (FENa), urea (FEUrea), and NGAL (FENGAL) at admission (d0t0), 4 (d0t4), and 24 hours (d1) was determined. Results Including versus not including the urinary-output criterion of RIFLE increased AKI from 43% to 64.5%. Median uNGAL levels and FENGAL were lower in no AKI versus transient AKI when AKI was defined based on creatinine (P = 0.002 and P = 0.04, respectively), but not when based on urinary output (P = 0.9 and P = 0.49, respectively). FENa < 1% and FEUrea <35% was present in 77.3% and 63.2% of patients. Urinary NGAL was higher (P < 0.001) in those with high versus low fractional sodium excretion, but this was only in patients with transient or intrinsic AKI (P < 0.001 in subgroups), and not in patients without AKI. The negative predictive value for either intrinsic AKI or not restoring diuresis in patients with FENa > 0.36% and FEUrea > 31.5% was 92% and 94.5% respectively. Conclusions A low FENa and FEUrea is highly prevalent in the first hours of sepsis. In sepsis, oliguria is an earlier sign of impending AKI than increase in serum creatinine. A combination of a high FENa and a low FEUrea is associated with intrinsic AKI, whereas a combined high FENa and FEUrea is strongly predictive of transient AKI. PMID:24119730

  11. Pathogenesis of group A streptococcal infections.

    PubMed

    Henningham, Anna; Barnett, Timothy C; Maamary, Peter G; Walker, Mark J

    2012-05-01

    Group A Streptococcus (GAS; Streptococcus pyogenes) is a human pathogen which causes significant morbidity and mortality globally. GAS typically infects the throat and skin of the host, causing mild infections such as pharyngitis and impetigo, in addition to life threatening conditions including necrotizing fasciitis, streptococcal toxic shock syndrome (STSS), and bacteremia. Repeated infection with GAS may result in the non-suppurative sequelae, acute rheumatic fever, and acute glomerulonephritis. GAS remains sensitive to the antibiotic penicillin which can be administered as a means to treat infection or as prophylaxis. However, issues with patient compliance and a growing concern over the possible emergence of resistant GAS strains may limit the usefulness of antibiotics in the future. A vaccine capable of preventing GAS infection may be the only effective way to control and eliminate GAS infection and disease. PMID:22642914

  12. Streptococcal infections of skin and PANDAS.

    PubMed

    Carelli, Rosanna; Pallanti, Stefano

    2014-01-01

    Group A streptococcal infections are associated with a variety of infections and a subset of obsessive-compulsive disorder and/or tic disorders. Screening of obsessive-compulsive symptoms and tics in patient with streptococcal infection of skin must be effective in identifying subjects who met published criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). PMID:24502308

  13. MITOCHONDRIAL FUNCTION IN SEPSIS.

    PubMed

    Arulkumaran, Nishkantha; Deutschman, Clifford S; Pinsky, Michael R; Zuckerbraun, Brian; Schumacker, Paul T; Gomez, Hernando; Gomez, Alonso; Murray, Patrick; Kellum, John A

    2016-03-01

    Mitochondria are an essential part of the cellular infrastructure, being the primary site for high-energy adenosine triphosphate production through oxidative phosphorylation. Clearly, in severe systemic inflammatory states, like sepsis, cellular metabolism is usually altered, and end organ dysfunction is not only common, but also predictive of long-term morbidity and mortality. Clearly, interest is mitochondrial function both as a target for intracellular injury and response to extrinsic stress have been a major focus of basic science and clinical research into the pathophysiology of acute illness. However, mitochondria have multiple metabolic and signaling functions that may be central in both the expression of sepsis and its ultimate outcome. In this review, the authors address five primary questions centered on the role of mitochondria in sepsis. This review should be used both as a summary source in placing mitochondrial physiology within the context of acute illness and as a focal point for addressing new research into diagnostic and treatment opportunities these insights provide. PMID:26871665

  14. Improving management of sepsis in the community.

    PubMed

    Culligan, Fiona

    2016-08-31

    Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Pathological changes in the circulation reduce the blood supply to major organs, causing them to fail. This may lead to death, therefore rapid recognition and treatment of sepsis is vital. Sepsis research has focused on patients in acute hospital settings. However, most cases of sepsis originate in the community, suggesting that the identification of sepsis and delivery of timely care is necessary before hospital admission. Therefore, it is essential that nurses practising in the community are provided with appropriate sepsis guidelines that can be implemented immediately. The UK Sepsis Trust has developed the General Practice Sepsis Decision Support Tool, which has been designed specifically for use in the community. This article provides an overview of how the tool is used in the community and how it works in conjunction with the 'Sepsis Six' care bundle and care bundles for hospital settings. Changes to the terminology used in relation to sepsis and recent guidelines are also explained. PMID:27577313

  15. Senegenin Ameliorate Acute Lung Injury Through Reduction of Oxidative Stress and Inhibition of Inflammation in Cecal Ligation and Puncture-Induced Sepsis Rats.

    PubMed

    Liu, Chun-Hong; Zhang, Wei-Dong; Wang, Jian-Jie; Feng, Shan-Dan

    2016-04-01

    The purpose of this study was to assess the protective effect of senegenin on acute lung injury (ALI) in rats induced by sepsis. Rat ALI model was reproduced by cecal ligation and puncture (CLP). All rats were randomly divided into five groups: group 1 (control), group 2 (CLP), group 3 (CLP + senegenin 15 mg/kg), group 4 (CLP + senegenin 30 mg/kg), and group 5 (CLP + senegenin 60 mg/kg). CLP + senegenin groups received senegenin by gavage daily for consecutive 5 days, respectively, while the mice in control and CLP groups were given an equivalent volume of saline. We detected the lung wet/dry weight ratios and the histopathology of the lung. The levels of lung tissue myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were determined. Meanwhile, the nuclear factor-kappa B (NF-κB) activation, tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β) levels were studied. The results demonstrated that senegenin treatment significantly attenuated CLP-induced lung injury, including reduction of lung wet/dry weight ratio, protein leak, infiltration of leukocytes, and MPO activity. In addition, senegenin markedly decreased MDA content and increased SOD activity and GSH level. Serum levels of TNF-α and IL-1β were also decreased by senegenin administration. Furthermore, senegenin administration inhibited the nuclear translocation of NF-κB in the lungs. These findings indicate that senegenin exerts protective effects on CLP-induced septic rats. Senegenin may be a potential therapeutic agent against sepsis. PMID:26945584

  16. Protective effect of quercetin on acute lung injury in rats with sepsis and its influence on ICAM-1 and MIP-2 expression.

    PubMed

    Meng, L; Lv, Z; Yu, Z Z; Xu, D; Yan, X

    2016-01-01

    This study aimed to explore the protective effect of quercetin on acute lung injury (ALI) in rats with sepsis and the related mechanism. Rats were administered different doses of quercetin intraperitoneally, and blood samples and lung tissue were collected at 24 h after treatment. Arterial blood gases, lung water content, protein content, and cell counts in bronchoalveolar lavage fluid (BALF) were measured. Morphological changes in lung tissue pathology were observed under a light microscope. Serum intercellular adhesion molecule (ICAM)-1 and macrophage inflammatory protein 2 (MIP-2) levels were detected and ICAM-1 and MIP-2 mRNA expression in lung tissue was determined. Compared with that in the control model group, arterial blood gases, lung water content, protein content, and cell counts in BALF improved in the high- and low-dose quercetin groups (P < 0.05), with maximal improvement observed for the high-dose quercetin (P < 0.05). Lesions on the lungs improved in the high- and low-dose quercetin groups than those in the control model group, and the high-dose quercetin group showed better improvement than the low-dose group (P < 0.05). Compared with that in the sham-operated group, both serum and lung tissue ICAM-1 and MIP-2 expression increased significantly in the model group (P < 0.05). The quercetin groups presented lower ICAM-1 and MIP-2 expression than the control model group, with the lowest expression observed in the high-dose group (P < 0.05). Quercetin may protect against ALI in rats with sepsis by inhibiting ICAM-1 and MIP-2 expression. PMID:27525872

  17. Staphylococcal and Streptococcal Superantigen Exotoxins

    PubMed Central

    Spaulding, Adam R.; Salgado-Pabón, Wilmara; Kohler, Petra L.; Horswill, Alexander R.; Leung, Donald Y. M.

    2013-01-01

    SUMMARY This review begins with a discussion of the large family of Staphylococcus aureus and beta-hemolytic streptococcal pyrogenic toxin T lymphocyte superantigens from structural and immunobiological perspectives. With this as background, the review then discusses the major known and possible human disease associations with superantigens, including associations with toxic shock syndromes, atopic dermatitis, pneumonia, infective endocarditis, and autoimmune sequelae to streptococcal illnesses. Finally, the review addresses current and possible novel strategies to prevent superantigen production and passive and active immunization strategies. PMID:23824366

  18. Granulomatous uveitis and reactive arthritis as manifestations of post-streptococcal syndrome.

    PubMed

    Abderrahim, Kais; Chebil, Ahmed; Falfoul, Yosra; Bouladi, Mejda; El Matri, Leila

    2015-10-01

    To report a case of bilateral granulomatous post-streptococcal syndrome uveitis in association with reactive arthritis as manifestation of post-streptococcal syndrome. To our knowledge, this could represent the first reported case in the literature. A 9-year-old girl, with no past ocular history, presented with a 5-day history of bilateral blurred vision, red eyes, photophobia and walking difficulties because of a right ankle pain. Ophthalmic examination disclosed a visual acuity limited to hand motion, mutton-fat keratic precipitates, anterior chamber cells and posterior synechiae in both eyes. Ocular pressure was normal. Physical examination showed a fever (38 °C), inflammatory ankle arthritis and scarlet fever (streptococcal lesion). Anti-streptococcal lysine O titer was 419 μ/ml. The patient was treated with topical steroids, cycloplegics, high-dose oral steroids and preventive course of penicillin with total improvement and no recurrence. Post-streptococcal syndrome should be considered in the etiology of acute bilateral granulomatous uveitis in children, and anti-streptococcal lysine O titer should be considered in serodiagnostic testing. PMID:22986580

  19. Differential Paradigms in Animal Models of Sepsis.

    PubMed

    Kingsley, S Manoj Kumar; Bhat, B Vishnu

    2016-09-01

    Sepsis is a serious clinical problem involving complex mechanisms which requires better understanding and insight. Animal models of sepsis have played a major role in providing insight into the complex pathophysiology of sepsis. There have been various animal models of sepsis with different paradigms. Endotoxin, bacterial infusion, cecal ligation and puncture, and colon ascendens stent peritonitis models are the commonly practiced methods at present. Each of these models has their own advantages and also confounding factors. We have discussed the underlying mechanisms regulating each of these models along with possible reasons why each model failed to translate into the clinic. In animal models, the timing of development of the hemodynamic phases and the varied cytokine patterns could not accurately resemble the progression of clinical sepsis. More often, the exuberant and transient pro-inflammatory cytokine response is only focused in most models. Immunosuppression and apoptosis in the later phase of sepsis have been found to cause more damage than the initial acute phase of sepsis. Likewise, better understanding of the existing models of sepsis could help us create a more relevant model which could provide solution to the currently failed clinical trials in sepsis. PMID:27432263

  20. Differential neutrophil responses to bacterial stimuli: Streptococcal strains are potent inducers of heparin-binding protein and resistin-release

    PubMed Central

    Snäll, Johanna; Linnér, Anna; Uhlmann, Julia; Siemens, Nikolai; Ibold, Heike; Janos, Marton; Linder, Adam; Kreikemeyer, Bernd; Herwald, Heiko; Johansson, Linda; Norrby-Teglund, Anna

    2016-01-01

    Neutrophils are critical for the control of bacterial infections, but they may also contribute to disease pathology. Here we explore neutrophil responses, in particular the release of sepsis-associated factors heparin-binding protein (HBP) and resistin in relation to specific bacterial stimuli and sepsis of varying aetiology. Analyses of HBP and resistin in plasma of septic patients revealed elevated levels as compared to non-infected critically ill patients. HBP and resistin correlated significantly in septic patients, with the strongest association seen in group A streptococcal (GAS) cases. In vitro stimulation of human neutrophils revealed that fixed streptococcal strains induced significantly higher release of HBP and resistin, as compared to Staphylococcus aureus or Escherichia coli. Similarly, neutrophils stimulated with the streptococcal M1-protein showed a significant increase in co-localization of HBP and resistin positive granules as well as exocytosis of these factors, as compared to LPS. Using a GAS strain deficient in M1-protein expression had negligible effect on neutrophil activation, while a strain deficient in the stand-alone regulator MsmR was significantly less stimulatory as compared to its wild type strain. Taken together, the findings suggest that the streptococcal activation of neutrophils is multifactorial and involves, but is not limited to, proteins encoded by the FCT-locus. PMID:26887258

  1. Streptococcal meningitis following myelogram procedures.

    PubMed

    Hsu, Jennifer; Jensen, Bette; Arduino, Matthew; Bergeron, Toni; Fox, Teresa; Gum, Greg; Pischke, Vera; Potts, David; Townes, John; Srinivasan, Arjun

    2007-05-01

    In September of 2004, we investigated 7 cases of post-myelography meningitis. Streptococcal species were recovered from blood or cerebrospinal fluid in all cases. Our findings suggest that droplet transmission of the oral flora of the clinician performing the procedure was the most likely source of these infections. The Centers for Disease Control and Prevention recommends the use of face masks by those performing myelograms. PMID:17464927

  2. Group A Streptococcal (GAS) Disease

    MedlinePlus

    ... Core surveillance (ABCs) Group A Strep Calculator CDC Streptococcus Laboratory Sepsis About Group A Strep Recommend on Facebook Tweet Share Compartir Group A Streptococcus (group A strep) are bacteria that can live ...

  3. Targeting sepsis as a performance improvement metric: role of the nurse.

    PubMed

    Kleinpell, Ruth; Schorr, Christa A

    2014-01-01

    Sepsis is the body's systemic response to infection that can be complicated by acute organ dysfunction and is associated with high mortality rates and adverse outcomes for acute and critically ill patients. The 2012 Surviving Sepsis Campaign guidelines advocated for implementation of evidence-based practice care for sepsis, with a focus on quality improvement. Nurses are directly involved in identification and management of sepsis. Implementing performance improvement strategies aimed at early recognition and targeted treatment can further improve sepsis care and patient outcomes. This article presents an overview of the process of implementing performance improvement initiatives for sepsis care, highlighting the significant contribution of nursing care. PMID:24752031

  4. The Severity of Cecal Ligature and Puncture-Induced Sepsis Correlates with the Degree of Encephalopathy, but the Sepsis Does Not Lead to Acute Activation of Spleen Lymphocytes in Mice.

    PubMed

    Jeremias, I C; Victorino, V J; Machado, J L; Barroso, W A; Ariga, S K; Lima, T M; Soriano, F G

    2016-07-01

    Septic encephalopathy represents the most frequently observed form of encephalopathy in intensive care units. Interactions between the immune and nervous systems have been observed in experimental sepsis. Therefore, the aim of the current study was to characterize the effect of different severities of sepsis on encephalopathy and the inflammatory profile of the spleen. We hypothesized that different grades of sepsis severity would lead to variations in encephalopathy and activation of spleen cells. We induced sepsis of different severities in Balb/c mice by cecal ligature and puncture (CLP). Six and 12 h after CLP induction, behavioral impairment was assessed by the SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment (SHIRPA) test. The animals were then killed, and the plasma, spleen, and hippocampus were removed. Levels of the encephalopathy marker S100β were measured in plasma. Spleens were weighed and then a characterization of splenic lymphocytes was performed by flow cytometry (cytotoxic T lymphocyte, T helper lymphocytes, B lymphocytes, T regulatory cells, and Th17 cells). Cytokine levels in the spleen and hippocampus were determined by enzyme-linked immunosorbent assay (ELISA), and cytokine levels in plasma were performed with MilliPlex® technology. Our results showed that behavioral impairment as measured by the SHIRPA test and elevation in plasma S100β levels were significant in moderate and severe CLP groups compared to those in the sham control group. Regarding immunological alterations, we were unable to observe changes in the weights of the spleen and the profile of lymphocytes 6 h after CLP. However, several cytokines, including IL-6, IL-10, and IL-1β, were increased in spleen and plasma. In conclusion, we observed variations in encephalopathy as measured by plasma S100β, which were mediated by the severity of sepsis; however, we did not observe a different activation of spleen cells 6 h post-CLP, despite evidence of

  5. The role of platelets in sepsis.

    PubMed

    de Stoppelaar, Sacha F; van 't Veer, Cornelis; van der Poll, Tom

    2014-10-01

    Platelets are small circulating anucleate cells that are of crucial importance in haemostasis. Over the last decade, it has become increasingly clear that platelets play an important role in inflammation and can influence both innate and adaptive immunity. Sepsis is a potentially lethal condition caused by detrimental host response to an invading pathogen. Dysbalanced immune response and activation of the coagulation system during sepsis are fundamental events leading to sepsis complications and organ failure. Platelets, being major effector cells in both haemostasis and inflammation, are involved in sepsis pathogenesis and contribute to sepsis complications. Platelets catalyse the development of hyperinflammation, disseminated intravascular coagulation and microthrombosis, and subsequently contribute to multiple organ failure. Inappropriate accumulation and activity of platelets are key events in the development of sepsis-related complications such as acute lung injury and acute kidney injury. Platelet activation readouts could serve as biomarkers for early sepsis recognition; inhibition of platelets in septic patients seems like an important target for immune-modulating therapy and appears promising based on animal models and retrospective human studies. PMID:24966015

  6. Role of kidney injury in sepsis.

    PubMed

    Doi, Kent

    2016-01-01

    Kidney injury, including acute kidney injury (AKI) and chronic kidney disease (CKD), has become very common in critically ill patients treated in ICUs. Many epidemiological studies have revealed significant associations of AKI and CKD with poor outcomes of high mortality and medical costs. Although many basic studies have clarified the possible mechanisms of sepsis and septic AKI, translation of the obtained findings to clinical settings has not been successful to date. No specific drug against human sepsis or AKI is currently available. Remarkable progress of dialysis techniques such as continuous renal replacement therapy (CRRT) has enabled control of "uremia" in hemodynamically unstable patients; however, dialysis-requiring septic AKI patients are still showing unacceptably high mortality of 60-80 %. Therefore, further investigations must be conducted to improve the outcome of sepsis and septic AKI. A possible target will be remote organ injury caused by AKI. Recent basic studies have identified interleukin-6 and high mobility group box 1 (HMGB1) as important mediators for acute lung injury induced by AKI. Another target is the disease pathway that is amplified by pre-existing CKD. Vascular endothelial growth factor and HMGB1 elevations in sepsis were demonstrated to be amplified by CKD in CKD-sepsis animal models. Understanding the role of kidney injury as an amplifier in sepsis and multiple organ failure might support the identification of new drug targets for sepsis and septic AKI. PMID:27011788

  7. A possible post-streptococcal movement disorder with chorea and tics.

    PubMed

    Kerbeshian, J; Burd, L; Pettit, R

    1990-07-01

    A 14-year-old girl developed a movement disorder after a streptococcal infection. In the acute phase of the illness she exhibited simple and complex motor tics and chorea, but all abnormal movements ceased over the following eight months, without recurrence. This case raises questions about the relationship between tics, chorea and auto-immune reactivity. PMID:2391015

  8. Invasive streptococcal infections in the era before the acquired immune deficiency syndrome: a 10 years' compilation of patients with streptococcal bacteraemia in North Yorkshire.

    PubMed

    Barnham, M

    1989-05-01

    Significant streptococcal (non-pneumococcal, non-enterococcal) bacteraemia was detected in 100 patients in two Health Districts of North Yorkshire in the decade 1978-1988. Patients with these infections accounted for 11% of the total 902 patients in the districts in whom bacteraemia was diagnosed during the period. Infection was most often seen with beta-haemolytic streptococci (52 patients) comprising Lancefield group A (Streptococcus pyogenes) (20 patients), group B (13), group C (5), group G (9), haemolytic Streptococcus milleri and non-groupable streptococci (5). The wide variety of serious infections included cellulitis, abscess, septicaemia, pneumonia, septic arthritis, necrotising fasciitis, acute endocarditis and mycotic aneurysm. Of these 52 patients, 21 (40%) died. alpha-Haemolytic streptococcal bacteraemia was diagnosed in 38 patients of whom 24 (63%) suffered from endocarditis and three (8%) died. Three of ten patients with non-haemolytic or anaerobic streptococcal bacteraemia died also. Six of the 100 patients with streptococcal bacteraemia had concomitant acute virus infections. Of the total 56 patients with infective endocarditis diagnosed in the districts during the period, streptococci were responsible in 30 (54%) of them. The predisposing factors, clinical features and outcome of the infections are described and discussed. PMID:2663996

  9. Seeking Sepsis in the Emergency Department- Identifying Barriers to Delivery of the Sepsis 6.

    PubMed

    Bentley, James; Henderson, Susan; Thakore, Shobhan; Donald, Michael; Wang, Weijie

    2016-01-01

    The Sepsis 6 is an internationally accepted management bundle that, when initiated within one hour of identifying sepsis, can reduce morbidity and mortality. This management bundle was advocated by the Scottish Patient Safety Programme as part of its Acute Adult campaign launched in 2008 and adopted by NHS Tayside in 2012. Despite this, the Emergency Department (ED) of Ninewells Hospital, a tertiary referral centre and major teaching hospital in Scotland, was displaying poor success in the Sepsis 6. We therefore set out to improve compliance by evaluating the application of all aspects of the NHS Tayside Sepsis 6 bundle within one hour of ED triage time, to identify what human factors may influence achieving the one hour The Sepsis 6 bundle. This allowed us to tailor a number of specific interventions including educational sessions, regular audit and personal feedback and check list Sepsis 6 sticker. These interventions promoted a steady increase in compliance from an initial rate of 51.0% to 74.3%. The project highlighted that undifferentiated patients create a challenge in initiating the Sepsis 6. Pyrexia is a key human factor-trigger for recognising sepsis with initial nursing assessment being vital in recognition and identifying the best area (resus) of the department to manage severely septic patients. EDs need to recognise these challenges and develop educational and feedback plans for staff and utilise available resources to maximise the Sepsis 6 compliance. PMID:27239303

  10. Seeking Sepsis in the Emergency Department- Identifying Barriers to Delivery of the Sepsis 6

    PubMed Central

    Bentley, James; Henderson, Susan; Thakore, Shobhan; Donald, Michael; Wang, Weijie

    2016-01-01

    The Sepsis 6 is an internationally accepted management bundle that, when initiated within one hour of identifying sepsis, can reduce morbidity and mortality. This management bundle was advocated by the Scottish Patient Safety Programme as part of its Acute Adult campaign launched in 2008 and adopted by NHS Tayside in 2012. Despite this, the Emergency Department (ED) of Ninewells Hospital, a tertiary referral centre and major teaching hospital in Scotland, was displaying poor success in the Sepsis 6. We therefore set out to improve compliance by evaluating the application of all aspects of the NHS Tayside Sepsis 6 bundle within one hour of ED triage time, to identify what human factors may influence achieving the one hour The Sepsis 6 bundle. This allowed us to tailor a number of specific interventions including educational sessions, regular audit and personal feedback and check list Sepsis 6 sticker. These interventions promoted a steady increase in compliance from an initial rate of 51.0% to 74.3%. The project highlighted that undifferentiated patients create a challenge in initiating the Sepsis 6. Pyrexia is a key human factor-trigger for recognising sepsis with initial nursing assessment being vital in recognition and identifying the best area (resus) of the department to manage severely septic patients. EDs need to recognise these challenges and develop educational and feedback plans for staff and utilise available resources to maximise the Sepsis 6 compliance. PMID:27239303

  11. Saline breast implant fluid collection and reactive arthritis in a patient with streptococcal toxic shock syndrome.

    PubMed

    Kohannim, Omid; Rubin, Zachary; Taylor, Mihaela

    2011-03-01

    Streptococcal toxic shock syndrome is a potentially lethal condition with an increasing incidence over the last 30 years. We present the case of a 55-year-old patient with signs and symptoms of streptococcal toxic shock syndrome. This patient's presentation was unique in that it was followed by an accumulation of fluid at her breast implant in addition to a polyarticular reactive arthritis. We propose that the patient's reactive arthritis is consistent with the diagnosis of post-streptococcal reactive arthritis, a variant of acute rheumatic fever, which similarly to its variant is immunologically driven. We hypothesize that the fluid collection around the patient's breast implant was triggered by her infection and was also immunologically mediated. PMID:21325958

  12. Sepsis Questions and Answers

    MedlinePlus

    ... has kidney problems, sepsis can lead to kidney failure that requires lifelong dialysis. Top of Page How ... to prevent healthcare-associated infections. Recently, CDC has projects specifically focused on sepsis prevention so that we ...

  13. Group G streptococcal lymphadenitis in rats.

    PubMed

    Corning, B F; Murphy, J C; Fox, J G

    1991-12-01

    Group G streptococci which have been isolated from the oral flora of rats are also normal inhabitants of the human skin, oropharynx, gastrointestinal tract, and female genital tract. This group of streptococci can cause a wide variety of clinical diseases in humans, including septicemia, pharyngitis, endocarditis, pneumonia, and meningitis. Ten days after oral gavage with 7,12-dimethylbenz[a]anthracene, 12 of 22 two-month-old, female, outbred, viral-antibody-free rats presented with red ocular and nasal discharges and marked swelling of the cervical region. Various degrees of firm, nonpitting edema in the region of the cervical lymph nodes and salivary glands as well as pale mucous membranes and dehydration were observed. Pure cultures of beta-hemolytic streptococci were obtained from the cervical lymph nodes of three rats that were necropsied. A rapid latex test system identified the isolates to have group G-specific antigen. These streptococcal isolates fermented trehalose and lactose but not sorbitol and inulin and did not hydrolize sodium hippurate or bile esculin. A Voges-Proskauer test was negative for all six isolates. Serologic tests to detect the presence of immunoglobulin G antibody to rat viral pathogens and Mycoplasma pulmonis were negative. Histopathologic changes included acute necrotizing inflammation of the cervical lymph nodes with multiple large colonies of coccoid bacteria at the perimeter of the necrotiz zone. To our knowledge, this is the first report of naturally occurring disease attributed to group G streptococci in rats. PMID:1757539

  14. Human pathogenic streptococcal proteomics and vaccine development.

    PubMed

    Cole, Jason N; Henningham, Anna; Gillen, Christine M; Ramachandran, Vidiya; Walker, Mark J

    2008-03-01

    Gram-positive streptococci are non-motile, chain-forming bacteria commonly found in the normal oral and bowel flora of warm-blooded animals. Over the past decade, a proteomic approach combining 2-DE and MS has been used to systematically map the cellular, surface-associated and secreted proteins of human pathogenic streptococcal species. The public availability of complete streptococcal genomic sequences and the amalgamation of proteomic, genomic and bioinformatic technologies have recently facilitated the identification of novel streptococcal vaccine candidate antigens and therapeutic agents. The objective of this review is to examine the constituents of the streptococcal cell wall and secreted proteome, the mechanisms of transport of surface and secreted proteins, and describe the current methodologies employed for the identification of novel surface-displayed proteins and potential vaccine antigens. PMID:21136841

  15. Diagnosis of streptococcal pharyngotonsillitis in children and adolescents: clinical picture limitations☆

    PubMed Central

    Barbosa, Aurelino Rocha; Oliveira, Cláudia Di Lorenzo; Fontes, Maria Jussara Fernandes; Lasmar, Laura Maria de Lima Bezário Facury; Camargos, Paulo Augusto Moreira

    2014-01-01

    OBJECTIVE: To assess the utility of clinical features for diagnosis of streptococcal pharyngotonsillitis in pediatrics. METHODS: A total of 335 children aged 1-18 years old and presenting clinical manifestations of acute pharyngotonsillitis (APT) were subjected to clinical interviews, physical examinations, and throat swab specimen collection to perform cultures and latex particle agglutination tests (LPATs) for group A streptococcus (GAS) detection. Signs and symptoms of patients were compared to their throat cultures and LPATs results. A clinical score was designed based on the multivariate logistic regression analysis and also was compared to throat cultures and LPATs results. Positive throat cultures and/or LPATs results were used as a reference standard to establish definitive streptococcal APT diagnosis. RESULTS: 78 children (23.4%) showed positivity for GAS in at least one of the two diagnostic tests. Coryza absence (odds ratio [OR]=1.80; p=0.040), conjunctivitis absence (OR=2.47; p=0.029), pharyngeal erythema (OR=3.99; p=0.006), pharyngeal exudate (OR=2.02; p=0.011), and tonsillar swelling (OR=2.60; p=0.007) were significantly associated with streptococcal pharyngotonsilitis. The highest clinical score, characterized by coryza absense, pharyngeal exudate, and pharyngeal erythema had a 45.6% sensitivity, a 74.5% especificity, and a likelihood ratio of 1.79 for streptococcal pharyngotonsilitis. CONCLUSIONS: Clinical presentation should not be used to confirm streptococcal pharyngotonsilitis, because its performance as a diagnostic test is low. Thus, it is necessary to enhance laboratory test availability, especially of LPATs that allow an acurate and fast diagnosis of streptococcal pharyngotonsilitis. PMID:25510990

  16. Discovery of the gene signature for acute lung injury in patients with sepsis Address for reprint requests and other correspondence: J. A. Howrylak, UPMC Montefiore NW 628, 3459 5th Ave., Pittsburgh, PA 15213 (e-mail: howrylakj@upmc.edu).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    PubMed Central

    Howrylak, Judie A.; Dolinay, Tamas; Lucht, Lorrie; Wang, Zhaoxi; Christiani, David C.; Sethi, Jigme M.; Xing, Eric P.; Donahoe, Michael P.; Choi, Augustine M. K.

    2009-01-01

    The acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) was described 30 yr ago, yet making a definitive diagnosis remains difficult. The identification of biomarkers obtained from peripheral blood could provide additional noninvasive means for diagnosis. To identify gene expression profiles that may be used to classify patients with ALI, 13 patients with ALI + sepsis and 20 patients with sepsis alone were recruited from the Medical Intensive Care Unit of the University of Pittsburgh Medical Center, and microarrays were performed on peripheral blood samples. Several classification algorithms were used to develop a gene signature for ALI from gene expression profiles. This signature was validated in an independently obtained set of patients with ALI + sepsis (n = 8) and sepsis alone (n = 1). An eight-gene expression profile was found to be associated with ALI. Internal validation found that the gene signature was able to distinguish patients with ALI + sepsis from patients with sepsis alone with 100% accuracy, corresponding to a sensitivity of 100%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 100%. In the independently obtained external validation set, the gene signature was able to distinguish patients with ALI + sepsis from patients with sepsis alone with 88.9% accuracy. The use of classification models to develop a gene signature from gene expression profiles provides a novel and accurate approach for classifying patients with ALI. PMID:19174476

  17. Hospital readmission and healthcare utilization following sepsis in community settings

    PubMed Central

    Liu, Vincent; Lei, Xingye; Prescott, Hallie C; Kipnis, Patricia; Iwashyna, Theodore J; Escobar, Gabriel J

    2014-01-01

    Background Sepsis, the most expensive cause of hospitalization in the US, is associated with high morbidity and mortality. However, healthcare utilization patterns following sepsis are poorly understood. Objective To identify patient-level factors which contribute to post-sepsis mortality and healthcare utilization. Design, Setting, Patients A retrospective study of sepsis patients drawn from 21 community-based hospitals in Kaiser Permanente Northern California in 2010. Measurements We determined one-year survival and use of outpatient and facility-based healthcare before and after sepsis and used logistic regression to identify the factors that contributed to early readmission (within 30 days) and high utilization (≥15% of living days spent in facility-based care). Results Among 6,344 sepsis patients, 5,479 (86.4%) survived to hospital discharge. Mean age was 72 years with 28.9% of patients aged <65 years. Post-sepsis survival was strongly modified by age; one-year survival was 94.1% for <45 year olds and 54.4% for ≥85 year olds. A total of 978 (17.9%) patients were readmitted within 30 days; only a minority of all rehospitalizations were for infection. After sepsis, adjusted healthcare utilization increased nearly threefold compared with pre-sepsis levels and was strongly modified by age. Patient factors including acute severity of illness, hospital length of stay, and the need for intensive care were associated with early readmission and high healthcare utilization, however, the dominant factors explaining variability—comorbid disease burden and high pre-sepsis utilization—were present prior to sepsis admission. Conclusion Post-sepsis survival and healthcare utilization were most strongly influenced by patient factors already present prior to sepsis hospitalization. PMID:24700730

  18. [Patients with sepsis].

    PubMed

    Oppert, M

    2016-05-01

    Sepsis is still the leading cause of mortality in noncardiac intensive care units. The new definition of sepsis emphasizes the importance of organ dysfunction. The Sepsis-related Organ Failure Assessment (SOFA) score is an indicator for organ dysfunction. The diagnosis of sepsis is for the most part made on clinical parameters with an altered mental status being a very sensitive indicator. Microbiological work-up is essential and two sets of blood cultures are the recommended minimum. Management includes prompt initiation of adequate antibiotic treatment and swift fluid resuscitation. Overinfusion is to be avoided as this itself can have a negative impact on patient outcome. PMID:27160262

  19. Pulmonary Renal Syndrome After Streptococcal Pharyngitis

    PubMed Central

    Mara-Koosham, Gopi; Stoltze, Karl; Aday, Jeffrey; Rendon, Patrick

    2016-01-01

    Pulmonary renal syndrome is a class of small vessel vasculitides that are characterized by the dual presentation of diffuse alveolar hemorrhage (DAH) and glomerulonephritis. Pulmonary renal syndrome has multiple etiologies, but its development has been rarely reported following infection with group A streptococcus. We present the case of a 36-year-old Native American male who was transferred to our facility due to refractory hypoxic respiratory failure. He had been diagnosed with streptococcal pharyngitis 2 weeks prior to admission. Given the presence of hemoptysis, bronchoscopy was performed and was consistent with DAH. Urinalysis demonstrated hematuria and proteinuria, in the setting of elevated creatinine and blood urea nitrogen. Additionally, antistreptolysin O titer was positive. Given the constellation of laboratory findings and history of streptococcal pharyngitis, the patient was diagnosed with PRS secondary to streptococcal infection. High-dose methylprednisolone was initiated with concomitant plasmapheresis. He was extubated successfully after his respiratory status improved and was eventually discharged home after making a full recovery within 2 weeks after admission. This case illustrates the importance of clinically relevant sequelae of streptococcal infection as well as the appropriate treatment of PRS secondary to streptococcal pharyngitis with plasmapheresis and intravenous corticosteroids. PMID:27231692

  20. A case of canine streptococcal meningoencephalitis diagnosed using universal bacterial polymerase chain reaction assay.

    PubMed

    Messer, Jeannette S; Wagner, Susan O; Baumwart, Ryan D; Colitz, Carmen M

    2008-01-01

    A 3-year-old, spayed female, mixed-breed dog was evaluated for acute, progressive neurological disease. Analysis of cerebrospinal fluid (CSF) showed neutrophilic pleocytosis. The dog later developed liver disease, thrombocytopenia, and anemia that were presumably secondary to ceftriaxone administration. Bacterial cultures of blood, urine, and CSF were negative. However, a universal bacterial polymerase chain reaction assay of CSF identified deoxyribonucleic acid from Streptococcus spp. The dog recovered with therapy for streptococcal encephalitis. PMID:18593857

  1. Bacteriology of viridans streptococcal bacteremia.

    PubMed

    Chang, S C; Luh, K T; Deng, L J; Hsieh, W C

    1987-11-01

    In order to assess the species distribution and the antibiotic susceptibility of viridans streptococci in various human infections, we reviewed 164 cases of viridans streptococcal bacteremia seen at the National Taiwan University Hospital between May 1981 and April 1987. The organisms were isolated from 83 patients with endocarditis. Among 81 nonendocarditis patients, only 54 had clinically recognizable foci of suppurative inflammation. Mainly based on API 20 STREP system of species identification, S. sanguis II accounted for 24.4%; S. mitis, 20.7%; S. sanguis I, 20.1%; and S. milleri 2, 11.6% of the 164 cases studied. Of 83 endocarditis patients, 27.7% were S. sanguis I; 21.7%, S. sanguis II; and 16.9%, S. mitis. In nonendocarditis bacteremia with known suppurative lesions, 3 most often isolated organisms were S. sanguis II (24.0%), S. mitis (24.0%), and S. milleri 2 (24.0%). In nonendocarditis bacteremia without suppurative infection, the most frequent isolates were S. sanguis II (33.3%) and S. mitis (25.9%). In terms of relative frequency between endocarditis and nonendocarditis cases, S. mutan, S. sanguis I, and S. bovis had the highest frequency ratio of 7:1, 3.5:1, and 1.5:1, respectively. All isolates were susceptible to penicillin G, ampicillin, and cephalothin. Tetracycline resistance, however, were observed in 35.4% of the isolates; oxacillin resistance, 11.0%; and erythromycin resistance, 9.1%. PMID:3449320

  2. Common Questions About Streptococcal Pharyngitis.

    PubMed

    Kalra, Monica G; Higgins, Kim E; Perez, Evan D

    2016-07-01

    Group A beta-hemolytic streptococcal (GABHS) infection causes 15% to 30% of sore throats in children and 5% to 15% in adults, and is more common in the late winter and early spring. The strongest independent predictors of GABHS pharyngitis are patient age of five to 15 years, absence of cough, tender anterior cervical adenopathy, tonsillar exudates, and fever. To diagnose GABHS pharyngitis, a rapid antigen detection test should be ordered in patients with a modified Centor or FeverPAIN score of 2 or 3. First-line treatment for GABHS pharyngitis includes a 10-day course of penicillin or amoxicillin. Patients allergic to penicillin can be treated with firstgeneration cephalosporins, clindamycin, or macrolide antibiotics. Nonsteroidal anti-inflammatory drugs are more effective than acetaminophen and placebo for treatment of fever and pain associated with GABHS pharyngitis; medicated throat lozenges used every two hours are also effective. Corticosteroids provide only a small reduction in the duration of symptoms and should not be used routinely. PMID:27386721

  3. Adult Zebrafish model of streptococcal infection

    PubMed Central

    Phelps, Hilary A.; Runft, Donna L.

    2009-01-01

    Streptococcal pathogens cause a wide array of clinical syndromes in humans, including invasive systemic infections resulting in high mortality rates. Many of these pathogens are human specific, and therefore difficult to analyze in vivo using typical animal models, as these models rarely replicate what is observed in human infections. This unit describes the use of the zebrafish (Danio rerio) as an animal model for streptococcal infection to analyze multiple disease states. This model closely mimics the necrotizing fasciitis/myositis pathology observed in humans from a Streptococcus pyogenes infection. The use of a zoonotic pathogen, Streptococcus iniae, which replicates systemic infections caused by many streptococcal pathogens, including dissemination to the brain, is also described. Included protocols describe both intraperitoneal and intramuscular infections, as well as methods for histological and quantitative measurements of infection. PMID:19412913

  4. Neuronal Antibody Biomarkers for Sydenham’s Chorea Identify a New Group of Children with Chronic Recurrent Episodic Acute Exacerbations of Tic and Obsessive Compulsive Symptoms Following a Streptococcal Infection

    PubMed Central

    Singer, Harvey S.; Mascaro-Blanco, Adda; Alvarez, Kathy; Morris-Berry, Christina; Kawikova, Ivana; Ben-Pazi, Hilla; Thompson, Carol B.; Ali, Syed F.; Kaplan, Edward L.; Cunningham, Madeleine W.

    2015-01-01

    Several autoantibodies (anti-dopamine 1 (D1R) and 2 (D2R) receptors, anti-tubulin, anti-lysoganglioside-GM1) and antibody-mediated activation of calcium calmodulin dependent protein kinase II (CaMKII) signaling activity are elevated in children with Sydenham’s chorea (SC). Recognizing proposed clinical and autoimmune similarities between SC and PANDAS (pediatric autoimmune neuropsychiatric disorder associated with a streptococcal infection), we sought to identify serial biomarker changes in a slightly different population. Antineuronal antibodies were measured in eight children (mean 11.3 years) with chronic, dramatic, recurrent tics and obsessive-compulsive disorder (OCD) associated with a group A β-hemolytic streptococcal (GABHS) respiratory tract infection, but differing because they lacked choreiform movements. Longitudinal serum samples in most subjects included two pre-exacerbation samples, Exac), one midst Exac (abrupt recurrence of tic/OCD; temporally association with a GABHS infection in six of eight subjects), and two post-Exac. Controls included four groups of unaffected children (n = 70; mean 10.8 years) obtained at four different institutions and published controls. Clinical exacerbations were not associated with a significant rise in antineuronal antibody titers. CaMKII activation was increased at the GABHS exacerbation point in 5/6 subjects, exceeded combined and published control’s 95th percentile at least once in 7/8 subjects, and median values were elevated at each time point. Anti-tubulin and anti-D2R titers did not differ from published or combined control group’s 95th percentile or median values. Differences in anti-lysoganglioside-GM1 and anti-D1R titers were dependent on the selected control. Variances in antibody titers and CaMKII activation were identified among the institutional control groups. Based on comparisons to published studies, results identify two groups of PANDAS: 1) a cohort, represented by this study, which lacks

  5. Increased extracellular heat shock protein 90α in severe sepsis and SIRS associated with multiple organ failure and related to acute inflammatory-metabolic stress response in children.

    PubMed

    Fitrolaki, Michaela-Diana; Dimitriou, Helen; Venihaki, Maria; Katrinaki, Marianna; Ilia, Stavroula; Briassoulis, George

    2016-08-01

    Mammalian heat-shock-protein (HSP) 90α rapidly responses to environmental insults. We examined the hypothesis that not only serum HSP72 but also HSP90α is increased in the systemic inflammatory response syndrome (SIRS), severe-sepsis (SS), and/or sepsis (S) compared to healthy children (H); we assessed HSP90α relation to (a) multiple organ system failure (MOSF) and (b) inflammatory-metabolic response and severity of illness.A total of 65 children with S, SS, or SIRS and 25 H were included. ELISA was used to evaluate extracellular HSP90α and HSP72, chemiluminescence interleukins (ILs), flow-cytometry neutrophil-CD64 (nCD64)-expression.HSP90α, along with HSP72, were dramatically increased among MOSF patients. Patients in septic groups and SIRS had elevated HSP90α compared to H (P < 0.01). HSP90α was independently related to predicted death rate and severity of illness; positively to HSP72, nCD64, ILs, length of stay, days on ventilator, and fever; negatively to HDL and LDL (P < 0.05). The HSP72 was increased in SS/S and related negatively to HDL and LDL (P < 0.05).Serum HSP90α is markedly elevated in children with severe sepsis and is associated with MOSF. Better than the HSP72, also increased in SS, SIRS, and MOSF, HSP90α is related to the inflammatory stress, fever, outcome endpoints, and predicted mortality and inversely related to the low-LDL/low-HDL stress metabolic pattern. PMID:27583886

  6. Increased extracellular heat shock protein 90α in severe sepsis and SIRS associated with multiple organ failure and related to acute inflammatory-metabolic stress response in children

    PubMed Central

    Fitrolaki, Michaela-Diana; Dimitriou, Helen; Venihaki, Maria; Katrinaki, Marianna; Ilia, Stavroula; Briassoulis, George

    2016-01-01

    Abstract Mammalian heat-shock-protein (HSP) 90α rapidly responses to environmental insults. We examined the hypothesis that not only serum HSP72 but also HSP90α is increased in the systemic inflammatory response syndrome (SIRS), severe-sepsis (SS), and/or sepsis (S) compared to healthy children (H); we assessed HSP90α relation to (a) multiple organ system failure (MOSF) and (b) inflammatory-metabolic response and severity of illness. A total of 65 children with S, SS, or SIRS and 25 H were included. ELISA was used to evaluate extracellular HSP90α and HSP72, chemiluminescence interleukins (ILs), flow-cytometry neutrophil-CD64 (nCD64)-expression. HSP90α, along with HSP72, were dramatically increased among MOSF patients. Patients in septic groups and SIRS had elevated HSP90α compared to H (P < 0.01). HSP90α was independently related to predicted death rate and severity of illness; positively to HSP72, nCD64, ILs, length of stay, days on ventilator, and fever; negatively to HDL and LDL (P < 0.05). The HSP72 was increased in SS/S and related negatively to HDL and LDL (P < 0.05). Serum HSP90α is markedly elevated in children with severe sepsis and is associated with MOSF. Better than the HSP72, also increased in SS, SIRS, and MOSF, HSP90α is related to the inflammatory stress, fever, outcome endpoints, and predicted mortality and inversely related to the low-LDL/low-HDL stress metabolic pattern. PMID:27583886

  7. Prospects for a group A streptococcal vaccine.

    PubMed

    McMillan, David J; Chhatwal, Gursharan S

    2005-02-01

    Group A streptococcal (GAS) infections are associated with a number of human diseases, including pharyngitis, impetigo, necrotizing fasciitis, streptococcal toxic shock syndrome and rheumatic heart disease. An increase in the incidence of severe GAS infections in Western countries, and the awareness of the burden of GAS-associated diseases in developing nations, which remains high in spite of the availability of antibiotics, has provided the impetus for development of a safe and efficacious GAS vaccine. This has focused on the M protein, a major GAS virulence factor, however, with the publication of several GAS genomes, a number of non-M vaccine candidates are now under investigation. PMID:15732524

  8. Sepsis-Induced Osteoblast Ablation Causes Immunodeficiency.

    PubMed

    Terashima, Asuka; Okamoto, Kazuo; Nakashima, Tomoki; Akira, Shizuo; Ikuta, Koichi; Takayanagi, Hiroshi

    2016-06-21

    Sepsis is a host inflammatory response to severe infection associated with high mortality that is caused by lymphopenia-associated immunodeficiency. However, it is unknown how lymphopenia persists after the accelerated lymphocyte apoptosis subsides. Here we show that sepsis rapidly ablated osteoblasts, which reduced the number of common lymphoid progenitors (CLPs). Osteoblast ablation or inducible deletion of interleukin-7 (IL-7) in osteoblasts recapitulated the lymphopenic phenotype together with a lower CLP number without affecting hematopoietic stem cells (HSCs). Pharmacological activation of osteoblasts improved sepsis-induced lymphopenia. This study demonstrates a reciprocal interaction between the immune and bone systems, in which acute inflammation induces a defect in bone cells resulting in lymphopenia-associated immunodeficiency, indicating that bone cells comprise a therapeutic target in certain life-threatening immune reactions. PMID:27317262

  9. Immunoreactivity of anti-streptococcal monoclonal antibodies to human heart valves. Evidence for multiple cross-reactive epitopes.

    PubMed Central

    Gulizia, J. M.; Cunningham, M. W.; McManus, B. M.

    1991-01-01

    Association of group A streptococci with acute rheumatic fever and valvular heart disease is well established; however the basis of valve injury remains unclear. In this study, anti-streptococcal monoclonal antibodies (MAbs) cross-reactive with myocardium were reacted with sections from 22 rheumatic valves, nine normal, five endocarditic, one 'floppy,' and one Marfan valve. In immunohistochemical studies, MAb reactivity was observed with cardiac myocytes, smooth muscle cells, cell surface and cytoplasm of endothelial cells lining valves, and valvular interstitial cells. Endothelial basement membrane and elastin fibrils reacted with the MAbs, whereas collagen was unreactive. Similar reactivity was seen with sera from acute rheumatic fever patients. The anti-streptococcal MAbs reacted with intravalvular myosin and vimentin in Western blots, and purified elastin competitively inhibited the binding of the anti-streptococcal MAbs to whole group A streptococci. The data show that human heart valves have numerous sites of immunoreactivity with anti-streptococcal MAbs and acute rheumatic fever sera of potential importance in the pathogenesis of rheumatic valvular injury. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 PMID:1704188

  10. Group B Streptococcal Septic Arthritis of the Shoulder and Potential Association with Pelvic Examination and PAP Smear.

    PubMed

    Daner, William E; Meeks, Brett D; Foster, William C; Boardman, Norman D

    2016-01-01

    Group B streptococcal (GBS) infection of a native joint in a nonpregnant adult is uncommon. While many women are colonized with this flora, it rarely becomes pathogenic in its adult host. GBS associated joint infections have been reported, most of which have been related to hematogenous seeding from unknown sources. To our knowledge, there are no published case reports of a GBS joint infection in association with a pelvic exam and Papanicolaou (PAP) smear. In this case report, we present a case of GBS sepsis of a native shoulder, possibly resulting from a routine pelvic exam and PAP smear. PMID:26981299

  11. Group B Streptococcal Septic Arthritis of the Shoulder and Potential Association with Pelvic Examination and PAP Smear

    PubMed Central

    Daner, William E.; Meeks, Brett D.; Foster, William C.; Boardman, Norman D.

    2016-01-01

    Group B streptococcal (GBS) infection of a native joint in a nonpregnant adult is uncommon. While many women are colonized with this flora, it rarely becomes pathogenic in its adult host. GBS associated joint infections have been reported, most of which have been related to hematogenous seeding from unknown sources. To our knowledge, there are no published case reports of a GBS joint infection in association with a pelvic exam and Papanicolaou (PAP) smear. In this case report, we present a case of GBS sepsis of a native shoulder, possibly resulting from a routine pelvic exam and PAP smear. PMID:26981299

  12. Pharmacological management of sepsis

    SciTech Connect

    Fletcher, J.R.

    1985-01-01

    Systemic sepsis continues to be the most-difficult management problem in caring for the combat casualty. The complications of sepsis pervade all areas of injury to soldiers in the field, whether it is mechanical (missiles), thermal (burns), chemical, biological, or radiation injury. With the advent of tactical nuclear weapons, the problem of sepsis will be much higher in future wars than has previously been experienced through the world. The purpose of this chapter is a) to review the data suggesting pharmacological agents that may benefit the septic patient, and b) to emphasize the adjunctive therapies that should be explored in clinical trials. The pharmacological management of sepsis remains controversial. Most of the drugs utilized clinically treat the symptoms of the disease and are not necessarily directed at fundamental mechanisms that are known to be present in sepsis. A broad data base is emerging, indicating that NSAID should be used in human clinical trials. Prostaglandins are sensitive indicators of cellular injury and may be mediators for a number of vasoactive chemicals. Opiate antagonists and calcium channel blockers require more in-depth data; however, recent studies generate excitement for their potential use in the critically ill patient. Pharmacological effects of antibiotics, in concert with other drugs, suggest an entirely new approach to pharmacological treatment in sepsis. There is no doubt that new treatment modalities or adjunctive therapies must be utilized to alter the poor prognosis of severe sepsis that we have observed in the past 4 decades.

  13. Biomarkers in sepsis.

    PubMed

    Walley, Keith R

    2013-10-01

    There is much enthusiasm and interest in sepsis biomarkers, particularly because sepsis is a highly lethal condition, its diagnosis is challenging, and even simple treatment with antibiotics has led to serious adverse consequences such as emergence of resistant pathogens. Yet development of a sepsis biomarker requires many more steps than simply finding an association between a particular molecule and a clinical state or outcome. Demonstration of improvement of therapeutic practice using receiver-operating characteristic and other analyses is important. Validation in independent, prospective and, preferably, multicenter trials is essential. Many promising candidate sepsis biomarkers have recently been proposed. While procalcitonin (PCT) is currently the most studied sepsis biomarker, evidence of potential value has been found for a wide array of blood biomarkers including proteins, mRNA expression in whole blood or leukocytes, micro-RNAs (miRNA), pathogen and host DNA, pathogen and host genetic variants and metabolomic panels, and even in the novel use of currently available clinical data. While the most common early reports link putative sepsis biomarker levels to severity of illness and outcome (prognostic), this is not anticipated to be their primary use. More important is the distinction between infection and noninfectious inflammatory responses (diagnostic) and the use of sepsis biomarkers to direct therapy (predictive). PMID:23975686

  14. Streptococcal Infections - Multiple Languages: MedlinePlus

    MedlinePlus

    ... List of All Topics All Streptococcal Infections - Multiple Languages To use the sharing features on this page, please enable JavaScript. Arabic (العربية) Korean (한국어) Spanish (español) Arabic (العربية) Strep ...

  15. Vertebral osteomyelitis combined streptococcal viridans endocarditis.

    PubMed

    Lee, Kuo-Chen; Tsai, Yi-Ting; Lin, Chih-Yuan; Tsai, Chien-Sung

    2003-01-01

    Endocarditis may be difficult to diagnose in patients with osteomyelitis in an early stage because they usually are treated for fever, bone pain and stiffness in the outpatient department. Herein we report an uncommon patient who developed severe lower back pain sustained for 2 months, and streptococcal viridans infected vertebral osteomyelitis combined endocarditis were diagnosed and cured. PMID:12493523

  16. Molecular Hydrogen Therapy Ameliorates Organ Damage Induced by Sepsis

    PubMed Central

    Zheng, Yijun; Zhu, Duming

    2016-01-01

    Since it was proposed in 2007, molecular hydrogen therapy has been widely concerned and researched. Many animal experiments were carried out in a variety of disease fields, such as cerebral infarction, ischemia reperfusion injury, Parkinson syndrome, type 2 diabetes mellitus, metabolic syndrome, chronic kidney disease, radiation injury, chronic hepatitis, rheumatoid arthritis, stress ulcer, acute sports injuries, mitochondrial and inflammatory disease, and acute erythema skin disease and other pathological processes or diseases. Molecular hydrogen therapy is pointed out as there is protective effect for sepsis patients, too. The impact of molecular hydrogen therapy against sepsis is shown from the aspects of basic vital signs, organ functions (brain, lung, liver, kidney, small intestine, etc.), survival rate, and so forth. Molecular hydrogen therapy is able to significantly reduce the release of inflammatory factors and oxidative stress injury. Thereby it can reduce damage of various organ functions from sepsis and improve survival rate. Molecular hydrogen therapy is a prospective method against sepsis. PMID:27413421

  17. Molecular Hydrogen Therapy Ameliorates Organ Damage Induced by Sepsis.

    PubMed

    Zheng, Yijun; Zhu, Duming

    2016-01-01

    Since it was proposed in 2007, molecular hydrogen therapy has been widely concerned and researched. Many animal experiments were carried out in a variety of disease fields, such as cerebral infarction, ischemia reperfusion injury, Parkinson syndrome, type 2 diabetes mellitus, metabolic syndrome, chronic kidney disease, radiation injury, chronic hepatitis, rheumatoid arthritis, stress ulcer, acute sports injuries, mitochondrial and inflammatory disease, and acute erythema skin disease and other pathological processes or diseases. Molecular hydrogen therapy is pointed out as there is protective effect for sepsis patients, too. The impact of molecular hydrogen therapy against sepsis is shown from the aspects of basic vital signs, organ functions (brain, lung, liver, kidney, small intestine, etc.), survival rate, and so forth. Molecular hydrogen therapy is able to significantly reduce the release of inflammatory factors and oxidative stress injury. Thereby it can reduce damage of various organ functions from sepsis and improve survival rate. Molecular hydrogen therapy is a prospective method against sepsis. PMID:27413421

  18. Late mortality after sepsis: propensity matched cohort study

    PubMed Central

    Osterholzer, John J; Langa, Kenneth M; Angus, Derek C; Iwashyna, Theodore J

    2016-01-01

    Objectives To determine whether late mortality after sepsis is driven predominantly by pre-existing comorbid disease or is the result of sepsis itself. Deign Observational cohort study. Setting US Health and Retirement Study. Participants 960 patients aged ≥65 (1998-2010) with fee-for-service Medicare coverage who were admitted to hospital with sepsis. Patients were matched to 777 adults not currently in hospital, 788 patients admitted with non-sepsis infection, and 504 patients admitted with acute sterile inflammatory conditions. Main outcome measures Late (31 days to two years) mortality and odds of death at various intervals. Results Sepsis was associated with a 22.1% (95% confidence interval 17.5% to 26.7%) absolute increase in late mortality relative to adults not in hospital, a 10.4% (5.4% to 15.4%) absolute increase relative to patients admitted with non-sepsis infection, and a 16.2% (10.2% to 22.2%) absolute increase relative to patients admitted with sterile inflammatory conditions (P<0.001 for each comparison). Mortality remained higher for at least two years relative to adults not in hospital. Conclusions More than one in five patients who survives sepsis has a late death not explained by health status before sepsis. PMID:27189000

  19. Plantar Purpura as the Initial Presentation of Viridians Streptococcal Shock Syndrome Secondary to Streptococcus gordonii Bacteremia

    PubMed Central

    Liao, Chen-Yi; Su, Kuan-Jen; Lin, Cheng-Hui; Huang, Shu-Fang; Chin, Hsien-Kuo; Chang, Chin-Wen; Kuo, Wu-Hsien; Ben, Ren-Jy; Yeh, Yen-Cheng

    2016-01-01

    Viridians streptococcal shock syndrome is a subtype of toxic shock syndrome. Frequently, the diagnosis is missed initially because the clinical features are nonspecific. However, it is a rapidly progressive disease, manifested by hypotension, rash, palmar desquamation, and acute respiratory distress syndrome within a short period. The disease course is generally fulminant and rarely presents initially as a purpura over the plantar region. We present a case of a 54-year-old female hospital worker diagnosed with viridians streptococcal shock syndrome caused by Streptococcus gordonii. Despite aggressive antibiotic treatment, fluid hydration, and use of inotropes and extracorporeal membrane oxygenation, the patient succumbed to the disease. Early diagnosis of the potentially fatal disease followed by a prompt antibiotic regimen and appropriate use of steroids are cornerstones in the management of this disease to reduce the risk of high morbidity and mortality. PMID:27366188

  20. Gamma globulin, Evan's blue, aprotinin A PLA2 inhibitor, tetracycline and antioxidants protect epithelial cells against damage induced by synergism among streptococcal hemolysins, oxidants and proteinases: relation to the prevention of post-streptococcal sequelae and septic shock.

    PubMed

    Ginsburg, I; Sadovnic, M

    1998-11-01

    An in vitro model was employed to study the potential role of streptococcal extra-cellular products, rich in streptolysin O, in cellular injury as related to streptococcal infections and post-streptococcal sequelae. Extra-cellular products (EXPA) rich in streptolysin O were isolated from type 4, group A hemolytic streptococci grown in a chemostat, in a synthetic medium. EXPA induced moderate cytopathogenic changes in monkey kidney epithelial cells and in rat heart cells pre-labeled with 3H-arachidonate. However very strong toxic effects were induced when EXP was combined with oxidants (glucose oxides generated H2O2, AAPH-induced peroxyl radical (ROO.), NO generated by sodium nitroprusside) and proteinases (plasmin, trypsin). Cell killing was distinctly synergistic in nature. Cell damage induced by the multi-component cocktails was strongly inhibited either by micromolar amounts of gamma globulin, and Evan's blue which neutralized SLO activity, by tetracycline, trasylol (aprotinin), epsilon amino caproic acid and by soybean trypsin inhibitor, all proteinase inhibitors as well as by a non-penetrating PLA2 inhibitor A. The results suggest that fasciitis, myositis and sepsis resulting from infections with hemolytic streptococci might be caused by a coordinated 'cross-talk' among microbial, leukocyte and additional host-derived pro-inflammatory agents. Since attempts to prolong lives of septic patients by the exclusive administration of single antagonists invariably failed, it is proposed that the administration of 'cocktails' of putative inhibitors against major pro-inflammatory agonizes generated in inflammation and infection might protect against the deleterious effects caused by the biochemical and pharmacological cascades which are known to be activated in sepsis. PMID:9848686

  1. The pathogenesis of sepsis.

    PubMed

    Bone, R C

    1991-09-15

    Sepsis and its sequelae (sepsis syndrome and septic shock) are increasingly common and are still potentially lethal diagnoses. Many mediators of the pathogenesis of sepsis have recently been described. These include tumor necrosis factor alpha (TNF alpha), interleukins, platelet activating factor, leukotrienes, thromboxane A2, and activators of the complement cascade. Neutrophil and platelet activation may also play a role. Other agents that may participate in the sepsis cascade include adhesion molecules, kinins, thrombin, myocardial depressant substance, beta-endorphin, and heat shock proteins. Endothelium-derived relaxing factor and endothelin-1 are released from the endothelium and seem to exert a regulatory effect, counterbalancing each other. A central mediator of sepsis does not seem to exist, although TNF alpha has been commonly proposed for this role. Animal studies are difficult to extrapolate to the clinical setting because of cross-species differences and variations in experimental design. Rather than being caused by any single pathogenic mechanism, it is more likely that sepsis is related to the state of activation of the target cell, the nearby presence of other mediators, and the ability of the target cell to release other mediators. Also important is the downregulation or negative feedback of these mediators or the generation of natural inflammation inhibitors, such as interleukin-4 and interleukin-8. Endothelial damage in sepsis probably results from persistent and repetitive inflammatory insults. Eventually, these insults produce sufficient damage that downregulation can no longer occur; this leads to a state of metabolic anarchy in which the body can no longer control its own inflammatory response. PMID:1872494

  2. Sepsis chronically in MARS: systemic cytokine responses are always mixed regardless of the outcome, magnitude, or phase of sepsis.

    PubMed

    Osuchowski, Marcin F; Craciun, Florin; Weixelbaumer, Katrin M; Duffy, Elizabeth R; Remick, Daniel G

    2012-11-01

    The paradigm of systemic inflammatory response syndrome-to-compensatory anti-inflammatory response syndrome transition implies that hyperinflammation triggers acute sepsis mortality, whereas hypoinflammation (release of anti-inflammatory cytokines) in late sepsis induces chronic deaths. However, the exact humoral inflammatory mechanisms attributable to sepsis outcomes remain elusive. In the first part of this study, we characterized the systemic dynamics of the chronic inflammation in dying (DIE) and surviving (SUR) mice suffering from cecal ligation and puncture sepsis (days 6-28). In the second part, we combined the current chronic and previous acute/chronic sepsis data to compare the outcome-dependent inflammatory signatures between these two phases. A composite cytokine score (CCS) was calculated to compare global inflammatory responses. Mice were never sacrificed but were sampled daily (20 μl) for blood. In the first part of the study, parameters from chronic DIE mice were clustered into the 72, 48, and 24 h before death time points and compared with SUR of the same post-cecal ligation and puncture day. Cytokine increases were mixed and never preceded chronic deaths earlier than 48 h (3- to 180-fold increase). CCS demonstrated simultaneous and similar upregulation of proinflammatory and anti-inflammatory compartments at 24 h before chronic death (DIE 80- and 50-fold higher versus SUR). In the second part of the study, cytokine ratios across sepsis phases/outcomes indicated steady proinflammatory versus anti-inflammatory balance. CCS showed the inflammatory response in chronic DIE was 5-fold lower than acute DIE mice, but identical to acute SUR. The systemic mixed anti-inflammatory response syndrome-like pattern (concurrent release of proinflammatory and anti-inflammatory cytokines) occurs irrespective of the sepsis phase, response magnitude, and/or outcome. Although different in magnitude, neither acute nor chronic septic mortality is associated with a

  3. Immunoinflammatory Response in Critically Ill Patients: Severe Sepsis and/or Trauma

    PubMed Central

    Popovic, Nada; Djordjevic, Dragan

    2013-01-01

    Immunoinflammatory response in critically ill patients is very complex. This review explores some of the new elements of immunoinflammatory response in severe sepsis, tumor necrosis factor-alpha in severe acute pancreatitis as a clinical example of immune response in sepsis, immune response in severe trauma with or without secondary sepsis, and genetic aspects of host immuno-inflammatory response to various insults in critically ill patients. PMID:24371374

  4. Use of Streptococcus salivarius K12 in the prevention of streptococcal and viral pharyngotonsillitis in children

    PubMed Central

    Di Pierro, Francesco; Colombo, Maria; Zanvit, Alberto; Risso, Paolo; Rottoli, Amilcare S

    2014-01-01

    Background Streptococcus salivarius K12 is an oral probiotic strain releasing two lantibiotics (salivaricin A2 and salivaricin B) that antagonize the growth of S. pyogenes, the most important bacterial cause of pharyngeal infections in humans also affected by episodes of acute otitis media. S. salivarius K12 successfully colonizes the oral cavity, and is endowed with an excellent safety profile. We tested its preventive role in reducing the incidence of both streptococcal and viral pharyngitis and/or tonsillitis in children. Materials and methods We enrolled 61 children with a diagnosis of recurrent oral streptococcal disorders. Thirty-one of them were enrolled to be treated daily for 90 days with a slow-release tablet for oral use, containing no less than 1 billion colony-forming units/tablet of S. salivarius K12 (Bactoblis®), and the remaining 30 served as the untreated control group. During treatment, they were all examined for streptococcal infection. Twenty children (ten per group) were also assessed in terms of viral infection. Secondary end points in both groups were the number of days under antibiotic and antipyretic therapy and the number of days off school (children) and off work (parents). Results The 30 children who completed the 90-day trial with Bactoblis® showed a significant reduction in their episodes of streptococcal pharyngeal infection (>90%), as calculated by comparing the infection rates of the previous year. No difference was observed in the control group. The treated group showed a significant decrease in the incidence (80%) of oral viral infections. Again, there was no difference in the control group. With regard to secondary end points, the number of days under antibiotic treatment of the treated and control groups were 30 and 900 respectively, days under antipyretic treatment 16 and 228, days of absence from school 16 and 228, and days of absence from work 16 and 228. The product was well tolerated by the subjects, with no side effects

  5. Medical treatment of multiple streptococcal liver abscesses

    SciTech Connect

    Matlow, A.; Vellend, H.

    1983-04-01

    We describe four cases of multiple, cryptogenic, and streptococcal liver abscesses which were cured with antibiotic therapy. Two of the patients were referred for medical management as a last resort after open surgical drainage failed to eradicate the suppurative process. The other two patients were treated from the time of diagnosis with antimicrobial agents alone. Blood cultures or needle aspirates of the abscesses yielded a pure growth of streptococci in all instances. All isolates were susceptible to penicillin G. Cryptogenic streptococcal abscesses may represent a subset of multiple hepatic abscesses particularly amenable to successful medical therapy consisting of a minimum of 6 weeks parenteral antibiotic therapy followed by a period of oral antibiotics until clinical, biochemical, and radiological resolution of the abscesses has occurred.

  6. Sepsis-Associated Encephalopathy

    PubMed Central

    Cotena, Simona; Piazza, Ornella

    2012-01-01

    Summary Sepsis-associated encephalopathy (SAE) is defined as a diffuse or multifocal cerebral dysfunction induced by the systemic response to the infection without clinical or laboratory evidence of direct brain infection. Its pathogenesis is multifactorial. SAE generally occurs early during severe sepsis and precedes multiple-organ failure. The most common clinical feature of SAE is the consciousness alteration which ranges from mildly reduced awareness to unresponsiveness and coma. Diagnosis of SAE is primarily clinical and depends on the exclusion of other possible causes of brain deterioration. Electroencephalography (EEG) is almost sensitive, but it is not specific for SAE. Computed Tomography (CT) head scan generally is negative in case of SAE, while Magnetic Resonance Imaging (MRI) can show brain abnormalities in case of SAE, but they are not specific for this condition. Somatosensitive Evoked Potentials (SEPs) are sensitive markers of developing cerebral dysfunction in sepsis. Cerebrospinal fluid (CBF) analysis is generally normal, a part an inconstant elevation of proteins concentration. S100B and NSE have been proposed like biomarkers for diagnosis of SAE, but the existing data are controversial. SAE is reversible even if survivors of severe sepsis have often long lasting or irreversible cognitive and behavioral sequel; however the presence of SAE can have a negative influence on survival. A specific therapy of SAE does not exist and the outcome depends on a prompt and appropriate treatment of sepsis as whole. PMID:23905041

  7. Post-infectious group A streptococcal autoimmune syndromes and the heart.

    PubMed

    Martin, William John; Steer, Andrew C; Smeesters, Pierre Robert; Keeble, Joanne; Inouye, Michael; Carapetis, Jonathan; Wicks, Ian P

    2015-08-01

    There is a pressing need to reduce the high global disease burden of rheumatic heart disease (RHD) and its harbinger, acute rheumatic fever (ARF). ARF is a classical example of an autoimmune syndrome and is of particular immunological interest because it follows a known antecedent infection with group A streptococcus (GAS). However, the poorly understood immunopathology of these post-infectious diseases means that, compared to much progress in other immune-mediated diseases, we still lack useful biomarkers, new therapies or an effective vaccine in ARF and RHD. Here, we summarise recent literature on the complex interaction between GAS and the human host that culminates in ARF and the subsequent development of RHD. We contrast ARF with other post-infectious streptococcal immune syndromes - post-streptococcal glomerulonephritis (PSGN) and the still controversial paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), in order to highlight the potential significance of variations in the host immune response to GAS. We discuss a model for the pathogenesis of ARF and RHD in terms of current immunological concepts and the potential for application of in depth "omics" technologies to these ancient scourges. PMID:25891492

  8. Short-term Gains with Long-term Consequences: The Evolving Story of Sepsis Survivorship.

    PubMed

    Maley, Jason H; Mikkelsen, Mark E

    2016-06-01

    Sepsis is an acute, life-threatening condition that afflicts millions of patients annually. Advances in care and heightened awareness have led to substantial declines in short-term mortality. An expanding body of literature describes the long-term impact of sepsis, revealing long-term cognitive and functional impairments, sustained inflammation and immune dysfunction, increased healthcare resource use, reduced health-related quality of life, and increased mortality. The evidence challenges the notion that sepsis is an acute, transient illness, revealing rather that sepsis is an acute illness with lingering consequences. This article provides a state-of-the-art review of the emerging literature of the long-term consequences of sepsis. PMID:27229651

  9. A plethora of angiopoietin-2 effects during clinical sepsis

    PubMed Central

    2010-01-01

    The interesting study by Davis and colleagues in the current issue of Critical Care expands on the increasingly recognized role of angiopoietins in human sepsis but raises a number of questions, which are discussed in this commentary. The authors describe an association between elevated angiopoietin (ang)-2 levels and impaired vascular reactivity, measured by the partly nitric oxide-dependent finger hyperemic response to forearm vascular occlusion, in patients with sepsis. This suggests that the ang-1/2-Tie2 system is involved in a number of pathophysiologic, phenotypic and perhaps prognostic alterations in human sepsis, on top of the effect on pulmonary endothelial barrier function. The novel inflammatory route may be a target for future therapeutic studies in human sepsis and acute lung injury, including those with activated protein C. PMID:20587077

  10. The diagnosis of sepsis revisited - a challenge for young medical scientists in the 21st century

    PubMed Central

    2014-01-01

    In 1991, a well-meaning consensus group of thought leaders derived a simple definition for sepsis which required the breach of only a few static thresholds. More than 20 years later, this simple definition has calcified to become the gold standard for sepsis protocols and research. Yet sepsis clearly comprises a complex, dynamic, and relational distortion of human life. Given the profound scope of the loss of life worldwide, there is a need to disengage from the simple concepts of the past. There is an acute need to develop 21st century approaches which engage sepsis in its true form, as a complex, dynamic, and relational pattern of death. PMID:24383420

  11. Nutrition and sepsis.

    PubMed

    Cohen, Jonathan; Chin, w Dat N

    2013-01-01

    The effect of nutritional support in critically ill patients with sepsis has received much attention in recent years. However, many of the studies have produced conflicting results. As for all critically ill patients, nutritional support, preferably via the enteral route, should be commenced once initial resuscitation and adequate perfusion pressure is achieved. Where enteral feeding is impossible or not tolerated, parenteral nutrition (either as total or complimentary therapy) may safely be administered. Most positive studies relating to nutritional support and sepsis have been in the setting of sepsis prevention. Thus, the administration of standard nutrition formulas to critically ill patients within 24 h of injury or intensive care unit admission may decrease the incidence of pneumonia. Both arginine-supplemented enteral diets, given in the perioperative period, and glutamine-supplemented parenteral nutrition have been shown to decrease infections in surgical patients. Parenteral fish oil lipid emulsions as well as probiotics given in the perioperative period may also reduce infections in patients undergoing major abdominal operations, such as liver transplantation. There is little support at the present time for the positive effect of specific pharmaconutrients, in particular fish oil, probiotics, or antioxidants, in the setting of established sepsis. More studies are clearly required on larger numbers of more homogeneous groups of patients. PMID:23075593

  12. Sepsis Associated Encephalopathy

    PubMed Central

    Chaudhry, Neera; Duggal, Ashish Kumar

    2014-01-01

    Sepsis associated encephalopathy (SAE) is a common but poorly understood neurological complication of sepsis. It is characterized by diffuse brain dysfunction secondary to infection elsewhere in the body without overt CNS infection. The pathophysiology of SAE is complex and multifactorial including a number of intertwined mechanisms such as vascular damage, endothelial activation, breakdown of the blood brain barrier, altered brain signaling, brain inflammation, and apoptosis. Clinical presentation of SAE may range from mild symptoms such as malaise and concentration deficits to deep coma. The evaluation of cognitive dysfunction is made difficult by the absence of any specific investigations or biomarkers and the common use of sedation in critically ill patients. SAE thus remains diagnosis of exclusion which can only be made after ruling out other causes of altered mentation in a febrile, critically ill patient by appropriate investigations. In spite of high mortality rate, management of SAE is limited to treatment of the underlying infection and symptomatic treatment for delirium and seizures. It is important to be aware of this condition because SAE may present in early stages of sepsis, even before the diagnostic criteria for sepsis can be met. This review discusses the diagnostic approach to patients with SAE along with its epidemiology, pathophysiology, clinical presentation, and differential diagnosis. PMID:26556425

  13. Revisiting caspases in sepsis

    PubMed Central

    Aziz, M; Jacob, A; Wang, P

    2014-01-01

    Sepsis is a life-threatening illness that occurs due to an abnormal host immune network which extends through the initial widespread and overwhelming inflammation, and culminates at the late stage of immunosupression. Recently, interest has been shifted toward therapies aimed at reversing the accompanying periods of immune suppression. Studies in experimental animals and critically ill patients have demonstrated that increased apoptosis of lymphoid organs and some parenchymal tissues contributes to this immune suppression, anergy and organ dysfunction. Immediate to the discoveries of the intracellular proteases, caspases for the induction of apoptosis and inflammation, and their striking roles in sepsis have been focused elaborately in a number of original and review articles. Here we revisited the different aspects of caspases in terms of apoptosis, pyroptosis, necroptosis and inflammation and focused their links in sepsis by reviewing several recent findings. In addition, we have documented striking perspectives which not only rewrite the pathophysiology, but also modernize our understanding for developing novel therapeutics against sepsis. PMID:25412304

  14. Severe sepsis and septic shock

    PubMed Central

    Schorr, Christa A; Zanotti, Sergio; Dellinger, R Phillip

    2014-01-01

    Morbidity and mortality from sepsis remains unacceptably high. Large variability in clinical practice, plus the increasing awareness that certain processes of care associated with improved critical care outcomes, has led to the development of clinical practice guidelines in a variety of areas related to infection and sepsis. The Surviving Sepsis Guidelines for Management of Severe Sepsis and Septic Shock were first published in 2004, revised in 2008, and recently revised again and published in 2013. The first part of this manuscript is a summary of the 2013 guidelines with some editorial comment. The second part of the manuscript characterizes hospital based sepsis performance improvement programs and highlights the sepsis bundles from the Surviving Sepsis Campaign as a key component of such a program. PMID:24335487

  15. Sepsis: pathophysiology and clinical management.

    PubMed

    Gotts, Jeffrey E; Matthay, Michael A

    2016-01-01

    Sepsis, severe sepsis, and septic shock represent increasingly severe systemic inflammatory responses to infection. Sepsis is common in the aging population, and it disproportionately affects patients with cancer and underlying immunosuppression. In its most severe form, sepsis causes multiple organ dysfunction that can produce a state of chronic critical illness characterized by severe immune dysfunction and catabolism. Much has been learnt about the pathogenesis of sepsis at the molecular, cell, and intact organ level. Despite uncertainties in hemodynamic management and several treatments that have failed in clinical trials, investigational therapies increasingly target sepsis induced organ and immune dysfunction. Outcomes in sepsis have greatly improved overall, probably because of an enhanced focus on early diagnosis and fluid resuscitation, the rapid delivery of effective antibiotics, and other improvements in supportive care for critically ill patients. These improvements include lung protective ventilation, more judicious use of blood products, and strategies to reduce nosocomial infections. PMID:27217054

  16. Group G streptococcal toxic shock-like syndrome in three cats.

    PubMed

    Taillefer, Mylène; Dunn, Marilyn

    2004-01-01

    Three 8-week-old kittens were presented with a history of acute, generalized weakness and severe fever. One cat was dead upon presentation, and necropsy findings were supportive of a group G Streptococcus spp. septicemia. During their clinical courses, two of the three kittens developed a progressive, marked swelling of one or more limbs. One moribund and severely hypothermic cat was euthanized a few hours after presentation, and necropsy was also supportive of a group G Streptococcus spp. septicemia. One kitten recovered. Group G streptococcal toxic shock-like syndrome was suspected because of the fulminant progression of the septicemia. PMID:15347623

  17. Neuroinflammation in sepsis: sepsis associated delirium.

    PubMed

    Piva, Simone; McCreadie, Victoria A; Latronico, Nicola

    2015-01-01

    Sepsis-associated delirium (SAD) is a clinical manifestation of the involvement of the central nervous system (CNS) during sepsis. The purpose of this review is to provide a concise overview of SAD including the epidemiology and current diagnostic criteria for SAD. We present in detail the pathophysiology with regards to blood-brain-barrier breakdown, cytokine activation and neurotransmitter deregulation. Treatment and prognosis for SAD are also briefly discussed. SAD is the most common form of delirium acquired in the ICU (Intensive Care Unit), and is described in about 50% of septic patients. Clinical features include altered level of consciousness, reduced attention, change in cognition and perceptual disturbances. Symptoms can reversible, but prolonged deficits can be observed in older patients. Pathophysiology of SAD is poorly understood, but involves microvascular, metabolic and, not least, inflammatory mechanisms leading to CNS dysfunction. These mechanisms can be different in SAD compared to ICU delirium associated with other conditions. SAD is diagnosed clinically using validated tools such as CAM-ICU (Confusion Assessment Method for the Intensive Care Medicine) or ICDSC (The Intensive Care Delirium Screening Checklist), which have good specificity but low sensitivity. Neuroimaging studies and EEG (Electroencephalography) can be useful complement to clinical evaluation to define the severity of the condition. Prompt diagnosis and eradication of septic foci whenever possible is vital. Preventive measures for SAD in the critically ill patient requiring long-term sedation include maintaining light levels of sedation using non-benzodiazepine sedatives (either propofol or dexmedetomidine). Early mobilization of patients in the ICU is also recommended. Antipsychotic drugs (haloperidol and atypical antipsychotics) are widely used to treat SAD, but firm evidence of their efficacy is lacking. PMID:25567339

  18. Streptococcal vertebral osteomyelitis: multiple faces of the same disease.

    PubMed

    Murillo, O; Roset, A; Sobrino, B; Lora-Tamayo, J; Verdaguer, R; Jiménez-Mejias, E; Nolla, J M; Colmenero, J de D; Ariza, J

    2014-01-01

    The role of Streptococcus species as an aetiological microorganism of vertebral osteomyelitis (VO) is considered to be of little relevance. We aimed to describe a large number of cases of streptococcal vertebral osteomyelitis (SVO), to analyze the clinical features associated with different Streptococcus species, and to compare them with a cohort of patients with VO caused by Staphylococcus aureus. An incidence study and a retrospective, multicenter, observational clinical study of cases of SVO (1991-2011) were performed. Statistical comparison of SVO by different species and between them and staphylococcal VO was carried out. Over the whole period there was an increasing incidence in the number of VOs and SVOs per year (p <0.05). Among 58 cases of SVO, those caused by non-viridans streptococcus (Streptococcus pneumoniae, Streptococcus agalactiae and Streptococcus pyogenes; n = 26) mimicked VO by S. aureus, and presented with more fever, neurological symptoms and paravertebral abscesses in comparison with those caused by the viridans group (remaining species). In contrast, the latter have a sub-acute clinical picture and were associated with the presence of endocarditis (p <0.05). Among non-viridans SVOs, concomitant infection was specifically related to S. pneumoniae (p <0.05). In conclusion, SVO presents a wide range of clinical patterns. The relationship between VO and diagnosis of endocarditis was established with SVO caused by the viridans group. Whereas non-viridans SVO mimics acute characteristics of VO caused by S. aureus, cases of viridans SVO are significantly more likely to have a sub-acute clinical presentation. The increased incidence of SVO during the last decades could support a new epidemiological scenario. PMID:23889700

  19. New paradigms in sepsis: from prevention to protection of failing microcirculation.

    PubMed

    Hawiger, J; Veach, R A; Zienkiewicz, J

    2015-10-01

    Sepsis, also known as septicemia, is one of the 10 leading causes of death worldwide. The rising tide of sepsis due to bacterial, fungal and viral infections cannot be stemmed by current antimicrobial therapies and supportive measures. New paradigms for the mechanism and resolution of sepsis and consequences for sepsis survivors are emerging. Consistent with Benjamin Franklin's dictum 'an ounce of prevention is worth a pound of cure', sepsis can be prevented by vaccinations against pneumococci and meningococci. Recently, the NIH NHLBI Panel redefined sepsis as 'severe endothelial dysfunction syndrome in response to intravascular and extravascular infections causing reversible or irreversible injury to the microcirculation responsible for multiple organ failure'. Microvascular endothelial injury underlies sepsis-associated hypotension, edema, disseminated intravascular coagulation, acute respiratory distress syndrome and acute kidney injury. Microbial genome products trigger 'genome wars' in sepsis that reprogram the human genome and culminate in a 'genomic storm' in blood and vascular cells. Sepsis can be averted experimentally by endothelial cytoprotection through targeting nuclear signaling that mediates inflammation and deranged metabolism. Endothelial 'rheostats' (e.g. inhibitors of NF-κB, A20 protein, CRADD/RAIDD protein and microRNAs) regulate endothelial signaling. Physiologic 'extinguishers' (e.g. suppressor of cytokine signaling 3) can be replenished through intracellular protein therapy. Lipid mediators (e.g. resolvin D1) hasten sepsis resolution. As sepsis cases rose from 387 330 in 1996 to 1.1 million in 2011, and are estimated to reach 2 million by 2020 in the US, mortality due to sepsis approaches that of heart attacks and exceeds deaths from stroke. More preventive vaccines and therapeutic measures are urgently needed. PMID:26190521

  20. Factors Associated with Streptococcal Bacteremia in Diarrheal Children under Five Years of Age and Their Outcome in an Urban Hospital in Bangladesh

    PubMed Central

    Shahid, Abu Sadat Mohammad Sayeem Bin; Ahmed, Tahmeed; Shahunja, K. M.; Kabir, Senjuti; Chowdhury, Fahmida; Faruque, Abu Syeed Golam; Das, Sumon Kumar; Sarker, Mohammad Habibur Rahman; Bardhan, Pradip Kumar; Chisti, Mohammod Jobayer

    2016-01-01

    Background Although Streptococcal bacteremia is common in diarrheal children with high morbidity and mortality, no systematic data are available on Streptococcal bacteremia in diarrheal children. We sought to evaluate the factors associated with Streptococcal bacteremia in diarrheal children under five years of age and their outcome. Methods We used an unmatched case-control design to investigate the associated factors with Streptococcal bacteremia in all the diarrheal children under five years of age through electronic medical record system of Dhaka hospital of International Centre for Diarrhoeal Disease Research, Bangladesh. We had simultaneously used a retrospective cohort design to further evaluate the outcome of our study children. All the enrolled children had their blood culture done between January 2010 and December 2012. Comparison was made among the children with (cases = 26) and without Streptococcal bacteremia (controls = 78). Controls were selected randomly from hospitalized diarrheal children under five years of age. Results Cases had proportionately higher deaths compared to controls, but it was statistically insignificant (15% vs. 10%, p = 0.49). The cases more often presented with severe dehydration, fever, respiratory distress, severe sepsis, and abnormal mental status compared to the controls (for all p<0.05). In the logistic regression analysis, after adjusting for potential confounders, it has been found that Streptococcal bacteremia in diarrheal children under five years of age was independently associated with nutritional edema (OR: 5.86, 95% CI = 1.28–26.80), hypoxemia (OR: 19.39, 95% CI = 2.14–175.91), fever (OR: 4.44, 95% CI = 1.13–17.42), delayed capillary refill time (OR: 7.00, 95% CI = 1.36–35.93), and respiratory distress (OR: 2.69, 95% CI = 1.02–7.12). Conclusions and Significance The results of our analyses suggest that diarrheal children under five years of age presenting with nutritional edema, hypoxemia, fever, delayed

  1. Selecting patients with severe sepsis for drotrecogin alfa (activated) therapy.

    PubMed

    Sollet, Jean-Pierre; Garber, Gary E

    2002-12-01

    Selecting patients for drotrecogin alfa (activated) (Xigris; Eli Lilly and Company, Indianapolis, IN) therapy outside of a clinical trial setting requires knowledge of the rationale that led the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) investigators to select the various entry criteria for the trial. Enrollment criteria for the study included a known or suspected infection, presence of at least 3 systemic inflammatory response syndrome (SIRS) criteria, and dysfunction of > or =1 organ or system. The infection criteria used in PROWESS were designed to be straightforward and were based on common clinical and radiological data. Although previous definitions of sepsis required only 2 SIRS criteria, the PROWESS trial investigators required the presence of > or =3 SIRS criteria to improve the sensitivity and specificity of these criteria for the diagnosis of sepsis. Acute organ dysfunction, the diagnostic criterion for severe sepsis, was used to define the study population because it identifies patients at significant risk of death. Characteristics of drotrecogin alfa (activated)-treated patients, including infection, modified SIRS criteria, and organ dysfunction, were similar to those of the placebo group and the general sepsis population. Proper clinical judgment and use of the these inclusion criteria as a guide will help clinicians select and treat sepsis patients with drotrecogin alfa (activated). PMID:12521613

  2. Sepsis-induced Cardiomyopathy

    PubMed Central

    Romero-Bermejo, Francisco J; Ruiz-Bailen, Manuel; Gil-Cebrian, Julián; Huertos-Ranchal, María J

    2011-01-01

    Myocardial dysfunction is one of the main predictors of poor outcome in septic patients, with mortality rates next to 70%. During the sepsis-induced myocardial dysfunction, both ventricles can dilate and diminish its ejection fraction, having less response to fluid resuscitation and catecholamines, but typically is assumed to be reversible within 7-10 days. In the last 30 years, It´s being subject of substantial research; however no explanation of its etiopathogenesis or effective treatment have been proved yet. The aim of this manuscript is to review on the most relevant aspects of the sepsis-induced myocardial dysfunction, discuss its clinical presentation, pathophysiology, etiopathogenesis, diagnostic tools and therapeutic strategies proposed in recent years. PMID:22758615

  3. Platelet depletion and severity of streptococcal endocarditis

    PubMed Central

    Dall, Lawrence; Miller, Todd; Herndon, Betty; Diez, Ireneo; Dew, Michelle

    1998-01-01

    OBJECTIVE: To evaluate the importance of thrombocytopenia in streptococcal endocarditis using an animal model. DESIGN: A model of human septic endocarditis was established in rats (polyethylene catheters across the aortic valve and administration of Streptococcus sanguis, 5×107 colony forming units [cfu] intravenous). Thrombocytopenia at four levels was produced by antiplatelet serum. Secondary methods of producing thrombocytopenia were also evaluated. At sacrifice (96 h after platelet depletion and 72 h after infection), vegetations were removed, weighed, diluted, plated and counted. Potential mechanisms of the dose-response relationship between vegetation density and platelet count were evaluated. SETTING: Controlled research laboratory experiments. POPULATION STUDIED: Animal models of streptococcal endocarditis. MAIN RESULTS: The bacterial density of the aortic valve vegetations significantly increased as the platelet count decreased (P=0.0007). In severely thrombocytopenic animals (two-dose antiplatelet serum), data suggest increased vegetation embolism. Platelet depletion, which was minimal with chemical methods, was produced most effectively by antithrombocyte serum. Platelet surfaces in endocarditis were found to express elevated CD62p proteins (72.7% endocarditis, 34.7% control). Platelet protein fractions were evaluated in vitro by both streptocidal (P=0.19) and phagocytosis-stimulating assays. Platelet presence in mature aortic valve vegetations averaged only about 2%. CONCLUSIONS: In platelet depletion experiments using a rat model, a dose-response relationship of peripheral circulating platelet depletion to aortic valve vegetation density was found. The mechanism relating thrombocytopenia to endocarditis severity remains unresolved. PMID:22346555

  4. Cellular dysfunction in sepsis.

    PubMed

    Singer, Mervyn

    2008-12-01

    Cellular dysfunction is a commonplace sequelum of sepsis and other systemic inflammatory conditions. Impaired energy production (related to mitochondrial inhibition, damage, and reduced protein turnover) appears to be a core mechanism underlying the development of organ dysfunction. The reduction in energy availability appears to trigger a metabolic shutdown that impairs normal functioning of the cell. This may well represent an adaptive mechanism analogous to hibernation that prevents a massive degree of cell death and thus enables eventual recovery in survivors. PMID:18954700

  5. Complicated Perianal Sepsis.

    PubMed

    Mitra, Abhishek; Yadav, Amitabh; Mehta, Naimish; Varma, Vibha; Kumaran, Vinay; Nundy, Samiran

    2015-12-01

    Management of benign anorectal conditions like abscesses and haemorrhoids is usually uneventful. However, complicated perianal complications can result and have sparsely been reported in literature. Hereby, we report a series of seven patients who presented with rare sequelae like necrotising fasciitis, intraperitoneal or retroperitoneal involvement. All patients responded well to surgical management. Accordingly, complicated perianal sepsis warrants a timely and aggressive surgical intervention. PMID:27011454

  6. Sepsis-associated hyperlactatemia.

    PubMed

    Garcia-Alvarez, Mercedes; Marik, Paul; Bellomo, Rinaldo

    2014-01-01

    There is overwhelming evidence that sepsis and septic shock are associated with hyperlactatemia (sepsis-associated hyperlactatemia (SAHL)). SAHL is a strong independent predictor of mortality and its presence and progression are widely appreciated by clinicians to define a very high-risk population. Until recently, the dominant paradigm has been that SAHL is a marker of tissue hypoxia. Accordingly, SAHL has been interpreted to indicate the presence of an 'oxygen debt' or 'hypoperfusion', which leads to increased lactate generation via anaerobic glycolysis. In light of such interpretation of the meaning of SAHL, maneuvers to increase oxygen delivery have been proposed as its treatment. Moreover, lactate levels have been proposed as a method to evaluate the adequacy of resuscitation and the nature of the response to the initial treatment for sepsis. However, a large body of evidence has accumulated that strongly challenges such notions. Much evidence now supports the view that SAHL is not due only to tissue hypoxia or anaerobic glycolysis. Experimental and human studies all consistently support the view that SAHL is more logically explained by increased aerobic glycolysis secondary to activation of the stress response (adrenergic stimulation). More importantly, new evidence suggests that SAHL may actually serve to facilitate bioenergetic efficiency through an increase in lactate oxidation. In this sense, the characteristics of lactate production best fit the notion of an adaptive survival response that grows in intensity as disease severity increases. Clinicians need to be aware of these developments in our understanding of SAHL in order to approach patient management according to biological principles and to interpret lactate concentrations during sepsis resuscitation according to current best knowledge. PMID:25394679

  7. Severe sepsis during pregnancy.

    PubMed

    Pacheco, Luis D; Saade, George R; Hankins, Gary D V

    2014-12-01

    Severe sepsis is a major cause of mortality among critically ill patients. Early recognition accompanied by early initiation of broad-spectrum antibiotics with source control and fluid resuscitation improves outcomes. Hemodynamic resuscitation starts with fluid therapy followed by vasopressors if necessary. Cases refractory to first-line vasopressors (norepinephrine) will require second-line vasopressors (epinephrine or vasopressin) and low-dose steroid therapy. Resuscitation goals should include optimization of central venous oxygenation and serum lactate. PMID:25286297

  8. Mitochondrial dysfunction during sepsis.

    PubMed

    Azevedo, Luciano Cesar Pontes

    2010-09-01

    Sepsis and multiple organ failure remain leading causes of death in intensive care patients. Recent advances in our understanding of the pathophysiology of these syndromes include a likely prominent role for mitochondria. Patient studies have shown that the degree of mitochondrial dysfunction is related to the eventual outcome. Associated mechanisms include damage to mitochondria or inhibition of the electron transport chain enzymes by nitric oxide and other reactive oxygen species (the effects of which are amplified by co-existing tissue hypoxia), hormonal influences that decrease mitochondrial activity, and downregulation of mitochondrial protein expression. Notably, despite these findings, there is minimal cell death seen in most affected organs, and these organs generally regain reasonably normal function should the patient survive. It is thus plausible that multiple organ failure following sepsis may actually represent an adaptive state whereby the organs temporarily 'shut down' their normal metabolic functions in order to protect themselves from an overwhelming and prolonged insult. A decrease in energy supply due to mitochondrial inhibition or injury may trigger this hibernation/estivation-like state. Likewise, organ recovery may depend on restoration of normal mitochondrial respiration. Data from animal studies show histological recovery of mitochondria after a septic insult that precedes clinical improvement. Stimulation of mitochondrial biogenesis could offer a new therapeutic approach for patients in multi-organ failure. This review will cover basic aspects of mitochondrial function, mechanisms of mitochondrial dysfunction in sepsis, and approaches to prevent, mitigate or speed recovery from mitochondrial injury. PMID:20509844

  9. Lysozyme, a mediator of sepsis that deposits in the systemic vasculature and kidney as a possible mechanism of acute organ dysfunction.

    PubMed

    Gotes, Jose; Kasian, Krika; Jacobs, Hans; Cheng, Zhao-Qin; Mink, Steven N

    2014-03-01

    In septic shock (SS), dysfunction of many organ systems develops during the course of the illness, although the mechanisms are not clear. In earlier studies, we reported that lysozyme-c (Lzm-S), a protein that is released from leukocytes and macrophages, was a mediator of the myocardial depression and vasodilation that develop in a canine model of Pseudomonas aeruginosa SS. Whereas both of these effects of Lzm-S are dependent on its ability to intrinsically generate hydrogen peroxide, we subsequently showed that Lzm-S can also deposit within the vascular smooth muscle layer of the systemic arteries in this model. In the present study, we extend our previous findings. We used a canine carotid artery organ bath preparation to study the time course and dose dependence of Lzm-S deposition within the vascular smooth muscle layer. We used a human aortic vascular smooth muscle cell preparation to determine whether Lzm-S can persistently inhibit contraction in this preparation. We also used a canine P. aeruginosa model to determine whether Lzm-S deposition might occur in other organs such as the kidney, liver, and small intestine. The results showed that, in the carotid artery organ bath preparation, Lzm-S deposition occurred within minutes of instillation and there was a dose-response effect. In the human aortic vascular smooth muscle cell preparation, Lzm-S inhibited contraction during a 4-day period. In the in vivo model, Lzm-S accumulated in the kidney and the superior mesenteric artery. In a canine renal epithelial preparation, we further showed that Lzm-S can be taken up by the renal tubules to activate inflammatory pathways. We conclude that Lzm-S can deposit in the systemic vasculature and kidneys in SS, where this deposition could lead to acute organ dysfunction. PMID:24296430

  10. Maternal Sepsis and Septic Shock.

    PubMed

    Chebbo, Ahmad; Tan, Susanna; Kassis, Christelle; Tamura, Leslie; Carlson, Richard W

    2016-01-01

    The year 2015 marked the 200th anniversary of the birth of Ignaz Semmelweis, the Hungarian physician who identified unhygienic practices of physicians as a major cause of childbed fever or puerperal sepsis. Although such practices have largely disappeared as a factor in the development of chorioamnionitis and postpartum or puerperal endometritis, it is appropriate that this article on sepsis in pregnancy acknowledges his contributions to maternal health. This review describes the incidence and mortality of sepsis in pregnancy, methods to identify and define sepsis in this population, including scoring systems, causes, and sites of infection during pregnancy and parturition and management guidelines. PMID:26600449

  11. Surviving Sepsis: Taming a Deadly Immune Response

    MedlinePlus

    ... disclaimer . Subscribe Surviving Sepsis Taming a Deadly Immune Response Many people have never heard of sepsis, or ... tract infection) and then a powerful and harmful response by your body’s own immune system . “With sepsis, ...

  12. Early alterations of the innate and adaptive immune statuses in sepsis according to the type of underlying infection

    PubMed Central

    2010-01-01

    Introduction Although major changes of the immune system have been described in sepsis, it has never been studied whether these may differ in relation to the type of underlying infection or not. This was studied for the first time. Methods The statuses of the innate and adaptive immune systems were prospectively compared in 505 patients. Whole blood was sampled within less than 24 hours of advent of sepsis; white blood cells were stained with monoclonal antibodies and analyzed though a flow cytometer. Results Expression of HLA-DR was significantly decreased among patients with severe sepsis/shock due to acute pyelonephritis and intraabdominal infections compared with sepsis. The rate of apoptosis of natural killer (NK) cells differed significantly among patients with severe sepsis/shock due to ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) compared with sepsis. The rate of apoptosis of NKT cells differed significantly among patients with severe sepsis/shock due to acute pyelonephritis, primary bacteremia and VAP/HAP compared with sepsis. Regarding adaptive immunity, absolute counts of CD4-lymphocytes were significantly decreased among patients with severe sepsis/shock due to community-acquired pneumonia (CAP) and intraabdominal infections compared with sepsis. Absolute counts of B-lymphocytes were significantly decreased among patients with severe sepsis/shock due to CAP compared with sepsis. Conclusions Major differences of the early statuses of the innate and adaptive immune systems exist between sepsis and severe sepsis/shock in relation to the underlying type of infection. These results may have a major impact on therapeutics. PMID:20504311

  13. Viridans Group Streptococcal Infections in Children After Chemotherapy or Stem Cell Transplantation

    PubMed Central

    Nielsen, Maryke J.; Claxton, Sarah; Pizer, Barry; Lane, Steven; Cooke, Richard P.D.; Paulus, Stéphane; Carrol, Enitan D.

    2016-01-01

    Abstract Viridans Group Streptococci (VGS) are associated with high mortality rates in febrile neutropenia; yet there are no recent European pediatric studies to inform antimicrobial therapy. The aim of this study was to describe the characteristics, outcome, and resistance patterns of children with VGS bacteremia (VGSB) undergoing treatment of malignancy or hematopoietic stem cell transplant. Patients aged 0 to 18 years, admitted to a tertiary pediatric hemato-oncology center with VGSB, from 2003 to 2013, were included in the study. All data were collected retrospectively from medical records. A total of 54 bacteremic episodes occurred in 46 patients. The most common underlying diagnosis was relapsed acute lymphoblastic leukemia. Streptococcus mitis was the most frequent organism. A total of 30% of isolates were resistant to penicillin and 100% sensitive to vancomycin. There were 8 episodes (14.8%) of Viridans Group Streptococcal Shock Syndrome; 6 resulted in admission to intensive care and 3 of these patients died of multiorgan failure. The potentially fatal nature of VGSB is confirmed. The high risk in relapsed acute lymphoblastic leukemia is of note. Research is needed to develop risk-stratification scores that identify children at risk of Viridans Group Streptococcal Shock Syndrome to guide empirical antimicrobial therapy in febrile neutropenia. PMID:26945409

  14. A one-year study of streptococcal infections and their complications among Ethiopian children.

    PubMed Central

    Tewodros, W.; Muhe, L.; Daniel, E.; Schalén, C.; Kronvall, G.

    1992-01-01

    Post-streptococcal complications are known to be common among Ethiopian children. Little is known, however, about the epidemiology of beta-haemolytic streptococci in Ethiopia. A total of 816 children were studied during a one-year period: 24 cases of acute rheumatic fever (ARF), 44 chronic rheumatic heart disease (CRHD), 44 acute post streptococcal glomerulonephritis (APSGN), 143 tonsillitis, 55 impetigo, and 506 were apparently healthy children. Both ARF and APSGN occurred throughout the year with two peaks during the rainy and cold seasons. The female:male ratio among ARF patients was 1.4:1 and 1:1.9 among APSGN. The monthly carrier rate of beta-haemolytic streptococci group A varied from 7.5-39%, average being 17%. T type 2 was the most frequent serotype. Marked seasonal fluctuations were noted in the distribution of serogroups among apparently healthy children. Beta-haemolytic streptococci group A dominated during the hot and humid months of February-May. Strains were susceptible to commonly used antibiotics, except for tetracycline. PMID:1397112

  15. Streptococcal cysteine proteinase releases biologically active fragments of streptococcal surface proteins.

    PubMed

    Berge, A; Björck, L

    1995-04-28

    Streptococcus pyogenes are important pathogenic bacteria which produce an extracellular cysteine proteinase contributing to their virulence and pathogenicity. S. pyogenes also express surface molecules, M proteins, that are major virulence determinants due to their antiphagocytic property. In the present work live S. pyogenes bacteria of the M1 serotype were incubated with purified cysteine proteinase. Several peptides were solubilized, and analysis of their protein-binding properties and amino acid sequences revealed two internal fibrinogen-binding fragments of M1 protein (17 and 21 kDa, respectively), and a 36-kDa IgG-binding NH2-terminal fragment of protein H, an IgGFc-binding surface molecule. M protein also plays a role in streptococcal adherence, and removal of this and other surface proteins could promote bacterial dissemination, whereas the generation of soluble complexes between immunoglobulins and immunoglobulin-binding streptococcal surface proteins could be an etiological factor in the development of glomerulonephritis and rheumatic fever. Thus, in these serious complications to S. pyogenes infections immune complexes are found in affected organs. The cysteine proteinase also solubilized a 116-kDa internal fragment of C5a peptidase, another streptococcal surface protein. Activation of the complement system generates C5a, a peptide stimulating leukocyte chemotaxis. C5a-mediated granulocyte migration was blocked by the 116-kDa fragment. This mechanism, by which phagocytes could be prevented from reaching the site of infection, may also contribute to the pathogenicity and virulence of S. pyogenes. PMID:7730368

  16. Streptococcal Infections, Rheumatic Fever and School Health Services.

    ERIC Educational Resources Information Center

    Markowitz, Milton

    1979-01-01

    Because rheumatic fever is a potentially serious complication of a streptococcal sore throat which can lead to permanent heart disease, this article advocates the expansion of school health services in medically underserved areas. (JMF)

  17. A case of postpartum Group B streptococcal meningitis

    PubMed Central

    Gayford, Kylie; McCarthy, Ana; Hague, William M

    2011-01-01

    A case of postpartum Group B streptococcal meningitis, a rare complication of an invasive infection by a common maternal commensal bacterium, which demonstrates the need to develop rapid and accurate antepartum and intrapartum screening methods for this organism.

  18. Clinical Microbiology of Bacterial and Fungal Sepsis in Very-Low-Birth-Weight Infants

    PubMed Central

    Kaufman, David; Fairchild, Karen D.

    2004-01-01

    Twenty percent of very-low-birth-weight (<1500 g) preterm infants experience a serious systemic infection, and despite advances in neonatal intensive care and antimicrobials, mortality is as much as threefold higher for these infants who develop sepsis than their counterparts without sepsis during their hospitalization. Outcomes may be improved by preventative strategies, earlier and accurate diagnosis, and adjunct therapies to combat infection and protect the vulnerable preterm infant during an infection. Earlier diagnosis on the basis of factors such as abnormal heart rate characteristics may offer the ability to initiate treatment prior to the onset of clinical symptoms. Molecular and adjunctive diagnostics may also aid in diagnosing invasive infection when clinical symptoms indicate infection but no organisms are isolated in culture. Due to the high morbidity and mortality, preventative and adjunctive therapies are needed. Prophylaxis has been effective in preventing early-onset group B streptococcal sepsis and late-onset Candida sepsis. Future research in prophylaxis using active and passive immunization strategies offers prevention without the risk of resistance to antimicrobials. Identification of the differences in neonatal intensive care units with low and high infection rates and implementation of infection control measures remain paramount in each neonatal intensive care unit caring for preterm infants. PMID:15258097

  19. Neuroanatomy and Physiology of Brain Dysfunction in Sepsis.

    PubMed

    Mazeraud, Aurelien; Pascal, Quentin; Verdonk, Franck; Heming, Nicholas; Chrétien, Fabrice; Sharshar, Tarek

    2016-06-01

    Sepsis-associated encephalopathy (SAE), a complication of sepsis, is often complicated by acute and long-term brain dysfunction. SAE is associated with electroencephalogram pattern changes and abnormal neuroimaging findings. The major processes involved are neuroinflammation, circulatory dysfunction, and excitotoxicity. Neuroinflammation and microcirculatory alterations are diffuse, whereas excitotoxicity might occur in more specific structures involved in the response to stress and the control of vital functions. A dysfunction of the brainstem, amygdala, and hippocampus might account for the increased mortality, psychological disorders, and cognitive impairment. This review summarizes clinical and paraclinical features of SAE and describes its mechanisms at cellular and structural levels. PMID:27229649

  20. AN INACTIVE PRECURSOR OF STREPTOCOCCAL PROTEINASE

    PubMed Central

    Elliott, Stuart D.; Dole, Vincent P.

    1947-01-01

    1. Streptococcal proteinase is derived from an inactive precursor found in culture filtrates of proteinase-producing streptococci. 2. The precursor can be converted into the proteinase by low concentrations of trypsin but not by chymotrypsin. 3. In cultures grown in suitable media the conversion of precursor to proteinase is effected autocatalytically. This reaction occurs under reducing conditions and is initiated by active proteinase present in low concentrations with the precursor. 4. The autocatalytic reaction is suppressed or retarded by conditions which decrease the activity of the proteinase, e.g. by growing cultures at 22°C. instead of at 37°C. or by growing them under markedly aerobic conditions. It is also retarded in the presence of casein. PMID:19871616

  1. Alcoholic leukopenic pneumococcal sepsis.

    PubMed

    Alraiyes, Abdul Hamid; Shaheen, Khaldoon; Alraies, M Chadi

    2013-04-01

    Alcohol abuse has been associated with an increased mortality and morbidity due to increased aspiration, delirium tremens, and seizures. The association of pneumococcal lung infections and leukopenia in the setting of alcohol abuse are rarely reported; however, when present, severe lung infections can happen with severe lung injury and poor response to conventional therapy and ultimately, death. We are reporting a case of 55-year-old-man presented with shortness of breath, cough and altered mental status and eventually found with severe pneumococcal lung infection in the setting of leukopenia and long-term alcohol abuse representing alcoholic leukopenic pneumococcal sepsis syndrome. PMID:23930244

  2. Blood transfusion practices in sepsis

    PubMed Central

    Murthy, TVSP

    2014-01-01

    Sepsis is a clinical syndrome characterised by systemic inflammation due to infection. There is a spectrum with severity ranging from sepsis to severe sepsis and septic shock. Even with optimal treatment, mortality due to severe sepsis or septic shock is significant and poses a challenge to management. Antibiotics, source control, resuscitation with fluids, vasopressor and inotropic agents are the main-stay of treatment for septic shock. These may be supplemented with transfusion of red blood cells and or blood products, in the case of anaemia to sustain sufficient oxygen delivery[1] or to manage associated haematological issues. Transfusion in sepsis has always been a debatable issue, especially in relation to choice of the fluid and the role of blood or blood product transfusion. PMID:25535429

  3. Incidence and clinical variables associated with streptococcal throat infections: a prospective diagnostic cohort study

    PubMed Central

    Little, Paul; Hobbs, FD Richard; Mant, David; McNulty, Cliodna AM; Mullee, Mark

    2012-01-01

    Background Management of pharyngitis is commonly based on features which are thought to be associated with Lancefield group A beta-haemolytic streptococci (GABHS) but it is debatable which features best predict GABHS. Non-group A strains share major virulence factors with group A, but it is unclear how commonly they present and whether their presentation differs. Aim To assess the incidence and clinical variables associated with streptococcal infections. Design and setting Prospective diagnostic cohort study in UK primary care. Method The presence of pathogenic streptococci from throat swabs was assessed among patients aged ≥5 years presenting with acute sore throat. Results Pathogenic streptococci were found in 204/597 patients (34%, 95% CI = 31 to 38%): 33% (68/204) were non-group A streptococci, mostly C (n = 29), G (n = 18) and B (n = 17); rarely D (n = 3) and Streptococcus pneumoniae (n = 1). Patients presented with similar features whether the streptococci were group A or non-group A. The features best predicting A, C or G beta-haemolytic streptococci were patient’s assessment of severity (odds ratio [OR] for a bad sore throat 3.31, 95% CI = 1.24 to 8.83); doctors’ assessment of severity (severely inflamed tonsils OR 2.28, 95% CI = 1.39 to 3.74); absence of a bad cough (OR 2.73, 95% CI = 1.56 to 4.76), absence of a coryza (OR 1.54, 95% CI = 0.99 to 2.41); and moderately bad or worse muscle aches (OR 2.20, 95% CI = 1.41 to 3.42). Conclusion Non-group A strains commonly cause streptococcal sore throats, and present with similar symptomatic clinical features to group A streptococci. The best features to predict streptococcal sore throat presenting in primary care deserve revisiting. PMID:23211183

  4. Functional and histopathologic changes in the liver during sepsis.

    PubMed

    Caruana, J A; Montes, M; Camara, D S; Ummer, A; Potmesil, S H; Gage, A A

    1982-05-01

    Although liver failure from sepsis is a frequent occurrence in serious ill, hospitalized patients, little information is available on the histologic changes of the liver. We examined the histopathology of the liver of 19 patients who died of clinical sepsis and attempted to relate certain features of the illness or treatment to the observed histopathologic changes. The most striking finding was midzonal and peripheral necrosis of a moderate to marked degree in 11 of 19 patients. Other important changes were acute inflammation and cholestasis. The severity of hepatocellular necrosis did not appear to be influenced by the premortem circulating pathogen, by the nutritional support administered or by the arterial blood pressure. It is suggested that hepatocellular necrosis is characteristic of sepsis and may be caused by loss of specific factors which normally maintain liver function and structure. PMID:6803371

  5. Transient EDTA-dependent pseudothrombocytopenia in a patient with sepsis.

    PubMed

    Mori, M; Kudo, H; Yoshitake, S; Ito, K; Shinguu, C; Noguchi, T

    2000-02-01

    Ethylenediaminetetraacetic acid-dependent pseudothrombocytopenia (EDTA-PTCP) is the phenomenon of a spurious low platelet count due to antiplatelet antibodies that cause platelet clumping in blood anticoagulated with EDTA. We describe a case of EDTA-PTCP that appeared transiently with the development of sepsis. A 50-year-old man underwent Bentall's aortic root replacement for acute aortic dissection with aortic insufficiency. Postoperatively the patient suffered paralytic ileus followed by methicillin-resistant Staphylococcus aureus enteritis and septicemia with endotoxemia. EDTA-PTCP appeared with the development of sepsis, and disappeared with its resolution. To avoid incorrect diagnoses and inappropriate treatment, EDTA-PTCP should always be considered as a possible cause of reported low platelet counts, even in patients with sepsis. PMID:10784313

  6. [Bacteraemia and sepsis].

    PubMed

    Kern, W V

    2011-02-01

    Recent news in the field of bloodstream infection and sepsis relevant for the practitioner include the recommendation in the newly revised German sepsis guideline to introduce selective intestinal decontamination with non-absorbable antimicrobial substances for the prevention of secondary infections in ventilated patients. This intervention, however, remains controversial because there are indications of unfavourable effects (increased development of resistance), and because the effect size has been rather low. Other news indicate not only that procalcitonin can be reasonably used as an aid to determine the duration of antibiotic treatment in community-acquired respiratory infection and pneumonia. A procalcitonin-based algorithm can also be used in critical care patients to shorten the duration of antibiotic administration without worsening outcomes. Recent data indicate that E. coli and S. aureus continue to be the most frequent pathogens isolated in bloodstream infection. The proportion of E. coli strains producing extended-spectrum beta lactamase (ESBL) is increasing. New epidemiologic evidence shows that infections with this pathogen, resistant to many standard antibiotics, are associated with an increased mortality rate, similar to infections due to methicillin-resistant Staphylococcus aureus (MSRA). The incidence of MRSA bacteraemia in Germany can now be estimated better as it has become a notifiable infection. PMID:21271477

  7. Totem and taboo: fluids in sepsis.

    PubMed

    Hilton, Andrew K; Bellomo, Rinaldo

    2011-01-01

    The need for early, rapid, and substantial fluid resuscitation in septic patients has long been an article of faith in the intensive care community, a tribal totem that is taboo to question. The results of a recent multicenter trial in septic children in Africa, published in The New England Journal of Medicine, powerfully challenge the fluid paradigm. The salient aspects of the trial need to be understood and reflected upon. In this commentary, we discuss the background to and findings of the trial and explain why they will likely trigger a re-evaluation of our thinking about fluids in sepsis, a re-evaluation that is already happening in the treatment of acute respiratory distress syndrome and acute kidney injury and in postoperative care. PMID:21672278

  8. Learning a Severity Score for Sepsis: A Novel Approach based on Clinical Comparisons

    PubMed Central

    Dyagilev, Kirill; Saria, Suchi

    2015-01-01

    Sepsis is one of the leading causes of death in the United States. Early administration of treatment has been shown to decrease sepsis-related mortality and morbidity. Existing scoring systems such as the Acute Physiology and Chronic Health Evaluation (APACHE II) and Sequential Organ Failure Assessment scores (SOFA) achieve poor sensitivity in distinguishing between the different stages of sepsis. Recently, we proposed the Disease Severity Score Learning (DSSL) framework that automatically derives a severity score from data based on clinical comparisons – pairs of disease states ordered by their severity. In this paper, we test the feasibility of using DSSL to develop a sepsis severity score. We show that the learned score significantly outperforms APACHE-II and SOFA in distinguishing between the different stages of sepsis. Additionally, the learned score is sensitive to changes in severity leading up to septic shock and post treatment administration. PMID:26958288

  9. Sepsis and ARDS: The Dark Side of Histones

    PubMed Central

    Xu, Zhiheng; Huang, Yongbo; Mao, Pu; Zhang, Jianrong; Li, Yimin

    2015-01-01

    Despite advances in management over the last several decades, sepsis and acute respiratory distress syndrome (ARDS) still remain major clinical challenges and the leading causes of death for patients in intensive care units (ICUs) due to insufficient understanding of the pathophysiological mechanisms of these diseases. However, recent studies have shown that histones, also known as chromatin-basic structure proteins, could be released into the extracellular space during severe stress and physical challenges to the body (e.g., sepsis and ARDS). Due to their cytotoxic and proinflammatory effects, extracellular histones can lead to excessive and overwhelming cell damage and death, thus contributing to the pathogenesis of both sepsis and ARDS. In addition, antihistone-based treatments (e.g., neutralizing antibodies, activated protein C, and heparin) have shown protective effects and have significantly improved the outcomes of mice suffering from sepsis and ARDS. Here, we review researches related to the pathological role of histone in context of sepsis and ARDS and evaluate the potential value of histones as biomarkers and therapeutic targets of these diseases. PMID:26609197

  10. Reduced Production of Creatinine Limits Its Use as Marker of Kidney Injury in Sepsis

    PubMed Central

    Doi, Kent; Yuen, Peter S.T.; Eisner, Christoph; Hu, Xuzhen; Leelahavanichkul, Asada; Schnermann, Jürgen; Star, Robert A.

    2009-01-01

    Although diagnosis and staging of acute kidney injury uses serum creatinine, acute changes in creatinine lag behind both renal injury and recovery. The risk for mortality increases when acute kidney injury accompanies sepsis; therefore, we sought to explore the limitations of serum creatinine in this setting. In mice, induction of sepsis by cecal ligation and puncture in bilaterally nephrectomized mice increased markers of nonrenal organ injury and serum TNF-α. Serum creatinine, however, was significantly lower in septic animals than in animals subjected to bilateral nephrectomy and sham cecal ligation and puncture. Under these conditions treatment with chloroquine decreased nonrenal organ injury markers but paradoxically increased serum creatinine. Sepsis dramatically decreased production of creatinine in nephrectomized mice, without changes in body weight, hematocrit, or extracellular fluid volume. In conclusion, sepsis reduces production of creatinine, which blunts the increase in serum creatinine after sepsis, potentially limiting the early detection of acute kidney injury. This may partially explain why small absolute increases in serum creatinine levels are associated with poor clinical outcomes. These data support the need for new biomarkers that provide better measures of renal injury, especially in patients with sepsis. PMID:19389851

  11. Severe Sepsis in Severely Malnourished Young Bangladeshi Children with Pneumonia: A Retrospective Case Control Study

    PubMed Central

    Chisti, Mohammod Jobayer; Salam, Mohammed Abdus; Bardhan, Pradip Kumar; Faruque, Abu S. G.; Shahid, Abu S. M. S. B.; Shahunja, K. M.; Das, Sumon Kumar; Hossain, Md Iqbal; Ahmed, Tahmeed

    2015-01-01

    Background In developing countries, there is no published report on predicting factors of severe sepsis in severely acute malnourished (SAM) children having pneumonia and impact of fluid resuscitation in such children. Thus, we aimed to identify predicting factors for severe sepsis and assess the outcome of fluid resuscitation of such children. Methods In this retrospective case-control study SAM children aged 0–59 months, admitted to the Intensive Care Unit (ICU) of the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh from April 2011 through July 2012 with history of cough or difficult breathing and radiologic pneumonia, who were assessed for severe sepsis at admission constituted the study population. We compared the pneumonic SAM children with severe sepsis (cases = 50) with those without severe sepsis (controls = 354). Severe sepsis was defined with objective clinical criteria and managed with fluid resuscitation, in addition to antibiotic and other supportive therapy, following the standard hospital guideline, which is very similar to the WHO guideline. Results The case-fatality-rate was significantly higher among the cases than the controls (40% vs. 4%; p<0.001). In logistic regression analysis after adjusting for potential confounders, lack of BCG vaccination, drowsiness, abdominal distension, acute kidney injury, and metabolic acidosis at admission remained as independent predicting factors for severe sepsis in pneumonic SAM children (p<0.05 for all comparisons). Conclusion and Significance We noted a much higher case fatality among under-five SAM children with pneumonia and severe sepsis who required fluid resuscitation in addition to standard antibiotic and other supportive therapy compared to those without severe sepsis. Independent risk factors and outcome of the management of severe sepsis in our study children highlight the importance for defining optimal fluid resuscitation therapy aiming at reducing the case

  12. Bench-to-bedside review: the role of nitric oxide in sepsis.

    PubMed

    De Cruz, Sharon J; Kenyon, Nicholas J; Sandrock, Christian E

    2009-10-01

    Sepsis is a state of systemic inflammation directed at microbes or their toxins in blood or tissues. Nitric oxide (NO) is one of many vasoactive molecules released from a variety of cell types during sepsis. Almost two decades ago, NO emerged as a potential therapeutic target in sepsis. NO produced by the constitutive NO synthase (NOS) isoform (endothelial NOS and neuronal NOS) in the vascular endothelium and elsewhere acts as a nonadrenergic, noncholinergic neurotransmitter, an inhibitor of platelet aggregation and a vasodilator. During sepsis, activation of inducible NOS (iNOS) in the lung epithelium and other organs occurs, leading to NO overproduction. The result of excessive circulating NO is enhanced bacterial destruction, but also profound vasodilatation, activation of inflammatory cascades and depression of cardiac function. Trials of nonselective NOS inhibitors have shown increased mean arterial pressure, but also increased pulmonary artery pressure and reduced cardiac output. Small animal studies of iNOS selective inhibition have produced dichotomous results, but larger clinical studies assessing mortality are lacking. Inhaled NO has been touted as a therapeutic option to improve systemic oxygenation in the acute lung injury of sepsis (hypoxic pulmonary vasoconstriction and pulmonary hypertension); however, studies of inhaled NO in acute respiratory distress syndrome have not shown survival efficacy. Further investigation into the role of NO in human sepsis, and the development of methods to assess NO balance in patients with sepsis is essential in this field. In this review, we outline the effects of NO in sepsis, and summarize the therapeutic outcomes of NOS inhibitors, and inhaled NO in sepsis and acute respiratory distress syndrome. PMID:20477340

  13. The Role of Nephritis-Associated Plasmin Receptor (NAPlr) in Glomerulonephritis Associated with Streptococcal Infection

    PubMed Central

    Oda, Takashi; Yoshizawa, Nobuyuki; Yamakami, Kazuo; Sakurai, Yutaka; Takechi, Hanako; Yamamoto, Kojiro; Oshima, Naoki; Kumagai, Hiroo

    2012-01-01

    It is well known that glomerulonephritis can occur after streptococcal infection, which is classically referred to as acute poststreptococcal glomerulonephritis (APSGN). The pathogenic mechanism of APSGN has been described by so-called immune complex theory, which involves glomerular deposition of nephritogenic streptococcal antigen and subsequent formation of immune complexes in situ and/or the deposition of circulating antigen-antibody complexes. However, the exact entity of the causative antigen has remained a matter of debate. We isolated a nephritogenic antigen for APSGN from the cytoplasmic fractions of group A streptococcus (GAS) depending on the affinity for IgG of APSGN patients. The amino acid and the nucleotide sequences of the isolated protein revealed to be highly identical to those of reported plasmin(ogen) receptor of GAS. Thus, we termed this antigen nephritis-associated plasmin receptor (NAPlr). Immunofluorescence staining of the renal biopsy tissues with anti-NAPlr antibody revealed glomerular NAPlr deposition in essentially all patients with early-phase APSGN. Furthermore, glomerular plasmin activity was detected by in situ zymography in the distribution almost identical to NAPlr deposition in renal biopsy tissues of APSGN patients. These data suggest that NAPlr has a direct, nonimmunologic function as a plasmin receptor and may contribute to the pathogenesis of APSGN by maintaining plasmin activity. PMID:23118507

  14. Pulmonary Renal Syndrome After Streptococcal Pharyngitis: A Case Report.

    PubMed

    Mara-Koosham, Gopi; Stoltze, Karl; Aday, Jeffrey; Rendon, Patrick

    2016-01-01

    Pulmonary renal syndrome is a class of small vessel vasculitides that are characterized by the dual presentation of diffuse alveolar hemorrhage (DAH) and glomerulonephritis. Pulmonary renal syndrome has multiple etiologies, but its development has been rarely reported following infection with group A streptococcus. We present the case of a 36-year-old Native American male who was transferred to our facility due to refractory hypoxic respiratory failure. He had been diagnosed with streptococcal pharyngitis 2 weeks prior to admission. Given the presence of hemoptysis, bronchoscopy was performed and was consistent with DAH. Urinalysis demonstrated hematuria and proteinuria, in the setting of elevated creatinine and blood urea nitrogen. Additionally, antistreptolysin O titer was positive. Given the constellation of laboratory findings and history of streptococcal pharyngitis, the patient was diagnosed with PRS secondary to streptococcal infection. High-dose methylprednisolone was initiated with concomitant plasmapheresis. He was extubated successfully after his respiratory status improved and was eventually discharged home after making a full recovery within 2 weeks after admission. This case illustrates the importance of clinically relevant sequelae of streptococcal infection as well as the appropriate treatment of PRS secondary to streptococcal pharyngitis with plasmapheresis and intravenous corticosteroids. PMID:27231692

  15. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): An Evolving Concept.

    PubMed

    Macerollo, Antonella; Martino, Davide

    2013-01-01

    Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS) originated from the observational work of Swedo and collaborators, who formalized their definition in 1998 in a set of operational criteria. The application of these criteria, which focuses on tics and obsessive-compulsive symptoms as core symptoms, has encountered difficulties, eventually leading to a high rate of misdiagnosis. In particular, the core feature represented by the association between newly diagnosed infections and neuropsychiatric symptom relapses in youths with this diagnosis could not be demonstrated by longitudinal studies. Exploratory studies aiming to identify clinical or cognitive features that could discriminate PANDAS from other pediatric obsessive-compulsive and tic disorders present methodological limitations, and therefore are not conclusive. Other behavioral features, in addition to obsessive-compulsive symptoms and tics, have been included in pediatric acute-onset neuropsychiatric syndromes (PANS) and childhood acute neuropsychiatric syndromes (CANS), two new concepts recently proposed in order to define a much broader clinical spectrum encompassing etiologically diverse entities. Given the uncertainties on the clinical definition of PANDAS, it is not surprising that evidence in support of a post-infectious, immune-mediated pathophysiology is also insufficient. Anti-dopamine receptor antibodies might be relevant to both Sydenham's chorea (SC)-the prototypical post-streptococcal neuropsychiatric disorder-and some rare forms of encephalitis targeting the basal ganglia specifically, but studies exploring their association with children fulfilling Swedo's criteria for PANDAS have been inconclusive. Moreover, we lack evidence in favor of the efficacy of antibiotic prophylaxis or tonsillectomy in patients fulfilling Swedo's criteria for PANDAS, whereas a response to immune-mediated treatments like intravenous immunoglobulins has been documented by

  16. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): An Evolving Concept

    PubMed Central

    Macerollo, Antonella; Martino, Davide

    2013-01-01

    Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS) originated from the observational work of Swedo and collaborators, who formalized their definition in 1998 in a set of operational criteria. The application of these criteria, which focuses on tics and obsessive-compulsive symptoms as core symptoms, has encountered difficulties, eventually leading to a high rate of misdiagnosis. In particular, the core feature represented by the association between newly diagnosed infections and neuropsychiatric symptom relapses in youths with this diagnosis could not be demonstrated by longitudinal studies. Exploratory studies aiming to identify clinical or cognitive features that could discriminate PANDAS from other pediatric obsessive-compulsive and tic disorders present methodological limitations, and therefore are not conclusive. Other behavioral features, in addition to obsessive-compulsive symptoms and tics, have been included in pediatric acute-onset neuropsychiatric syndromes (PANS) and childhood acute neuropsychiatric syndromes (CANS), two new concepts recently proposed in order to define a much broader clinical spectrum encompassing etiologically diverse entities. Given the uncertainties on the clinical definition of PANDAS, it is not surprising that evidence in support of a post-infectious, immune-mediated pathophysiology is also insufficient. Anti-dopamine receptor antibodies might be relevant to both Sydenham’s chorea (SC)—the prototypical post-streptococcal neuropsychiatric disorder—and some rare forms of encephalitis targeting the basal ganglia specifically, but studies exploring their association with children fulfilling Swedo’s criteria for PANDAS have been inconclusive. Moreover, we lack evidence in favor of the efficacy of antibiotic prophylaxis or tonsillectomy in patients fulfilling Swedo’s criteria for PANDAS, whereas a response to immune-mediated treatments like intravenous immunoglobulins has been

  17. [A study on early-onset group "B" streptococcal neonatal infection].

    PubMed

    Vacheva, R; Todorova, M; Decheva, A; Yarakova, N; Kraleva, I; Takova, Ts; Dimitrova, N; Dobreva, A

    2012-01-01

    The results achieved with 80% reduction in the incidence of early-onset neonatal group B streptococcal (GBS) sepsis following the implementation of the preliminary (1996, 2002) and subsequently the revised (2010) guidelines for intrapartum antibiotic prophylaxis imposed the discussion on a large scale of the updated:--algorithms for GBS screening (35-37 weeks of gestation) with the recommended dosage of penicillin-G for intrapartum antibiotic prophylaxis for women having normal labor and delivery;--algorithms for GBS screening and intrapartum antibiotic prophylaxis for women with preterm labor (PPROM) or premature rupture of membranes (PROM);--intrapartum antibiotic prophylaxis regimens for women with penicillin allergy;--algorithm for management of newborns with respect to risk of early-onset GBS disease. The present study is aimed at studying the distribution of the early-onset GBS disease in our country based on the data of leading obstetrics & gynecology clinics and wards. The aim is to diferrentiate clinically the cases and investigate the influence of the known risk factors on the part of the mother. A special accent is put over the microbiological diagnostics of cases in view of CDC expanded recommendations on the laboratory methods for identification of GBS. As a final conclusion the necessity for introduction of an official registration of the early- and late-onset GBS disease in the country is emphasized. PMID:23390859

  18. Group A β-hemolytic streptococcal pharyngotonsillitis outbreak.

    PubMed

    Culqui, Dante R; Manzanares-Laya, Sandra; Van Der Sluis, Sarah Lafuente; Fanlo, Albert Anton; Comas, Rosa Bartolomé; Rossi, Marcello; Caylá, Joán A

    2014-04-01

    The aim was to describe an outbreak of group A β-hemolytic streptococcal pharyngotonsillitis in health care professionals. This is a cross-sectional descriptive study of 17 clients who dined at the same table in a restaurant in Barcelona in July 2012. The frequency, timing and severity of symptoms were analyzed, as were demographic variables and others concerning the food ingested. The attack rate was 58.8%. Six of the 10 clients were positive for group A β-hemolytic streptococcal. Six of the 13 individuals who handled the food involved in the dinner had symptoms. No association was identified with the food consumed. There is epidemiological evidence of foodborne group A β-hemolytic streptococcal transmission, but respiratory transmission could not be ruled out. PMID:24897054

  19. Group A β-hemolytic streptococcal pharyngotonsillitis outbreak

    PubMed Central

    Culqui, Dante R; Manzanares-Laya, Sandra; Van Der Sluis, Sarah Lafuente; Fanlo, Albert Anton; Comas, Rosa Bartolomé; Rossi, Marcello; Caylá, Joán A

    2014-01-01

    The aim was to describe an outbreak of group A β-hemolytic streptococcal pharyngotonsillitis in health care professionals. This is a cross-sectional descriptive study of 17 clients who dined at the same table in a restaurant in Barcelona in July 2012. The frequency, timing and severity of symptoms were analyzed, as were demographic variables and others concerning the food ingested. The attack rate was 58.8%. Six of the 10 clients were positive for group A β-hemolytic streptococcal. Six of the 13 individuals who handled the food involved in the dinner had symptoms. No association was identified with the food consumed. There is epidemiological evidence of foodborne group A β-hemolytic streptococcal transmission, but respiratory transmission could not be ruled out. PMID:24897054

  20. Synergistic inhibition of Streptococcal biofilm by ribose and xylitol.

    PubMed

    Lee, Heon-Jin; Kim, Se Chul; Kim, Jinkyung; Do, Aejin; Han, Se Yeong; Lee, Bhumgey David; Lee, Hyun Ho; Lee, Min Chan; Lee, So Hui; Oh, Taejun; Park, Sangbin; Hong, Su-Hyung

    2015-02-01

    Streptococcus mutans and Streptococcus sobrinus are the major causative agents of human dental caries. Therefore, the removal or inhibition of these streptococcal biofilms is essential for dental caries prevention. In the present study, we evaluated the effects of ribose treatment alone or in combination with xylitol on streptococcal biofilm formation for both species. Furthermore, we examined the expression of genes responsible for dextran-dependent aggregation (DDAG). In addition, we investigated whether ribose affects the biofilm formation of xylitol-insensitive streptococci, which results from long-term exposure to xylitol. The viability of streptococci biofilms formed in a 24-well polystyrene plate was quantified by fluorescent staining with the LIVE/DEAD bacterial viability and counting kit, which was followed by fluorescence activated cell sorting analysis. The effects of ribose and/or xylitol on the mRNA expression of DDAG-responsible genes, gbpC and dblB, was evaluated by RT-qPCR. Our data showed that ribose and other pentose molecules significantly inhibited streptococcal biofilm formation and the expression of DDAG-responsible genes. In addition, co-treatment with ribose and xylitol decreased streptococcal biofilm formation to a further extent than ribose or xylitol treatment alone in both streptococcal species. Furthermore, ribose attenuated the increase of xylitol-insensitive streptococcal biofilm, which results in the reduced difference of biofilm formation between S. mutans that are sensitive and insensitive to xylitol. These data suggest that pentose may be used as an additive for teeth-protective materials or in sweets. Furthermore, ribose co-treatment with xylitol might help to increase the anti-cariogenic efficacy of xylitol. PMID:25463908

  1. Group A streptococcal meningitis in a patient with palmoplantar pustulosis.

    PubMed

    Hagiya, Hideharu; Otsuka, Fumio

    2013-01-01

    A 64-year-old man with a 10-year history of palmoplantar pustulosis, a recent history of cranial surgery and a persistent upper airway infection presented with a high fever and deep coma. The patient was diagnosed with Group A Streptococcal meningitis and promptly treated with antibiotics. Although his general condition recovered well, sensorineural hearing loss and facial palsy remained. Group A Streptococcal meningitis is a rare condition, and its typical clinical picture and epidemiological features remain poorly understood. Physicians need to be more aware of this infection, which is extremely rare but frequently causes various complications and yields a high mortality. PMID:24292762

  2. Heparanase mediates renal dysfunction during early sepsis in mice

    PubMed Central

    Lygizos, Melissa I; Yang, Yimu; Altmann, Christopher J; Okamura, Kayo; Hernando, Ana Andres; Perez, Mario J; Smith, Lynelle P; Koyanagi, Daniel E; Gandjeva, Aneta; Bhargava, Rhea; Tuder, Rubin M; Faubel, Sarah; Schmidt, Eric P

    2013-01-01

    Heparanase, a heparan sulfate-specific glucuronidase, mediates the onset of pulmonary neutrophil adhesion and inflammatory lung injury during early sepsis. We hypothesized that glomerular heparanase is similarly activated during sepsis and contributes to septic acute kidney injury (AKI). We induced polymicrobial sepsis in mice using cecal ligation and puncture (CLP) in the presence or absence of competitive heparanase inhibitors (heparin or nonanticoagulant N-desulfated re-N-acetylated heparin [NAH]). Four hours after surgery, we collected serum and urine for measurement of renal function and systemic inflammation, invasively determined systemic hemodynamics, harvested kidneys for histology/protein/mRNA, and/or measured glomerular filtration by inulin clearance. CLP-treated mice demonstrated early activation of glomerular heparanase with coincident loss of glomerular filtration, as indicated by a >twofold increase in blood urea nitrogen (BUN) and a >50% decrease in inulin clearance (P < 0.05) in comparison to sham mice. Administration of heparanase inhibitors 2 h prior to CLP attenuated sepsis-induced loss of glomerular filtration rate, demonstrating that heparanase activation contributes to early septic renal dysfunction. Glomerular heparanase activation was not associated with renal neutrophil influx or altered vascular permeability, in marked contrast to previously described effects of pulmonary heparanase on neutrophilic lung injury during sepsis. CLP induction of renal inflammatory gene (IL-6, TNF-α, IL-1β) expression was attenuated by NAH pretreatment. While serum inflammatory indices (KC, IL-6, TNF-α, IL-1β) were not impacted by NAH pretreatment, heparanase inhibition attenuated the CLP-induced increase in serum IL-10. These findings demonstrate that glomerular heparanase is active during sepsis and contributes to septic renal dysfunction via mechanisms disparate from heparanase-mediated lung injury. PMID:24400155

  3. Sepsis-associated AKI: epithelial cell dysfunction.

    PubMed

    Emlet, David R; Shaw, Andrew D; Kellum, John A

    2015-01-01

    Acute kidney injury (AKI) occurs frequently in critically ill patients with sepsis, in whom it doubles the mortality rate and half of the survivors suffer permanent kidney damage or chronic kidney disease. Failure in the development of viable therapies has prompted studies to better elucidate the cellular and molecular etiologies of AKI, which have generated novel theories and paradigms for the mechanisms of this disease. These studies have shown multifaceted origins and elements of AKI that, in addition to/in lieu of ischemia, include the generation of damage-associated molecular patterns and pathogen-associated molecular patterns, the inflammatory response, humoral and cellular immune activation, perturbation of microvascular flow and oxidative stress, bioenergetic alterations, cell-cycle alterations, and cellular de-differentiation/re-differentiation. It is becoming clear that a major etiologic effector of all these inputs is the renal tubule epithelial cell (RTEC). This review discusses these elements and their effects on RTECs, and reviews the current hypotheses of how these effects may determine the fate of RTECs during sepsis-induced AKI. PMID:25795502

  4. The Italian SEPSIS study: preliminary results on the incidence and evolution of SIRS, sepsis, severe sepsis and septic shock.

    PubMed

    Salvo, I; de Cian, W; Musicco, M; Langer, M; Piadena, R; Wolfler, A; Montani, C; Magni, E

    1995-11-01

    This prospective, multicenter, epidemiological study was carried out in 99 Italian ICUs, distributed throughout the country, from April 1993 to March 1994. In the study, we applied the new ACCP/SCCM classification system for sepsis (SIRS, sepsis, severe sepsis and septic shock) and determined the prevalence, incidence, evolution and outcome of these categories in critically ill patients. The preliminary analysis of 1101 patients showed that on admission SIRS accounted for about half of the diagnoses (52%) with sepsis, severe sepsis and septic shock accounting for 4.5%, 2.1% and 3% of patients, respectively. Patients with severe sepsis or septic shock more frequently had high SAPS scores than patients without sepsis. Mortality rates were similar in patients with SIRS (26.5%) and without SIRS or infection (24%), but rose to 36% in patients with sepsis, to 52% in those with severe sepsis and to 81.8% in those with septic shock. Sepsis, severe sepsis and septic shock were more common in patients with medical diagnoses, and neither severe sepsis nor septic shock was observed in trauma patients. With respect to evolution, the incidence of septic shock was progressively higher in patients admitted with more severe "sepsis-related" diagnoses, while only a trivial difference in rates of incidence was observed between SIRS patients and those admitted without SIRS or any septic disorder (nil). The breakdown of the various ACCP/SCCM "sepsis-related" diagnoses at any time during the study was: SIRS in 58% of the population, sepsis in 16.3%, severe sepsis in 5.5% and septic shock in 6.1%. It seems reasonable to expect from the final evaluation of our study answers to the questions raised by the ACCP/SCCM Consensus Conference about the correlations between "sepsis-related" diagnosis, severity score, organ dysfunction score and outcome. PMID:8636531

  5. Reduced Immunocompetent B Cells and Increased Secondary Infection in Elderly Patients With Severe Sepsis.

    PubMed

    Suzuki, Kodai; Inoue, Shigeaki; Kametani, Yoshie; Komori, Yukako; Chiba, Sayuri; Sato, Takehito; Inokuchi, Sadaki; Ogura, Shinji

    2016-09-01

    Lymphocyte exhaustion was recently recognized as a mechanism of immunosuppression in sepsis. While B cells are known to play pivotal roles in bacterial infection and sepsis, changes in B-cell-mediated humoral immunity have not been evaluated in critically ill septic patients. We aimed to investigate changes in humoral immunity caused by defective B-cell function during severe sepsis. Thirty-three severe sepsis patients and 44 healthy subjects were prospectively enrolled. Blood was collected from patients within 72 h of and 8 to 11 h after sepsis onset to measure B-cell subtypes, serum immunoglobulin M concentration, and CpG-B oligodeoxynucleotide-induced immunoglobulin M (IgM) production ex vivo. Participants were divided into two age groups: adults (18-64 years) and elderly (≥65 years). The fraction of CD21 exhausted B cells in acute sepsis patients (3.18%) was higher than that observed in healthy donors (0.77%, respectively, P <0.01). Significantly, serum IgM in elderly septic patients (≥65 years) was negatively correlated with acute physiology and chronic health evaluation II score (r = -0.57, P <0.05). Consistently, in B cells stimulated ex vivo, both aging and sepsis induced significant reductions in supernatant IgM (P <0.01). This finding was clinically relevant, as elderly patients with decreased IgM production might be more susceptible to infection by Gram-negative bacteria and fungi. Reduced immunocompetent B cells may be related to increased secondary infection after sepsis, especially in the elderly. Finally, impaired humoral immunity with increased CD21 exhausted B cells and insufficient immunoglobulin M production may be a critical immunological change in sepsis. PMID:27172158

  6. Hyperuricemia: An Early Marker for Severity of Illness in Sepsis

    PubMed Central

    Akbar, Sana R.; Long, Dustin M.; Hussain, Kashif; Alhajhusain, Ahmad; Ahmed, Umair S.; Iqbal, Hafiz I.; Ali, Ailia W.; Leonard, Rachel; Dalton, Cheryl

    2015-01-01

    Background. Uric acid can acutely activate various inflammatory transcription factors. Since high levels of oxyradicals and lower antioxidant levels in septic patients are believed to result in multiorgan failure, uric acid levels could be used as a marker of oxidative stress and poor prognosis in patients with sepsis. Design. We conducted a prospective cohort study on Medical Intensive Care Unit (MICU) patients and hypothesized that elevated uric acid in patients with sepsis is predictive of greater morbidity. The primary end point was the correlation between hyperuricemia and the morbidity rate. Secondary end points were Acute Kidney Injury (AKI), mortality, Acute Respiratory Distress Syndrome (ARDS), and duration of stay. Results. We enrolled 144 patients. 54 (37.5%) had the primary end point of hyperuricemia. The overall morbidity rate was 85.2%. The probability of having hyperuricemia along with AKI was 68.5% and without AKI was 31.5%. Meanwhile the probability of having a uric acid value <7 mg/dL along with AKI was 18.9% and without AKI was 81.1% (p value < 0.0001). Conclusion. We report that elevated uric acid levels on arrival to the MICU in patients with sepsis are associated with poor prognosis. These patients are at an increased risk for AKI and ARDS. PMID:26294973

  7. Role of presepsin for the evaluation of sepsis in the emergency department.

    PubMed

    Pizzolato, Elisa; Ulla, Marco; Galluzzo, Claudia; Lucchiari, Manuela; Manetta, Tilde; Lupia, Enrico; Mengozzi, Giulio; Battista, Stefania

    2014-10-01

    Sepsis, severe sepsis and septic shock are among the most common conditions handled in the emergency department (ED). According to new Sepsis Guidelines, early diagnosis and treatment are the keys to improve survival. Plasma C-reactive protein (CRP) and procalcitonin (PCT) levels, when associated with documented or suspected infection, are now part of the definitions of sepsis. Blood culture is the gold standard method for detecting microorganisms but it requires too much time for results to be known. Sensitive biomarkers are required for early diagnosis and as indexes of prognosis sepsis. CRP is one of the acute phase proteins synthesized by the liver: it has a great sensitivity but a very poor specificity for bacterial infections. Moreover, the evolution of sepsis does not correlate with CRP plasma changes. In recent years PCT has been widely used for sepsis differential diagnosis, because of its close correlation with infections, but it still retains some limitations and false positivity (such as in multiple trauma and burns). Soluble CD14 subtype (sCD14-ST), also known as presepsin, is a novel and promising biomarker that has been shown to increase significantly in patients with sepsis, in comparison to the healthy population. Studies pointed out the capability of this biomarker for diagnosing sepsis, assessing the severity of the disease and providing a prognostic evaluation of patient outcome. In this mini review we mainly focused on presepsin: we evaluate its diagnostic and prognostic roles in patients presenting to the ED with systemic inflammatory response syndrome (SIRS), suspected sepsis or septic shock. PMID:24897403

  8. Antimicrobial Peptides in Human Sepsis.

    PubMed

    Martin, Lukas; van Meegern, Anne; Doemming, Sabine; Schuerholz, Tobias

    2015-01-01

    Nearly 100 years ago, antimicrobial peptides (AMPs) were identified as an important part of innate immunity. They exist in species from bacteria to mammals and can be isolated in body fluids and on surfaces constitutively or induced by inflammation. Defensins have anti-bacterial effects against Gram-positive and Gram-negative bacteria as well as anti-viral and anti-yeast effects. Human neutrophil peptides (HNP) 1-3 and human beta-defensins (HBDs) 1-3 are some of the most important defensins in humans. Recent studies have demonstrated higher levels of HNP 1-3 and HBD-2 in sepsis. The bactericidal/permeability-increasing protein (BPI) attenuates local inflammatory response and decreases systemic toxicity of endotoxins. Moreover, BPI might reflect the severity of organ dysfunction in sepsis. Elevated plasma lactoferrin is detected in patients with organ failure. HNP 1-3, lactoferrin, BPI, and heparin-binding protein are increased in sepsis. Human lactoferrin peptide 1-11 (hLF 1-11) possesses antimicrobial activity and modulates inflammation. The recombinant form of lactoferrin [talactoferrin alpha (TLF)] has been shown to decrease mortality in critically ill patients. A phase II/III study with TLF in sepsis did not confirm this result. The growing number of multiresistant bacteria is an ongoing problem in sepsis therapy. Furthermore, antibiotics are known to promote the liberation of pro-inflammatory cell components and thus augment the severity of sepsis. Compared to antibiotics, AMPs kill bacteria but also neutralize pathogenic factors such as lipopolysaccharide. The obstacle to applying naturally occurring AMPs is their high nephro- and neurotoxicity. Therefore, the challenge is to develop peptides to treat septic patients effectively without causing harm. This overview focuses on natural and synthetic AMPs in human and experimental sepsis and their potential to provide significant improvements in the treatment of critically ill with severe infections. PMID

  9. Antimicrobial Peptides in Human Sepsis

    PubMed Central

    Martin, Lukas; van Meegern, Anne; Doemming, Sabine; Schuerholz, Tobias

    2015-01-01

    Nearly 100 years ago, antimicrobial peptides (AMPs) were identified as an important part of innate immunity. They exist in species from bacteria to mammals and can be isolated in body fluids and on surfaces constitutively or induced by inflammation. Defensins have anti-bacterial effects against Gram-positive and Gram-negative bacteria as well as anti-viral and anti-yeast effects. Human neutrophil peptides (HNP) 1–3 and human beta-defensins (HBDs) 1–3 are some of the most important defensins in humans. Recent studies have demonstrated higher levels of HNP 1–3 and HBD-2 in sepsis. The bactericidal/permeability-increasing protein (BPI) attenuates local inflammatory response and decreases systemic toxicity of endotoxins. Moreover, BPI might reflect the severity of organ dysfunction in sepsis. Elevated plasma lactoferrin is detected in patients with organ failure. HNP 1–3, lactoferrin, BPI, and heparin-binding protein are increased in sepsis. Human lactoferrin peptide 1–11 (hLF 1–11) possesses antimicrobial activity and modulates inflammation. The recombinant form of lactoferrin [talactoferrin alpha (TLF)] has been shown to decrease mortality in critically ill patients. A phase II/III study with TLF in sepsis did not confirm this result. The growing number of multiresistant bacteria is an ongoing problem in sepsis therapy. Furthermore, antibiotics are known to promote the liberation of pro-inflammatory cell components and thus augment the severity of sepsis. Compared to antibiotics, AMPs kill bacteria but also neutralize pathogenic factors such as lipopolysaccharide. The obstacle to applying naturally occurring AMPs is their high nephro- and neurotoxicity. Therefore, the challenge is to develop peptides to treat septic patients effectively without causing harm. This overview focuses on natural and synthetic AMPs in human and experimental sepsis and their potential to provide significant improvements in the treatment of critically ill with severe infections

  10. Rationale and design of the African group A streptococcal infection registry: the AFROStrep study

    PubMed Central

    Barth, Dylan D; Engel, Mark E; Whitelaw, Andrew; Alemseged, Abdissa; Sadoh, Wilson E; Ali, Sulafa K M; Sow, Samba O; Dale, James; Mayosi, Bongani M

    2016-01-01

    Introduction Group A β-haemolytic Streptococcus (GAS), a Gram-positive bacterium, also known as Streptococcus pyogenes, causes pyoderma, pharyngitis and invasive disease. Repeated GAS infections may lead to autoimmune diseases such as acute post-streptococcal glomerulonephritis, acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Invasive GAS (iGAS) disease is an important cause of mortality and morbidity worldwide. The burden of GAS infections is, however, unknown in Africa because of lack of surveillance systems. Methods and analysis The African group A streptococcal infection registry (the AFROStrep study) is a collaborative multicentre study of clinical, microbiological, epidemiological and molecular characteristics for GAS infection in Africa. The AFROStrep registry comprises two components: (1) active surveillance of GAS pharyngitis cases from sentinel primary care centres (non-iGAS) and (2) passive surveillance of iGAS disease from microbiology laboratories. Isolates will also be subjected to DNA isolation to allow for characterisation by molecular methods and cryopreservation for long-term storage. The AFROStrep study seeks to collect comprehensive data on GAS isolates in Africa. The biorepository will serve as a platform for vaccine development in Africa. Ethics and dissemination Ethics approval for the AFROStrep registry has been obtained from the Human Research Ethics Committee at the University of Cape Town (HREC/REF: R006/2015). Each recruiting site will seek ethics approval from their local ethics’ committee. All participants will be required to provide consent for inclusion into the registry as well as for the storage of isolates and molecular investigations to be conducted thereon. Strict confidentiality will be applied throughout. Findings and updates will be disseminated to collaborators, researchers, health planners and colleagues through peer-reviewed journal articles, conference publications and proceedings. PMID:26916694

  11. Autoimmune neurological disorders associated with group-A beta-hemolytic streptococcal infection.

    PubMed

    Hachiya, Yasuo; Miyata, Rie; Tanuma, Naoyuki; Hongou, Kazuhisa; Tanaka, Keiko; Shimoda, Konomi; Kanda, Sachiko; Hoshino, Ai; Hanafusa, Yukiko; Kumada, Satoko; Kurihara, Eiji; Hayashi, Masaharu

    2013-08-01

    Although central nervous system (CNS) disorders associated with group-A beta-hemolytic streptococcal (GABHS) infection occur only rarely, Sydenham's chorea is a well-recognized disease that can arise following infection. Children may develop a tic, obsessive compulsive disorder (OCD), and extrapyramidal movement subsequent to GABHS infection. These disorders have been termed pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS). Herein we report one case each of acute disseminated encephalomyelitis (ADEM), PANDAS and subacute encephalitis associated with GABHS infection. To evaluate the pathogenesis of the CNS disorders associated with GABHS infection, we measured levels of neurotransmitters, cytokines, anti-neuronal autoantibodies, and performed immunohistochemistry using patient sera to stain human brain sections. All three cases showed psychiatric behavioral disorders. Immunotherapy was effective, and homovanillic acid levels in the cerebrospinal fluid (CSF) were elevated at the acute stage in all three cases. In each case of ADEM and PANDAS, immunohistochemistry demonstrated neuronal impairment in the basal ganglia during the acute stage. Neuronal immunoreactivity was visualized in the cerebral cortex at the acute stage in the case of subacute encephalitis. There was no direct correlation between immunoreactivity of patient sera on the brain sections and positivity of anti-neuronal autoantibodies or CSF biomarkers. The results suggest that autoimmune responses may modulate neurotransmission, and the use of patient serum for immunohistochemistry is a sensitive screening method for the detection of anti-neuronal autoantibodies in CNS disorders associated with GABHS infection. PMID:23142103

  12. Antibiotic Stewardship: Reassessment of Guidelines for Management of Neonatal Sepsis

    PubMed Central

    Cotten, C. Michael

    2016-01-01

    Since publication of the first Guidelines to Prevent Perinatal Group B Strep (GBS) disease in 1996, the incidence and mortality from early onset sepsis (EOS), and particularly GBS, the leading cause of EOS, has drastically decreased. In 2010, the Centers for Disease Control (CDC) provided updated Guidelines for the prevention of perinatal Group B streptococcal disease. In 2012, the AAP Committee on Fetus and Newborn (COFN) provided a Clinical Report that provided a thorough review of EOS and voiced overall support of the 2010 CDC Guidelines. In addition, the COFN authors suggested an approach different from the 2010 CDC Guidelines for at-risk asymptomatic infants. The COFN also ventured into the uncertain territory of recommending longer duration of empirical antibiotic treatment for asymptomatic infants with negative cultures, but abnormal CBC and/or CRP values. With the current focus on antibiotic stewardship, the 2012 COFN Clinical Report algorithms evoked questions from the Neonatology community. The COFN has recently responded with modified recommendations for empirical antibiotic duration and explanations for the recommendations for use of antibiotics in subgroups of infants for whom the CDC did not recommend starting antibiotics. Our goal in this article is to review the 2010 CDC and 2012 COFN guidelines and COFN's recently published guideline modifications and discuss mechanisms that may reduce the number of term and near term infants to be started on antibiotics. PMID:25678005

  13. Soluble Suppression of Tumorigenicity 2 and Echocardiography in Sepsis.

    PubMed

    Yang, Hyun Suk; Hur, Mina; Kim, Hanah; Magrini, Laura; Marino, Rossella; Di Somma, Salvatore

    2016-11-01

    Soluble suppression of tumorigenicity 2 (sST2) has emerged as a biomarker of cardiac stretch or remodeling, and has demonstrated a role in acutely decompensated heart failure. However, its role in sepsis-induced cardiac dysfunction is still unknown. We explored whether sST2 serum concentration reflects either systolic or diastolic dysfunction as measured by Doppler echocardiography. In a total of 127 patients with sepsis, correlations between sST2 and blood pressure, left ventricular (LV) ejection fraction, LV diastolic filling (ratio of early transmitral flow velocity to early diastolic mitral annulus velocity), and resting pulmonary arterial pressure were evaluated. Correlations between sST2 and other sepsis biomarkers (high-sensitivity C-reactive protein [hs-CRP] and procalcitonin) were also examined. sST2 showed a moderate correlation with mean arterial pressure (r=-0.3499) but no correlation with LV ejection fraction, diastolic filling, or resting pulmonary hypertension. It showed moderate correlations with hs-CRP and procalcitonin (r=0.2608 and r=0.3829, respectively). sST2 might have a role as a biomarker of shock or inflammation, but it cannot reflect echocardiographic findings of LV ejection fraction or diastolic filling in sepsis. PMID:27578513

  14. Post-streptococcal autoimmune disorders of the central nervous system.

    PubMed

    Dale, Russell C

    2005-11-01

    Group A Streptococcus can induce autoimmune disease in humans with particular involvement of the heart, joints, and brain. The spectrum of post-streptococcal disease of the central nervous system (CNS) has been widened recently and includes movement disorders (chorea, tics, dystonia, and Parkinsonism), psychiatric disorders (particularly emotional disorders), and associated sleep disorders. Neuroimaging and pathological studies indicate that the most vulnerable brain region is the basal ganglia. The immunopathogenesis of the disease is incompletely defined, and although there is some support for autoantibody-mediated disease, several conflicting studies cast doubt on the autoantibody hypothesis. It has been speculated that post-streptococcal autoimmunity has a role in common neuropsychiatric disease but the evidence is conflicting and routine screening of patients with Tourette syndrome and obsessive-compulsive disorder for post-streptococcal autoimmune abnormalities is not be recommended at present. However, post-streptococcal disorders of the CNS remain a useful model of neuropsychiatric disease, which may improve our understanding of abnormal movements and behaviours in children. PMID:16225745

  15. Atypical streptococcal infection of gingiva associated with chronic mouth breathing.

    PubMed

    Haytac, M Cenk; Oz, I Attila

    2007-01-01

    Streptococcal infections of oral tissues are mainly seen in young children who experience a variety of upper respiratory tract infections. The disease is characterized by fever, lymphadenopathy, and ulcers on the gingiva, lips, and tonsils. This case report presents an atypical streptococcal infection of the gingiva in an 18-year-old man. The patient was referred to the periodontology department complaining of a 2-month history of gingival enlargement. He had persistent fever (39.5 degrees C) and general malaise for 2 weeks. Intraoral examination revealed extremely inflamed and enlarged gingiva with spontaneous bleeding and suppuration. Based on the otolaryngologic consultation and the hematologic, immunologic, and microbiologic tests, the final diagnosis was an atypical streptococcal gingivitis with chronic adenoid-related mouth breathing and oral hygiene neglect as contributing factors. Treatment consisted of a broad-spectrum antibiotic regimen, supragingival and subgingival debridement, adenoidectomy, and scaling and root planing. A good response to nonsurgical therapy was achieved despite poor patient compliance, and no recurrence of gingival enlargement was observed after 1 year. Streptococcal gingivitis should be included in the differential diagnosis of suppurative gingival enlargements. Furthermore, chronic mouth breathing may initiate and/or contribute to this disease. PMID:18197316

  16. Sepsis-induced morbidity in mice: effects on body temperature, body weight, cage activity, social behavior and cytokines in brain

    PubMed Central

    Granger, Jill I.; Ratti, Pietro-Luca; Datta, Subhash C.; Raymond, Richard M.; Opp, Mark R.

    2012-01-01

    Infection negatively impacts mental health, as evidenced by the lethargy, malaise, and cognitive deficits experienced during illness. These changes in central nervous system processes, collectively termed sickness behavior, have been shown in animal models to be mediated primarily by the actions of cytokines in brain. Most studies of sickness behavior to date have used bolus injection of bacterial lipopolysaccharide (LPS) or selective administration of the proinflammatory cytokines interleukin-1β (IL-1β) or IL-6 as the immune challenge. Such models, although useful for determining mechanisms responsible for acute changes in physiology and behavior, do not adequately represent the more complex effects on central nervous system (CNS) processes of a true infection with replicating pathogens. In the present study, we used the cecal ligation and puncture (CLP) model to quantify sepsis-induced alterations in several facets of physiology and behavior of mice. We determined the impact of sepsis on cage activity, body temperature, food and water consumption and body weights of mice. Because cytokines are critical mediators of changes in behavior and temperature regulation during immune challenge, we also quantified sepsis-induced alterations in cytokine mRNA and protein in brain during the acute period of sepsis onset. We now report that cage activity and temperature regulation in mice that survive are altered for up to 23 days after sepsis induction. Food and water consumption are transiently reduced, and body weight is lost during sepsis. Furthermore, sepsis decreases social interactions for 24 – 48 hours. Finally, mRNA and protein for IL-1β, IL-6, and tumor necrosis factor-α (TNFα) are upregulated in the hypothalamus, hippocampus, and brain stem during sepsis onset, from 6–72 hour post sepsis induction. Collectively, these data indicate that sepsis not only acutely alters physiology, behavior and cytokine profiles in brain, but that some brain functions are

  17. Fast Action Can Prevent Sepsis Death: CDC

    MedlinePlus

    ... fullstory_160574.html Fast Action Can Prevent Sepsis Death: CDC Know the signs of extreme response to ... treated long before it causes severe illness or death, U.S. health officials report. Sepsis, or septicemia, occurs ...

  18. Sepsis caused by Flavimonas oryzihabitans.

    PubMed

    Lucas, K G; Kiehn, T E; Sobeck, K A; Armstrong, D; Brown, A E

    1994-07-01

    Previous reports of F. oryzihabitans sepsis involving central venous access devices reveal a relatively high rate of complications, including device removal, despite a course of broad-spectrum anti-microbials with compatible in vitro susceptibility results. In the present report of 22 cases of F. oryzihabitans sepsis treated at Memorial Sloan-Kettering Cancer Center from February 1986 through September 1993, the majority of CVAD-related infections with F. oryzihabitans were successfully treated with a 14-day course of antimicrobials with antipseudomonal activity, and removal of the device was usually not required. Factors that may complicate successful treatment of CVAD-related sepsis caused by F. oryzihabitans include polymicrobial infections and premature discontinuation of antibiotic therapy. PMID:8041243

  19. Transfusion-associated bacterial sepsis.

    PubMed Central

    Wagner, S J; Friedman, L I; Dodd, R Y

    1994-01-01

    The incidence of sepsis caused by transfusion of bacterially contaminated blood components is similar to or less than that of transfusion-transmitted hepatitis C virus infection, yet significantly exceeds those currently estimated for transfusion-associated human immunodeficiency and hepatitis B viruses. Outcomes are serious and may be fatal. In addition, transfusion of sterile allogenic blood can have generalized immunosuppressive effects on recipients, resulting in increased susceptibility to postoperative infection. This review examines the frequency of occurrence of transfusion-associated sepsis, the organisms implicated, and potential sources of bacteria. Approaches to minimize the frequency of sepsis are discussed, including the benefits and disadvantages of altering the storage conditions for blood. In addition, the impact of high levels of bacteria on the gross characteristics of erythrocyte and platelet concentrates is described. The potentials and limitations of current tests for detecting bacteria in blood are also discussed. PMID:7923050

  20. Rheumatic fever, autoimmunity, and molecular mimicry: the streptococcal connection.

    PubMed

    Cunningham, Madeleine W

    2014-01-01

    The group A streptococcus, Streptococcus pyogenes, and its link to autoimmune sequelae, has acquired a new level of understanding. Studies support the hypothesis that molecular mimicry between the group A streptococcus and heart or brain are important in directing immune responses in rheumatic fever. Rheumatic carditis, Sydenham chorea and a new group of behavioral disorders called pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections are reviewed with consideration of autoantibody and T cell responses and the role of molecular mimicry between the heart, brain and group A streptococcus as well as how immune responses contribute to pathogenic mechanisms in disease. In rheumatic carditis, studies have investigated human monoclonal autoantibodies and T cell clones for their crossreactivity and their mechanisms leading to valve damage in rheumatic heart disease. Although studies of human and animal sera from group A streptococcal diseases or immunization models have been crucial in providing clues to molecular mimicry and its role in the pathogenesis of rheumatic fever, study of human monoclonal autoantibodies have provided important insights into how antibodies against the valve may activate the valve endothelium and lead to T cell infiltration. Passive transfer of anti-streptococcal T cell lines in a rat model of rheumatic carditis illustrates effects of CD4+ T cells on the valve. Although Sydenham chorea has been known as the neurological manifestation of rheumatic fever for decades, the combination of autoimmunity and behavior is a relatively new concept linking brain, behavior and neuropsychiatric disorders with streptococcal infections. In Sydenham chorea, human mAbs and their expression in transgenic mice have linked autoimmunity to central dopamine pathways as well as dopamine receptors and dopaminergic neurons in basal ganglia. Taken together, the studies reviewed provide a basis for understanding streptococcal sequelae and

  1. The interplay between microbiota and inflammation: lessons from peritonitis and sepsis

    PubMed Central

    Lobo, Leandro A; Benjamim, Claudia F; Oliveira, Ana Carolina

    2016-01-01

    Mammals harbor a complex gut-associated microbiota, comprising bacteria that provide immunological, metabolic and neurological benefits to the host, and contribute to their well-being. However, dysregulation of the microbiota composition, known as dysbiosis, along with the associated mucosal immune response have a key role in the pathogenesis of many inflammatory diseases, including inflammatory bowel diseases (IBDs), type 1 and type 2 diabetes, asthma, multiple sclerosis, among others. In addition, outside the gut lumen, bacteria from microbiota are the causative agent of peritoneal inflammation, abdominal sepsis and systemic sepsis. Critical care interventions during sepsis by antibiotics induce dysbiosis and present acute and long-term poor prognosis. In this review, we discuss immunomodulatory effects of the microbial molecules and products, highlighting the role of Bacteroides fragilis, a human commensal with ambiguous interactions with the host. Moreover, we also address the impact of antibiotic treatment in sepsis outcome and discuss new insights for microbiota modulation. PMID:27525063

  2. The interplay between microbiota and inflammation: lessons from peritonitis and sepsis.

    PubMed

    Lobo, Leandro A; Benjamim, Claudia F; Oliveira, Ana Carolina

    2016-07-01

    Mammals harbor a complex gut-associated microbiota, comprising bacteria that provide immunological, metabolic and neurological benefits to the host, and contribute to their well-being. However, dysregulation of the microbiota composition, known as dysbiosis, along with the associated mucosal immune response have a key role in the pathogenesis of many inflammatory diseases, including inflammatory bowel diseases (IBDs), type 1 and type 2 diabetes, asthma, multiple sclerosis, among others. In addition, outside the gut lumen, bacteria from microbiota are the causative agent of peritoneal inflammation, abdominal sepsis and systemic sepsis. Critical care interventions during sepsis by antibiotics induce dysbiosis and present acute and long-term poor prognosis. In this review, we discuss immunomodulatory effects of the microbial molecules and products, highlighting the role of Bacteroides fragilis, a human commensal with ambiguous interactions with the host. Moreover, we also address the impact of antibiotic treatment in sepsis outcome and discuss new insights for microbiota modulation. PMID:27525063

  3. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis.

    PubMed

    Cheng, Shih-Chin; Scicluna, Brendon P; Arts, Rob J W; Gresnigt, Mark S; Lachmandas, Ekta; Giamarellos-Bourboulis, Evangelos J; Kox, Matthijs; Manjeri, Ganesh R; Wagenaars, Jori A L; Cremer, Olaf L; Leentjens, Jenneke; van der Meer, Anne J; van de Veerdonk, Frank L; Bonten, Marc J; Schultz, Marcus J; Willems, Peter H G M; Pickkers, Peter; Joosten, Leo A B; van der Poll, Tom; Netea, Mihai G

    2016-04-01

    The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might represent a therapeutic target in sepsis. PMID:26950237

  4. Vitamin D level and risk of community-acquired pneumonia and sepsis.

    PubMed

    Jovanovich, Anna J; Ginde, Adit A; Holmen, John; Jablonski, Kristen; Allyn, Rebecca L; Kendrick, Jessica; Chonchol, Michel

    2014-06-01

    Previous research has reported reduced serum 25-hydroxyvitamin D (25(OH)D) levels is associated with acute infectious illness. The relationship between vitamin D status, measured prior to acute infectious illness, with risk of community-acquired pneumonia (CAP) and sepsis has not been examined. Community-living individuals hospitalized with CAP or sepsis were age-, sex-, race-, and season-matched with controls. ICD-9 codes identified CAP and sepsis; chest radiograph confirmed CAP. Serum 25(OH)D levels were measured up to 15 months prior to hospitalization. Regression models adjusted for diabetes, renal disease, and peripheral vascular disease evaluated the association of 25(OH)D levels with CAP or sepsis risk. A total of 132 CAP patients and controls were 60 ± 17 years, 71% female, and 86% Caucasian. The 25(OH)D levels <37 nmol/L (adjusted odds ratio (OR) 2.57, 95% CI 1.08-6.08) were strongly associated with increased odds of CAP hospitalization. A total of 422 sepsis patients and controls were 65 ± 14 years, 59% female, and 91% Caucasian. The 25(OH)D levels <37 nmol/L (adjusted OR 1.75, 95% CI 1.11-2.77) were associated with increased odds of sepsis hospitalization. Vitamin D status was inversely associated with risk of CAP and sepsis hospitalization in a community-living adult population. Further clinical trials are needed to evaluate whether vitamin D supplementation can reduce risk of infections, including CAP and sepsis. PMID:24918697

  5. Antihypertensive agents acting on the renin–angiotensin system and the risk of sepsis

    PubMed Central

    Dial, Sandra; Nessim, Sharon J; Kezouh, Abbas; Benisty, Jacques; Suissa, Samy

    2014-01-01

    Aims In response to safety concerns from two large randomized controlled trials, we investigated whether the use of telmisartan, an angiotensin receptor blocker (ARB), ARBs as a class and angiotensin-converting enzyme inhibitors (ACEIs) increase the risk of sepsis, sepsis-associated mortality and renal failure in hypertensive patients. Methods We performed a nested case–control study from a retrospective cohort of adults with hypertension from the UK General Practice Research Database diagnosed between 1 January 2000 and 30 June 2009. All subjects hospitalized with sepsis during follow-up were matched for age, sex, practice and duration of follow-up with 10 control subjects. Exposure was defined as current use of antihypertensive drugs. Results From the cohort of 550 436 hypertensive patients, 1965 were hospitalized with sepsis during follow-up (rate 6.9 per 10 000 per year), of whom 824 died and 346 developed acute renal failure within 30 days. Compared with use of β-blockers, calcium-channel blockers or diuretics, use of ARBs, including telmisartan, was not associated with an elevated risk of sepsis (relative risk 1.09; 95% confidence interval 0.83–1.43); but use ACEIs was (relative risk 1.65; 95% confidence interval 1.42–1.93). Users of ARBs, β-blockers, calcium-channel blockers or diuretics, but not users of ACEIs, had lower rates of hospitalization for sepsis compared with untreated hypertensive patients. Findings were similar for sepsis-related 30 day mortality and renal failure. Conclusions Hypertensive patients treated with ARBs, including telmisartan, do not appear to be at increased risk of sepsis or sepsis-related 30 day mortality or renal failure. On the contrary, users of ACEIs may have an increased risk. PMID:24803383

  6. Therapeutic effects of compound hypertonic saline on rats with sepsis.

    PubMed

    Dong, Fang; Chen, Wei; Xu, Liang; Wang, Huabing; Lu, Huizhi

    2014-01-01

    Sepsis is one of the major causes of death and is the biggest obstacle preventing improvement of the success rate in curing critical illnesses. Currently, isotonic solutions are used in fluid resuscitation technique. Several studies have shown that hypertonic saline applied in hemorrhagic shock can rapidly increase the plasma osmotic pressure, facilitate the rapid return of interstitial fluid into the blood vessels, and restore the effective circulating blood volume. Here, we established a rat model of sepsis by using the cecal ligation and puncture approach. We found that intravenous injection of hypertonic saline dextran (7.5% NaCl/6% dextran) after cecal ligation and puncture can improve circulatory failure at the onset of sepsis. We found that the levels of tumor necrosis factor-α, interleukin-1β, interleukin-6 and intracellular adhesion molecule 1 levels in the lung tissue of cecal ligation and puncture rats treated with hypertonic saline dextran were significantly lower than the corresponding levels in the control group. We inferred that hypertonic saline dextran has a positive immunoregulatory effect and inhibits the overexpression of the inflammatory response in the treatment of sepsis. The percentage of neutrophils, lung myeloperoxidase activity, wet to dry weight ratio of lung tissues, histopathological changes in lung tissues, and indicators of arterial blood gas analysis was significantly better in the hypertonic saline dextran-treated group than in the other groups in this study. Hypertonic saline dextran-treated rats had significantly improved survival rates at 9 and 18 h compared to the control group. Our results suggest that hypertonic saline dextran plays a protective role in acute lung injury caused after cecal ligation and puncture. In conclusion, hypertonic/hyperoncotic solutions have beneficial therapeutic effects in the treatment of an animal model of sepsis. PMID:24983672

  7. Scintigraphic evaluation in musculoskeletal sepsis

    SciTech Connect

    Merkel, K.D.; Fitzgerald, R.H. Jr.; Brown, M.L.

    1984-07-01

    In this article, the mechanism of technetium, gallium, and indium-labeled white blood cell localization in septic processes is detailed, and the method of interpretation of these three isotopes with relationship to musculoskeletal infection is outlined. Specific clinical application of technetium, gallium, and indium-labeled white blood cell imaging for musculoskeletal sepsis is reviewed.

  8. The role of the liver in sepsis

    PubMed Central

    Yan, Jun; Li, Song; Li, Shulin

    2014-01-01

    Despite the progress made in the clinical management of sepsis, sepsis morbidity and mortality rates remain high. The inflammatory pathogenesis and organ injury leading to death from sepsis are not fully understood for vital organs, especially the liver. Only recently has the role of the liver in sepsis begun to be revealed. Pre-existing liver dysfunction is a risk factor for the progression of infection to sepsis. Liver dysfunction after sepsis is an independent risk factor for multiple organ dysfunction and sepsis-induced death. The liver works as a lymphoid organ in response to sepsis. Acting as a double-edged sword in sepsis, the liver-mediated immune response is responsible for clearing bacteria and toxins but also causes inflammation, immunosuppression, and organ damage. Attenuating liver injury and restoring liver function lowers morbidity and mortality rates in patients with sepsis. This review summarizes the central role of liver in the host immune response to sepsis and in clinical outcomes. PMID:24611785

  9. New approaches to the study of sepsis

    PubMed Central

    Ward, Peter A

    2012-01-01

    Models of sepsis have been instructive in understanding the sequence of events in animals and, to an extent, in humans with sepsis. Events developing early in sepsis suggest that a hyperinflammatory state exists, accompanied by a buildup of oxidants in tissues reflective of a redox imbalance. Development of immunosuppression and degraded innate and adaptive immune responses are well-established complications of sepsis. In addition, there is robust activation of the complement system, which contributes to the harmful effects of sepsis. These events appear to be associated with development of multiorgan failure. The relevance of animal models of sepsis to human sepsis and the failure of human clinical trials are discussed, together with suggestions as to how clinical trial design might be improved. PMID:23208733

  10. Antibody to streptococcal cysteine proteinase as a seromarker of group A Streptococcal (Streptococcus pyogenes) infections.

    PubMed

    Batsford, Stephen; Brundiers, Mechtild; Schweier, Oliver; Horbach, Elmar; Mönting, Jürgen Schulte

    2002-01-01

    Serological tests are commonly employed to aid the diagnosis of Streptococcus pyogenes infections, particularly when non-suppurative sequelae are suspected. Conventional laboratory practice is to measure antibody levels to various combinations of the extracellular group A Streptococcus (GAS) antigens streptolysin O (SLO), DNase B, streptokinase and hyaluronidase. Antibody to the extracellular cysteine proteinase streptococcal pyrogenic exotoxin B (SPE B) and its precursor zymogen is also produced in response to GAS infections. An indirect hemagglutination test for antibody to zymogen/SPE B was established and evaluated in serum samples from 168 patients with proven (n = 27) or suspected GAS (n = 141) infections, which were also screened for antibodies using the 4 conventional tests. For comparison, sera from 56 patients infected with a variety of other pathogens, as well as sera from 16 patients infected with either S. agalactiae or S. pneumoniae and 34 sera from healthy subjects, were tested. Statistical analysis confirmed that antibody to zymogen/SPE B is a serological marker that can discriminate GAS infections. It can be ranked with the anti-SLO titer, currently the most widely used test, as a marker of an antecedent GAS infection. PMID:12160165

  11. Restless legs syndrome: association with streptococcal or mycoplasma infection.

    PubMed

    Matsuo, Muneaki; Tsuchiya, Katsunori; Hamasaki, Yuhei; Singer, Harvey S

    2004-08-01

    Group A beta-hemolytic streptococcal infections have been reported to cause neuropsychiatric symptoms, such as chorea, tics, and obsessive-compulsive disorder, presumably through autoimmune damage to basal ganglia. Mycoplasma pneumoniae infections have also been reported to cause damage to the basal ganglia. Restless legs syndrome is a movement disorder with focal restlessness, an irresistible desire to move, and exacerbation by long periods of sitting or lying. We present three children with transient restless legs syndrome-like symptoms possibly associated with group A beta-hemolytic streptococcal infection or Mycoplasma pneumoniae infection. One of three patients had persistently elevated enzyme-linked immunosorbent optical density values against human caudate and putamen. PMID:15301831

  12. PANDAS (Paediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection).

    PubMed

    Lynch, N E; Deiratany, S; Webb, D W; McMenamin, J B

    2006-05-01

    PANDAS (Paediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection) is a rare condition first described in 1998. It describes the presence of obsessive-compulsive disorder (OCD) or tics with an episodic course, and a temporal relationship to Group A beta haemolytic streptococcal infection (GABHS). Recurrent episodes can be disruptive and upsetting for a child, but the best way to treat the condition has yet to be established. Penicillin prophylaxis has not proved effective, and other therapies are experimental. There is some evidence in the literature to support the role of tonsillectomy in improving the condition. We report a case of a 6-year-old boy who presented with tic and hemi-chorea associated with GABHS throat infection. He had a recurrence of his symptoms associated with a further GABHS infection, but has had no further symptoms following tonsillectomy. This case report lends further evidence to the role of tonsillectomy in the management of PANDAS. PMID:16892924

  13. Outcomes and Resource Use of Sepsis-associated Stays by Presence on Admission, Severity, and Hospital Type

    PubMed Central

    Ashton, Carol M.; Kiehne, Lisa B.; Nicolas, Juan C.; Rose, Alexis L.; Shirkey, Beverly A.; Masud, Faisal; Wray, Nelda P.

    2016-01-01

    Objective: To establish a baseline for the incidence of sepsis by severity and presence on admission in acute care hospital settings before implementation of a broad sepsis screening and response initiative. Methods: A retrospective cohort study using hospital discharge abstracts of 5672 patients, aged 18 years and above, with sepsis-associated stays between February 2012 and January 2013 at an academic medical center and 5 community hospitals in Texas. Results: Sepsis was present on admission in almost 85% of cases and acquired in-hospital in the remainder. The overall inpatient death rate was 17.2%, but was higher in hospital-acquired sepsis (38.6%, medical; 29.2%, surgical) and Stages 2 (17.6%) and 3 (36.4%) compared with Stage 1 (5.9%). Patients treated at the academic medical center had a higher death rate (22.5% vs. 15.1%, P<0.001) and were more costly ($68,050±184,541 vs. $19,498±31,506, P<0.001) versus community hospitals. Conclusions: Greater emphasis is needed on public awareness of sepsis and the detection of sepsis in the prehospitalization and early hospitalization period. Hospital characteristics and case mix should be accounted for in cross-hospital comparisons of sepsis outcomes and costs. PMID:26759980

  14. GENETIC BASIS OF MURINE ANTIBACTERIAL DEFENSE TO STREPTOCOCCAL LUNG INFECTION

    EPA Science Inventory

    To evaluate the effect of genetic background and toll-like receptor 2 on antibacterial defense to streptococcal infection, eight genetically diverse strains of mice (A/J, DBA/2J, CAST/Ei, FVB/NJ, BALB/cJ, C57BL/6J, 129/SvImJ, and C3H/HeJ) and tlr2-deficient mice (C57BL/6

  15. The Group A Streptococcal Carrier State Reviewed: Still an Enigma.

    PubMed

    DeMuri, Gregory P; Wald, Ellen R

    2014-12-01

    Despite the common nature of group A streptococcal (GAS) infections, the carrier state of this organism is not well understood. In this article, we review the historical and recent research on the definition, epidemiology, and pathogenesis of the GAS carrier state. In addition, we outline trials of antimicrobial agents in the eradication of the carrier state and discuss indications for providing treatment to patients in the clinical setting. PMID:26625454

  16. PIRO concept: Staging of sepsis

    PubMed Central

    Rathour, S; Kumar, S; Hadda, V; Bhalla, A; Sharma, N; Varma, S

    2015-01-01

    Introduction: Sepsis is common presenting illness to the emergency services and one of the leading causes of hospital mortality. Researchers and clinicians have realized that the systemic inflammatory response syndrome concept for defining sepsis is less useful and lacks specificity. The predisposition, infection (or insult), response and organ dysfunction (PIRO) staging of sepsis similar to malignant diseases (TNM staging) might give better information. Materials and Methods: A prospective observational study was conducted in emergency medical services attached to medicine department of a tertiary care hospital in Northern India. Patients with age 18 years or more with proven sepsis were included in the first 24 hours of the diagnosis. Two hundred patients were recruited. Multivariate logistic regression analysis was done to assess the factors that predicted in-hospital mortality. Results: Two hundred patients with proven sepsis, admitted to the emergency medical services were analysed. Male preponderance was noted (M: F ratio = 1.6:1). Mean age of study cohort was 50.50 ± 16.30 years. Out of 200 patients, 116 (58%) had in-hospital mortality. In multivariate logistic regression analysis, the factors independently associated with in-hospital mortality for predisposition component of PIRO staging were age >70 years, chronic obstructive pulmonary disease, chronic liver disease, cancer and presence of foley's catheter; for infection/insult were pneumonia, urinary tract infection and meningitis/encephalitis; for response variable were tachypnea (respiratory rate >20/minute) and bandemia (band >5%). Organ dysfunction variables associated with hospital mortality were systolic blood pressure <90mm Hg, prolonged activated partial thromboplastin time, raised serum creatinine, partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio <300, decreased urine output in first two hours of emergency presentation and Glasgow coma scale ≤9. Each

  17. Clinical Presentation of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections in Research and Community Settings

    PubMed Central

    Seidlitz, Jakob; Kovacevic, Miro; Latimer, M. Elizabeth; Hommer, Rebecca; Lougee, Lorraine; Grant, Paul

    2015-01-01

    Abstract Background: The first cases of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) were described>15 years ago. Since that time, the literature has been divided between studies that successfully demonstrate an etiologic relationship between Group A streptococcal (GAS) infections and childhood-onset obsessive-compulsive disorder (OCD), and those that fail to find an association. One possible explanation for the conflicting reports is that the diagnostic criteria proposed for PANDAS are not specific enough to describe a unique and homogeneous cohort of patients. To evaluate the validity of the PANDAS criteria, we compared clinical characteristics of PANDAS patients identified in two community practices with a sample of children meeting full research criteria for PANDAS. Methods: A systematic review of clinical records was used to identify the presence or absence of selected symptoms in children evaluated for PANDAS by physicians in Hinsdale, Illinois (n=52) and Bethesda, Maryland (n=40). Results were compared against data from participants in National Institute of Mental Health (NIMH) research investigations of PANDAS (n=48). Results: As described in the original PANDAS cohort, males outnumbered females (95:45) by ∼ 2:1, and symptoms began in early childhood (7.3±2.7 years). Clinical presentations were remarkably similar across sites, with all children reporting acute onset of OCD symptoms and multiple comorbidities, including separation anxiety (86–92%), school issues (75–81%), sleep disruptions (71%), tics (60–65%), urinary symptoms (42–81%), and others. Twenty of the community cases (22%) failed to meet PANDAS criteria because of an absence of documentation of GAS infections. Conclusions: The diagnostic criteria for PANDAS can be used by clinicians to accurately identify patients with common clinical features and shared etiology of symptoms. Although difficulties in documenting an association

  18. Functional brain imaging in Sydenham's chorea and streptococcal tic disorders.

    PubMed

    Citak, Elvan Caglar; Gücüyener, Kivilcim; Karabacak, Nese Ilgin; Serdaroğlu, Ayşe; Okuyaz, Cetin; Aydin, Kurşad

    2004-05-01

    Group A streptococcal infections cause a wide range of neuropsychiatric disorders, such as Sydenham's chorea, tics, obsessive-compulsive disorders, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Structural (computed tomography and magnetic resonance imaging) and functional (positron emission tomography, single-photon emission computed tomography) imaging studies in patients with Sydenham's chorea have suggested reversible striatal abnormalities. The objective of this study was to investigate the cerebral perfusion patterns of the subcortical structures by using hexamethylpropylenamine oxime single-photon emission computed tomography (HMPAO-SPECT) in seven cases of Sydenham's chorea and two cases of streptococcal tic disorder. HMPAO-SPECT studies revealed a hyperperfusion pattern in two and a hypoperfusion pattern in five of the chorea patients and in two patients with tic disorder. The results are discussed in relation to the duration and severity of the symptoms and the response to therapy. Functional imaging findings can be variable in Sydenham's chorea, and hyperperfusion of the striatum and thalamus could be an indicator of the response to therapy and the severity of symptoms. However, the number of cases so far investigated by either SPECT or positron emission tomography is still too limited to draw any firm conclusions. PMID:15224712

  19. Molecular markers for the study of streptococcal epidemiology.

    PubMed

    McMillan, David J; Sanderson-Smith, Martina L; Smeesters, Pierre Robert; Sriprakash, Kadaba S

    2013-01-01

    Diseases caused by Streptococcus pyogenes (Group A streptococcus, GAS) range from superficial infections such as pharyngitis and impetigo to potentially fatal rheumatic heart disease and invasive disease. Studies spanning emm-typing surveillance to population genomics are providing new insights into the epidemiology, pathogenesis, and biology of this organism. Such studies have demonstrated the differences that exist in the epidemiology of streptococcal disease between developing and developed nations. In developing nations, where streptococcal disease is endemic, the diversity of GAS emm-types circulating is much greater than that found in developed nations. An association between emm-type and disease, as observed in developed countries is also lacking. Intriguingly, comparative genetic studies suggest that emm-type is not always a good predictor of the evolutionary relatedness of geographically distant isolates. A view of GAS as a highly dynamic organism, in possession of a core set of virulence genes that contribute to host niche specialization and common pathogenic processes, augmented by accessory genes that change the relative virulence of specific lineages is emerging. Our inability to definitively identify genetic factors that contribute to specific disease outcome underscores the complex nature of streptococcal diseases. PMID:23179674

  20. Heterogeneity of group A streptococcal pyrogenic exotoxin type B.

    PubMed Central

    Barsumian, E L; Cunningham, C M; Schlievert, P M; Watson, D W

    1978-01-01

    Streptococcal pyrogenic exotoxin type B purified from culture filtrates of either the NY-5 or T-19 strain of group A streptococcus was found to be heterogeneous in charge. Three protein fractions with isoelectric points of 8.0, 8.4, and 9.0 were isolated by differential solubility in ethanol and acetate-buffered saline followed by isoelectric focusing and shown to be antigenically identical to streptococcal pyrogenic exotoxin type B. The molecular weights of all three fractions were approximately 17,500, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, with aggregates forming in the presence of hyaluronic acid. Only the pI 8.4 fraction showed the characteristic activities of streptococcal pyrogenic exotoxin in rabbits: pyrogenicity and ability to enhance susceptibility to lethal endotoxin shock. The pI 8.0 and pI 9.0 fractions were not pyrogenic, but could be used to immunize against pyrogenicity. These two fractions failed either to enhance lethal endotoxin shock or to immunize against enhancement activity. When the isolated fractions were electrofocused again they appeared heterogeneous, suggesting an instability of the B toxin molecular forms. Images PMID:352946

  1. Diagnosing sepsis - The role of laboratory medicine.

    PubMed

    Fan, Shu-Ling; Miller, Nancy S; Lee, John; Remick, Daniel G

    2016-09-01

    Sepsis is the host response to microbial pathogens resulting in significant morbidity and mortality. An accurate and timely diagnosis of sepsis allows prompt and appropriate treatment. This review discusses laboratory testing for sepsis because differentiating systemic inflammation from infection is challenging. Procalcitonin (PCT) is currently an FDA approved test to aid in the diagnosis of sepsis but with questionable efficacy. However, studies support the use of PCT for antibiotic de-escalation. Serial lactate measurements have been recommended for monitoring treatment efficacy as part of sepsis bundles. The 2016 sepsis consensus definitions include lactate concentrations >2mmol/L (>18mg/dL) as part of the definition of septic shock. Also included in the 2016 definitions are measuring bilirubin and creatinine to determine progression of organ failure indicating worse prognosis. Hematologic parameters, including a simple white blood cell count and differential, are frequently part of the initial sepsis diagnostic protocols. Several new biomarkers have been proposed to diagnose sepsis or to predict mortality, but they currently lack sufficient sensitivity and specificity to be considered as stand-alone testing. If sepsis is suspected, new technologies and microbiologic assays allow rapid and specific identification of pathogens. In 2016 there is no single laboratory test that accurately diagnoses sepsis. PMID:27387712

  2. Postmortem serum protein growth arrest-specific 6 levels in sepsis-related deaths.

    PubMed

    Palmiere, Cristian; Augsburger, Marc

    2015-09-01

    Growth arrest-specific 6 (Gas6) is widely expressed in leukocytes, platelets, endothelial cells, and monocytes. It regulates various processes including granulocyte adhesion to the endothelium, cell migration, thrombus stabilization, and cytokine release. In humans, increased plasma Gas6 levels have been described in patients with sepsis and septic shock. In this study, Gas6 concentrations were measured in postmortem serum from femoral blood in a series of sepsis-related fatalities and control cases. The aims were twofold: first, to determine whether Gas6 can be reliably determined in postmortem serum; and second, to assess its diagnostic potential in identifying sepsis-related deaths. Two study groups were prospectively formed, a sepsis-related fatalities group (24 cases) and a control group (24 cases) including cases of deep vein thrombosis and fatal pulmonary embolism, cases of systemic inflammatory response syndrome in severe trauma, cases of end-stage renal failure, and cases of hanging (non-septic, non-SIRS, non-end stage renal failure cases). The preliminary results of this study seem to indicate that Gas6 can be effectively measured in postmortem serum. However, Gas6 levels in sepsis-related fatalities do not appear to be clearly distinguishable from concentrations in pulmonary embolism, severe trauma, and end-stage renal failure cases. These findings tend to support previous reports that indicated that Gas6 behaves as an acute phase reactant and can be considered a general marker of inflammation rather than a specific biomarker of sepsis. PMID:26233610

  3. Randomized, single-blind evaluation of cefadroxil and phenoxymethyl penicillin in the treatment of streptococcal pharyngitis.

    PubMed Central

    Pichichero, M E; Disney, F A; Aronovitz, G H; Talpey, W B; Green, J L; Francis, A B

    1987-01-01

    A total of 150 children from two pediatric practices with clinical and bacteriologic evidence of acute group A beta-hemolytic streptococcal (GABHS) pharyngitis randomly received cefadroxil monohydrate (75 children) or phenoxymethyl penicillin (75 children). Cefadroxil was given once daily, while penicillin was given three times daily. The treatment groups were similar in age, sex, race, illness severity, and acute GABHS symptomatology. Throat cultures were routine 3 to 5 days after the start of therapy and 2 and 14 days after the end of therapy. The bacterial cure rates were 90% (62 of 69) for cefadroxil-treated patients and 76% (52 of 68) for penicillin-treated patients. This difference was significant (P less than 0.04). The clinical response was satisfactory in 91% of cefadroxil-treated patients and 89% of penicillin-treated patients. We conclude that once-daily cefadroxil is at least as effective as three-times-daily penicillin in producing bacteriologic eradication and clinical symptomatic improvement in children with GABHS pharyngitis. PMID:3113329

  4. Ras regulates alveolar macrophage formation of CXC chemokines and neutrophil activation in streptococcal M1 protein-induced lung injury.

    PubMed

    Zhang, Songen; Hwaiz, Rundk; Rahman, Milladur; Herwald, Heiko; Thorlacius, Henrik

    2014-06-15

    Streptococcal toxic shock syndrome (STSS) is associated with a high mortality rate. The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, we examined the role of Ras signaling in M1 protein-induced lung injury. Male C57BL/6 mice received the Ras inhibitor (farnesylthiosalicylic acid, FTS) prior to M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Quantitative RT-PCR was used to determine gene expression of CXC chemokines in alveolar macrophages. Administration of FTS reduced M1 protein-induced neutrophil recruitment, edema formation and tissue damage in the lung. M1 protein challenge increased Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Inhibition of Ras activity decreased M1 protein-induced expression of Mac-1 on neutrophils and secretion of CXC chemokines in the lung. Moreover, FTS abolished M1 protein-provoked gene expression of CXC chemokines in alveolar macrophages. Ras inhibition decreased chemokine-mediated neutrophil migration in vitro. Taken together, our novel findings indicate that Ras signaling is a potent regulator of CXC chemokine formation and neutrophil infiltration in the lung. Thus, inhibition of Ras activity might be a useful way to antagonize streptococcal M1 protein-triggered acute lung injury. PMID:24704370

  5. Early PREdiction of Severe Sepsis (ExPRES-Sepsis) study: protocol for an observational derivation study to discover potential leucocyte cell surface biomarkers

    PubMed Central

    Antonelli, Jean; Warner, Noel; Brown, Kenneth Alun; Wright, John; Simpson, A John; Rennie, Jillian; Hulme, Gillian; Lewis, Sion Marc; Mare, Tracey Anne; Cookson, Sharon; Weir, Christopher John; Dimmick, Ian; Keenan, Jim; Rossi, Adriano Giorgio; Shankar-Hari, Manu; Walsh, Timothy S

    2016-01-01

    Introduction Sepsis is an acute illness resulting from infection and the host immune response. Early identification of individuals at risk of developing life-threatening severe sepsis could enable early triage and treatment, and improve outcomes. Currently available biomarkers have poor predictive value for predicting subsequent clinical course in patients with suspected infection. Circulating leucocytes provide readily accessible tissues that reflect many aspects of the complex immune responses described in sepsis. We hypothesise that measuring cellular markers of immune responses by flow cytometry will enable early identification of infected patients at risk of adverse outcomes. We aim to characterise leucocyte surface markers (biomarkers) and their abnormalities in a population of patients presenting to the hospital emergency department with suspected sepsis, and explore their ability to predict subsequent clinical course. Methods and analysis We will conduct a prospective, multicentre, clinical, exploratory, cohort observational study. To answer our study question, 3 patient populations will be studied. First, patients with suspected sepsis from the emergency department (n=300). To assess performance characteristics of potential tests, critically ill patients with established sepsis, and age and gender matched patients without suspicion of infection requiring hospital admission (both n=100) will be recruited as comparator populations. In all 3 groups, we plan to assess circulating biomarker profiles using flow cytometry. We will select candidate biomarkers by cross-cohort comparison, and then explore their predictive value for clinical outcomes within the cohort with suspected sepsis. Ethics and dissemination The study will be carried out based on the principles in the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice. Ethics approval has been granted from the Scotland A Research Ethics Committee (REC) and Oxford C

  6. The neutrophil elastase inhibitor, sivelestat, attenuates sepsis-related kidney injury in rats.

    PubMed

    Li, Guofu; Jia, Jia; Ji, Kaiqiang; Gong, Xiaoying; Wang, Rui; Zhang, Xiaoli; Wang, Haiyuan; Zang, Bin

    2016-09-01

    Sepsis-induced acute kidney injury (AKI) represents a major cause of mortality in intensive care units. Sivelestat, a selective inhibitor of neutrophil elastase (NE), can attenuate sepsis-related acute lung injury. However, whether sivelestat can preserve kidney function during sepsis remains unclear. In this study, we thus examined the effects of sivelestat on sepsis-related AKI. Cecal ligation and puncture (CLP) was performed to induce multiple bacterial infection in male Sprague-Dawley rats, and subsequently, 50 or 100 mg/kg sivelestat were administered by intraperitoneal injection immediately after the surgical procedure. In the untreated rats with sepsis, the mean arterial pressure (MAP) and glomerular filtration rate (GFR) were decreased, whereas serum blood urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL) levels were increased. We found that sivelestat promoted the survival of the rats with sepsis, restored the impairment of MAP and GFR, and inhibited the increased BUN and NGAL levels; specifically, the higher dose was more effective. In addition, sivelestat suppressed the CLP-induced macrophage infiltration, the overproduction of pro-inflammatory mediators (tumor necrosis factor‑α, interleukin-1β, high-mobility group box 1 and inducible nitric oxide synthase) and serine/threonine kinase (Akt) pathway activation in the rats. Collectively, our data suggest that the inhibition of NE activity with the inhibitor, sivelestat, is beneficial in ameliorating sepsis-related kidney injury. PMID:27430552

  7. Early-Onset Neonatal Sepsis

    PubMed Central

    Simonsen, Kari A.; Anderson-Berry, Ann L.; Delair, Shirley F.

    2014-01-01

    SUMMARY Early-onset sepsis remains a common and serious problem for neonates, especially preterm infants. Group B streptococcus (GBS) is the most common etiologic agent, while Escherichia coli is the most common cause of mortality. Current efforts toward maternal intrapartum antimicrobial prophylaxis have significantly reduced the rates of GBS disease but have been associated with increased rates of Gram-negative infections, especially among very-low-birth-weight infants. The diagnosis of neonatal sepsis is based on a combination of clinical presentation; the use of nonspecific markers, including C-reactive protein and procalcitonin (where available); blood cultures; and the use of molecular methods, including PCR. Cytokines, including interleukin 6 (IL-6), interleukin 8 (IL-8), gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), and cell surface antigens, including soluble intercellular adhesion molecule (sICAM) and CD64, are also being increasingly examined for use as nonspecific screening measures for neonatal sepsis. Viruses, in particular enteroviruses, parechoviruses, and herpes simplex virus (HSV), should be considered in the differential diagnosis. Empirical treatment should be based on local patterns of antimicrobial resistance but typically consists of the use of ampicillin and gentamicin, or ampicillin and cefotaxime if meningitis is suspected, until the etiologic agent has been identified. Current research is focused primarily on development of vaccines against GBS. PMID:24396135

  8. Biosensor of endotoxin and sepsis

    NASA Astrophysics Data System (ADS)

    Shao, Yang; Wang, Xiang; Wu, Xi; Gao, Wei; He, Qing-hua; Cai, Shaoxi

    2001-09-01

    To investigate the relation between biosensor of endotoxin and endotoxin of plasma in sepsis. Method: biosensor of endotoxin was designed with technology of quartz crystal microbalance bioaffinity sensor ligand of endotoxin were immobilized by protein A conjugate. When a sample soliton of plasma containing endotoxin 0.01, 0.03, 0.06, 0.1, 0.5, 1.0Eu, treated with perchloric acid and injected into slot of quartz crystal surface respectively, the ligand was released from the surface of quartz crystal to form a more stable complex with endotoxin in solution. The endotoxin concentration corresponded to the weight change on the crystal surface, and caused change of frequency that occurred when desorbed. The result was biosensor of endotoxin might detect endotoxin of plasma in sepsis, measurements range between 0.05Eu and 0.5Eu in the stop flow mode, measurement range between 0.1Eu and 1Eu in the flow mode. The sensor of endotoxin could detect the endotoxin of plasm rapidly, and use for detection sepsis in clinically.

  9. Evaluation of procalcitonin for diagnosis of neonatal sepsis of vertical transmission

    PubMed Central

    López Sastre, José B; Solís, David Pérez; Serradilla, Vicente Roqués; Colomer, Belén Fernández; Cotallo, Gil D Coto

    2007-01-01

    Background The results of recent studies suggest the usefulness of PCT for early diagnosis of neonatal sepsis, with varying results. The aim of this prospective multicenter study was to determine the behavior of serum PCT concentrations in both uninfected and infected neonates, and to assess the value of this marker for diagnosis of neonatal sepsis of vertical transmission. Methods PCT was measured in 827 blood samples collected prospectively from 317 neonates admitted to 13 acute-care teaching hospitals in Spain over one year. Serum PCT concentrations were determined by a specific immunoluminometric assay. The diagnostic efficacy of PCT at birth and within 12–24 h and 36–48 h of life was evaluated calculating the sensitivity, specificity, and likelihood ratio of positive and negative results. Results 169 asymptomatic newborns and 148 symptomatic newborns (confirmed vertical sepsis: 31, vertical clinical sepsis: 38, non-infectious diseases: 79) were studied. In asymptomatic neonates, PCT values at 12–24 h were significantly higher than at birth and at 36–48 h of life. Resuscitation at birth and chorioamnionitis were independently associated to PCT values. Neonates with confirmed vertical sepsis showed significantly higher PCT values than those with clinical sepsis. PCT thresholds for the diagnosis of sepsis were 0.55 ng/mL at birth (sensitivity 75.4%, specificity 72.3%); 4.7 ng/mL within 12–24 h of life (sensitivity 73.8%, specificity 80.8%); and 1.7 ng/mL within 36–48 h of life (sensitivity 77.6%, specificity 79.2%). Conclusion Serum PCT was moderately useful for the detection of sepsis of vertical transmission, and its reliability as a maker of bacterial infection requires specific cutoff values for each evaluation point over the first 48 h of life. PMID:17324267

  10. Acute glomerulonephritis.

    PubMed

    Yoshizawa, N

    2000-09-01

    Acute glomerulonephritis (AGN) is a representative disease of acute nephritic syndrome characterized by the sudden appearance of edema, hematuria, proteinuria, and hypertension. The prototype of AGN is acute poststreptococcal glomerulonephritis (APSGN). "Nephritogenic streptococci" are defined as organisms that are cultured from a patient who develops AGN. Although only a limited number of M-types of streptococci have been recognized as "nephritogenic streptococci", all M-types of streptococci may have nephritogenic potential because the genes for major putative nephritogenic antigens such as SPEB and NAPIr are found to be present in all group A streptococci thus far examined. Pathogenic mechanisms for APSGN involving both humoral and cell-mediated immunity have been recently proposed. The role of humoral immunity is presumed to be mediated by the in situ formation of nephritogenic streptococcal antigen-antibody complexes and circulating immune complexes. While in the cellular immune component a role for delayed-type hypersensitivity has been suggested to contribute to the pathogenesis of APSGN. PMID:10969898

  11. Neuropsychiatric Disorders Associated with Streptococcal Infection: A Case-Control Study among Privately Insured Children

    ERIC Educational Resources Information Center

    Leslie, Douglas L.; Kozma, Laura; Martin, Andres; Landeros, Angeli; Katsovich, Liliya; King, Robert A.; Leckman, James F.

    2008-01-01

    The link between streptococcal infections and the onset of a variety of neuropsychiatric disorders is studied using a national sample of privately insured children. Findings suggest that patients with new-onset of obsessive-compulsive disorder, Tourette syndrome or tic orders were more likely to have been diagnosed with streptococcal infections in…

  12. Aeromonas hydrophila Sepsis Associated with Consumption of Raw Oysters

    PubMed Central

    Goldman, John; Cheriyath, Pramil; Nookala, Vinod

    2014-01-01

    Introduction. Aeromonas hydrophila is a gram negative bacillus that is native to aquatic environments that is increasingly reported in humans. This case is remarkable for A. hydrophila with an initial presentation of acute pancreatitis. Case Presentation. A 61-year-old male presented to the emergency department with nausea, vomiting, and abdominal pain for two days. His past medical history was significant for alcohol abuse. Initial laboratory examination showed an elevated white blood cell count, elevated lipase, and elevated liver function tests (LFT). Computer tomography (CT) showed peripancreatic inflammatory changes and retroperitoneal free fluid, suggestive of acute pancreatitis. The patient was treated with intravenous (IV) fluids and IV meropenem. After two days, the patient developed sepsis and respiratory failure and was intubated. Blood cultures were positive for Aeromonas hydrophila sensitive to ciprofloxacin which was added to his treatment. Additionally, it was discovered that this patient had recently vacationed in Florida where he consumed raw oysters. He was discharged home on the eighth day of the hospital admission. Conclusion. This is a rare case of A. hydrophila sepsis in an elderly patient with acute pancreatitis and a history of consumption of raw oysters. This case suggests that A. hydrophila can cause disseminated infection in immunocompetent individuals. PMID:25506003

  13. Aeromonas hydrophila Sepsis Associated with Consumption of Raw Oysters.

    PubMed

    Nikiforov, Ivan; Goldman, John; Cheriyath, Pramil; Vyas, Anix; Nookala, Vinod

    2014-01-01

    Introduction. Aeromonas hydrophila is a gram negative bacillus that is native to aquatic environments that is increasingly reported in humans. This case is remarkable for A. hydrophila with an initial presentation of acute pancreatitis. Case Presentation. A 61-year-old male presented to the emergency department with nausea, vomiting, and abdominal pain for two days. His past medical history was significant for alcohol abuse. Initial laboratory examination showed an elevated white blood cell count, elevated lipase, and elevated liver function tests (LFT). Computer tomography (CT) showed peripancreatic inflammatory changes and retroperitoneal free fluid, suggestive of acute pancreatitis. The patient was treated with intravenous (IV) fluids and IV meropenem. After two days, the patient developed sepsis and respiratory failure and was intubated. Blood cultures were positive for Aeromonas hydrophila sensitive to ciprofloxacin which was added to his treatment. Additionally, it was discovered that this patient had recently vacationed in Florida where he consumed raw oysters. He was discharged home on the eighth day of the hospital admission. Conclusion. This is a rare case of A. hydrophila sepsis in an elderly patient with acute pancreatitis and a history of consumption of raw oysters. This case suggests that A. hydrophila can cause disseminated infection in immunocompetent individuals. PMID:25506003

  14. The molecular pathogenesis of cholestasis in sepsis

    PubMed Central

    Bhogal, Harjit K.; Sanyal, Arun J.

    2016-01-01

    Sepsis-induced cholestasis is a complication of infection. Infections cause systemic and intrahepatic increase in proinflammatory cytokines which result in impaired bile flow ie. cholestasis. Several other mediators of impairment in bile flow have been identified under conditions of sepsis such as increased nitric oxide production and decreased aquaporin channels. The development of cholestasis may also further worsen inflammation. The molecular basis of normal bile flow and mechanisms of impairment in sepsis are discussed. PMID:23276972

  15. Epigenetic coordination of acute systemic inflammation: potential therapeutic targets

    PubMed Central

    Vachharajani, Vidula; Liu, Tiefu; McCall, Charles E.

    2015-01-01

    Epigenetic reprogramming of thousands of genes directs the course of acute systemic inflammation, which is highly lethal when dysregulated during sepsis. No molecular-based treatments for sepsis are available. A new concept supports that sepsis is an immunometabolic disease and that loss of control of nuclear epigenetic regulator Sirtuin 1 (SIRT-1), a NAD+ sensor directs immune and metabolic pathways during sepsis. SIRT-1, acting as homeostasis checkpoint, controls hyper and hypo inflammatory responses of sepsis at the microvascular interface, which disseminates inflammatory injury to cause multiple organ failure. Modifying SIRT-1 activity, which can prevent or treat established sepsis in mice, may provide a new way treat sepsis by epigenetically restoring immunometabolic homeostasis. PMID:25088223

  16. [Massive intravascular hemolysis secondary to sepsis due to Clostridium perfringens].

    PubMed

    Pita Zapata, E; Sarmiento Penide, A; Bautista Guillén, A; González Cabano, M; Agulla Budiño, J A; Camba Rodríguez, M A

    2010-05-01

    Massive hemolysis secondary to sepsis caused by Clostridium perfringens is a rare entity but appears fairly often in the literature. In nearly all published reports, the clinical course is rapid and fatal. We describe the case of a 75-year-old woman with diabetes who was admitted with symptoms consistent with acute cholecystitis. Deteriorating hemodynamics and laboratory findings were consistent with intravascular hemolysis, coagulation disorder, and renal failure. Gram-positive bacilli of the Clostridium species were detected in blood along with worsening indicators of hemolysis. In spite of antibiotic and surgical treatment, hemodynamic support and infusion of blood products, the patient continued to decline and died in the postoperative recovery unit 14 hours after admission. Mortality ranges from 70% to 100% in sepsis due to Clostridium perfringens, and risk of death is greater if massive hemolysis is present, as in the case we report. Only a high degree of clinical suspicion leading to early diagnosis and treatment can improve the prognosis. This bacterium should therefore be considered whenever severe sepsis and hemolysis coincide. PMID:20527348

  17. Protective effect of Aloe vera on polymicrobial sepsis in mice.

    PubMed

    Yun, Nari; Lee, Chan-Ho; Lee, Sun-Mee

    2009-06-01

    Sepsis is an acute life-threatening clinical condition and remains the major cause of death in intensive care units. The primary pathophysiologic event central to the septic response is an overwhelming activation of the inflammatory system and countervailing response from the anti-inflammatory system. However, the cause of this perturbation has yet to be elucidated. In this study, we report that Aloe vera therapeutically reverses the lethality induced by cecal ligation and puncture (CLP), a clinically relevant model of sepsis. The administration of Aloe vera ameliorated the multiple organ dysfunction syndrome, as evidenced by the serum levels of biochemical parameters and histological changes. In order to investigate the pharmacological mechanism of Aloe vera, the levels of the cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were determined by ELISA at various time points. The increases in the levels of TNF-alpha, IL-1beta, and IL-6 were attenuated by Aloe vera.In vivo administration of Aloe vera also markedly enhanced bacterial clearance. Our findings suggest that Aloe vera could be a potential therapeutic agent for the clinical treatment of sepsis. PMID:19298839

  18. [Assessment of severity of meningococcal sepsis in children].

    PubMed

    Oom, Paulo; Rossi, Renata; Correia, Manuela; Rodrigues, Gustavo

    2003-01-01

    Despite advances in critical care medicine, acute meningococcal infection remains complicated by high mortality. Different prognostic scoring systems have been developed but none of them is largely used. The objective of this study was to evaluate the performance at admission to the pediatric intensive care unit (PICU) of five severity scores in children with proven and unproven meningococcal infection. Our results seem to indicate that the Neisseria Sepsis Index (NESI) and the Rotterdam Score (RS) perform better than the other scores, being appropriate tools to assess severity of illness at admission to the PICU in children with proven or presumed meningococcal infection. PMID:14750274

  19. Sepsis management in the deployed field hospital.

    PubMed

    Johnston, Andrew McD; Easby, D; Ewington, I

    2013-09-01

    Sepsis, a syndrome caused by severe infection, affects a small proportion of military casualties but has a significant effect in increasing morbidity and mortality, including causing some preventable deaths. Casualties with abdominal trauma and those with significant tissue loss appear to be at a greater risk of sepsis. In this article, the diagnosis and management of sepsis in military casualties with reference to the Surviving Sepsis Campaign guidelines are examined. We discuss the management considerations specific to military casualties in the deployed setting and also discuss factors affecting evacuation by the UK Royal Air Force Critical Care Air Support Team. PMID:24109139

  20. Autophagy in sepsis: Degradation into exhaustion?

    PubMed

    Ho, Jeffery; Yu, Jun; Wong, Sunny H; Zhang, Lin; Liu, Xiaodong; Wong, Wai T; Leung, Czarina C H; Choi, Gordon; Wang, Maggie H T; Gin, Tony; Chan, Matthew T V; Wu, William K K

    2016-07-01

    Autophagy is one of the innate immune defense mechanisms against microbial challenges. Previous in vitro and in vivo models of sepsis demonstrated that autophagy was activated initially in sepsis, followed by a subsequent phase of impairment. Autophagy modulation appears to be protective against multiple organ injuries in these murine sepsis models. This is achieved in part by preventing apoptosis, maintaining a balance between the productions of pro- and anti-inflammatory cytokines, and preserving mitochondrial functions. This article aims to discuss the role of autophagy in sepsis and the therapeutic potential of autophagy enhancers. PMID:27172163

  1. Systems for Paediatric Sepsis: A Global Survey

    PubMed Central

    Kang, KT; Chandler, HK; Espinosa, V; Kissoon, N

    2014-01-01

    ABSTRACT Objectives: To evaluate the resources available for early diagnosis and treatment of paediatric sepsis at hospitals in developing and developed countries. Methods: This was a voluntary online survey involving 101 hospitals from 41 countries solicited through the World Federation of Pediatric Intensive and Critical Care Societies contact list and website. The survey was designed to assess the spectrum of sepsis epidemiology, patterns of applied therapies, availability of resources and barriers to optimal sepsis treatment. Results: Ninety per cent of respondents represented a tertiary or general hospital with paediatric intensive care facilities, including 63% from developed countries. Adequate triage services were absent in more than 20% of centres. Insufficiently trained personnel and lack of a sepsis protocol was reported in 40% of all sites. While there were specific guidelines for sepsis management in 78% of centres (n = 100), protocols for assessing sepsis patients were not applied in nearly 70% of centres. Lack of parental recognition of sepsis and failure of referring centres to diagnose sepsis were identified as major barriers by more than 50% of respondents. Conclusions: Even among centres with no significant resource constraints and advanced medical systems, significant deficits in sepsis care exist. Early recognition and management remains a key issue and may be addressed through improved triage, augmented support for referring centres and public awareness. Focussed research is necessary at the institutional level to identify and address specific barriers. PMID:25867557

  2. Development and Implementation of Sepsis Alert Systems.

    PubMed

    Harrison, Andrew M; Gajic, Ognjen; Pickering, Brian W; Herasevich, Vitaly

    2016-06-01

    Development and implementation of sepsis alert systems is challenging, particularly outside the monitored intensive care unit (ICU) setting. Barriers to wider use of sepsis alerts include evolving clinical definitions of sepsis, information overload, and alert fatigue, due to suboptimal alert performance. Outside the ICU, barriers include differences in health care delivery models, charting behaviors, and availability of electronic data. Current evidence does not support routine use of sepsis alert systems in clinical practice. Continuous improvement in the afferent and efferent aspects will help translate theoretic advantages into measurable patient benefit. PMID:27229639

  3. Procalcitonin is not sufficiently reliable to be the sole marker of neonatal sepsis of nosocomial origin

    PubMed Central

    López Sastre, José B; Pérez Solís, David; Roqués Serradilla, Vicente; Fernández Colomer, Belén; Coto Cotallo, Gil D; Krauel Vidal, Xavier; Narbona López, Eduardo; García del Río, Manuel; Sánchez Luna, Manuel; Belaustegui Cueto, Antonio; Moro Serrano, Manuel; Urbón Artero, Alfonso; Álvaro Iglesias, Emilio; Cotero Lavín, Ángel; Martínez Vilalta, Eduardo; Jiménez Cobos, Bartolomé

    2006-01-01

    Background It has recently been suggested that serum procalcitonin (PCT) is of value in the diagnosis of neonatal sepsis, with varying results. The aim of this prospective multicenter study was to assess the usefulness of PCT as a marker of neonatal sepsis of nosocomial origin. Methods One hundred infants aged between 4 and 28 days of life admitted to the Neonatology Services of 13 acute-care teaching hospitals in Spain over 1-year with clinical suspicion of neonatal sepsis of nosocomial origin were included in the study. Serum PCT concentrations were determined by a specific immunoluminometric assay. The reliability of PCT for the diagnosis of nosocomial neonatal sepsis at the time of suspicion of infection and at 12–24 h and 36–48 h after the onset of symptoms was calculated by receiver-operating characteristics (ROC) curves. The Youden's index (sensitivity + specificity - 1) was used for determination of optimal cutoff values of the diagnostic tests in the different postnatal periods. Sensitivity, specificity, and the likelihood ratio of a positive and negative result with the 95% confidence interval (CI) were calculated. Results The diagnosis of nosocomial sepsis was confirmed in 61 neonates. Serum PCT concentrations were significantly higher at initial suspicion and at 12–24 h and 36–48 h after the onset of symptoms in neonates with confirmed sepsis than in neonates with clinically suspected but not confirmed sepsis. Optimal PCT thresholds according to ROC curves were 0.59 ng/mL at the time of suspicion of sepsis (sensitivity 81.4%, specificity 80.6%); 1.34 ng/mL within 12–24 h of birth (sensitivity 73.7%, specificity 80.6%), and 0.69 ng/mL within 36–48 h of birth (sensitivity 86.5%, specificity 72.7%). Conclusion Serum PCT concentrations showed a moderate diagnostic reliability for the detection of nosocomial neonatal sepsis from the time of suspicion of infection. PCT is not sufficiently reliable to be the sole marker of sepsis, but would be

  4. Sepsis in Buraidah Central Hospital, Qassim, Kingdom of Saudi Arabia

    PubMed Central

    Gasim, Gasim I.; Musa, Imad R; Yassin, Taha; Al Shobaili, Hani A.; Adam, Ishag

    2016-01-01

    Objectives Severe sepsis is a major public health concern and a frequent cause of intensive care unit (ICU) admission with a high fatality rate. Higher (Sequential Organ Failure Assessment score) SOFA score and co-morbidity of acute renal failure (ARF) are risk factors contributing to fatal outcome. This work was meant to study the epidemiology of sepsis in Buraidah central hospital. Methods This is a descriptive study conducted in the period from January 1, 2012, to June 29, 2012 to determine the epidemiology (incidence, clinical characteristics) and the outcome of sepsis in Buraidah hospital, Saudi Arabia. Results Out of 387 patients admitted to ICU, 62 (16%) patients had sepsis, their mean (SD) age was 62.7 (21.3) years. Three quarters of them 47 (75.8%) presented with septic shock. The median APACHE II score was 26.5 (8 to 48) and SOFA score 11 (5 to 21). The mean of duration of hospital stay was 11.95 days. The most frequent infection site was the pulmonary (69.5%). There were 37 isolated organism, gram-negative organisms (13; 35.13%) were the predominant isolates. There were 25 (40.3%) deaths; the majority of the deaths were due to septic shock 20(80%). There was a significant difference between deaths and the survivors, in the APACHI II score, SOFA score), and whether ventilated or not. Conclusions There was a high incidence of septic shock (and higher mortality) among the patients admitted to the ICU of Buraidah central hospital, especially among the elderly patients with respiratory infections. PMID:27103899

  5. AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-Induced Lung Injury

    PubMed Central

    Liu, Zhongyu; Bone, Nathaniel; Jiang, Shaoning; Park, Dae Won; Tadie, Jean-Marc; Deshane, Jessy; Rodriguez, Cilina Ann; Pittet, Jean-Francois; Abraham, Edward; Zmijewski, Jaroslaw W

    2015-01-01

    Alterations in metabolic and bioenergetic homeostasis contribute to sepsis-mediated organ injury. However, how AMP-activated protein kinase (AMPK), a major sensor and regulator of energy expenditure and production, affects development of organ injury and loss of innate capacity during polymicrobial sepsis remains unclear. In the present experiments, we found that cross-talk between the AMPK and GSK3β signaling pathways controls chemotaxis and the ability of neutrophils and macrophages to kill bacteria ex vivo. In mice with polymicrobial abdominal sepsis or more severe sepsis induced by the combination of hemorrhage and intraabdominal infection, administration of the AMPK activator metformin or the GSK3β inhibitor SB216763 reduced the severity of acute lung injury (ALI). Improved survival in metformin-treated septic mice was correlated with preservation of mitochondrial complex V (ATP synthase) function and increased amounts of ETC complex III and IV. Although immunosuppression is a consequence of sepsis, metformin effectively increased innate immune capacity to eradicate P. aeruginosa in the lungs of septic mice. We also found that AMPK activation diminished accumulation of the immunosuppressive transcriptional factor HIF-1α as well as the development of endotoxin tolerance in LPS-treated macrophages. Furthermore, AMPK-dependent preservation of mitochondrial membrane potential also prevented LPS-mediated dysfunction of neutrophil chemotaxis. These results indicate that AMPK activation reduces the severity of polymicrobial sepsis-induced lung injury and prevents the development of sepsis-associated immunosuppression. PMID:26650187

  6. Type-Specific Opsonic Antibodies in Streptococcal Pyoderma

    PubMed Central

    Bisno, Alan L.; Nelson, Kenrad E.

    1974-01-01

    Prospective studies of streptococcal pyoderma were carried out among black children enrolled in Project Headstart centers in Holmes County, Miss. Sera collected from 28 of these children in early October were tested for opsonic antibodies to one of two prevalent skin strains of group A streptococci isolated from them on one or more occasions over the preceding 3 months. The two streptococcal strains (A and B) belong to M-types previously unrecognized. Ten subjects (36%) had antibody to their homologous serotypes detectable by the indirect bactericidal test: this included 6 of 10 subjects infected with strain B but only 4 of 18 infected with strain A (P < 0.05). Of 17 children who had strains A or B isolated from skin lesions only, 12% developed type-specific antibodies (TSA) against the infecting serotype. In contrast, 11 subjects had these strains isolated from throat cultures (either with or without associated pyoderma), and 72% had detectable TSA (P < 0.01). There was no demonstrable relationship between the development of antibodies to streptococcal extracellular products or to non-type-specific cellular antigens and the development of TSA. These results demonstrate that type-specific immune responses do occur following infection with pyoderma streptococci. The frequency with which such antibodies develop is variable and appears related to a number of factors, including the immunologic properties of the infecting strain and the site of bacterial colonization. Pharyngeal carriage may represent an important mechanism for development of acquired immunity to skin strains of group A streptococci. PMID:4435959

  7. M protein mediates streptococcal adhesion to HEp-2 cells.

    PubMed

    Wang, J R; Stinson, M W

    1994-02-01

    Streptococcus pyogenes adheres to human epithelial cells in vitro and in vivo. To identify adhesins, cell wall components were extracted from S. pyogenes M6 with alkali or by treatment with mutanolysin and lysozyme. HEp-2 cells were incubated with extracts of S. pyogenes M6 and then analyzed by Western blot (immunoblot) assays, using antibodies to S. pyogenes. Only one streptococcal component (62 kDa) was bound to HEp-2 cells and was identified serologically as M6 protein. Experiments with pepsin-cleaved fragments of M protein indicated that the binding site was located at the N-terminal half of the molecule. M protein was bound selectively to two trypsin-sensitive surface components, 97 and 205 kDa, of HEp-2 cells on nitrocellulose blots of sodium dodecyl sulfate-polyacrylamide gels. Tritium-labeled lipoteichoic acid bound to different HEp-2 cell components, 34 and 35 kDa, in a parallel experiment, indicating that lipoteichoic acid was not complexed with M protein and does not mediate M-protein binding. The four HEp-2 components were unrelated to fibronectin since they did not react with specific antibodies. An M-protein-deficient (M-) strain of streptococcus (JRS75), grown in chemically defined medium, showed 73% less adhesion activity to HEp-2 monolayers than an M+ strain (JRS4). Streptococcal adhesion was insensitive to competitive inhibition by selected monosaccharides. These results indicate that M protein binds directly to certain HEp-2 cell membrane components and mediates streptococcal adhesion. PMID:8300205

  8. Chlorhexidine susceptibilities of mutans streptococcal serotypes and ribotypes.

    PubMed Central

    Grönroos, L; Mättö, J; Saarela, M; Luoma, A R; Luoma, H; Jousimies-Somer, H; Pyhälä, L; Asikainen, S; Alaluusua, S

    1995-01-01

    The susceptibilities of 379 clinical mutans streptococcal isolates to chlorhexidine (CHX) were tested by agar dilution according to the standards of the National Committee for Clinical Laboratory Standards. Isolates were obtained from saliva samples of 34 young mothers who had high or moderate salivary levels of mutans streptococci at baseline. Samples were collected on three occasions, before childbirth, when each child was 6 months old, and 1 year later. Of these isolates, 50% were inhibited at 1 microgram of CHX per ml, 90% were inhibited at 2.0 micrograms/ml, and all were inhibited at 4.0 micrograms/ml. The MICs for Streptococcus mutans isolates (serotypes c, e, and f) were lower than those for Streptococcus sobrinus isolates (serotypes d and g). In some subjects, the MICs for isolates of the same serotype were different. This phenomenon was studied by ribotyping isolates (n = 45) from selected subjects (n = 7). It was found that if there were intraindividual differences in the MICs for isolates of the same serotype, then the ribotypes of these isolates were different. In order to decrease the mutans streptococcal infection risk for children, 24 mothers (test group) brushed their teeth periodically with a gel that contained 0.3% CHX digluconate and 0.2% NaF, pH 5.8, between the second and third sampling occasions. The gel was used twice a day for the first 10 days of each month. Development of resistant strains during CHX-NaF gel use was not detected. The serotype distribution of isolates from the test group after 1 year of periodic CHX-NaF gel use did not differ from that at baseline. Periodic CHX-NaF gel brushing did not lead to lower salivary mutans streptococcal counts. PMID:7785991

  9. [Disturbances of hemostasis in sepsis].

    PubMed

    Novotný, J; Penka, M

    2012-06-01

    Immune system and hemostasis are closely bound together. When one of these systems is activated, another is set in motion too. This is especially noticeable in polytraumas, inflammation, shocks etc. The most important activator of immune system and hemostasis is sepsis. In sepsis there is a vigorous stimulation of immune response because of a liberation of a lot of cytokines and proinflammatory molecules. This may lead to an extrem picture of systemic inflammatory response syndrome. In systemic inflammatory response syndrome a downregulation of thrombomodulin and endothelial protein C receptor on the surface of intact endothel may be detected and there is an upregulation of release of the tissue-type plasminogen activator with a switch to plasminogen activator inhibitor 1 release. There is lowering of activated protein C and fibrinolytic activation followed by fibrinolytic inhibition in septic patients. Consequently we can see consumption of coagulation factors, inhibitors (antithrombin, protein C, and tissue factor pathway inhibitor), microangiopatic hemolysis and thrombocytopenia with a picture of disseminated intravascular coagulation in these patients. The diagnosis of disseminated intravascular coagulation is not uniforme in the literature. Expression of tissue factor on monocytes and endothelium may aggravate this "circulus vitiosus" with serious microcirculatory failure in sense of MOF/MODS (mutliorgan failure/multiorgan dysfunction syndrome). The first steps in the therapy of sepsis represent the treatment of cause of sepsis, vigorous hydratation and maintenance of circulation and pulmonary function, glycemic control etc, the prevention and blocking of the undesirable activation of hemostasis and inflammation being equally important. The treatment with minidoses of heparin was implemented in the past and the question, if this therapy is indicated is not answered yet. The clinical studies of the suitability of the treatment with natural inhibitors of

  10. Estrogen sulfotransferase ablation sensitizes mice to sepsis

    PubMed Central

    Chai, Xiaojuan; Guo, Yan; Jiang, Mengxi; Hu, Bingfang; Li, Zhigang; Fan, Jie; Deng, Meihong; Billiar, Timothy R.; Kucera, Heidi; Gaikwad, Nilesh W.; Xu, Meishu; Lu, Peipei; Yan, Jiong; Fu, Haiyan; Liu, Youhua; Yu, Lushan; Huang, Min; Zeng, Su; Xie, Wen

    2015-01-01

    Sepsis is the host's deleterious systemic inflammatory response to microbial infections. Here we report an essential role for the estrogen sulfotransferase (EST or SULT1E1), a conjugating enzyme that sulfonates and deactivates estrogens, in sepsis response. Both the cecal ligation and puncture (CLP) and lipopolysacharide (LPS) models of sepsis induce the expression of EST and compromise the activity of estrogen, an anti-inflammatory hormone. Surprisingly, EST ablation sensitizes mice to sepsis-induced death. Mechanistically, EST ablation attenuates sepsis-induced inflammatory responses due to compromised estrogen deactivation, leading to increased sepsis lethality. In contrast, transgenic overexpression of EST promotes estrogen deactivation and sensitizes mice to CLP-induced inflammatory response. The induction of EST by sepsis is NF-κB dependent and EST is a NF-κB target gene. The reciprocal regulation of inflammation and EST may represent a yet to be explored mechanism of endocrine regulation of inflammation, which has an impact on the clinical outcome of sepsis. PMID:26259151

  11. Oestrogen sulfotransferase ablation sensitizes mice to sepsis.

    PubMed

    Chai, Xiaojuan; Guo, Yan; Jiang, Mengxi; Hu, Bingfang; Li, Zhigang; Fan, Jie; Deng, Meihong; Billiar, Timothy R; Kucera, Heidi R; Gaikwad, Nilesh W; Xu, Meishu; Lu, Peipei; Yan, Jiong; Fu, Haiyan; Liu, Youhua; Yu, Lushan; Huang, Min; Zeng, Su; Xie, Wen

    2015-01-01

    Sepsis is the host's deleterious systemic inflammatory response to microbial infections. Here we report an essential role for the oestrogen sulfotransferase (EST or SULT1E1), a conjugating enzyme that sulfonates and deactivates estrogens, in sepsis response. Both the caecal ligation and puncture (CLP) and lipopolysaccharide models of sepsis induce the expression of EST and compromise the activity of oestrogen, an anti-inflammatory hormone. Surprisingly, EST ablation sensitizes mice to sepsis-induced death. Mechanistically, EST ablation attenuates sepsis-induced inflammatory responses due to compromised oestrogen deactivation, leading to increased sepsis lethality. In contrast, transgenic overexpression of EST promotes oestrogen deactivation and sensitizes mice to CLP-induced inflammatory response. The induction of EST by sepsis is NF-κB dependent and EST is a NF-κB-target gene. The reciprocal regulation of inflammation and EST may represent a yet-to-be-explored mechanism of endocrine regulation of inflammation, which has an impact on the clinical outcome of sepsis. PMID:26259151

  12. Improving the Odds of Surviving Sepsis

    MedlinePlus

    ... Improving the Odds of Surviving Sepsis Inside Life Science View All Articles | Inside Life Science Home Page Improving the Odds of Surviving Sepsis ... Threatening Bacterial Infection Remains Mysterious This Inside Life Science article also appears on LiveScience . Learn about related ...

  13. Cytokine profile in elderly patients with sepsis

    PubMed Central

    Kumar, Anil T.; Sudhir, U.; Punith, K.; Kumar, Rahul; Ravi Kumar, V. N.; Rao, Medha Y.

    2009-01-01

    Context: Sepsis is a serious health problem in the elderly with a high degree of mortality. There is very limited data available in elderly subjects regarding the markers for sepsis. Development of good markers will help in overall management and prediction of sepsis. Objectives: Serial estimation of Interleukin-6 (IL-6) and Tumor Necrosis Factor-Alpha (TNF-α) and their correlation with mortality in sepsis in elderly patients and to determine the influence of gender on cytokine production and mortality in elderly patients with sepsis. Settings and Design: The prospective study was conducted at our tertiary care center from April 2007 to September 2008. Elderly Patients satisfying the Systemic Inflammatory Response Syndrome (SIRS) criteria were included. Methods and Material: TNF-α and IL-6 were estimated in 30 elderly patients admitted to our intensive care unit with SIRS and sepsis. The estimations were done on day 1, 3 and 7 of admission. Statistical Analysis Used: Student and paired ‘t’ tests, and ANOVA, which were further followed up by post-hoc ‘t’ tests with Bonferroni correction using SPSS. Results: Reducing levels of IL-6 levels from day 1 to 7 was found in the survivor group. TNF-α level was significantly low on day 1 in the nonsurvivor female group. Conclusions: Serial estimation of cytokines in elderly patients with sepsis will help in prediction of mortality. Female gender was an independent predictor of increased morality in critically ill patients with sepsis. PMID:19881187

  14. Post-streptococcal vasculopathy with evolution to Degos' disease.

    PubMed

    Pati, Sandipan; Muley, Suraj A; Grill, Marie F; Coons, Stephen; Walker, Russell

    2011-01-15

    Degos' disease or malignant atrophic papulosis is a rare disseminated occlusive vasculopathy affecting the skin, gastrointestinal tract, central nervous system, and less often other organ systems. The exact etiology of this vasculopathy has not been established. Infections, autoimmune disease and coagulation defects have been proposed as underlying pathogenic mechanisms, but none have been confirmed. Here, we report the clinical, radiological and histopathologic features of Degos' disease in a 41-year-old man following streptococcal throat infection. Prior postulated hypothesis as post-infectious immunologic mechanism may be further supported by this case. PMID:21035145

  15. Hemostasis and endothelial damage during sepsis.

    PubMed

    Johansen, Maria Egede

    2015-08-01

    The sepsis syndrome represents a disease continuum, including severe sepsis and septic shock associated with high mortality. One of the main problems in severe sepsis and septic shock, resulting in organ failure and death, are disturbances in the hemostasis due to sepsis-related coagulopathy. Sepsis-related coagulopathy affects not only traditional coagulation factors, but also the platelets and endothelium. Functional testing of the hemostatic system has found application in critical illness. Thrombelastography (TEG) provides an overview of the hemostatic system allowing for an evaluation of interactions between coagulation factors and platelets. Additionally, the role of the endothelium during sepsis can be explored through testing of biomarkers of endothelial damage. The three studies comprising this PhD thesis all investigate important aspects of the disturbed hemostasis during sepsis, including endothelial damage. Together, the specific findings from the three studies improve the existing understanding of sepsis-related coagulopathy, and the possible influences of some of the treatments offered these patients. The first study investigates the occurrence of antimicrobial-induced thrombocytopenia among critically ill patients. In sepsis, thrombocytopenia is a predictor of poor outcome, and reports, of mainly casuistic nature, have previously hypothesized that specific antimicrobial agents could induce in sepsis-related thrombocytopenia. This hypothesis was tested using a randomized designed set-up, encompassing 1147 critically ill patients, and no significant difference in risk of thrombocytopenia was observed among patients receiving large amounts of antimicrobials vs. patients receiving standard-of-care. As a consequence, the risk of antimicrobial-induced thrombocytopenia in the general population of critically ill patients seemingly does not represent a substantial problem and thrombocytopenia during critical illness is most likely due to other factors such

  16. Purpura fulminans and severe sepsis due to Pasteurella multocida infection in an immunocompetent patient.

    PubMed

    Konda, Monoj Kumar; Chang, Stephanie; Zaccheo, Mathew

    2016-01-01

    A 75-year-old woman was admitted into the intensive care unit, with severe sepsis and renal failure. She developed purpura fulminans (PF) of bilateral upper and lower extremities along with gangrene on the tips of her fingers and toes. Blood cultures confirmed Pasteurella multocida as the causative organism. Despite aggressive supportive measures, the patient remained dependent on high doses of vasopressors and the gangrene progressed. She ultimately succumbed to her underlying severe sepsis. PF is a rare and fatal dermatological emergency commonly seen in children, but it also occurs in adults. Acute infectious PF occurs secondary to severe sepsis and P. multocida is a rare cause of PF. To the best of our knowledge, this is only the second reported case of PF due to P. multocida in an adult. PMID:27298290

  17. Evaluation of IL-6, CRP and hs-CRP as Early Markers of Neonatal Sepsis

    PubMed Central

    Ganesan, Purushothaman; Sattar, Shameem Banu Abdul; Shankar, Shenbaga Lalitha

    2016-01-01

    Introduction Bacterial sepsis is a life threatening crisis with high mortality and morbidity in neonates. Due to non-specific clinical presentation, diagnosis of sepsis is still a challenge. It can be diagnosed by blood culture but it is time consuming. So, a reliable marker is needed for the diagnosis of neonatal sepsis so that early treatment can be initiated. Various cytokines, chemokines, acute phase reactants, cell surface markers and interferons have been evaluated to find out the effective marker for early diagnosis of neonatal sepsis. In this study, levels of IL-6, CRP and hs-CRP have been analysed which would favour the diagnosis of neonatal sepsis. Aim This study aimed to detect the levels of IL-6, CRP and hs-CRP in clinically suspected cases of neonatal sepsis and to evaluate and analyze the above parameters as the early markers of neonatal sepsis in comparison with blood culture. Materials and Methods Eighty neonates were included in this study of which 40 were clinically suspected cases of neonatal sepsis who met the inclusion criteria and the other 40 were normal healthy neonates that were taken as controls. After obtaining written informed consent from either parent of all neonates, venous blood samples were collected. Blood culture was performed by conventional method. Estimation of serum IL-6 was done by ELISA method and serum CRP and hs-CRP were done by immunofluorescence assay. Results The CRP level >13.49 mg/l showed sensitivity and specificity of 80% and 65.70% respectively. The IL-6 >51.29 pg/ml showed sensitivity of 100% and specificity of 62.86% and hs-CRP showed sensitivity of 90% and specificity of 32.86%. Combination of IL-6 and CRP showed sensitivity and specificity of 100% and 75.71% respectively. Conclusion Our study suggests that IL-6 is a highly sensitive marker and CRP is a more specific marker for the diagnosis of neonatal sepsis. hs-CRP is a less reliable marker. So, the combination of IL-6 and CRP are the better predictors of

  18. Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis

    PubMed Central

    Takasu, Osamu; Gaut, Joseph P.; Watanabe, Eizo; To, Kathleen; Fagley, R. Eliot; Sato, Brian; Jarman, Steve; Efimov, Igor R.; Janks, Deborah L.; Srivastava, Anil; Bhayani, Sam B.; Drewry, Anne; Swanson, Paul E.

    2013-01-01

    Rationale: The mechanistic basis for cardiac and renal dysfunction in sepsis is unknown. In particular, the degree and type of cell death is undefined. Objectives: To evaluate the degree of sepsis-induced cardiomyocyte and renal tubular cell injury and death. Methods: Light and electron microscopy and immunohistochemical staining for markers of cellular injury and stress, including connexin-43 and kidney-injury-molecule-1 (Kim-1), were used in this study. Measurements and Main Results: Rapid postmortem cardiac and renal harvest was performed in 44 septic patients. Control hearts were obtained from 12 transplant and 13 brain-dead patients. Control kidneys were obtained from 20 trauma patients and eight patients with cancer. Immunohistochemistry demonstrated low levels of apoptotic cardiomyocytes (<1–2 cells per thousand) in septic and control subjects and revealed redistribution of connexin-43 to lateral membranes in sepsis (P < 0.020). Electron microscopy showed hydropic mitochondria only in septic specimens, whereas mitochondrial membrane injury and autophagolysosomes were present equally in control and septic specimens. Control kidneys appeared relatively normal by light microscopy; 3 of 20 specimens showed focal injury in approximately 1% of renal cortical tubules. Conversely, focal acute tubular injury was present in 78% of septic kidneys, occurring in 10.3 ± 9.5% and 32.3 ± 17.8% of corticomedullary-junction tubules by conventional light microscopy and Kim-1 immunostains, respectively (P < 0.01). Electron microscopy revealed increased tubular injury in sepsis, including hydropic mitochondria and increased autophagosomes. Conclusions: Cell death is rare in sepsis-induced cardiac dysfunction, but cardiomyocyte injury occurs. Renal tubular injury is common in sepsis but presents focally; most renal tubular cells appear normal. The degree of cell injury and death does not account for severity of sepsis-induced organ dysfunction. PMID:23348975

  19. Predictive Value of IL-8 for Sepsis and Severe Infections after Burn Injury - A Clinical Study

    PubMed Central

    Kraft, Robert; Herndon, David N; Finnerty, Celeste C; Cox, Robert A; Song, Juquan; Jeschke, Marc G

    2014-01-01

    The inflammatory response induced by burn injury contributes to increased incidence of infections, sepsis, organ failure, and mortality. Thus, monitoring post-burn inflammation is of paramount importance but so far there are no reliable biomarkers available to monitor and/or predict infectious complications after burn. As IL-8 is a major mediator for inflammatory responses, the aim of our study was to determine whether IL-8 expression can be used to predict post-burn sepsis, infections, and mortality other outcomes post-burn. Plasma cytokines, acute phase proteins, constitutive proteins, and hormones were analyzed during the first 60 days post injury from 468 pediatric burn patients. Demographics and clinical outcome variables (length of stay, infection, sepsis, multiorgan failure (MOF), and mortality were recorded. A cut-off level for IL-8 was determined using receiver operating characteristic (ROC) analysis. Statistical significance is set at (p<0.05). ROC analysis identified a cut-off level of 234 pg/ml for IL-8 for survival. Patients were grouped according to their average IL-8 levels relative to this cut off and stratified into high (H) (n=133) and low (L) (n=335) groups. In the L group, regression analysis revealed a significant predictive value of IL-8 to percent of total body surface area (TBSA) burned and incidence of MOF (p<0.001). In the H group IL-8 levels were able to predict sepsis (p<0.002). In the H group, elevated IL-8 was associated with increased inflammatory and acute phase responses compared to the L group (p<0.05). High levels of IL-8 correlated with increased MOF, sepsis, and mortality. These data suggest that serum levels of IL-8 may be a valid biomarker for monitoring sepsis, infections, and mortality in burn patients. PMID:25514427

  20. Nitric oxide, prostaglandins, and impaired cerebral blood flow autoregulation in group B streptococcal neonatal meningitis.

    PubMed

    Mertineit, C; Samlalsingh-Parker, J; Glibetic, M; Ricard, G; Noya, F J; Aranda, J V

    2000-03-01

    Impaired autoregulation of cerebral blood flow (CBF) contributes to CNS damage during neonatal meningitis. We tested (i) the hypothesis that cerebrovascular autoregulation is impaired during early onset group B streptococcal (GBS) meningitis, (ii) whether this impairment is regulated by vasoactive mediators such as prostaglandins and (or) nitric oxide (NO), and (iii) whether this impairment is preventable by specific and (or) nonspecific inhibitors: dexamethasone, ibuprofen, and Nomega-nitro-L-arginine, a NO inhibitor. Sterile saline or 10(9) colony-forming units (cfu) of heat-killed GBS was injected into the cerebral ventricle of newborn piglets. CBF autoregulation was determined by altering cerebral perfusion pressure (CPP) with balloon-tipped catheters placed in the aorta. GBS produced a narrow range of CBF autoregulation due to an impairment at the upper limit of CPP. We report that in vivo in the early stages (first 2 h) of induced GBS inflammation (i) GBS impairs the upper limit of cerebrovascular autoregulation; (ii) ibuprofen, dexamethasone, and Nomega-nitro-L-arginine not only prevent this GBS-induced autoregulatory impairment but improve the range of cerebrovascular autoregulation; (iii) these autoregulatory changes do not involve circulating cerebral prostanoids; and (iv) the observed changes correlate with the induction of NO synthase gene expression. Thus, acute early onset GBS-induced impairment of the upper limit of CBF autoregulation can be correlated with increases of NO synthase production, suggesting that NO is a vasoactive mediator of CBF. PMID:10721813

  1. A link between perianal strep and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS).

    PubMed

    Toufexis, Megan; Deoleo, Caroline; Elia, Josephine; Murphy, Tanya K

    2014-04-01

    Perianal streptococcal dermatitis is an infection caused by group A streptococcus (GAS). Children with a pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) phenotype may have tics or obsessive compulsive symptoms secondary to a systemic immune activation by GAS infecting perianal areas. In this retrospective case series, the authors describe three children with symptoms consistent with PANDAS and a confirmed perianal streptococcal dermatitis as the likely infectious trigger. Concomitant perianal dermatitis and new-onset obsessive-compulsive symptoms and/or tics are strong indications for perianal culture and rapid antigen detection test in young children. PMID:24763762

  2. [Group a streptococcal necrotizing fasciitis of the genital area (Fournier's gangrene): a case report].

    PubMed

    Ochi, Atsuhiko; Naoi, Makito; Enatsu, Noritoshi; Fujisaki, Akira; Funada, Satoshi; Suzuki, Koichiro; Shiga, Naoki; Ota, Tomonori; Kuji, Hiroshi; Hosokawa, Naoto; Iwata, Kentaro

    2011-07-01

    A necrotizing fasciitis especially caused by group A streptococcal infection is a life-threatening disease. This infection cause death due to septic shock and multiple organ failure in a short time without the immediate and adequate treatment. Currently a rapid test kit for streptococcal pharyngitis (strep A) is useful for prediction of group A streptococcal infection. We here demonstrate a 61 years old man's case of life-saved necrotizing fasciitis in genital area (Fournier's gangrene) by group A streptococcus infection, and usefulness of this kit for rapid diagnosis, aggressive debridement, and selection of adequate antibiotics. PMID:21961278

  3. Anti-brain antibodies in PANDAS versus uncomplicated streptococcal infection.

    PubMed

    Pavone, Piero; Bianchini, Rio; Parano, Enrico; Incorpora, Gemma; Rizzo, Renata; Mazzone, Luigi; Trifiletti, Rosario R

    2004-02-01

    The objective of this study was to assess brain involvement through the presence of antineuronal antibodies in Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) and in uncomplicated active Group A streptococcal infection. We compared serum antibrain antibody to human basal ganglia sections assessed by indirect tissue immunofluorescence in two groups: a PANDAS group, comprised of 22 patients (mean age 10.1 years; 20 male, 2 female) who met strict National Institutes of Mental Health diagnostic criteria for PANDAS and had clinically active tics or obsessive-compulsive disorder, or both; and a GABHS control group consisting of 22 patients (mean age 9.1 years; 15 mol/L, 7 female) with clinical evidence of active Group A beta-hemolytic streptococcal (GABHS) infection confirmed by throat culture and elevated antistreptolysin O titers but without history or clinical evidence of tics or obsessive-compulsive disorder. We observed positive anti-basal ganglia staining (defined as detectable staining at 1:10 serum dilution) in 14/22 patients in the PANDAS group (64%) but only 2/22 (9%) in the GABHS control group (P < 0.001, Fisher's exact test). These results suggest that antibrain antibodies are present in children with PANDAS that cannot be explained merely by a history of GABHS infection. PMID:14984902

  4. Streptococcal C5a peptidase is a highly specific endopeptidase.

    PubMed Central

    Cleary, P P; Prahbu, U; Dale, J B; Wexler, D E; Handley, J

    1992-01-01

    Compositional analysis of streptococcal C5a peptidase (SCPA) cleavage products from a synthetic peptide corresponding to the 20 C-terminal residues of C5a demonstrated that the target cleavage site is His-Lys rather than Lys-Asp, as previously suggested. A C5a peptide analog with Lys replaced by Gln was also subject to cleavage by SCPA. This confirmed that His-Lys rather than Lys-Asp is the scissile bond. Cleavage at histidine is unusual but is the same as that suggested for a peptidase produced by group B streptococci. Native C5 protein was also resistant to SCPA, suggesting that the His-Lys bond is inaccessible prior to proteolytic cleavage by C5 convertase. These experiments showed that the streptococcal C5a peptidase is highly specific for C5a and suggest that its function is not merely to process protein for metabolic consumption but to act primarily to eliminate this chemotactic signal from inflammatory foci. Images PMID:1452354

  5. Assessment of Diagnostic and Prognostic Role of Copeptin in the Clinical Setting of Sepsis

    PubMed Central

    Battista, Stefania; Audisio, Umberto; Galluzzo, Claudia; Maggiorotto, Matteo; Masoero, Monica; Forno, Daniela; Pizzolato, Elisa; Ulla, Marco; Lucchiari, Manuela; Vitale, Annarita; Moiraghi, Corrado; Lupia, Enrico; Settanni, Fabio; Mengozzi, Giulio

    2016-01-01

    The diagnostic and prognostic usefulness of copeptin were evaluated in septic patients, as compared to procalcitonin assessment. In this single centre and observational study 105 patients were enrolled: 24 with sepsis, 25 with severe sepsis, 15 with septic shock, and 41 controls, divided in two subgroups (15 patients with gastrointestinal bleeding and 26 with suspected SIRS secondary to trauma, acute coronary syndrome, and pulmonary embolism). Biomarkers were determined at the first medical evaluation and thereafter 24, 48, and 72 hours after admission. Definitive diagnosis and in-hospital survival rates at 30 days were obtained through analysis of medical records. At entry, copeptin proved to be able to distinguish cases from controls and also sepsis group from septic shock group, while procalcitonin could distinguish also severe sepsis from septic shock group. Areas under the ROC curve for copeptin and procalcitonin were 0.845 and 0.861, respectively. Noteworthy, patients with copeptin concentrations higher than the threshold value (23.2 pmol/L), calculated from the ROC curve, at admission presented higher 30-day mortality. No significant differences were found in copeptin temporal profile among different subgroups. Copeptin showed promising diagnostic and prognostic role in the management of sepsis, together with its possible role in monitoring the response to treatment. PMID:27366743

  6. Actinonin, a meprin A inhibitor, protects the renal microcirculation during sepsis.

    PubMed

    Wang, Zhen; Herzog, Christian; Kaushal, Gur P; Gokden, Neriman; Mayeux, Philip R

    2011-02-01

    Sepsis-induced acute kidney injury occurs in 20% to 50% of septic patients and nearly doubles the mortality rate of sepsis. Because treatment in the septic patient is usually begun only after the onset of symptoms, therapy that is effective even when delayed would have the greatest impact on patient survival. The metalloproteinase meprin A, an oligomeric complex made of α- and β-subunits, is highly expressed at the brush-border membranes of the kidney and capable of degrading numerous substrates including extracellular matrix proteins and cytokines. The goal of the present study was to compare the therapeutic potential of actinonin, an inhibitor of meprin A, when administered before and after the onset of sepsis. Mice were treated with actinonin at 30 min before or 7 h after induction of sepsis by cecal ligation and puncture (CLP). Intravital videomicroscopy was used to image renal peritubular capillary perfusion and reactive nitrogen species. Actinonin treatment 30 min before CLP reduced IL-1β levels and prevented the fall in renal capillary perfusion at 7 and 18 h. Actinonin also prevented the fall in renal capillary perfusion even when administered at 7 h after CLP. In addition, even late administration of actinonin preserved renal morphology and lowered blood urea nitrogen and serum creatinine concentrations. These data suggest that agents such as actinonin should be evaluated further as possible therapeutic agents because targeting both the early systemic and later organ-damaging effects of sepsis should have the highest likelihood of success. PMID:20577148

  7. Assessment of Diagnostic and Prognostic Role of Copeptin in the Clinical Setting of Sepsis.

    PubMed

    Battista, Stefania; Audisio, Umberto; Galluzzo, Claudia; Maggiorotto, Matteo; Masoero, Monica; Forno, Daniela; Pizzolato, Elisa; Ulla, Marco; Lucchiari, Manuela; Vitale, Annarita; Moiraghi, Corrado; Lupia, Enrico; Settanni, Fabio; Mengozzi, Giulio

    2016-01-01

    The diagnostic and prognostic usefulness of copeptin were evaluated in septic patients, as compared to procalcitonin assessment. In this single centre and observational study 105 patients were enrolled: 24 with sepsis, 25 with severe sepsis, 15 with septic shock, and 41 controls, divided in two subgroups (15 patients with gastrointestinal bleeding and 26 with suspected SIRS secondary to trauma, acute coronary syndrome, and pulmonary embolism). Biomarkers were determined at the first medical evaluation and thereafter 24, 48, and 72 hours after admission. Definitive diagnosis and in-hospital survival rates at 30 days were obtained through analysis of medical records. At entry, copeptin proved to be able to distinguish cases from controls and also sepsis group from septic shock group, while procalcitonin could distinguish also severe sepsis from septic shock group. Areas under the ROC curve for copeptin and procalcitonin were 0.845 and 0.861, respectively. Noteworthy, patients with copeptin concentrations higher than the threshold value (23.2 pmol/L), calculated from the ROC curve, at admission presented higher 30-day mortality. No significant differences were found in copeptin temporal profile among different subgroups. Copeptin showed promising diagnostic and prognostic role in the management of sepsis, together with its possible role in monitoring the response to treatment. PMID:27366743

  8. Nephrilin peptide modulates a neuroimmune stress response in rodent models of burn trauma and sepsis

    PubMed Central

    Mascarenhas, Desmond D; ElAyadi, Amina; Singh, Baljit K; Prasai, Anesh; Hegde, Sachin D; Herndon, David N; Finnerty, Celeste C

    2013-01-01

    Sepsis occurs three times more often in burns than in other types of trauma, suggesting an overlap or synergy between underlying immune mechanisms in burn trauma and sepsis. Nephrilin peptide, a designed inhibitor of mTORC2, has previously been shown to modulate a neuroimmune stress response in rodent models of xenobiotic and metabolic stress. Here we investigate the effect of nephrilin peptide administration in different rodent models of burn trauma and sepsis. In a rat scald burn model, daily subcutaneous bolus injection of 4 mg/kg nephrilin significantly reduced the elevation of kidney tissue substance P, S100A9 gene expression, PMN infiltration and plasma inflammatory markers in the acute phase, while suppressing plasma CCL2 and insulin C-peptide, kidney p66shc-S36 phosphorylation and PKC-beta and CGRP in dorsal root ganglia at 14 days (chronic phase). In the mouse cecal ligation and puncture model of sepsis, nephrilin fully protected mice from mortality between surgery and day 7, compared to 67% mortality in saline-treated animals, while significantly reducing elevated CCL2 in plasma. mTORC2 may modulate important neuroimmune responses in both burn trauma and sepsis. PMID:24273694

  9. Sepsis

    MedlinePlus

    ... 100.4°F [38°C] and above rectal temperature) in newborns and young infants labored or unusual breathing change in skin color (paler than usual or mildly bluish) or a rash listlessness or lethargy change in the sound of the baby's cry or excessive crying change ...

  10. Antithrombotic Agents in the Management of Sepsis.

    PubMed

    Iqbal, Omer; Tobu, Mahmut; Hoppenstead, Debra; Aziz, Salim; Messmore, Harry; Fareed, Jawed

    2002-09-01

    Sepsis, a systemic inflammatory syndrome, is a response to infection and when associated with multiple organ dysfunction is termed, severe sepsis. It remains a leading cause of mortality in the critically ill. The response to the invading bacteria may be considered as a balance between proinflammatory and antiinflammatory reaction. While an inadequate proinflammatory reaction and a strong antiinflammatory response could lead to overwhelming infection and death of the patient, a strong and uncontrolled proinflammatory response, manifested by the release of proinflammatory mediators may lead to microvascular thrombosis and multiple organ failure. Endotoxin triggers sepsis by releasing various mediators including tumor necrosis factor-alpha and interleukin-1(IL-1). These cytokines activate the complement and coagulation systems, release adhesion molecules, prostaglandins, leukotrienes, reactive oxygen species and nitric oxide (NO). Other mediators involved in the sepsis syndrome include IL-1, IL-6 and IL-8; arachidonic acid metabolites; platelet activating factor (PAF); histamine; bradykinin; angiotensin; complement components and vasoactive intestinal peptide. These proinflammatory responses are counteracted by IL-10. Most of the trials targeting the different mediators of proinflammatory response have failed due a lack of correct definition of sepsis. Understanding the exact pathophysiology of the disease will enable better treatment options. Targeting the coagulation system with various anticoagulant agents including antithrombin, activated protein C (APC), tissue factor pathway inhibitor (TFPI) is a rational approach. Many clinical trials have been conducted to evaluate these agents in severe sepsis. While trials on antithrombin and TFPI were not so successful, the double-blind, placebo-controlled, phase III trial of recombinant human activated protein C worldwide evaluation in severe sepsis (PROWESS) was successful, significantly decreasing mortality when

  11. Invasive Group B Streptococcal Disease in South Africa: Importance of Surveillance Methodology.

    PubMed

    Quan, Vanessa; Verani, Jennifer R; Cohen, Cheryl; von Gottberg, Anne; Meiring, Susan; Cutland, Clare L; Schrag, Stephanie J; Madhi, Shabir A

    2016-01-01

    Data on neonatal group B streptococcal (GBS) invasive disease burden are needed to refine prevention policies. Differences in surveillance methods and investigating for cases can lead to varying disease burden estimates. We compared the findings of laboratory-based passive surveillance for GBS disease across South Africa, and for one of the provinces compared this to a real-time, systematic, clinical surveillance in a population-defined region in Johannesburg, Soweto. Passive surveillance identified a total of 799 early-onset disease (EOD, <7 days age) and 818 LOD (late onset disease, 7-89 days age) cases nationwide. The passive surveillance provincial incidence varied for EOD (range 0.00 to 1.23/1000 live births), and was 0.03 to 1.04/1000 live births for LOD. The passive surveillance rates for Soweto, were not significantly different compared to those from the systematic surveillance (EOD 1.23 [95%CI 1.06-1.43] vs. 1.50 [95%CI 1.30-1.71], respectively, rate ratio 0.82 [95%CI 0.67-1.01]; LOD 1.04 [95% CI 0.90-1.23] vs. 1.22 [95%CI 1.05-1.42], rate ratio 0.85 [95% CI 0.68-1.07]). A review of the few cases missed in the passive system in Soweto, suggested that missing key identifiers, such as date of birth, resulted in their omission during the electronic data extraction process. Our analysis suggests that passive surveillance provides a modestly lower estimate of invasive GBS rates compared to real time sentinel-site systematic surveillance, however, this is unlikely to be the reason for the provincial variability in incidence of invasive GBS disease in South Africa. This, possibly reflects that invasive GBS disease goes undiagnosed due to issues related to access to healthcare, poor laboratory capacity and varying diagnostic procedures or empiric antibiotic treatment of neonates with suspected sepsis in the absence of attempting to making a microbiological diagnosis. An efficacious GBS vaccine for pregnant women, when available, could be used as a probe to better

  12. Invasive Group B Streptococcal Disease in South Africa: Importance of Surveillance Methodology

    PubMed Central

    Cohen, Cheryl; von Gottberg, Anne; Meiring, Susan; Cutland, Clare L.; Schrag, Stephanie J.; Madhi, Shabir A.

    2016-01-01

    Data on neonatal group B streptococcal (GBS) invasive disease burden are needed to refine prevention policies. Differences in surveillance methods and investigating for cases can lead to varying disease burden estimates. We compared the findings of laboratory-based passive surveillance for GBS disease across South Africa, and for one of the provinces compared this to a real-time, systematic, clinical surveillance in a population-defined region in Johannesburg, Soweto. Passive surveillance identified a total of 799 early-onset disease (EOD, <7 days age) and 818 LOD (late onset disease, 7–89 days age) cases nationwide. The passive surveillance provincial incidence varied for EOD (range 0.00 to 1.23/1000 live births), and was 0.03 to 1.04/1000 live births for LOD. The passive surveillance rates for Soweto, were not significantly different compared to those from the systematic surveillance (EOD 1.23 [95%CI 1.06–1.43] vs. 1.50 [95%CI 1.30–1.71], respectively, rate ratio 0.82 [95%CI 0.67–1.01]; LOD 1.04 [95% CI 0.90–1.23] vs. 1.22 [95%CI 1.05–1.42], rate ratio 0.85 [95% CI 0.68–1.07]). A review of the few cases missed in the passive system in Soweto, suggested that missing key identifiers, such as date of birth, resulted in their omission during the electronic data extraction process. Our analysis suggests that passive surveillance provides a modestly lower estimate of invasive GBS rates compared to real time sentinel-site systematic surveillance, however, this is unlikely to be the reason for the provincial variability in incidence of invasive GBS disease in South Africa. This, possibly reflects that invasive GBS disease goes undiagnosed due to issues related to access to healthcare, poor laboratory capacity and varying diagnostic procedures or empiric antibiotic treatment of neonates with suspected sepsis in the absence of attempting to making a microbiological diagnosis. An efficacious GBS vaccine for pregnant women, when available, could be used as a

  13. Dysglycemia and Glucose Control During Sepsis.

    PubMed

    Plummer, Mark P; Deane, Adam M

    2016-06-01

    Sepsis predisposes to disordered metabolism and dysglycemia; the latter is a broad term that includes hyperglycemia, hypoglycemia, and glycemic variability. Dysglycemia is a marker of illness severity. Large randomized controlled trials have provided considerable insight into the optimal blood glucose targets for critically ill patients with sepsis. However, it may be that the pathophysiologic consequences of dysglycemia are dynamic throughout the course of a septic insult and also altered by premorbid glycemia. This review highlights the relevance of hyperglycemia, hypoglycemia, and glycemic variability in patients with sepsis with an emphasis on a rational approach to management. PMID:27229647

  14. Sepsis Resuscitation: Fluid Choice and Dose.

    PubMed

    Semler, Matthew W; Rice, Todd W

    2016-06-01

    Sepsis is a common and life-threatening inflammatory response to severe infection treated with antibiotics and fluid resuscitation. Despite the central role of intravenous fluid in sepsis management, fundamental questions regarding which fluid and in what amount remain unanswered. Recent advances in understanding the physiologic response to fluid administration, and large clinical studies examining resuscitation strategies, fluid balance after resuscitation, colloid versus crystalloid solutions, and high- versus low-chloride crystalloids, inform the current approach to sepsis fluid management and suggest areas for future research. PMID:27229641

  15. Sepsis after autologous fat grafting.

    PubMed

    Talbot, Simon G; Parrett, Brian M; Yaremchuk, Michael J

    2010-10-01

    Autologous fat grafting is an increasingly popular technique, with numerous examples of excellent results. Adherence to key principles, including sterile technique and low-volume injection throughout layers of tissue, appears to be critical to obtaining good results. Reports of adverse outcomes are infrequent, but several case reports document both infectious and aesthetic complications. This case report represents an extreme complication, including abscess formation, life-threatening sepsis, and residual deformity. It serves as yet another reminder that early adoption of surgical procedures by those without a sound understanding of the underlying principles and techniques can have disastrous consequences. Furthermore, physicians operating on any patient must understand the potential for complications and be able to manage these appropriately when they occur. PMID:20885205

  16. Sepsis, venous return, and teleology.

    PubMed

    McNeilly, R G

    2014-11-01

    An understanding of heart-circulation interaction is crucial to our ability to guide our patients through an episode of septic shock. Our knowledge has advanced greatly in the last one hundred years. There are, however, certain empirical phenomena that may lead us to question the wisdom of our prevailing treatment algorithm. Three extreme but iatrogenically possible haemodynamic states exist. Firstly, inappropriately low venous return; secondly, overzealous arteriolar constriction; and finally, misguided inotropy and chronotropy. Following an unsuccessful fluid challenge, it would be logical to first set the venous tone, then set the cardiac rate and contractility, and finally set the peripheral vascular resistance. It is hypothesized that a combination of dihydroergotamine, milrinone and esmolol should be superior to a combination of noradrenaline and dobutamine for surviving sepsis. PMID:25245463

  17. Viridans Group Streptococcal Infections in Children After Chemotherapy or Stem Cell Transplantation: A 10-year Review From a Tertiary Pediatric Hospital.

    PubMed

    Nielsen, Maryke J; Claxton, Sarah; Pizer, Barry; Lane, Steven; Cooke, Richard P D; Paulus, Stéphane; Carrol, Enitan D

    2016-03-01

    Viridans Group Streptococci (VGS) are associated with high mortality rates in febrile neutropenia; yet there are no recent European pediatric studies to inform antimicrobial therapy. The aim of this study was to describe the characteristics, outcome, and resistance patterns of children with VGS bacteremia (VGSB) undergoing treatment of malignancy or hematopoietic stem cell transplant.Patients aged 0 to 18 years, admitted to a tertiary pediatric hemato-oncology center with VGSB, from 2003 to 2013, were included in the study. All data were collected retrospectively from medical records.A total of 54 bacteremic episodes occurred in 46 patients. The most common underlying diagnosis was relapsed acute lymphoblastic leukemia.Streptococcus mitis was the most frequent organism. A total of 30% of isolates were resistant to penicillin and 100% sensitive to vancomycin. There were 8 episodes (14.8%) of Viridans Group Streptococcal Shock Syndrome; 6 resulted in admission to intensive care and 3 of these patients died of multiorgan failure.The potentially fatal nature of VGSB is confirmed. The high risk in relapsed acute lymphoblastic leukemia is of note. Research is needed to develop risk-stratification scores that identify children at risk of Viridans Group Streptococcal Shock Syndrome to guide empirical antimicrobial therapy in febrile neutropenia. PMID:26945409

  18. A prospective treatment for sepsis.

    PubMed

    Shahidi Bonjar, Mohammad Rashid; Shahidi Bonjar, Leyla

    2015-01-01

    The present paper proposes a prospective auxiliary treatment for sepsis. There exists no record in the published media on the subject. As an auxiliary therapy, efficacious extracorporeal removal of sepsis-causing bacterial antigens and their toxins (BATs) from the blood of septic patients is discussed. The principal component to this approach is a bacterial polyvalent antibody-column (BPVAC), which selectively traps wide spectrum of BATs from blood in an extracorporeal circuit, and detoxified blood returns back to the patient's body. BPVAC treatment would be a device of targeted medicine. Detoxification is performed under supervision of trained personnel using simple blood-circulating machines in which blood circulates from the patient to BPVAC and back to the patient aseptically. BPVACs' reactive sites consist of carbon nanotubes on which a vast spectra of polyvalent BATs-antibodies are bond to. The devise acts as a biological filter that selectively immobilizes harmful BATs from intoxicated blood; however, no dialysis is involved. For effective neutralization, BPVAC provides large contact surface area with blood. BPVAC approach would have advantages of: 1) urgent neutralization of notorious BATs from blood of septic patients; 2) applicability in parallel with conventional treatments; 3) potential to minimize side effects of the malady; 4) applicability for a vast range of BATs; 5) potential to eliminate contact of BATs with internal tissues and organs; 6) tolerability by patients sensitive to antiserum injections; 7) capability for universal application; 8) affectivity when antibiotic-resistant bacteria are involved and the physician has no or limited access to appropriate antibiotics; and 10) being a single-use, disposable, and stand-alone device. Before using it for clinical trials in human beings, it should pass animal evaluations accurately; however, research works should optimize its implementation in human beings. For optimization, it needs appropriate

  19. Post-streptococcal 'complex' movement disorders: unusual concurrence of psychogenic and organic symptoms.

    PubMed

    Squintani, Giovanna; Tinazzi, Michele; Gambarin, Mattia; Bravi, Elena; Moretto, Giuseppe; Buttiglione, Maura; Defazio, Giovanni; Martino, Davide

    2010-01-15

    Post-streptococcal neuropsychiatric disorders encompass a broad spectrum of movement disorders, including tics, stereotypies, dystonia and tremor. We report the case of a 15-year-old boy who presented with a relapsing-remitting combination of psychogenic and organic movement disorders. Both relapses occurred after an episode of streptococcal pharyngitis and consisted in motor and phonic tics, an atypical gait disorder, and severe worsening of a pre-existing psychogenic tremor of the right hand. After each relapse, both psychogenic and 'organic' symptoms concomitantly remitted after the administration of an association of oral steroids and antibiotics. The peculiarity of this case consists in the coexistence of psychogenic and organic symptoms subsequent to streptococcal infection, and broadens the clinical spectrum of post-streptococcal neuropsychiatric disorders. PMID:19896680

  20. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS): an indication for tonsillectomy.

    PubMed

    Alexander, Alan A Z; Patel, Nitin J; Southammakosane, Cathy A; Mortensen, Melissa M

    2011-06-01

    Children with obsessive compulsive disorder or tic disorders that are associated with streptococcal infections (Group A beta-hemolytic) in the oro-pharyngeal region are given the diagnosis of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Tonsillectomy has been reported to resolve the neuro-psychiatric symptoms in these children. We have a case of a 9-year-old boy who was seen in our clinic with multiple recurrent streptococcal infections of the oro-pharyngeal cavity. He also exhibited neuro-psychiatric symptoms including agitation, hyperactivity, and tics. These symptoms followed his recurrent infections. Tonsillectomy was performed and in one year follow-up the patient did not have any recurrent streptococcal infections, and his neuro-psychiatric symptoms resolved completely. Guidelines for medical and surgical management of recurrent strep infections in the face of PANDAS are reviewed. PMID:21466900

  1. Immunosuppression after Sepsis: Systemic Inflammation and Sepsis Induce a Loss of Naïve T-Cells but No Enduring Cell-Autonomous Defects in T-Cell Function

    PubMed Central

    Markwart, Robby; Condotta, Stephanie A.; Requardt, Robert P.; Borken, Farina; Schubert, Katja; Weigel, Cynthia; Bauer, Michael; Griffith, Thomas S.; Förster, Martin; Brunkhorst, Frank M.; Badovinac, Vladimir P.; Rubio, Ignacio

    2014-01-01

    Sepsis describes the life-threatening systemic inflammatory response (SIRS) of an organism to an infection and is the leading cause of mortality on intensive care units (ICU) worldwide. An acute episode of sepsis is characterized by the extensive release of cytokines and other mediators resulting in a dysregulated immune response leading to organ damage and/or death. This initial pro-inflammatory burst often transits into a state of immune suppression characterised by loss of immune cells and T-cell dysfunction at later disease stages in sepsis survivors. However, despite these appreciations, the precise nature of the evoked defect in T-cell immunity in post-acute phases of SIRS remains unknown. Here we present an in-depth functional analysis of T-cell function in post-acute SIRS/sepsis. We document that T-cell function is not compromised on a per cell basis in experimental rodent models of infection-free SIRS (LPS or CpG) or septic peritonitis. Transgenic antigen-specific T-cells feature an unaltered cytokine response if challenged in vivo and ex vivo with cognate antigens. Isolated CD4+/CD8+ T-cells from post-acute septic animals do not exhibit defects in T-cell receptor-mediated activation at the the level of receptor-proximal signalling, activation marker upregulation or expansion. However, SIRS/sepsis induced transient lymphopenia and gave rise to an environment of immune attenuation at post acute disease stages. Thus, systemic inflammation has an acute impact on T-cell numbers and adaptive immunity, but does not cause major cell-autonomous enduring functional defects in T-cells. PMID:25541945

  2. Persistent inflammation and T cell exhaustion in severe sepsis in the elderly

    PubMed Central

    2014-01-01

    Introduction Sepsis is known as a complex immunological response with hyperinflammation in the acute phase followed by immunosuppression. Although aging is crucial in sepsis, the impact of aging on inflammation and immunosuppression is still unclear. The purpose of this study was to investigate the relationship between inflammation and immunosuppression in aged patients and mice after sepsis. Methods Fifty-five patients with severe sepsis and 30 healthy donors were prospectively enrolled, and 90-day survival was compared between elderly (≥65 years) and adult (18–64 years) septic patients with serial measurement of serum interleukin (IL)-6. Within 24 h after diagnosis of severe sepsis, peripheral blood mononuclear cells were stimulated ex vivo to measure expression of the activation maker CD25 in T cells, IL-2 levels in the supernatant, and proliferation. In the mouse study, young (6–8 weeks) and aged (20–22 months) C57/B6 mice were subjected to cecal ligation and puncture (CLP), and survival was compared after 7 days with serial measurement of serum IL-6. Expression of the negative co-stimulatory molecules, CD25, and IL-2 in CD4+ T cells was measured. Results The survival rate in elderly sepsis patients and aged septic mice was significantly lower than that in adult patients and young septic mice (60% vs. 93% in septic patients, 0% vs. 63% in septic mice, P < 0.05). Serum IL-6 levels in elderly sepsis patients and aged septic mice were persistently higher than those in adult patients and young septic mice. Expression of negative co-stimulatory molecules in CD4+ T cells in the spleen, lymph nodes, and peripheral blood was significantly higher in aged mice than in young mice (P < 0.01). Ex vivo stimulation decreased CD25 expression, IL-2 production, and proliferation to a greater extent in CD4+ T cells from elderly patients and aged septic mice than in those from adult patients and young septic mice. Elderly patients demonstrated increased

  3. Sepsis in Pregnancy: Identification and Management.

    PubMed

    Albright, Catherine M; Mehta, Niharika D; Rouse, Dwight J; Hughes, Brenna L

    2016-01-01

    Sepsis accounts for up to 28% of all maternal deaths. Prompt, appropriate treatment improves maternal and fetal morbidity and mortality. To date, there are no validated tools for identification of sepsis in pregnant women, and tools used in the general population tend to overestimate mortality. Once identified, management of pregnancy-associated sepsis is goal-directed, but because of the lack of studies of sepsis management in pregnancy, it must be assumed that modifications need to be made on the basis of the physiologic changes of pregnancy. Key to management is early fluid resuscitation and early initiation of appropriate antimicrobial therapy directed toward the likely source of infection or, if the source is unknown, empiric broad-spectrum therapy. Efforts directed at identifying the source of infection and appropriate source control measures are critical. Development of an illness severity scoring system and treatment algorithms validated in pregnant women needs to be a research priority. PMID:26825620

  4. Clinical features and outcome of bone and joint infections with streptococcal involvement: 5-year experience of interregional reference centres in the south of France.

    PubMed

    Seng, P; Vernier, M; Gay, A; Pinelli, P-O; Legré, R; Stein, A

    2016-07-01

    Streptococcal bone and joint infections are less common than staphylococcal cases. Few studies have reported the cases with well-identified Streptococcus species. Their clinical features and prognosis are not clearly known to date. Moreover, no treatment regimen has yet been clarified. We reviewed the streptococcal bone and joint infection cases managed in our centres from January 2009 to December 2013. We described the epidemiology, clinical and microbiologic characteristics, treatment approach and outcome. Among the 93 cases, 83% of patients were men with a median age of 60 years, and 90% of patients had comorbidities or risk factors. Bacteraemia occurred in 14% of cases. Serious complications occurred in six patients, including severe sepsis (two cases) and infective endocarditis (two cases). Orthopaedic device infections were observed in 35% of cases, including 17 patients with internal osteosynthesis device infection, 14 with prosthetic joint infection and three with vertebral osteosynthesis device infection. The median time between orthopaedic device implantation and onset of infection was 447 days. Fourteen species of Streptococcus were identified, including 97 isolates using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and three isolates using molecular identification. The five most represented species included S. agalactiae (37%), S. dysgalactiae (12%), S. anginosus (11%), S. constellatus (10%) and S. pneumoniae (9%). Streptococci isolates were susceptible to amoxicillin, with the exception of one S. mitis isolate. Remission 1 year after the end of treatment was recorded in 83%. One patient died of infection; eight patients had infections that failed to respond to treatment; and seven patients experienced relapse. Twenty patients (22%) had an unfavourable functional outcome, including 19 amputations and one arthrodesis. Five significant prognostic factors associated with an unfavourable clinical outcome were identified

  5. Neonatal Infectious Diseases: Evaluation of Neonatal Sepsis

    PubMed Central

    Spearman, Paul W.; Stoll, Barbara J.

    2015-01-01

    Synopsis Neonatal sepsis remains a feared cause of morbidity and mortality in the neonatal period. Maternal, neonatal and environmental factors are associated with risk of infection, and a combination of prevention strategies, judicious neonatal evaluation and early initiation of therapy are required to prevent adverse outcomes. The following chapter reviews recent trends in epidemiology, and provides an update on risk factors, diagnostic methods and management of neonatal sepsis. PMID:23481106

  6. Case of Sepsis Caused by Bifidobacterium longum

    PubMed Central

    Ha, Gyoung Yim; Yang, Chang Heon; Kim, Heesoo; Chong, Yunsop

    1999-01-01

    We report a case of sepsis caused by Bifidobacterium longum in a 19-year-old male who had developed high fever, jaundice, and hepatomegaly after acupuncture therapy with small gold needles. Anaerobic, non-spore-forming, gram-positive bacilli were isolated from his blood and finally identified as B. longum. He recovered completely after treatment with ticarcillin and metronidazole. To our knowledge, this is the first report of incidental sepsis caused by B. longum. PMID:10074561

  7. Streptococcal M1 protein constructs a pathological host fibrinogen network

    PubMed Central

    Macheboeuf, Pauline; Buffalo, Cosmo; Fu, Chi-yu; Zinkernagel, Annelies S.; Cole, Jason N.; Johnson, John E.; Nizet, Victor; Ghosh, Partho

    2012-01-01

    M1 protein, a major virulence factor of the leading invasive strain of group A Streptococcus, is sufficient to induce toxic shock-like vascular leakage and tissue injury. These events are triggered by the formation of a complex between M1 and fibrinogen (Fg) that, unlike M1 or Fg alone, leads to neutrophil activation. Here we provide a structural explanation for the pathological properties of the M1-Fg complex. A conformationally dynamic coiled-coil dimer of M1 was found to organize four Fg molecules into a specific cross-like pattern. This pattern supported the construction of a supramolecular network that was required for neutrophil activation but was distinct from a fibrin clot. Disruption of this network into other supramolecular assemblies was not tolerated. These results have bearing on the pathophysiology of streptococcal toxic shock. PMID:21475196

  8. Group G streptococcal myositis in a patient with myeloproliferative neoplasm.

    PubMed

    Midha, Monica; Rosenthal, Marnie E

    2016-01-01

    While many cases of streptococcal infection are due to Lancefield groups A and B, there has been a rise in reported cases of infections due to group G streptococcus. We present a case of an individual with a hematologic malignancy who developed myositis secondary to group G streptococcus, with no clearly identifiable source of infection. The patient was managed with antibiotic therapy rather than surgical intervention due to high surgical risk related to severe thrombocytopenia. Targeted antibiotics initiated early in the course of disease may prevent the need for surgical intervention. Early diagnosis and treatment are critical to avoid the high morbidity and mortality of life-threatening infections caused by group G streptococcus. PMID:27500083

  9. Group G streptococcal epizootic in a closed cat colony.

    PubMed Central

    Tillman, P C; Dodson, N D; Indiveri, M

    1982-01-01

    An epizootic of beta-hemolytic Lancefield group G streptococcal infections occurred in a specific-pathogen-free colony of laboratory cats. A total of 19 out of 68 animals in a single building were affected over a 10-day period. Clinical signs included fever, depression, lymphadenopathy, pharyngitis, and submandibular edema. The organism was recovered from the pharynx in two of five clinically normal cats from the affected building. Cultures from 12 animals in the same colony but housed in unaffected buildings were negative. Two doses of long-acting penicillin G 72 h apart stopped the outbreak and resulted in negative cultures for previously affected animals. Three months later, two new cases occurred in the same building. The disease was finally eradicated from the colony by depopulating the affected building. PMID:7161373

  10. Bacterial phenotype variants in group B streptococcal toxic shock syndrome.

    PubMed

    Sendi, Parham; Johansson, Linda; Dahesh, Samira; Van-Sorge, Nina M; Darenberg, Jessica; Norgren, Mari; Sjölin, Jan; Nizet, Victor; Norrby-Teglund, Anna

    2009-02-01

    We conducted genetic and functional analyses of isolates from a patient with group B streptococcal (GBS) necrotizing fasciitis and toxic shock syndrome. Tissue cultures simultaneously showed colonies with high hemolysis (HH) and low hemolysis (LH). Conversely, the HH and LH variants exhibited low capsule (LC) and high capsule (HC) expression, respectively. Molecular analysis demonstrated that the 2 GBS variants were of the same clonal origin. Genetic analysis found a 3-bp deletion in the covR gene of the HH/LC variant. Functionally, this isolate was associated with an increased growth rate in vitro and with higher interleukin-8 induction. However, in whole blood, opsonophagocytic and intracellular killing assays, the LH/HC phenotype demonstrated higher resistance to host phagocytic killing. In a murine model, LH/HC resulted in higher levels of bacteremia and increased host mortality rate. These findings demonstrate differences in GBS isolates of the same clonal origin but varying phenotypes. PMID:19193266

  11. Inflammasome/IL-1β Responses to Streptococcal Pathogens

    PubMed Central

    LaRock, Christopher N.; Nizet, Victor

    2015-01-01

    Inflammation mediated by the inflammasome and the cytokine IL-1β are some of the earliest and most important alarms to infection. These pathways are responsive to the virulence factors that pathogens use to subvert immune processes, and thus are typically activated only by microbes with potential to cause severe disease. Among the most serious human infections are those caused by the pathogenic streptococci, in part because these species numerous strategies for immune evasion. Since the virulence factor armament of each pathogen is unique, the role of IL-1β and the pathways leading to its activation varies for each infection. This review summarizes the role of IL-1β during infections caused by streptococcal pathogens, with emphasis on emergent mechanisms and concepts countering paradigms determined for other organisms. PMID:26500655

  12. Ly6Chigh Monocytes Protect against Kidney Damage during Sepsis via a CX3CR1-Dependent Adhesion Mechanism.

    PubMed

    Chousterman, Benjamin G; Boissonnas, Alexandre; Poupel, Lucie; Baudesson de Chanville, Camille; Adam, Julien; Tabibzadeh, Nahid; Licata, Fabrice; Lukaszewicz, Anne-Claire; Lombès, Amélie; Deterre, Philippe; Payen, Didier; Combadière, Christophe

    2016-03-01

    Monocytes have a crucial role in both proinflammatory and anti-inflammatory phenomena occurring during sepsis. Monocyte recruitment and activation are orchestrated by the chemokine receptors CX3CR1 and CCR2 and their cognate ligands. However, little is known about the roles of these cells and chemokines during the acute phase of inflammation in sepsis. Using intravital microscopy in a murine model of polymicrobial sepsis, we showed that inflammatory Ly6C(high) monocytes infiltrated kidneys, exhibited altered motility, and adhered strongly to the renal vascular wall in a chemokine receptor CX3CR1-dependent manner. Adoptive transfer of Cx3cr1-proficient monocyte-enriched bone marrow cells into septic Cx3cr1-depleted mice prevented kidney damage and promoted mouse survival. Modulation of CX3CR1 activation in septic mice controlled monocyte adhesion, regulated proinflammatory and anti-inflammatory cytokine expression, and was associated with the extent of kidney lesions such that the number of lesions decreased when CX3CR1 activity increased. Consistent with these results, the pro-adhesive I249 CX3CR1 allele in humans was associated with a lower incidence of AKI in patients with sepsis. These data show that inflammatory monocytes have a protective effect during sepsis via a CX3CR1-dependent adhesion mechanism. This receptor might be a new therapeutic target for kidney injury during sepsis. PMID:26160897

  13. Sepsis: From Pathophysiology to Individualized Patient Care

    PubMed Central

    László, Ildikó; Trásy, Domonkos; Molnár, Zsolt; Fazakas, János

    2015-01-01

    Sepsis has become a major health economic issue, with more patients dying in hospitals due to sepsis related complications compared to breast and colorectal cancer together. Despite extensive research in order to improve outcome in sepsis over the last few decades, results of large multicenter studies were by-and-large very disappointing. This fiasco can be explained by several factors, but one of the most important reasons is the uncertain definition of sepsis resulting in very heterogeneous patient populations, and the lack of understanding of pathophysiology, which is mainly based on the imbalance in the host-immune response. However, this heroic research work has not been in vain. Putting the results of positive and negative studies into context, we can now approach sepsis in a different concept, which may lead us to new perspectives in diagnostics and treatment. While decision making based on conventional sepsis definitions can inevitably lead to false judgment due to the heterogeneity of patients, new concepts based on currently gained knowledge in immunology may help to tailor assessment and treatment of these patients to their actual needs. Summarizing where we stand at present and what the future may hold are the purpose of this review. PMID:26258150

  14. A Multiplex Assay for Detection of Staphylococcal and Streptococcal Exotoxins.

    PubMed

    Sharma, Preeti; Wang, Ningyan; Chervin, Adam S; Quinn, Cheryl L; Stone, Jennifer D; Kranz, David M

    2015-01-01

    Staphylococcal and streptococcal exotoxins, also known as superantigens, mediate a range of diseases including toxic shock syndrome, and they exacerbate skin, pulmonary and systemic infections caused by these organisms. When present in food sources they can cause enteric effects commonly known as food poisoning. A rapid, sensitive assay for the toxins would enable testing of clinical samples and improve surveillance of food sources. Here we developed a bead-based, two-color flow cytometry assay using single protein domains of the beta chain of T cell receptors engineered for high-affinity for staphylococcal (SEA, SEB and TSST-1) and streptococcal (SpeA and SpeC) toxins. Site-directed biotinylated forms of these high-affinity agents were used together with commercial, polyclonal, anti-toxin reagents to enable specific and sensitive detection with SD50 values of 400 pg/ml (SEA), 3 pg/ml (SEB), 25 pg/ml (TSST-1), 6 ng/ml (SpeA), and 100 pg/ml (SpeC). These sensitivities were in the range of 4- to 80-fold higher than achieved with standard ELISAs using the same reagents. A multiplex format of the assay showed reduced sensitivity due to higher noise associated with the use of multiple polyclonal agents, but the sensitivities were still well within the range necessary for detection in food sources or for rapid detection of toxins in culture supernatants. For example, the assay specifically detected toxins in supernatants derived from cultures of Staphylococcus aureus. Thus, these reagents can be used for simultaneous detection of the toxins in food sources or culture supernatants of potential pathogenic strains of Staphylococcus aureus and Streptococcus pyogenes. PMID:26305471

  15. Immunochemistry of the streptococcal group R cell wall polysaccharide antigen.

    PubMed

    Soprey, P; Slade, H D

    1972-01-01

    The group R streptococcal group antigen has been shown to be a polysaccharide located at the surface of the cell wall of the organism. The antigen was extracted from cell walls in 0.05 n HCl or 5% trichloracetic acid at 100 C, from whole cells at room temperature in 0.85% NaCl or 0.1 m acetate (pH 5.0), and by sonic oscillation. The antigen is largely destroyed when extracted from whole cells in 0.05 n HCl at 100 C. Acetate is recommended for routine extraction. The antigen extracted by sonic treatment was separated into six immunologically active fractions on diethylaminoethyl-Sephadex. The fractions were found to possess a common antigen which exhibited similar properties on immunodiffusion and immunoelectrophoresis. The purified antigen did not react with any other streptococcal group antisera. Adsorption of group R serum with the antigen removed all antibodies against whole cell antigen extracts of R cells. Chemical and enzymatic analysis of three fractions showed that the antigen was composed of d-glucose, d-galactose, rhamnose, and glucosamine. No significant quantities of phosphorus, glycerol, ribitol, or muramic acid were present. Significant inhibition of the quantitative precipitin determination by d-galactose and stachyose indicated that galactose in terminal alpha linkage was the immunodominant hexose in the antigen. d-Glucose and d-glucosamine possessed a partial inhibitory activity. N-acetyl-d-glucosamine and l-rhamnose did not produce significant inhibition. The results indicate that the R antigen is an immunologically specific structure which serves as a reliable means of identification of these streptococci as a serological group. PMID:4632470

  16. Transfusion-related risk of secondary bacterial infections in sepsis patients: a retrospective cohort study.

    PubMed

    Juffermans, Nicole P; Prins, David J; Vlaar, Alexander P J; Nieuwland, Rienk; Binnekade, Jan M

    2011-04-01

    There is a need for insight into factors that contribute to late mortality of sepsis patients. Immunomodulatory effects have been ascribed to blood transfusion. This retrospective cohort study investigates the association between the development of nosocomial bacterial infection and transfusion of leukodepleted red blood cells (RBCs) or platelets (PLTs) in survivors of the initial phase of sepsis. Patients diagnosed with sepsis after admission to the intensive care unit of a tertiary referral hospital were included. Of 134 patients with sepsis, 67 received a blood transfusion (50%). A secondary infection developed in 19 patients (14%). A multiple logistic regression model revealed that the use of immunosuppressive medication with an odds ratio (OR) of 1.17 (95% confidence interval [CI], 1.04-1.31), but not Acute Physiology and Chronic Health Evaluation II score, malignancy, HIV infection, alcohol abuse, or diabetes mellitus, was a risk factor for nosocomial infection. In an adjusted model, the amount of transfused RBCs was associated with secondary infection with an OR of 1.18 (95% CI, 1.01-1.37). Storage time of RBCs was a relevant confounder of the effect of the amount of RBCs on infection, with an adjusted OR of 1.25 (95% CI, 1.04-1.51), P = 0.02. Also, the amount of transfused PLTs was associated with secondary infection, with an OR of 1.36 (95% CI, 1.05-1.78). In conclusion, transfusion of RBCs and PLTs is associated with the onset of secondary bacterial infection in sepsis patients. Storage time of RBCs influences this increased risk. These findings suggest that immunomodulatory effects of blood transfusion contribute to adverse outcome in the convalescent phase of sepsis. PMID:21192282

  17. Role of mitochondrial oxidants in an in vitro model of sepsis-induced renal injury.

    PubMed

    Pathak, Elina; MacMillan-Crow, Lee Ann; Mayeux, Philip R

    2012-01-01

    Oxidative stress has been implicated to play a major role in multiorgan dysfunction during sepsis. To study the mechanism of oxidant generation in acute kidney injury (AKI) during sepsis, we developed an in vitro model of sepsis using primary cultures of mouse cortical tubular epithelial cells exposed to serum (2.5-10%) collected from mice at 4 h after induction of sepsis by cecal ligation and puncture (CLP) or Sham (no sepsis). CLP serum produced a concentration-dependent increase in nitric oxide (NO) (nitrate + nitrite) release at 6 h and cytotoxicity (lactate dehydrogenase release) at 18 h compared with Sham serum treatment. Before cytotoxicity there was a decrease in mitochondrial membrane potential, which was followed by increased superoxide and peroxynitrite levels compared with Sham serum. The role of oxidants was evaluated by using the superoxide dismutase mimetic and peroxynitrite scavenger manganese(III)tetrakis(1-methyl-4-pyridyl)porphyrin tetratosylate hydroxide (MnTmPyP). MnTmPyP (10-100 μM) produced a concentration-dependent preservation of ATP and protection against cytotoxicity. MnTmPyP blocked mitochondrial superoxide and peroxynitrite generation produced by CLP serum but had no effect on NO levels. Although MnTmPyP did not block the initial CLP serum-induced fall in mitochondrial membrane potential, it allowed mitochondrial membrane potential to recover. Data from this in vitro model suggest a time-dependent generation of mitochondrial oxidants, mitochondrial dysfunction, and renal tubular epithelial cell injury and support the therapeutic potential of manganese porphyrin compounds in preventing sepsis-induced AKI. PMID:22011433

  18. CECAL LIGATION AND PUNCTURE INDUCED MURINE SEPSIS DOES NOT CAUSE LUNG INJURY

    PubMed Central

    Iskander, Kendra N.; Craciun, Florin L.; Stepien, David M.; Duffy, Elizabeth R.; Kim, Jiyoun; Moitra, Rituparna; Vaickus, Louis J.; Osuchowski, Marcin F.; Remick, Daniel G.

    2012-01-01

    Objective The cause of death in murine models of sepsis remains unclear. The primary purpose of this study was to determine if significant lung injury develops in mice predicted to die following cecal ligation and puncture induced sepsis compared to those predicted to live. Design Prospective, laboratory controlled experiments. Setting University research laboratory. Subjects Adult, female, outbred ICR mice. Interventions Mice underwent cecal ligation and puncture (CLP) to induce sepsis. Two groups of mice were sacrificed at 24 and 48 hours post-CLP and samples were collected. These mice were further stratified into groups predicted to die (Die-P) and predicted to live (Live-P) based on plasma interleukin 6 (IL-6) levels obtained 24 hours post-CLP. Multiple measures of lung inflammation and lung injury were quantified in these two groups. Results from a group of mice receiving intratracheal normal saline without surgical intervention were also included as a negative control. As a positive control, bacterial pneumonia was induced with Pseudomonas aeruginosa to cause definitive lung injury. Separate mice were followed for survival until day 28 post-CLP. These mice were used to verify the IL-6 cut-offs for survival prediction. Measurements and Main Results Following sepsis, both the Die-P and Live-P mice had significantly suppressed measures of respiratory physiology but maintained normal levels of arterial oxygen saturation. Bronchoalveolar lavage (BAL) levels of pro and anti-inflammatory cytokines were not elevated in the Die-P mice compared to the Live-P. Additionally, there was no increase in the recruitment of neutrophils to the lung, pulmonary vascular permeability, or histological evidence of damage. In contrast, all of these pulmonary injury and inflammatory parameters were increased in mice with Pseudomonas pneumonia. Conclusions These data demonstrate that mice predicted to die during sepsis have no significant lung injury. In murine intra-abdominal sepsis

  19. Response of lung γδ T cells to experimental sepsis in mice

    PubMed Central

    Hirsh, Mark; Dyugovskaya, Larissa; Kaplan, Viktoria; Krausz, Michael M

    2004-01-01

    γδ T cells link innate and adaptive immune systems and may regulate host defence. Their role in systemic inflammation induced by trauma or infection (sepsis) is still obscured. The present study was aimed to investigate functions of lung γδ T cells and their response to experimental sepsis. Mice were subjected to caecal ligation and puncture (CLP) to induce sepsis and acute lung injury (ALI), or to the sham operation. Animals were killed 1, 4, and 7 days postoperatively; lungs were examined by histology, and isolated cells were studied by flow cytometry. Absolute number of γδ T cells progressively increased in lungs during sepsis, and reached a seven-fold increase at day 7 after CLP (3·84 ± 0·41 × 105/lung; P = 0·0002 versus sham). A cellular dysfunction was revealed one day after CLP, as manifested by low cytolytic activity (22·3 ± 7·1%; P < 0·05 versus sham), low interferon-γ (IFN-γ; 8·5 ± 2·5%; P < 0·05 versus control) and interleukin-10 (IL-10) expression, and high tumour necrosis factor-α expression (19·5 ± 1·7%; P < 0·05 versus control). The restoration of cytotoxicity, and increase in IFN-γ and IL-10 expression was observed at day 7 of CLP-induced sepsis. In summary, our results demonstrate significant progressive accumulation of γδ T cells in lungs during CLP-induced ALI. The temporary functional suppression of lung γδ T cells found early after CLP may influence the outcome of sepsis, possibly being associated with uncontrolled inflammatory lung damage. PMID:15096194

  20. The Role of ACTH and Corticosteroids for Sepsis and Septic Shock: An Update

    PubMed Central

    Annane, Djillali

    2016-01-01

    Sepsis is a common disorder associated with high morbidity and mortality. It is now defined as an abnormal host response to infection, resulting in life-threatening dysfunction of organs. There is evidence from in vitro and in vivo experiments in various animal models and in patients that endotoxin or sepsis may directly and indirectly alter the hypothalamic–pituitary–adrenal response to severe infection. These alterations may include necrosis or hemorrhage or inflammatory mediator-mediated decreased ACTH synthesis, steroidogenesis, cortisol delivery to tissues, clearance from plasma, and decreased sensitivity of tissues to cortisol. Disruption of the hypothalamic–pituitary–adrenal axis may translate in patients with sepsis into cardiovascular and other organ dysfunction, and eventually an increase in the risk of death. Exogenous administration of corticosteroids at moderate dose, i.e., <400 mg of hydrocortisone or equivalent for >96 h, may help reversing sepsis-associated shock and organ dysfunction. Corticosteroids may also shorten the duration of stay in the ICU. Except for increased blood glucose and sodium levels, treatment with corticosteroids was rather well tolerated in the context of clinical trials. The benefit of treatment on survival remains controversial. Based on available randomized controlled trials, the likelihood of survival benefit is greater in septic shock versus sepsis patients, in sepsis with acute respiratory distress syndrome or with community-acquired pneumonia versus patients without these conditions, and in patients with a blunted cortisol response to 250 μg of ACTH test versus those with normal response. PMID:27379022

  1. Acute Biliary Septic Shock

    PubMed Central

    1990-01-01

    Forty-seven cases of biliary tract infection with septic shock are presented. The sepsis was caused by empyema of the gallbladder in 23 cases and by cholangitis in the remainder. Gallstones were most frequently the cause of the sepsis. An appropriate diagnostic description of the syndrome of biliary tract infection and septic shock should therefore include a description of the underlying biliary disease as well as the term acute biliary shock. In this series, emergency surgical management by removal of gallstones and drainage of suppuration was felt to be the most appropriate treatment. There was a high incidence of gallbladder rupture (10.6%) and intrahepatic stones (53.2%). Of the 13 patients who died, 8 might have survived if early operation had been performed after the diagnosis of acute biliary septic shock was established. PMID:2278914

  2. Prevention of Early-onset Neonatal Group B Streptococcal Disease

    PubMed Central

    Marió, M. J. Soto; Valenzuela, I; Vásquez, A. E; Illanes, S. E

    2013-01-01

    Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is an opportunistic pathogen that colonizes the gastrointestinal and genitourinary tracts of up to 50% of healthy adults and newborns; it is responsible for significant morbidity and mortality. Early detection can be used to establish the use of antibiotic prophylaxis to significantly reduce neonatal sepsis. This article reviews methods of detection and prevention of GBS infection in the neonate. PMID:24358406

  3. Pathophysiology of sepsis and recent patents on the diagnosis, treatment and prophylaxis for sepsis.

    PubMed

    Okazaki, Yasumasa; Matsukawa, Akihiro

    2009-01-01

    Despite advances in the development of powerful antibiotics and intensive care unit, sepsis is still life threatening and the mortality rate remains unchanged for the past three decades. Recent prospective trials with biological response modifiers have shown a modest clinical benefit. The pathological basis of sepsis is initially an excessive inflammatory response against invading pathogens, leading to systemic inflammatory response syndrome (SIRS). Evidence reveals that a variety of inflammatory mediators orchestrate the intense inflammation through complicated cellular interactions. More recent data indicate that most septic patients survive this stage and then subjected to an immunoparalysis phase, termed compensatory anti-inflammatory response syndrome (CARS), which is more fatal than the initial phase. Sepsis is a complicated clinical syndrome with multiple physiologic and immunologic abnormalities. In this review, we summarize the recent understandings of the pathophysiology of sepsis, and introduce recent patents on diagnosis, treatment and prophylaxis for sepsis. PMID:19149743

  4. Monocyte Tumor Necrosis Factor-α–Converting Enzyme Catalytic Activity and Substrate Shedding in Sepsis and Noninfectious Systemic Inflammation*

    PubMed Central

    O’Callaghan, David J. P.; O’Dea, Kieran P.; Scott, Alasdair J.; Takata, Masao

    2015-01-01

    Objectives: To determine the effect of severe sepsis on monocyte tumor necrosis factor-α–converting enzyme baseline and inducible activity profiles. Design: Observational clinical study. Setting: Mixed surgical/medical teaching hospital ICU. Patients: Sixteen patients with severe sepsis, 15 healthy volunteers, and eight critically ill patients with noninfectious systemic inflammatory response syndrome. Interventions: None. Measurements and Main Results: Monocyte expression of human leukocyte antigen-D-related peptide, sol-tumor necrosis factor production, tumor necrosis factor-α–converting enzyme expression and catalytic activity, tumor necrosis factor receptor 1 and 2 expression, and shedding at 48-hour intervals from day 0 to day 4, as well as p38-mitogen activated protein kinase expression. Compared with healthy volunteers, both sepsis and systemic inflammatory response syndrome patients’ monocytes expressed reduced levels of human leukocyte antigen-D-related peptide and released less sol-tumor necrosis factor on in vitro lipopolysaccharide stimulation, consistent with the term monocyte deactivation. However, patients with sepsis had substantially elevated levels of basal tumor necrosis factor-α–converting enzyme activity that were refractory to lipopolysaccharide stimulation and this was accompanied by similar changes in p38-mitogen activated protein kinase signaling. In patients with systemic inflammatory response syndrome, monocyte basal tumor necrosis factor-α–converting enzyme, and its induction by lipopolysaccharide, appeared similar to healthy controls. Changes in basal tumor necrosis factor-α–converting enzyme activity at day 0 for sepsis patients correlated with Acute Physiology and Chronic Health Evaluation II score and the attenuated tumor necrosis factor-α–converting enzyme response to lipopolysaccharide was associated with increased mortality. Similar changes in monocyte tumor necrosis factor-α–converting enzyme activity could

  5. Clostridium perfringens Sepsis and Fetal Demise after Genetic Amniocentesis

    PubMed Central

    Hendrix, Nancy W.; Mackeen, A. Dhanya; Weiner, Stuart

    2011-01-01

    Clostridium perfringens is a rare cause of intrauterine infection. There have been five case reports concerning infection associated with invasive procedures. We report a woman who underwent a genetic amniocentesis due to her history of chronic granulomatous disease. She presented to the hospital ∼38 hours after the amniocentesis complaining of fever and chills. Due to acute decompensation, she underwent an emergent dilatation and evacuation. During her stay, blood cultures came back positive for C. perfringens. Gradual improvement with intensive monitoring led to hospital discharge 4 days after the procedure. Uterine infection due to C. perfringens leading to maternal sepsis is associated with a high morbidity and mortality rate. Our patient was able to survive without a hysterectomy due to the rapid administration of antibiotics and surgical intervention while being evaluated. PMID:23705080

  6. Clinical course of sepsis, severe sepsis, and septic shock in a cohort of infected patients from ten Colombian hospitals

    PubMed Central

    2013-01-01

    Background Sepsis has several clinical stages, and mortality rates are different for each stage. Our goal was to establish the evolution and the determinants of the progression of clinical stages, from infection to septic shock, over the first week, as well as their relationship to 7-day and 28-day mortality. Methods This is a secondary analysis of a multicenter cohort of inpatients hospitalized in general wards or intensive care units (ICUs). The general estimating equations (GEE) model was used to estimate the risk of progression and the determinants of stages of infection over the first week. Cox regression with time-dependent covariates and fixed covariates was used to determine the factors related with 7-day and 28-day mortality, respectively. Results In 2681 patients we show that progression to severe sepsis and septic shock increases with intraabdominal and respiratory sources of infection [OR = 1,32; 95%IC = 1,20-1,46 and OR = 1.21, 95%CI = 1,11-1,33 respectively], as well as according to Acute Physiology and Chronic Health Evaluation II (APACHE II) [OR = 1,03; 95%CI = 1,02-1,03] and Sequential Organ Failure Assessment (SOFA) [OR = 1,16; 95%CI = 1,14-1,17] scores. The variables related with first-week mortality were progression to severe sepsis [HR = 2,13; 95%CI = 1,13-4,03] and septic shock [HR = 3,00; 95%CI = 1,50-5.98], respiratory source of infection [HR = 1,76; 95%IC = 1,12-2,77], APACHE II [HR = 1,07; 95% CI = 1,04-1,10] and SOFA [HR = 1,09; 95%IC = 1,04-1,15] scores. Conclusions Intraabdominal and respiratory sources of infection, independently of SOFA and APACHE II scores, increase the risk of clinical progression to more severe stages of sepsis; and these factors, together with progression of the infection itself, are the main determinants of 7-day and 28-day mortality. PMID:23883312

  7. Mechanisms of Intestinal Barrier Dysfunction in Sepsis.

    PubMed

    Yoseph, Benyam P; Klingensmith, Nathan J; Liang, Zhe; Breed, Elise R; Burd, Eileen M; Mittal, Rohit; Dominguez, Jessica A; Petrie, Benjamin; Ford, Mandy L; Coopersmith, Craig M

    2016-07-01

    Intestinal barrier dysfunction is thought to contribute to the development of multiple organ dysfunction syndrome in sepsis. Although there are similarities in clinical course following sepsis, there are significant differences in the host response depending on the initiating organism and time course of the disease, and pathways of gut injury vary widely in different preclinical models of sepsis. The purpose of this study was to determine whether the timecourse and mechanisms of intestinal barrier dysfunction are similar in disparate mouse models of sepsis with similar mortalities. FVB/N mice were randomized to receive cecal ligation and puncture (CLP) or sham laparotomy, and permeability was measured to fluoresceinisothiocyanate conjugated-dextran (FD-4) six to 48 h later. Intestinal permeability was elevated following CLP at all timepoints measured, peaking at 6 to 12 h. Tight junction proteins claudin 1, 2, 3, 4, 5, 7, 8, 13, and 15, Junctional Adhesion Molecule-A (JAM-A), occludin, and ZO-1 were than assayed by Western blot, real-time polymerase chain reaction, and immunohistochemistry 12 h after CLP to determine potential mechanisms underlying increases in intestinal permeability. Claudin 2 and JAM-A were increased by sepsis, whereas claudin-5 and occludin were decreased by sepsis. All other tight junction proteins were unchanged. A further timecourse experiment demonstrated that alterations in claudin-2 and occludin were detectable as early as 1 h after the onset of sepsis. Similar experiments were then performed in a different group of mice subjected to Pseudomonas aeruginosa pneumonia. Mice with pneumonia had an increase in intestinal permeability similar in timecourse and magnitude to that seen in CLP. Similar changes in tight junction proteins were seen in both models of sepsis although mice subjected to pneumonia also had a marked decrease in ZO-1 not seen in CLP. These results indicate that two disparate, clinically relevant models of sepsis

  8. A blueprint for a sepsis protocol.

    PubMed

    Shapiro, Nathan I; Howell, Michael; Talmor, Daniel

    2005-04-01

    Despite numerous advances in medicine, sepsis remains an unconquered challenge. Although outcomes have improved slightly over decades, the unacceptably high mortality rate of 30%-50% for severe sepsis and septic shock continues. However, after years of unsuccessful clinical trials, several investigations over the last few years have reported survival benefit in the treatment of sepsis. Physicians now have several proven therapies to treat sepsis, but have yet to implement them on a widespread, systematic basis. This led 11 international professional societies spanning multiple specialties and continents to come together to create the Surviving Sepsis Campaign. The product of their work is an international effort organized to improve care of patients with sepsis and includes consensus, evidence-based guidelines for care that improves survival in septic patients, and an action plan for change. Given the clear role of early identification and treatment in stopping the sepsis cascade, therapy must start early in the emergency department (ED) and continue throughout the hospital course. The first of the recommendations by the Surviving Sepsis Campaign is the aggressive resuscitation strategy of early goal-directed therapy (EGDT). EGDT is reported to reduce absolute mortality by a staggering 16%. The use of recombinant activated protein C was demonstrated to confer a 6% absolute survival benefit. Steroid supplementation in adrenal insufficiency produced a 10% benefit. Additionally, early and appropriate use of antibiotics remains a cornerstone of therapy. Although no randomized trial will be performed, the effects are undisputed. Finally, although predominantly intensive care unit therapies, tight glucose control and low-tidal-volume ventilation strategies have also led to improved survival. Armed with these new therapies, the medical community must rise to this call to action. Clinicians must change the approach to this disease, as well as the way the septic patient is

  9. Group A β-hemolytic Streptococcal Infection in Children and the Resultant Neuro-psychiatric Disorder; a Cross Sectional Study; Tehran, Iran

    PubMed Central

    Ebrahimi Taj, Farideh; Noorbakhsh, Samileh; Ghavidel Darestani, Sahar; Shirazi, Elham; Javadinia, Shima

    2015-01-01

    Introduction: Group A Beta-Hemolytic Streptococcus (GABHS) can induce PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection). GABHS is the most important and common bacterial cause of acute pharyngitis in Iranian children. We studied the role of GABHS (anti-streptococcal antibodies) in suspected cases of PANDAS in a cross sectional studies. Methods: Across sectional study was done in 2 pediatric psychiatric/and neurologic clinics in Tehran (Rasul Akram and Aliasghar Hospital) during 2008–2010. We studied serum anti-streptococcal antibodies (anti streptolysin O, anti Deoxyribonuclease B, and anti-streptokinase (ABcam-ELISA, USA) in 76 cases with psychiatric manifestation (OCD, ADHD) in compare with 39 healthy controls. These antibodies were studied in 53 cases with movement disorders (Tic/Tourette syndrome) in compare with 76 healthy controls. Sensitivity, specificity and positive predictive value of tests were calculated. Results: In movement disorders ASOT, Anti-DNase and Anti streptokinase was significantly higher than controls (P<0.0001, P=0.000, P<0.00001) ASOT (cut off level> 200 IU/ml) had 75% sensitivity; 84% specificity and 80% PPV; Anti-streptokinase (cut off level > 332 IU/ml) had 34% sensitivity; 85% specificity, and 72% PPV; Anti-DNase (cut off level > 140 IU/ml) had 70% sensitivity; 99% specificity and PPV 90% for differentiating the group. ASOT, Anti-DNase and Anti streptokinase titer was significantly higher than controls (P<0.0001, P=0.000, P<0.0001). ASOT had 90% sensitivity; 82% specificity, PPV 92%; Anti streptokinase: 82% sensitivity; 82% specificity, PPV 95%; Anti DNase: 92% sensitivity; 82% specificity, PPV 92% for differentiation the cases from normal controls. Discussion: These findings support that a post infectious immune mechanism to GABHS may play a role in the pathogenesis of PANDAS in our children. A combination of throat culture, rapid antigen detection test, and serologic testing for GABHS

  10. Neuromuscular Dysfunction in Experimental Sepsis and Glutamine

    PubMed Central

    Çankayalı, İlkin; Boyacılar, Özden; Demirağ, Kubilay; Uyar, Mehmet; Moral, Ali Reşat

    2016-01-01

    Background: Electrophysiological studies show that critical illness polyneuromyopathy appears in the early stage of sepsis before the manifestation of clinical findings. The metabolic response observed during sepsis causes glutamine to become a relative essential amino acid. Aims: We aimed to assess the changes in neuromuscular transmission in the early stage of sepsis after glutamine supplementation. Study Design: Animal experimentation. Methods: Twenty male Sprague-Dawley rats were randomized into two groups. Rats in both groups were given normal feeding for one week. In the study group, 1 g/kg/day glutamine was added to normal feeding by feeding tube for one week. Cecal ligation and perforation (CLP) surgery was performed at the end of one week. Before and 24 hours after CLP, compound muscle action potentials were recorded from the gastrocnemius muscle. Results: Latency measurements before and 24 hours after CLP were 0.68±0.05 ms and 0.80±0.09 ms in the control group and 0.69±0.07 ms and 0.73±0.07 ms in the study group (p<0.05). Conclusion: Since enteral glutamine prevented compound muscle action potentials (CMAP) latency prolongation in the early phase of sepsis, it was concluded that enteral glutamine replacement might be promising in the prevention of neuromuscular dysfunction in sepsis; however, further studies are required. PMID:27308070

  11. Sepsis: a roadmap for future research.

    PubMed

    Cohen, Jonathan; Vincent, Jean-Louis; Adhikari, Neill K J; Machado, Flavia R; Angus, Derek C; Calandra, Thierry; Jaton, Katia; Giulieri, Stefano; Delaloye, Julie; Opal, Steven; Tracey, Kevin; van der Poll, Tom; Pelfrene, Eric

    2015-05-01

    Sepsis is a common and lethal syndrome: although outcomes have improved, mortality remains high. No specific anti-sepsis treatments exist; as such, management of patients relies mainly on early recognition allowing correct therapeutic measures to be started rapidly, including administration of appropriate antibiotics, source control measures when necessary, and resuscitation with intravenous fluids and vasoactive drugs when needed. Although substantial developments have been made in the understanding of the basic pathogenesis of sepsis and the complex interplay of host, pathogen, and environment that affect the incidence and course of the disease, sepsis has stubbornly resisted all efforts to successfully develop and then deploy new and improved treatments. Existing models of clinical research seem increasingly unlikely to produce new therapies that will result in a step change in clinical outcomes. In this Commission, we set out our understanding of the clinical epidemiology and management of sepsis and then ask how the present approaches might be challenged to develop a new roadmap for future research. PMID:25932591

  12. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis

    PubMed Central

    Schmidt, Eric P; Yang, Yimu; Janssen, William J; Gandjeva, Aneta; Perez, Mario J; Barthel, Lea; Zemans, Rachel L; Bowman, Joel C; Koyanagi, Dan E; Yunt, Zulma X; Smith, Lynelle P; Cheng, Sara S; Overdier, Katherine H; Thompson, Kathy R; Geraci, Mark W; Douglas, Ivor S; Pearse, David B; Tuder, Rubin M

    2013-01-01

    Sepsis, a systemic inflammatory response to infection, commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity. We postulated that sepsis-associated ALI is initiated by degradation of the pulmonary endothelial glycocalyx, leading to neutrophil adherence and inflammation. Using intravital microscopy, we found that endotoxemia in mice rapidly induced pulmonary microvascular glycocalyx degradation via tumor necrosis factor-α (TNF-α)-dependent mechanisms. Glycocalyx degradation involved the specific loss of heparan sulfate and coincided with activation of endothelial heparanase, a TNF-α–responsive, heparan sulfate–specific glucuronidase. Glycocalyx degradation increased the availability of endothelial surface adhesion molecules to circulating microspheres and contributed to neutrophil adhesion. Heparanase inhibition prevented endotoxemia-associated glycocalyx loss and neutrophil adhesion and, accordingly, attenuated sepsis-induced ALI and mortality in mice. These findings are potentially relevant to human disease, as sepsis-associated respiratory failure in humans was associated with higher plasma heparan sulfate degradation activity; moreover, heparanase content was higher in human lung biopsies showing diffuse alveolar damage than in normal human lung tissue. PMID:22820644

  13. Metabolites in Blood for Prediction of Bacteremic Sepsis in the Emergency Room

    PubMed Central

    Kauppi, Anna M.; Edin, Alicia; Ziegler, Ingrid; Mölling, Paula; Sjöstedt, Anders; Gylfe, Åsa; Strålin, Kristoffer; Johansson, Anders

    2016-01-01

    A metabolomics approach for prediction of bacteremic sepsis in patients in the emergency room (ER) was investigated. In a prospective study, whole blood samples from 65 patients with bacteremic sepsis and 49 ER controls were compared. The blood samples were analyzed using gas chromatography coupled to time-of-flight mass spectrometry. Multivariate and logistic regression modeling using metabolites identified by chromatography or using conventional laboratory parameters and clinical scores of infection were employed. A predictive model of bacteremic sepsis with 107 metabolites was developed and validated. The number of metabolites was reduced stepwise until identifying a set of 6 predictive metabolites. A 6-metabolite predictive logistic regression model showed a sensitivity of 0.91(95% CI 0.69–0.99) and a specificity 0.84 (95% CI 0.58–0.94) with an AUC of 0.93 (95% CI 0.89–1.01). Myristic acid was the single most predictive metabolite, with a sensitivity of 1.00 (95% CI 0.85–1.00) and specificity of 0.95 (95% CI 0.74–0.99), and performed better than various combinations of conventional laboratory and clinical parameters. We found that a metabolomics approach for analysis of acute blood samples was useful for identification of patients with bacteremic sepsis. Metabolomics should be further evaluated as a new tool for infection diagnostics. PMID:26800189

  14. Current concept of abdominal sepsis: WSES position paper

    PubMed Central

    2014-01-01

    Although sepsis is a systemic process, the pathophysiological cascade of events may vary from region to region. Abdominal sepsis represents the host’s systemic inflammatory response to bacterial peritonitis. It is associated with significant morbidity and mortality rates, and is the second most common cause of sepsis-related mortality in the intensive care unit. The review focuses on sepsis in the specific setting of severe peritonitis. PMID:24674057

  15. Anticoagulant modulation of inflammation in severe sepsis

    PubMed Central

    Allen, Karen S; Sawheny, Eva; Kinasewitz, Gary T

    2015-01-01

    Inflammation and coagulation are so tightly linked that the cytokine storm which accompanies the development of sepsis initiates thrombin activation and the development of an intravascular coagulopathy. This review examines the interaction between the inflammatory and coagulation cascades, as well as the role of endogenous anticoagulants in regulating this interaction and dampening the activity of both pathways. Clinical trials attempting to improve outcomes in patients with severe sepsis by inhibiting thrombin generation with heparin and or endogenous anticoagulants are reviewed. In general, these trials have failed to demonstrate that anticoagulant therapy is associated with improvement in mortality or morbidity. While it is possible that selective patients who are severely ill with a high expected mortality may be shown to benefit from such therapy, at the present time none of these anticoagulants are neither approved nor can they be recommended for the treatment of sepsis. PMID:25938026

  16. Host innate immune responses to sepsis

    PubMed Central

    Wiersinga, Willem Joost; Leopold, Stije J; Cranendonk, Duncan R; van der Poll, Tom

    2014-01-01

    The immune response to sepsis can be seen as a pattern recognition receptor-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital. Invasive infection triggers both pro-inflammatory and anti-inflammatory host responses, the magnitude of which depends on multiple factors, including pathogen virulence, site of infection, host genetics, and comorbidities. Toll-like receptors, the inflammasomes, and other pattern recognition receptors initiate the immune response after recognition of danger signals derived from microorganisms, so-called pathogen-associated molecular patterns or derived from the host, so-called danger-associated molecular patterns. Further dissection of the role of host–pathogen interactions, the cytokine response, the coagulation cascade, and their multidirectional interactions in sepsis should lead toward the development of new therapeutic strategies in sepsis. PMID:23774844

  17. Role of immunoglobulins in neonatal sepsis

    PubMed Central

    Capasso, L; Borrelli, AC; Cerullo, J; Pisanti, R; Figliuolo, C; Izzo, F; Paccone, M; Ferrara, T; Lama, S; Raimondi, F

    2015-01-01

    Neonates, especially VLBW, are at high risk for sepsis related morbidity and mortality for immaturity of their immune system and invasive NICU practices. The paucity of immunoglobulins in preterm neonates consequently to the immaturity of immune system contributes to their high risk for systemic infection. The use of intravenous IgM enriched immunoglobulins, with higher antimicrobial activity than standard IgG, has been demonstrated in a retrospective study to reduce short term mortality in VLBW infant with proven sepsis. Larger, randomized prospective trials given the enormous burden of morbidity and mortality imposed by neonatal sepsis should urgently be addressed not only to validate this results but also to tailor the optimal scheme of treatment. PMID:25674546

  18. Mitochondrial dysfunction and resuscitation in sepsis.

    PubMed

    Ruggieri, Albert J; Levy, Richard J; Deutschman, Clifford S

    2010-07-01

    Sepsis is among the most common causes of death in patients in intensive care units in North America and Europe. In the United States, it accounts for upwards of 250,000 deaths each year. Investigations into the pathobiology of sepsis have most recently focused on common cellular and subcellular processes. One possibility would be a defect in the production of energy, which translates to an abnormality in the production of adenosine triphosphate and therefore in the function of mitochondria. This article presents a clear role for mitochondrial dysfunction in the pathogenesis and pathophysiology of sepsis. What is less clear is the teleology underlying this response. Prolonged mitochondrial dysfunction and impaired biogenesis clearly are detrimental. However, early inhibition of mitochondrial function may be adaptive. PMID:20643307

  19. Performance improvement in the management of sepsis.

    PubMed

    Schorr, Christa

    2011-03-01

    Sepsis guidelines, although creating a base to allow change in health care practitioner behavior, do not, in and of themselves, effect change. Change only comes with institution of a PI program, converting a core of key goals of guideline recommendations to quality indicators, and giving feedback on performance. These quality indicators are tracked before or during (recommended approach) initiation of hospital-wide education to evaluate baseline performance. When combining multispecialty and multidisciplinary champions in the ED, hospital wards, ICU, and hospital administrative leadership with timely performance feedback, case failure analysis, and re-education, an opportunity to succeed in decreasing mortality in severe sepsis can be achieved. Sepsis bundle indicators require updating as new evidence emerges and new guidelines are published.(30,31) PMID:21316576

  20. An Evidence Based Approach to Sepsis: Educational Program

    ERIC Educational Resources Information Center

    Perez, Dolores

    2015-01-01

    Evidence-based guidelines for recognizing and treating sepsis have been available for decades, yet healthcare providers do not adhere to the recommendations. Sepsis can progress rapidly if not recognized early. Literature reports reveal that sepsis is the leading cause of death in non-cardiac intensive care units (ICUs), and it is one of the most…

  1. The Use of Fluids in Sepsis.

    PubMed

    Avila, Audrey A; Kinberg, Eliezer C; Sherwin, Nomi K; Taylor, Robinson D

    2016-01-01

    Sepsis is a systemic inflammatory response to severe infection causing significant morbidity and mortality that costs the health care system $20.3 billion annually within the United States. It is well established that fluid resuscitation is a central component of sepsis management; however, to date there is no consensus as to the ideal composition of fluid used for resuscitation. In this review, we discuss the progression of clinical research comparing various fluids, as well as the historical background behind fluid selection for volume resuscitation. We conclude that the use of balanced fluids, such as Ringer's Lactate, seems very promising but further research is needed to confirm their role. PMID:27081589

  2. Hepatosplanchnic circulation in cirrhosis and sepsis

    PubMed Central

    Prin, Meghan; Bakker, Jan; Wagener, Gebhard

    2015-01-01

    Hepatosplanchnic circulation receives almost half of cardiac output and is essential to physiologic homeostasis. Liver cirrhosis is estimated to affect up to 1% of populations worldwide, including 1.5% to 3.3% of intensive care unit patients. Cirrhosis leads to hepatosplanchnic circulatory abnormalities and end-organ damage. Sepsis and cirrhosis result in similar circulatory changes and resultant multi-organ dysfunction. This review provides an overview of the hepatosplanchnic circulation in the healthy state and in cirrhosis, examines the signaling pathways that may play a role in the physiology of cirrhosis, discusses the physiology common to cirrhosis and sepsis, and reviews important issues in management. PMID:25759525

  3. Fluid Resuscitation in Sepsis: Reexamining the Paradigm

    PubMed Central

    Tirupakuzhi Vijayaraghavan, Bharath Kumar; Cove, Matthew Edward

    2014-01-01

    Sepsis results in widespread inflammatory responses altering homeostasis. Associated circulatory abnormalities (peripheral vasodilation, intravascular volume depletion, increased cellular metabolism, and myocardial depression) lead to an imbalance between oxygen delivery and demand, triggering end organ injury and failure. Fluid resuscitation is a key part of treatment, but there is little agreement on choice, amount, and end points for fluid resuscitation. Over the past few years, the safety of some fluid preparations has been questioned. Our paper highlights current concerns, reviews the science behind current practices, and aims to clarify some of the controversies surrounding fluid resuscitation in sepsis. PMID:25180196

  4. [Bacterial meningitis in patients with sepsis syndrome].

    PubMed

    Olejnik, Z; Janeczko, J; Lipowski, D; Przyjałkowski, W; Strzelecki, R; Romanowska, B; Pogorzelska, E

    1994-01-01

    The authors discuss problems connected with diagnosis, management and treatment of bacterial meningitis among patients with the sepsis syndrome. Considering secondary organ changes bacterial meningitis belongs to the severest one and as a life-threathing sequel of sepsis demands immediate use of proper casual treatment. The authors show the therapeutic difficulties in this group of patients particularly when the etiological organism is unknown. They discuss this problems and present their own schemes of tretment. They indicate the value of passive immunotherapy and surgical removal of the primary source of infection. They emphasize final result depends on secondary organ changes, age, immunity of patient and the kind of etiological agent. PMID:7938619

  5. Novel Conserved Group A Streptococcal Proteins Identified by the Antigenome Technology as Vaccine Candidates for a Non-M Protein-Based Vaccine ▿

    PubMed Central

    Fritzer, Andrea; Senn, Beatrice M.; Minh, Duc Bui; Hanner, Markus; Gelbmann, Dieter; Noiges, Birgit; Henics, Tamás; Schulze, Kai; Guzman, Carlos A.; Goodacre, John; von Gabain, Alexander; Nagy, Eszter; Meinke, Andreas L.

    2010-01-01

    Group A streptococci (GAS) can cause a wide variety of human infections ranging from asymptomatic colonization to life-threatening invasive diseases. Although antibiotic treatment is very effective, when left untreated, Streptococcus pyogenes infections can lead to poststreptococcal sequelae and severe disease causing significant morbidity and mortality worldwide. To aid the development of a non-M protein-based prophylactic vaccine for the prevention of group A streptococcal infections, we identified novel immunogenic proteins using genomic surface display libraries and human serum antibodies from donors exposed to or infected by S. pyogenes. Vaccine candidate antigens were further selected based on animal protection in murine lethal-sepsis models with intranasal or intravenous challenge with two different M serotype strains. The nine protective antigens identified are highly conserved; eight of them show more than 97% sequence identity in 13 published genomes as well as in approximately 50 clinical isolates tested. Since the functions of the selected vaccine candidates are largely unknown, we generated deletion mutants for three of the protective antigens and observed that deletion of the gene encoding Spy1536 drastically reduced binding of GAS cells to host extracellular matrix proteins, due to reduced surface expression of GAS proteins such as Spy0269 and M protein. The protective, highly conserved antigens identified in this study are promising candidates for the development of an M-type-independent, protein-based vaccine to prevent infection by S. pyogenes. PMID:20624906

  6. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: an overview.

    PubMed

    Esposito, S; Bianchini, S; Baggi, E; Fattizzo, M; Rigante, D

    2014-12-01

    The acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) has been used to describe a syndrome characterized by various obsessions, compulsions, tics, hyperactivity, motor stereotypies, and paroxysmal movement disorders that are correlated with prior infection by group A beta-hemolytic Streptococcus pyogenes (GABHS) infections. Five clinical criteria can be used to diagnose PANDAS: (1) the presence of obsessive-compulsive disorder (OCD) and/or any other tic disorders; (2) prepuberal onset (between 3 years of age and the start of puberty); (3) abrupt onset and relapsing-remitting symptom course; (4) a distinct association with GABHS infection; and (5) association with neurological abnormalities during exacerbations (adventitious movements or motoric hyperactivity). The exact pathogenesis of PANDAS remains unclear, and several theories that focus on multiple etiologic or contributive factors have emerged. PANDAS appears to be a neurobiological disorder that potentially complicates GABHS infections in genetically susceptible individuals. The current standard of care for PANDAS patients remains symptomatic, and cognitive behavioral therapy, such as exposure and response prevention, combined with family counseling and psychoeducation, should be the first approach for treating PANDAS. This review examines current theories of PANDAS pathogenesis, identifies possible treatments for managing this complex condition, and highlights areas for future research. Moving forward, developing more standardized diagnostic criteria and identifying specific laboratory markers to facilitate PANDAS diagnoses are crucial. PMID:24953744

  7. [Obsessive-compulsive disorder in children induced by streptococcal infection].

    PubMed

    Kochman, F; Hantouche, E G; Karila, L; Bayart, D; Bailly, D

    2001-11-24

    FROM OBSESSIVE-COMPULSIVE DISORDER TO PANDAS: Obsessive-compulsive disorder (OCD) represents a potentially severe and handicapping disorder that affects several hundreds of thousands of children in France. OCD has, for many years, been considered as a neurosis resulting from mental conflicts. It is currently seen as a neurobiological disorder, the etiological substratum of which is more organic than mental. Recently a sub-type of OCD was isolated in children following infection by Group A b-hemolytic streptococci. This sub-type has been described as Paediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS). A NEW PHYSIOPATHOLOGICAL APPROACH: The putative dysimmune relationship between bacterial infection and neurotic disorder has led to the development of an original etiopathogenic model that may lead to new therapeutic strategies. The clinical case report of an adolescent presenting with trichotillomania associated with recurrent pharyngitis is a good illustration of this. PUBLISHED DATA: Data published in medical literature over the last 10 years indicates a 10% prevalence in the young suffering from OCD, i.e. 0.1 to 0.3% of the young population. PMID:11769071

  8. Pressure Sensitivity of Streptococcal Growth in Relation to Catabolism

    PubMed Central

    Marquis, Robert E.; Brown, William P.; Fenn, Wallace O.

    1971-01-01

    The sensitivity of Streptococcus faecalis growth to hydrostatic pressures ranging up to 550 atm was found to depend on the source of adenosine triphosphate for growth. Barotolerance of cultures growing in a complex medium with ribose as major catabolite appeared to be determined primarily by the pressure sensitivity of ribose-degrading enzymes. Apparent activation volumes for growth were nearly identical to those for lactate production from ribose, and yield coefficients per mole of ribose degraded were relatively independent of pressure. In contrast, cultures with glucose as main catabolite were less sensitive to pressure; glycolysis was less severely restricted under high pressure than was growth, and yield coefficients declined with pressure, especially above 400 atm. Thus, two distinct types of barotolerance could be defined—one dominated by catabolic reactions and one dominated by noncatabolic reactions. The results of experiments with a series of other catabolites further supported the view that catabolic reactions can determine streptococcal barotolerance. We also found that growing, glucose-degrading cultures increased in volume under pressure in the same manner that they do at 1 atm. Thus, it appeared that the bacterium has no alternative means of carrying out glycolysis under pressure without dilatation. Also, the observation that cultures grown under pressure did not contain abnormally large or morphologically deformed cells suggested that pressure did not inhibit cell division more than cell growth. PMID:4925191

  9. Clinical Characteristics of Community-Acquired Viridans Streptococcal Pneumonia

    PubMed Central

    Choi, Sun Ha; Choi, Keum-Ju; Lim, Jae-Kwang; Seo, Hyewon; Yoo, Seung-Soo; Lee, Jaehee; Lee, Shin-Yup; Kim, Chang-Ho; Park, Jae-Yong

    2015-01-01

    Background Viridans streptococci (VS) are a large group of streptococcal bacteria that are causative agents of community-acquired respiratory tract infection. However, data regarding their clinical characteristics are limited. The purpose of the present study was to investigate the clinical and radiologic features of community-acquired pneumonia (CAP) with or without parapneumonic effusion caused by VS. Methods Of 455 consecutive CAP patients with or without parapneumonic effusion, VS were isolated from the blood or pleural fluid in 27 (VS group, 5.9%) patients. Streptococcus pneumoniae was identified as a single etiologic agent in 70 (control group) patients. We compared various clinical parameters between the VS group and the control group. Results In univariate analysis, the VS group was characterized by more frequent complicated parapneumonic effusion or empyema and bed-ridden status, lower incidences of productive cough, elevated procalcitonin (>0.5 ng/mL), lower age-adjusted Charlson comorbidity index score, and more frequent ground glass opacity (GGO) or consolidation on computed tomography (CT) scans. Multivariate analysis demonstrated that complicated parapneumonic effusion or empyema, productive cough, bed-ridden status, and GGO or consolidation on CT scans were independent predictors of community-acquired respiratory tract infection caused by VS. Conclusion CAP caused by VS commonly presents as complicated parapneumonic effusion or empyema. It is characterized by less frequent productive cough, more frequent bed-ridden status, and less common CT pulmonary parenchymal lesions. However, its treatment outcome and clinical course are similar to those of pneumococcal pneumonia. PMID:26175772

  10. AN ELECTROPHORETIC STUDY OF A STREPTOCOCCAL PROTEINASE AND ITS PRECURSOR

    PubMed Central

    Shedlovsky, Theodore; Elliott, S. D.

    1951-01-01

    An electrophoretic study of crystalline preparations of a streptococcal proteinase and its precursor established their isoelectric points at pH values of 8.42 and 7.35 respectively (ionic strength 0.10). Preparations of the proteinase appeared to be electrophoretically homogeneous over a pH range of 5 to 8.5. Precursor preparations contained a relatively low concentration of the active enzyme visible as a separate peak in electrophoretic patterns of sufficiently concentrated solutions. Autocatalytic conversion of precursor to active enzyme was complete and resulted in a corresponding change in the electrophoretic pattern. Treatment of precursor preparations with trypsin produced incomplete conversion to the active enzyme and resulted in the formation of a modified precursor protein. This differed from the parent substance in electrophoretic mobility and in susceptibility to trypsin, but resembled it in immunological specificity and, as previously shown, in susceptibility to conversion to active enzyme by autocatalysis. Serological reactions of precursor and active enzyme components withdrawn from the cell after electrophoresis are described. It appears that the precursor protein may have two antigenic groups, one specific, the other shared by the active enzyme which behaves as a single antigen. PMID:14888818

  11. Degradation of 14C-labeled streptococcal cell walls by egg white lysozyme and lysosomal enzymes.

    PubMed Central

    Gallis, H A; Miller, S E; Wheat, R W

    1976-01-01

    The resistance of native and trypsin-treated [14C] glucose-labeled cell walls to degradation by lysozyme and human lysosomal enzymes was confirmed. In contrast, chemically N-acetylated cell walls undergo significant degradation by these enzymes in the pH range of 4.5 to 5.5 without prior removal of the group-specific carbohydrate. N-acetylation after removal of the group A carbohydrate by formamide extraction renders the cell walls considerably more susceptible to these enzymes than by formamaide extraction alone. It appears, therefore, that unless N-acetylation can occur in vivo, streptococcal cell walls are minimally degraded, if at all, by human peripheral blood leukocytes or lysozyme. Examination of leukocyte extracts from normal subjects and patients with post-streptococcal syndromes revealed no qualitative differences in ability to dissolve streptococcal cell walls. Images PMID:773836

  12. Case report: group B streptococcal bacteremia and sacroiliitis after mid-trimester dilation and evacuation.

    PubMed

    McKenna, T; O'Brien, K

    2009-09-01

    Group B streptococcal bacteremia with septic arthritis is a rare complication of second trimester dilation and evacuation, and may cause substantial post-operative morbidity. A 37-year-old gravida 4 para 1-0-2-1 presented with fever and right hip pain on post-operative day 11 from a second trimester dilation and evacuation for fetal trisomy 21. She was initially found to have septic arthritis involving the right sacroiliac joint and group B streptococcal bacteremia. Transesophageal echocardiogram showed a tricuspid valve, vegetation consistent with endocarditis. After prolonged parenteral antibiotic therapy, she developed septic pulmonary emboli that were successfully treated with anticoagulation therapy. Group B streptococcal infection is a potentially serious post-abortion complication that can cause sacroiliitis, endocarditis and septic pulmonary emboli. PMID:19710658

  13. Streptococcal pyrogenic exotoxin B antibodies in a mouse model of glomerulonephritis.

    PubMed

    Luo, Y-H; Kuo, C-F; Huang, K-J; Wu, J-J; Lei, H-Y; Lin, M T; Chuang, W-J; Liu, C-C; Lin, C-F; Lin, Y-S

    2007-09-01

    Streptococcal pyrogenic exotoxin B is an extracellular cysteine protease. Only nephritis-associated strains of group A streptococci secrete this protease and this may be involved in the pathogenesis of post-streptococcal glomerulonephritis. Mice were actively immunized with a recombinant protease inactive exotoxin B mutant or passively immunized with exotoxin B antibody. Characteristics of glomerulonephritis were measured using histology, immunoglobulin deposition, complement activation, cell infiltration, and proteinuria. None of the mice given bovine serum albumin or exotoxin A as controls showed any marked changes. Immunoglobulin deposition, complement activation, and leukocyte infiltration occurred only in the glomeruli of exotoxin B-hyperimmunized mice. One particular anti-exotoxin B monoclonal antibody, 10G, was cross-reactive with kidney endothelial cells and it caused kidney injury and proteinuria when infused into mice. This cross-reactivity may be involved in the pathogenesis of glomerulonephritis following group A streptococcal infection. PMID:17637712

  14. GADD34 suppresses lipopolysaccharide-induced sepsis and tissue injury through the regulation of macrophage activation.

    PubMed

    Ito, S; Tanaka, Y; Oshino, R; Okado, S; Hori, M; Isobe, K-I

    2016-01-01

    Growth arrest and DNA damage inducible protein 34 (GADD34) is induced by various cellular stresses, such as DNA damage, endoplasmic reticulum stress, and amino-acid deprivation. Although the major roles of GADD34 are regulating ER stress responses and apoptosis, a recent study suggested that GADD34 is linked to innate immune responses. In this report, we investigated the roles of GADD34 in inflammatory responses against bacterial infection. To explore the effects of GADD34 on systemic inflammation in vivo, we employed a lipopolysaccharide (LPS)-induced murine sepsis model and assessed the lethality, serum cytokine levels, and tissue injury in the presence or absence of GADD34. We found that GADD34 deficiency increased the lethality and serum cytokine levels in LPS-induced sepsis. Moreover, GADD34 deficiency enhanced tissue destruction, cell death, and pro-inflammatory cytokine expression in LPS-induced acute liver injury. Pro-inflammatory cytokine production after LPS stimulation is regulated by the Toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway. In vitro experiments revealed that GADD34 suppressed pro-inflammatory cytokine production by macrophages through dephosphorylation of IKKβ. In conclusion, GADD34 attenuates LPS-induced sepsis and acute tissue injury through suppressing macrophage activation. Targeting this anti-inflammatory role of GADD34 may be a promising area for the development of therapeutic agents to regulate inflammatory disorders. PMID:27171261

  15. Use of antiplatelet agents in sepsis: a glimpse into the future.

    PubMed

    Akinosoglou, Karolina; Alexopoulos, Dimitrios

    2014-02-01

    As mechanisms of sepsis pathophysiology have been elucidated with time, sepsis may be considered nowadays, as an uncontrolled inflammatory and pro-coagulant response to a pathogen. In this cascade of events, platelets play a key role, via interaction with endothelial cells and modulation of both innate and adaptive immune system. In that manner, inhibition of platelet function could represent a useful tool for attenuating inflammatory response and improving outcomes. Data on current antiplatelet agents, including acetylsalicylic acid, P2Y12 inhibitors and GPIIb/IIIa antagonists, in animal models are promising. Clinical data in patients hospitalized for pneumonia, at risk for acute lung injury, and/or critically ill revealed an association between antiplatelet therapy and reduction in both short-term mortality and prevalence of acute lung injury, as well as, the need for intensive care unit admission, without a concomitant increased bleeding risk. In need of innovative approach in the treatment of sepsis, further prospective, interventional, randomized trials are pivotal to establish potential use of antiplatelet agents in this context. PMID:24103487

  16. Acute abdomen due to group A streptococcus bacteremia caused by an isolate with a mutation in the csrS gene.

    PubMed

    Kaneko, Masahiko; Maruta, Masaki; Shikata, Hisaharu; Hanayama, Masakazu; Ikebe, Tadayoshi

    2015-11-01

    Streptococcus pyogenes (group A streptococcus) is an aerobic gram-positive coccus that causes infections ranging from non-invasive pharyngitis to severely invasive necrotizing fasciitis. Mutations in csrS/csrR and rgg, negative regulator genes of group A streptococcus, are crucial factors in the pathogenesis of streptococcal toxic shock syndrome, which is a severe, invasive infection characterized by sudden onset of shock and multiorgan failure, resulting in a high mortality rate. Here we present a case of group A streptococcal bacteremia in a 28-year-old Japanese woman with no relevant previous medical history. The patient developed progressive abdominal symptoms that may have been due to spontaneous bacterial peritonitis, followed by a state of shock, which did not fulfill the proposed criteria for streptococcal toxic shock. The isolate was found to harbor a mutation in the negative regulator csrS gene, whereas the csrR and rgg genes were intact. It was noteworthy that this strain carrying a csrS mutation had caused group A streptococcal bacteremia characterized by acute abdomen as the presenting symptom in a young individual who had been previously healthy. This case indicates that group A streptococcus with csrS mutations has potential virulence factors that are associated with the onset of group A streptococcal bacteremia that does not meet the diagnostic criteria for streptococcal toxic shock syndrome. PMID:26231317

  17. Can we use C-reactive protein levels to predict severe infection or sepsis in severely burned patients?

    PubMed Central

    Jeschke, Marc G; Finnerty, Celeste C; Kulp, Gabriela A; Kraft, Robert; Herndon, David N

    2013-01-01

    This is a large cohort analysis in severely burned pediatric children to determine whether C-reactive protein (CRP) can be used as a predictor for severe infection or sepsis. Nine-hundred eighteen pediatric burn patients were enrolled in this study. CRP values were measured throughout acute hospitalization and for up to 6 months postburn. Demographic data, incidence of infection, surgical interventions and other relevant clinical information was compiled from medical records. We performed an extensive literature search to identify models that other groups have developed to determine the effects of CRP levels postburn to assess the value of these parameters as predictors of sepsis or severe infection. Statistical analysis was performed using ANOVA and regression analysis where appropriate. Three-hundred fifteen female and 603 male pediatric patients were enrolled in this study. Average total body surface area (TBSA) burn was 45±23%, with full thickness burn over 32±27% TBSA, and patients were 7±6 years old. CRP values significantly correlated with burn size, survival and gender. Significantly higher levels of CRP were found in large burns, in non-survivors, and in females, p<0.05. Using various described models to determine whether CRP levels change before and after an event can predict sepsis or severe infection, we found that CRP cannot predict severe infection or sepsis. Although CRP is a marker of the inflammatory response postburn, CRP fails to predict infection or sepsis in severely burn patients. PMID:23875119

  18. The influence of genetic polymorphisms in TLR4 and TIRAP, and their expression levels in peripheral blood, on susceptibility to sepsis

    PubMed Central

    ZHANG, JIANPING; YANG, JINGPING; XU, XIYUAN; LIANG, LIANGSHEN; SUN, HAIXIA; LIU, GUOHUA; ZHANG, LIHONG; SU, YUN

    2016-01-01

    The present study aimed to investigate whether genetic polymorphisms in the Toll-like receptor (TLR)-4 and Toll/interleukin-1 receptor (TIR)-associated protein (TIRAP) genes, and/or their expression levels, influence the susceptibility of a patient to sepsis. A total of 106 patients with sepsis were divided into two groups on the basis of their acute physiology and chronic health evaluation (APACHE) II scores: i) Sepsis group A (APACHE II <20) and ii) Sepsis group B (APACHE II >20). In addition, 100 healthy volunteers were enrolled into the control group. Polymerase chain reaction-restriction fragment length polymorphism assay was used to detect the following genetic polymorphisms: The Ser180Leu allele of the TIRAP gene and the Asp299Gly and Thr399I1e alleles of the TLR4 gene. Furthermore, the protein expression levels of TLR4 and TIRAP were analyzed using an enzyme-linked immunosorbent assay. Genetic polymorphisms were not detected for the TLR4 and TIRAP genes; however, the protein expression levels of TLR4 and TIRAP differed significantly between the control, sepsis A and sepsis B groups (P<0.01). An APACHE II score of 20 was used as a baseline in order to differentiate sepsis severity. Pearson analysis demonstrated that TLR4 and TIRAP protein expression levels were positively correlated with sepsis severity (r=0.931 and 0.972; P<0.05), and TLR4 protein expression levels were positively correlated with those of TIRAP (r=0.936; P<0.05). The results of the present study suggested that the protein expression levels of, but not genetic polymorphisms in, TLR4 and TIRAP were associated with the severity of sepsis. PMID:26889229

  19. Therapeutic Targets in Sepsis: Past, Present, and Future.

    PubMed

    Seeley, Eric J; Bernard, Gordon R

    2016-06-01

    Antibiotics and fluids have been standard treatment for sepsis since World War II. Many molecular mediators of septic shock have since been identified. In models of sepsis, blocking these mediators improved organ injury and decreased mortality. Clinical trials, however, have failed. The absence of new therapies has been vexing to clinicians, clinical researchers, basic scientists, and the pharmaceutical industry. This article examines the evolution of sepsis therapy and theorizes about why so many well-reasoned therapies have not worked in human trials. We review new molecular targets for sepsis and examine trial designs that might lead to successful treatments for sepsis. PMID:27229636

  20. [An inquiry into the relevant issues about burn sepsis].

    PubMed

    Zhang, Qin; Liao, Zhenjiang

    2014-02-01

    Since the definition of sepsis was proposed in Chest by American College of Chest Physicians and Society of Critical Care Medicine in 1992, researches on burn sepsis have focused on the regulation of immune-inflammation response resulting in minimizing tissue injury resulted from excessive inflammatory response. Treatment of sepsis should focus on effect of early circulation oxygenation support in preventing and treating multiple organ dysfunction. The hypothesis of producing a hibernation-like state which might prevent multiple organ dysfunction in patients with sepsis provides us a new therapeutic strategy in protecting organs in the early stage of sepsis in future. PMID:24684982

  1. Global Epidemiology of Pediatric Severe Sepsis: The Sepsis Prevalence, Outcomes, and Therapies Study

    PubMed Central

    Weiss, Scott L.; Pappachan, John; Wheeler, Derek; Jaramillo-Bustamante, Juan C.; Salloo, Asma; Singhi, Sunit C.; Erickson, Simon; Roy, Jason A.; Bush, Jenny L.; Nadkarni, Vinay M.; Thomas, Neal J.

    2015-01-01

    Rationale: Limited data exist about the international burden of severe sepsis in critically ill children. Objectives: To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials. Methods: A point prevalence study was conducted on 5 days throughout 2013–2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality. Measurements and Main Results: Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6–8.9%). The patients’ median age was 3.0 (interquartile range [IQR], 0.7–11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0–25), and vasoactive-free days were 23 (IQR, 12–28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5–10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,437 patients per group. Conclusions: Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted. PMID:25734408

  2. T cell activation and cytokine release in streptococcal toxic shock-like syndrome.

    PubMed

    Nadal, D; Lauener, R P; Braegger, C P; Kaufhold, A; Simma, B; Lütticken, R; Seger, R A

    1993-05-01

    A 5-year-old girl with streptococcal toxic shock-like syndrome during varicella infection had high levels of tumor necrosis factor alpha and interleukin-6 but no interleukin-1 or interleukin-2 in the serum. Intravenous administration of gamma-globulin coincided with clinical improvement and with reduction of the levels of tumor necrosis factor alpha and interleukin-6. The data suggest that streptococcal pyrogenic exotoxins trigger synthesis of tumor necrosis factor alpha and interleukin-6 in vivo; intravenously administered gamma-globulin may down-regulate the cytokine response. PMID:8496751

  3. From juvenile parkinsonism to encephalitis lethargica, a new phenotype of post-streptococcal disorders: case report.

    PubMed

    Beleza, Pedro; Soares-Fernandes, João; Jordão, Maria J; Almeida, Fátima

    2008-11-01

    We report the case of a 16-year-old boy presented with a mild akinetic-rigid parkinsonism shortly after a post-streptococcal infection. After stopping corticoids, he had a rapid neurological deterioration to a fatal encephalitis lethargica-like syndrome. Serum analysis demonstrated consistently elevated anti-streptolysin-O. This case illustrates a new severe phenotype in the spectrum of the post-streptococcal disorders. This etiology should be considered in the differential diagnosis of a movement disorder with a rapid detrimental evolution. PMID:18221898

  4. Methods and compositions for diagnosing and preventing a group B streptococcal infection

    DOEpatents

    Brady, Linda Jeannine; Seifert, Kyle N.; Adderson, Elisabeth E.; Bohnsack, John F.

    2009-09-15

    The present invention provides a group B streptococcal (GBS) surface antigen, designated epsilon antigen, that is co-expressed with the delta antigen on a subset of serotype III GBS. Epsilon is expressed on more pathogenic Restriction Digest Pattern (RDP) III-3 GBS, but not on RDP types 1, 2, or 4. Accordingly, the present invention provides compositions and methods for detecting a group B streptococcus serotype III, RDP III-3 strain. Vaccines and methods of identifying agents which inhibit adhesion of a group B streptococcal cell to a host cell are also provided.

  5. Intra-abdominal sepsis after hepatic resection.

    PubMed Central

    Pace, R F; Blenkharn, J I; Edwards, W J; Orloff, M; Blumgart, L H; Benjamin, I S

    1989-01-01

    One hundred and thirty hepatic resections performed over an 8-year period were reviewed for evidence of postoperative intra-abdominal sepsis. Of 126 patients who survived for more than 24 hours after operation, 36 developed culture positive intra-abdominal collections (28.6%). Significant independent variables associated with the development of intra-abdominal sepsis were diagnoses of trauma or cholangiocarcinoma, and the need for reoperation to control hemorrhage during the postoperative period. Before 1984, infected fluid collections were treated predominantly by operative drainage, but this has largely been replaced by percutaneous methods, which have proven effective in most cases. Eighteen (50%) of the infections were caused by a mixed bacterial culture, with Streptococcus faecalis, Staphylococcus epidermidis, Staphylococcus aureus and Escherichia coli being the most common isolates. Six patients with clinical signs of sepsis had a sterile fluid collection drained with complete relief of symptoms. This review suggests that intra-abdominal sepsis is a frequent complication after hepatic resection, and can often be managed successfully by nonoperative percutaneous drainage. PMID:2493775

  6. [Innate immunity, Toll receptor and sepsis].

    PubMed

    Carrillo-Esper, Raúl

    2003-01-01

    The innate immune response is the first line of defense against infection. Toll-like receptors (TLRs) recognize bacterial lipopolysaccharide and other pathogen-associated molecular patterns (PAMPs). Intracellular signals initiated by interaction between Toll receptors and specific PAMPs results in inflammatory response. Sepsis and septic shock are the result of an exaggerated inflammatory systemic response induced by innate immune dysregulation. PMID:14617415

  7. Clinical analysis of cases of neonatal Streptococcus agalactiae sepsis.

    PubMed

    Zeng, S J; Tang, X S; Zhao, W L; Qiu, H X; Wang, H; Feng, Z C

    2016-01-01

    With the advent of antibiotic resistance, pathogenic bacteria have become a major threat in cases of neonatal sepsis; however, guidelines for treatment have not yet been standardized. In this study, 15 cases of neonatal Streptococcus agalactiae sepsis from our hospital were retrospectively analyzed. Of these, nine cases showed early-onset and six cases showed late-onset sepsis. Pathogens were characterized by genotyping and antibiotic sensitivity tests on blood cultures. Results demonstrated that in cases with early-onset sepsis, clinical manifestations affected mainly the respiratory tract, while late-onset sepsis was accompanied by intracranial infection. Therefore, we suggest including a cerebrospinal fluid examination when diagnosing neonatal sepsis. Bacterial genotyping indicated the bacteria were mainly type Ib, Ia, and III S. agalactiae. We recommend treatment with penicillin or ampicillin, since bacteria were resistant to clindamycin and tetracycline. In conclusion, our results provide valuable information for the clinical treatment of S. agalactiae sepsis in neonatal infants. PMID:27323190

  8. Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients.

    PubMed

    Claushuis, Theodora A M; van Vught, Lonneke A; Scicluna, Brendon P; Wiewel, Maryse A; Klein Klouwenberg, Peter M C; Hoogendijk, Arie J; Ong, David S Y; Cremer, Olaf L; Horn, Janneke; Franitza, Marek; Toliat, Mohammad R; Nürnberg, Peter; Zwinderman, Aeilko H; Bonten, Marc J; Schultz, Marcus J; van der Poll, Tom

    2016-06-16

    Preclinical studies have suggested that platelets influence the host response during sepsis. We sought to assess the association of admission thrombocytopenia with the presentation, outcome, and host response in patients with sepsis. Nine hundred thirty-one consecutive sepsis patients were stratified according to platelet counts (very low <50 × 10(9)/L, intermediate-low 50 × 10(9) to 99 × 10(9)/L, low 100 × 10(9) to 149 × 10(9)/L, or normal 150 × 10(9) to 399 × 10(9)/L) on admission to the intensive care unit. Sepsis patients with platelet counts <50 × 10(9)/L and 50 × 10(9) to 99 × 10(9)/L presented with higher Acute Physiology and Chronic Health Evaluation scores and more shock. Both levels of thrombocytopenia were independently associated with increased 30-day mortality (hazard ratios with 95% confidence intervals 2.00 [1.32-3.05] and 1.72 [1.22-2.44], respectively). To account for baseline differences besides platelet counts, propensity matching was performed, after which the association between thrombocytopenia and the host response was tested, as evaluated by measuring 17 plasma biomarkers indicative of activation and/or dysregulation of pathways implicated in sepsis pathogenesis and by whole genome blood leukocyte expression profiling. In the propensity matched cohort, platelet counts < 50 × 10(9)/L were associated with increased cytokine levels and enhanced endothelial cell activation. All thrombocytopenic groups showed evidence of impaired vascular integrity, whereas coagulation activation was similar between groups. Blood microarray analysis revealed a distinct gene expression pattern in sepsis patients with <50 × 10(9)/L platelets, showing reduced signaling in leukocyte adhesion and diapedesis and increased complement signaling. These data show that admission thrombocytopenia is associated with enhanced mortality and a more disturbed host response during sepsis independent of disease severity, thereby providing clinical validity to animal

  9. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

    PubMed Central

    Singer, Mervyn; Deutschman, Clifford S.; Seymour, Christopher Warren; Shankar-Hari, Manu; Annane, Djillali; Bauer, Michael; Bellomo, Rinaldo; Bernard, Gordon R.; Chiche, Jean-Daniel; Coopersmith, Craig M.; Hotchkiss, Richard S.; Levy, Mitchell M.; Marshall, John C.; Martin, Greg S.; Opal, Steven M.; Rubenfeld, Gordon D.; van der Poll, Tom; Vincent, Jean-Louis; Angus, Derek C.

    2016-01-01

    IMPORTANCE Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination. OBJECTIVE To evaluate and, as needed, update definitions for sepsis and septic shock. PROCESS A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment). KEY FINDINGS FROMEVIDENCE SYNTHESIS Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant. RECOMMENDATIONS Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a

  10. Objective Sepsis Surveillance Using Electronic Clinical Data

    PubMed Central

    Rhee, Chanu; Kadri, Sameer; Huang, Susan S.; Murphy, Michael V.; Li, Lingling; Platt, Richard; Klompas, Michael

    2016-01-01

    OBJECTIVE To compare the accuracy of surveillance of severe sepsis using electronic health record clinical data vs claims and to compare incidence and mortality trends using both methods. DESIGN We created an electronic health record–based surveillance definition for severe sepsis using clinical indicators of infection (blood culture and antibiotic orders) and concurrent organ dysfunction (vasopressors, mechanical ventilation, and/or abnormal laboratory values). We reviewed 1,000 randomly selected medical charts to characterize the definition’s accuracy and stability over time compared with a claims-based definition requiring infection and organ dysfunction codes. We compared incidence and mortality trends from 2003–2012 using both methods. SETTING Two US academic hospitals. PATIENTS Adult inpatients. RESULTS The electronic health record–based clinical surveillance definition had stable and high sensitivity over time (77% in 2003–2009 vs 80% in 2012, P=.58) whereas the sensitivity of claims increased (52% in 2003–2009 vs 67% in 2012, P=.02). Positive predictive values for claims and clinical surveillance definitions were comparable (55% vs 53%, P=.65) and stable over time. From 2003 to 2012, severe sepsis incidence imputed from claims rose by 72% (95% CI, 57%–88%) and absolute mortality declined by 5.4% (95% CI, 4.6%–6.7%). In contrast, incidence using the clinical surveillance definition increased by 7.7% (95% CI, −1.1% to 17%) and mortality declined by 1.7% (95% CI, 1.1%–2.3%). CONCLUSIONS Sepsis surveillance using clinical data is more sensitive and more stable over time compared with claims and can be done electronically. This may enable more reliable estimates of sepsis burden and trends. PMID:26526737

  11. Hospitalization Type and Subsequent Severe Sepsis

    PubMed Central

    Dickson, Robert P.; Rogers, Mary A. M.; Langa, Kenneth M.; Iwashyna, Theodore J.

    2015-01-01

    Rationale: Hospitalization is associated with microbiome perturbation (dysbiosis), and this perturbation is more severe in patients treated with antimicrobials. Objectives: To evaluate whether hospitalizations known to be associated with periods of microbiome perturbation are associated with increased risk of severe sepsis after hospital discharge. Methods: We studied participants in the U.S. Health and Retirement Study with linked Medicare claims (1998–2010). We measured whether three hospitalization types associated with increasing severity of probable dysbiosis (non–infection-related hospitalization, infection-related hospitalization, and hospitalization with Clostridium difficile infection [CDI]) were associated with increasing risk for severe sepsis in the 90 days after hospital discharge. We used two study designs: the first was a longitudinal design with between-person comparisons and the second was a self-controlled case series design using within-person comparison. Measurements and Main Results: We identified 43,095 hospitalizations among 10,996 Health and Retirement Study–Medicare participants. In the 90 days following non–infection-related hospitalization, infection-related hospitalization, and hospitalization with CDI, adjusted probabilities of subsequent admission for severe sepsis were 4.1% (95% confidence interval [CI], 3.8–4.4%), 7.1% (95% CI, 6.6–7.6%), and 10.7% (95% CI, 7.7–13.8%), respectively. The incidence rate ratio (IRR) of severe sepsis was 3.3-fold greater during the 90 days after hospitalizations than during other observation periods. The IRR was 30% greater after an infection-related hospitalization versus a non–infection-related hospitalization. The IRR was 70% greater after a hospitalization with CDI than an infection-related hospitalization without CDI. Conclusions: There is a strong dose–response relationship between events known to result in dysbiosis and subsequent severe sepsis hospitalization that is not present

  12. [Initial antibiotic therapy of neonatal sepsis].

    PubMed

    Jesić, Milos; Jesić, Maja; Maglajlić, Svjetlana; Lukac, Marija; Sindjić, Sanja; Vujović, Dragana; Grković, Slobodanka

    2004-10-01

    It is certain that in the past the types of bacterial agents responsible for neonatal sepsis and their sensitivity to antibiotics were not the same in all historical periods. However, the reports confirming the conclusion have been published only in the last three years. According to these facts, the bacterial causes of neonatal sepsis were analyzed in patients treated at the University children's hospital in Belgrade (S&M) as well as their sensitivity to antibiotics to determine the most effective initial therapy. Between January 2001 and June 2004, 35 neonates, aged from 1-30 days, with positive blood culture were treated. Gram-negative bacteria were the cause of sepsis in 57% of patients (Pseudomonas--20%, Klebsiella--20%, E. coli--8.5%, Acinetobacter--8.5%), gram-positive in 43% (coagulase-negative Staphylococci--14%, Staphylococcus epidermidis--14%, Staphylococcus aureus--9%, Streptococcus group B--3%, Listeria monocytogenes--3%). The bacteria were the most sensitive to carbapenems (85-89%), amikacin (68%), third-generation cephalosporins (47-50%), while the sensitivity to gentamicin was less than expected (48.5%). Sensitivity to ampicillin (8%) confirmed a high level of resistance to this antibiotic. All isolated Staphylococci were sensitive to vancomycin, and the overall methicillin resistance was 46%. Combined cefotaxime and amikacin therapy was the most effective of all suggested initial combinations of antibiotics (74%). The sensitivity to all other combinations of antibiotics was 51-71%. The most adequate initial combination of antibiotics for the treatment of neonatal sepsis is cefotaxime plus amikacin. The most adequate antibiotic for the treatment of nosocomial neonatal sepsis is carbapenem. PMID:15615466

  13. Factors associated with severe sepsis: prospective study of 94 neutropenic febrile episodes.

    PubMed

    Jeddi, Ramzi; Achour, Mériem; Amor, Ramzi Ben; Aissaoui, Lamia; Bouterâa, Walid; Kacem, Karima; Lakhal, Raihane Ben; Abid, Héla Ben; BelHadjAli, Zaher; Turki, Amel; Meddeb, Balkis

    2010-02-01

    Severe sepsis defined as infection-induced organ dysfunction or hypoperfusion abnormalities predispose to septic shock and increased mortality in neutropenic setting. We aimed at determining predictors of severe sepsis in neutropenic patients. Between 1 October and 31 December 2007, 41 patients (21 with acute myeloid leukemia, 19 with acute lymphoid leukemia and one with autologous stem cell transplantation for a mantle cell lymphoma) with chemotherapy-induced neutropenia (<0.5 x 10(9)/l) lasting for more than 7 days were included in this study. The median age was 28 years (range: 3-58 years). All patients were on oral antibacterial (colistin and gentamicin) and anti-fungal (amphotericin B) prophylaxis. The first neutropenic febrile episode was treated with piperacillin/tazobactam and colistin IV; if the patient remains febrile at 48 h from the start of this first line of treatment, amphotericin B i.v. is added. Imipenem was introduced in the case of non-response and finally glycopeptides were introduced according to the IDSA criteria. Severe sepsis and septic shock are defined according to the criteria of the consensus conference of the ACCP/SCCM excluding the leukocyte count since all the patients were neutropenic. Ninety-four febrile episodes were observed: 27 microbiologically documented (28.7%), six clinically documented (6.3%) and 61 fever of unknown origin (65%). Microbiologically documented infections were: 13 Gram-negative organisms, 11 Gram-positive organisms and three combined (Gram+ and -). Clinically documented infections were pneumonia (two), neutropenic enterocolitis (one), sinuses infection (one) and cutaneous infection (two). Severe sepsis accounted for 22 febrile episodes. Factors associated with the occurrence of severe sepsis were: hypophosphatemia (<0.8 mmol/l; p=0.05, OR=3.9, 95% CI: 1.3-45.7), hypoproteinemia (<62 g/l; p=0.006, OR=4.1, 95% CI: 1.4-11.4) and non-adapted antibiotherapy at the onset of severe sepsis (p=0.019, OR=2.7, 95% CI: 1

  14. Polymerase chain reaction in rapid diagnosis of neonatal sepsis.

    PubMed

    Yadav, Ashok K; Wilson, C G; Prasad, P L; Menon, P K

    2005-07-01

    In a prospective study a total of hundred neonates who fulfilled the American College of Obstetrics and Gynecology's (ACOG) criteria for probable sepsis admitted to NICU of tertiary care armed forces hospital were investigated for evidence of sepsis. The investigation protocol included sepsis screen, blood culture and 1 mL of venous blood for molecular analysis by polymerase chain reaction (PCR) for bacterial DNA component encoding 16 s RNA in all cases. 100 newborns with probable sepsis were studied to evaluate the molecular diagnosis of sepsis using PCR amplification of 16 S RNA in newborns with risk factors for sepsis or those who have clinical evidence of sepsis. We compared the results of PCR with blood culture and other markers of sepsis screen (total leucocyte count (TLC), absolute neutrophil count (ANC), immature/total neutrophil count ratio (I/T ratio), peripheral blood smear, micro ESR and C reactive protein (CRP). Controls consisted of 30 normal healthy newborns with no overt evidence of sepsis. Sepsis screen was positive in 24 (24%) of cases in study group with sensitivity and specificity of 100% and 83.5% respectively. Blood culture was positive in 09(9%t) with sensitivity of 69.2% and specificity of 100%. PCR was positive in 13(13%) of cases (9% are both blood culture and sepsis screen positive and 4% are positive by sepsis screen); the sensitivity of PCR was 100% and specificity was 95.6%. Blood culture is the most reliable method for diagnosis of neonatal sepsis. Polymerase chain reaction is useful and superior to blood culture for early diagnosis of sepsis in neonates. PMID:16085969

  15. In vitro cow's milk protein-specific inflammatory and regulatory cytokine responses in preterm infants with necrotizing enterocolitis and sepsis.

    PubMed

    Abdelhamid, Adel E; Chuang, Shu-Ling; Hayes, Peter; Fell, John M E

    2011-02-01

    Enteral feeding with cow's milk formula is associated with neonatal necrotizing enterocolitis (NEC) and sepsis. Dietary antigen sensitization may play a role in promoting and/or sustaining inflammation in both conditions. Aiming at investigating cow's milk protein (CMP)-specific cytokine responses in preterm infants with NEC and sepsis, 14 babies with NEC, 14 matched healthy controls, and 10 septic controls were recruited. Unstimulated and stimulated peripheral blood mononuclear cells (PBMCs) secreting IFN-γ, IL-4, IL-10, and TGF-β1 were counted by the single-cell enzyme-linked immunospot (ELISPOT) assay. During the acute phase of NEC, patients showed a general pattern of a high level of cytokine secretion both when unstimulated and stimulated by mitogen [phytohaemagglutinin (PHA)] and CMPs: beta-lactoglobulin (β-lg) and casein. These responses were more marked to β-lg for IFN-γ, IL-4, and IL-10 than TGF-β1. Cytokine responses in sepsis were lower than in NEC (lowest in healthy controls, with a minimal TGF-β1 response). At term, lower frequencies of cytokine-secreting cells were elicited than during the acute phase, except for TGF-β1 secreting cells, which increased at term (in response to PHA and CMPs) particularly following not only NEC but also sepsis. PMID:20975616

  16. Impact of corticosteroids on experimental meningococcal sepsis in mice.

    PubMed

    Levy, Michaël; Antunes, Ana; Fiette, Laurence; Deghmane, Ala-Eddine; Taha, Muhamed-Kheir

    2015-09-01

    Neisseria meningitidis is responsible for septicemia and meningitis with high fatality that is associated with an excessive inflammatory reaction particularly with hyperinvasive isolates of the clonal complex ST-11 (cc11). However, anti-inflammatory adjuvant treatment remains controversial and difficult to assess in patients. We addressed this topic in a well-defined experimental meningococcal infection in transgenic mice expressing the human transferrin. Mice were infected by intra-peritoneal challenge with bioluminescent serogroup C/cc11 strain. After 3h of infection mice were differentially treated every 6h by saline, amoxicillin alone or amoxicillin and dexamethasone (DXM). Infected mice were scored for clinical status, temperature and weight. Biological markers of inflammation were also quantified. Significant clinical improvement was observed in mice treated with amoxicillin and DXM compared to the two other groups. A significant reduction of the inflammatory reaction assessed by CRP and Lipocalin 2 (two acute phase proteins) was also observed with this treatment. DXM significantly increased blood levels of IL-10 at 6h post-infection. DXM/amoxicillin treated mice, compared to the two other groups, also showed lower levels of TNF-α and lower bacterial blood load assessed by serial dilutions of blood and bioluminescence dynamic imaging. Our results suggest that DXM, added to an appropriate antibiotic therapy, has a beneficial effect on experimental sepsis with a hyperinvasive meningococcal strain in transgenic mice expressing human transferrin. This is most likely due to the reduction of inflammatory response by an early induction of IL-10 cytokine. These data may allow better decision-making to use or not corticotherapy during meningococcal sepsis. PMID:26066898

  17. Alterations of T helper lymphocyte subpopulations in sepsis, severe sepsis, and septic shock: a prospective observational study.

    PubMed

    Li, Jia; Li, Ming; Su, Longxiang; Wang, Huijuan; Xiao, Kun; Deng, Jie; Jia, Yanhong; Han, Gencheng; Xie, Lixin

    2015-01-01

    Circulating lymphocyte number was significantly decreased in patients with sepsis. However, it remains unknown which severity phase (sepsis, severe sepsis, and septic shock) does it develop and what happen on each subpopulation. Eight patients with differing severities of sepsis (31 sepses, 33 severe sepses, and 16 septic shocks) were enrolled. Quantitative real-time polymerase chain reaction (RT-PCR) of Th1, Th2, and Th17; regulatory T (Treg) cell-specific transcription factor T-bet; GATA-3; RORgammat (RORγt); forkhead box P3 (FOXP3); and IL-17 mRNA were performed, and the enzyme-linked immunosorbent assay (ELISA) was used to detect serum interferon (IFN)-γ, IL-4, and IL-10. In this study, the Th1, Th2, Treg transcription factors, and related cytokines IFN-γ, IL-4, and IL-10 levels of sepsis and severe sepsis patients in peripheral blood were significantly higher than those of the normal controls. Except for IL-17, the T-bet, GATA-3, and IFN-γ levels of septic shock patients were lower than those of sepsis patients. We also observed that the proportions of Th17/Treg in the sepsis and septic shock groups were inversed. From the above, the inflammatory response especially the adaptive immune response is still activated in sepsis and severe sepsis, but significant immunosuppression was developed in septic shock. In addition, the proportion of Th17/Treg inversed may be associated with the illness aggravation of patients with sepsis. PMID:25403265

  18. [Acute rheumatic fever, Sydenham's chorea and psychopathology].

    PubMed

    Gimzal, Aylan; Topçuoğlu, Volkan; Yazgan, M Yanki

    2002-01-01

    Acute rheumatic fever (ARF) is an autoimmune disorder that is triggered by group A beta-hemolytic streptococcal infections. ARF consists of several combinations of carditis, polyarthritis and Sydenham's chorea, and rarely seen erythema marginatum and subcutaneous nodules. Sydenham's chorea is seen in about 20% of patients with ARF. As a late symptom of ARF, Sydenham's chorea usually occurs 3 months or longer after the streptococcal infection. Sydenham's chorea is a neuropsychiatric disorder that may present with emotional lability, anxiety, obsessive compulsive symptoms, attention deficit and hyperactivity symptoms or tics. Obsessive-compulsive symptoms occur in 70% of patients with Sydenham's chorea. The role of the autoimmune mechanisms and the dysfunction of the basal ganglia have been demonstrated in Sydenham's chorea. Antibodies against group A beta-hemolytic streptococcus cross-react with basal ganglia. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) shares the same mechanism with Sydenham's chorea, but PANDAS has not been shown to require penicillin prophylaxis. Thus it is important to distinguish between them. Sydenham's chorea is associated with adulthood OCD, Tourette syndrome and schizophrenia. These features make Sydenham's chorea an explanatory model for obsessive-compulsive disorder (OCD) and related disorders. This poststreptococcal disorder provides a treatment opportunity with new therapies like antibiotic therapy, plasma exchange and intravenous immunoglobulin therapy for psychiatric disorders. In this paper we summarize the phenomenological and treatment studies of OCD, attention deficit and hyperactivity disorder (ADHD), and tic disorders in subjects with ARF, with or without Sydenham's chorea. PMID:12794666

  19. Inhibition of streptococcal pyrogenic exotoxin B using allicin from garlic.

    PubMed

    Arzanlou, Mohsen

    2016-04-01

    Streptococcal pyrogenic exotoxin B (SpeB) is an important virulence factor of group A streptococci (GAS) and inactivation of SpeB results in the significantly decreased virulence of the bacterium. The protein is secreted as an inactive zymogen of 40 KDa (SpeBz) and undergoes proteolytic truncation to result in a 28 KDa mature active protease (SpeBm). In this study the effect of allicin on the proteolytic activity of SpeBm was evaluated using azocasein assay. Allicin neutralized the SpeBm proteolytic activity in a concentration dependent manner (IC50 = 15.71 ± 0.45 μg/ml). The loss of activity was completely reversed by subsequent treatment with a reducing agent, dithiothreitol (DTT; 10 mM final concentration), suggesting that allicin likely inhibits the SpeBm by forming a disulfide linkage with an active thiol group in its active site. This mechanism of action was further confirmed with the fact that DTT did not reverse the SpeBm activity in the presence of E-64, a cysteine protease-specific inhibitor, which works specially by forming a thioether linkage with free sulfhydryl groups in enzymes active site. The MIC of allicin against GAS was found to be 32 μg/ml. Exposure of GAS culture to allicin (25 μg/ml) inhibited maturation of SpeBz to the SpeBm. In conclusion, the results of this study suggest that allicin inhibits the maturation of SpeBz and proteolytic activity of SpeBm and could be a potential therapeutic agent for the treatment of GAS infections. PMID:26911644

  20. Towards Prevention of Acute Syndromes

    PubMed Central

    Ahmed, A.; Thongprayoon, C.; Pickering, B.W.; Akhoundi, A.; Wilson, G.; Pieczkiewicz, D.; Herasevich, V.

    2014-01-01

    Summary Background Identifying patients at risk for acute respiratory distress syndrome (ARDS) before their admission to intensive care is crucial to prevention and treatment. The objective of this study is to determine the performance of an automated algorithm for identifying selected ARDS predisposing conditions at the time of hospital admission. Methods This secondary analysis of a prospective cohort study included 3,005 patients admitted to hospital between January 1 and December 31, 2010. The automated algorithm for five ARDS predisposing conditions (sepsis, pneumonia, aspiration, acute pancreatitis, and shock) was developed through a series of queries applied to institutional electronic medical record databases. The automated algorithm was derived and refined in a derivation cohort of 1,562 patients and subsequently validated in an independent cohort of 1,443 patients. The sensitivity, specificity, and positive and negative predictive values of an automated algorithm to identify ARDS risk factors were compared with another two independent data extraction strategies, including manual data extraction and ICD-9 code search. The reference standard was defined as the agreement between the ICD-9 code, automated and manual data extraction. Results Compared to the reference standard, the automated algorithm had higher sensitivity than manual data extraction for identifying a case of sepsis (95% vs. 56%), aspiration (63% vs. 42%), acute pancreatitis (100% vs. 70%), pneumonia (93% vs. 62%) and shock (77% vs. 41%) with similar specificity except for sepsis and pneumonia (90% vs. 98% for sepsis and 95% vs. 99% for pneumonia). The PPV for identifying these five acute conditions using the automated algorithm ranged from 65% for pneumonia to 91 % for acute pancreatitis, whereas the NPV for the automated algorithm ranged from 99% to 100%. Conclusion A rule-based electronic data extraction can reliably and accurately identify patients at risk of ARDS at the time of hospital

  1. Improving the management of sepsis in a district general hospital by implementing the 'Sepsis Six' recommendations.

    PubMed

    Kumar, Prashant; Jordan, Mark; Caesar, Jenny; Miller, Sarah

    2015-01-01

    Sepsis is a common condition with a major global impact on healthcare resources and expenditure. The Surviving Sepsis Campaign has been vigorous in promoting internationally recognised pathways to improve the management of septic patients and decrease mortality. However, translating recommendations into practice is a challenging and complex task that requires a multi-faceted approach with sustained engagement from local stakeholders. Whilst working at a district general hospital in New Zealand, we were concerned by the seemingly inconsistent management of septic patients, often leading to long delays in the initiation of life-saving measures such as antibiotic, fluid, and oxygen administration. In our hospital there were no clear systems, protocols or guidelines in place for identifying and managing septic patients. We therefore launched the Sepsis Six resuscitation bundle of care in our hospital in an attempt to raise awareness amongst staff and improve the management of septic patients. We introduced a number of simple low-cost interventions that included educational sessions for junior doctors and nursing staff, as well as posters and modifications to phlebotomy trolleys that acted as visual reminders to implement the Sepsis Six bundle. Overall, we found there to a be a steady improvement in the delivery of the Sepsis Six bundle in septic patients with 63% of patients receiving appropriate care within one hour, compared to 29% prior to our interventions. However this did not translate to an improvement in patient mortality. This project forms part of an on going process to instigate a fundamental culture change among local healthcare professionals regarding the management of sepsis. Whilst we have demonstrated improved implementation of the Sepsis Six bundle, the key challenge remains to ensure that momentum of this project continues and forms a platform for sustainable clinical improvement in the long term. PMID:26734403

  2. Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice

    PubMed Central

    Wang, Xianfeng; Buechler, Nancy L.; Martin, Ayana; Wells, Jonathan; Yoza, Barbara; McCall, Charles E.; Vachharajani, Vidula

    2016-01-01

    Objective Obesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early/hyper-inflammatory to late/hypo-inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that sirtuins (SIRTs) modulate this transition. Here, we investigated the role of sirtuins, especially the adipose-tissue abundant SIRT-2 on transition from early to late sepsis in obese with sepsis. Methods Sepsis was induced using cecal ligation and puncture (CLP) in ob/ob mice. We measured microvascular inflammation in response to lipopolysaccharide/normal saline re-stimulation as a “second-hit” (marker of immune function) at different time points to track phases of sepsis in ob/ob mice. We determined SIRT-2 expression during different phases of sepsis. We studied the effect of SIRT-2 inhibition during the hypo-inflammatory phase on immune function and 7-day survival. We used a RAW264.7 (RAW) cell model of sepsis for mechanistic studies. We confirmed key findings in diet induced obese (DIO) mice with sepsis. Results We observed that the ob/ob-septic mice showed an enhanced early inflammation and a persistent and prolonged hypo-inflammatory phase when compared to WT mice. Unlike WT mice that showed increased SIRT1 expression, we found that SIRT2 levels were increased in ob/ob mice during hypo-inflammation. SIRT-2 inhibition in ob/ob mice during the hypo-inflammatory phase of sepsis reversed the repressed microvascular inflammation in vivo via activation of endothelial cells and circulating leukocytes and significantly improved survival. We confirmed the key finding of the role of SIRT2 during hypo-inflammatory phase of sepsis in this project in DIO-sepsis mice. Mechanistically, in the sepsis cell model, SIRT-2 expression modulated inflammatory response by deacetylation of NFκBp65. Conclusion SIRT-2 regulates microvascular inflammation in obese mice with sepsis and may

  3. Invasive group A streptococcal infection concurrent with 2009 H1N1 influenza.

    PubMed

    Jean, Cynthia; Louie, Janice K; Glaser, Carol A; Harriman, Kathleen; Hacker, Jill K; Aranki, Faisal; Bancroft, Elizabeth; Farley, Susan; Ginsberg, Michele; Hernandez, Lisa B; Sallenave, Catherine S; Radner, Allen B

    2010-05-15

    We describe 10 patients with 2009 H1N1 influenza and concurrent invasive group A streptococcal infection with marked associated morbidity and mortality. Seven patients required intensive care, 8 required mechanical ventilation, and 7 died. Five of the patients, including 4 of the fatalities, were previously healthy. PMID:20377405

  4. Application of Whole-Genome Sequencing to an Unusual Outbreak of Invasive Group A Streptococcal Disease

    PubMed Central

    Galloway-Peña, Jessica; Clement, Meredith E.; Sharma Kuinkel, Batu K.; Ruffin, Felicia; Flores, Anthony R.; Levinson, Howard; Shelburne, Samuel A.; Moore, Zack; Fowler, Vance G.

    2016-01-01

    Whole-genome analysis was applied to investigate atypical point-source transmission of 2 invasive group A streptococcal (GAS) infections. Isolates were serotype M4, ST39, and genetically indistinguishable. Comparison with MGAS10750 revealed nonsynonymous polymorphisms in ropB and increased speB transcription. This study demonstrates the usefulness of whole-genome analyses for GAS outbreaks. PMID:27006966

  5. Paedatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection in an Indian Adolescent--A Case Report

    ERIC Educational Resources Information Center

    Sharma, Sachin; Vaish, Supriya; Chopra, Saurabh; Singh, Vindyaprakash; Sharma, Priyanka

    2012-01-01

    Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal infection (PANDAS) is a unique constellation of signs and symptoms that exist in a subset of children with rapid onset or exacerbation of obsessive-compulsive disorder (OCD) and/or tic disorders due to an initial autoimmune reaction to a Group A Beta Hemolytic…

  6. Vigilant keratinocytes trigger pathogen-associated molecular pattern signaling in response to streptococcal M1 protein.

    PubMed

    Persson, Sandra T; Wilk, Laura; Mörgelin, Matthias; Herwald, Heiko

    2015-12-01

    The human skin exerts many functions in order to maintain its barrier integrity and protect the host from invading microorganisms. One such pathogen is Streptococcus pyogenes, which can cause a variety of superficial skin wounds that may eventually progress into invasive deep soft tissue infections. Here we show that keratinocytes recognize soluble M1 protein, a streptococcal virulence factor, as a pathogen-associated molecular pattern to release alarming inflammatory responses. We found that this interaction initiates an inflammatory intracellular signaling cascade involving the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK), p38, and Jun N-terminal protein kinase and the subsequent induction and mobilization of the transcription factors NF-κB and AP-1. We also determined the imprint of the inflammatory mediators released, such as interleukin-8 (IL-8), growth-related oncogene alpha, migration inhibitory factor, extracellular matrix metalloproteinase inducer, IL-1α, IL-1 receptor a, and ST2, in response to streptococcal M1 protein. The expression of IL-8 is dependent on Toll-like receptor 2 activity and subsequent activation of the mitogen-activated protein kinases ERK and p38. Notably, this signaling seems to be distinct for IL-8 release, and it is not shared with the other inflammatory mediators. We conclude that keratinocytes participate in a proinflammatory manner in streptococcal pattern recognition and that expression of the chemoattractant IL-8 by keratinocytes constitutes an important protective mechanism against streptococcal M1 protein. PMID:26416902

  7. MYOCARDIAL NECROSIS PRODUCED IN ANIMALS BY MEANS OF CRYSTALLINE STREPTOCOCCAL PROTEINASE

    PubMed Central

    Kellner, Aaron; Robertson, Theodore

    1954-01-01

    Focal myocardial necrosis that was often extensive was found in a high percentage of rabbits, guinea pigs, and mice given a single intravenous injection of crystalline streptococcal proteinase. The findings are discussed in relation to their possible implications for the pathogenesis of the cardiac lesions of rheumatic fever. PMID:13163324

  8. Vigilant Keratinocytes Trigger Pathogen-Associated Molecular Pattern Signaling in Response to Streptococcal M1 Protein

    PubMed Central

    Wilk, Laura; Mörgelin, Matthias; Herwald, Heiko

    2015-01-01

    The human skin exerts many functions in order to maintain its barrier integrity and protect the host from invading microorganisms. One such pathogen is Streptococcus pyogenes, which can cause a variety of superficial skin wounds that may eventually progress into invasive deep soft tissue infections. Here we show that keratinocytes recognize soluble M1 protein, a streptococcal virulence factor, as a pathogen-associated molecular pattern to release alarming inflammatory responses. We found that this interaction initiates an inflammatory intracellular signaling cascade involving the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK), p38, and Jun N-terminal protein kinase and the subsequent induction and mobilization of the transcription factors NF-κB and AP-1. We also determined the imprint of the inflammatory mediators released, such as interleukin-8 (IL-8), growth-related oncogene alpha, migration inhibitory factor, extracellular matrix metalloproteinase inducer, IL-1α, IL-1 receptor a, and ST2, in response to streptococcal M1 protein. The expression of IL-8 is dependent on Toll-like receptor 2 activity and subsequent activation of the mitogen-activated protein kinases ERK and p38. Notably, this signaling seems to be distinct for IL-8 release, and it is not shared with the other inflammatory mediators. We conclude that keratinocytes participate in a proinflammatory manner in streptococcal pattern recognition and that expression of the chemoattractant IL-8 by keratinocytes constitutes an important protective mechanism against streptococcal M1 protein. PMID:26416902

  9. National variation in United States sepsis mortality: a descriptive study

    PubMed Central

    2010-01-01

    Background The regional distribution of a disease may provide important insights regarding its pathophysiology, risk factors and clinical care. While sepsis is a prominent cause of death in the United States (US), few studies have examined regional variations with this malady. We identified the national variation in sepsis deaths in the US. We conducted a descriptive analysis of 1999-2005 national vital statistics data from the National Center for Health Statistics summarized at the state-level. We defined sepsis deaths as deaths attributed to an infection, classified according to the International Classification of Diseases, Version 10. We calculated national and state age-adjusted sepsis-attributed mortality rates. Results National age-adjusted sepsis mortality was 65.5 per 100,000 persons (95% CI: 65.8 - 66.0). State level sepsis mortality varied more than two-fold (range 41 to 88.6 per 100,000 persons; median 60.8 per 100,000, IQR 53.9-74.4 per 100,000). A cluster extending from the Southeastern to the mid-Atlantic US encompassed states with the highest sepsis mortality. Conclusions Sepsis mortality varies across the US. The states with highest sepsis mortality form a contiguous cluster in the Southeastern and mid-Atlantic US. These observations highlight unanswered questions regarding the characteristics and care of sepsis. PMID:20156361

  10. Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE.

    PubMed

    Nguyen, H Bryant; Jaehne, Anja Kathrin; Jayaprakash, Namita; Semler, Matthew W; Hegab, Sara; Yataco, Angel Coz; Tatem, Geneva; Salem, Dhafer; Moore, Steven; Boka, Kamran; Gill, Jasreen Kaur; Gardner-Gray, Jayna; Pflaum, Jacqueline; Domecq, Juan Pablo; Hurst, Gina; Belsky, Justin B; Fowkes, Raymond; Elkin, Ronald B; Simpson, Steven Q; Falk, Jay L; Singer, Daniel J; Rivers, Emanuel P

    2016-01-01

    Prior to 2001 there was no standard for early management of severe sepsis and septic shock in the emergency department. In the presence of standard or usual care, the prevailing mortality was over 40-50 %. In response, a systems-based approach, similar to that in acute myocardial infarction, stroke and trauma, called early goal-directed therapy was compared to standard care and this clinical trial resulted in a significant mortality reduction. Since the publication of that trial, similar outcome benefits have been reported in over 70 observational and randomized controlled studies comprising over 70,000 patients. As a result, early goal-directed therapy was largely incorporated into the first 6 hours of sepsis management (resuscitation bundle) adopted by the Surviving Sepsis Campaign and disseminated internationally as the standard of care for early sepsis management. Recently a trio of trials (ProCESS, ARISE, and ProMISe), while reporting an all-time low sepsis mortality, question the continued need for all of the elements of early goal-directed therapy or the need for protocolized care for patients with severe and septic shock. A review of the early hemodynamic pathogenesis, historical development, and definition of early goal-directed therapy, comparing trial conduction methodology and the changing landscape of sepsis mortality, are essential for an appropriate interpretation of these trials and their conclusions. PMID:27364620

  11. Sepsis in the severely immunocompromised patient.

    PubMed

    Kalil, Andre C; Opal, Steven M

    2015-06-01

    The prevention and treatment of sepsis in the immunocompromised host present a challenging array of diagnostic and management issues. The neutropenic patient has a primary defect in innate immune responses and is susceptible to conventional and opportunistic pathogens. The solid organ transplant patient has a primary defect in adaptive immunity and is susceptible to a myriad of pathogens that require an effective cellular immune response. Risk for infections in organ transplant recipients is further complicated by mechanical, vascular, and rejection of the transplanted organ itself. The immune suppressed state can modify the cardinal signs of inflammation, making accurate and rapid diagnosis of infection and sepsis difficult. Empiric antimicrobial agents can be lifesaving in these patients, but managing therapy in an era of progressive antibiotic resistance has become a real issue. This review discusses the challenges faced when treating severe infections in these high-risk patients. PMID:25939918

  12. Sepsis management: An evidence-based approach.

    PubMed

    Baig, Muhammad Akbar; Shahzad, Hira; Jamil, Bushra; Hussain, Erfan

    2016-03-01

    The Surviving Sepsis Campaign (SSC) guidelines have outlined an early goal directed therapy (EGDT) which demonstrates a standardized approach to ensure prompt and effective management of sepsis. Having said that, there are barriers associated with the application of evidence-based practice, which often lead to an overall poorer adherence to guidelines. Considering the global burden of disease, data from low- to middle-income countries is scarce. Asia is the largest continent but most Asian countries do not have a well-developed healthcare system and compliance rates to resuscitation and management bundles are as low as 7.6% and 3.5%, respectively. Intensive care units are not adequately equipped and financial concerns limit implementation of expensive treatment strategies. Healthcare policy-makers should be notified in order to alleviate financial restrictions and ensure delivery of standard care to septic patients. PMID:26968289

  13. Emergency department antimicrobial considerations in severe sepsis.

    PubMed

    Green, Robert S; Gorman, Sean K

    2014-11-01

    Severe sepsis and septic shock are common problems in the emergency department patient population and require expert clinical skill by members of the emergency department team to maximize optimal patient outcomes. Although various guidelines have been developed for the management of these patients, issues around antimicrobial-related considerations in critically ill patients require further evidence-based attention. In this review article, important factors related to patient illness, microorganism, timing of antimicrobial administration, and source control are discussed. PMID:25441038

  14. Acute neonatal appendicitis in a preterm.

    PubMed

    Mammou, Sihem; Ayadi, Imen; Ben Hamida, Emira; Marrakchi, Zahra

    2015-01-01

    Acute neonatal appendicitis is very rare in the neonatal period. It is usually associated with comorbidity including prematurity. Symptoms are non-specific. The prognosis is marked by high risk of mortality and morbidity. Here, we report a case of preterm new born who presented with sepsis, apnoea, and digestive signs. The laparotomy revealed perforated appendicitis complicated with peritonitis. PMID:26712299

  15. Acute neonatal appendicitis in a preterm

    PubMed Central

    Mammou, Sihem; Ayadi, Imen; Hamida, Emira Ben; Marrakchi, Zahra

    2015-01-01

    Acute neonatal appendicitis is very rare in the neonatal period. It is usually associated with comorbidity including prematurity. Symptoms are non-specific. The prognosis is marked by high risk of mortality and morbidity. Here, we report a case of preterm new born who presented with sepsis, apnoea, and digestive signs. The laparotomy revealed perforated appendicitis complicated with peritonitis. PMID:26712299

  16. Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury.

    PubMed

    Patil, Naeem K; Parajuli, Nirmala; MacMillan-Crow, Lee Ann; Mayeux, Philip R

    2014-04-01

    Acute kidney injury (AKI) is a complication of sepsis and leads to a high mortality rate. Human and animal studies suggest that mitochondrial dysfunction plays an important role in sepsis-induced multi-organ failure; however, the specific mitochondrial targets damaged during sepsis remain elusive. We used a clinically relevant cecal ligation and puncture (CLP) murine model of sepsis and assessed renal mitochondrial function using high-resolution respirometry, renal microcirculation using intravital microscopy, and renal function. CLP caused a time-dependent decrease in mitochondrial complex I and II/III respiration and reduced ATP. By 4 h after CLP, activity of manganese superoxide dismutase (MnSOD) was decreased by 50% and inhibition was sustained through 36 h. These events were associated with increased mitochondrial superoxide generation. We then evaluated whether the mitochondria-targeted antioxidant Mito-TEMPO could reverse renal mitochondrial dysfunction and attenuate sepsis-induced AKI. Mito-TEMPO (10 mg/kg) given at 6 h post-CLP decreased mitochondrial superoxide levels, protected complex I and II/III respiration, and restored MnSOD activity by 18 h. Mito-TEMPO also improved renal microcirculation and glomerular filtration rate. Importantly, even delayed therapy with a single dose of Mito-TEMPO significantly increased 96-h survival rate from 40% in untreated septic mice to 80%. Thus, sepsis causes sustained inactivation of three mitochondrial targets that can lead to increased mitochondrial superoxide. Importantly, even delayed therapy with Mito-TEMPO alleviated kidney injury, suggesting that it may be a promising approach to treat septic AKI. PMID:24500690

  17. Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury

    PubMed Central

    Patil, Naeem K.; Parajuli, Nirmala; Mayeux, Philip R.

    2014-01-01

    Acute kidney injury (AKI) is a complication of sepsis and leads to a high mortality rate. Human and animal studies suggest that mitochondrial dysfunction plays an important role in sepsis-induced multi-organ failure; however, the specific mitochondrial targets damaged during sepsis remain elusive. We used a clinically relevant cecal ligation and puncture (CLP) murine model of sepsis and assessed renal mitochondrial function using high-resolution respirometry, renal microcirculation using intravital microscopy, and renal function. CLP caused a time-dependent decrease in mitochondrial complex I and II/III respiration and reduced ATP. By 4 h after CLP, activity of manganese superoxide dismutase (MnSOD) was decreased by 50% and inhibition was sustained through 36 h. These events were associated with increased mitochondrial superoxide generation. We then evaluated whether the mitochondria-targeted antioxidant Mito-TEMPO could reverse renal mitochondrial dysfunction and attenuate sepsis-induced AKI. Mito-TEMPO (10 mg/kg) given at 6 h post-CLP decreased mitochondrial superoxide levels, protected complex I and II/III respiration, and restored MnSOD activity by 18 h. Mito-TEMPO also improved renal microcirculation and glomerular filtration rate. Importantly, even delayed therapy with a single dose of Mito-TEMPO significantly increased 96-h survival rate from 40% in untreated septic mice to 80%. Thus, sepsis causes sustained inactivation of three mitochondrial targets that can lead to increased mitochondrial superoxide. Importantly, even delayed therapy with Mito-TEMPO alleviated kidney injury, suggesting that it may be a promising approach to treat septic AKI. PMID:24500690

  18. A Study of Sepsis in Surgical Wounds

    PubMed Central

    Hnatko, S. I.; Macdonald, G. R.; Rodin, A. E.

    1963-01-01

    Published records of the frequency of wound sepsis are often unreliable sources of information on the general frequency of this complication because of unstandardized methods of reporting and because of the various views of different investigators as to what constitutes sepsis. A method of infection reporting, its study and analysis are outlined. A survey of postoperative infections by this method for the years 1959, 1960 and 1961 revealed infection rates of 2.02%, 1.20% and 1.14%, respectively. For the same period the percentages of wound infections caused by Staph. aureus were 83.06%, 69.8% and 51.8%, respectively. The most prevalent phage types were 55/53/54 and 52/80/81/82, although types 80/81/82 and 80 were also involved. Infections with Gram-negative organisms were encountered more often in 1961 than in 1959. The majority of these were of mixed type, and followed abdominal surgery. There is need for more comprehensive study and analysis of postoperative wound sepsis and its complications. It was apparent from this study that, statistically, a relatively low rate of postoperative infections may mask a high rate following a specific surgical procedure. PMID:13954844

  19. Reduction in maternal mortality due to sepsis.

    PubMed

    Chhabra, S; Kaipa, A; Kakani, A

    2005-02-01

    The present study was undertaken at a rural medical institute in India to analyse the trends in maternal mortality due to sepsis and the factors associated with change, if any. During the study period of 20 years, a total of 37,155 women delivered, 192 deaths occurred and forty deaths (20.83%) were due to sepsis and it's sequlae. It was revealed that there is a definite decrease in the proportion of deaths due to sepsis, to 10% in the last five years from 35% in earlier years. The change seems to be due to the advocacy of clean deliveries and reduction in case fatality because of alterations in medication and earlier surgical intervention. However the percentage contribution of septic abortion has remained the same. Septic abortion continues to exist inspite of all the current laws and discussion about the availability of a liberal law, which permits abortion almost on request. Most of the women who had died due to septic abortion were married (65%). Deaths due to septic abortion, are persisting even in married women and it is a matter of concern for health providers, policy makers and governments. PMID:15814392

  20. THE EPITHELIUM AS A TARGET IN SEPSIS.

    PubMed

    Chawla, Lakhmir S; Fink, Mitchell; Goldstein, Stuart L; Opal, Steven; Gómez, Alonso; Murray, Patrick; Gómez, Hernando; Kellum, John A

    2016-03-01

    Organ dysfunction induced by sepsis has been consistently associated with worse outcome and death. Regardless of the organ compromised, epithelial dysfunction is present throughout the body, affecting those organs that contain epithelia like the skin, lungs, liver, gut, and kidneys. Despite their obvious differences, sepsis seems to alter common features of all epithelia, such as barrier function and vectorial ion transport. Such alterations in the lung, the gut, and the kidney have direct implications that may explain the profound organ functional impairments in the absence of overt cell death. Epithelial injury in this context is not only an explanatory real pathophysiologic event, but also represents a source of biomarkers that have been explored to identify organ compromise earlier, predict outcome, and even to test novel therapeutic interventions such as blood purification. However, this remains largely experimental, and despite promising results, work is still required to better understand the response of the epithelial cells to sepsis, to define their role in adaptation to insults, to comprehend the interorgan cross-talk that occurs in these circumstances, and to exploit these aspects in pursuit of targeted therapies like blood purification, which may improve outcome for these patients in the future. PMID:26863125

  1. A two-stage clinical decision support system for early recognition and stratification of patients with sepsis: an observational cohort study

    PubMed Central

    Lyons, Jason J; Greene, Tracy L; Haley, James M

    2015-01-01

    Objective To examine the diagnostic accuracy of a two-stage clinical decision support system for early recognition and stratification of patients with sepsis. Design Observational cohort study employing a two-stage sepsis clinical decision support to recognise and stratify patients with sepsis. The stage one component was comprised of a cloud-based clinical decision support with 24/7 surveillance to detect patients at risk of sepsis. The cloud-based clinical decision support delivered notifications to the patients’ designated nurse, who then electronically contacted a provider. The second stage component comprised a sepsis screening and stratification form integrated into the patient electronic health record, essentially an evidence-based decision aid, used by providers to assess patients at bedside. Setting Urban, 284 acute bed community hospital in the USA; 16,000 hospitalisations annually. Participants Data on 2620 adult patients were collected retrospectively in 2014 after the clinical decision support was implemented. Main outcome measure ‘Suspected infection’ was the established gold standard to assess clinical decision support clinimetric performance. Results A sepsis alert activated on 417 (16%) of 2620 adult patients hospitalised. Applying ‘suspected infection’ as standard, the patient population characteristics showed 72% sensitivity and 73% positive predictive value. A postalert screening conducted by providers at bedside of 417 patients achieved 81% sensitivity and 94% positive predictive value. Providers documented against 89% patients with an alert activated by clinical decision support and completed 75% of bedside screening and stratification of patients with sepsis within one hour from notification. Conclusion A clinical decision support binary alarm system with cross-checking functionality improves early recognition and facilitates stratification of patients with sepsis. PMID:26688744

  2. Implications of the new international sepsis guidelines for nursing care.

    PubMed

    Kleinpell, Ruth; Aitken, Leanne; Schorr, Christa A

    2013-05-01

    Sepsis is a serious worldwide health care condition that is associated with high mortality rates, despite improvements in the ability to manage infection. New guidelines for the management of sepsis were recently released that advocate for implementation of care based on evidence-based practice for both adult and pediatric patients. Critical care nurses are directly involved in the assessment of patients at risk for developing sepsis and in the treatment of patients with sepsis and can, therefore, affect outcomes for critically ill patients. Nurses' knowledge of the recommendations in the new guidelines can help to ensure that patients with sepsis receive therapies that are based on the latest scientific evidence. This article presents an overview of new evidence-based recommendations for the treatment of adult patients with sepsis, highlighting the role of critical care nurses. PMID:23635930

  3. Recognizing and managing sepsis: what needs to be done?

    PubMed

    Yealy, Donald M; Huang, David T; Delaney, Anthony; Knight, Marian; Randolph, Adrienne G; Daniels, Ron; Nutbeam, Tim

    2015-01-01

    Sepsis is associated with significant morbidity and mortality if not promptly recognized and treated. Since the development of early goal-directed therapy, mortality rates have decreased, but sepsis remains a major cause of death in patients arriving at the emergency department or staying in hospital. In this forum article, we asked clinicians and researchers with expertise in sepsis care to discuss the importance of rapid detection and treatment of the condition, as well as special considerations in different patient groups. PMID:25927426

  4. [Prevention and treatment strategy for burn wound sepsis in children].

    PubMed

    Niu, Xihua; Li, Xiaoling

    2016-02-01

    Wound sepsis is one of the main causes of death in patients with severe burn and trauma. The high incidence of burn wound sepsis in children is attributed to their imperfect immune system function, poor resistance against infection, and the weakened skin barrier function after burn. The key to reduce the mortality of pediatric patients with burn wound sepsis is to enhance the understanding of its etiology, epidemiology, pathogenesis, and diagnostic criteria, in order to improve its early diagnosis and treatment. PMID:26902271

  5. Inhibition of Intestinal Thiamin Transport in Rat Model of Sepsis

    PubMed Central

    Sassoon, Catherine S.; Zhu, Ercheng; Fang, Liwei; Subramanian, Veedamali S.; Said, Hamid M.

    2016-01-01

    Objective Thiamin deficiency is highly prevalent in patients with sepsis, but the mechanism by which sepsis induces thiamin deficiency is unknown. This study aimed to determine the influence of various severity of sepsis on carrier-mediated intestinal thiamin uptake, level of expressions of thiamin transporters (thiamin transporter-1 (THTR-1) and thiamin transporter-2 (THTR-2)), and mitochondrial thiamin pyrophosphate transporter (MTPPT). Design Randomized, controlled study Setting Research laboratory at a Veterans Affairs Medical Center Subjects Twenty-four Sprague-Dawley rats were randomized into controls, mild, moderate and severe sepsis with equal number of animals in each group. Measurements and Main Results Sepsis was induced by cecal ligation and puncture with the cecum ligated below the cecal valve at 25 %, 50 % and 75 % of cecal length, defined as severe, moderate and mild sepsis, respectively. Control animals underwent laparotomy only. After 2 days of induced sepsis, carrier-mediated intestinal thiamin uptake was measured using [3H]thiamin. Expressions of THTR-1, THTR-2, and MTPPT proteins and mRNA were measured. Proinflammatory cytokines (IL-1β and IL-6), and adenosine triphosphate (ATP) were also measured. Sepsis inhibited [3H]thiamin uptake and the inhibition was a function of sepsis severity. Both cell membranes thiamin transporters and MTPPT expression levels were suppressed; also levels of ATP in the intestine of animals with moderate and severe sepsis were significantly lower than that of sham operated controls. Conclusions For the first time we demonstrated that sepsis inhibited carrier-mediated intestinal thiamin uptake as a function of sepsis severity, suppressed thiamin transporters and MTPPT, leading to ATP depletion. PMID:27065466

  6. Are there new approaches for diagnosis, therapy guidance and outcome prediction of sepsis?

    PubMed Central

    Kojic, Dubravka; Siegler, Benedikt H; Uhle, Florian; Lichtenstern, Christoph; Nawroth, Peter P; Weigand, Markus A; Hofer, Stefan; Brenner, Thorsten

    2015-01-01

    Beside many efforts to improve outcome, sepsis is still one of the most frequent causes of death in critically ill patients. It is the most common condition with high mortality in intensive care units. The complexity of the septic syndrome comprises immunological aspects - i.e., sepsis induced immunosuppression - but is not restricted to this fact in modern concepts. So far, exact mechanisms and variables determining outcome and mortality stay unclear. Since there is no typical risk profile, early diagnosis and risk stratification remain difficult, which hinders rapid and effective treatment initiation. Due to the heterogeneous nature of sepsis, potential therapy options should be adapted to the individual. Biomarkers like C-reactive protein and procalcitonin are routinely used as complementary tools in clinical decision-making. Beyond the acute phase proteins, a wide bunch of promising substances and non-laboratory tools with potential diagnostic and prognostic value is under intensive investigation. So far, clinical decision just based on biomarker assessment is not yet feasible. However, biomarkers should be considered as a complementary approach. PMID:25992320

  7. Public Awareness of Sepsis Is Low in Sweden

    PubMed Central

    Mellhammar, Lisa; Christensson, Bertil; Linder, Adam

    2015-01-01

    Background. Sepsis is a serious and common condition with high mortality and morbidity. The public awareness, knowledge, and perception of sepsis in Sweden are unknown. Methods. A survey was performed using an online interview distributed to adults, aged 18–74, between March 6 and 9, 2015. Results. A total of 1001 people responded to the survey. Twenty-one percent of participants had heard of sepsis, whereas more than 86% had heard of each of the other conditions listed; for example, stroke (95%), chronic obstructive pulmonary disease (COPD) (95%), and leukemia (92%). Of those who had heard of sepsis, 93% responded that it is an infection or blood poisoning in an open question. The respondents who had heard of each disease estimated its mortality. For sepsis, the mortality was estimated at an average of 30%, which was at the same level as estimated mortalities for prostate and breast cancer but lower than for stroke, COPD, and leukemia. Conclusions. The awareness and knowledge of sepsis is low. The mortality for sepsis is not as overestimated as for many other diseases. The lack of awareness of sepsis might be a target to improve the outcome for sepsis patients by reducing the prehospital delay and hence enable early interventions. An increased general awareness might also raise interest for funding for research in this area and for its priority in healthcare support. PMID:26634220

  8. Biology and Metabolism of Sepsis: Innate Immunity, Bioenergetics, and Autophagy.

    PubMed

    Lewis, Anthony J; Billiar, Timothy R; Rosengart, Matthew R

    2016-06-01

    Sepsis is a complex, heterogeneous physiologic condition that represents a significant public health concern. While many insights into the pathophysiology of sepsis have been elucidated over the past decades of research, important questions remain. This article serves as a review of several important areas in sepsis research. Understanding the innate immune response has been at the forefront as of late, especially in the context of cytokine-directed therapeutic trials. Cellular bioenergetic changes provide insight into the development of organ dysfunction in sepsis. Autophagy and mitophagy perform crucial cell housekeeping and stress response functions. Finally, age-related changes and their potential impact on the septic response are reviewed. PMID:27093228

  9. Experimental treatments for mitochondrial dysfunction in sepsis: A narrative review

    PubMed Central

    Zheng, Guilang; Lyu, Juanjuan; Huang, Jingda; Xiang, Dan; Xie, Meiyan; Zeng, Qiyi

    2015-01-01

    Sepsis is a systemic inflammatory response to infection. Sepsis, which can lead to severe sepsis, septic shock, and multiple organ dysfunction syndrome, is an important cause of mortality. Pathogenesis is extremely complex. In recent years, cell hypoxia caused by mitochondrial dysfunction has become a hot research field. Sepsis damages the structure and function of mitochondria, conversely, mitochondrial dysfunction aggravated sepsis. The treatment of sepsis lacks effective specific drugs. The aim of this paper is to undertake a narrative review of the current experimental treatment for mitochondrial dysfunction in sepsis. The search was conducted in PubMed databases and Web of Science databases from 1950 to January 2014. A total of 1,090 references were retrieved by the search, of which 121 researches met all the inclusion criteria were included. Articles on the relationship between sepsis and mitochondria, and drugs used for mitochondrial dysfunction in sepsis were reviewed retrospectively. The drugs were divided into four categories: (1) Drug related to mitochondrial matrix and respiratory chain, (2) drugs of mitochondrial antioxidant and free radical scavengers, (3) drugs related to mitochondrial membrane stability, (4) hormone therapy for septic mitochondria. In animal experiments, many drugs show good results. However, clinical research lacks. In future studies, the urgent need is to develop promising drugs in clinical trials. PMID:25983774

  10. TRPV1 and SP: key elements for sepsis outcome?

    PubMed Central

    Bodkin, Jennifer Victoria; Fernandes, Elizabeth Soares

    2013-01-01

    Sensory neurons play important roles in many disorders, including inflammatory diseases, such as sepsis. Sepsis is a potentially lethal systemic inflammatory reaction to a local bacterial infection, affecting thousands of patients annually. Although associated with a high mortality rate, sepsis outcome depends on the severity of systemic inflammation, which can be directly influenced by several factors, including the immune response of the patient. Currently, there is a lack of effective drugs to treat sepsis, and thus there is a need to develop new drugs to improve sepsis outcome. Several mediators involved in the formation of sepsis have now been identified, but the mechanisms underlying the pathology remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) receptor and the neuropeptide substance P (SP) have recently been demonstrated as important targets for sepsis and are located on sensory neurones and non-neuronal cells. Herein, we highlight and review the importance of sensory neurones for the modulation of sepsis, with specific focus on recent findings relating to TRPV1 and SP, with their distinct abilities to alter the transition from local to systemic inflammation and also modify the overall sepsis outcome. We also emphasize the protective role of TRPV1 in this context. LINKED ARTICLES This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7 PMID:23145480

  11. Streptococcal-vimentin cross-reactive antibodies induce microvascular cardiac endothelial proinflammatory phenotype in rheumatic heart disease.

    PubMed

    Delunardo, F; Scalzi, V; Capozzi, A; Camerini, S; Misasi, R; Pierdominici, M; Pendolino, M; Crescenzi, M; Sorice, M; Valesini, G; Ortona, E; Alessandri, C

    2013-09-01

    Rheumatic heart disease (RHD) is characterized by the presence of anti-streptococcal group A antibodies and anti-endothelial cell antibodies (AECA). Molecular mimicry between streptococcal antigens and self proteins is a hallmark of the pathogenesis of rheumatic fever. We aimed to identify, in RHD patients, autoantibodies specific to endothelial autoantigens cross-reactive with streptococcal proteins and to evaluate their role in inducing endothelial damage. We used an immunoproteomic approach with endothelial cell-surface membrane proteins in order to identify autoantigens recognized by AECA of 140 RHD patients. Cross-reactivity of purified antibodies with streptococcal proteins was analysed. Homologous peptides recognized by serum cross-reactive antibodies were found through comparing the amino acid sequence of streptococcal antigens with human antigens. To investigate interleukin (IL)-1R-associated kinase (IRAK1) and nuclear factor-κB (NF-κB) activation, we performed a Western blot analysis of whole extracts proteins from unstimulated or stimulated human microvascular cardiac endothelial cells (HMVEC-C). Adhesion molecule expression and release of proinflammatory cytokines and growth factors were studied by multiplex bead based immunoassay kits. We observed anti-vimentin antibodies in sera from 49% RHD AECA-positive patients. Cross-reactivity of purified anti-vimentin antibodies with heat shock protein (HSP)70 and streptopain streptococcal proteins was shown. Comparing the amino acid sequence of streptococcal HSP70 and streptopain with human vimentin, we found two homologous peptides recognized by serum cross-reactive antibodies. These antibodies were able to stimulate HMVEC-C inducing IRAK and NF-κB activation, adhesion molecule expression and release of proinflammatory cytokines and growth factors. In conclusion, streptococcal-vimentin cross-reactive antibodies were able to activate microvascular cardiac endothelium by amplifying the inflammatory response

  12. Regulation of IL-17 Family Members by Adrenal Hormones During Experimental Sepsis in Mice

    PubMed Central

    Bosmann, Markus; Meta, Fabien; Ruemmler, Robert; Haggadone, Mikel D.; Sarma, J. Vidya; Zetoune, Firas S.; Ward, Peter A.

    2014-01-01

    Severe sepsis is a life-threatening disease that causes major morbidity and mortality. Catecholamines and glucocorticoids often have been used for the treatment of sepsis. Several recent studies have suggested a potential role of IL-17 during the development and progression of sepsis in small animal models. In this study, the cross-talk of catecholamines and glucocorticoids with members of the IL-17 family was investigated during sepsis in C57BL/6 mice. The concentrations in plasma of IL-17A, IL-17F, and the IL-17AF heterodimer all were increased greatly in mice after endotoxemia or cecal ligation and puncture as compared with sham mice. Surprisingly, when compared with IL-17A (487 pg/mL), the concentrations of IL-17F (2361 pg/mL) and the heterodimer, IL-17AF (5116 pg/mL), were much higher 12 hours after endotoxemia. After surgical removal of the adrenal glands, mice had much higher mortality after endotoxemia or cecal ligation and puncture. The absence of endogenous adrenal gland hormones (cortical and medullary) was associated with 3- to 10-fold higher concentrations of IL-17A, IL-17F, IL-17AF, and IL-23. The addition of adrenaline, noradrenaline, hydrocortisone, or dexamethasone to lipopolysaccharide-activated peritoneal macrophages dose-dependently suppressed the expression and release of IL-17s. The production of IL-17s required activation of c-Jun-N-terminal kinase, which was antagonized by both catecholamines and glucocorticoids. These data provide novel insights into the molecular mechanisms of immune modulation by catecholamines and glucocorticoids during acute inflammation. PMID:23499051

  13. Efficacy of traditional Chinese medicine on sepsis: a systematic review and Meta-Analysis

    PubMed Central

    Liang, Xiao; Zhou, Miao; Ge, Xin-Yu; Li, Cheng-Bao; Fang, Shang-Ping; Tang, Ling; Shao, Dong-Hua; Xu, Guo

    2015-01-01

    Background: Traditional Chinese medicine (TCM) has been used for treatment of sepsis in China, but results still remain equivocal. To evaluate the safety and efficacy of TCM for sepsis, we conducted this Meta-analysis. Methods: Databases searched included randomized controlled trials (RCTs) published in PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) (up to December 2014). The studies included used routine therapy treating sepsis in the control group and TCM was added on that basis in the experimental group. Methodological quality was assessed by Cochrane criteria for risk of bias. Results: Ten RCTs with 691 participants were identified and analyzed. In the meta-analysis, TCM plus routine therapy reduced the 28-day mortality compared to routine therapy alone, [RR = 0.67; 95% CI: 0.51~0.87; P = 0.002]; The decrease in length of ICU-stay [MD = -1.82; 95% CI: -2.60~-1.04; P<0.00001]; Acute physiology and chronic health evaluation system (APACHE II) score [MD = -2.95; 95% CI: -3.99~-1.91; P<0.00001]; Serum inflammatory factors concentration after treatment [SMD = -0.50; 95% CI:-0.68~-0.33; P<0.00001], including TNF-α [SMD = -0.61; 95% CI: -0.85~-0.38; P<0.00001] and IL-6 [SMD = -0.40; 95% CI: -0.75~-0.04; P = 0.03] in subgroup analysis all had statistical significance. Conclusion: Addition of TCM has better effects in participants with sepsis, while more high-quality studies are needed to draw firm conclusion. PMID:26884914

  14. Different regulation of Toll-like receptor 4 expression on blood CD14+ monocytes by simvastatin in patients with sepsis and severe sepsis

    PubMed Central

    Shao, Huanzhang; Wang, Cunzhen; Zhu, Wenliang; Huang, Xiaopei; Guo, Zhisong; Zhang, Huifeng; Qin, Bingyu

    2015-01-01

    We have demonstrated that regulation of Toll-like receptor 4 (TLR4) surface expression levels on blood CD14+ monocytes by simvastatin treatment in patient with sepsis is different from that in patients with severe sepsis. In patients with sepsis simvastatin treatment statistically significantly decreased TLR4 surface expression level on blood CD14+ monocytes, while in patients with severe sepsis simvastatin treatment had no significant influence on TLR4 surface expression level on blood CD14+ monocytes. The changes of plasma interleukin-6 (IL-6) induced by simvastatin in patients with sepsis and severe sepsis were similar with that of TLR4. Our results indicated simvastatin treatment differently influenced inflammation process in patients with sepsis and severe sepsis, which might partially explain the discrepancy, presented by previous trials, about the therapeutic effects of simvastatin treatment in patients with sepsis and severe sepsis. PMID:26550333

  15. Streptococcal necrotising fasciitis: comparison between histological and clinical features.

    PubMed Central

    Barker, F G; Leppard, B J; Seal, D V

    1987-01-01

    Nineteen acute and 17 subacute cases of necrotising fasciitis due to beta haemolytic streptococci are described. Excised tissue from seven and four cases, respectively, was available for histological examination. The two clinical types showed remarkable similarities, with inflammation and necrosis from epidermis to subcutaneous fat. Haemorrhage was present in variable amounts in both types. Gram positive cocci were not always identified in tissue, nor cultured, when serological tests were required to confirm the diagnosis. The only apparent difference between the acute and subacute type was the higher incidence of thrombi in some blood vessels of acute cases, whereas patent vessels or recanalized thrombus were usually found in subacute cases. This quantitative difference in the degree of thrombosis may alone be responsible for the varying clinical features and response to antibiotics. Images Fig 2 Fig 3 Fig 4a Fig 4b Fig 1 PMID:3558868

  16. MFHAS1 Is Associated with Sepsis and Stimulates TLR2/NF-κB Signaling Pathway Following Negative Regulation

    PubMed Central

    Zhong, Jing; Shi, Qi-Qing; Zhu, Min-Min; Shen, Jian; Wang, Hui-Hui; Ma, Duan; Miao, Chang-Hong

    2015-01-01

    Malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) has a potential immunoregulatory role dependent on Toll-like receptors (TLRs). TLR2, associated with deleterious systemic inflammation, cardiac dysfunction, and acute kidney injury, acts synergistically in sepsis. The role of MFHAS1 in targeting TLR2 involved in sepsis has not been examined thus far. This study aimed to examine the relationship of MFHAS1 and sepsis, and the effect of MFHAS1 on the TLR2 signaling pathway. Blood samples were collected from eight sepsis patients after surgery and eight patients undergoing selective surgery to determine blood MFHAS1 levels. HEK 293 cells, RAW 264.7 macrophages and THP-1 monocytes were used to confirm the effect of MFHAS1 on TLR2 signaling pathway. Our study showed that blood MFHAS1 was significantly elevated in septic patients, and MFHAS1 was more increased in mononuclear cells from septic patients. Pam3CSK4 (TLR2 ligand) was found to induce MFHAS1 production in RAW 264.7 murine macrophages and THP-1 human monocytes in a time-dependent manner. MFHAS1 has dual effects on TLR2 signaling pathway and inflammation, i.e., inhibitory effect at 6 hours, and then stimulatory effect after 24 hours through the activation of TLR2/NF-κB signaling pathway, and MFHAS1 induced the phosphorylation of JNK and p38 after TLR2 stimulation. PMID:26599367

  17. Fatal purpura fulminans and Waterhouse-Friderichsen syndrome from fulminant Streptococcus pneumoniae sepsis in an asplenic young adult.

    PubMed

    Hale, Andrew J; LaSalvia, Mary; Kirby, James E; Kimball, Allison; Baden, Rachel

    2016-01-01

    Asplenic patients are at increased risk for sepsis and fulminant infection. Sepsis in these patients is typically secondary to encapsulated bacteria, with Streptococcus pneumoniae being the most frequent pathogen. Rare complications of severe sepsis include purpura fulminans and bilateral adrenal hemorrhage (Waterhouse-Friderichsen syndrome). We present the case of a 36-year-old woman, healthy except for splenectomy years prior for idiopathic thrombocytopenic purpura treatment, who presented with fever. Upon presentation to our hospital, three hours after symptoms onset, she had purpura fulminans and shock. Despite timely antimicrobials and maximal resuscitative efforts, her disease progressed and she expired 12 hours after symptoms onset. Autopsy revealed bilateral adrenal hemorrhage; acute adrenal crisis likely contributed to her refractory shock. Prior to her presentation, she had not received guideline-based post-splenectomy care. Sepsis in asplenic patients can be fulminant and rapidly fatal. Streptococcus pneumoniae remains the most frequent cause, despite decreasing rates in recent years related to widespread pneumococcal vaccination. Guideline-based vaccinations and "pill-in-pocket" therapy can be life-saving for asplenic patients. Purpura fulminans represents an extreme manifestation of disseminated intravascular coagulation, is more common in asplenic patients, and portends a poor prognosis. Waterhouse-Friderichsen syndrome can be seen concurrently with purpura fulminans and further portends a poor prognosis; pre-mortem diagnosis requires a high index of suspicion. PMID:27583208

  18. Sepsis-Induced Takotsubo Cardiomyopathy Leading to Torsades de Pointes.

    PubMed

    Patel, Nirav; Shenoy, Abhishek; Dous, George; Kamran, Haroon; El-Sherif, Nabil

    2016-01-01

    Background. Takotsubo cardiomyopathy (TCM) is sudden and reversible myocardial dysfunction often attributable to physical or emotional triggers. Case Report. We describe a 51-year-old man presented to emergency department with sepsis from urinary tract infection (UTI). He was placed on cefepime for UTI and non-ST-elevation myocardial infarction protocol given elevated troponins with chest pain. Subsequently, patient was pulseless with torsades de pointes (TdP) and then converted to sinus rhythm with cardioversion. An echocardiogram revealed low ejection fraction with hypokinesis of the apical wall. Over 48 hours, the patient was extubated and stable on 3 L/min nasal cannula. He underwent a cardiac catheterization to evaluate coronary artery disease (CAD) and was found to have mild nonobstructive CAD with no further findings. Conclusion. TCM is a rare disorder presenting with symptoms similar to acute coronary syndrome. Though traditionally elicited by physical and emotional triggers leading to transient left ventricular dysfunction, our case suggests that it may also be triggered by a urinary tract infection and lead to severe QT prolongation and a malignant ventricular arrhythmia in TdP. PMID:27525128

  19. Hemofiltration treatment for sepsis: is it time for controlled trials?

    PubMed

    Rogiers, P

    1999-11-01

    While the use of hemofiltration to treat septic shock has potential benefits, the existing studies are difficult to compare because of their variety of inclusion criteria. The concept is to remove the various mediators of severe sepsis and septic shock, such as cytokines and eicosanoids, so that acute renal failure and the resultant multi-organ failure and possible death can be delayed or prevented. The dilemmas include: (a) hemofiltration cannot distinguish between these pro-inflammatory mediators as they are of similar molecular weights, and thus it is difficult to determine which one or combination should be eliminated for the best hemodynamics; (b) timing of the hemofiltration to remove a particular cytokine may make a difference in patient outcome; (c) the most efficacious convection rate of ultrafiltration has not been determined yet; (d) since these mediators quickly saturate the membrane, it should be frequently changed, and thus biocompatibility, availability and costs are added issues; (e) the choice of buffer is different according to the diagnosis of these critically ill patients. Before designing clinical trials, further experimentation is necessary to explore these problems. PMID:10560816

  20. A CLEAR CASE OF MRSA SEPSIS, OF AN UNEXPECTED ORIGIN.

    PubMed

    DeWitt, A; Patel, C; Kuapati, R; Reddy, K

    2015-01-01

    A 56-year-old man with a history of uncontrolled type 2 diabetes mellitus, benign prostatic hypertrophy and history of recent knee and elbow abscess presented to the emergency department with nausea, vomiting, and fevers. Two days prior, he presented to the ER and was diagnosed with acute presumed prostatitis and urinary retention. He was discharged on ciprofloxacin and an indwelling Foley catheter with urology follow-up. After being unable to tolerate oral medications, he presented again to the emergency department, at which time, he was febrile and tachycardic. Physical exam was benign except for a boggy and tender prostate and bilateral CVA tenderness. Labs demonstrated leukocytosis, elevated HbA1C, and pyuria on urinalysis. Urine cultures collected at the patient's earlier emergency department visit demonstrated no growth. Computed tomography indicated an enlarged prostate with patchy areas of low density. He was admitted with sepsis secondary to prostatitis. Blood cultures on day one showed gram-positive cocci , methicillin resistant staph aureus (MRSA isolate) and persistent bacteremia for three days despite therapy with vancomycin. After adequate dosing of vancomycin, sterilization of the blood was achieved, yet urine culture demonstrated growth of MRSA. Transthoracic rchocardiogram (TTE) showed no signs of endocarditis with good visualization of valves. He was successfully treated with 14 days of vancomycin. PMID:27159482

  1. Sepsis-Induced Takotsubo Cardiomyopathy Leading to Torsades de Pointes

    PubMed Central

    Kamran, Haroon; El-Sherif, Nabil

    2016-01-01

    Background. Takotsubo cardiomyopathy (TCM) is sudden and reversible myocardial dysfunction often attributable to physical or emotional triggers. Case Report. We describe a 51-year-old man presented to emergency department with sepsis from urinary tract infection (UTI). He was placed on cefepime for UTI and non-ST-elevation myocardial infarction protocol given elevated troponins with chest pain. Subsequently, patient was pulseless with torsades de pointes (TdP) and then converted to sinus rhythm with cardioversion. An echocardiogram revealed low ejection fraction with hypokinesis of the apical wall. Over 48 hours, the patient was extubated and stable on 3 L/min nasal cannula. He underwent a cardiac catheterization to evaluate coronary artery disease (CAD) and was found to have mild nonobstructive CAD with no further findings. Conclusion. TCM is a rare disorder presenting with symptoms similar to acute coronary syndrome. Though traditionally elicited by physical and emotional triggers leading to transient left ventricular dysfunction, our case suggests that it may also be triggered by a urinary tract infection and lead to severe QT prolongation and a malignant ventricular arrhythmia in TdP. PMID:27525128

  2. Application of the C3-Binding Motif of Streptococcal Pyrogenic Exotoxin B to Protect Mice from Invasive Group A Streptococcal Infection

    PubMed Central

    Kuo, Chih-Feng; Tsao, Nina; Cheng, Miao-Hui; Yang, Hsiu-Chen; Wang, Yu-Chieh; Chen, Ying-Pin; Lin, Kai-Jen

    2015-01-01

    Group A streptococcus (GAS) is an important human pathogen that produces several extracellular exotoxins to facilitate invasion and infection. Streptococcal pyrogenic exotoxin B (SPE B) has been demonstrated to be an important virulence factor of GAS. Our previous studies indicate that SPE B cleaves complement 3 (C3) and inhibits the activation of complement pathways. In this study, we constructed and expressed recombinant fragments of SPE B to examine the C3-binding site of SPE B. Using enzyme-linked immunosorbent assays and pull-down assays, we found that the C-terminal domain, containing amino-acid residues 345–398, of SPE B was the major binding site of human serum C3. We further identified a major, Ala376-Pro398, and a minor C3-binding motif, Gly346-Gly360, that both mediated the binding of C3 complement. Immunization with the C3-binding motifs protected mice against challenge with a lethal dose of non-invasive M49 strain GAS but not invasive M1 strains. To achieve higher efficiency against invasive M1 GAS infection, a combination of synthetic peptides derived from C-terminal epitope of streptolysin S (SLSpp) and from the major C3-binding motif of SPE B (PP6, Ala376-Pro398) was used to elicit specific immune response to those two important streptococcal exotoxins. Death rates and the severity of skin lesions decreased significantly in PP6/SLSpp-immunized mice that were infected with invasive M1 strains of GAS. These results indicate a combination of the C3-binding motif of SPE B and the protective epitope of SLS could be used as a subunit vaccine against invasive M1 strains group A streptococcal infection. PMID:25629609

  3. Designing a Pediatric Severe Sepsis Screening Tool

    PubMed Central

    Sepanski, Robert J.; Godambe, Sandip A.; Mangum, Christopher D.; Bovat, Christine S.; Zaritsky, Arno L.; Shah, Samir H.

    2014-01-01

    We sought to create a screening tool with improved predictive value for pediatric severe sepsis (SS) and septic shock that can be incorporated into the electronic medical record and actively screen all patients arriving at a pediatric emergency department (ED). “Gold standard” SS cases were identified using a combination of coded discharge diagnosis and physician chart review from 7,402 children who visited a pediatric ED over 2 months. The tool’s identification of SS was initially based on International Consensus Conference on Pediatric Sepsis (ICCPS) parameters that were refined by an iterative, virtual process that allowed us to propose successive changes in sepsis detection parameters in order to optimize the tool’s predictive value based on receiver operating characteristics (ROC). Age-specific normal and abnormal values for heart rate (HR) and respiratory rate (RR) were empirically derived from 143,603 children seen in a second pediatric ED over 3 years. Univariate analyses were performed for each measure in the tool to assess its association with SS and to characterize it as an “early” or “late” indicator of SS. A split-sample was used to validate the final, optimized tool. The final tool incorporated age-specific thresholds for abnormal HR and RR and employed a linear temperature correction for each category. The final tool’s positive predictive value was 48.7%, a significant, nearly threefold improvement over the original ICCPS tool. False positive systemic inflammatory response syndrome identifications were nearly sixfold lower. PMID:24982852

  4. Administration of bone marrow stromal cells in sepsis attenuates sepsis-related coagulopathy.

    PubMed

    Tan, Lifei; Huang, Yueyue; Pan, Xiaojun; Quan, Shichao; Xu, Shunyao; Li, Dequan; Song, Lijun; Zhang, Xiaomin; Chen, Wanzhou; Pan, Jingye

    2016-06-01

    Introduction Coagulopathy plays an important role in sepsis. The aim of this study was to determine whether bone marrow stromal cell (BMSC) administration could attenuate coagulopathy in sepsis. Materials and methods In vitro: endothelial cells were cultured with/without BMSCs for 6 h following LPS stimulation and were collected for thrombomodulin (TM) and endothelial protein C receptor (EPCR) measurements. In vivo: Thirty-six mice were randomized into sham, sepsis, and sepsis + BMSC groups (n = 12 each group). Sepsis was induced through cecal ligation and puncture (CLP). BMSC infusion was started at 6 h after CLP. Lung tissues and plasma samples were collected at 24 h after CLP for enzyme-linked immunosorbent assay (ELISA), quantitative real-time RT-PCR, western blot, and immunohistochemistry analysis. Results In vitro: BMSCs attenuated the decrease in TM and EPCR mRNA and protein expression levels in LPS-stimulated endothelial cells. In vivo: BMSC treatment decreased lung injury and mesenteric perfusion impairment, and ameliorated coagulopathy, as suggested by the reduction in elevated TF, vWF, and TAT circulation levels. BMSC infusion decreased TF mRNA transcription and protein expression levels in lung tissues, and increased TM and EPCR mRNA transcription and expression levels. Discussion BMSC administration attenuated coagulopathy, and decreased lung injury and mesenteric perfusion impairment in sepsis. Key messages BMSCs increased the expression of TM and EPCR from endothelium cells exposed to LPS in vitro. BMSC treatment attenuated lung injury and coagulopathy in the mice cecal ligation and puncture (CLP) model. BMSC administration-attenuated coagulopathy is related to the reduced expression of TF and increased expression of TM and EPCR. PMID:26969493

  5. Streptococcal Toxic Shock Syndrome: Life Saving Role of Peritoneal Lavage and Drainage

    PubMed Central

    Yokoyama, Minako; Oyama, Fumie; Ito, Asami; Yokota, Megumi; Matsukura, Daisuke; Tsutsumi, Shinji; Kasai, Tomonori; Nitobe, Yohshiro; Morikawa, Akiko; Ozaki, Takashi; Yokoyama, Yoshihito

    2016-01-01

    PURPOSE We encountered a case where an infection with group A streptococcus (GAS; ie, Streptococcus pyogenes) initially caused primary peritonitis and then subsequently caused streptococcal toxic shock syndrome. The patient’s life was likely saved by an emergency laparotomy followed by extensive peritoneal lavage and drainage. CASE PRESENTATION A 40-year-old woman was admitted to the Emergency Department for lower abdominal pain and numbness in the extremities. She presented with systemic inflammatory response syndrome. An emergency laparotomy was performed, and ascites that resembled pus and general peritonitis were noted. Peritoneal lavage and drainage were performed, and GAS was isolated from peritoneal fluid. Gram staining of cervical polyp specimens revealed Gram-positive bacteria. CONCLUSIONS The patient was diagnosed with streptococcal toxic shock syndrome due to an ascending GAS infection originating from vagina. PMID:27579001

  6. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS): a Controversial Diagnosis.

    PubMed

    de Oliveira, Sheila Knupp Feitosa; Pelajo, Christina Feitosa

    2010-03-01

    Despite more than a decade of studying pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), it is still not possible to confirm its existence and whether it is a poststreptococcal autoimmune disorder. Many controversies remain: the diagnostic criteria have not been validated, evidence of autoimmunity remains inconclusive, evidence of a genetic predisposition is weak, and streptococcal infections are common in childhood and could represent only a trigger of exacerbations of tics and obsessive-compulsive disorder. Patients who fit the PANDAS criteria appear to represent a subgroup of children with chronic tic disorder and/or obsessive-compulsive disorder who may experience symptom exacerbations after group A β-hemolytic streptococci infections; however, those infections are not the sole or even the most common antecedent of exacerbations. There is not enough evidence to support PANDAS as a unique clinical entity. PMID:21308506

  7. The Streptococcal Cysteine Protease SpeB Is Not a Natural Immunoglobulin-Cleaving Enzyme

    PubMed Central

    Persson, Helena; Vindebro, Reine

    2013-01-01

    The human bacterial pathogen Streptococcus pyogenes has developed a broad variety of virulence mechanisms to evade the actions of the host immune defense. One of the best-characterized factors is the streptococcal cysteine protease SpeB, an important multifunctional protease that contributes to group A streptococcal pathogenesis in vivo. Among many suggested activities, SpeB has been described to degrade various human plasma proteins, including immunoglobulins (Igs). In this study, we show that SpeB has no Ig-cleaving activity under physiological conditions and that only Igs in a reduced state, i.e., semimonomeric molecules, are cleaved and degraded by SpeB. Since reducing conditions outside eukaryotic cells have to be considered nonphysiological and IgG in a reduced state lacks biological effector functions, we conclude that SpeB does not contribute to S. pyogenes virulence through the proteolytic degradation of Igs. PMID:23569114

  8. Group A Streptococcal Bacteremia without a Source is Associated with Less Severe Disease in Children

    PubMed Central

    Gauguet, Stefanie; Ahmed, Asim A.; Zhou, Jing; Pfoh, Elizabeth R.; Ahnger-Pier, Kathryn K.; Harper, Marvin B.; Ozonoff, Al; Wessels, Michael R.; Lee, Grace M.

    2014-01-01

    We analyzed characteristics of 86 Group A streptococcal (GAS) bacteremia cases at Boston Children’s Hospital from 1992-2012. Twenty-three percent of children had severe disease, using ICU admission (18), disability (7), or death (2) as indicators. Children with bacteremia without a source (30% of cases) were less likely to have severe disease than children with focal infections in adjusted models. PMID:25319760

  9. Sepsis in Old Age: Review of Human and Animal Studies

    PubMed Central

    Starr, Marlene E; Saito, Hiroshi

    2014-01-01

    Sepsis is a serious problem among the geriatric population as its incidence and mortality rates dramatically increase with advanced age. Despite a large number of ongoing clinical and basic research studies, there is currently no effective therapeutic strategy that rescues elderly patients with severe sepsis. Recognition of this problem is relatively low as compared to other age-associated diseases. The disparity between clinical and basic studies is a problem, and this is likely due, in part, to the fact that most laboratory animals used for sepsis research are not old while the majority of sepsis cases occur in the geriatric population. The objective of this article is to review recent epidemiological studies and clinical observations, and compare these with findings from basic laboratory studies which have used aged animals in experimental sepsis. PMID:24729938

  10. Improving the management and care of people with sepsis.

    PubMed

    Fitzpatrick, David; McKenna, Michael; Rooney, Kevin; Beckett, Dan; Pringle, Norma

    2014-04-01

    Many hospitals struggle to implement the full sepsis care bundle, but research suggests that many patients with sepsis are transported to hospital by ambulance. In 2011, the Scottish Ambulance Service introduced a pre-hospital sepsis screening tool (PSST) to expedite sepsis identification and care delivery. However, ambulance clinicians have reported varying degrees of interest and enthusiasm from hospital staff during handover. Therefore, an online survey was set up to investigate medical and nursing staff perceptions and experiences of the introduction of a PSST. This article discusses the results, which show that participants perceive the PSST reduces time to treatment, improves continuity of care, benefits patients and is accurately applied by ambulance clinicians, but which also highlight problems with communication. The delivery of in-hospital and pre-hospital sepsis care is challenging, but simple measures such as improving and standardising communication and alert systems between ambulance services and receiving hospitals could improve the clinical effects of a PSST. PMID:24689480

  11. How Can the Microbiologist Help in Diagnosing Neonatal Sepsis?

    PubMed Central

    Paolucci, Michela; Landini, Maria Paola; Sambri, Vittorio

    2012-01-01

    Neonatal sepsis can be classified into two subtypes depending upon whether the onset of symptoms is before 72 hours of life (early-onset neonatal sepsis—EONS) or later (late-onset neonatal sepsis—LONS). These definitions have contributed greatly to diagnosis and treatment by identifying which microorganisms are likely to be responsible for sepsis during these periods and the expected outcomes of infection. This paper focuses on the tools that microbiologist can offer to diagnose and eventually prevent neonatal sepsis. Here, we discuss the advantages and limitation of the blood culture, the actual gold standard for sepsis diagnosis. In addition, we examine the utility of molecular techniques in the diagnosis and management of neonatal sepsis. PMID:22319539

  12. Continuous evaluation of changes in the serum proteome from early to late stages of sepsis caused by Klebsiella pneumoniae.

    PubMed

    Raju M, Swathi; V, Jahnavi; Kamaraju, Ratnakar S; Sritharan, Venkataraman; Rajkumar, Karthik; Natarajan, Sumathi; Kumar, Anil D; Burgula, Sandeepta

    2016-06-01

    Serum protein profiles of patients with bacterial sepsis from the day of diagnosis until recovery/mortality were compared from early to late stages in response to severe sepsis using two dimensional electrophoresis. The proteins exhibiting changes during the course of sepsis (20‑28 day mortality) were selected and identified by matrix‑assisted laser desorption ionization‑time of flight‑tandem mass spectrometry. Among the proteins identified, haptoglobin (Hp), transthyretin (TTR), orosomucoid 1/α1 acid glycoprotein (ORM1), α1 antitrypsin (A1AT), serum amyloid A (SAA) and S100A9 exhibited differential expression patterns between survivors (S; n=6) and non‑survivors (NS; n=6), particularly during the early stages of sepsis. Expression factors (EFs), taken as the ratio between the NS and S during early stages, showed ratios of Hp, 0.39 (P≤0.012); TTR, 3.96 (P≤0.03); ORM1, 0.69 (P≤0.79); A1AT, 0.92 (P≤0.87) and SAA, 0.69 (P≤0.01). S100A9, an acute phase protein, exhibited an EF ratio of 1.68 (P≤0.004) during the end stages of sepsis. A delayed rise in levels was observed in Hp, A1AT, ORM1, S100A9 and SAA, whereas TTR levels increased during the early stages of sepsis in NS. Analysis of inflammatory responses in the early stages of sepsis revealed increased mRNA expression in leukocytes of interleukin (IL)‑6 (EF, 2.50), IL‑10 (EF, 1.70) and prepronociceptin (EF, 1.6), which is a precursor for nociceptin in NS compared with S, and higher Toll‑like receptor‑4 (EF, 0.30) levels in S compared with NS. Therefore, a weaker acute phase response in the early stages of sepsis in NS, combined with an inefficient inflammatory response, may contribute to sepsis mortality. PMID:27082932

  13. Identification, purification and characterization of a streptococcal protein antigen with a molecular weight of 3800.

    PubMed Central

    Giasuddin, A S; Lehner, T; Evans, R W

    1983-01-01

    A small molecular weight streptococcal antigen of about 3800 was isolated from Streptococcus mutans. The peptide was obtained by gel filtration of a predominantly 185,000 mol. wt. antigen preparation, with two major antigenic determinants (I/II), on Sephacryl S-200, in the presence of sodium dodecyl sulphate (SDS). The 185,000 mol. wt. antigen was prepared from the culture supernatant of S. mutans by ammonium sulphate precipitation, DEAE cellulose chromatography and gel filtration on Sepharose 6B. The 3800 mol. wt. material gave a single band on SDS/polyacrylamide gel and reacted with antisera to streptococcal antigen I/II, I and II but not III. Furthermore, it was digested by pronase, contained only traces of carbohydrate and lipids were not detected. It is suggested that SA I/II is either synthesized in a range of molecular sizes from 185,000 to 3800 or the former is broken down by streptococcal proteases into smaller fragments. Images Figure 1 Figure 3 PMID:6197355

  14. Autoimmune neuropsychiatric disorders associated with streptococcal infection: Sydenham chorea, PANDAS, and PANDAS variants.

    PubMed

    Pavone, Piero; Parano, Enrico; Rizzo, Renata; Trifiletti, Rosario R

    2006-09-01

    Streptococcal infection in children is usually benign and self-limited. In a small percentage of children, prominent neurologic and/or psychiatric sequelae can occur. Sydenham chorea is the best defined and best recognized. PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) is a well-defined syndrome in which tics (motor and/or vocal) and/or obsessive-compulsive disorder consistently exacerbate in temporal correlation to a group A beta-hemolytic streptococcal infection. PANDAS constitutes a subset of children with tics, Tourette syndrome, and obsessive-compulsive disorder. In addition to strictly defined PANDAS, we and others have recognized several PANDAS variants, including adult-onset variant, a dystonic variant, a myoclonic variant, and a "chronic" PANDAS variant. The nosology and classification of these entities are rapidly evolving. The recognition that some pediatric neurobehavioral syndromes have infectious and/or immunologic triggers points to important new avenues of disease treatment. In this review, we summarize this complex and rapidly evolving area of clinical research. PMID:16970875

  15. Pediatric autoimmune neuropsychiatric disorder associated with group a streptococcal infection: the role of surgical treatment.

    PubMed

    Pavone, P; Rapisarda, V; Serra, A; Nicita, F; Spalice, A; Parano, E; Rizzo, R; Maiolino, L; Di Mauro, P; Vitaliti, G; Coco, A; Falsaperla, A; Trifiletti, R R; Cocuzza, S

    2014-01-01

    Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) is a well-defined syndrome in which tics (motor and/or vocal) and/or obsessive compulsive disorders (OCD) consistently exacerbate in temporal correlation to a Group A beta-haemolytic streptococcal infection. In children with PANDAS, there is speculation about whether tonsillectomy or adenotonsillectomy might improve the neuropsychiatric course. Our objective was to examine whether such surgery impacted remission or, in patients without remission, modified clinical course of the disease, streptococcal antibody titers, neuronal antibodies or clinical severity of Obsessive-Compulsive Disorder (OCD) and/or tics. Study participants (n = 120) with positive PANDAS criteria were recruited, examined, and divided into surgical or non-surgery groups. The surgical group consisted of children with tonsillectomy or adenotonsillectomy (n=56). The remaining children were categorized as non-surgery (n=64). Clinical follow-up was made every 2 months for more than 2 years. Surgery did not affect symptomatology progression, streptococcal and neuronal antibodies, or the clinical severity of neuropsychiatric symptoms in these children. In conclusion, in our series clinical progression, antibody production, and neuropsychiatric symptom severity did not differ on the basis of surgical status. We cannot uphold surgical management as likely to impact positive remission rates, course of OCD/tics, or antibody concentrations in children with PANDAS. PMID:25280028

  16. Selective modulation of superantigen-induced responses by streptococcal cysteine protease.

    PubMed

    Kansal, Rita G; Nizet, Victor; Jeng, Arthur; Chuang, Woei-Jer; Kotb, Malak

    2003-02-01

    Streptococcal pyrogenic exotoxin (Spe) B, a streptococcal cysteine protease, is believed to be important in group A streptococcal (GAS) pathogenesis. The present study examined the effect of SpeB on the activity of superantigenic exotoxins secreted by M1T1 GAS isolates. The proliferative response of human lymphocytes to culture supernatant (SUP) from an SpeB(+) isolate increased significantly (P<.05) when the isolate was grown with N-[N-(L-3-trans-carboxyoxirane-2-carbonyl)-L-leucyl]-agmatine, a cysteine protease inhibitor. The lymphocyte-stimulating activity of SUP from a spontaneous SpeB(-) variant or SpeB(-) knockout (DeltaSpeB) mutant was also significantly higher than that of SUP from the SpeB(+) parent isolate (P<.001). The addition of recombinant SpeB to the DeltaSpeB mutant reduced the lymphocyte response to a level comparable to that with the SpeB(+) isolate. SpeB affected superantigens that stimulate cells expressing T cell receptor Vbeta (TCRBV)-4, TCRBV7, and TCRBV8 but not those that stimulate TCRBV2. SpeB has a selective proteolytic effect on GAS superantigens. PMID:12552423

  17. Oral streptococcal glyceraldehyde-3-phosphate dehydrogenase mediates interaction with Porphyromonas gingivalis fimbriae.

    PubMed

    Maeda, Kazuhiko; Nagata, Hideki; Nonaka, Aya; Kataoka, Kosuke; Tanaka, Muneo; Shizukuishi, Satoshi

    2004-11-01

    Interaction of Porphyromonas gingivalis with plaque-forming bacteria is necessary for its colonization in periodontal pockets. Participation of Streptococcus oralis glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and P. gingivalis fimbriae in this interaction has been reported. In this investigation, the contribution of various oral streptococcal GAPDHs to interaction with P. gingivalis fimbriae was examined. Streptococcal cell surface GAPDH activity was measured by incubation of a constant number of streptococci with glyceraldehyde-3-phosphate and analysis for the conversion of NAD+ to NADH based on the absorbance at 340 nm. Coaggregation activity was measured by a turbidimetric assay. Cell surface GAPDH activity was correlated with coaggregation activity (r = 0.854, P < 0.01) with Spearman's rank correlation coefficient. S. oralis ATCC 9811 and ATCC 10557, Streptococcus gordonii G9B, Streptococcus sanguinis ATCC 10556, and Streptococcus parasanguinis ATCC 15909 exhibited high cell surface GAPDH activity and coaggregation activity; consequently, their cell surface GAPDHs were extracted with mutanolysin and purified on a Cibacron Blue Sepharose column. Subsequently, their DNA sequences were elucidated. Purified GAPDHs bound P. gingivalis recombinant fimbrillin by Western blot assay, furthermore, their DNA sequences displayed a high degree of homology with one another. Moreover, S. oralis recombinant GAPDH inhibited coaggregation between P. gingivalis and the aforementioned five streptococcal strains in a dose-dependent manner. These results suggest that GAPDHs of various plaque-forming streptococci may be involved in their attachment to P. gingivalis fimbriae and that they may contribute to P. gingivalis colonization. PMID:15488735

  18. Streptococcal-vimentin cross-reactive antibodies induce microvascular cardiac endothelial proinflammatory phenotype in rheumatic heart disease

    PubMed Central

    Delunardo, F; Scalzi, V; Capozzi, A; Camerini, S; Misasi, R; Pierdominici, M; Pendolino, M; Crescenzi, M; Sorice, M; Valesini, G; Ortona, E; Alessandri, C

    2013-01-01

    Summary Rheumatic heart disease (RHD) is characterized by the presence of anti-streptococcal group A antibodies and anti-endothelial cell antibodies (AECA). Molecular mimicry between streptococcal antigens and self proteins is a hallmark of the pathogenesis of rheumatic fever. We aimed to identify, in RHD patients, autoantibodies specific to endothelial autoantigens cross-reactive with streptococcal proteins and to evaluate their role in inducing endothelial damage. We used an immunoproteomic approach with endothelial cell-surface membrane proteins in order to identify autoantigens recognized by AECA of 140 RHD patients. Cross-reactivity of purified antibodies with streptococcal proteins was analysed. Homologous peptides recognized by serum cross-reactive antibodies were found through comparing the amino acid sequence of streptococcal antigens with human antigens. To investigate interleukin (IL)-1R-associated kinase (IRAK1) and nuclear factor-κB (NF-κB) activation, we performed a Western blot analysis of whole extracts proteins from unstimulated or stimulated human microvascular cardiac endothelial cells (HMVEC-C). Adhesion molecule expression and release of proinflammatory cytokines and growth factors were studied by multiplex bead based immunoassay kits. We observed anti-vimentin antibodies in sera from 49% RHD AECA-positive patients. Cross-reactivity of purified anti-vimentin antibodies with heat shock protein (HSP)70 and streptopain streptococcal proteins was shown. Comparing the amino acid sequence of streptococcal HSP70 and streptopain with human vimentin, we found two homologous peptides recognized by serum cross-reactive antibodies. These antibodies were able to stimulate HMVEC-C inducing IRAK and NF-κB activation, adhesion molecule expression and release of proinflammatory cytokines and growth factors. In conclusion, streptococcal–vimentin cross-reactive antibodies were able to activate microvascular cardiac endothelium by amplifying the inflammatory

  19. Lactoferrin for prevention of neonatal sepsis

    PubMed Central

    Turin, Christie G.; Zea-Vera, Alonso; Pezo, Alonso; Cruz, Karen; Zegarra, Jaime; Bellomo, Sicilia; Cam, Luis; Llanos, Raul; Castañeda, Anne; Tucto, Lourdes; Ochoa, Theresa J.

    2015-01-01

    Preterm neonates are at risk to acquire infections. In addition to the high mortality associated with sepsis, these patients are at risk for long-term disabilities, particularly neurodevelopment impairment. Several interventions have been evaluated to reduce rates of infections in neonates but have not proven efficacy. Lactoferrin (LF), a milk glycoprotein with anti-inflammatory, immunomodulatory and anti-microbial properties, has the potential to prevent infections in young children. We performed a review of current and ongoing clinical trials of LF for prevention of neonatal sepsis, and found eleven registered clinical trials that include more than 6000 subjects. Few of these trials have finished; despite their small sample size, the preliminary results show a trend towards a positive protective effect of LF on neonatal infections. Larger trials are underway to confirm the findings of these initial studies. This information will help to define LF´s role in clinical settings and, if proven effective, would profoundly affect the treatment of low birth weight neonates as a cost-effective intervention worldwide. PMID:24935001

  20. Intestinal radiation syndrome: sepsis and endotoxin

    SciTech Connect

    Geraci, J.P.; Jackson, K.L.; Mariano, M.S.

    1985-03-01

    Rats were whole-body irradiated with 8-MeV cyclotron-produced neutrons and /sup 137/Cs ..gamma.. rays to study the role of enteric bacteria and endotoxin in the intestinal radiation syndrome. Decrease in intestinal weight was used as an index of radiation-induced breakdown of the mucosa. Neutron and ..gamma..-ray doses that were sublethal for intestinal death resulted in a dose-dependent decrease in intestinal weight, reaching minimal values 2 to 3 days after exposure, followed by recovery within 5 days after irradiation. Neutron and photon doses that caused intestinal death resulted in greater mucosal breakdown with little or no evidence of mucosal recovery. The presence of fluid in the intestine and diarrhea, but not bacteremia or endotoxemia, were related to mucosal breakdown and recovery. Neither sepsis nor endotoxin could be detected in liver samples taken at autopsy from animals which died a short time earlier from intestinal injury. These results suggest that overt sepsis and endotoxemia do not play a significant role in the intestinal radiation syndrome.

  1. Matrix metalloproteinase-2 and metalloproteinase-9 activities are associated with blood-brain barrier dysfunction in an animal model of severe sepsis.

    PubMed

    Dal-Pizzol, Felipe; Rojas, Hugo Alberto; dos Santos, Emilia Marcelina; Vuolo, Francieli; Constantino, Larissa; Feier, Gustavo; Pasquali, Matheus; Comim, Clarissa M; Petronilho, Fabrícia; Gelain, Daniel Pens; Quevedo, João; Moreira, José Cláudio Fonseca; Ritter, Cristiane

    2013-08-01

    There is no description on the mechanisms associated with blood-brain barrier (BBB) disruption during sepsis development. Thus, we here determined changes in permeability of the BBB in an animal model of severe sepsis and the role of matrix metalloproteinase (MMP)-2 and MMP-9 in the dysfunction of the BBB. Sepsis was induced in Wistar rats by cecal ligation and perforation. BBB permeability was assessed using the Evans blue dye method. The content of MMP-2 and MMP-9 in the cerebral microvessels was determined by western blot. The activity of MMP-2 and MMP-9 was determined using zymography. An inhibitor of MMP-2 and MMP-9 or specific inhibitors of MMP-2 or MMP-9 were administered to define the role of MMPs on BBB permeability, brain inflammatory response, and sepsis-induced cognitive alterations. The increase of BBB permeability is time-related to the increase of MMP-9 and MMP-2 in the microvessels, both in cortex and hippocampus. Using an MMP-2 and MMP-9 inhibitor, or specific MMP-2 or MMP-9 inhibitors, the increase in the permeability of the BBB was reversed. This was associated with lower brain levels of interleukin (IL)-6 and lower oxidative damage. In contrast, only the inhibition of both MMP-9 and MMP-2 was able to improve acute cognitive alterations associated with sepsis. In conclusion, MMP-2 and MMP-9 activation seems to be a major step in BBB dysfunction, but BBB dysfunction seems not to be associated with acute cognitive dysfunction during sepsis development. PMID:23479197

  2. WISP1-αvβ3 integrin signaling positively regulates TLR-triggered inflammation response in sepsis induced lung injury.

    PubMed

    Chen, Zhixia; Ding, Xibing; Jin, Shuqing; Pitt, Bruce; Zhang, Liming; Billiar, Timothy; Li, Quan

    2016-01-01

    We recently noted that the matricellular protein WISP1 contributes to sepsis induced acute lung injury (ALI) via integrin β6. In the current study, we pursued further aspects of WISP1 modulation of TLR signaling in lungs of mice after sepsis and TLR4 mediated release of TNF-α in macrophages. After confirming that TLR4 and CD14 are critical in transducing sepsis mediated ALI, we now demonstrate that intrapulmonary αvβ3 is increased by polymicrobrial sepsis in a TLR4, CD14 dependent fashion. Comparison of cultured macrophages revealed that WISP1 increased release of TNF-α from RAW264.7 cells with baseline expression of αvβ3, but primary cultures of peritoneal macrophages (PMø) required activation of TLR4 to induce de novo synthesis of αvβ3 enabling WISP1 to stimulate release of TNF-α. The specific requirement for β3 integrin was apparent when the effect of WISP1 was lost in PMø isolated from β3(-/-) mice. WISP1 enhanced TLR4 mediated ERK signaling and U0126 (an ERK inhibitor) blocked LPS induced β3 integrin expression and WISP1 enhanced TNF-α release. Collectively these data suggest that WISP1-αvβ3 integrin signaling is involved in TLR4 pathways in macrophages and may be an important contributor to TLR4/CD14 mediated inflammation in sepsis induced lung injury. PMID:27349568

  3. Blood-Brain Barrier Deterioration and Hippocampal Gene Expression in Polymicrobial Sepsis: An Evaluation of Endothelial MyD88 and the Vagus Nerve.

    PubMed

    Honig, Gerard; Mader, Simone; Chen, Huiyi; Porat, Amit; Ochani, Mahendar; Wang, Ping; Volpe, Bruce T; Diamond, Betty

    2016-01-01

    Systemic infection can initiate or exacerbate central nervous system (CNS) pathology, even in the absence of overt invasion of bacteria into the CNS. Recent epidemiological studies have demonstrated that human survivors of sepsis have an increased risk of long-term neurocognitive decline. There is thus a need for improved understanding of the physiological mechanisms whereby acute sepsis affects the CNS. In particular, MyD88-dependent activation of brain microvascular endothelial cells and a resulting loss of blood-brain barrier integrity have been proposed to play an important role in the effects of systemic inflammation on the CNS. Signaling through the vagus nerve has also been considered to be an important component of CNS responses to systemic infection. Here, we demonstrate that blood-brain barrier permeabilization and hippocampal transcriptional responses during polymicrobial sepsis occur even in the absence of MyD88-dependent signaling in cerebrovascular endothelial cells. We further demonstrate that these transcriptional responses can occur without vagus nerve input. These results suggest that redundant signals mediate CNS responses in sepsis. Either endothelial or vagus nerve activation may be individually sufficient to transmit systemic inflammation to the central nervous system. Transcriptional activation in the forebrain in sepsis may be mediated by MyD88-independent endothelial mechanisms or by non-vagal neuronal pathways. PMID:26790027

  4. WISP1-αvβ3 integrin signaling positively regulates TLR-triggered inflammation response in sepsis induced lung injury

    PubMed Central

    Chen, Zhixia; Ding, Xibing; Jin, Shuqing; Pitt, Bruce; Zhang, Liming; Billiar, Timothy; Li, Quan

    2016-01-01

    We recently noted that the matricellular protein WISP1 contributes to sepsis induced acute lung injury (ALI) via integrin β6. In the current study, we pursued further aspects of WISP1 modulation of TLR signaling in lungs of mice after sepsis and TLR4 mediated release of TNF-α in macrophages. After confirming that TLR4 and CD14 are critical in transducing sepsis mediated ALI, we now demonstrate that intrapulmonary αvβ3 is increased by polymicrobrial sepsis in a TLR4, CD14 dependent fashion. Comparison of cultured macrophages revealed that WISP1 increased release of TNF-α from RAW264.7 cells with baseline expression of αvβ3, but primary cultures of peritoneal macrophages (PMø) required activation of TLR4 to induce de novo synthesis of αvβ3 enabling WISP1 to stimulate release of TNF-α. The specific requirement for β3 integrin was apparent when the effect of WISP1 was lost in PMø isolated from β3−/− mice. WISP1 enhanced TLR4 mediated ERK signaling and U0126 (an ERK inhibitor) blocked LPS induced β3 integrin expression and WISP1 enhanced TNF-α release. Collectively these data suggest that WISP1-αvβ3 integrin signaling is involved in TLR4 pathways in macrophages and may be an important contributor to TLR4/CD14 mediated inflammation in sepsis induced lung injury. PMID:27349568

  5. Blood-Brain Barrier Deterioration and Hippocampal Gene Expression in Polymicrobial Sepsis: An Evaluation of Endothelial MyD88 and the Vagus Nerve

    PubMed Central

    Honig, Gerard; Mader, Simone; Chen, Huiyi; Porat, Amit; Ochani, Mahendar; Wang, Ping; Volpe, Bruce T.; Diamond, Betty

    2016-01-01

    Systemic infection can initiate or exacerbate central nervous system (CNS) pathology, even in the absence of overt invasion of bacteria into the CNS. Recent epidemiological studies have demonstrated that human survivors of sepsis have an increased risk of long-term neurocognitive decline. There is thus a need for improved understanding of the physiological mechanisms whereby acute sepsis affects the CNS. In particular, MyD88-dependent activation of brain microvascular endothelial cells and a resulting loss of blood-brain barrier integrity have been proposed to play an important role in the effects of systemic inflammation on the CNS. Signaling through the vagus nerve has also been considered to be an important component of CNS responses to systemic infection. Here, we demonstrate that blood-brain barrier permeabilization and hippocampal transcriptional responses during polymicrobial sepsis occur even in the absence of MyD88-dependent signaling in cerebrovascular endothelial cells. We further demonstrate that these transcriptional responses can occur without vagus nerve input. These results suggest that redundant signals mediate CNS responses in sepsis. Either endothelial or vagus nerve activation may be individually sufficient to transmit systemic inflammation to the central nervous system. Transcriptional activation in the forebrain in sepsis may be mediated by MyD88-independent endothelial mechanisms or by non-vagal neuronal pathways. PMID:26790027

  6. Antiseptic effect of sea cucumber (Holothuria atra) against multi-organ failure induced by sepsis: Molecular and histopathological study

    PubMed Central

    SAAD, DALIA Y.; BAIOMY, AHMED A.; MANSOUR, AHMED A.

    2016-01-01

    Sepsis is a systemic inflammatory response to infection and severe sepsis patients can develop acute lung and liver injury. The aim of the present study was to evaluate the efficacy of Holothuria atra methanolic body wall extract (HaE), as an antioxidant and anti-inflammatory agent against induced sepsis in a cecal ligation and puncture (CLP) rat model. In total, 30 males albino rats were divided into three groups (n=10 each) as follows: Sham (Sh), which was used as negative control; sepsis (Se), which was used as a positive control and was subjected to CLP surgery; and Ho, which was subjected to CLP and fed with 200 mg/kg (body weight) of HaE, once daily for 7 days. Subsequently, the expression of various genes was detected by polymerase chain reaction, while liver and lung tissues were examined by immunohistochemistry. The expression of Caspase-3 was significantly reduced in liver and lung tissues in the Ho group, while the expression levels of Gsta2, Cat and Sod1 genes were slightly reduced in the Ho group, when compared with the Se group. In addition, expression levels of tumor necrosis factor, interferon-γ, liver interleukin (IL)1b and lung IL1a were reduced in the Ho group compared with the Se group. Furthermore, histopathological changes were observed in liver tissues of the Se group, including congestion of hepatoportal blood vessel and focal hepatic necrosis, while lung tissues showed marked edema, hemorrhage and alveolar septal thickening. The Ho group showed apparent normal hepatic parenchyma and slight interstitial pneumonia. Immunohistochemical staining of caspase-3 in liver and lung tissues showed no expression in the Sh group, strong expression in the Se group and moderate expression in the Ho group. In conclusion, HaE demonstrated beneficial effect against induced sepsis, which may be attributed to its antioxidant and antiapoptotic activities. PMID:27347042

  7. The gene for type A streptococcal exotoxin (erythrogenic toxin) is located in bacteriophage T12.

    PubMed Central

    Weeks, C R; Ferretti, J J

    1984-01-01

    The infection of Streptococcus pyogenes T25(3) with the temperate bacteriophage T12 results in the conversion of the nontoxigenic strain to type A streptococcal exotoxin (erythrogenic toxin) production. Although previous research has established that integration of the bacteriophage genome into the host chromosome is not essential for exotoxin production, the location of the gene on the bacteriophage or bacterial chromosome had not been determined. In the present investigation, recombinant DNA techniques were used to determine whether the gene specifying type A streptococcal exotoxin (speA) production is located on the bacteriophage chromosome. Bacteriophage T12 was obtained from S. pyogenes T25(3)(T12) by induction with mitomycin C, and after isolation of bacteriophage DNA by phenol-chloroform extraction, the DNA was digested with restriction enzymes and ligated with Escherichia coli plasmid pHP34 or the Streptococcus-E. coli shuttle vector pSA3. Transformation of E. coli HB101 with the recombinant molecules allowed selection of E. coli clones containing bacteriophage T12 genes. Immunological assays with specific antibody revealed the presence of type A streptococcal exotoxin in sonicates of E. coli transformants. Subcloning experiments localized the speA gene to a 1.7-kilobase segment of the bacteriophage T12 genome flanked by SalI and HindIII sites. Introduction of the pSA3 vector containing the speA gene into Streptococcus sanguis (Challis) resulted in transformants that secreted the type A exotoxin. Immunological analysis showed that the type A streptococcal exotoxin produced by E. coli and S. sanguis transformants was identical to the type A exotoxin produced by S. pyogenes T25(3)(T12). Southern blot hybridizations with the cloned fragment confirmed its presence in the bacteriophage T12 genome and its absence in the T25(3) nonlysogen. Therefore, the gene for type A streptococcal exotoxin is located in the bacteriophage genome, and conversion of S. pyogenes T

  8. Stage 3 pyomyositis of the gluteus minimus; Staphylococcus aureus sepsis, autoanticoagulation, proximal femoral osteomyelitis and the role of surgical intervention

    PubMed Central

    Dacombe, Peter Jonathan; Evans, Jennifer; Gosling, Oliver Burton; Heal, James

    2013-01-01

    Primary pyomyositis is a rare bacterial infection of the skeletal muscle. Traditionally a tropical disease, it is increasingly described in westernised urban populations. The aetiology is due to transient bacteraemia in the presence of risk factors such as traumatised muscle, or immunocompromise. The condition presents in one of three stages, representing progression of disease severity. Intravenous antibiotic therapy is often sufficient for this disease at its early stage, but surgical drainage is necessary for advanced presentations. We report a severe case of stage 3 pyomyositis of the gluteus minimus, which led to Staphylococcus aureus sepsis, deranged liver function, acute kidney injury, autoanticoagulation and proximal femoral osteomyelitis in a healthy 64-year-old Caucasian man. This illustrates the potential severity of the disease, the life-threatening sequelae when diagnosis is delayed and the role of surgical drainage in averting the progression of systemic sepsis to end-organ dysfunction, disseminated intravascular coagulation and potentially death. PMID:24293538

  9. Multicenter clinical trials in sepsis: understanding the big picture and building a successful operation at your hospital.

    PubMed

    Dellinger, R Phillip; Schorr, Christa; Trzeciak, Stephen

    2009-10-01

    The environment for clinical trials in sepsis has long been identified as challenging and full of road blocks and land mines. Unlike many other diagnoses (ie, cancer, acute myocardial infarction) relevance of animal studies and predictive capability of phase II trials for dose generation is less clear. The members of the investigative team must realize the essentials for success in a multicenter clinical trial. It is also useful and important to understand the big picture of clinical trial development as well as properly functioning interfaces among sponsor, contract research organizations, and investigative sites. Because early enrollment into sepsis clinical trials is usually required, collaboration between emergency medicine and critical care is needed. PMID:19892258

  10. Streptococcal infection in the pathogenesis of Behçet's disease and clinical effects of minocycline on the disease symptoms.

    PubMed

    Kaneko, F; Oyama, N; Nishibu, A

    1997-12-01

    Although the precise pathoetiology of Behçet's disease (BD) remains obscure, patients with BD have a high incidence of chronic infectious foci, indicating an enhanced susceptibility to chronic tonsillitis, and dental caries. Sometimes, clinical symptoms appear after treatment of these foci in BD patients. It is believed that BD might be related to an allergic reaction to a bacterial infection in view of the many clinical symptoms, especially the presence of aphthous and genital ulcerations. An attempt to obtain cutaneous responses to bacterial antigens has been carried out using various vaccines developed from bacteria isolated from the ulcerative lesions and oral cavities of BD patients. BD patients often show intense hypersensitivity to various strains of streptococci, not only by their cutaneous reactions but also by in vitro testing. In this report, we describe our previous studies on the correlation between streptococcal antigens and the pathogenesis of BD and also discuss the recent reports of other authors. The intense hypersensitivity to streptococcal antigens acquired after streptococcal infection is thought to play an important role in the appearance of symptoms in BD patients since the production of pro-inflammatory cytokines by peripheral blood mononuclear cells (PBMC) was enhanced when stimulated with streptococcal antigen in a culture system. Minocycline, an antibiotic to which certain strains of streptococci are sensitive, reduced the frequency of clinical symptoms in BD patients as well as the production of pro-inflammatory cytokines by BD-PBMC stimulated with streptococcal antigen. PMID:9509915

  11. Brain microabscesses in a porcine model of Staphylococcus aureus sepsis

    PubMed Central

    2013-01-01

    Background Sepsis caused by Staphylococcus aureus often leads to brain microabscesses in humans. Animal models of haematogenous brain abscesses would be useful to study this condition in detail. Recently, we developed a model of S. aureus sepsis in pigs and here we report that brain microabscesses develop in pigs with such induced S. aureus sepsis. Twelve pigs were divided into three groups. Nine pigs received an intravenous inoculation of S. aureus once at time 0 h (group 1) or twice at time 0 h and 12 h (groups 2 and 3). In each group the fourth pig served as control. The pigs were euthanized at time 12 h (Group 1), 24 h (Group 2) and 48 h (Group 3) after the first inoculation. The brains were collected and examined histopathologically. Results All inoculated pigs developed sepsis and seven out of nine pigs developed brain microabscesses. The microabscesses contained S. aureus and were located in the prosencephalon and mesencephalon. Chorioditis and meningitis occurred from 12 h after inoculation. Conclusions Pigs with experimental S. aureus sepsis often develop brain microabscesses. The porcine brain pathology mirrors the findings in human sepsis patients. We therefore suggest the pig as a useful animal model of the development of brain microabscesses caused by S. aureus sepsis. PMID:24176029

  12. Challenges in the diagnosis and management of neonatal sepsis

    PubMed Central

    Zea-Vera, Alonso

    2015-01-01

    Neonatal sepsis is the third leading cause of neonatal mortality and a major public health problem, especially in developing countries. Although recent medical advances have improved neonatal care, many challenges remain in the diagnosis and management of neonatal infections. The diagnosis of neonatal sepsis is complicated by the frequent presence of noninfectious conditions that resemble sepsis, especially in preterm infants, and by the absence of optimal diagnostic tests. Since neonatal sepsis is a high-risk disease, especially in preterm infants, clinicians are compelled to empirically administer antibiotics to infants with risk factors and/or signs of suspected sepsis. Unfortunately, both broad-spectrum antibiotics and prolonged treatment with empirical antibiotics are associated with adverse outcomes and increase antimicrobial resistance rates. Given the high incidence and mortality of sepsis in preterm infants and its long-term consequences on growth and development, efforts to reduce the rates of infection in this vulnerable population are one of the most important interventions in neonatal care. In this review, we discuss the most common questions and challenges in the diagnosis and management of neonatal sepsis, with a focus on developing countries. PMID:25604489

  13. Mortality in Sepsis and its relationship with Gender

    PubMed Central

    Nasir, Nosheen; Jamil, Bushra; Siddiqui, Shahla; Talat, Najeeha; Khan, Fauzia A.; Hussain, Rabia

    2015-01-01

    Background and Objective: Sepsis remains a leading cause of death across the world, carrying a mortality rate of 20–50%. Women have been reported to be less likely to suffer from sepsis and to have a lower risk of mortality from sepsis compared to men. The objective of this study was to determine the relationship between gender and mortality in sepsis, and compare cytokine profiles of male and female patients. Methods: This was a prospective case series on 97 patients admitted with sepsis. Clinical and microbiological data was gathered, blood samples were collected for cytokine (IL-10, IL-6 and TNFα) levels and patients were followed up for clinical outcome. Results: There were 54% males and 46% females, with no significant difference of age or comorbids between genders. Respiratory tract infection was the commonest source of sepsis, and was more common in females (60%) compared to males (39%) (p=0.034). Males had a higher mortality (p=0.048, RR 1.73) and plasma IL-6 level(p=0.040) compared to females. Mean IL-6 plasma level was significantly (p<0.01) higher in patients who died vs. who recovered. Conclusion: Our study shows that males with sepsis have a 70% greater mortality rate, and mortality is associated with a higher IL-6 plasma level. PMID:26649014

  14. Proteomic and epigenomic markers of sepsis-induced delirium (SID)

    PubMed Central

    Sfera, Adonis; Price, Amy I.; Gradini, Roberto; Cummings, Michael; Osorio, Carolina

    2015-01-01

    In elderly population sepsis is one of the leading causes of intensive care unit (ICU) admissions in the United States. Sepsis-induced delirium (SID) is the most frequent cause of delirium in ICU (Martin et al., 2010). Together delirium and SID represent under-recognized public health problems which place an increasing financial burden on the US health care system, currently estimated at 143–152 billion dollars per year (Leslie et al., 2008). The interest in SID was recently reignited as it was demonstrated that, contrary to prior beliefs, cognitive deficits induced by this condition may be irreversible and lead to dementia (Pandharipande et al., 2013; Brummel et al., 2014). Conversely, it is construed that diagnosing SID early or mitigating its full blown manifestations may preempt geriatric cognitive disorders. Biological markers specific for sepsis and SID would facilitate the development of potential therapies, monitor the disease process and at the same time enable elderly individuals to make better informed decisions regarding surgeries which may pose the risk of complications, including sepsis and delirium. This article proposes a battery of peripheral blood markers to be used for diagnostic and prognostic purposes in sepsis and SID. Though each individual marker may not be specific enough, we believe that together as a battery they may achieve the necessary accuracy to answer two important questions: who may be vulnerable to the development of sepsis, and who may develop SID and irreversible cognitive deficits following sepsis? PMID:26579527

  15. Proteomic and epigenomic markers of sepsis-induced delirium (SID).

    PubMed

    Sfera, Adonis; Price, Amy I; Gradini, Roberto; Cummings, Michael; Osorio, Carolina

    2015-01-01

    In elderly population sepsis is one of the leading causes of intensive care unit (ICU) admissions in the United States. Sepsis-induced delirium (SID) is the most frequent cause of delirium in ICU (Martin et al., 2010). Together delirium and SID represent under-recognized public health problems which place an increasing financial burden on the US health care system, currently estimated at 143-152 billion dollars per year (Leslie et al., 2008). The interest in SID was recently reignited as it was demonstrated that, contrary to prior beliefs, cognitive deficits induced by this condition may be irreversible and lead to dementia (Pandharipande et al., 2013; Brummel et al., 2014). Conversely, it is construed that diagnosing SID early or mitigating its full blown manifestations may preempt geriatric cognitive disorders. Biological markers specific for sepsis and SID would facilitate the development of potential therapies, monitor the disease process and at the same time enable elderly individuals to make better informed decisions regarding surgeries which may pose the risk of complications, including sepsis and delirium. This article proposes a battery of peripheral blood markers to be used for diagnostic and prognostic purposes in sepsis and SID. Though each individual marker may not be specific enough, we believe that together as a battery they may achieve the necessary accuracy to answer two important questions: who may be vulnerable to the development of sepsis, and who may develop SID and irreversible cognitive deficits following sepsis? PMID:26579527

  16. Toward an operative diagnosis in sepsis: a latent class approach

    PubMed Central

    De La Rosa, Gisela D; Valencia, Marta L; Arango, Clara M; Gomez, Carlos I; Garcia, Alex; Ospina, Sigifredo; Osorno, Susana; Henao, Adriana; Jaimes, Fabián A

    2008-01-01

    Background Recent data have suggested that 18 million of new sepsis cases occur each year worldwide, with a mortality rate of almost 30%. There is not consensus on the clinical definition of sepsis and, because of lack of training or simply unawareness, clinicians often miss or delay this diagnosis. This is especially worrying; since there is strong evidence supporting that early treatment is associated with greater clinical success. There are some difficulties for sepsis diagnosis such as the lack of an appropriate gold standard to identify this clinical condition. This situation has hampered the assessment of the accuracy of clinical signs and biomarkers to diagnose sepsis. Methods/design Cross-sectional study to determine the operative characteristics of three biological markers of inflammation and coagulation (D-dimer, C-reactive protein and Procalcitonin) as diagnostic tests for sepsis, in patients admitted to hospital care with a presumptive infection as main diagnosis. Discussion There are alternative techniques that have been used to assess the accuracy of tests without gold standards, and they have been widely used in clinical disciplines such as psychiatry, even though they have not been tested in sepsis diagnosis. Considering the main importance of diagnosis as early as possible, we propose a latent class analysis to evaluate the accuracy of three biomarkers to diagnose sepsis. PMID:18284667

  17. Choice of Fluid Therapy in the Initial Management of Sepsis, Severe Sepsis, and Septic Shock.

    PubMed

    Chang, Ronald; Holcomb, John B

    2016-07-01

    Sepsis results in disruption of the endothelial glycocalyx layer and damage to the microvasculature, resulting in interstitial accumulation of fluid and subsequently edema. Fluid resuscitation is a mainstay in the initial treatment of sepsis, but the choice of fluid is unclear. The ideal resuscitative fluid is one that restores intravascular volume while minimizing edema; unfortunately, edema and edema-related complications are common consequences of current resuscitation strategies. Crystalloids are recommended as first-line therapy, but the type of crystalloid is not specified. There is increasing evidence that normal saline is associated with increased mortality and kidney injury; balanced crystalloids may be a safer alternative. Albumin is similar to crystalloids in terms of outcomes in the septic population but is costlier. Hydroxyethyl starches appear to increase mortality and kidney injury in the critically ill and are no longer indicated in these patients. In the trauma population, the shift to plasma-based resuscitation with decreased use of crystalloid and colloid in the treatment of hemorrhagic shock has led to decreased inflammatory and edema-mediated complications. Studies are needed to determine if these benefits also occur with a similar resuscitation strategy in the setting of sepsis. PMID:26844975

  18. Impact of chemically-modified tetracycline 3 on intertwined physiological, biochemical, and inflammatory networks in porcine sepsis/ARDS

    PubMed Central

    Sadowsky, David; Nieman, Gary; Barclay, Derek; Mi, Qi; Zamora, Ruben; Constantine, Gregory; Golub, Lorne; Lee, Hsi-Ming; Roy, Shreyas; Gatto, Louis A; Vodovotz, Yoram

    2015-01-01

    Sepsis can lead to multiple organ dysfunction, including the Acute Respiratory Distress Syndrome (ARDS), due to intertwined, dynamic changes in inflammation and organ physiology. We have demonstrated the efficacy of Chemically-Modified Tetracycline 3 (CMT-3) at reducing inflammation and ameliorating pathophysiology in the setting of a clinically realistic porcine model of ARDS. Here, we sought to gain insights into the derangements that characterize sepsis/ARDS and the possible impact of CMT-3 thereon, by combined experimental and computational studies. Two groups of anesthetized, ventilated pigs were subjected to experimental sepsis via placement of a peritoneal fecal clot and intestinal ischemia/reperfusion by clamping the superior mesenteric artery for 30 min. The treatment group (n = 3) received CMT-3 at 1 hour after injury (T1), while the control group (n = 3) received a placebo. Multiple inflammatory mediators, along with clinically relevant physiologic and blood chemistry variables, were measured serially until death of the animal or T48. Principal Component Analysis (PCA) and Dynamic Bayesian Network (DBN) inference were used to relate these variables. PCA revealed a separation of cardiac and pulmonary physiologic variables by principal component, and a decreased rank of oxygen index and arterial PO2/FiO2 ratio in the treatment group compared to control. DBN suggested a conserved network structure in both control and CMT-3 animals: a response driven by positive feedback between interleukin-6 and lung dysfunction. Resulting networks further suggested that in control animals, acute kidney injury, acidosis, and respiratory failure play an increased role in the response to insult compared to CMT-3 animals. These combined in vivo and in silico studies in a high fidelity, clinically applicable animal model suggest a dynamic interplay between inflammatory, physiologic, and blood chemistry variables in the setting of sepsis and ARDS that may be dramatically altered

  19. Challenges with Diagnosing and Managing Sepsis in Older Adults.

    PubMed

    Clifford, Kalin M; Dy-Boarman, Eliza A; Haase, Krystal K; Maxvill, Kristen; Pass, Steven E; Alvarez, Carlos A

    2016-02-01

    Sepsis in older adults has many challenges that affect rate of septic diagnosis, treatment, and monitoring parameters. Numerous age-related changes and comorbidities contribute to increased risk of infections in older adults, but also atypical symptomatology that delays diagnosis. Due to various pharmacokinetic/pharmacodynamic changes in the older adult, medications are absorbed, metabolized, and eliminated at different rates as compared to younger adults, which increases risk of adverse drug reactions due to use of drug therapy needed for sepsis management. This review provides information to aid in diagnosis and offers recommendations for monitoring and treating sepsis in the older adult population. PMID:26687340

  20. Potential of surface acoustic wave biosensors for early sepsis diagnosis.

    PubMed

    Csete, Marie; Hunt, William D

    2013-08-01

    Early diagnosis of sepsis is a difficult problem for intensivists and new biomarkers for early diagnosis have been difficult to come by. Here we discuss the potential of adapting a technology from the electronics industry, surface acoustic wave (SAW) sensors, for diagnosis of multiple markers of sepsis in real time, using non-invasive assays of exhaled breath condensate. The principles and advantages of the SAW technology are reviewed as well as a proposed plan for adapting this flexible technology to early sepsis detection. PMID:23471596

  1. Update on the management of neonatal sepsis in horses.

    PubMed

    Palmer, Jon

    2014-08-01

    Despite advances in neonatal intensive care sepsis, severe sepsis and septic shock remain the biggest killers of neonatal foals. Management of this severe syndrome remains difficult, requiring intensive intervention. Key aspects of management include infection control, hemodynamic support, immunomodulatory interventions, and metabolic/endocrine support. Infection control largely consists of early antimicrobial therapy, plasma transfusions, and local therapy for the infected focus. In cases with severe sepsis or septic shock, hemodynamic support with fluids, vasoactive agents, and respiratory support insuring oxygen delivery to vital organs is important. Nutritional support is important, but close monitoring is needed to avoid hyperglycemia and hypoglycemia. PMID:25016494

  2. Metabolism, Metabolomics, and Nutritional Support of Patients with Sepsis.

    PubMed

    Englert, Joshua A; Rogers, Angela J

    2016-06-01

    Sepsis is characterized by profound changes in systemic and cellular metabolism that disrupt normal metabolic homeostasis. These metabolic changes can serve as biomarkers for disease severity. Lactate, a metabolite of anaerobic metabolism, is the most widely used ICU biomarker and it is incorporated into multiple management algorithms. Technological advances now make broader metabolic profiling possible, with early studies identifying metabolic changes associated with sepsis mortality. Finally, given the marked changes in metabolism in sepsis and the association of worse prognosis in patients with severe metabolic derangements, we summarize the seminal trials conducted to optimize nutrition in the ICU. PMID:27229648

  3. Sepsis in pregnancy and early goal-directed therapy

    PubMed Central

    Joseph, Julie; Sinha, Aneeta; Paech, Michael; Walters, Barry N J

    2009-01-01

    Sepsis is a major cause of serious morbidity and mortality in pregnant women and their babies. Conventional management has evolved over many years. Improved understanding of the underlying pathophysiology and randomized clinical trials have led to recommendations for the formalization and standardization of the management of severe sepsis in non-pregnant patients. Most of these recommendations are applicable to pregnancy. The Surviving Sepsis Campaign and Early Goal Directed Therapy have relevance to the care of pregnant women with serious infection and are reviewed here.

  4. An Immunological Perspective on Neonatal Sepsis.

    PubMed

    Kan, Bernard; Razzaghian, Hamid Reza; Lavoie, Pascal M

    2016-04-01

    Despite concerted international efforts, mortality from neonatal infections remains unacceptably high in some areas of the world, particularly for premature infants. Recent developments in flow cytometry and next-generation sequencing technologies have led to major discoveries over the past few years, providing a more integrated understanding of the developing human immune system in the context of its microbial environment. We review these recent findings, focusing on how in human newborns incomplete maturation of the immune system before a full term of gestation impacts on their vulnerability to infection. We also discuss some of the clinical implications of this research in guiding the design of more-accurate age-adapted diagnostic and preventive strategies for neonatal sepsis. PMID:26993220

  5. In-111 WBC imaging in musculoskeletal sepsis

    SciTech Connect

    Thompson, L.; Ouzounian, T.J.; Webber, M.M.; Amstutz, H.C.

    1984-01-01

    This study evaluated the accuracy and utility of the In-111 labeled WBC imaging in a series of patients who were suspected of having musculoskeletal sepsis. The labeling of the WBCs was patterned after a method previously described, in which the WBCs are labeled with In-111 oxine in plasma. The WBCs from 100 ml of blood are separated and incubated with In-111 oxine complex, and then 500 ..mu..Ci. of the labeled cells were reinjected into the patient. Images of the areas in question were obtained at 24 hrs. In some instances, 48 hour images were also obtained. Images were interpreted using consistent criteria. Forty imaging procedures were done on 39 patients. These included 39 total joint protheses, and 17 other images to evaluate possible osteomyelitis, septic arthritis or deep abscesses. Of these studies, 15 were positive, and 42 negative. The findings were then correlated with operative culture and pathology in 21, aspiration cultures and gram stains in 14, and with clinical findings in the remaining 21. This correlation showed 41 true negatives, 12 true positives, 1 false negative, and 2 false positives. The sensitivity was 92.9% and the specificity was 95.2%l. The false negative occurred in a patient on chronic suppressive antibiotic therapy for an infected total hip replacement. The false positive images occurred in a patient with active rheumatoid arthritis and in a patient imaged one month post operative placement of the prosthesis. These images were very useful in several septic patients who had many possible sites of infection. The authors conclude that In-III imaging is an accurate and useful non-invasive method of evaluating musculoskeletal sepsis.

  6. Sphingosine 1-phosphate and its carrier apolipoprotein M in human sepsis and in Escherichia coli sepsis in baboons.

    PubMed

    Frej, Cecilia; Linder, Adam; Happonen, Kaisa E; Taylor, Fletcher B; Lupu, Florea; Dahlbäck, Björn

    2016-06-01

    Sphingosine 1-phosphate (S1P) is an important regulator of vascular integrity and immune cell migration, carried in plasma by high-density lipoprotein (HDL)-associated apolipoprotein M (apoM) and by albumin. In sepsis, the protein and lipid composition of HDL changes dramatically. The aim of this study was to evaluate changes in S1P and its carrier protein apoM during sepsis. For this purpose, plasma samples from both human sepsis patients and from an experimental Escherichia coli sepsis model in baboons were used. In the human sepsis cohort, previously studied for apoM, plasma demonstrated disease-severity correlated decreased S1P levels, the profile mimicking that of plasma apoM. In the baboons, a similar disease-severity dependent decrease in plasma levels of S1P and apoM was observed. In the lethal E. coli baboon sepsis, S1P decreased already within 6-8 hrs, whereas the apoM decrease was seen later at 12-24 hrs. Gel filtration chromatography of plasma from severe human or baboon sepsis on Superose 6 demonstrated an almost complete loss of S1P and apoM in the HDL fractions. S1P plasma concentrations correlated with the platelet count but not with erythrocytes or white blood cells. The liver mRNA levels of apoM and apoA1 decreased strongly upon sepsis induction and after 12 hr both were almost completely lost. In conclusion, during septic challenge, the plasma levels of S1P drop to very low levels. Moreover, the liver synthesis of apoM decreases severely and the plasma levels of apoM are reduced. Possibly, the decrease in S1P contributes to the decreased endothelial barrier function observed in sepsis. PMID:26990127

  7. A latent class approach for sepsis diagnosis supports use of procalcitonin in the emergency room for diagnosis of severe sepsis

    PubMed Central

    2013-01-01

    Background Given the acknowledged problems in sepsis diagnosis, we use a novel way with the application of the latent class analysis (LCA) to determine the operative characteristics of C-reactive protein (CRP), D-dimer (DD) and Procalcitonin (PCT) as diagnostic tests for sepsis in patients admitted to hospital care with a presumptive infection. Methods Cross-sectional study to determine the diagnostic accuracy of three biological markers against the gold standard of clinical definition of sepsis provided by an expert committee, and also against the likelihood of sepsis according to LCA. Patients were recruited in the emergency room within 24 hours of hospitalization and were follow-up daily until discharge. Results Among 765 patients, the expert committee classified 505 patients (66%) with sepsis, 112 (15%) with infection but without sepsis and 148 (19%) without infection. The best cut-offs points for CRP, DD, and PCT were 7.8 mg/dl, 1616 ng/ml and 0.3 ng/ml, respectively; but, neither sensitivity nor specificity reach 70% for any biomarker. The LCA analysis with the same three tests identified a “cluster” of 187 patients with several characteristics suggesting a more severe condition as well as better microbiological confirmation. Assuming this subset of patients as the new prevalence of sepsis, the ROC curve analysis identified new cut-off points for the tests and suggesting a better discriminatory ability for PCT with a value of 2 ng/ml. Conclusions Under a “classical” definition of sepsis three typical biomarkers (CRP, PCT and DD) are not capable enough to differentiate septic from non-septic patients in the ER. However, a higher level of PCT discriminates a selected group of patients with severe sepsis. PMID:24050481

  8. [Therapeutic response to plasmapheresis in four cases with obsessive-compulsive disorder and tic disorder triggered by streptococcal infections].

    PubMed

    Beşiroğlu, Lütfullah; Ağargün, Mehmet Yücel; Ozbebit, Ozgür; Sözen, Mehmet; Dilek, Imdat; Güleç, Mustafa

    2007-01-01

    The acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) has been assigned to a subgroup of patients experiencing pediatric onset obsessive-compulsive symptoms and tics as a result of autoimmune response to group A beta-hemolytic streptococcal infection. It has been hypothesized that an immune process initiated by infection affects the basal ganglia and causes neuropsychiatric symptoms. In cases with severe neuropsychiatric symptoms, the use of treatment strategies that interrupt the autoimmune process responsible for the pathogenesis of PANDAS, such as therapeutic plasmapheresis or intravenous immunoglobulin, has been proposed. In this paper, we discuss the effect of plasmapheresis treatment in 4 adult cases of obsessive-compulsive disorder and tic disorder triggered by streptococcal infections. PMID:17853982

  9. Enzyme-linked immunosorbent assay for detection of type A streptococcal exotoxin: kinetics and regulation during growth of Streptococcus pyogenes.

    PubMed Central

    Houston, C W; Ferretti, J J

    1981-01-01

    We describe the detection and quantitation of type A streptococcal exotoxin (erythrogenic toxin, streptococcal pyrogenic exotoxin) by an enzyme-linked immunosorbent assay. This sensitive and specific technique detected microgram amounts of type A exotoxin and was useful for studying the kinetics and regulation of type A exotoxin production during the growth of Streptococcus pyogenes NY5. Maximum production of type A exotoxin was observed during the mid-log phase of growth, similar to the production of other streptococcal extracellular products. When S. pyogenes NY5 was grown at 42 degrees C, decreases in both growth and type A exotoxin production were observed. The results obtained when we studied the influence of nutrient additives and metal ions on the production of type A exotoxin led to the conclusion that none of these factors significantly affected type A exotoxin synthesis and that regulation was constitutive. Images PMID:7026447

  10. HDL in sepsis – risk factor and therapeutic approach

    PubMed Central

    Morin, Emily E.; Guo, Ling; Schwendeman, Anna; Li, Xiang-An

    2015-01-01

    High-density lipoprotein (HDL) is a key component of circulating blood and plays essential roles in regulation of vascular endothelial function and immunity. Clinical data demonstrate that HDL levels drop by 40–70% in septic patients, which is associated with a poor prognosis. Experimental studies using Apolipoprotein A-I (ApoAI) null mice showed that HDL deficient mice are susceptible to septic death, and overexpressing ApoAI in mice to increase HDL levels protects against septic death. These clinical and animal studies support our hypothesis that a decrease in HDL level is a risk factor for sepsis, and raising circulating HDL levels may provide an efficient therapy for sepsis. In this review, we discuss the roles of HDL in sepsis and summarize the efforts of using synthetic HDL as a potential therapy for sepsis. PMID:26557091

  11. Development of an e-learning package for sepsis care.

    PubMed

    Davis, Anna; Henderson, James; Langmack, Gill

    Severe sepsis is a major cause of morbidity and mortality in the UK. This article describes the collaborative development and implementation of an interactive online learning package to understand the key role nurses have in recognising and then starting to apply the Sepsis Six care bundle in clinical practice. The e-learning package, developed in a UK teaching hospital, uses a case study approach to address the knowledge that is required to be able to recognise sepsis, to understand the processes that occur and the ongoing care and treatment required. The package is relevant to final-year student nurses, newly registered nurses in preceptorship and other health professionals involved in assessing and treating patients who may be developing sepsis. PMID:27019164

  12. Biomarkers for Sepsis: What Is and What Might Be?

    PubMed Central

    Biron, Bethany M.; Ayala, Alfred; Lomas-Neira, Joanne L.

    2015-01-01

    Every year numerous individuals develop the morbid condition of sepsis. Therefore, novel biomarkers that might better inform clinicians treating such patients are sorely needed. Difficulty in identifying such markers is in part due to the complex heterogeneity of sepsis, resulting from the broad and vague definition of this state/condition based on numerous possible clinical signs and symptoms as well as an incomplete understanding of the underlying pathobiology of this complex condition. This review considers some of the attempts that have been made so far, looking at both the pro- and anti-inflammatory response to sepsis, as well as genomic analysis, as sources of potential biomarkers. Irrespective, for functional biomarker(s) of sepsis to successfully translate from the laboratory to a clinical setting, the biomarker must be target specific and sensitive as well as easy to implement/interpret, and be cost effective, such that they can be utilized routinely in patient diagnosis and treatment. PMID:26417200

  13. Neutrophils, nitric oxide, and microvascular permeability in severe sepsis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    STUDY OBJECTIVES: Alterations in microvascular permeability are prevalent in patients with sepsis; a recent study reported that patients with septic shock had increased capillary filtration coefficient (Kf), a noninvasive index of microvascular permeability. We aimed to determine whether patients wi...

  14. Paradoxical Roles of the Neutrophil in Sepsis: Protective and Deleterious

    PubMed Central

    Sônego, Fabiane; Castanheira, Fernanda Vargas e Silva; Ferreira, Raphael Gomes; Kanashiro, Alexandre; Leite, Caio Abner Vitorino Gonçalves; Nascimento, Daniele Carvalho; Colón, David Fernando; Borges, Vanessa de Fátima; Alves-Filho, José Carlos; Cunha, Fernando Queiróz

    2016-01-01

    Sepsis, an overwhelming inflammatory response syndrome secondary to infection, is one of the costliest and deadliest medical conditions worldwide. Neutrophils are classically considered to be essential players in the host defense against invading pathogens. However, several investigations have shown that impairment of neutrophil migration to the site of infection, also referred to as neutrophil paralysis, occurs during severe sepsis, resulting in an inability of the host to contain and eliminate the infection. On the other hand, the neutrophil antibacterial arsenal contributes to tissue damage and the development of organ dysfunction during sepsis. In this review, we provide an overview of the main events in which neutrophils play a beneficial or deleterious role in the outcome of sepsis. PMID:27199981

  15. Case of streptococcal toxic shock syndrome caused by rapidly progressive group A hemolytic streptococcal infection during postoperative chemotherapy for cervical cancer.

    PubMed

    Nogami, Yuya; Tsuji, Kousuke; Banno, Kouji; Umene, Kiyoko; Katakura, Satomi; Kisu, Iori; Tominaga, Eiichiro; Aoki, Daisuke

    2014-01-01

    Streptococcal toxic shock syndrome (STSS) is a severe infectious disease caused by group A hemolytic streptococcus (Streptococcus pyogenes). This condition is a serious disease that involves rapidly progressive septic shock. We experienced a case of STSS caused by primary peritonitis during treatment with paclitaxel and cisplatin (TP therapy) as postoperative chemotherapy for cervical cancer. STSS mostly develops after extremity pain, but initial influenza-like symptoms of fever, chill, myalgia and gastrointestinal symptoms may also occur. TP therapy is used to treat many cancers, including gynecological cancer, but may cause adverse reactions of neuropathy and nephrotoxicity and sometimes fever, arthralgia, myalgia, abdominal pain and general malaise. The case reported here indicates that development of STSS can be delayed after chemotherapy and that primary STSS symptoms may be overlooked because they may be viewed as adverse reactions to chemotherapy. To our knowledge, this is the first report of a case of STSS during chemotherapy. PMID:23937219

  16. Anti-inflammatory effect of Momordica charantia in sepsis mice.

    PubMed

    Chao, Che-Yi; Sung, Ping-Jyun; Wang, Wei-Hsien; Kuo, Yueh-Hsiung

    2014-01-01

    Wild bitter gourd (Momordica charantia L. var. abbreviate Seringe), a common vegetable in Asia, is used in traditional medicine to treat various diseases, including inflammation. Extant literature indicates that wild bitter gourds have components that activate PPARα and PPARγ. This research probed the influence of adding wild bitter gourd to diets on inflammation responses in mice with sepsis induced by intraperitoneal injection of LPS. Male BALB/c mice were divided normal, sepsis, positive control, and three experimental groups. The latter ate diets with low (1%), moderate (2%), and high (10%) ratios of wild bitter gourd lyophilized powder. Before mice were sacrificed, with the exception of the normal group, intraperitoneal injection of LPS induced sepsis in each group; positive control group was injected with LPS after PDTC. This experiment revealed starkly lower weights in groups with added wild bitter gourd than those of the remaining groups. Blood lipids (TG, cholesterol, and NEFA) were also lower in comparison to the sepsis group, and blood glucose concentrations recovered and approached normal levels. Blood biochemistry values related to inflammation reactions indicated GOT, GPT, C-RP, and NO concentrations of groups with added wild bitter gourd were all lower than those of the sepsis group. Secretion levels of the spleen pro-inflammatory cytokines IL-1, IL-6, and TNF-α tallied significantly lower in comparison to the sepsis group, whereas secretion levels of IL-10 anti-inflammatory cytokine increased. Expression level of proteins NF-κB, iNOS, and COX-2 were significantly inhibited. Results indicate wild bitter gourd in diets promoted lipid metabolism, reducing fat accumulation, and improving low blood glucose in sepsis. Addition of wild bitter gourd can reduce inflammation biochemical markers or indicators and pro-inflammatory cytokines in the body, hence improving the inflammation responses in mice with sepsis. PMID:25153878

  17. Maternal and neonatal sepsis caused by Haemophilus influenzae type d.

    PubMed

    Warren, S; Tristram, S; Bradbury, R S

    2010-03-01

    A 29-year-old pregnant woman was admitted to hospital with signs of sepsis and threatened pre-term labour. The premature neonate also showed signs of sepsis. Haemophilus influenzae biotype III was cultured from a midstream urine sample taken from the mother, maternal placental swabs and neonatal blood cultures. The placental and neonatal isolates were both found to be serotype d by PCR, and were indistinguishable by PFGE. PMID:19926730

  18. A Review of GM-CSF Therapy in Sepsis.

    PubMed

    Mathias, Brittany; Szpila, Benjamin E; Moore, Frederick A; Efron, Philip A; Moldawer, Lyle L

    2015-12-01

    Determine what clinical role, if any, GM-CSF may have in the clinical treatment of sepsis in the adult patient. Advancements in the management of sepsis have led to significant decreases in early mortality; however, sepsis remains a significant source of long-term mortality and disability which places strain on healthcare resources with a substantial growing economic impact. Historically, early multiple organ failure (MOF) and death in patients with severe sepsis was thought to result from an exaggerated proinflammatory response called the systemic inflammatory response syndrome (SIRS). Numerous prospective randomized controlled trials (PRCTs) tested therapies aimed at decreasing the organ injury associated with an exaggerated inflammatory response. With few exceptions, the results from these PRCTs have been disappointing, and currently no specific therapeutic agent is approved to counteract the early SIRS response in patients with severe sepsis. It has long been recognized that there is a delayed immunosuppressive state that contributes to long-term morbidity. However, recent findings now support a concurrent proinflammatory and anti-inflammatory response present throughout sepsis. Multiple immunomodulating agents have been studied to combat the immunosuppressive phase of sepsis with the goal of decreasing secondary infection, reducing organ dysfunction, decreasing ICU stays, and improving survival. Granulocyte-macrophage colony stimulating factor (GM-CSF), a myelopoietic growth factor currently used in patients with neutropenia secondary to chemotherapy-induced myelosuppression, has been studied as a potential immune-activating agent. The applicability of GM-CSF as a standard therapy for generalized sepsis is still largely understudied; however, small-scale studies available have demonstrated some improved recovery from infection, decreased hospital length of stay, decreased days requiring mechanical ventilation, and decreased medical costs. PMID:26683913

  19. Heart Rate Variability in Porcine Progressive Peritonitis-Induced Sepsis

    PubMed Central

    Jarkovska, Dagmar; Valesova, Lenka; Chvojka, Jiri; Benes, Jan; Sviglerova, Jitka; Florova, Blanka; Nalos, Lukas; Matejovic, Martin; Stengl, Milan

    2016-01-01

    Accumulating evidence suggests that heart rate variability (HRV) alterations could serve as an indicator of sepsis progression and outcome, however, the relationships of HRV and major pathophysiological processes of sepsis remain unclear. Therefore, in this experimental study HRV was investigated in a clinically relevant long-term porcine model of severe sepsis/septic shock. HRV was analyzed by several methods and the parameters were correlated with pathophysiological processes of sepsis. In 16 anesthetized, mechanically ventilated, and instrumented domestic pigs of either gender, sepsis was induced by fecal peritonitis. Experimental subjects were screened up to the refractory shock development or death. ECG was continuously recorded throughout the experiment, afterwards RR intervals were detected and HRV parameters computed automatically using custom made measurement and analysis MATLAB routines. In all septic animals, progressive hyperdynamic septic shock developed. The statistical measures of HRV, geometrical measures of HRV and Poincaré plot analysis revealed a pronounced reduction of HRV that developed quickly upon the onset of sepsis and was maintained throughout the experiment. The frequency domain analysis demonstrated a decrease in the high frequency component and increase in the low frequency component together with an increase of the low/high frequency component ratio. The reduction of HRV parameters preceded sepsis-associated hemodynamic changes including heart rate increase or shock progression. In a clinically relevant porcine model of peritonitis-induced progressive septic shock, reduction of HRV parameters heralded sepsis development. HRV reduction was associated with a pronounced parasympathetic inhibition and a shift of sympathovagal balance. Early reduction of HRV may serve as a non-invasive and sensitive marker of systemic inflammatory syndrome, thereby widening the therapeutic window for early interventions. PMID:26779039

  20. Etiology of Cellulitis and Clinical Prediction of Streptococcal Disease: A Prospective Study

    PubMed Central

    Bruun, Trond; Oppegaard, Oddvar; Kittang, Bård R.; Mylvaganam, Haima; Langeland, Nina; Skrede, Steinar

    2016-01-01

    Background. The importance of bacteria other than group A streptococci (GAS) in different clinical presentations of cellulitis is unclear, commonly leading to treatment with broad-spectrum antibiotics. The aim of this study was to describe the etiological and clinical spectrum of cellulitis and identify clinical features predicting streptococcal etiology. Methods. We prospectively enrolled 216 patients hospitalized with cellulitis. Clinical details were registered. Bacterial culture was performed from blood, cutaneous or subcutaneous tissue, and/or swabs from skin lesions. Paired serum samples were analyzed for anti-streptolysin O and anti-deoxyribonuclease B antibodies. Results. Serology or blood or tissue culture confirmed β-hemolytic streptococcal (BHS) etiology in 72% (146 of 203) of cases. An additional 13% (27 of 203) of cases had probable BHS infection, indicated by penicillin response or BHS cultured from skin swabs. β-hemolytic streptococcal etiology was predominant in all clinical subgroups, including patients without sharply demarcated erythema. β-hemolytic group C or G streptococci (GCS/GGS) were more commonly isolated than GAS (36 vs 22 cases). This predominance was found in the lower extremity infections. Group C or G streptococci in swabs were associated with seropositivity just as often as GAS. Staphylococcus aureus was cultured from swabs as a single pathogen in 24 cases, 14 (64%) of which had confirmed BHS etiology. Individual BHS-associated clinical characteristics increased the likelihood of confirmed BHS disease only slightly; positive likelihood ratios did not exceed 2.1. Conclusions. β-hemolytic streptococci were the dominating cause of cellulitis in all clinical subgroups and among cases with S aureus in cutaneous swabs. Group C or G streptococci were more frequently detected than GAS. No single clinical feature substantially increased the probability of confirmed BHS etiology. PMID:26734653

  1. Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies

    PubMed Central

    Spinello, Chiara; Laviola, Giovanni; Macrì, Simone

    2016-01-01

    Accumulating evidence suggests that Tourette's Syndrome (TS) – a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances – can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes

  2. Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies.

    PubMed

    Spinello, Chiara; Laviola, Giovanni; Macrì, Simone

    2016-01-01

    Accumulating evidence suggests that Tourette's Syndrome (TS) - a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances - can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes

  3. Mechanisms of neutropenia involving myeloid maturation arrest in burn sepsis.

    PubMed Central

    Shoup, M; Weisenberger, J M; Wang, J L; Pyle, J M; Gamelli, R L; Shankar, R

    1998-01-01

    OBJECTIVE: To determine the mechanisms that lead to the decrease in bone marrow production of neutrophils during burn sepsis. SUMMARY BACKGROUND DATA: Impaired bone marrow granulopoiesis during burn sepsis often results in neutropenia despite elevated circulating levels of granulocyte colony-stimulating factor (G-CSF). To date, neither the specific stages of neutrophil maturation involved in the bone marrow suppression nor the mechanisms for the impairment have been determined. METHODS: Peripheral blood absolute neutrophil count and G-CSF levels were determined in mice 3 days after randomization to control, burn alone, or burn plus a topical inoculation of Pseudomonas aeruginosa (1000 colony-forming units). Bone marrow aspirates were analyzed for their neutrophil differentiation patterns by Gr-1 antigen expression and their G-CSF receptor status. Histologic analysis of liver, lung, spleen, and wound site was performed. RESULTS: In burn sepsis, absolute neutrophil count was reduced whereas plasma G-CSF levels were elevated, and myeloid differentiation was significantly shifted toward the immature mitotic myeloid cells. Bone marrow G-CSF receptor mRNA levels and G-CSF-stimulated proliferation were substantially decreased in burn sepsis. Histologic analysis revealed no significant neutrophil infiltration into the tissues. CONCLUSIONS: In thermal injury with superimposed sepsis, neutropenia and myeloid maturation arrest, despite the elevated levels of G-CSF, correlate with the reduction in bone marrow G-CSF receptor expression. These observations may provide a potential mechanism for neutropenia in sepsis. Images Figure 5. Figure 6. Figure 8. Figure 9. PMID:9671075

  4. HMGB1 Mediates Anemia of Inflammation in Murine Sepsis Survivors

    PubMed Central

    Valdés-Ferrer, Sergio I; Papoin, Julien; Dancho, Meghan E; Olofsson, Peder S; Li, Jianhua; Lipton, Jeffrey M; Avancena, Patricia; Yang, Huan; Zou, Yong-Rui; Chavan, Sangeeta S; Volpe, Bruce T; Gardenghi, Sara; Rivella, Stefano; Diamond, Betty; Andersson, Ulf; Steinberg, Bettie M; Blanc, Lionel; Tracey, Kevin J

    2015-01-01

    Patients surviving sepsis develop anemia, but the molecular mechanism is unknown. Here we observed that mice surviving polymicrobial gram-negative sepsis develop hypochromic, microcytic anemia with reticulocytosis. The bone marrow of sepsis survivors accumulates polychromatophilic and orthochromatic erythroblasts. Compensatory extramedullary erythropoiesis in the spleen is defective during terminal differentiation. Circulating tumor necrosis factor (TNF) and interleukin (IL)-6 are elevated for 5 d after the onset of sepsis, and serum high-mobility group box 1 (HMGB1) levels are increased from d 7 until at least d 28. Administration of recombinant HMGB1 to healthy mice mediates anemia with extramedullary erythropoiesis and significantly elevated reticulocyte counts. Moreover, administration of anti-HMGB1 monoclonal antibodies after sepsis significantly ameliorates the development of anemia (hematocrit 48.5 ± 9.0% versus 37.4 ± 6.1%, p < 0.01; hemoglobin 14.0 ± 1.7 versus 11.7 ± 1.2 g/dL, p < 0.01). Together, these results indicate that HMGB1 mediates anemia by interfering with erythropoiesis, suggesting a potential therapeutic strategy for anemia in sepsis. PMID:26736178

  5. Betulin attenuates lung and liver injuries in sepsis.

    PubMed

    Zhao, Hongyu; Liu, Zhenning; Liu, Wei; Han, Xinfei; Zhao, Min

    2016-01-01

    Sepsis is a complex condition with unacceptable mortality. Betulin is a natural extract with multiple bioactivities. This study aims to evaluate the potential effects of betulin on lung and liver injury in sepsis. Cecal ligation and puncture was used to establish the rat model of sepsis. A single dose of 4mg/kg or 8mg/kg betulin was injected intraperitoneally immediately after the model establishment. The survival rate was recorded every 12h for 96h. The organ injury was examined using hematoxylin and eosin staining and serum biochemical test. The levels of proinflammatory cytokines and high mobility group box 1 in the serum were measured using ELISA. Western blotting was used to detect the expression of proteins in NF-κB and MAPK signaling pathways. Betulin treatment significantly improved the survival rate of septic rats, and attenuated lung and liver injury in sepsis, including the reduction of lung wet/dry weight ratio and activities of alanine aminotransferase and aspartate aminotransferase in the serum. In addition, levels of tumor necrosis factor-α, interleukin-1β, interleukin-6 and high mobility group box 1 in the serum were also lowered by betulin treatment. Moreover, sepsis-induced activation of the NF-κB and MAPK signaling pathway was inhibited by betulin as well. Our findings demonstrate the protective effect of betulin in lung and liver injury in sepsis. This protection may be mediated by its anti-inflammatory and NF-κB and MAPK inhibitory effects. PMID:26644168

  6. New Approaches to Sepsis: Molecular Diagnostics and Biomarkers

    PubMed Central

    Bauer, Michael; Riedemann, Niels C.; Hartog, Christiane S.

    2012-01-01

    Summary: Sepsis is among the most common causes of death in hospitals. It arises from the host response to infection. Currently, diagnosis relies on nonspecific physiological criteria and culture-based pathogen detection. This results in diagnostic uncertainty, therapeutic delays, the mis- and overuse of antibiotics, and the failure to identify patients who might benefit from immunomodulatory therapies. There is a need for new sepsis biomarkers that can aid in therapeutic decision making and add information about screening, diagnosis, risk stratification, and monitoring of the response to therapy. The host response involves hundreds of mediators and single molecules, many of which have been proposed as biomarkers. It is, however, unlikely that one single biomarker is able to satisfy all the needs and expectations for sepsis research and management. Among biomarkers that are measurable by assays approved for clinical use, procalcitonin (PCT) has shown some usefulness as an infection marker and for antibiotic stewardship. Other possible new approaches consist of molecular strategies to improve pathogen detection and molecular diagnostics and prognostics based on transcriptomic, proteomic, or metabolic profiling. Novel approaches to sepsis promise to transform sepsis from a physiologic syndrome into a group of distinct biochemical disorders and help in the development of better diagnostic tools and effective adjunctive sepsis therapies. PMID:23034322

  7. Circulating MicroRNAs as Biomarkers for Sepsis

    PubMed Central

    Benz, Fabian; Roy, Sanchari; Trautwein, Christian; Roderburg, Christoph; Luedde, Tom

    2016-01-01

    Sepsis represents a major cause of lethality during intensive care unit (ICU) treatment. Pharmacological treatment strategies for sepsis are still limited and mainly based on the early initiation of antibiotic and supportive treatment. In this context, numerous clinical and serum based markers have been evaluated for the diagnosis, the severity, and the etiology of sepsis. However until now, few of these factors could be translated into clinical use. MicroRNAs (miRNAs) do not encode for proteins but regulate gene expression by inhibiting the translation or transcription of their target mRNAs. Recently it was demonstrated that miRNAs are released into the circulation and that the spectrum of circulating miRNAs might be altered during various pathologic conditions, such as inflammation, infection, and sepsis. By using array- and single PCR-based methods, a variety of deregulated miRNAs, including miR-25, miR-133a, miR-146, miR-150, and miR-223, were described in the context of sepsis. Some of the miRNAs correlated with the disease stage, as well as patients’ short and long term prognosis. Here, we summarize the current findings on the role of circulating miRNAs in the diagnosis and staging of sepsis in critically ill patients. We compare data from patients with findings from animal models and, finally, highlight the challenges and drawbacks that currently prevent the use of circulating miRNAs as biomarkers in clinical routine. PMID:26761003

  8. New approaches to sepsis: molecular diagnostics and biomarkers.

    PubMed

    Reinhart, Konrad; Bauer, Michael; Riedemann, Niels C; Hartog, Christiane S

    2012-10-01

    Sepsis is among the most common causes of death in hospitals. It arises from the host response to infection. Currently, diagnosis relies on nonspecific physiological criteria and culture-based pathogen detection. This results in diagnostic uncertainty, therapeutic delays, the mis- and overuse of antibiotics, and the failure to identify patients who might benefit from immunomodulatory therapies. There is a need for new sepsis biomarkers that can aid in therapeutic decision making and add information about screening, diagnosis, risk stratification, and monitoring of the response to therapy. The host response involves hundreds of mediators and single molecules, many of which have been proposed as biomarkers. It is, however, unlikely that one single biomarker is able to satisfy all the needs and expectations for sepsis research and management. Among biomarkers that are measurable by assays approved for clinical use, procalcitonin (PCT) has shown some usefulness as an infection marker and for antibiotic stewardship. Other possible new approaches consist of molecular strategies to improve pathogen detection and molecular diagnostics and prognostics based on transcriptomic, proteomic, or metabolic profiling. Novel approaches to sepsis promise to transform sepsis from a physiologic syndrome into a group of distinct biochemical disorders and help in the development of better diagnostic tools and effective adjunctive sepsis therapies. PMID:23034322

  9. Role of Circulating Lymphocytes in Patients with Sepsis

    PubMed Central

    de Pablo, Raul; Monserrat, Jorge; Prieto, Alfredo; Alvarez-Mon, Melchor

    2014-01-01

    Sepsis is a systemic inflammatory response syndrome due to infection. The incidence rate is estimated to be up to 19 million cases worldwide per year and the number of cases is rising. Infection triggers a complex and prolonged host response, in which both the innate and adaptive immune response are involved. The disturbance of immune system cells plays a key role in the induction of abnormal levels of immunoregulatory molecules. Furthermore, the involvement of effector immune system cells also impairs the host response to the infective agents and tissue damage. Recently, postmortem studies of patients who died of sepsis have provided important insights into why septic patients die and showed an extensive depletion of CD4 and CD8 lymphocytes and they found that circulating blood cells showed similar findings. Thus, the knowledge of the characterization of circulating lymphocyte abnormalities is relevant for the understanding of the sepsis pathophysiology. In addition, monitoring the immune response in sepsis, including circulating lymphocyte subsets count, appears to be potential biomarker for predicting the clinical outcome of the patient. This paper analyzes the lymphocyte involvement and dysfunction found in patients with sepsis and new opportunities to prevent sepsis and guide therapeutic intervention have been revealed. PMID:25302303

  10. Sepsis-induced elevation in plasma serotonin facilitates endothelial hyperpermeability

    PubMed Central

    Li, Yicong; Hadden, Coedy; Cooper, Anthonya; Ahmed, Asli; Wu, Hong; Lupashin, Vladimir V.; Mayeux, Philip R.; Kilic, Fusun

    2016-01-01

    Hyperpermeability of the endothelial barrier and resulting microvascular leakage are a hallmark of sepsis. Our studies describe the mechanism by which serotonin (5-HT) regulates the microvascular permeability during sepsis. The plasma 5-HT levels are significantly elevated in mice made septic by cecal ligation and puncture (CLP). 5-HT-induced permeability of endothelial cells was associated with the phosphorylation of p21 activating kinase (PAK1), PAK1-dependent phosphorylation of vimentin (P-vimentin) filaments, and a strong association between P-vimentin and ve-cadherin. These findings were in good agreement with the findings with the endothelial cells incubated in serum from CLP mice. In vivo, reducing the 5-HT uptake rates with the 5-HT transporter (SERT) inhibitor, paroxetine blocked renal microvascular leakage and the decline in microvascular perfusion. Importantly, mice that lack SERT showed significantly less microvascular dysfunction after CLP. Based on these data, we propose that the increased endothelial 5-HT uptake together with 5-HT signaling disrupts the endothelial barrier function in sepsis. Therefore, regulating intracellular 5-HT levels in endothelial cells represents a novel approach in improving sepsis-associated microvascular dysfunction and leakage. These new findings advance our understanding of the mechanisms underlying cellular responses to intracellular/extracellular 5-HT ratio in sepsis and refine current views of these signaling processes during sepsis. PMID:26956613

  11. Detection of streptococcal mutants presumed to be defective in sugar catabolism.

    PubMed

    Feary, T W; Mayo, J A

    1984-06-01

    The tetrazolium method for detection of bacterial mutants defective in sugar catabolism was modified for use with streptococci. The critical factors were (i) the concentration of tetrazolium, which must be titrated to determine the optimum concentration for each species or even strain, and (ii) anaerobic incubation of tetrazolium-containing agar plates. When used with standard mutagenesis protocols, this method yielded lactose-negative mutants of nine streptococcal strains representing six species. A collection of lactose-negative mutants of streptococcus, sanguis Challis was characterized and contained phospho-beta-galactosidase, lactose phosphotransferase, and general phosphotransferase mutants. PMID:6378096

  12. Biochemical basis of heterogeneity in acute presentations of propionic acidemia.

    PubMed

    Sindgikar, Seema Pavaman; Rao, Suchetha; Shenoy, Rathika D; Kamath, Nutan

    2013-01-01

    Propionic acidemia (PA), an uncommon organic acidemia has varied clinical and metabolic presentation causing difficulty and delay in the diagnosis. We report a case of PA in an infant who presented with failure to thrive, acute encephalopathy due to severe hyperammonemia without acidosis and fungal sepsis. The biochemical basis of severe hyperammonemia is discussed. PMID:24381430

  13. Identification of adults with sepsis in the prehospital environment: a systematic review

    PubMed Central

    Smyth, Michael A; Brace-McDonnell, Samantha J; Perkins, Gavin D

    2016-01-01

    Objective Early identification of sepsis could enable prompt delivery of key interventions such as fluid resuscitation and antibiotic administration which, in turn, may lead to improved patient outcomes. Limited data indicate that recognition of sepsis by paramedics is often poor. We systematically reviewed the literature on prehospital sepsis screening tools to determine whether they improved sepsis recognition. Design Systematic review. The electronic databases MEDLINE, EMBASE, CINAHL, the Cochrane Library and PubMed were systematically searched up to June 2015. In addition, subject experts were contacted. Setting Prehospital/emergency medical services (EMS). Study selection All studies addressing identification of sepsis (including severe sepsis and septic shock) among adult patients managed by EMS. Outcome measures Recognition of sepsis by EMS clinicians. Results Owing to considerable variation in the methodological approach adopted and outcome measures reported, a narrative approach to data synthesis was adopted. Three studies addressed development of prehospital sepsis screening tools. Six studies addressed paramedic diagnosis of sepsis with or without use of a prehospital sepsis screening tool. Conclusions Recognition of sepsis by ambulance clinicians is poor. The use of screening tools, based on the Surviving Sepsis Campaign diagnostic criteria, improves prehospital sepsis recognition. Screening tools derived from EMS data have been developed, but they have not yet been validated in clinical practice. There is a need to undertake validation studies to determine whether prehospital sepsis screening tools confer any clinical benefit. PMID:27496231

  14. Complement factor B is the downstream effector of TLRs and plays an important role in a mouse model of severe sepsis.

    PubMed

    Zou, Lin; Feng, Yan; Li, Yan; Zhang, Ming; Chen, Chan; Cai, Jiayan; Gong, Yu; Wang, Larry; Thurman, Joshua M; Wu, Xiaobo; Atkinson, John P; Chao, Wei

    2013-12-01

    Severe sepsis involves massive activation of the innate immune system and leads to high mortality. Previous studies have demonstrated that various types of TLRs mediate a systemic inflammatory response and contribute to organ injury and mortality in animal models of severe sepsis. However, the downstream mechanisms responsible for TLR-mediated septic injury are poorly understood. In this article, we show that activation of TLR2, TLR3, and TLR4 markedly enhanced complement factor B (cfB) synthesis and release by macrophages and cardiac cells. Polymicrobial sepsis, created by cecal ligation and puncture in a mouse model, augmented cfB levels in the serum, peritoneal cavity, and major organs including the kidney and heart. Cecal ligation and puncture also led to the alternative pathway activation, C3 fragment deposition in the ki