Early onset neonatal group B streptococcal (GBS) sepsis is a serious neonatal illness with high morbidity and mortality. The disease can present in two forms: early clinical manifestation with respiratory distress soon after birth or late presentation with gradual onset of signs of sepsis. The former carries a high risk for serious cardiovascular complication with persistent pulmonary hypertension; the latter is often complicated with meningitis that may lead to serious neurodevelopmental impairment. An important advance in the past three decades is the development and implementation of preventive strategy for this disease by universal screening and identification of maternal GBS carriers and/or risk factors with subsequent use of intrapartum antibiotic prophylaxis. The strategy has resulted in a significant reduction of the disease from 1.5 to 0.3/1,000 live births over the past three decades. Some women may have unknown GBS status. The American Academy of Pediatrics has developed an algorithm as guidance for the management of the newborns. PMID:23322392
Acute post-streptococcal glomerulonephritis, also known as "proliferative-exudative nephritis" is morphologically characterized by intense endocapillary proliferation and massive accumulation of inflammatory cells. PMID:15593046
Ferrario, Franco; Rastaldi, Maria Pia
Objectives: We describe strategies employed in achiev- ing a high level of compliance with Centers for Disease Control and Prevention guidelines for the prevention of early-onset Group B streptococcal neonatal sepsis. Methods: This is a retrospective review of all deliveries at or beyond 37 weeks gestation at Gundersen Lutheran Medical Center to determine 1) whether and when cultures were obtained
Kenneth W. Merkitch; Charles W. Schauberger; Becky A. Fruechte
Objective: To assess the effectiveness and feasibility of implementing the Centers for Disease Control and Prevention (CDC) screening–based guidelines for preventing early-onset group B streptococcal sepsis.Methods: We compared prevalence of early-onset group B streptococcal sepsis after institution of the CDC screening–based protocol (October 1, 1995 through August 31, 1999) with that of historical controls (January 1, 1992 through June 30,
Beverly S Brozanski; Judith G Jones; Marijane A Krohn; Richard L Sweet
A case of acute encephalopathy with posterior corticosubcortical vasogenic edema on magnetic resonance imaging is reported. Angiography showed cerebral arterial vasospasm. A diagnosis of acute post-streptococcal glomerulonephritis was made 2 days after admission. This report highlights the fact that acute post-streptococcal glomerulonephritis can be revealed by a posterior reversible encephalopathy syndrome and that cerebral vasospasm can concur with vasogenic edema in this condition. PMID:16901429
Aeby, Alec; David, Philippe; Fricx, Christophe; Jissendi, Patrice; Blecic, Serge; Van Bogaert, Patrick
The case of a 6-year-old boy who presented with acute post-streptococcal glomerulonephritis is reported. C3 levels and complement alternative pathway activity remained low for at least 10 months after presentation, before returning to normal. There was no evidence of other renal disease. This case highlights that hypocomplementaemia in acute post-streptococcal glomerulonephritis may persist for several months, and that prolonged hypocomplementaemia does not exclude this diagnosis. PMID:18820103
Payne, D; Houtman, P; Browning, M
Although maternal screening and the administration of prophylactic intrapartum antibiotics have decreased the incidence of early onset group B streptococcal (GBS) disease in neonates, there is still significant morbidity and mortality as a result of neonatal GBS disease.Maternal GBS infections are not uncommon, but with appropriate therapy there is almost a uniformly good outcome. Little is written about the appropriate management of well infants born to mothers with postpartum GBS sepsis.The question of whether well infants born to mothers with GBS puerperal sepsis should be treated empirically with antibiotics and the lack of literature concerning this issue became apparent when an untreated term infant died of late onset GBS meningitis following maternal puerperal GBS sepsis. We describe this event in the following case presentation.With the current paucity of literature regarding the management of well infants born to mothers with postpartum GBS sepsis, it seems prudent to treat such infants empirically with antibiotics (following a full septic work-up) until this matter has been investigated further. PMID:20019951
Barnard, Chantelle; Goldbach, Mort; Whyte, Hilary; Ford-Jones, Lee; King, Susan
Objectives To quantify risk factors for and the prevalence of early onset group B streptococcal sepsis in neonates in a geographically defined population. Design Cases were collected prospectively for two years from April 1998 and compared with four controls each, matched for time and place of delivery. Setting The former Northern health region of the United Kingdom. Participants Infants infected with group B streptococcus in the first week of life. Results The prevalence of early onset group B streptococcal sepsis was 0.57 per 1000 live births. Premature infants comprised 38% of all cases and 83% of the deaths. Prematurity (odds ratio 10.4, 95% confidence interval 3.9 to 27.6), rupture of the membranes more than 18 hours before delivery (25.8, 10.2 to 64.8), rupture of the membranes before the onset of labour (11.1, 4.8 to 25.9), and intrapartum fever (10.0, 2.4 to 40.8) were significant risk factors for infection. Had the interim recommendations on best practice issued by the Group B Streptococcus Working Group of the Public Health Laboratory Service been uniformly applied to the fetuses alive at the onset of labour, 29 of 37 (78%) might have been given antibiotic prophylaxis during labour. At least 23 of these 29 (79%) could have had antibiotics for four hours or more before delivery. To achieve this, 16% of all women would have been given antibiotics during labour. Conclusions Early onset group B streptococcal sepsis remains an important problem in the United Kingdom. Prevention based on risk factors might reduce the prevalence at the cost of treating many women with risk factors. Using rupture of the membranes before the onset of labour as a risk factor might be expected to improve the success of guidelines for prophylaxis. What is already known on this topicGroup B streptococcal infection is the leading cause of neonatal sepsis in the United Kingdom and an important, yet potentially preventable, cause of deathThe prevalence of early onset group B streptococcal sepsis in the United Kingdom is not well definedData from the United States and Australia show that the prevalence may be reduced drastically by using selective antibiotic prophylaxis during labourWhat this study addsOdds ratios for established risk factors, calculated for a British population, might aid the development of prophylactic guidelinesRupture of the membranes before the onset of labour should be considered as an important risk factor and might identify potential cases at an earlier stageCurrent prophylactic guidelines might prevent or ameliorate three quarters of all cases of infection at the cost of giving antibiotics to 16% of all women in labour
Oddie, Sam; Embleton, Nicholas D
Acute post-streptococcal glomerulonephritis (APSGN) is very rare below the age of two years. We report a 14-month-old girl who presented with frank hematuria and nephrotic syndrome following group A streptococcal pharyngitis (GAS), which was confirmed by laboratory investigations. The patient underwent a renal biopsy to confirm the diagnosis and was treated with prednisolone. The proteinuria and hematuria resolved completely in eight weeks. Our case demonstrates that APSGN should be considered in evaluating hematuria and nephrotic syndrome in infants and children below two years of age. PMID:23640628
Kari, Jameela A; Bamagai, Ahmed; Jalalah, Sawsan M
Acute kidney injury (AKI) is a common sequel of sepsis in the intensive care unit. It is being suggested that sepsis-induced AKI may have a distinct pathophysiology and identity. Availability of biomarkers now enable us to detect AKI as early as four hours after it's inception and may even help us to delineate sepsis-induced AKI. Protective strategies such as preferential use of vasopressin or prevention of intra-abdominal hypertension may help, in addition to the other global management strategies of sepsis. Pharmacologic interventions have had limited success, may be due to their delayed usage. Newer developments in extracorporeal blood purification techniques may proffer effects beyond simple replacement of renal function, such as metabolic functions of the kidney or modulation of the sepsis cascade.
A 5-year-old girl sought treatment for pyrexia of unknown origin. Despite prompt surgical drainage of a streptococcal septic arthritis of the ankle joint, her condition deteriorated. Multifocal pyomyositis was subsequently diagnosed. This was complicated by acute compartment syndrome in three extremities. With aggressive surgical and medical management, the child made a complete recovery. Orthopaedic clinicians in nontropical areas must familiarize themselves with this rare, potentially life-threatening, but eminently curable disease. PMID:11360777
Harrington, P; Scott, B; Chetcuti, P
Objective: To compare two protocols for intrapartum antibiotic prophylaxis (IAP) against neonatal group B streptococcal (GBS) sepsis, with respect to staff compliance, in a prospective cohort study in the obstetric units of a community hospital (A) and a university teaching hospital (B). Methods: Cohorts comprised about 500 women attending antenatal clinics at each hospital (total 1096). Women identified as GBS carriers at 26–32 weeks'gestation and those who had intrapartum clinical risk factors (CRF) were eligible for IAP. Compliance was defined as the proportion of women eligible for IAP who received it according to protocol–as determined by audit of case records–and compared between hospitals and according to indication. Results: Overall, 39% of women were eligible for IAP. Indications were GBS carriage alone (21%), CRF alone (13% ) and both (5% ). Compliance was similar for GBS carriers at both hospitals: 78% at Hospital A and 76% at Hospital B. However, because of the poor predictive value of screening before 32 weeks, only 65%of intrapartum GBS carriers actually received IAP. For women with CRF only, compliance was significantly lower at Hospital B than Hospital A (56 vs. 75%; p= 0.03). Conclusions: According to currently recommended protocols, about one-third of healthy women are eligible for intrapartum antibiotics to prevent neonatal GBS sepsis. In practice, antibiotics are often used inefficiently because of poor compliance with protocols and poor predictive values of selection criteria. Better implementation strategies should improve compliance, but GBS vaccines are needed to replace prophylactic antibiotic use, with its associated disadvantages.
Hewitt, Moira C.; Turner, Catherine M.; Leeder, Stephen R.
Retrospective analysis of 99 consecutive cases of acute severe pancreatitis established presence of systemic inflammation in all patients. Magnitude of acute phase response was characterised by C-reactive protein and Interleukin-6 values. Progression to multiple organ failure raised considerably lethality. Failure developed more frequently in respiratory system, liver and kidneys. General mortality was 38,4%. PMID:16927913
Hotineanu, V F; Balica, I M; Bogdan, V I
Objective: The purpose of this study was to determine the compliance rate with a maternal risk-factor-based guideline for the prevention of neonatal group B streptococcal (GBS) sepsis. Methods: In August 1994, a risk-factor-based guideline for selective intrapartum prophylaxis against neonatal GBS was adopted by a group model health maintenance organization. This guideline identified the following maternal risk factors for neonatal GBS sepsis: preterm delivery, rupture of membranes for >18 h, fever/chorioamnionitis, and history of a previous GBS-affected child. Patients with one or more risk factors were to receive intrapartum antibiotic prophylaxis consisting of either ampicillin, erythromycin, or clindamycin. We conducted a retrospective chart review to record risk factors and use of antibiotics. We hypothesized that >90% of patients with risk factors would receive intrapartum chemoprophylaxis. Results: A total of 805 maternal charts were reviewed. Of these, 105 (13%) were candidates for intrapartum prophylaxis. We found an overall compliance rate of 65%. Compliance rates by risk factor were preterm delivery (51%), prolonged rupture of membranes (73%), fever/chorioamnionitis (87%), and previous affected child (100%). Conclusions: Our results show unexpectedly low compliance rates with a risk-factor-based guideline for the prevention of neonatal GBS sepsis. Only 65% of women with any risk factor for neonatal GBS sepsis received intrapartum antibiotic prophylaxis appropriately. Educational efforts to improve compliance with a risk-factor-based guideline should specifically address mothers delivering at 34–36 weeks gestation and mothers with prolonged rupture of membranes.
McDuffie, Robert S.; Russell, Kathy; Meikle, Susan
Sepsis-related acute kidney injury (AKI) is an important complicating feature of sepsis, and is associated with greater complexity of care and higher mortality. Until recently, AKI lacked a standard, widely accepted definition, rendering it difficult to compare previously published strategies to prevent, recognize and treat this entity. Recently, the RIFLE classification of AKI has been developed, and confirmed in observational
Andrew A. House; Claudio Ronco
Recent studies have suggested that T cells play a critical role in the pathogenesis of psoriasis. Guttate psoriasis is a well-defined form of psoriasis frequently associated with streptococcal throat infection. This study tested the hypothesis that T cells in acute guttate psoriasis skin lesions may be activated by streptococcal superantigens. Peripheral blood as well as lesional and perilesional skin biopsies were analyzed for T cell receptor V beta repertoire using monoclonal antibodies against 10 different V beta families. Skin biopsies from all patients with acute guttate psoriasis, but not skin biopsies from patients with acute atopic dermatitis or inflammatory skin lesions induced in normal subjects with sodium lauryl sulfate, demonstrated selective accumulation of V beta 2+ T cells (P < 0.05). The expansion of V beta 2+ T cells occurred in both the CD4+ and the CD8+ T cell subsets. Sequence analysis of T cell receptor beta chain genes of V beta 2-expressing T cells from skin biopsies of patients with guttate psoriasis showed extensive junctional region diversity that is more compatible with a superantigen rather than a conventional (nominal) antigen-driven T cell response. All streptococcal isolates from patients with guttate psoriasis secreted streptococcal pyrogenic exotoxin C, a superantigen known to stimulate marked V beta 2+ T cell expansion. These data support the concept that acute guttate psoriasis is associated with superantigenic stimulation of T cells triggered by streptococcal superantigen(s). Images
Leung, D Y; Travers, J B; Giorno, R; Norris, D A; Skinner, R; Aelion, J; Kazemi, L V; Kim, M H; Trumble, A E; Kotb, M
Newly introduced rapid diagnostic tests for group A streptococcal pharyngitis should facilitate appropriate antimicrobial use in patients with group A streptococcal pharyngitis. Because of high rates of acute pharyngitis in Tuba City, AZ, at the Navajo Indian reservation, the use of rapid diagnostic test was prospectively evaluated. The sensitivity and specificity of the test was measured and changes in physician prescribing patterns attributable to use of the test were correlated. Of 320 patients with pharyngitis enrolled during the present 3-week study, 86 met the study's definition of a patient with streptococcal pharyngitis and 163 met the study's definition of a patient with nonstreptococcal pharyngitis. The rapid test was 62.8% sensitive and 96.9% specific in identifying patients from whom group A streptococci were isolated. Although treatment of patients with streptococcal pharyngitis at the time of the first visit increased from 36.5% in a retrospective sample to 72.5% during the study, treatment of patients in whom cultures were negative remained the same. Further analyses showed that physicians tended to treat patients with signs characteristic of streptococcal pharyngitis and, as the study progressed, to rely less on negative rapid test results as a reason to withhold antimicrobial agents. It was concluded that rapid tests with good specificity but limited sensitivity may improve treatment of patients with streptococcal pharyngitis by allowing earlier specific therapy. A more sensitive test with a higher negative predictive value would be necessary to prevent treatment of persons with nonstreptococcal pharyngitis. PMID:3050865
Redd, S C; Facklam, R R; Collin, S; Cohen, M L
Sepsis-related acute kidney injury (AKI) is an important complicating feature of sepsis, and is associated with greater complexity of care and higher mortality. Until recently, AKI lacked a standard, widely accepted definition, rendering it difficult to compare previously published strategies to prevent, recognize and treat this entity. Recently, the RIFLE classification of AKI has been developed, and confirmed in observational studies to be associated with subsequent morbidity and mortality. The management of sepsis-related AKI is evolving with new basic discoveries and ongoing translational clinical research, and will likely include nephroprotective strategies to protect kidneys in patients at risk, early recognition and amelioration of renal damage and pharmacological interventions to minimize injury and promote recovery. Furthermore, extracorporeal blood purification (EBP) has an important role to play, not only in the replacement of certain aspects of renal organ function such as acid-base/electrolyte homeostasis and extracellular fluid volume, but also in an immunomodulatory fashion. As a therapy that has the potential to influence the course of disease in sepsis, EBP in sepsis and sepsis-related AKI is the subject of this review. PMID:18182792
House, Andrew A; Ronco, Claudio
Post-streptococcal glomerulonephritis (PSGN) is the commonest cause of severe acute glomerulonephritis in New Zealand children, with the majority (85%) of the patients being of either Pacific Island or Maori ethnicity. We have performed a retrospective study on 27 pediatric patients with acute PSGN. Of these patients, those with crescentic glomerulonephritis (n = 11) had a greater tendency (72.7%) for needing acute dialysis and were left with persistent urinary sediment abnormalities after a mean follow-up of 3.2 years (95% confidence interval 2.1-4.3). The efficacy of immunosuppression in the group with crescentic disease was uncertain. The severity of renal histopathological abnormalities as judged by the total biopsy score did not correlate with either presentation or eventual outcome. Severe childhood acute post-streptococcal glomerulonephritis, although uncommon, results in significant long-term renal morbidity, particularly among Maori and Pacific Island children. PMID:19096879
Wong, William; Morris, Maxwell Clarke; Zwi, Jonathan
The organ that is affected first and most severely in intraabdominal sepsis is the lung. Oxygen radicals and active neutrophils\\u000a in the lung are important sources for severe pulmonary inflammation leading to acute lung injury (ALI)\\/acute respiratory distress\\u000a syndrome. The aim of this study was to investigate the effects of leflunomide, an immunomodulatory agent, on oxidant\\/antioxidant\\u000a status with nitric oxide
Erdogan Ozturk; Semra Demirbilek; Zekine Begec; Murat Surucu; Ersin Fadillioglu; Hale K?r?ml?oglu; M. Ozcan Ersoy
We describe a child with acute post-streptococcal glomerulonephritis (APSGN), who developed a very low plasma high-density lipoprotein cholesterol (?-lipoprotein) in association with transient but massive proteinuria. The hypoalphalipoproteinaemia resolved spontaneously concomitant with the remission in proteinuria and the patient had a complete clinical recovery. Urinary loss of apolipoprotein A1 may have contributed to the hypoalphalipoproteinaemia. To our knowledge, this has not been reported previously in APSGN. PMID:24194163
Alayli, Mohammad B; Sanjad, Sami A
Scrub typhus is a major infectious threat in the Asia-Pacific region. We report an unusual case of scrub typhus in a patient in Singapore who presented with sepsis and acute respiratory distress syndrome but lacked the pathognomonic eschar. The patient recovered after appropriate diagnosis and doxycycline treatment. Rickettsial diseases should be included in the differential diagnosis of febrile illnesses in regions where the diseases are endemic, and absence of eschar should not be the criterion used to rule out scrub typhus.
Kurup, Asok; Issac, Aneesh; Loh, Jin Phang; Lee, Too Bou; Chua, Robert; Bist, Pradeep; Chao, Chien-Chung; Lewis, Michael; Gubler, Duane J.; Ching, Wei Mei; Ooi, Eng Eong
The systemic inflammatory response syndrome can be self-limited or can progress to severe sepsis and septic shock. Despite significant advances in the understanding of the molecular and cellular mechanisms of septic shock, it is still one of the most frequent and serious problems confronting clinicians in the treatments. And the effects of cannabinoid receptor 2 (CB2R) on the sepsis still remain undefined. The present study was aimed to explore the role and mechanism of CB2R in acute sepsis model of mice. Here, we found that mice were more vulnerable for lipopolysaccharide- (LPS-) induced death and inflammation after CB2R deletion (CB2R?/?). CB2R agonist, GW405833, could significantly extend the survival rate and decrease serum proinflammatory cytokines in LPS-treated mice. GW405833 dose-dependently inhibits proinflammatory cytokines release in splenocytes and peritoneal macrophages as well as splenocytes proliferation, and these effects were partly abolished in CB2R?/? splenocytes but completely abolished in CB2R?/? peritoneal macrophages. Further studies showed that GW405833 inhibits LPS-induced phosphorylation of ERK1/2 and STAT3 and blocks I?B? degradation and NF-?B p65 nuclear translocation in macrophages. All data together showed that CB2R provides a protection and is a potential therapeutic target for the sepsis.
Gui, Huan; Sun, Yang; Luo, Zhu-Min; Dai, Sheng-Ming; Liu, Xia
Acute liver failure is a life threatening disease mostly triggered by drug-induced or toxic liver damage or viral hepatitis. Herpes Simplex virus (HSV) hepatitis is rare and accounts for only 1% of all acute liver failures. The importance of HSV-induced acute liver failure is based on its extremely severe clinical course with lethality rates of almost 75%. HSV hepatitis is just one of several clinical manifestations of HSV sepsis leading more frequently to encephalitis, pneumonia and esophagitis. Local herpes infection or recurrence of dermal lesions (herpes labialis, herpes genitalis), however, is common and account for the high prevalence of HSV-1 or HSV-2 infection in adults. Another rare entity is visual dissemination, which mostly affects immunocompromised patients. Compromised cellular immunity is a major risk factor for HSV sepsis because of either primary infection or reactivation of occult chronic HSV infection. Delayed diagnosis without antiviral therapy significantly contributes to the unfavorable outcome. Typically, anicteric hepatitis is seen in patients with HSV hepatitis. Because of its low incidence, however, and the lack of dermal manifestations, HSV hepatitis is rarely considered in the context of acute liver failure. In addition, diagnostic tests might not always be available. Therefore, it is a generally accepted consensus to begin antiviral therapy pre-emptively with acyclovir in cases of acute liver failure of unknown origin, in which high urgency (HU) liver transplantation remains the only therapeutical option. Even in the case of early specific therapy, sepsis may prevail and the indication for HU transplantation must be evaluated carefully. The outcome after liver transplantation for HSV-induced liver failure with reported survival rates of more than 40% is good. Because of the risk of recurrence, lifelong prophylaxis with acyclovir is recommended. PMID:19930315
Riediger, C; Sauer, P; Matevossian, E; Müller, M W; Büchler, P; Friess, H
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.
Acute post-streptococcal glomerulonephritis (APSGN) is rare in children under 2 years of age. This is related in part to the disease patterns of group A streptococcus (GAS) and in part to impaired immunogenicity in infants. We report the case of a 14-month-old child with APSGN following GAS pharyngitis. This case illustrates that APSGN needs to be considered in the evaluation of both gross and microscopic hematuria in this age group. We review the literature of both GAS and APSGN and discuss the pathogenesis and epidemiologic reasons for this association. PMID:17043882
Bingler, Michael A; Ellis, Demetrius; Moritz, Michael L
Myocarditis consists of an inflammation of the cardiac muscle, definitively diagnosed by endomyocardial biopsy. The causal agents are primarily infectious: in developed countries, viruses appear to be the main cause, whereas in developing countries rheumatic carditis, Chagas disease, and HIV are frequent causes. Furthermore, myocarditis can be indirectly induced by an infectious agent and occurs following a latency period during which antibodies are created. Typically, myocarditis observed in rheumatic fever related to group A streptococcal (GAS) infection occurs after 2- to 3-week period of latency. In other instances, myocarditis can occur within few days following a streptococcal infection; thus, it does not fit the criteria for rheumatic fever. Myocarditis classically presents as acute heart failure, and can also be manifested by tachyarrhythmia or chest pain. Likewise, GAS-related myocarditis reportedly mimics myocardial infarction (MI) with typical chest pain, electrocardiograph changes, and troponin elevation. Here we describe a case of recurrent myocarditis, 5 years apart, with clinical presentation imitating an acute MI in an otherwise healthy 37-year-old man. Both episodes occurred 3 days after GAS pharyngitis and resolved quickly following medical treatment.
Cerebral vasculitis associated with acute post-streptococcal glomerulonephritis (APSGN) is rare. A 13-year-old girl presented with severe headache, vomiting, oedema and macroscopic haematuria. There was a history of upper respiratory infection 2 weeks previously. A diagnosis of APSGN was made. On admission, she was normotensive and biochemically well balanced. She experienced a tonic-clonic seizure 2 hours later. An MRI brain scan demonstrated multiple areas of abnormal signal intensity in the cerebral and cerebellar white matter, and subarachnoid haemorrhage consistent with vasculitis was diagnosed. A sixth-nerve palsy developed on the 6th day of admission. An elevated anti-streptolysin titre and low serum C3 complement level together with typical features on renal biopsy supported the diagnosis of APSGN. All clinical and laboratory abnormalities improved with corticosteroid therapy, pulse methyl-prednisolone. APSGN can present with central nervous system abnormalities without hypertension, uraemia and electrolyte disturbance. PMID:18510827
Dursun, Ismail; Gunduz, Zubeyde; Poyrazoglu, Hakan M; Gumus, Hakan; Yikilmaz, Ali; Dusunsel, Ruhan
Introduction: At present, there is no obligatory guideline for the prevention of early-onset neonatal group B streptococcal disease in Hungary. Aim: The aim of the present study was to gain insight into the spontaneously developed preventive strategy of the domestic obstetric divisions and departments in Hungary. Method: Standardized questionnaire was sent out to each of the 71 obstetric divisions and departments in Hungary. Results: Overall, 20 (27.4%) of the chairpersons replied, and thus, 39.9% of the total number of live births in Hungary were included in the study. Despite missing public health guidelines, each of the divisions and departments developed their own strategy to prevent neonatal group B streptococcal disease. In 95% of cases, bacterial culture of the lower vagina was the method of identifying pregnant women at risk. In 5% of the cases intrapartum antibiotic prophylaxis was based on risk assessment only. Of the departments using culture-based prophylaxis, 58% departments sampled women after completion of 36th gestational weeks. Antibiotic of choice was penicillin or ampicillin in 100% of cases. Of the study participants, 80% reported on multiple administration of colonized pregnant women after onset of labor or rupture of the membranes. Conclusions: The authors concluded that the rate of participation in the study was low. However, prevention of early-onset neonatal group B streptococcal infection is a priority of obstetric care in Hungary. Lack of a nation-wide public health policy did not prevent obstetric institutions in this country to develop their own prevention strategy. In the majority of cases and institutions, the policy is consistent with the widely accepted international standards. Orv. Hetil., 2014, 155(29), 1167-1172. PMID:25016449
Sziller, István; Szabó, Miklós; Valek, Andrea; Rigó, Barbara; Acs, Nándor
The aim of this study was to define the current demographic, clinical and prognostic characteristics of acute post-streptococcal glomerulonephritis (APSGN) in French Polynesia and to compare these features with those of other populations. Fifty children, all of whom were <15 years old and had been admitted to the Territorial Hospital of Papeete for APSGN between January 2005 and December 2007, were retrospectively enrolled in the study. Diagnostic criteria were microscopic or macroscopic haematuria, decreased C3 fraction of the complement and evidence of recent streptococcal infection. The annual incidence was 18 cases per 100,000 children <15 years of age in 2007. Most of the children (98%) enrolled in the study were of Polynesian ethnic origin, 27 were male (54%), and the average age at presentation was 6.7 years. Signs of previous respiratory infections were clearly evident in 40% of the children. Most of the patients presented during the rainy season, correlating with the relatively high incidence of skin infections at this time. The majority of patients had proteinuria (98%), with 25% having proteinuria in the nephrotic range (proteinuria/urinary creatinine >3 g/g). The presentation was severe in 22% of the children (congestive cardiac failure, severe hypertension and/or encephalopathy), and renal failure was an initial presenting symptom in 43.7%. The C3 fraction was lower in severe presentations, but the type of haematuria, level of proteinuria and inflammatory syndrome were not correlated with immediate severe forms or with initial renal failure. Haematuria resolved in a mean of 7.7 months and proteinuria in a mean of 3.9 months. None of the children had hypocomplementemia for more than 8 weeks. Acute post-streptococcal glomerulonephritis is endemic among French Polynesians, and they can be considered to be a high-risk population. Despite a high incidence of skin infections, however, the predominance of respiratory infections potentially indicates that French Polynesia is on the way to become a low-incidence area. Systematic detection and treatment of group A Streptococcus should be intensified. PMID:19876655
Becquet, Odile; Pasche, Jérôme; Gatti, Hélène; Chenel, Claude; Abély, Michel; Morville, Patrice; Pietrement, Christine
Introduction Sepsis has been a factor of acute kidney injury (AKI); however, little is known about dialysis-requiring AKI and the risk of severe sepsis after survival to discharge. Methods We conducted a population-based cohort study based on the Taiwan National Health Insurance Research Database from 1999 to 2009. We identified patients with AKI requiring dialysis during hospitalization and survived for at least 90 days after discharge, and matched them with those without AKI according to age, sex, and concurrent diabetes. The primary outcome was severe sepsis, defined as sepsis with a diagnosis of acute organ dysfunction. Individuals who recovered enough to survive without acute dialysis were further analyzed. Results We identified 2983 individuals (mean age, 62 years; median follow-up, 3.96 years) with dialysis-requiring AKI and 11,932 matched controls. The incidence rate of severe sepsis was 6.84 and 2.32 per 100 person-years among individuals with dialysis-requiring AKI and without AKI in the index hospitalization, respectively. Dialysis-requiring AKI patients had a higher risk of developing de novo severe sepsis than the non-AKI group. In subgroup analysis, even individuals with recovery from dialysis-requiring AKI were at high risk of developing severe sepsis. Conclusions AKI is an independent risk factor for severe sepsis. Even patients who recovered from AKI had a high risk of long-term severe sepsis.
Acute kidney injury (AKI) is a severe complication of sepsis, which largely contributes to the high mortality rate of sepsis. Honokiol, a natural product isolated from Magnolia officinalis (Houpo), has been shown to exhibit anti-inflammatory and antioxidant properties. Here, we investigated the effects of honokiol on sepsis-associated AKI in rats subjected to cecal ligation and puncture (CLP). We found that the administration of honokiol improved the survival of septic rats. Periodic acid-Schiff stain revealed that the morphological changes of kidney tissues in CLP rats were restored after honokiol treatment. Furthermore, honokiol reduced CLP-induced oxidative stress and inflammatory cytokine production. The levels of nitric oxide (NO) and inducible NO synthetase (iNOS) were attenuated by honokiol in septic rats. Finally, honokiol inhibited CLP-induced activation of NF-?B signaling in CLP rats. Our findings suggest that honokiol might be used as a potential therapeutic agent for complications of sepsis, especially for sepsis-induced AKI. PMID:24531855
Li, Nan; Xie, Hua; Li, Longkai; Wang, Jing; Fang, Ming; Yang, Ning; Lin, Hongli
Plasma and erythrocyte samples from acute post-streptococcal glomerulonephritis (APSGN) children and control children were enrolled in this study. Lipid peroxidation (LPO), measured in terms of thiobarbituric acid-reactive substances (TBARS) was found to be significantly increased in plasma and RBCs of APSGN children (P<0.05) than in control children. Osmotic fragility of erythrocytes was examined. RBCs of APSGN patients were found to be osmotically more sensitive towards hypotonic saline (50% hemolysis at 7 g/l saline) when compared to control RBCs (50% hemolysis at 4 g/l saline). The activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST) were significantly lowered (P<0.05) in APSGN RBCs when compared to control RBCs. Plasma ascorbic acid, reduced glutathione (GSH), RBC ascorbic acid, GSH and RBC total sulphydryl content (TSH) were significantly depleted in APSGN children relative to controls. The susceptibility of RBCs of APSGN children to lipid peroxidation was confirmed in this study. PMID:11412828
Devasena, T; Lalitha, S; Padma, K
Autoantibodies against complement C1q (anti-C1q) strongly correlate with the occurrence of severe lupus nephritis. Recent data suggest that anti-C1q might also correlate with more severe forms of acute post-streptococcal glomerulonephritis (APSGN). Therefore, we prospectively investigated the role of anti-C1q in 50 children with newly diagnosed APSGN. Associations between anti-C1q and disease manifestations as well as serum complement concentrations were analyzed. Nineteen of the 50 children (38%) with APSGN were positive for anti-C1q compared to 0/40 healthy controls. Levels of anti-C1q correlated negatively with serum C1q and C3 concentrations. Anti-C1q positive patients had significantly higher proteinuria and serum creatinine as well as more often oliguria, hypertension and delayed resolution of the disease than patients without anti-C1q. The data point to a potential pathogenic role of anti-C1q in APSGN. Determination of anti-C1q might help to identify patients at risk for prolonged courses of the disease. PMID:18544473
Kozyro, Ina; Korosteleva, Ludmila; Chernoshej, Dmitryj; Danner, Doris; Sukalo, Alexander; Trendelenburg, Marten
The incidence and mortality of sepsis and the associated development of acute kidney injury (AKI) remain high, despite intense research into potential treatments. Targeting the inflammatory response and\\/or sepsis-induced alterations in the (micro)circulation are two therapeutic strategies. Another approach could involve modulating the downstream mechanisms that are responsible for organ system dysfunction. Activation of inducible nitric oxide (NO) synthase (iNOS)
Rosalinde Masereeuw; Frans G. M. Russel; Peter Pickkers; Suzanne Heemskerk
The objective of this study was to review the epidemiological patterns of acute post-streptococcal glomerulonephritis (APSGN) in a pediatric population. We compared incidence, pathogenesis, clinical presentation and outcomes in two APSGN pediatric patient cohorts in northeastern Florida. Retrospective medical records were reviewed of children who were admitted to our institution with a diagnosis of APSGN. Patients admitted between 1999 and 2006 (recent cohort) were compared with a previously reported cohort of patients admitted between 1957 and 1973 (earlier cohort). The recent cohort comprised 45 children with APSGN of whom 87% were male and 13% were female; the median age was 7 years, and there was an average incidence of 6.4 patients per year. The earlier cohort comprised 153 children with APSGN of whom 62% were male and 38% were female; the median age 4.25 years, and there was an average incidence of 10.9 patients per year. The recent cohort was predominantly White-American (62%) and the earlier cohort predominately African American (87%). In the recent cohort, 64% of patients had antecedent pharyngitis, and in the earlier cohort, 66% of patients had antecedent pyoderma. In the recent cohort, 11% of APSGN cases occurred between August to October, and in the earlier cohort, 50% occurred during these months. In the recent cohort, symptoms of APSGN at presentation were milder and all cases recovered, but in the earlier cohort two deaths (1.3% mortality) were reported. In conclusion, there has been a decline in the incidence and severity of APSGN at our institute in recent decades. Pharyngitis has replaced impetigo as the predominant cause of APSGN. The etiological agent for impetigo has changed over the last decade, which has impacted the incidence, racial distribution, seasonal variation and severity of APSGN. PMID:18373105
Ilyas, Mohammad; Tolaymat, Asad
Sepsis with subsequent multiple organ dysfunction is a distinctly systemic inflammatory response to concealed or known infection and is a leading cause of death in intensive care units. In the initial stage of sepsis, a phase of immune activation can be evident, but a marked apoptosis-induced depletion of lymphocytes and a nonspecific anergy of immune function after severe trauma and burns might be responsible for the increased susceptibility of the host to subsequent septic complications. Recent studies indicated that negative regulation of immune function plays a pivotal role in the maintenance of peripheral homeostasis and regulation of immune responses; therefore, an understanding of the basic pathways might give rise to novel insights into the mechanisms of sepsis and immune homeostasis. This review is an attempt to provide a summary of the different pathways of negative regulation that are involved in the pathogenesis of sepsis, secondary to acute insults.
Luan, Ying-yi; Sheng, Zhi-yong
We herein report the case of a 17-year-old man who developed an increased plasma creatinine level (11.1 mg/dL) and oliguria with massive proteinuria (27.3 g/day) four weeks after an abraded wound to his right knee. The histology of the renal biopsy specimens showed diffuse endocapillary proliferative glomerulonephritis with the deposition of nephritis-associated plasmin receptor in the glomerulus. A case of acute kidney injury due to nephrotic syndrome caused by acute post-streptococcal glomerulonephritis was diagnosed. His renal function and proteinuria were improved with supportive care, including hemodialysis, without the administration of immunosuppressive agents. PMID:24042518
Kokuzawa, Ayako; Morishita, Yoshiyuki; Yoshizawa, Hiromichi; Iwazu, Kana; Komada, Takanori; Akimoto, Tetsu; Saito, Osamu; Oda, Takashi; Takemoto, Fumi; Ando, Yasuhiro; Muto, Shigeaki; Yumura, Wako; Kusano, Eiji
The mechanisms involved in sepsis-induced acute kidney injury (AKI) are unknown. We investigated the role of nitrosative stress in sepsis-induced AKI by studying the effects of manganese (III) tetrakis-(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP), a peroxynitrite decomposition catalyst, and aminoguanidine (AG), a selective nitric oxide synthase 2 (NOS2) inhibitor and peroxynitrite scavenger, on kidney function of rats subjected to cecal ligation and puncture (CLP). Sprague-Dawley rats (weighing 350 [SD, 50] g) were treated with MnTMPyP (6 mg/kg i.p.) or AG (50 mg/kg i.p.) at t = 12 and 24 h after CLP or sham procedure. At t = 36 h, mean arterial pressure and aortic blood flow were measured, and blood and urine samples were obtained for biochemical determinations, including creatinine clearance, fractional excretion of sodium, and neutrophil gelatinase-associated lipocalin concentration in the urine. Kidney tissue samples were obtained for (i) light microscopy, (ii) immunofluorescence and Western blot for 3-nitrotyrosine and NOS2, (iii) gene expression (quantitative real-time polymerase chain reaction) studies (NOS1, NOS2, NOS3, and superoxide dismutase 1), and (iv) matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Mean arterial pressure was unchanged and aortic blood flow decreased 25% in CLP animals. The sepsis-induced (i) decreased urine output and creatinine clearance and increased fractional excretion of sodium and urinary neutrophil gelatinase-associated lipocalin concentration, (ii) increased protein nitration and NOS2 protein, and (iii) NOS1 and NOS2 upregulation were all significantly attenuated by treatment with MnTMPyP or AG. Nitrated proteins in renal tissue from CLP animals (matrix-assisted laser desorption ionization time-of-flight mass spectrometry) were glutamate dehydrogenase, methylmalonate-semialdehyde dehydrogenase, and aldehyde dehydrogenase, mitochondrial proteins involved in energy metabolism or antioxidant defense. Nitro-oxidative stress is involved in sepsis-induced AKI, and protein nitration seems to be one mechanism involved. PMID:22777123
Seija, Mariana; Baccino, Cecilia; Nin, Nicolás; Sánchez-Rodríguez, Carolina; Granados, Rosario; Ferruelo, Antonio; Martínez-Caro, Leticia; Ruíz-Cabello, Jesús; de Paula, Marta; Noboa, Oscar; Esteban, Andrés; Lorente, José Angel
Salmonella infection can cause an asymptomatic intestinal carrier state or clinical diseases such as enterocolitis presenting abdominal pain, fever, vomiting, or diarrhea. Salmonella usually invades Peyer's patch of terminal ileum or ascending colon. Sepsis is not common and acute renal failure secondary to rhabdomyolysis is rare. The causes of rhabdomyolysis are trauma, excessive exercise, alcohol, seizure, metabolic abnormality, and infection. Infections account for less than 5% of the reported causes of rhabdomyolysis and resulting acute renal failure. The mechanisms underlying rhabdomyolysis due to infection are direct muscle invasion, toxin production, and nonspecific effects that can occur with infections such as fever, dehydration, acidosis, and electrolyte imbalance. We report a case of sepsis and acute renal failure secondary to rhabdomyolysis associated with Salmonella infection. PMID:19077503
Kim, Chul Han; Suk, Ki Tae; Kim, Jae Woo
Background Apolipoprotein A1 (ApoA1) is the major apoprotein constituent of high density lipoprotein (HDL) which exerts innate protective effects in systemic inflammation. However, its role in the acute lung injury (ALI) has not been well studied. In the present study we investigated the association between polymorphisms of ApoA1 gene and ALI in a Chinese population. Methods Three polymorphisms of the ApoA1 gene (rs11216153, rs2070665, and rs632153) were genotyped by TaqMan method in 290 patients with sepsis-associated ALI, 285 patients sepsis alone and 330 age- and sex-matched healthy controls. Results We found rs11216153 polymorphism of ApoA1 was associated with ALI, the GG genotype and G allele was common in the ALI patients (76.9%, 88.1%, respectively) than both in the control subjects (55.8%, 75.8%, respectively) and in the sepsis alone patients (58.2%, 78.4%, respectively). Haplotype consisting of these three SNPs strengthened the association with ALI susceptibility. The frequency of haplotype GTG in the ALI samples was significantly higher than that in the healthy control group (OR?=?2.261, 95% CI: 1.735?~?2.946, P <0.001) and the sepsis alone group (OR?=?1.789, 95% CI: 1.373?~?2.331.P?0.001). Carriers of the haplotype TTG had a lower risk for ALI compared with healthy control group (OR?=?0.422, 95% CI: 0.310?~?0.574, P?0.001) and sepsis alone group (OR?=?0.491, 95% CI: 0.356?~?0.676, P <0.001). Conclusions These results indicated that genetic variants in the ApoA1 gene might be associated with susceptibility to sepsis-associated ALI in Han Chinese population.
Chronic deficiencies in the complement pathway proteins are associated with an increased risk of meningococcal disease. Such deficiencies are caused by primary congenital immunodeficiency of a complement protein, properdin or mannose binding lectin, or are secondary to consumption of complement by systemic lupus erythematosus (SLE) or membranoproliferative glomerulonephritis (MPGN). Whatever the cause, the complement deficiency is always chronic. Here we report a case of meningococcal disease (MCD) in a child with a transient complement deficiency (CD), caused by post-streptococcal glomerulonephritis (PSGN). PMID:17294226
Daskas, Nikolaos; Farmer, Katie; Coward, Richard; Erlewyn-Lajeunesse, Michel
Background. Patients with acute respiratory distress syndrome (ARDS) have a deficiency of surfac- tant. Surfactant replacement improves physiologic func- tion in such patients, and preliminary data suggest that it may improve survival. Methods. We conducted a prospective, multicenter, double-blind, randomized, placebo-controlled trial involv- ing 725 patients with sepsis-induced ARDS. Patients were stratified according to the risk of death at base
R OBERT P. B AUGHMAN; K ALPALATHA; K. G UNTUPALLI; J OHN G. W EG; H ERBERT P. W IEDEMANN; F RANÇOIS L EMAIRE; W ALKER L ONG; D AVID S. Z ACCARDELLI; N. P ATTISHALL
BackgroundThe decline of proteasomal activity is known to be associated with the age-related disorders but the early events involved in this process are not apparent. To address this, we investigated the early-age-related (pediatric vs. adult) mechanisms that augment immunopathogenesis of sepsis and acute lung injury.Methodology\\/Principal FindingsThe 3-weeks (pediatric) and 6-months (adult) old C57BL\\/6 mice were selected as the study groups.
Manish Bodas; Taehong Min; Neeraj Vij; Amit Gaggar
Study objectives Disseminated strongyloides is a rarely reported phenomenon and occurs in immuno-suppressed patients with chronic Strongyloides stercoralis infection. Typically, patients present with pulmonary symptoms but subsequently acquire Gram-negative sepsis. Several cases have been noted in Minnesota, and their presentation, diagnostic evaluation, and clinical outcomes were reviewed. Design A retrospective chart review was conducted of complicated strongyloides infections from 1993 to 2002 in Minneapolis and St. Paul, MN. Cases were identified by reviewing hospital microbiology databases. Setting Metropolitan hospitals with large immigrant populations. Results Nine patients, all of Southeast Asian heritage, were identified. Eight patients immigrated to the United States ? 3 years prior to acute presentation. All patients were receiving antecedent corticosteroids; in five patients, therapy was for presumed asthma. Absolute eosinophil counts > 500/?L occurred in only two patients prior to steroid initiation. Eight patients presented with respiratory distress, and Gram-negative sepsis developed in four patients. Four patients had evidence of right-heart strain on ECG or echocardiography at the time of presentation. Three patients died; all had eosinophil counts of < 400/?L. Conclusions Serious complications, including death, may occur in patients with chronic strongyloides infection treated with corticosteroids. Strongyloides hyperinfection usually presents as acute respiratory failure and may initially mimic an asthma exacerbation or pulmonary embolism. Southeast Asian patients presenting with new-onset “asthma,” acute respiratory distress, and/or Gram-negative sepsis should undergo evaluation to exclude strongyloides infection.
Newberry, Ashley M.; Williams, David N.; Stauffer, William M.; Boulware, David R.; Hendel-Paterson, Brett R.; Walker, Patricia F.
Acute poststreptococcal glomerulonephritis is a common cause of acute nephritis in children. Transient hypocomplementemia and complete recovery are typical, with only a minority developing chronic disease. We describe a young girl who developed persistent kidney disease and hypocomplementemia after a streptococcal throat infection. Kidney biopsy 1 year after presentation showed isolated glomerular complement C3 deposition, membranoproliferative changes, and subendothelial, intramembranous and occasional subepithelial electron-dense deposits consistent with C3 glomerulopathy. Complement gene screening revealed a heterozygous single nucleotide insertion in exon 4 of the complement factor H–related protein 5 gene (CFHR5), resulting in a premature stop codon. This variant was not detected in 198 controls. Serum CFHR5 levels were reduced. The mother and sister of the index patient were heterozygous for the sequence variant, with no overt evidence of kidney disease. We speculate that this heterozygous CFHR5 sequence variant is a risk factor for the development of chronic kidney disease after streptococcal infection.
Vernon, Katherine A.; Goicoechea de Jorge, Elena; Hall, Angela E.; Fremeaux-Bacchi, Veronique; Aitman, Timothy J.; Cook, H. Terence; Hangartner, Robert; Koziell, Ania; Pickering, Matthew C.
The group A streptococcus causes the widest range of disease in humans of all bacterial pathogens. Group A streptococcal diseases are more common in children than adults with diseases ranging from pharyngitis and impetigo to invasive infections and the post-streptococcal sequelae--acute rheumatic fever and acute post-streptococcal glomerulonephritis. The global burden of severe group A streptococcal disease is concentrated largely in developing countries and Indigenous populations such as Aboriginal Australians. Control of group A streptococcal disease is poor in these settings and the need for a vaccine has been argued. With an ever-increasing understanding of the group A streptococcus at a molecular level, new and sophisticated vaccines are currently in human trials and the next decade holds exciting prospects for curbing group A streptococcal diseases. PMID:17444820
Steer, Andrew C; Danchin, Margaret H; Carapetis, Jonathan R
Context Severe sepsis, defined as infection complicated by acute organ dysfunction, occurs more frequently and leads to more deaths in black than in white individuals. The optimal approach to minimize these disparities is unclear. Objective To determine the extent to which higher severe sepsis rates in black than in white patients are due to higher infection rates or to a higher risk of acute organ dysfunction. Design, Setting, and Participants Analysis of infection-related hospitalizations from the 2005 hospital discharge data of 7 US states and infection-related emergency department visits from the 2003-2007 National Hospital Ambulatory Care Survey. Main Outcome Measure Age- and sex-standardized severe sepsis and infection hospitalization rates and the risk of acute organ dysfunction. Results Of 8 661 227 non–childbirth-related discharges, 2 261 857 were associated with an infection, and of these, 381 787 (16.8%) had severe sepsis. Black patients had a 67% higher age- and sex-standardized severe sepsis rate than did white patients (9.4; 95% confidence interval [CI], 9.3-9.5 vs 5.6; 95% CI, 5.6-5.6 per 1000 population; P<.001) and 80% higher standardized mortality (1.8, 95% CI, 1.8-1.9 vs 1.0, 95% CI, 1.0-1.1 per 1000 population; P<.001). The higher severe sepsis rate was explained by both a higher infection rate in black patients (47.3; 95% CI, 47.1-47.4 vs 34.0; 95% CI, 33.9-34.0 per 1000 population; incidence rate ratio, 1.39; P<.001) and a higher risk of developing acute organ dysfunction (age- and sex-adjusted odds ratio [OR],1.29; 95% CI, 1.27-1.30; P<.001). Differences in infection presented broadly across different sites and etiology of infection and for community- and hospital-acquired infections and occurred despite a lower likelihood of being admitted for infection from the emergency department (adjusted OR, 0.70; 95% CI, 0.64-0.76; P<.001). The higher risk of organ dysfunction persisted but was attenuated after adjusting for age, sex, comorbid conditions, poverty, and hospital effect (OR, 1.14; 95% CI, 1.13-1.16; P<.001). Racial disparities in infection and severe sepsis incidence and mortality rates were largest among younger adults (eg, the proportion of invasive pneumococcal disease occurring in adults <65 years was 73.9% among black patients vs 44.5% among white patients, P<.001). Conclusion Racial differences in severe sepsis are explained by both a higher infection rate and a higher risk of acute organ dysfunction in black than in white individuals.
Mayr, Florian B.; Yende, Sachin; Linde-Zwirble, Walter T.; Peck-Palmer, Octavia M.; Barnato, Amber E.; Weissfeld, Lisa A.; Angus, Derek C.
OBJECTIVE: Comparison of the incidence and case fatality of early-onset group B streptococcus sepsis and sepsis caused by other pathogens in neonates after change of management of intrauterine infection. METHODS: All infants delivered from 1988 through 1997 at a gestational age > or = 24 weeks with a birth weight > or = 500 gram without lethal congenital abnormalities were eligible for inclusion. Infants delivered by cesarean section before the onset of labor or rupture of membranes were excluded. During the first period (1988-1991) intrauterine infection was diagnosed by a temperature > 38 degrees C, during the second period (1992-1997) this diagnosis was made at a lower temperature (> or = 37.8 degrees C) or by fetal tachycardia > or = 160/min. Treatment of intrauterine infection was similar during both periods with 3 x 2 gram amoxicillin and 1 x 240 mg gentamicin every 24 hours intravenously during labor. Prophylactic treatment during labor was only given to women with a history of an earlier infant with early-onset group B streptococcus sepsis. RESULTS: During the first period 6,103 infants were included, during the second period 8,504. Intrauterine infection was diagnosed and treated more often in the second period (7.1% vs. 2.6%). The incidence of early-onset group B streptococcus sepsis was significantly lower in the second period than in the first period [0.2% vs. 0.4%; OR 0.5 (0.3-0.9)] and survival without disability higher [80% vs. 52%; OR 4.5 (1.4-16.5)]. However, in both periods the overall incidence of neonatal sepsis (3.6% vs. 3.5%) and overall mortality because of sepsis (14.3% vs.13.1%) were similar. CONCLUSIONS: Although the early detection of clinical signs of intrauterine infection might have been effective for the prevention of serious sequelae of early-onset group B streptococcus sepsis the overall incidence and mortality from neonatal sepsis remained unchanged. Evaluation of preventive measures for early-onset group B streptococcus sepsis should always take the incidence of neonatal sepsis caused by other pathogens into account.
Wolf, H; Schaap, A H; Smit, B J; Spanjaard, L; Adriaanse, A H
Rheumatic fever is an immunologically mediated disease that follows infection by group A beta-hemolytic Streptococcus (GABHS). In rheumatic fever, antibodies generated against GABHS cross-react with the heart, joints, skin, and other sites, inducing an inflammatory, multisystem disease. Brain tissue-specific antibodies have been demonstrated in a subset of children with Sydenham chorea (a component of the Jones criteria for the diagnosis of rheumatic fever), and most Sydenham chorea patients manifest obsessive-compulsive symptoms very similar to those in traditional obsessive-compulsive disorder. The parallels drawn from the paradigm of Sydenham's chorea to Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is an area of active controversy. Newly emerging information on the role of GABHS superantigens in the pathogenesis of rheumatic fever is of particular interest. In this article, we review the microbial characteristics of GABHS and the subsequent immune responses to GABHS as a possible etiology of PANDAS. PMID:15377732
Kim, Suck Won; Grant, Jon E; Kim, Sandra I; Swanson, Todd A; Bernstein, Gail A; Jaszcz, Waclaw B; Williams, Kyle A; Schlievert, Patrick M
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.
Maddens, B.; Ghesquiere, B.; Vanholder, R.; Demon, D.; Vanmassenhove, J.; Gevaert, K.; Meyer, E.
Introduction The role of nitric oxide synthase (NOS) in the pathophysiology of acute respiratory distress syndrome (ARDS) is not well understood. Inducible NOS is upregulated during physiologic stress; however, if NOS substrate is insufficient then NOS can uncouple and switch from NO generation to production of damaging peroxynitrites. We hypothesized that NOS substrate levels are low in patients with severe sepsis and that low levels of the NOS substrate citrulline would be associated with end organ damage including ARDS in severe sepsis. Methods Plasma citrulline, arginine and ornithine levels and nitrate/nitrite were measured at baseline in 135 patients with severe sepsis. ARDS was diagnosed by consensus definitions. Results Plasma citrulline levels were below normal in all patients (median 9.2 uM, IQR 5.2 - 14.4) and were significantly lower in ARDS compared to the no ARDS group (6.0 (3.3 - 10.4) vs. 10.1 (6.2 - 16.6), P = 0.002). The rate of ARDS was 50% in the lowest citrulline quartile compared to 15% in the highest citrulline quartile (P = 0.002). In multivariable analyses, citrulline levels were associated with ARDS even after adjustment for covariates including severity of illness. Conclusions In severe sepsis, levels of the NOS substrate citrulline are low and are associated with ARDS. Low NOS substrate levels have been shown in other disease states to lead to NOS uncoupling and oxidative injury suggesting a potential mechanism for the association between low citrulline and ARDS. Further studies are needed to determine whether citrulline supplementation could prevent the development of ARDS in patients with severe sepsis and to determine its role in NOS coupling and function.
INTRODUCTION: To evaluate the utility of urinary cystatin C (uCysC) as a diagnostic marker of acute kidney injury (AKI) and sepsis, and predictor of mortality in critically ill patients. METHODS: This was a two-center, prospective AKI observational study and post hoc sepsis subgroup analysis of 444 general intensive care unit (ICU) patients. uCysC and plasma creatinine were measured at entry
Maryam Nejat; John W Pickering; Robert J Walker; Justin Westhuyzen; Geoffrey M Shaw; Christopher M Frampton; Zoltán H Endre
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
JOHN K. MCCORMICK; ALEXA A. PRAGMAN; JOHN C. STOLPA; DONALD Y. M. LEUNG; PATRICK M. SCHLIEVERT
Introduction Cannabinoid receptor 2 (CB2R) expression is upregulated during sepsis. However, there are conflicting results regarding the effects of CB2R modulation in the hyperinflammatory phase of the disease. The aim of this study was therefore to investigate the effects of CB2R manipulation on leukocyte activation within the intestinal microcirculation in two acute experimental sepsis models. Methods In the endotoxemia model we studied four groups of Lewis rats: controls, lipopolysaccharide (LPS), LPS + CB2R agonist HU308 (2.5 mg/kg), and LPS + CB2R antagonist AM630 (2.5 mg/kg). In the colon ascendens stent peritonitis (CASP)-induced sepsis model we also studied four groups: sham group, CASP and CASP + CB2R agonist (HU308, 2.5 or 10 mg/kg). Intravital microscopy was performed 2 hours following LPS/placebo administration or 16 hours following CASP/sham surgery to quantify intestinal leukocyte recruitment. Additionally, hemodynamic monitoring, histological examinations and measurements of inflammatory mediators were performed. Results HU308 administration significantly reduced intestinal leukocyte adhesion in both acute sepsis models. The systemic levels of inflammatory mediators were significantly reduced by 10 mg/kg HU308 treatment in CASP animals. Conclusion CB2R activation reduces leukocyte activation and systemic release of inflammatory mediators in acute experimental sepsis. Drugs targeting the CB2R pathway may have therapeutic potential in sepsis.
Mortality from sepsis has remained high despite recent advances in supportive and targeted therapies. Toll-like receptors (TLRs) sense bacterial products and stimulate pathogenic innate immune responses. Mice deficient in the common adapter protein MyD88, downstream from most TLRs, have reduced mortality and acute kidney injury (AKI) from polymicrobial sepsis. However, the identity of the TLR(s) responsible for the host response to polymicrobial sepsis is unknown. Here, we show that chloroquine, an inhibitor of endocytic TLRs (TLR3, 7, 8, 9), improves sepsis-induced mortality and acute kidney injury in a clinically relevant polymicrobial sepsis mouse model, even when administered 6h after the septic insult. Chloroquine administration attenuated the decline in renal function, splenic apoptosis, serum markers of damage to other organs, and prototypical serum pro- and anti-inflammatory cytokines TNF-alpha and IL-10. An oligodeoxynucleotide inhibitor (H154) of TLR9 and TLR9-deficient mice mirror the actions of chloroquine in all functional parameters that we tested. In addition, chloroquine decreased TLR9 protein abundance in spleen, further suggesting that TLR9 signaling may be a major target for the protective actions of chloroquine. Our findings indicate that chloroquine improves survival by inhibiting multiple pathways leading to polymicrobial sepsis, and that chloroquine and TLR9 inhibitors represent viable broad-spectrum and targeted therapeutic strategies, respectively, that are promising candidates for further clinical development.
Yasuda, Hideo; Leelahavanichkul, Asada; Tsunoda, Shinichiro; Dear, James W.; Takahashi, Yoshiyuki; Ito, Shuichi; Hu, Xuzhen; Zhou, Hua; Doi, Kent; Childs, Richard; Klinman, Dennis M.; Yuen, Peter S.T.; Star, Robert A.
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.
DeRubertis, Frederick R.; Woeber, Kenneth A.
Introduction To evaluate the utility of urinary cystatin C (uCysC) as a diagnostic marker of acute kidney injury (AKI) and sepsis, and predictor of mortality in critically ill patients. Methods This was a two-center, prospective AKI observational study and post hoc sepsis subgroup analysis of 444 general intensive care unit (ICU) patients. uCysC and plasma creatinine were measured at entry to the ICU. AKI was defined as a 50% or 0.3-mg/dL increase in plasma creatinine above baseline. Sepsis was defined clinically. Mortality data were collected up to 30 days. The diagnostic and predictive performances of uCysC were assessed from the area under the receiver operator characteristic curve (AUC) and the odds ratio (OR). Multivariate logistic regression was used to adjust for covariates. Results Eighty-one (18%) patients had sepsis, 198 (45%) had AKI, and 64 (14%) died within 30 days. AUCs for diagnosis by using uCysC were as follows: sepsis, 0.80, (95% confidence interval (CI), 0.74 to 0.87); AKI, 0.70 (CI, 0.64 to 0.75); and death within 30 days, 0.64 (CI, 0.56 to 0.72). After adjustment for covariates, uCysC remained independently associated with sepsis, AKI, and mortality with odds ratios (CI) of 3.43 (2.46 to 4.78), 1.49 (1.14 to 1.95), and 1.60 (1.16 to 2.21), respectively. Concentrations of uCysC were significantly higher in the presence of sepsis (P < 0.0001) or AKI (P < 0.0001). No interaction was found between sepsis and AKI on the uCysC concentrations (P = 0.53). Conclusions Urinary cystatin C was independently associated with AKI, sepsis, and death within 30 days. Trial registration Australian New Zealand Clinical Trials Registry ACTRN012606000032550.
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.
Sepsis remains a serious problem in critically ill patients with the mortality increasing to over half when there is attendant acute kidney injury. ?-Melanocyte-stimulating hormone is a potent anti-inflammatory cytokine that inhibits many forms of inflammation including that with acute kidney injury. We tested whether a new ?-melanocyte-stimulating hormone analogue (AP214), which has increased binding affinity to melanocortin receptors, improves
K Doi; X Hu; P S T Yuen; A Leelahavanichkul; H Yasuda; S M Kim; J Schnermann; T E N Jonassen; J Frøkiær; S Nielsen; R A Star
Data relating to acute post-streptococcal glomerulonephritis (APSGN) from the notifiable diseases surveillance system in the Northern Territory of Australia was extracted and analyzed. Isolates of Streptococcus pyogenes from confirmed cases were emm sequence typed. From 1991 to July 2008, there were 415 confirmed cases and 23 probable cases of APSGN notified. Four hundred fifteen (94.7%) of these were Indigenous Australians and 428 (97.7%) were people living in remote or very remote locations. The median age of cases was 7 years (range 0–54). The incidence of confirmed cases was 12.5/100,000 person-years, with an incidence in Indigenous Australian children younger than 15 years of age of 94.3 cases/100,000 person-years. The overall rate ratio of confirmed cases in Indigenous Australians to non-Indigenous Australians was 53.6 (95% confidence interval 32.6–94.8). Outbreaks of disease across multiple communities occurred in 1995 (N = 68), 2000 (N = 55), and 2005 (N = 87 [confirmed cases]). Various emm types of S. pyogenes were isolated from cases of APSGN including some types not previously recognized to be nephritogenic. The widespread outbreak in 2005 was caused by emm55.0 S. pyogenes. Acute post-streptococcal glomerulonephritis continues to occur in remote Indigenous communities in Australia at rates comparable to or higher than those estimated in developing countries. Improvements in preventative and outbreak control strategies are needed.
Marshall, Catherine S.; Cheng, Allen C.; Markey, Peter G.; Towers, Rebecca J.; Richardson, Leisha J.; Fagan, Peter K.; Scott, Lesley; Krause, Vicki L.; Currie, Bart J.
Data relating to acute post-streptococcal glomerulonephritis (APSGN) from the notifiable diseases surveillance system in the Northern Territory of Australia was extracted and analyzed. Isolates of Streptococcus pyogenes from confirmed cases were emm sequence typed. From 1991 to July 2008, there were 415 confirmed cases and 23 probable cases of APSGN notified. Four hundred fifteen (94.7%) of these were Indigenous Australians and 428 (97.7%) were people living in remote or very remote locations. The median age of cases was 7 years (range 0-54). The incidence of confirmed cases was 12.5/100,000 person-years, with an incidence in Indigenous Australian children younger than 15 years of age of 94.3 cases/100,000 person-years. The overall rate ratio of confirmed cases in Indigenous Australians to non-Indigenous Australians was 53.6 (95% confidence interval 32.6-94.8). Outbreaks of disease across multiple communities occurred in 1995 (N = 68), 2000 (N = 55), and 2005 (N = 87 [confirmed cases]). Various emm types of S. pyogenes were isolated from cases of APSGN including some types not previously recognized to be nephritogenic. The widespread outbreak in 2005 was caused by emm55.0 S. pyogenes. Acute post-streptococcal glomerulonephritis continues to occur in remote Indigenous communities in Australia at rates comparable to or higher than those estimated in developing countries. Improvements in preventative and outbreak control strategies are needed. PMID:21976576
Marshall, Catherine S; Cheng, Allen C; Markey, Peter G; Towers, Rebecca J; Richardson, Leisha J; Fagan, Peter K; Scott, Lesley; Krause, Vicki L; Currie, Bart J
This study aimed to determine the effect of induced mild hypothermia (34°C) on the production of two cytokines (interleukin (IL-6) and tumor necrosis factor (TNF)alpha) and reactive nitrogen and oxygen species in plasma and the heart of acutely septic rats. After anesthesia and in conditions of normothermia (38°C) or mild hypothermia (34°C), acute sepsis was induced by cecal ligation and perforation. For each temperature three groups were formed: (1) baseline (blood sample collected at T0 hour), (2) sham (blood sample at T4 hours) and (3) septic (blood sample at T4 hours). At either temperature sepsis induced a significant increase in plasma IL-6, TNF-alpha and HO• concentration, compared with the sham groups (P?0.016). Compared with the normothermic septic group, septic rats exposed to mild hypothermia showed a mild decrease in TNF-alpha concentration (104±50 pg/ml vs. 215±114 pg/ml; P>0.05) and a significant decrease in IL-6 (1131±402 pg/ml vs. 2494±691 pg/ml, P=0.038). At either temperature sepsis induced no enhancement within the heart of lipoperoxidation (malondialdehyde content) or antioxidant activities (superoxide dismutase and catalase). In conclusion, during acute sepsis, induced mild hypothermia appears to reduce some pro-inflammatory and oxidative responses. This may, in part, explain the beneficial effect of hypothermia on survival duration of septic rats. PMID:23746123
Léon, Karelle; Moisan, Christine; Amérand, Aline; Poupon, Gwladys; L'Her, Erwan
The mortality rate of patients who develop acute kidney injury during sepsis nearly doubles. The effectiveness of therapy is hampered because it is usually initiated only after the onset of symptoms. As renal microvascular failure during sepsis is correlated with the generation of reactive nitrogen species, the therapeutic potential of resveratrol, a polyphenol vasodilator that is also capable of scavenging
Joseph H Holthoff; Zhen Wang; Kathryn A Seely; Neriman Gokden; Philip R Mayeux
Sepsis-induced acute kidney injury (AKI) is the most common form of AKI observed in critically ill patients. AKI mortality in septic critically ill patients remains high despite our increasing ability to support vital organ systems. This high mortality is partly due to our poor understanding of the pathophysiological mechanisms of sepsis-induced AKI. Recent experimental studies have suggested that the pathogenesis of sepsis-induced AKI is much more complex than isolated hypoperfusion due to decreased cardiac output and hypotension. In nonresuscitated septic patients with a low cardiac output, a decrease in renal blood flow (RBF) could contribute to the development of AKI. In resuscitated septic patients with a hyperdynamic circulatory state, RBF is unchanged or increased. However, in resuscitated septic patients, sepsis-induced AKI can occur in the setting of renal hyperemia in the absence of renal hypoperfusion or renal ischemia. Alterations in the microcirculation in the renal cortex or renal medulla can occur despite normal or increased global RBF. Increased renal vascular resistance (RVR) may represent a key hemodynamic factor that is involved in sepsis-associated AKI. Sepsis-induced renal microvascular alterations (vasoconstriction, capillary leak syndrome with tissue edema, leukocytes and platelet adhesion with endothelial dysfunction and/or microthrombosis) and/or an increase in intra-abdominal pressure could contribute to an increase in RVR. Further studies are needed to explore the time course of renal microvascular alterations during sepsis as well as the initiation and development of AKI. Doppler ultrasonography combined with the calculation of the resistive indices may indicate the extent of the vascular resistance changes and may help predict persistent AKI and determine the optimal systemic hemodynamics required for renal perfusion. PMID:21921613
Bouglé, Adrien; Duranteau, Jacques
Acute kidney injury is a frequent and serious complication of sepsis. To better understand the development of sepsis-induced acute kidney injury, we performed the first time-dependent studies to document changes in renal hemodynamics and oxidant generation in the peritubular microenvironment using the murine cecal ligation and puncture (CLP) model of sepsis. CLP caused an increase in renal capillary permeability at 2 hours, followed by decreases in mean arterial pressure, renal blood flow (RBF), and renal capillary perfusion at 4 hours, which were sustained through 18 hours. The decline in hemodynamic parameters was associated with hypoxia and oxidant generation in the peritubular microenvironment and a decrease in glomerular filtration rate. The role of oxidants was assessed using the superoxide dismutase mimetic/peroxynitrite scavenger MnTMPyP [Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin]. At 10 mg/kg administered 6 hours after CLP, MnTMPyP did not alter blood pressure, but blocked superoxide and peroxynitrite generation, reversed the decline in RBF, capillary perfusion, and glomerular filtration rate, preserved tubular architecture, and increased 48-hour survival. However, MnTMPyP administered at CLP did not prevent capillary permeability or the decrease in RBF and capillary perfusion, which suggests that these early events are not mediated by oxidants. These data demonstrate that renal hemodynamic changes occur early after sepsis and that targeting the later oxidant generation can break the cycle of injury and enable the microcirculation and renal function to recover. PMID:22119717
Wang, Zhen; Holthoff, Joseph H; Seely, Kathryn A; Pathak, Elina; Spencer, Horace J; Gokden, Neriman; Mayeux, Philip R
A 9-year-old boy in Hawai'i presented with bleeding and thrombocytopenia and was subsequently found to have post-streptococcal glomerulonephritis. He recovered completely with intravenous immune globulin, antibiotics, short-term antihypertensive therapy, and supportive management. This case was similar to the 5 cases previously reported in the literature, with the exception that steroids were not used as the primary immune-modulating therapy. PMID:19441614
Guerrero, Anthony P S; Musgrave, James E; Lee, Eric K W
Cerebral vasculitis following acute post-streptococcal glomerulonephritis (APSGN) is a rare neurological complication. An 11-year-old girl with biopsy proven APSGN developed an acute seizure disorder. Clinical and computed tomography findings were consistent with vasculitis. PMID:11903844
Wong, W; Morris, M C
Background Sepsis is a common syndrome in critically ill patients and easily leads to the occurrence of acute kidney injury (AKI), with high mortality rates. This study aimed to investigate the diagnostic value of urine soluble CD163 (sCD163) for identification of sepsis, severity of sepsis, and for secondary AKI, and to assess the patients’ prognosis. Methods We enrolled 20 cases with systemic inflammatory response syndrome (SIRS), 40 cases with sepsis (further divided into 17 sepsis cases and 23 severe sepsis cases) admitted to the intensive care unit (ICU), and 20 control cases. Results for urine sCD163 were recorded on the day of admission to the ICU, and AKI occurrence was noted. Results On the day of ICU admission, the sepsis group exhibited higher levels of urine sCD163 (74.8 ng/ml; range: 47.9-148.3 ng/ml) compared with those in the SIRS group (31.9 ng/ml; 16.8-48.0, P?0.001). The area under the curve (AUC) was 0.83 (95% confidence interval [CI]: 0.72-0.94, P?0.001) the sensitivity was 0.83, and the specificity was 0.75 (based on a cut-off point of 43.0 ng/ml). Moreover, the severe sepsis group appeared to have a higher level of sCD163 compared with that in the sepsis group (76.2; 47.2-167.5 ng/ml vs. 74.2; 46.2-131.6 ng/ml), but this was not significant. For 15 patients with AKI, urine sCD163 levels at AKI diagnosis were significantly higher than those of the remaining 35 sepsis patients upon ICU admission (121.0; 74.6-299.1 ng/ml vs. 61.8; 42.8-128.3 ng/ml, P?=?0.049). The AUC for urine sCD163 was 0.688 (95% CI: 0.51-0.87, P?=?0.049). Sepsis patients with a poor prognosis showed a higher urine sCD163 level at ICU admission (98.6; 50.3-275.6 ng/ml vs. 68.0; 44.8-114.5 ng/ml), but this was not significant. Patients with AKI with a poor prognosis had higher sCD163 levels than those in patients with a better prognosis (205.9; 38.6-766.0 ng/ml vs. 80.9; 74.9-141.0 ng/ml), but this was not significant. Conclusions This study shows, for the first time, the potential value of urine sCD163 levels for identifying sepsis and diagnosing AKI, as well as for assessment of patients’ prognosis. Trial Registration ChiCTR-ONC-10000812
The objective of this investigation is to review existing research pertaining to cognitive impairment and decline following critical illness and describe a case involving a 49-year-old female with sepsis and acute respiratory distress syndrome (ARDS) with no prior neurologic history who, compared to baseline neuropsychological test data, experienced dramatic cognitive decline and brain atrophy following treatment in the medical intensive care unit (ICU) at Vanderbilt University Medical Center. The patient participated in detailed clinical interviews and underwent comprehensive neuropsychological testing and neurological magnetic resonance imaging (MRI) at approximately 8 months and 3.5 years after ICU discharge. Compared to pre-ICU baseline test data, her intellectual function declined approximately 2 standard deviations from 139 to 106 (from the 99th to the 61st percentile) on a standardized intelligence test 8 months post-discharge, with little subsequent improvement. Initial diffusion tensor brain magnetic resonance imaging (DT-MRI) at the end of ICU hospitalization showed diffuse abnormal hyperintense areas involving predominately white matter in both hemispheres and the left cerebellum. A brain MRI nearly 4 years after ICU discharge demonstrated interval development of profound and generalized atrophy with sulcal widening and ventricular enlargement. The magnitude of cognitive decline experienced by ICU survivors is difficult to quantify due to the unavailability of pre-morbid neuropsychological data. The current case, conducted on a patient with baseline neuropsychological data, illustrates the trajectory of decline occurring after critical illness and ICU-associated brain injury with marked atrophy and concomitant cognitive impairments.
Jackson, James C.; Hopkins, Ramona O.; Miller, Russell R.; Gordon, Sharon M.; Wheeler, Arthur P.; Ely, E. Wesley
Clarithromycin was administered intravenously to 55 rabbits to evaluate its effect on experimental sepsis caused by multidrug-resistant Pseudomonas aeruginosa. Acute pyelonephritis was induced after ligation of the right ureter and injection of 108 CFU of the test isolate per kg of body weight into the renal pelvis. The animals were divided into six groups: group A, controls; group B, rabbits that received one intravenous dose of 80 mg of clarithromycin per kg concomitantly with bacterial challenge; group C, rabbits that received two doses of clarithromycin, the second one of which was given 2 h after the first one; group D, rabbits that received 15 mg of amikacin per kg; group E, rabbits that received one dose of clarithromycin and amikacin; and group F, rabbits that received two doses of clarithromycin and amikacin. Serum endotoxin levels were estimated by the QCL-1000 Limulus amoebocyte lysate assay, tumor necrosis factor alpha (TNF-?) levels were measured by a bioassay, and malondialdehyde (MDA) levels were measured by the thiobarbiturate assay. Viable bacterial counts in various tissue samples were also assessed. The mean survival times of the animals in groups A, B, C, D, E, and F were 4.50, 7.69, 4.07, 4.55, 11.55, and 11.60 days, respectively (P = 0.033 for group D versus group F, P = 0.006 for group D versus group E, P = not significant for group B versus group E, P = 0.042 for group C versus group F). Serum endotoxin levels were similar between groups at all sampling times; TNF-? and MDA levels in groups B, C, E, and F decreased significantly over follow-up. The numbers of viable bacterial cells in the infected kidney were similar among the groups; those in the liver, spleen, lungs, and mesenteral lymph nodes were significantly decreased in groups B, E, and F compared to those in groups A and D. It is concluded that a prolongation of survival in animals with experimental sepsis caused by multidrug-resistant P. aeruginosa was achieved after coadministration of clarithromycin and amikacin and that the increased survival was probably attributable to the immunomodulatory properties of clarithromycin.
Giamarellos-Bourboulis, Evangelos J.; Adamis, Theodoros; Laoutaris, George; Sabracos, Lambros; Koussoulas, Vassilios; Mouktaroudi, Maria; Perrea, Despina; Karayannacos, Panayotis E.; Giamarellou, Helen
Oxidative damage and inflammation occur early in the brain after sepsis and are resolved when long-term cognitive impairment occurs. There is no information of a direct relation between acute levels of brain inflammation and oxidative damage and long-term cognitive deficits. We hypothesized that higher levels of early oxidative damage and inflammation are followed by long-term cognitive deficits, and this is related to a decrease in the levels of brain-derived neurotropic factor (BDNF). Wistar rats were subjected to sham operation or cecal ligation and perforation and the cerebrospinal fluid (CSF) was obtained 6 and 24 h after the determination of thiobarbituric acid-reactive species, interleukin 1 (IL-1), IL-10, and tumor necrosis factor ? (TNF-?). Animals were followed until 30 days after surgery and were subjected to the step-down inhibitory avoidance (IA) task, and the hippocampus levels of BDNF were determined. At 6 h, higher CSF levels of thiobarbituric acid-reactive species and TNF-? were observed in septic animals that had a better performance in the IA task and presented higher BDNF levels in the hippocampus. At 24 h, higher CSF levels of IL-1? and TNF-? were observed in septic animals that had a worse performance in the IA task, and this was associated with lower BDNF levels. The persistence of brain inflammation during the acute phase of sepsis is associated with long-term hippocampus levels of BDNF and memory impairment in sepsis survivors. PMID:23603768
Biff, Daiane; Petronilho, Fabrícia; Constantino, Larissa; Vuolo, Francieli; Zamora-Berridi, Grettel J; Dall'Igna, Dhébora Mozena; Comim, Clarissa M; Quevedo, João; Kapczinski, Flávio; Dal-Pizzol, Felipe
Summary Background Acute respiratory distress syndrome (ARDS) is the inflammatory disorder of the lung most commonly caused by sepsis. It was hypothesized that treating the lung with penehyclidine hydrochloride (PHC), a new type of hyoscyamus drug, early in the development of sepsis could diminish the lung dysfunction. Material/Methods Sprague-Dawley rats were divided into 4 groups: 1) a control group; 2) a sham-operated group; 3) a cecal ligation and puncture (CLP) group; 4) a PHC-treated group. One hour after CLP surgery, rats were either untreated or treated with PHC via intraperitoneal injection. Lung wet/dry weight ratio, bronchoalveolar lavage fluid (BALF), serum tumor necrosis factor (TNF-?), interleukin 6 (IL-6), interleukin 10 (IL-10), total nitrite/nitrate (NOx), superoxide dismutase (SOD), malondialdehyde (MDA) in lung tissues, and pulmonary functions were examined 24 hour after surgery. Another 60 rats were randomly assigned to 4 equal groups to observe survival status 96 hours after surgery. Results Treatment of PHC markedly decreased TNF-?, IL-6, NOx, SOD, MDA content, protein concentration in BALF, and lung wet/dry weight ratio and enhanced SOD activity (p<0.05), which are indicative of PHC-induced suppression in the pathogenesis of ARDS caused by sepsis. In comparison to group CLP/saline, plasma IL-10 level markedly increased in group CLP/PHC. In PHC-treated groups, the administered PHC had a significant protective effect on the lung dysfunction induced by sepsis. Conclusions We conclude that administration of PHC at the time of a systemic insult can protect the lung from the damaging effects of sepsis.
Li, Hao; Qian, Zhaoxin; Li, Jianmin; Han, Xiaotong; Liu, Min
The aim of the present study was to explore the protective effect of small interfering RNA (siRNA) against nuclear factor ?B (NF-?B) p65 on sepsis-induced acute lung injury (ALI) in mice. In total, 70 male Kunming mice were randomly divided into a healthy control group, a sepsis group, a specific interfering group and a scrambled control group (Sc), and the latter three groups were divided into post-operational 6 and 12 h subgroups, each of which consisted of 10 mice. The mice were administered with NF-?B siRNA, scrambled siRNA and normal saline via tail vein injection. Following 1 h, a mouse model of septic ALI was produced by cecal ligation and puncture (CLP) in the two siRNA groups and the sepsis control group. At 6 and 12 h post?operation, the experimental mice were sacrificed and the lung tissue samples were collected. Histopathological changes, wet/dry ratio of lung weight, NF-?B protein and NF-?B p65 mRNA levels, matrix metalloproteinase-9 (MMP-9) mRNA and protein activity were detected. Compared with the sepsis group and the Sc at the corresponding time, the expression levels of NF-?B p65 mRNA, the lung injury of experimental mice, the wet/dry ratio and the levels of MMP-9 mRNA and protein activity decreased, and significant differences were observed at 6 h post-operation (P<0.05). RNA interference against NF-?B p65 was able to decrease the expression of NF-?B and further inhibit the early phasic excessive inflammatory reaction in sepsis, which may alleviate ALI. PMID:24913772
Jin, Li-Yan; Li, Cong-Feng; Zhu, Guang-Fa; Wu, Chun-Ting; Wang, Jun; Yan, Shu-Feng
The aim of the present study was to explore the protective effect of small interfering RNA (siRNA) against nuclear factor ?B (NF-?B) p65 on sepsis-induced acute lung injury (ALI) in mice. In total, 70 male Kunming mice were randomly divided into a healthy control group, a sepsis group, a specific interfering group and a scrambled control group (Sc), and the latter three groups were divided into post-operational 6 and 12 h subgroups, each of which consisted of 10 mice. The mice were administered with NF-?B siRNA, scrambled siRNA and normal saline via tail vein injection. Following 1 h, a mouse model of septic ALI was produced by cecal ligation and puncture (CLP) in the two siRNA groups and the sepsis control group. At 6 and 12 h post-operation, the experimental mice were sacrificed and the lung tissue samples were collected. Histopathological changes, wet/dry ratio of lung weight, NF-?B protein and NF-?B p65 mRNA levels, matrix metalloproteinase-9 (MMP-9) mRNA and protein activity were detected. Compared with the sepsis group and the Sc at the corresponding time, the expression levels of NF-?B p65 mRNA, the lung injury of experimental mice, the wet/dry ratio and the levels of MMP-9 mRNA and protein activity decreased, and significant differences were observed at 6 h post-operation (P<0.05). RNA interference against NF-?B p65 was able to decrease the expression of NF-?B and further inhibit the early phasic excessive inflammatory reaction in sepsis, which may alleviate ALI.
JIN, LI-YAN; LI, CONG-FENG; ZHU, GUANG-FA; WU, CHUN-TING; WANG, JUN; YAN, SHU-FENG
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.
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
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
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
ABSTRACT: INTRODUCTION: Renal resistive index (RI), determined by Doppler ultrasonography, directly reveals and quantifies modifications in renal vascular resistance. The aim of this study was to evaluate if mean arterial pressure (MAP) is determinant of renal RI in septic, critically ill patients suffering or not from acute kidney injury (AKI). METHODS: This prospective observational study included 96 patients. AKI was defined according to RIFLE criteria and transient or persistent AKI according to renal recovery within 3 days. RESULTS: Median renal RIs were 0.72 (0.68-0.75) in patients without AKI and 0.76 (0.72-0.80) in patients with AKI (P=0.001). RIs were 0.75 (0.72-0.79) in transient AKI and 0.77 (0.70-0.80) in persistent AKI (P=0.84). RI did not differ in patients given norepinephrine infusion and was not correlated with norepinephrine dose. RI was correlated with MAP (?= -0.47; P=0.002), PaO2/FiO2 ratio (?= -0.33; P=0.04) and age (?=0.35; P=0.015) only in patients without AKI. CONCLUSIONS: A poor correlation between renal RI and MAP, age, or PaO2/FiO2 ratio was found in septic and critically ill patients without AKI compared to patients with AKI. These findings suggest that determinants of RI are multiple. Renal circulatory response to sepsis estimated by Doppler ultrasonography cannot reliably be predicted simply from changes in systemic hemodynamics. As many factors influence its value, the interest in a single RI measurement at ICU admission to determine optimal MAP remains uncertain. PMID:22971333
Dewitte, Antoine; Coquin, Julien; Meyssignac, Bertrand; Joannès-Boyau, Olivier; Fleureau, Catherine; Roze, Hadrien; Ripoche, Jean; Janvier, Gérard; Combe, Christian; Ouattara, Alexandre
Background Acute respiratory failure (ARF) and severe sepsis (SS) are possible complications in patients with community-acquired pneumonia (CAP). The aim of the study was to evaluate prevalence, characteristics, risk factors and impact on mortality of hospitalized patients with CAP according to the presence of ARF and SS on admission. Methods This was a multicenter, observational, prospective study of consecutive CAP patients admitted to three hospitals in Italy, Spain, and Scotland between 2008 and 2010. Three groups of patients were identified: those with neither ARF nor SS (Group A), those with only ARF (Group B) and those with both ARF and SS (Group C) on admission. Results Among the 2,145 patients enrolled, 45% belonged to Group A, 36% to Group B and 20% to Group C. Patients in Group C were more severe than patients in Group B. Isolated ARF was correlated with age (p?0.001), COPD (p?0.001) and multilobar infiltrates (p?0.001). The contemporary occurrence of ARF and SS was associated with age (p?=?0.002), residency in nursing home (p?=?0.007), COPD (p?0.001), multilobar involvement (p?0.001) and renal disease (p?0.001). 4.2% of patients in Group A died, 9.3% in Group B and 26% in Group C, p?0.001. After adjustment, the presence of only ARF had an OR for in-hospital mortality of 1.85 (p?=?0.011) and the presence of both ARF and SS had an OR of 6.32 (p?0.001). Conclusions The identification of ARF and SS on hospital admission can help physicians in classifying CAP patients into three different clinical phenotypes.
ABSTRACT Infective endocarditis and kidney infections are serious complications of Staphylococcus aureus sepsis. We investigated the role of superantigens (SAgs) in the development of lethal sepsis, infective endocarditis, and kidney infections. SAgs cause toxic shock syndrome, but it is unclear if SAgs contribute to infective endocarditis and kidney infections secondary to sepsis. We show in the methicillin-resistant S. aureus strain MW2 that lethal sepsis, infective endocarditis, and kidney infections in rabbits are critically dependent on high-level SAgs. In contrast, the isogenic strain lacking staphylococcal enterotoxin C (SEC), the major SAg in this strain, is attenuated in virulence, while complementation restores disease production. SAgs’ role in infective endocarditis appears to be both superantigenicity and direct endothelial cell stimulation. Maintenance of elevated blood pressure by fluid therapy significantly protects from infective endocarditis, possibly through preventing bacterial accumulation on valves and increased SAg elimination. These data should facilitate better methods to manage these serious illnesses.
Salgado-Pabon, Wilmara; Breshears, Laura; Spaulding, Adam R.; Merriman, Joseph A.; Stach, Christopher S.; Horswill, Alexander R.; Peterson, Marnie L.; Schlievert, Patrick M.
The authors aimed to evaluate age-related differences in inflammation biomarkers during the first 72 h of hospitalization for sepsis. This was a secondary analysis of a prospective observational cohort of adult patients (n = 855) from 10 urban academic emergency departments with confirmed infection and two or more systemic inflammatory response syndrome criteria. Six inflammation-related biomarkers were analyzed-chemokine (CC-motif) ligand-23, C-reactive protein, interleukin-1 receptor antagonist, neutrophil gelatinase-associated lipocalin (NGAL), peptidoglycan recognition protein, and tumor necrosis factor receptor-1a (TNFR-1a)-measured at presentation and 3, 6, 12, 24, 48, or 72 h later. The median age was 56 (interquartile range, 43 - 72) years, and sepsis severity was 38% sepsis, 16% severe sepsis without shock, and 46% septic shock; the overall 30-day mortality was 12%. Older age was associated with higher sepsis severity: 41% of subjects aged 18 to 34 years had severe sepsis or septic shock compared with 71% for those aged 65 years or older (P < 0.001). In longitudinal models adjusting for demographics, comorbidities, and infection source, older age was associated with higher baseline values for chemokine (CC-motif) ligand-23, interleukin-1 receptor antagonist, NGAL, and TNFR-1a (all P < 0.05). However, older adults had higher mean values during the entire 72-h period only for NGAL and TNFR-1a and higher final 72-h values only for TNFR-1a. Adjustment or stratification by sepsis severity did not change the age-inflammation associations. Although older adults had higher levels of inflammation at presentation and an increased incidence of severe sepsis and septic shock, these age-related differences in inflammation largely resolved during the first 72 h of hospitalization. PMID:24978893
Ginde, Adit A; Blatchford, Patrick J; Trzeciak, Stephen; Hollander, Judd E; Birkhahn, Robert; Otero, Ronny; Osborn, Tiffany M; Moretti, Eugene; Nguyen, H Bryant; Gunnerson, Kyle J; Milzman, David; Gaieski, David F; Goyal, Munish; Cairns, Charles B; Rivers, Emanuel P; Shapiro, Nathan I
Survivors from sepsis present long-term cognitive deficits and some of these alterations resemble the pathophysiological mechanisms of neurodegenerative diseases. For this reason, we analyzed beta-amyloid peptide (A?) and synaptophysin levels in the brain of rats that survived from sepsis and their relation to cognitive dysfunction and to acute brain inflammation. Sepsis was induced in rats by cecal ligation and puncture, and 30 days after surgery, the hippocampus and prefrontal cortex were isolated just after cognitive evaluation by the inhibitory avoidance test. The immunocontent of A? and synaptophysin were analyzed by Western blot analysis. A? increased and synaptophysin decreased in septic animals both in the hippocampus and prefrontal cortex concurrent with the presence of cognitive deficits. Prefrontal levels of synaptophysin correlated to the performance in the inhibitory avoidance. Two different treatments known to decrease brain inflammation and oxidative stress when administered at the acute phase of sepsis decreased A? levels both in the prefrontal cortex and hippocampus, increased synaptophysin levels only in the prefrontal cortex, and improved cognitive deficit in sepsis-survivor animals. In conclusion, we demonstrated that brain from sepsis-survivor animals presented an increase in A? content and a decrease in synaptophysin levels and cognitive impairment. These alterations can be prevented by treatments aimed to decrease acute brain inflammation and oxidative stress. PMID:23990375
Schwalm, Mágada T; Pasquali, Matheus; Miguel, Samantha P; Dos Santos, João Paulo A; Vuolo, Francieli; Comim, Clarissa M; Petronilho, Fabrícia; Quevedo, João; Gelain, Daniel P; Moreira, José Cláudio F; Ritter, Cristiane; Dal-Pizzol, Felipe
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an energy metabolism-related enzyme in the glycolytic pathway. Recently, it has been reported that GAPDH has other physiological functions, such as apoptosis, DNA repair and autophagy. Some in vitro studies have indicated immunological aspects of GAPDH function, although there is no definite study discussing the advantage of GAPDH as a therapeutic target. Here, we show that GAPDH has an anti-inflammatory function by using a lipopolysaccharide (LPS)-induced, sepsis-related severe acute lung injury (ALI) mouse model, which is referred to as acute respiratory distress syndrome (ARDS) in humans. GAPDH pre-injected mice were protected from septic death, and their serum levels of proinflammatory cytokines were significantly suppressed. In lung tissue, LPS-induced acute injury and neutrophil accumulation were strongly inhibited by GAPDH pre-injection. Pulmonary, proinflammatory cytokine gene expression and serum chemokine expression in GAPDH pre-injected mice were also reduced. These data suggest the therapeutic potential of GAPDH for sepsis-related ALI/ARDS.
Takaoka, Yuki; Goto, Shigeru; Nakano, Toshiaki; Tseng, Hui-Peng; Yang, Shih-Ming; Kawamoto, Seiji; Ono, Kazuhisa; Chen, Chao-Long
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an energy metabolism-related enzyme in the glycolytic pathway. Recently, it has been reported that GAPDH has other physiological functions, such as apoptosis, DNA repair and autophagy. Some in vitro studies have indicated immunological aspects of GAPDH function, although there is no definite study discussing the advantage of GAPDH as a therapeutic target. Here, we show that GAPDH has an anti-inflammatory function by using a lipopolysaccharide (LPS)-induced, sepsis-related severe acute lung injury (ALI) mouse model, which is referred to as acute respiratory distress syndrome (ARDS) in humans. GAPDH pre-injected mice were protected from septic death, and their serum levels of proinflammatory cytokines were significantly suppressed. In lung tissue, LPS-induced acute injury and neutrophil accumulation were strongly inhibited by GAPDH pre-injection. Pulmonary, proinflammatory cytokine gene expression and serum chemokine expression in GAPDH pre-injected mice were also reduced. These data suggest the therapeutic potential of GAPDH for sepsis-related ALI/ARDS. PMID:24902773
Takaoka, Yuki; Goto, Shigeru; Nakano, Toshiaki; Tseng, Hui-Peng; Yang, Shih-Ming; Kawamoto, Seiji; Ono, Kazuhisa; Chen, Chao-Long
The question of whether hypersensitivity to streptococcal antigens plays a role in the pathogenesis of the nonsuppurative sequelae of streptococcal infections remains at present unclear. As a first step in the approach to this question, the degree of cellular reactivity of peripheral blood leucocytes to streptococcal antigens was investigated in a number of rheumatic fever patients, patients with uncomplicated streptococcal infections, as well as normal healthy subjects. Using the in vitro technique for the inhibition of capillary migration of peripheral blood leucocytes as an index of the degree of sensitivity to streptococcal antigens, the results indicate that patients with acute rheumatic fever exhibit an exaggerated cellular reactivity to these antigens and in particular to streptococcal cell membrane antigens. This abnormal response to streptococcal membrane antigens appears to persist in rheumatic subjects for at least 5 yr after the initial attack of rheumatic fever. Only Group A streptococcal membrane antigens elicited this unusual response in rheumatic subjects, since the cellular reactivity to Group C and D streptococcal membranes was the same in all groups. Patients with evidence of valvular disease exhibited the same degree of cellular reactivity to these antigens as did patients without clinical evidence of rheumatic heart disease. The nature of the antigens responsible for the observed cellular response remains unknown. Enzymatic treatment of streptococcal cell walls and membranes designed to remove type-specific M proteins did not alter the observed cellular reactivity to the streptococcal antigens. The finding that an abnormal cellular response to certain streptococcal antigens is present only in rheumatic patients suggests that cell-mediated factors may play an important role in the disease process.
Read, Stanley E.; Fischetti, Vincent A.; Utermohlen, Virginia; Falk, Rudolf E.; Zabriskie, John B.
Identifying neonates with sepsis is complicated by variability in clinical presentation. The incidence of early onset sepsis (EOS) resulting from invasive group B streptococcal (GBS) infections has been notably reduced by the widespread delivery of intrapartum antibiotic prophylaxis. Rates of EOS attributable to non-GBS etiologies have remained constant, and ampicillin-resistant Escherichia coli has become more prevalent. Late-onset sepsis (LOS) attributable to gram-positive organisms including coagulase-negative Staphylococci and Staphylococcus aureus is associated with increased morbidity and mortality among premature infants. Invasive candidiasis is an emerging cause of LOS, especially among infants who receive broad-spectrum antimicrobial agents. Prophylactic fluconazole administration to very low-birth-weight (VLBW) neonates during the first 6 weeks of life prevents invasive candidiasis in neonatal intensive care units (NICU) with high rates of fungal infections. Targeted fluconazole prophylaxis may be beneficial in VLBW neonates who receive care in NICUs with lower rates of invasive fungal infections. Assessment of immune function, neutrophil markers, acute phase reactants, and utilization of sepsis screening scores may contribute to the management of sepsis. Maternal decolonization, antimicrobial stewardship, early enteral feeding, and optimal infection control practices are potential practical strategies for reducing the burden of neonatal sepsis. PMID:23297182
Shane, Andi L; Stoll, Barbara J
We here evaluated the central dopaminergic response in sepsis survivor rats using the administration of D-amphetamine. Male Wistar rats underwent cecal ligation and perforation (CLP) or were sham-operated. After 10 days of recovery, rats received an intraperitoneal injection of D-amphetamine 0.5, 1 and 2 mg/kg or saline, and were subjected to the open field test. We did not observe alterations in locomotor and exploratory activities in CLP compared to sham group. Treatment with amphetamine 0.5 mg/kg did not have effect in sham and CLP groups; D-amphetamine 1 mg/kg increased locomotor and exploratory activities only in sham group, and D-amphetamine 2 mg/kg increased in both sham and CLP groups. We suggest that, in part, dopamine pathway may be altered in sepsis. PMID:19423170
Comim, Clarissa M; Constantino, Larissa S; Petronilho, Fabrícia; de Souza, Bruna; Barichello, Tatiana; Quevedo, João; Dal-Pizzol, Felipe
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 perm-selectivity. 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-? 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.
Xu, Chang; Chang, Anthony; Hack, Bradley K.; Eadon, Michael T.; Alper, Seth L.; Cunningham, Patrick N.
NLRP3 inflammasome activation contributes to acute lung injury (ALI), accelerating caspase-1 maturation, and resulting in IL-1? and IL-18 over-production. Heme oxygenase-1 (HO-1) plays a protective role in ALI. This study investigated the effect of hemin (a potent HO-1 inducer) on NLRP3 inflammasome in sepsis-induced ALI. The sepsis model of cecal ligation and puncture (CLP) was used in C57BL6 mice. In vivo induction and suppression of HO-1 were performed by pretreatment with hemin and zinc protoporphyrin IX (ZnPP, a HO-1 competitive inhibitor) respectively. CLP triggered significant pulmonary damage, neutrophil infiltration, increased levels of IL-1? and IL-18, and edema formation in the lung. Hemin pretreatment exerted inhibitory effect on lung injury and attenuated IL-1? and IL-18 secretion in serum and lung tissue. In lung tissues, hemin down-regulated mRNA and protein levels of NLRP3, ASC and caspase-1. Moreover, hemin reduced malondialdehyde and reactive oxygen species production, and inhibited NF-?B and NLRP3 inflammasome activity. Meanwhile, hemin significantly increased HO-1 mRNA and protein expression and HO-1 enzymatic activity. In contrast, no significant differences were observed between the CLP and ZnPP groups. Our study suggests that hemin-inhibited NLRP3 inflammasome activation involved HO-1, reducing IL-1? and IL-18 secretion and limiting the inflammatory response. PMID:24583148
Luo, Yun-peng; Jiang, Lei; Kang, Kai; Fei, Dong-sheng; Meng, Xiang-lin; Nan, Chuan-chuan; Pan, Shang-ha; Zhao, Ming-ran; Zhao, Ming-yan
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-1?, 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 responses. Conclusions Volemic status should be taken into account during RMs, since in this sepsis-induced ALI model hypervolemia promoted and potentiated lung injury compared to hypo- and normovolemia.
Sepsis rapidly activates the host inflammatory response and acute phase response. Severe sepsis, complicated by multiple organ failure, is associated with overwhelming inflammation and high mortality. We previously observed that zinc (Zn) deficiency significantly increases mortality in a mouse model of polymicrobial sepsis due to over-activation of the inflammatory response. In order to identify potential mechanisms that account for Zn-responsive effects, we generated whole exome expression profiles from the lung tissue of septic mice that were maintained on Zn modified diets. Based on systems analysis, we observed that Zn deficiency enhances the acute phase response and particularly the JAK-STAT3 pathway, resulting in increased serum amyloid A production. In vitro studies of primary hepatocytes and HepG2 cells substantiated that Zn-deficiency augments serum amyloid A production through up-regulation of the JAK-STAT3 and NF-?B pathways. In contrast, Zn inhibited STAT3 activation through the up-regulation of SHP1 activity. Collectively, these findings demonstrate that Zn deficiency enhances the acute phase response through up-regulation of the JAK-STAT3 pathway, thereby perpetuating increased inflammation that may lead to increased morbidity and mortality in response to sepsis. PMID:24732911
Liu, Ming-Jie; Bao, Shengying; Napolitano, Jessica R; Burris, Dara L; Yu, Lianbo; Tridandapani, Susheela; Knoell, Daren L
Acute kidney injury (AKI) is a common and major complication of sepsis. Sepsis-induced AKI is associated with higher morbidity and mortality. A prospective study was designed to include all the patients with a provisional diagnosis of sepsis with AKI admitted in our inten-sive care unit from August 2009 to September 2010. Detailed demographic data including various clinical parameters, co-morbidities, investigations, complications and outcome were entered in a designated proforma and were analyzed. A total of 53 subjects with the provisional diagnosis of sepsis with AKI were included in the study. The majority of patients (60.37%) were female. The mean age of the study population was 45.84 ± 20.5 years. Forty-nine percent of the subjects were <45 years old and 26.4% patients were >65 years. Among the co-morbid conditions, 9.4% subjects had diabetes mellitus type 2. Among the primary causes of AKI, 72% of the cases were due to medical causes, in which pneumonia was the major cause, and 28% were due to surgical causes, in which cholecystitis was the major cause. 47.1% cases expired, 11.3% subjects left against medical advice and 41.5% cases had favorable outcome. Among the expired cases, 20.7% subjects expired within 24 h; for others, the median hospital stay was four days. This prospective study showed that the major causes of AKI were medical illness and pneumonia. Mortality in sepsis-induced AKI is significantly high. This highlights the importance of prevention of AKI in sepsis by early and renal-friendly aggressive treatment of sepsis and the need for improvement in the management of such AKI cases. PMID:24969216
Ghimire, Madhav; Pahari, Bishnu; Sharma, Sanjib Kumar; Thapa, Lekhjung; Das, Gayatri; Das, G C
Material and Method The study comprised 52 pediatric patients with acute poststreptoccal glomerulonephritis; 29 males (56%) and 23 females (44%) with a mean age of 97±33 months. The control group consisted of 140 healthy individuals including 83 males (59%) and 57 females (41%) with a mean age of 42±13 years. Results: ACE genotypes were significantly different between the patients and
Ümit Çelik; Aytül Noyan; Gülen Atila; Selcuk Matyar; Aysun K. Bayazit; Mithat Büyükçelik; Hasan Dursun; Ali Anarat
Severe sepsis is a leading cause of death in the United States and the most common cause of death among critically ill patients in non-coronary intensive care units (ICU). Respiratory tract infections, particularly pneumonia, are the most common site of infection, and associated with the highest mortality. The type of organism causing severe sepsis is an important determinant of outcome, and gram-positive organisms as a cause of sepsis have increased in frequency over time and are now more common than gram-negative infections. Recent studies suggest that acute infections worsen pre-existing chronic diseases or result in new chronic diseases, leading to poor long-term outcomes in acute illness survivors. People of older age, male gender, black race, and preexisting chronic health conditions are particularly prone to develop severe sepsis; hence prevention strategies should be targeted at these vulnerable populations in future studies.
Mayr, Florian B; Yende, Sachin; Angus, Derek C
We describe the case of a 48-year-old man with an acute nephritis and respiratory failure. Clinical history, streptococcal antibody titres and renal biopsy led to a diagnosis of post-streptococcal glomerulonephritis. Respiratory investigations excluded pulmonary oedema and infection. We hypothesize that this man had a co-existing post-streptococcal glomerulonephritis and an immune-mediated pneumonitis. This is a very rare association, which was last described in 1982. PMID:21926403
Wiles, Kate S; Lee, Mihye; Brindle, Richard; Railton, Nicholas J; Clark, Robin J; Poller, David N; Mason, Juan C
Acute kidney injury (AKI) in the intensive care unit (ICU) is commonly caused by severe sepsis and septic shock. There is limited data regarding the incidence and outcomes of patients developing AKI treated with early goal-directed therapy (EGDT). Our aim was to observe the incidence and outcomes of patients with AKI in severe sepsis and septic shock, treated with EGDT as compared with historic controls. Study subjects included all adults admitted to the ICU with a diagnosis of severe sepsis and septic shock prior to (historic controls) and after introduction of EGDT (intervention group). Two groups were compared for incidence of AKI, length of ICU and hospital stay, incidence and requirement for renal replacement therapy, serum creatinine at discharge, maximum RIFLE (Risk, injury, failure, loss, end stage) in each group and 28-day mortality. Two groups were well matched for age, sex, (April 16, 2014) and acute physiological and chronic health evaluation (APACHE) II scores. We found no significant difference in the incidence of AKI (51% vs. 46%). There was no statistical difference in any of the above outcomes, including 28-day mortality in historic controls versus patients treated with EGDT. Septic AKI is a complex syndrome. The incidence and outcomes have not improved despite advances in sepsis management and EGDT. Very early detection of septic AKI and targeted therapies may improve outcomes. PMID:24821150
Ahmed, Wasim; Memon, Ahmed I; Rehmani, Rifat; Al Juhaiman, Abdulmajeed
Objectives The development of hyperglycemia and the use of early parenteral feeding are associated with poor outcomes in critically ill patients. We therefore examined the impact of exogenous glucose administration on the integrated metabolic function of endotoxemic mice using our recently developed frequently sampled intravenous glucose tolerance test (FSIVGTT). We next extended our findings using a cecal ligation and puncture (CLP) sepsis model administered early parenteral glucose support. Methods Male C57BL/6J mice, 8-12 weeks, were instrumented with chronic indwelling arterial and venous catheters. Endotoxemia was initiated with intra-arterial lipopolysaccharide (LPS; 1 mg/kg) in the presence of saline or glucose infusion (100 µL/hr), and an FSIVGTT was performed after five hours. In a second experiment, catheterized mice underwent CLP and the impact of early parenteral glucose administration on glucose homeostasis and mortality was assessed over 24 hrs. Measurements And MAIN RESULTS: Administration of LPS alone did not impair metabolic function, whereas glucose administration alone induced an insulin sensitive state. In contrast, LPS and glucose combined caused marked glucose intolerance and insulin resistance and significantly impaired pancreatic insulin secretion. Similarly, CLP mice receiving parenteral glucose developed fulminant hyperglycemia within 18 hrs (all > 600 mg/dl) associated with increased systemic cytokine release and 40% mortality, whereas CLP alone (85 ± 2 mg/dL) or sham mice receiving parenteral glucose (113 ± 3 mg/dL) all survived and were not hyperglycemic. Despite profound hyperglycemia, plasma insulin in the CLP glucose-infused mice (3.7 ± 1.2 ng/ml) was not higher than sham glucose infused mice (2.1 ± 0.3 ng/ml). Conclusions The combination of parenteral glucose support and the systemic inflammatory response in the acute phase of sepsis induces profound insulin resistance and impairs compensatory pancreatic insulin secretion, leading to the development of fulminant hyperglycemia.
Zou, Baobo; Guo, Lanping; Stefanovski, Darko; Alonso, Laura C.; Garcia-Ocana, Adolfo; O'Donnell, Christopher P.; McVerry, Bryan J.
The genetic mechanisms underlying the susceptibility to acute respiratory distress syndrome (ARDS) are poorly understood. We previously demonstrated that sphingosine 1-phosphate (S1P) and the S1P receptor S1PR3 are intimately involved in lung inflammatory responses and vascular barrier regulation. Furthermore, plasma S1PR3 protein levels were shown to serve as a biomarker of severity in critically ill ARDS patients. This study explores the contribution of single nucleotide polymorphisms (SNPs) of the S1PR3 gene to sepsis-associated ARDS. S1PR3 SNPs were identified by sequencing the entire gene and tagging SNPs selected for case-control association analysis in African- and ED samples from Chicago, with independent replication in a European case-control study of Spanish individuals. Electrophoretic mobility shift assays, luciferase activity assays, and protein immunoassays were utilized to assess the functionality of associated SNPs. A total of 80 variants, including 29 novel SNPs, were identified. Because of limited sample size, conclusive findings could not be drawn in African-descent ARDS subjects; however, significant associations were found for two promoter SNPs (rs7022797 -1899T/G; rs11137480 -1785G/C), across two ED samples supporting the association of alleles -1899G and -1785C with decreased risk for sepsis-associated ARDS. In addition, these alleles significantly reduced transcription factor binding to the S1PR3 promoter; reduced S1PR3 promoter activity, a response particularly striking after TNF-? challenge; and were associated with lower plasma S1PR3 protein levels in ARDS patients. These highly functional studies support S1PR3 as a novel ARDS candidate gene and a potential target for individualized therapy. PMID:23911438
Sun, Xiaoguang; Ma, Shwu-Fan; Wade, Michael S; Acosta-Herrera, Marialbert; Villar, Jesús; Pino-Yanes, Maria; Zhou, Tong; Liu, Bin; Belvitch, Patrick; Moitra, Jaideep; Han, Yoo-Jeong; Machado, Roberto; Noth, Imre; Natarajan, Viswanathan; Dudek, Steven M; Jacobson, Jeffrey R; Flores, Carlos; Garcia, Joe G N
Background Dementia increases the risk of death in older patients hospitalized for acute illnesses. However, the effect of dementia on the risks of developing acute organ dysfunction and severe sepsis as well as on the risk of hospital mortality in hospitalized older patients remains unknown, especially when treatments for these life-threatening situations are considered. Methods In this population-based cohort study, we analyzed 41,672 older (?65 years) patients, including 3,487 (8.4%) with dementia, from the first-time admission claim data between 2005 and 2007 for a nationally representative sample of one million beneficiaries enrolled in the Taiwan National Health Insurance Research Database. Outcomes included acute organ dysfunction, severe sepsis, and hospital mortality. The effect of dementia on outcomes was assessed using multivariable logistic regression. Results Dementia was associated with a 32% higher risk of acute organ dysfunction (adjusted odds ratio [aOR] 1.32, 95% confidence interval [CI] 1.19–1.46), a 50% higher risk of severe sepsis (aOR 1.50, 95% CI 1.32–1.69) and a 28% higher risk of hospital mortality (aOR 1.28, 95% CI 1.10–1.48) after controlling age, sex, surgical condition, comorbidity, principal diagnosis, infection status, hospital level, and length of hospital stay. However, the significant adverse effect of dementia on hospital mortality disappeared when life-support treatments, including vasopressor use, hemodialysis, mechanical ventilation, and intensive care, were also controlled. Conclusions In hospitalized older patients, the presence of dementia increased the risks of acute organ dysfunction, severe sepsis and hospital mortality. However, after intervention using life-support treatments, dementia only exhibited a minor role on short-term mortality.
Shen, Hsiu-Nien; Lu, Chin-Li; Li, Chung-Yi
Ignaz Semmelweiss made one of the most important contributions to modern medicine when he instituted handwashing in an obstetric clinic in Austria in 1847, decreasing mortality there from more than 10% to 2%. Unfortunately, puerperal sepsis remains a leading cause of maternal mortality throughout the world. Group A streptococcus (GAS), Streptococcus pyogenes, is an organism associated with high rates of morbidity and mortality from puerperal infections. When associated with sepsis, known as streptococcal toxic shock syndrome, mortality rates approach 30-50%. Group A streptococcus can cause invasive infections in the form of endometritis, necrotizing fasciitis, or streptococcal toxic shock syndrome. The clinical presentation of women with puerperal GAS infections is often atypical with extremes of temperature, unusual and vague pain, and pain in extremities. Toxin production by the organism may allow GAS to spread across tissue planes and cause necrosis while evading containment by the maternal immune system in the form of a discrete abscess. Endometrial aspiration in addition to blood cultures may be a useful rapid diagnostic tool. Imaging may appear normal and should not dissuade the clinician from aggressive management. When suspected, invasive GAS infections should be treated emergently with fluid resuscitation, antibiotic administration, and source control. The optimal antibiotic regimen contains penicillin and clindamycin. Source control may require extensive wound or vulvar debridement, hysterectomy, or a combination of these, which may be life-saving. The benefit of immunoglobulins in management of puerperal GAS infections is unclear. PMID:24785617
Anderson, Brenna L
To test the hypothesis that the interaction between nuclear factor-?B (NF-?B) and glucocorticoid receptor ? (GR?) is a key pathogenetic mechanism regulating the progression of systemic and pulmonary inflammation in sepsis and acute respiratory distress syndrome (ARDS), we used an ex vivo model of systemic inflammation. Naïve peripheral blood leukocytes (PBL) were exposed to longitudinal (days 1–10) plasma samples from
G. Umberto Meduri; Muthiah P. Muthiah; Pierluigi Carratu; Mahmoud Eltorky; George P. Chrousos
Background Sepsis-induced organ failure is the major cause of death in critical care units, and is characterized by a massive dysregulated inflammatory response and oxidative stress. We investigated the effects of treatment with antioxidants that protect mitochondria (MitoQ, MitoE, or melatonin) in a rat model of lipopolysaccharide (LPS) plus peptidoglycan (PepG)-induced acute sepsis, characterized by inflammation, mitochondrial dysfunction and early organ damage. Methods Anaesthetized and ventilated rats received an i.v. bolus of LPS and PepG followed by an i.v. infusion of MitoQ, MitoE, melatonin, or saline for 5 h. Organs and blood were then removed for determination of mitochondrial and organ function, oxidative stress, and key cytokines. Results MitoQ, MitoE, or melatonin had broadly similar protective effects with improved mitochondrial respiration (P<0.002), reduced oxidative stress (P<0.02), and decreased interleukin-6 levels (P=0.0001). Compared with control rats, antioxidant-treated rats had lower levels of biochemical markers of organ dysfunction, including plasma alanine amino-transferase activity (P=0.02) and creatinine concentrations (P<0.0001). Conclusions Antioxidants that act preferentially in mitochondria reduce mitochondrial damage and organ dysfunction and decrease inflammatory responses in a rat model of acute sepsis.
Lowes, D. A.; Webster, N. R.; Murphy, M. P.; Galley, H. F.
Background The storage duration of red blood cells transfused to critically ill patients is associated with increased morbidity and mortality. Whether the association exists between storage duration of red blood cells transfused to patients with sepsis and the risk of developing ALI/ARDS is unknown. We aimed to determine the association of the storage duration of red blood cells transfused to patients with sepsis and risk of developing acute lung injury in the subsequent 96 hours, with comparator trauma and nonsepsis/nontrauma groups. Methods We conducted a retrospective observational study of 96 transfused, critically ill patients with sepsis, 176 transfused, critically ill patients with traumatic injury, and 125 transfused, critically ill nontrauma, nonsepsis patients. The primary outcome was the development of ALI/ARDS up to 96 hours after transfusion. Results In 96 patients with sepsis, 49 (51%) patients developed ALI/ARDS. The median storage duration of transfused blood in the ALI/ARDS group was greater (24.5 days, interquartile range (IQR) 20–31) compared with the patients who did not develop ALI/ARDS (21 days, IQR 15–27, p = 0.018). Longer median storage duration was independently associated with an increased risk of developing ALI/ARDS in the subsequent 4 days (odds ratio 1.8, p = 0.028). The same association was not seen in the trauma or nonsepsis, nontrauma patients. Conclusions Transfusion of blood with longer median storage duration to patients with sepsis is associated with a higher risk of developing ALI up to 4 days after transfusion. This same association is not seen in other critically ill patient populations.
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-?B activity and inhibition of TNF-?, 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
Wang, Ning; Liu, Xin; Zheng, Xinchuan; Cao, Hongwei; Wei, Guo; Zhu, Yuanfeng; Fan, Shijun; Zhou, Hong; Zheng, Jiang
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-?) 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-? 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 LPS stimulation (P?=?0.009 and P?=?0.005). Moreover, the concentrations of TNF-? and IL-6 in cell culture supernatants were also significantly higher in the subjects with rs4755453GG genotype than in subjects with CG and CC genotype. None of the 14 tagSNPs showed associations with risk of death and severity among ALI cases. Conclusions Our findings indicated that common genetic variants in TRAF6 were significantly associated with susceptibility to sepsis-induced ALI in Chinese Han population. This was the first genetic evidence supporting a role for TRAF6 in ALI.
Acute neonatal parotitis (ANP) is a very rare disease. Most cases are managed conservatively; early antibiotics and adequate hydration may reduce the need for surgery. The most common cause of ANP is Staphylococcus aureus. We report a rare case of acute neonatal parotitis with late-onset septic shock due to Streptococcus agalactiae. The diagnosis was confirmed with ultrasound and isolation of Streptococcus agalactiae from blood culture. The patient was treated successfully with 10 days of intravenous antibiotics and supportive measures. Despite being rare, streptococcal ANP should be considered in the etiological diagnosis of neonatal sepsis. Early diagnosis and appropriate antibiotic might prevent serious complications.
High tidal volume mechanical ventilation-induced lung injury in rats is greater after acid instillation than after sepsis-induced acute lung injury, but does not increase systemic inflammation: an experimental study
Background To examine whether acute lung injury from direct and indirect origins differ in susceptibility to ventilator-induced lung injury (VILI) and resultant systemic inflammatory responses. Methods Rats were challenged by acid instillation or 24 h of sepsis induced by cecal ligation and puncture, followed by mechanical ventilation (MV) with either a low tidal volume (Vt) of 6 mL/kg and 5 cm H2O positive end-expiratory pressure (PEEP; LVt acid, LVt sepsis) or with a high Vt of 15 mL/kg and no PEEP (HVt acid, HVt sepsis). Rats sacrificed immediately after acid instillation and non-ventilated septic animals served as controls. Hemodynamic and respiratory variables were monitored. After 4 h, lung wet to dry (W/D) weight ratios, histological lung injury and plasma mediator concentrations were measured. Results Oxygenation and lung compliance decreased after acid instillation as compared to sepsis. Additionally, W/D weight ratios and histological lung injury scores increased after acid instillation as compared to sepsis. MV increased W/D weight ratio and lung injury score, however this effect was mainly attributable to HVt ventilation after acid instillation. Similarly, effects of HVt on oxygenation were only observed after acid instillation. HVt during sepsis did not further affect oxygenation, compliance, W/D weight ratio or lung injury score. Plasma interleukin-6 and tumour necrosis factor-? concentrations were increased after acid instillation as compared to sepsis, but plasma intercellular adhesion molecule-1 concentration increased during sepsis only. In contrast to lung injury parameters, no additional effects of HVt MV after acid instillation on plasma mediator concentrations were observed. Conclusions During MV more severe lung injury develops after acid instillation as compared to sepsis. HVt causes VILI after acid instillation, but not during sepsis. However, this differential effect was not observed in the systemic release of mediators.
Reversible posterior leukoencephalopathy syndrome is characterized by an acute, usually reversible encephalopathy, with radiological findings that mainly involve the white or grey matter of the parieto-occipital lobes. We report a case of post streptococcal glomerulonephritis presenting as reversible leukoencephalopathy syndrome. Immediate control of hypertension resulted in rapid and complete neurological recovery. PMID:20371895
Gupta, Shalu; Goyal, Vishnu Kumar; Talukdar, B
Objectives To characterize the use of mechanical ventilation in the emergency department (ED), with respect to ventilator settings, monitoring, and titration; and to determine the incidence of progression to acute lung injury (ALI) after admission, examining the influence of factors present in the ED on ALI progression. Methods This was a retrospective, observational cohort study of mechanically ventilated patients with severe sepsis and septic shock (June 2005 to May 2010), presenting to an academic ED with an annual census of >95,000 patients. All patients in the study (n = 251) were analyzed for characterization of mechanical ventilation use in the ED. The primary outcome variable of interest was the incidence of ALI progression after ICU admission from the ED and risk factors present in the ED associated with this outcome. Secondary analyses included ALI present in the ED and clinical outcomes comparing all patients progressing to ALI versus no ALI. To assess predictors of progression to ALI, statistically significant variables in univariable analyses at a p ? 0.10 level were candidates for inclusion in a bidirectional, stepwise, multivariable logistic regression analysis. Results Lung-protective ventilation was used in 68 patients (27.1%), and did not differ based on ALI status. Delivered tidal volume was highly variable, with a median tidal volume delivered of 8.8 mL/kg ideal body weight (IBW) (IQR 7.8 to 10.0), and a range of 5.2 to 14.6 mL/kg IBW. Sixty-nine patients (27.5%) in the entire cohort progressed to ALI after admission to the hospital, with a mean onset of 2.1 days (SD ± 1 day). Multivariable logistic regression analysis demonstrated that a higher body mass index, higher Sequential Organ Failure Assessment score, and ED vasopressor use were associated with progression to ALI. There was no association between ED ventilator settings and progression to ALI. Compared to patients who did not progress to ALI, patients progressing to ALI after admission from the ED had an increase in mechanical ventilator duration, vasopressor dependence, and hospital length of stay. Conclusions Lung-protective ventilation is uncommon in the ED, regardless of ALI status. Given the frequency of ALI in the ED, the progression shortly after ICU admission, and the clinical consequences of this syndrome, the effect of ED-based interventions aimed at reducing the sequelae of ALI should be investigated further.
Fuller, Brian M.; Mohr, Nicholas M.; Dettmer, Matthew; Kennedy, Sarah; Cullison, Kevin; Bavolek, Rebecca; Rathert, Nicholas; McCammon, Craig
Neonatal group B streptococcus meningitis causes neurologic morbidity and mortality. Cerebrovascular involvement is a common, poorly studied, and potentially modifiable pathologic process. We hypothesized that imaging patterns of focal brain infarction are recognizable in neonatal group B streptococcal meningitis. A consecutive case series included term neonates with the following: (1) bacterial meningitis, (2) acute group B streptococcal infection (positive cerebrospinal fluid/blood culture), (3) brain magnetic resonance imaging within 14 days, and (4) acute intraparenchymal focal infarctions (restricted diffusion). Lesions within known arterial territories were classified as arterial ischemic stroke. Clinical presentations, investigations, and neurologic outcomes were recorded. Eight newborns (50% female) with focal infarction were identified. Five presented early (<1 week), and all manifested clinical shock and elevated acute-phase reactants. Less than 50% had prenatal group B streptococcal screening, while 2 of 3 screened were negative. Two distinct patterns of focal infarction were identified: (1) deep perforator arterial stroke to basal ganglia, thalamus, and periventricular white matter (7/8, 88%), and (2) superficial injury with patchy, focal infarctions of the cortical surface (6/8, 75%). Outcomes (mean 23.8 months) were poor, with severe disability or death in 6/8 (75%). Recognizable stroke patterns contribute to severe neurologic outcomes and represent a potentially modifiable pathophysiologic process in neonatal group B streptococcal meningitis. PMID:21397170
Hernández, Marta I; Sandoval, Carmen C; Tapia, Jose L; Mesa, Tomas; Escobar, Raul; Huete, Isidro; Wei, Xing-Chang; Kirton, Adam
Dense deposit disease (DDD, formerly known as membranoproliferative glomerulonephritis (MPGN) type II) is a subtype of C3 glomerulopathy (C3G). Electron-dense deposits in the glomerular basement membrane characterize this glomerulonephritis. DDD typically presents with a nephritic syndrome that progresses to end-stage renal failure in 50 % of patients despite treatment. The pathogenic basis of DDD is uncontrolled activation of the alternative complement cascade although the potential triggering events that precipitate the development of complement dysregulation are typically unknown. There are isolated reports of an apparent association between streptococcal infection and DDD, as well as with MPGN types I and III. However, this association has not been deemed compelling, perhaps because so few cases have been reported or because of a current lack of evidence for a plausible hypothesis to connect a streptococcal infection with subsequent disease. In this report, we describe two patients with DDD who definitely had an antecedent streptococcal infection with the phenotype of acute post-streptococcal glomerulonephritis and whose initial kidney biopsy findings on light microscopy were indistinguishable from acute post-streptococcal glomerulonephritis. These patients had additional points of interest: recurrence of gross hematuria with recurrent streptococcal infections, slowly progressive course, persistently low serum C3 concentration, positive C3 nephritic factor, and positive risk alleles in the complement factor H (CFH) gene. Conclusion: We suggest that streptococcal infection may trigger DDD in individuals genetically predisposed by virtue of a disorder in complement regulation. PMID:24384791
Prasto, Julianne; Kaplan, Bernard S; Russo, Pierre; Chan, Elaine; Smith, Richard J; Meyers, Kevin E C
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.
It has been found by immunoelectrophoresis, that Group A streptococci release at least 20 distinct extracellular antigens in human tissues, as judged by naturally occurring antibodies present in normal pooled human gamma globulin. Several of these precipitin arcs have been identified with streptococcal antigens previously purified by electrophoresis and chromatography. Human gamma globulin, as well as several rheumatic fever sera, were shown to be remarkably potent in antistreptococcal antibodies, when compared to four horse antibody concentrates obtained by hyperimmunization with several streptococcal filtrates. A Group C streptococcal culture concentrate revealed 8 or 9 antigens for which corresponding antibodies were present in human gamma globulin.
Halbert, Seymour P.; Keatinge, Suzanne L.
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.
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.
Cunningham, Madeleine W.
Thirty cases of Candida sepsis occurring at Howard University Hospital between January 1983 and December 1985 were studied. A retrospective analysis was done to determine which risk factors or methods of treatment led to higher morbidity and mortality. Nosocomial infections with fungi are becoming more widespread as patients survive illnesses once deemed terminal. Patients had positive blood cultures for Candida accompanied by signs of systemic sepsis. Risk factors included diabetes, central hyperalimentation, malignancy, intraabdominal abscesses, and fistulae. The correlation between the total dose of amphotericin administered and patient recovery was analyzed.
Smallhorne, Violet E.; Siram, Suryanarayana M.; Walker, Mark
Sepsis often is characterized by an acute brain dysfunction, which is associated with increased morbidity and mortality. Its pathophysiology is highly complex, resulting from both inflammatory and noninflammatory processes, which may induce significant alterations in vulnerable areas of the brain. Important mechanisms include excessive microglial activation, impaired cerebral perfusion, blood-brain-barrier dysfunction, and altered neurotransmission. Systemic insults, such as prolonged inflammation, severe hypoxemia, and persistent hyperglycemia also may contribute to aggravate sepsis-induced brain dysfunction or injury. The diagnosis of brain dysfunction in sepsis relies essentially on neurological examination and neurological tests, such as EEG and neuroimaging. A brain MRI should be considered in case of persistent brain dysfunction after control of sepsis and exclusion of major confounding factors. Recent MRI studies suggest that septic shock can be associated with acute cerebrovascular lesions and white matter abnormalities. Currently, the management of brain dysfunction mainly consists of control of sepsis and prevention of all aggravating factors, including metabolic disturbances, drug overdoses, anticholinergic medications, withdrawal syndromes, and Wernicke's encephalopathy. Modulation of microglial activation, prevention of blood-brain-barrier alterations, and use of antioxidants represent relevant therapeutic targets that may impact significantly on neurologic outcomes. In the future, investigations in patients with sepsis should be undertaken to reduce the duration of brain dysfunction and to study the impact of this reduction on important health outcomes, including functional and cognitive status in survivors. PMID:23718252
Sonneville, Romain; Verdonk, Franck; Rauturier, Camille; Klein, Isabelle F; Wolff, Michel; Annane, Djillali; Chretien, Fabrice; Sharshar, Tarek
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.
Spaulding, Adam R.; Salgado-Pabon, Wilmara; Kohler, Petra L.; Horswill, Alexander R.; Leung, Donald Y. M.
Patient: Male, 0 Final Diagnosis: Purpura fulminans Symptoms: Fever • letargy Medication: — Clinical Procedure: — Specialty: Pediatrics and Neonatology Objective: Rare disease Background: Neonatal purpura fulminans (PF) is a rare but frequently fatal disorder associated with high morbidity and mortality. It may be congenital, as a result of protein C and S deficiency, or acquired due to severe infection. Gram-negative organisms and Staphylococcus species are the most common causes of the acute infectious type, and a few cases of causative neonatal group B Streptococcus (GBS) disease have been reported worldwide. Case Report: We present a full-term male neonate with purpura fulminans secondary to early-onset group B streptococcal (GBS) infection. The mother brought the infant to the emergency department at the age of 43 hours of life, with fever (39.5°C) and lethargy. Neonatal sepsis was suspected, and he was immediately started on intravenous ampicillin and gentamicin. The initial workup revealed disseminated intravascular coagulopathy, and both blood and CSF cultures grew GBS. He had normal levels of protein C and protein S for his age. The infant died 48 hours after admission due to multiorgan system failure despite aggressive neonatal intensive care support. Conclusions: Neonatal PF secondary to early-onset GBS infection is a fatal condition that should not be missed. Screening pregnant women for GBS colonization and use of protocols for preventing perinatal GBS infection is considered the most important preventive measure of this fatal condition, especially among Saudi women, who have a relatively high rate of GBS infection.
AlBarrak, May; Al-Matary, Abdulrahman
An increased incidence and severity of invasive group A streptococcus (GAS) infections over the past decade have been reported by several authors, but GAS remains an uncommon cause of bacterial meningitis. The aim of this study was to describe and analyze the clinical and biological data of GAS meningitis by reporting 10 new cases of pediatric GAS meningitis and making a literature review. The mean age of patients, seven girls and three boys, was 3 years. There was a history of preexisting or concomitant community-acquired infection in five patients over 10. The outcome was fatal in two cases. All patients received an initial empirical antimicrobial therapy with a third generation cephalosporin switched in six cases to amoxicillin. The prognosis for this type of streptococcal meningitis is usually good, but death may occur even in children without any identified risk factor for severe infection. PMID:23102429
Jouhadi, Z; Sadiki, H; Lehlimi, M; Honsali, Z; Najib, J; Zerouali, K; Belabess, H; Mdaghri, N
Background Organ dysfunction consequent to infection (‘severe sepsis’) is the leading cause of admission to an intensive care unit (ICU). In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on organ function. The aims of the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial are to identify whether a 24-hour infusion of levosimendan will improve organ dysfunction in adults who have septic shock and to establish the safety profile of levosimendan in this group of patients. Methods/Design This is a multicenter, randomized, double-blind, parallel group, placebo-controlled trial. Adults fulfilling the criteria for systemic inflammatory response syndrome due to infection, and requiring vasopressor therapy, will be eligible for inclusion in the trial. Within 24 hours of meeting these inclusion criteria, patients will be randomized in a 1:1 ratio stratified by the ICU to receive either levosimendan (0.05 to 0.2 ?g.kg-1.min-1 or placebo for 24 hours in addition to standard care. The primary outcome measure is the mean Sequential Organ Failure Assessment (SOFA) score while in the ICU. Secondary outcomes include: central venous oxygen saturations and cardiac output; incidence and severity of renal failure using the Acute Kidney Injury Network criteria; duration of renal replacement therapy; serum bilirubin; time to liberation from mechanical ventilation; 28-day, hospital, 3 and 6 month survival; ICU and hospital length-of-stay; and days free from catecholamine therapy. Blood and urine samples will be collected on the day of inclusion, at 24 hours, and on days 4 and 6 post-inclusion for investigation of the mechanisms by which levosimendan might improve organ function. Eighty patients will have additional blood samples taken to measure levels of levosimendan and its active metabolites OR-1896 and OR-1855. A total of 516 patients will be recruited from approximately 25 ICUs in the United Kingdom. Discussion This trial will test the efficacy of levosimendan to reduce acute organ dysfunction in adult patients who have septic shock and evaluate its biological mechanisms of action. Trial registration Current controlled trials ISRCTN12776039 (19 September 2013)
Sepsis is a systemic, deleterious host response to widespread infection. Patients with sepsis will have documented or suspected infection which can progress to a state of septic shock or acute organ dysfunction. Since sepsis is responsible for nearly 3 million cases per year in China and severe sepsis is a common, expensive fatal condition in America, developing new therapies becomes a significant and worthwhile challenge. Clinical research has shown that sepsis-associated immunosuppression plays a central role in patient mortality, and targeted immune-enhancing therapy may be an effective treatment approach in these patients. As part of the inflammatory response during sepsis, there are elevations in the number of myeloid-derived suppressor cells (MDSCs). MDSCs are a heterogeneous population of immature myeloid cells that possess immunosuppressive activities via suppressing T-cell proliferation and activation. The role of MDSCs in sepsis remains uncertain. Some believe activated MDSCs are beneficial to the sepsis host by increasing innate immune responses and antimicrobial activities, while others think expansion of MDSCs leads to adaptive immune suppression and secondary infection. Herein, we discuss the complex role of MDSCs in immune regulation during sepsis, as well as the potential to target these cells for therapeutic benefit.
Qin, Chaojin; Shu, Qiang
Scoring systems for prediction of mortality in patients with intensive care unit-acquired sepsis: a comparison of the Pitt bacteremia score and the Acute Physiology and Chronic Health Evaluation II scoring systems.
This study compares the effectiveness of the Pitt bacteremia score, the Charlson weighted index of comorbidity, and the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring systems for the prediction of mortality in intensive care unit (ICU) patients with sepsis using the retrospective observational method on 134 patients with ICU-acquired sepsis. The statistical analyses show several important findings. First, Pitt bacteremia score is significantly correlated with the APACHE II scoring system (correlation coefficient = 0.738, P < 0.001). Second, the APACHE II scoring system, the Pitt bacteremia score, and the Charlson weighted index of comorbidity are independently correlated with mortality. Third, the Pitt bacteremia score and the APACHE II scores are positively related to mortality in patients with ICU-acquired sepsis. As the result of the analyses, the mortality rate in patients with sepsis in the ICU is better predicted with the Pitt bacteremia score because it provides better estimation of sensitivity and specificity than the APACHE II scoring system and the Charlson weighted index of comorbidity. PMID:18636041
Rhee, Ji-Young; Kwon, Ki Tae; Ki, Hyun Kyun; Shin, Sang Yop; Jung, Dong Sik; Chung, Doo-Ryeon; Ha, Byoung-Chun; Peck, Kyong Ran; Song, Jae-Hoon
Bradykinesia and rigidity developed in a 10-year-old girl during an episode of Sydenham chorea. These parkinsonian features improved over 6 months. Serum analysis demonstrated elevated anti-streptolysin-O and anti-basal ganglia antibodies. We suggest that autoimmune antibodies may cause remitting parkinsonian signs subsequent to streptococcal tonsillitis as part of the spectrum of poststreptococcal CNS disease. PMID:12970645
Ben-Pazi, Hilla; Livne, Amir; Shapira, Yehuda; Dale, Russell C
Otherwise uncomplicated infections with Streptococcus pyogenes can cause two insidious immune sequelae known as post-streptococcal glomerulonephritis (PSGN) and acute rheumatic fever (ARF). These diseases follow with a latency of a few weeks or months after primary infection and are responsible for high mortality and morbidity. PSGN has also been linked to infections with group C streptococci of the species S. equi ssp. zooepidemicus (SESZ). Moreover, there are some indications that infection with group C and G streptococci (GCGS) of the subspecies Streptococcus dysgalactiae ssp. equisimilis (SDSE) leads to ARF. Despite decades of research, the picture of the molecular pathogenesis of streptococcal immune sequelae resembles a jigsaw puzzle. Herein we try to put some of the puzzle bits together that have been collected till date. PMID:23212184
Nitsche-Schmitz, D Patric; Chhatwal, Gursharan S
We present the case of a 29-year-old type 1 diabetic patient with the diagnosis of acute post-streptococcal glomerulonephritis. The incidence of this textbook example of acute glomerulonephritis has dropped dramatically in the developed world during the past decades due to the more widespread use of antibiotics. However, the present case illustrates that it is not an extinct disease and that clinicians should be aware of this entity. Particular attention is needed for the fact that the clinical context in which the disease occurs may be different from the classical "post-angina" presentation. PMID:24156223
Demuynck, M; Lerut, E; Kuypers, D; Evenepoel, P; Claes, K; Naesens, M; Meijers, B; Vanrenterghem, Y; Bammens, B
Previous reports have shown the presence of streptococcal erythrogenic exotoxin type B (ETB), leukocyte infiltration, interleukin-8\\u000a (IL-8), transforming growth factor-beta (TGF-?) and glomerular proliferation in renal biopsies from patients with acute post-streptococcal\\u000a glomerulonephritis (APSGN). In addition, increased levels of plasma interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF?),\\u000a and urinary IL-6, have also been reported in this disease. To determine
Ninoska Viera; Adriana Pedreanez; Jaimar Rincon; Jesus Mosquera
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
Kleinpell, Ruth; Schorr, Christa A
Direct hemoperfusion using polymyxin B-immobilized column (PMX-DHP) is recognized as an effective treatment for septic shock. However, whether its efficacy is limited to cardiovascular dysfunction remains unknown. Therefore, we planned to examine the effects of PMX-DHP in an acute lung injury model. [Materials and methods] Rats were assigned to either PMX-DHP group or control group (n= 7 in each). A lung injury was created by the intratracheal instillation of LPS. In PMX-DHP group, an arteriovenous extracorporeal circuit using PMX column was applied for three hours. The same procedure using a dummy column was applied in control group. The lung microcirculation was observed, and adherent leukocytes, RBC velocity, and the arterial PaO2 were calculated. Pathological changes and the wet/dry weight ratio of the lungs were examined. [Results] Adherent leukocytes and platelets to the lung venules were recognized at 3 hours, and their numbers increased over time. Treatment with PMX-DHP significantly suppressed these events and helped maintenance of the blood flow and PaO2 levels. The lung edema and the histologic damages were also suppressed. [Conclusions] PMX-DHP improved the microcirculation by suppressing leukocyte and platelet adhesion. PMX-DHP had beneficial effects in a model for acute lung injury. PMID:24516349
Iba, Toshiaki; Nagaoka, Isao; Yamada, Atsushi; Nagayama, Masataka; Miki, Takahiro
Recent evidence suggests that the pathogenesis of Sydenham's chorea following group A streptococcal infection is due to antibodies which develop due to the infection and infiltrate the brain and basal ganglia. Antibodies present in acute chorea react with the surface of neuronal cells and signal the induction of calcium calmodulin dependent protein kinase II with elevation of tyrosine hydroxylase and
Christine A. Kirvan; Susan E. Swedo; David Kurahara; Madeleine W. Cunningham
Movement disorders as postinfectious manifestation of group A streptococcal infections have been reported and are thought to occur on an autoimmune basis. We describe an unusual case of multifocal myoclonus following strep throat infection. Clinical description and chart review were the method used. A 10-year-old boy developed focal myoclonus involving his right arm and shoulder 1 week after streptococcal throat
Penelope Smyth; D. Barry Sinclair
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, biol...
J. R. Fletcher
Background: A causal relationship of common streptococcal infections and childhood neuropsychiatric disorders has been postulated. Objective: To test the hypothesis of an increased rate of streptococcal infections preceding the onset of neuropsychiatric disorders. Methods: Case-control study of a large primary care database comparing the rate of possible streptococcal infections in patients aged 2–25 years with obsessive-compulsive disorder (OCD), Tourette syndrome (TS), and tics with that in controls matched for age, gender, and practice (20 per case). We also examined the influence of sociodemographic factors. Results: There was no overall increased risk of prior possible streptococcal infection in patients with a diagnosis of OCD, TS, or tics. Subgroup analysis showed that patients with OCD had a slightly higher risk than controls of having had possible streptococcal infections without prescription of antibiotics in the 2 years prior to the onset of OCD (odds ratio 2.59, 95% confidence interval 1.18, 5.69; p = 0.02). Cases with TS or tics were not more likely to come from more affluent or urban areas, but more cases lived in areas with a greater proportion of white population (p value for trend = 0.05). Conclusions: The present study does not support a strong relationship between streptococcal infections and neuropsychiatric syndromes such as obsessive-compulsive disorder and Tourette syndrome. However, it is possible that a weak association (or a stronger association in a small susceptible subpopulation) was not detected due to nondifferential misclassification of exposure and limited statistical power. The data are consistent with previous reports of greater rates of diagnosis of Tourette syndrome or tics in white populations. GLOSSARY CI = confidence interval; GP = general practice; OCD = obsessive-compulsive disorder; OR = odds ratio; PANDAS = pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; SI = streptococcal infection; TS = Tourette syndrome.
Schrag, A; Gilbert, R; Giovannoni, G; Robertson, M M.; Metcalfe, C; Ben-Shlomo, Y
Introduction Biomarkers can be useful for identifying or ruling out sepsis, identifying patients who may benefit from specific therapies or assessing the response to therapy. Methods We used an electronic search of the PubMed database using the key words "sepsis" and "biomarker" to identify clinical and experimental studies which evaluated a biomarker in sepsis. Results The search retrieved 3370 references covering 178 different biomarkers. Conclusions Many biomarkers have been evaluated for use in sepsis. Most of the biomarkers had been tested clinically, primarily as prognostic markers in sepsis; relatively few have been used for diagnosis. None has sufficient specificity or sensitivity to be routinely employed in clinical practice. PCT and CRP have been most widely used, but even these have limited ability to distinguish sepsis from other inflammatory conditions or to predict outcome.
Objective Sepsis-associated delirium is a common and poorly understood neurological complication of sepsis. This review provides an\\u000a update of the diagnostic criteria and treatment strategies and the current knowledge about the mechanisms involved in sepsis\\u000a associated brain dysfunction.\\u000a \\u000a \\u000a \\u000a Data sources Articles published between 1981 and 2006 were identified through a Medline search for “encephalopathy” and “sepsis” and by\\u000a hand searching of articles cited in
Marion Ebersoldt; Tarek Sharshar; Djillali Annane
Sepsis is a complex syndrome with its wide spectrum of severity, and is one of the most common causes of death in Critical Care Units. The Surviving Sepsis campaign launched in 2004, is aimed at improving diagnosis, management and survival of patients with sepsis. Care bundles are a group of best evidence based interventions which when instituted together, gives maximum outcome benefit. Care Bundles are simple, uniform and have universal practical applicability. Surviving Sepsis campaign guidelines in 2008 incorporated two sepsis care bundles. The Resuscitation bundle includes seven key interventions to be achieved in 6-h while four interventions have to be completed within 24-h in the Management bundle. Compliance with a bundle implies achieving all the specified goals in that bundle. Limitations to care bundles include the quality of the evidence on which they are based, and that the relative contributions of each element of the bundle are not known. Several observational studies support the hypothesis that sepsis care bundles have an important role in improving outcomes from sepsis. Critical Care Units should develop management strategies to ensure compliance with the sepsis bundles in order to decrease hospital mortality due to severe sepsis.
Khan, Parvez; Divatia, J. V.
Objectives (1) To describe the epidemiology of neonatal group B streptococcal (GBS) disease over five years (1997–2001) in the Netherlands, stratified for proven and probable sepsis and for very early (<12?h), late early (12?h – <7?days) and late (7–90?days) onset sepsis. (2) To evaluate the effect of the introduction in January 1999 of guidelines for prevention of early onset GBS disease based on risk factors. Methods Data on cases were collected in collaboration with the Dutch Paediatric Surveillance Unit and corrected for under?reporting by the capture?recapture technique. Results Total incidence of proven very early onset, late early onset and late onset GBS sepsis was 0.32, 0.11 and 0.14 per 1000 live births, respectively, and of probable very early onset, late early onset and late onset GBS sepsis was 1.10, 0.18 and 0.02 per 1000 live births, respectively. Maternal risk factors were absent in 46% of the proven early onset cases. Considerably more infants with proven GBS sepsis were boys. 64% of the infants with proven very early onset GBS sepsis were first borns compared with 47% in the general population. After the introduction of guidelines the incidence of proven early onset sepsis decreased considerably from 0.54 per 1000 live births in 1997–8 to 0.36 per 1000 live births in 1999–2001. However, there was no decrease in the incidence of meningitis and the case fatality rate in the first week of life. The incidence of late onset sepsis also remained unchanged. Conclusion After the introduction prevention guidelines based on risk factors there has been a limited decrease in the incidence of proven early onset GBS sepsis in the Netherlands. This study therefore recommends changing the Dutch GBS prevention guidelines.
Trijbels-Smeulders, M; de Jonge, G A; Jong, P C M Pasker-de; Gerards, L J; Adriaanse, A H; van Lingen, R A; Kollee, L A A
Sepsis is one of the leading causes of death worldwide. While the management of critically ill patients with sepsis is certainly better now compared to 20 years ago, sepsis-associated mortality remains unacceptably high. Annual deaths from sepsis in both children and adults far surpass the number of deaths from acute myocardial infarction (AMI), stroke, or cancer. Given the substantial toll that sepsis takes worldwide, prevention of sepsis remains a global priority. Multiple effective prevention strategies exist. Antibiotic prophylaxis, immunizations, and healthcare quality improvement initiatives are important means through which we may reduce the morbidity and mortality from sepsis around the world. Inclusion of these strategies in a coordinated and thoughtful campaign to reduce the global burden of sepsis is necessary for the improvement of pediatric health worldwide.
Riley, Carley; Wheeler, Derek S.
The burden of thromboembolism (TE) in severe sepsis is largely unknown. We assessed the prevalence of venous and arterial TE in patients with severe sepsis over a four-week period. We performed a retrospective analysis of a pooled database of three randomized, placebo-controlled trials of two novel pharmacological agents for the treatment of severe sepsis, drotrecogin alfa (activated) (DrotAA) and secretory phospholipase A2 inhibitor (sPLA(2)I). The study was conducted at intensive care units of the participating institutions. A total of 2,649 patients with known or suspected infection and sepsis-associated acute organ dysfunction were enrolled in the three trials and were assigned to treatment groups (DrotAA=850; sPLA2I=578; placebo=1221). The database was queried for venous and arterial TE, using investigator reports of serious adverse events. Eighty-four of 2,649 patients (3.2%; 95% confidence interval, 2.5% to 3.9%) developed at least one thromboembolic event over 28 days. Nearly three-quarters of episodes were atheroembolic (n=62); 25% involved the deep venous system (n=25). Ischemic stroke (n=30) and venous thromboembolism (n=25) each occurred in about 1% of patients. Ischemic stroke and acute coronary syndrome had a higher peak incidence during the first five days compared to venous TE onset, which was more constant over the 28-day period. Subgroup analysis by pooled treatment groups yielded TE rates of 2.0% (DrotAA), 3.5% (placebo), and 4.0% (sPLA2I), respectively. Clinically manifest TE occurred in about 3% of severe sepsis patients treated in the intensive care unit over a 28-day period. Arterial TE may be more common than previously recognized. More accurate estimates of TE prevalence and relationship to sepsis await future studies. PMID:18449418
Levine, Robert L; LeClerc, Jacques R; Bailey, Joan E; Monberg, Matthew J; Sarwat, Samiha
Sepsis is an unusual systemic reaction to what is sometimes an otherwise ordinary infection, and it probably represents a pattern of response by the immune system to injury. A hyper-inflammatory response is followed by an immunosuppressive phase during which multiple organ dysfunction is present and the patient is susceptible to nosocomial infection. Biomarkers to diagnose sepsis may allow early intervention which, although primarily supportive, can reduce the risk of death. Although lactate is currently the most commonly used biomarker to identify sepsis, other biomarkers may help to enhance lactate’s effectiveness; these include markers of the hyper-inflammatory phase of sepsis, such as pro-inflammatory cytokines and chemokines; proteins such as C-reactive protein and procalcitonin which are synthesized in response to infection and inflammation; and markers of neutrophil and monocyte activation. Recently, markers of the immunosuppressive phase of sepsis, such as anti-inflammatory cytokines, and alterations of the cell surface markers of monocytes and lymphocytes have been examined. Combinations of pro- and anti-inflammatory biomarkers in a multi-marker panel may help identify patients who are developing severe sepsis before organ dysfunction has advanced too far. Combined with innovative approaches to treatment that target the immunosuppressive phase, these biomarkers may help to reduce the mortality rate associated with severe sepsis which, despite advances in supportive measures, remains high.
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.
Phelps, Hilary A.; Runft, Donna L.
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
Gulizia, J. M.; Cunningham, M. W.; McManus, B. M.
Competence for natural genetic transformation is widespread in the genus Streptococcus. The current view is that all streptococcal species possess this property. In addition to the proteins required for DNA uptake and recombination, competent streptococci secrete muralytic enzymes termed fratricins. Since the synthesis and secretion of these cell wall-degrading enzymes are always coupled to competence development in streptococci, fratricins are believed to carry out an important function associated with natural transformation. This minireview summarizes what is known about the properties of fratricins and discusses their possible biological roles in streptococcal transformation.
Berg, Kari Helene; Bi?rnstad, Truls Johan; Johnsborg, Ola
Rationale: The risk of cardiovascular events after severe sepsis is not known, and these events may explain increased long-term mortality in survivors of severe sepsis. Objectives: To determine whether survivors of severe sepsis hospitalization have high long-term risk of cardiovascular events. We examined whether higher risk is due to severe sepsis hospitalization or poor prehospitalization health status, and if the higher risk is also observed in patients hospitalized for infectious and noninfectious reasons, and in other critically ill patients. Methods: Unmatched and matched-cohort analyses of Medicare beneficiaries. For unmatched analysis, we compared patients with severe sepsis admitted to the intensive care unit (ICU) and survived hospitalization (n = 4,179) to unmatched population control subjects (n = 819,283). For matched analysis, we propensity-score-matched each patient with severe sepsis to four control subjects (population, hospitalized, non-severe sepsis ICU control subjects, and infection hospitalization). Primary outcome was 1-year incidence rate of hospitalization for cardiovascular events. Measurements and Main Results: Cardiovascular events were common among patients discharged alive after severe sepsis hospitalization (29.5%; 498.2 events/1,000 person-years). Survivors of severe sepsis had a 13-fold higher risk of cardiovascular events compared with unmatched control subjects (498.2 vs. 36 events/1,000 person-years; P < 0.0001), and a 1.9-fold higher risk compared with matched-population control subjects (P < 0.0001). Survivors of severe sepsis had 1.1-fold higher risk compared with matched hospitalized patients and infection hospitalizations (P = 0.002 and 0.001) and similar risk compared with matched-ICU control subjects. Conclusions: Survivors of severe sepsis have high risk of cardiovascular events. The higher risk is mainly due to poor prehospitalization health status, and is also seen in a broader population of acutely ill patients. PMID:24456535
Yende, Sachin; Linde-Zwirble, Walter; Mayr, Florian; Weissfeld, Lisa A; Reis, Steven; Angus, Derek C
We describe an outbreak of an illness with fever, mono-, pauci- or polyarticular arthritis, and high antideoxyribonuclease B (ADNB) titres in 11 patients. Two patients had concomitant non-purulent conjunctivitis and one had endogenous endophthalmitis. There was no clinical or echocardiographic (6 patients) evidence of carditis. Blood culture grew Group A beta haemolytic streptococci in one patient. A simultaneous synovial fluid culture in this patient and similar cultures in four more patients yielded no microorganism. Most patients recovered completely, but one developed rheumatoid factor negative spondyloarthropathy. Monoarticular arthritis in several patients, the absence of carditis, and the presence of high ADNB titres without high anti-streptolysin O titres indicate that this was not acute rheumatic fever but post-streptococcal reactive arthritis (PSRA). PMID:9277035
Madhuri, V; Mathai, E; Brahmadathan, K N; Korula, R J; John, T J
Platelet dysfunction and thrombocytopenia are common responses to sepsis, but how sepsis changes platelet function is not completely understood. This is due, in part, to our lack of understanding of how sepsis alters platelet protein patterns. The aim of the present study, accordingly, was to investigate the response of the platelet proteome to sepsis. We applied proteomic technology to analyze platelet samples of rats with sepsis. Rats were divided into two groups: 1) sham surgery and 2) sepsis induced by cecal ligation and puncture (CLP) surgery. Platelet samples were collected from surviving rats 12 and 24h after surgery, and platelet proteins were separated by two-dimensional electrophoresis (2-DE). Differentially expressed proteins were identified by mass spectrometry (MS). In the CLP group, there were 20 spots that were statistically significantly different at 12h. Of these spots, 16 spots were increased and four spots were decreased. At 24h, there were six spots increased in the CLP group. Of the 26 spots, 12 proteins associated with platelet activation, acute phase proteins, cytoskeleton structure, and energy production were identified. Of interest, alpha-1-antitrypsin precursor (AAT) and ATP synthase beta subunit (ATPB) were both increased at 12 and 24h of sepsis by 2-DE and immunoblotting. By providing the platelet profiles, our results demonstrate that this proteomic approach brings us closer to understanding how platelet dysfunction develops after sepsis. PMID:22014900
Hu, Jin-Yu; Li, Chang-Lin; Wang, Ying-Wei
Sepsis is a serious clinical condition that represents a patient’s response to a severe infection and has a very high mortality rate. Normal immune and physiologic responses eradicate pathogens, and the pathophysiology of sepsis is due to the inappropriate regulation of these normal reactions. In an ideal scenario, the first pathogen contact with the inflammatory system should eliminate the microbe and quickly return the host to homeostasis. The septic response may accelerate due to continued activation of neutrophils and macrophages/monocytes. Upregulation of lymphocyte costimulatory molecules and rapid lymphocyte apoptosis, delayed apoptosis of neutrophils, and enhanced necrosis of cells/tissues also contribute to the pathogenesis of sepsis. The coagulation system is closely tied to the inflammatory response, with cross talk between the two systems driving the dysregulated response. Biomarkers may be used to help diagnose patients with sepsis, and they may also help to identify patients who would benefit from immunomodulatory therapies.
Stearns-Kurosawa, Deborah J.; Osuchowski, Marcin F.; Valentine, Catherine; Kurosawa, Shinichiro; Remick, Daniel G.
Sepsis is currently a leading cause of death in hospital intensive care units. Previous studies suggest that the pathophysiology of sepsis involves the hyperactivation of complex proinflammatory cascades that include the activation of various immune cells and the exuberant secretion of proinflammatory cytokines by these cells. Natural killer T-cells (NKTs) are a sublineage of T cells that share characteristics of conventional T cells and NK cells and bridge innate and adaptive immunity. More recently, NKT cells have been implicated in microbial immunity, including the onset of sepsis. Moreover, apolipoprotein E (apoE), a component of triglyceride-rich lipoproteins, has been shown to be protective in endotoxemia and gram-negative infections in addition to its well-known role in lipid metabolism. Here, we will review the role of NKT cells in sepsis and septic shock, the immunoregulatory role of apoE in the host immune response to infection, and propose a mechanism for this immunoregulation.
Leung, Briana; Harris, Hobart W.
\\u000a The transition from sepsis to severe life-threatening disease frequently develops well before admission to an intensive care\\u000a unit (ICU), often in the pre-hospital setting, the emergency department (ED), general medical-surgical floors, operating room\\u000a or the outpatient clinic setting. One would hope that as soon as possible after the sepsis syndrome occurs, treatment with\\u000a resuscitation fluids, restoration of adequate oxygen delivery
Emanuel P. Rivers; David Amponsah; Victor Coba
Sepsis remains a common, serious, and heterogeneous clinical entity that is difficult to define adequately. Despite its importance as a public health problem, efforts to develop and gain regulatory approval for a specific therapeutic agent for the adjuvant treatment of sepsis have been remarkably unsuccessful. One step in the critical pathway for the development of a new agent for adjuvant treatment of sepsis is evaluation in an appropriate animal model of the human condition. Unfortunately, the animal models that have been used for this purpose have often yielded misleading findings. It is likely that there are multiple reasons for the discrepancies between the results obtained in tests of pharmacological agents in animal models of sepsis and the outcomes of human clinical trials. One of important reason may be that the changes in gene expression, which are triggered by trauma or infection, are different in mice, a commonly used species for preclinical testing, and humans. Additionally, many species, including mice and baboons, are remarkably resistant to the toxic effects of bacterial lipopolysaccharide, whereas humans are exquisitely sensitive. New approaches toward the use of animals for sepsis research are being investigated. But, at present, results from preclinical studies of new therapeutic agents for sepsis must be viewed with a degree of skepticism.
Fink, Mitchell P
This article is meant to serve as a summary of scientific advances from the past 5 years with regard to genetic polymorphisms in sepsis. It is also meant to highlight some of the discoveries that may improve our ability to identify vulnerable patients at earlier time points in sepsis, when interventions are more likely to have a positive effect. The article begins with an overview of polymorphism studies and a discussion of candidate gene versus genome-wide association studies. Next, an overview of polymorphisms associated with sepsis is presented. The overview includes detailed descriptions of E-selectin, apolipoprotein E, and C-reactive protein polymorphisms and a table in which numerous other sepsis-related polymorphisms are introduced. An examination of consortia-based projects that have the potential to catalyze sepsis research is included as is a preview of technological advancements that are likely to strongly influence sepsis studies in the near future. The article concludes with a brief consideration of ethical and social issues relevant to human genomic studies. PMID:19892256
Namath, Allen; Patterson, Andrew J
Despite an increasingly understanding of the pathogenetic mechanisms of sepsis, its mortality remains extremely high, caused mainly by hemodynamic impairment-related alterations frequently present in severe sepsis. Currently, treatment of sepsis is based on hemodynamic support, antibiotic therapy, surgical excision of infectious foci and immunomodulatory therapy. In fact, a massive host inflammatory infection response has recently emerged to substantially contribute to the development of septic shock and multiple organ dysfunction. Many clinical trials on various pharmacological agents have been conducted: glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), antithrombin III (AT III), anti-endotoxin monoclonal antibodies, nitric oxide inhibitors, interleukin-1 receptor antagonist, anti-tumor necrosis factor (TNF) antibodies. Apart from some likely favourable findings connected to low doses of glucocorticoids, most studies yielded disappointing results. Nevertheless, the use of recombinant human activated protein C (drotrecogin-alpha) has recently proven to have a mortality reduction effect particularly in patients with severe sepsis and dysfunction of at least two organs. Furthermore, the early treatment of hemodynamic instability with volume expanders and vasopressors (early goal-directed therapy), and a strict glycemic control represent important measures in order to significantly reduce mortality from severe sepsis and septic shock, and are fundamental guidelines recommended by most scientific societies (Surviving Sepsis Campaign). PMID:17068734
Guzzo, I; Morabito, S; Stucchi, R; Poli, G; Fumagalli, R
A 28 year old female patient developed hematuria in the 32th week of her pregnancy. She was given antibiotic treatment, since a urinary tract infection was suspected. After delivery symptoms of acute pyelonephritis, then sepsis developed, and conservative therapy had no effect. Ultrasound examination showed unusual renal destruction, so nephrectomy was performed. Surgical intervention revealed the presence of an advanced tumor of the kidney, while histological examination confirmed a Bellini duct carcinoma of the kidney. PMID:14688832
Szendrôi, Attila; Rusz, András; Székely, Eszter; Riesz, Péter; Kelemen, Zsolt
The prognosis for adults with acute post-streptococcal glomerulonephritis (PSGN) who present with crescentic glomerulonephritis and nephrotic proteinuria is not known. We report a patient with rapidly progressive glomerulonephritis and nephrotic-range proteinuria following acute pharyngitis, in whom serologic and kidney biopsy findings led to a diagnosis of PSGN. The patient was treated with corticosteroids and anti-hypertensive medications resulting in improvement in renal function and decrease in proteinuria. These results suggest that aggressive treatment of crescentic PSGN with nephrotic syndrome can result in a favorable outcome. PMID:15909597
Raff, A; Hebert, T; Pullman, J; Coco, M
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 ?l) 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 predominating proinflammatory and/or anti-inflammatory signature in the blood. PMID:23008446
Osuchowski, Marcin F; Craciun, Florin; Weixelbaumer, Katrin M; Duffy, Elizabeth R; Remick, Daniel G
The paradigm of SIRS-to-CARS transition implies that hyperinflammation triggers acute sepsis mortality, while 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 part I of the study, we characterized the systemic dynamics of the chronic inflammation in dying (DIE) and surviving (SUR) mice suffering from CLP sepsis (days 6-28). In part II, we combined the current chronic and previous acute/chronic sepsis data to compare the outcome-dependent inflammatory signatures between these two phases. To compare global inflammatory responses, a composite cytokine score (CCS) was calculated. Mice were never sacrificed but sampled daily (20?l) for blood. Part I: parameters from chronic DIE mice were clustered into the 72h, 48h and 24h prior-to-death time-points and compared to SUR of the same post-CLP day. Cytokine increases were mixed and never preceded chronic deaths earlier than 48h (3 to 180-fold increase). CCS demonstrated simultaneous and similar upregulation of pro-and anti-inflammatory compartments at 24h prior to chronic death (DIE 80 and 50-fold higher vs. SUR). Part II: cytokine ratios across sepsis phases/outcomes indicated steady pro-vs. anti-inflammatory balance. CCS showed the inflammatory response in chronic DIE was 5-fold lower versus acute DIE mice, yet identical to acute SUR. Concluding, the systemic MARS-like pattern (concurrent release of pro-and anti-inflammatory cytokines) occurs irrespectively of the sepsis phase, response magnitude and/or outcome. Although different in magnitude, neither acute nor chronic septic mortality is associated with a predominating pro-and/or anti-inflammatory signature in the blood.
Osuchowski, Marcin F.; Craciun, Florin; Weixelbaumer, Katrin; Duffy, Elizabeth R.; Remick, Daniel G.
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.
Cotena, Simona; Piazza, Ornella
Pivotal sepsis clinical trials and preclinical research in 2012 are reviewed. For interventions ranging from synthetic complex starch solutions to recombinant human activated protein C, large multicenter randomized controlled trials generally failed to show benefit and some even demonstrated harm in the intervention group. In smaller innovative clinical trials simple interventions such as external cooling to control fever and biomarker-guided weaning from mechanical ventilation found potential benefit. Biomarkers for sepsis, including multimarker panels, are increasingly showing promise for clinical application. Breakthroughs in basic research in sepsis continue to highlight the complexity of the systemic inflammatory response and its consequences. A series of publications in AJRCCM follow the septic inflammatory response starting from intracellular structures and organelles to mitochondria and the cytoskeleton. Additional publications explore the key leukocyte subsets acting in sepsis, highlighting the underappreciated role of helper T-cell type 2-related pathways. Cellular remnants in the form of microparticles contribute to coagulopathy and further organ dysfunction. As a consequence, we suggest that sepsis may be the paradigm disease or condition requiring personalized care first to discover and validate new therapies and second to increase survival. PMID:23767902
Russell, James A; Walley, Keith R
Sepsis is the most common and severe cause of morbidity and mortality among critically ill patients. Multiple organ dysfunction syndrome often complicates sepsis, leading to a worse prognosis that is proportional to the severity and number of damaged organs. Acute kidney injury (AKI) also complicates sepsis, with a linear relationship between the severity of kidney damage and sepsis prognosis. The
Zaccaria Ricci; Andrea Polito; Angelo Polito; Claudio Ronco
Bloodstream infections are a major concern because of high levels of antibiotic consumption and of the increasing prevalence of antimicrobial resistance. Bacteraemia is identified in a small percentage of patients with signs and symptoms of sepsis. Biomarkers are widely used in clinical practice and they are useful for monitoring the infectious process. Procalcitonin (PCT) and C-reactive protein (CRP) have been most widely used, but even these have limited abilities to distinguish sepsis from other inflammatory conditions or to predict outcome. PCT has been used to guide empirical antibacterial therapy in patients with respiratory infections and help to determine if antibacterial therapy can be stopped. New biomarkers such as those in this review will discuss the major types of biomarkers of bloodstream infections/sepsis, including soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), soluble urokinase-type plasminogen receptor (suPAR), proadrenomedullin (ProADM), and presepsin.
Henriquez-Camacho, Cesar; Losa, Juan
Lymphoma presenting as a parotid gland tumour without systemic involvement is rare, especially with respect to a non-Hodgkin's lymphoma. Furthermore, when such cases present there is often a low degree of clinical suspicion as there may be few clinical features to suggest the diagnosis. We describe an unexpected case that presented during an acute medical intake. The case was an 84-year-old man presenting acutely unwell with an ulcerating mass over the right side of the face, septicaemia and acute kidney injury. Following aggressive initial management the patient improved. Later cytological examination of a fine needle aspiration from the mass confirmed a B-cell non-Hodgkin's lymphoma. He had no evidence of other systemic involvement or of B-symptoms. We report on the case and briefly review the available literature relating to the prevalence of non-Hodgkin's lymphoma of the parotid gland. PMID:23355582
Anthony, Victoria Angharad; Rees, David Owen; Stephens, Jeffrey W
Purpura fulminans is an acute and frequently fatal disorder characterized by sudden onset of progressive cutaneous hemorrhage and necrosis due to dermal vascular thrombosis and disseminated intravascular coagulation. The authors present a neonate with extensive purpura fulminans due to group B streptoccoccal septicemia and evaluated the attributable clinical mortality and morbidity of this potentially lethal syndrome. Clinicians especially neonatologists should be aware that early-onset sepsis of group B Streptococcus in the newborn infant with purpura fulminans could be a cause of maternal carriage due to colonization of this pathogen microorganism. PMID:20795772
Zenciroglu, Aysegul; Karagol, Belma Saygili; Ipek, Mehmet Sah; Okumus, Nurullah; Yarali, Nese; Aydin, Mustafa
The failure of the PROWESS-SHOCK study of recombinant human activated protein C (drotrecogin alfa) has generated much scepticism about the future of immunomodulatory interventions in sepsis. This review presents a summary of the few remaining promising strategies for immunointervention. These comprise intravenous clarithromycin, haemoperfusion through a polymyxin B-embedded fibre device (PMX-B), recombinant thrombomodulin (rTM) and intravenous immunoglobulin preparations enriched in IgM and IgA (IgMA). The great heterogeneity in the pathophysiology of sepsis mandates a highly individualised approach. This approach comprises: septic shock and multiple organ dysfunction syndrome arising in the field of ventilator-associated pneumonia as an indication for intravenous clarithromycin; abdominal severe sepsis/shock for PMX-B haemoperfusion; sepsis and acute coagulopathy for rTM; and early septic shock for IgMA. However, specific diagnostic tools should be developed to make this personalised approach more robust. PMID:23664229
Giamarellos-Bourboulis, Evangelos J
INTRODUCTION: The receptor for advanced glycation end products (RAGE), a multi-ligand member of the immunoglobulin superfamily, contributes to acute and chronic disease processes, including sepsis. METHODS: We studied the possible therapeutic role of RAGE inhibition in the cecal ligation and puncture (CLP) model of polymicrobial sepsis and a model of systemic listeriosis using mice genetically deficient in RAGE expression or
Emily C Lutterloh; Steven M Opal; Debra D Pittman; James C Keith Jr; Xiang-Yang Tan; Brian M Clancy; Helen Palmer; Kim Milarski; Ying Sun; John E Palardy; Nicholas A Parejo; Noubar Kessimian
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.
Matlow, A.; Vellend, H.
Group B Streptococcus is the most common cause of bacterial infection in the newborn. Infection in many cases causes persistent pulmonary hypertension, which impairs gas exchange in the lung. We purified the bacterial components causing pulmonary hypertension and identified them as cardiolipin and phosphatidylglycerol. Synthetic cardiolipin or phosphatidylglycerol also induced pulmonary hypertension in lambs. The recognition that bacterial phospholipids may cause pulmonary hypertension in newborns with Group B streptococcal infection opens new avenues for therapeutic intervention.
Curtis, Jerri; Kim, Geumsoo; Wehr, Nancy B.; Levine, Rodney L.
Group A streptococci (GAS) are important causes of morbidity and mortality worldwide. These organisms cause a wide spectrum of disease, ranging from uncomplicated sore throat to invasive, life-threatening infections, as well as immune complications such as acute rheumatic fever (ARF), rheumatic heart disease (RHD) and acute post-streptococcal glomerulonephritis (APSGN). Vaccine prevention of GAS infections and their immunological complications has been a goal of researchers for decades. Several vaccine candidates against GAS infection are in various stages of pre-clinical and clinical development, including M protein-based vaccines (N-terminal vaccine candidates and M protein conserved region vaccines), and non-M protein vaccine candidates representing conserved GAS antigens. Some of the obstacles to GAS vaccine development are related to the complexity of the global epidemiology of GAS infections, the limitation in the criteria for selection of antigens to include in combination vaccines as well as the issues around autoimmunity and vaccine safety, among others. Overcoming these obstacles will require collaborative efforts to develop innovative strategies that address key steps in the pre-clinical and clinical development process, as well as clearly defining the global burden of GAS diseases and the molecular epidemiology of infections. Specific recommendations are presented for an accelerated plan leading to the introduction of a broadly protective vaccine designed for deployment in low-, middle-, and high-income countries. PMID:23598485
Dale, James B; Fischetti, Vincent A; Carapetis, Jonathan R; Steer, Andrew C; Sow, Samba; Kumar, Rajesh; Mayosi, Bongani M; Rubin, Fran A; Mulholland, Kim; Hombach, Joachim Maria; Schödel, Florian; Henao-Restrepo, Ana Maria
Previous reports have shown the presence of streptococcal erythrogenic exotoxin type B (ETB), leukocyte infiltration, interleukin-8 (IL-8), transforming growth factor-beta (TGF-beta) and glomerular proliferation in renal biopsies from patients with acute post-streptococcal glomerulonephritis (APSGN). In addition, increased levels of plasma interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha), and urinary IL-6, have also been reported in this disease. To determine the effect of streptococcal proteins on leukocyte proliferation and leukocyte production of IL-6, TNFalpha, IL-8 and TGF-beta1, we cultured human mononuclear leukocytes with ETB or ETB precursor (ETBP). After 24 h, 48 h and 96 h, culture supernatants were assessed for cytokines by enzyme-linked immunosorbent assay (ELISA), and for leukocyte proliferation by a monoclonal antibody anti-proliferating cellular nuclear antigen (PCNA). A significant increase in all cytokines was found in ETB- or ETBP-treated cultures when compared with controls. A polyclonal anti-ETB antibody diminished the cytokine stimulatory effect of ETB. An increased number of PCNA-positive cells was observed in ETB or ETBP treated cultures at 48 h and 96 h. Cytokine production and proliferation were not correlated. The stimulatory effect of streptococcal exotoxin B on leukocyte cytokine production may be relevant in renal tissue during the course of APSGN. PMID:17530297
Viera, Ninoska; Pedreanez, Adriana; Rincon, Jaimar; Mosquera, Jesus
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
Elvan Caglar Citak; Kivilcim Gücüyener; Nese Ilgin Karabacak; Ayse Serdaroglu; Cetin Okuyaz; Kursad Aydin
Background In light of increasing rates and severity of sepsis worldwide, this study aimed to estimate the incidence of, and describe the causative organisms, sources of infection, and risk factors for, severe maternal sepsis in the UK. Methods and Findings A prospective case-control study included 365 confirmed cases of severe maternal sepsis and 757 controls from all UK obstetrician-led maternity units from June 1, 2011, to May 31, 2012. Incidence of severe sepsis was 4.7 (95% CI 4.2–5.2) per 10,000 maternities; 71 (19.5%) women developed septic shock; and five (1.4%) women died. Genital tract infection (31.0%) and the organism Escherichia coli (21.1%) were most common. Women had significantly increased adjusted odds ratios (aORs) of severe sepsis if they were black or other ethnic minority (aOR?=?1.82; 95% CI 1.82–2.51), were primiparous (aOR?=?1.60; 95% CI 1.17–2.20), had a pre-existing medical problem (aOR?=?1.40; 95% CI 1.01–1.94), had febrile illness or were taking antibiotics in the 2 wk prior to presentation (aOR?=?12.07; 95% CI 8.11–17.97), or had an operative vaginal delivery (aOR?=?2.49; 95% CI 1.32–4.70), pre-labour cesarean (aOR?=?3.83; 95% CI 2.24–6.56), or cesarean after labour onset (aOR?=?8.06; 95% CI 4.65–13.97). Median time between delivery and sepsis was 3 d (interquartile range?=?1–7 d). Multiple pregnancy (aOR?=?5.75; 95% CI 1.54–21.45) and infection with group A streptococcus (aOR?=?4.84; 2.17–10.78) were associated with progression to septic shock; for 16 (50%) women with a group A streptococcal infection there was <2 h—and for 24 (75%) women, <9 h—between the first sign of systemic inflammatory response syndrome and a diagnosis of severe sepsis. A limitation of this study was the proportion of women with sepsis without an identified organism or infection source (16.4%). Conclusions For each maternal sepsis death, approximately 50 women have life-threatening morbidity from sepsis. Follow-up to ensure infection is eradicated is important. The rapid progression to severe sepsis highlights the importance of following the international Surviving Sepsis Campaign guideline of early administration of high-dose intravenous antibiotics within 1 h of admission to hospital for anyone with suspected sepsis. Signs of severe sepsis in peripartum women, particularly with confirmed or suspected group A streptococcal infection, should be regarded as an obstetric emergency. Please see later in the article for the Editors' Summary
Acosta, Colleen D.; Kurinczuk, Jennifer J.; Lucas, D. Nuala; Tuffnell, Derek J.; Sellers, Susan; Knight, Marian
The deiodination of l-thyroxine (T4) in vitro by peripheral leukocytes isolated from healthy rhesus monkeys was compared to that of leukocytes from monkeys with acute Salmonella typhimurium sepsis, an infection associated with accelerated metabolism of T4...
F. R. DeRubertis
Group B streptococcal (GBS) infection is still an important cause of morbidity and mortality in newborn infants. In The Netherlands, there are no published data on the incidence of neonatal GBS infection. We collected data of all infants with GBS disease during the first 3 months of life, as reported to the Dutch Paediatric Surveillance Unit (DPSU) during a period of 2 years (1997-98). Neonates with early-onset GBS disease (both sepsis and probable sepsis) were included for further analysis. The level of completeness of the DPSU data was determined by capture-recapture techniques. The incidence of early-onset GBS disease in The Netherlands in 1997-98, as calculated from the DPSU data, was 0.9 per 1000 live births. After correction for under-reporting, the incidence was estimated to be 1.9 per 1000 live births. The case fatality rate of early-onset GBS disease was only 5%. Despite the decrease in the mortality rate during the last decades, it remains a serious condition with potential irreversible brain damage. Therefore, formal guidelines for the prevention of neonatal early-onset GBS disease in The Netherlands were introduced in 1999. The data collected in this study may serve as baseline data for evaluation of the effect of these guidelines. PMID:12445150
Trijbels-Smeulders, Monique; Gerards, Leo J; M, Pieternel C; de Jong, Pasker; van Lingen, Richard A; Adriaanse, Albert H; de Jonge, Guus A; Kollée, Louis A A
Streptococcal pyrogenic exotoxins (SPEs) are superantigens that have been implicated in causing strepto- coccal toxic shock syndrome (STSS). Most notably, SPE serotype A is made by nearly all M-protein serotype 1 and 3 streptococci, the M types most associated with the illness (these strains contain one or more other SPEs, and those proteins are likely also to contribute to disease).
MANUELA ROGGIANI; JENNIFER A. STOEHR; STEPHEN B. OLMSTED; YURY V. MATSUKA; SUBRAMONIA PILLAI; DOUGLAS H. OHLENDORF; PATRICK M. SCHLIEVERT
Background Group A streptococcus (GAS) is an etiological agent for the immune mediated sequela post streptococcal glomerulonephritis (PSGN). In some populations PSGN is recognized as a risk factor for chronic kidney disease (CKD) and end-stage renal disease (ESRD). It was found that a significantly greater proportion of subjects with past history of PSGN than without the history exhibited seroreactions to streptococcal antigens called streptococcal inhibitor of complement (SIC) and to distantly related SIC (DRS). These antigens are expressed by major PSGN-associated GAS types. We therefore predicted that in populations such as India, which is endemic for streptococcal diseases and which has high prevalence of CKD and ESRD, greater proportions of CKD and ESRD patients exhibit seroreaction to SIC and DRS than healthy controls. Methods To test this we conducted a SIC and DRS seroprevalence study in subjects from Mumbai area. We recruited 100 CKD, 70 ESRD and 70 healthy individuals. Results Nineteen and 35.7% of CKD and ESRD subjects respectively were SIC antibody-positive, whereas only 7% of healthy cohort was seropositive to SIC. Furthermore, significantly greater proportion of the ESRD patients than the CKD patients is seropositive to SIC (p=0.02; odds ratio 2.37). No association was found between the renal diseases and DRS-antibody-positivity. Conclusions Past infection with SIC-positive GAS is a risk factor for CKD and ESRD in Mumbai population. Furthermore, SIC seropositivity is predictive of poor prognosis of CKD patients.
A patient with homozygous hemoglobin SS disease presented with an intracerebral hemorrhage complicating reversible posterior leucoencephalopathy syndrome (RPLS), secondary to hypertension associated with acute post-streptococcal glomerulonephritis (APSGN). Distinguishing potentially reversible causes of central nervous system events from primary cerebral infarction or hemorrhage in patients with sickle cell disease is important because the management and prognosis of these complications is very different. Similarly, because of the difference in prognosis between APSGN and other forms of sickle cell nephropathy, it is also important to differentiate these conditions. PMID:17973321
Pashankar, Farzana D; Ment, Laura R; Pearson, Howard A
Septic shock is a common and deadly disease that traditionally has been diagnosed and treated by evaluation and optimization of global hemodynamic indices. However, microcirculatory dysfunction is a critically important element in the pathophysiology of this disease. New techniques of in vivo video microscopy permit the assessment of microcirculatory function in human subjects. With the advent of these techniques, the microcirculation may represent a new frontier for developing novel therapies for sepsis. PMID:21316568
Lundy, David J; Trzeciak, Stephen
For over 30 years, it has been recognized that an aggressive team approach to the management of the multiple trauma victim is both life-saving and morbidity-reducing1. That this assertive approach might also be productive and life-saving in the management of sepsis in the emergency department (ED) has become more recently recognized in current publications starting with Rivers et al. goal-directed
Kevin M. Ban; Peter Rosen
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
Azevedo, Luciano Cesar Pontes
Background & objectives: We evaluated pro- and anti-oxidant disturbances in sepsis and non-sepsis burn patients with systemic inflammatory response syndrome (SIRS). Adhesion molecules and inflammation markers on leukocytes were also analyzed. We hypothesized that oxidative stress and leukocyte activation markers can lead to the severity of sepsis. Methods: In 28 severe sepsis and 27 acute burn injury patients blood samples were collected at admission and 4 days consecutively. Oxidative stress markers: production of reactive oxygen species (ROS), myeloperoxidase, malondialdehyde and endogenous antioxidants: plasma protein sulphydryl groups, reduced glutathione, superoxide dismutase and catalase were measured. Flow cytometry was used to determine CD11a, CD14, CD18, CD49d and CD97 adhesion molecules on leukocytes. Procalcitonin, C-reactive protein, fibrinogen, platelet count and lactate were also analyzed. Results: Pro-oxidant parameters were significantly elevated in sepsis patients at admission, ROS intensity increased in burn patients until the 5th day. Endogenous antioxidant levels except catalase showed increased levels after burn trauma compared to sepsis. Elevated granulocyte activation and suppressed lymphocyte function were found at admission and early activation of granulocytes caused by increasing activation/migration markers in sepsis. Leukocyte adhesion molecule expression confirmed the suppressed lymphocyte and monocyte function in sepsis. Interpretation & conclusions: Severe sepsis is accompanied by oxidative stress and pathological leukocyte endothelial cell interactions. The laboratory parameters used for the evaluation of sepsis and several markers of pro- and antioxidant status were different between sepsis and non-sepsis burn patients. The tendency of changes in these parameters may refer to major oxidative stress in sepsis and developing SIRS in burns.
Muhl, Diana; Woth, Gabor; Drenkovics, Livia; Varga, Adrienn; Ghosh, Subhamay; Csontos, Csaba; Bogar, Lajos; Weber, Gyorgy; Lantos, Janos
Background Severe sepsis is a common cause for admission to the general medical ward. Previous work has demonstrated substantial new long-term disability in patients with severe sepsis, but the short-term functional outcomes of patients admitted to the general medical floor -- where the majority of severe sepsis is treated -- are largely unknown. Methods A retrospective cohort study was performed of patients initially admitted to non-ICU medical wards at a tertiary care academic medical center. Severe sepsis was confirmed by three physician reviewers, using the International Consensus Conference definition of sepsis. Baseline functional status, disposition location, and receipt of post-acute skilled care were recorded using a structured abstraction instrument. Results 3,146 discharges had severe sepsis by coding algorithm; from a random sample of 111 patients, 64 had the diagnosis of severe sepsis confirmed by reviewers. The mean age of the 64 patients was 63.5 years +/- 18.0. Prior to admission, 80% of patients lived at home and 50.8% of patients were functionally independent. Inpatient mortality was 12.5% and 37.5% of patients were discharged to a nursing facility. Of all patients in the cohort, 50.0% were discharged home, and 66.7% of patients who were functionally independent at baseline were discharged to home. Conclusions New physical debility is a common feature of severe sepsis in patients initially cared for on the general medical floor. Debility occurs even in those with good baseline physical function. Interventions to improve the poor functional outcomes of this population are urgently needed.
The global burden of disease caused by group A streptococcus (GAS) is not known. We review recent population-based data to estimate the burden of GAS diseases and highlight deficiencies in the available data. We estimate that there are at least 517,000 deaths each year due to severe GAS diseases (eg, acute rheumatic fever, rheumatic heart disease, post-streptococcal glomerulonephritis, and invasive infections). The prevalence of severe GAS disease is at least 18.1 million cases, with 1.78 million new cases each year. The greatest burden is due to rheumatic heart disease, with a prevalence of at least 15.6 million cases, with 282,000 new cases and 233,000 deaths each year. The burden of invasive GAS diseases is unexpectedly high, with at least 663,000 new cases and 163,000 deaths each year. In addition, there are more than 111 million prevalent cases of GAS pyoderma, and over 616 million incident cases per year of GAS pharyngitis. Epidemiological data from developing countries for most diseases is poor. On a global scale, GAS is an important cause of morbidity and mortality. These data emphasise the need to reinforce current control strategies, develop new primary prevention strategies, and collect better data from developing countries. PMID:16253886
Carapetis, Jonathan R; Steer, Andrew C; Mulholland, E Kim; Weber, Martin
We studied the long-term outcome of children with mild acute post streptococcal glomerulonephritis (APSGN) APSGN hospitalized at St. Al Zahra hospital, Isfahan, Iran from 1993-1998. The patients were subdivided into two groups according to the duration of follow-up. Group A consisted of 15 patients and group B consisted of 12 patients, followed up for 4 and 8 years, respectively. The male to female ratio was 1.45/1. The mean GFR in group A and B was 127.7 +/- 26 mL/min/1.73 m2 and 128.57 +/- 7 mL/min/1.73 m2, respectively. There was no statistically significant difference between GFRs in two groups. Comparing the mean systolic blood pressure in two groups did not demonstrate a significant difference; 95.33 +/- 7.1 mmHg in group A and 102.5 +/- 14.06 mmHg in group B. However the mean diastolic blood pressure in group B was significantly higher than group A; 65.4 +/- 11.71 mmHg vs 61.33 +/- 3.51 mmHg. Our study found that even mild APSGN may lead to some degree of renal impairment, and rising diastolic blood pressure maybe an early clinical sign of renal impairment in APSGN. PMID:20427896
Gheissari, Alaleh; Adjodani, Taj Saadat; Hashemi, Maryam; Mokhtarian, Arghavan; Sirous, Mehri
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.
Kaufman, David; Fairchild, Karen D.
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.
Jovanovich, Anna J.; Ginde, Adit A.; Holmen, John; Jablonski, Kristen; Allyn, Rebecca L.; Kendrick, Jessica; Chonchol, Michel
Induction of inducible nitric oxide synthase (iNOS) expression is likely important in the pathogenesis of sepsis. However, the sepsis-mediated induction of iNOS is associated with a decrease in constitutive NO synthase (cNOS) activity (which is reversible following acute but not chronic sepsis). Whether this decreased cNOS activity is due to functional inhibition of cNOS by the high concentrations of NO produced by iNOS or to downregulation of cNOS expression is not clear. Thus, we tested the hypothesis that sepsis produces a reversible iNOS/NO-mediated inhibition of cNOS activity. Using a rat cecal ligation and perforation (CLP) model of sepsis, we examined the time course of the changes in iNOS and cNOS activities in lung and thoracic aortae. Reversibility of the sepsis-induced decrease in cNOS activity was assessed in vitro by enzyme activity determination following selective inhibition of iNOS. iNOS and endothelial cNOS protein concentrations were determined by Western blotting. In all septic tissues, cNOS activity was depressed at 6, 12, 24, and 48 hours post-CLP. Inhibition of the increased iNOS activity with aminoguanidine, in vitro, partially restored cNOS activity following acute (6-12 hours) but not chronic sepsis (24-48 hours post-CLP). Consistent with the irreversible depression of cNOS activities in tissues following chronic sepsis, endothelial NOS protein concentrations declined progressively during the time course of sepsis. We have demonstrated the restoration of cNOS activity following in vitro inhibition of iNOS, early, and the downregulation of endothelial NOS, later, in a rat CLP model of sepsis. This suggests that further study is required before iNOS-selective inhibition can be considered in human sepsis. PMID:12016107
Scott, Jeremy A; Mehta, Sanjay; Duggan, Michele; Bihari, Aurelia; McCormack, David G
A 16-day-old male infant initially was in septic shock. Following intensive resuscitation, thrombohemorrhagic lesions developed over his extremities, except for the limb with an arterial line maintained by a continuous heparin sodium infusion. Blood and CSF cultures yielded group B beta-hemolytic streptococci. Results of laboratory studies and clinical appearance supported the diagnosis of purpura fulminans (PF). Systemic heparinization was therefore started, and subsequently his condition improved. Because of the distinct difference in limb sparing, we concluded heparin has a beneficial effect on the evolution of PF. PMID:6383017
Issacman, S H; Heroman, W M; Lightsey, A L
Early, appropriate antibiotic therapy is critical to the treatment of the septicemic patient. The degree of organ dysfunction, underlying medical conditions, and physiologic abnormalities are important prognostic factors but are not important in initial antibiotic selection. Initial empiric therapy should be directed against the resident flora of the organ, which is primarily involved in the infectious process. Blood cultures should be obtained in all patients for the initiation of antibiotic therapy, and methods should be employed for the early detection of septicemia. Other conditions that mimic sepsis, e.g., pseudosepsis, should be ruled out initially to avoid an incorrect diagnosis and unnecessary antibiotic therapy. Monotherapy and fully recommended doses of antimicrobial drugs delivered by the intravenous route as soon as the diagnosis is established remain the cornerstone of therapy in treating the septic patient. Monotherapy with an antibiotic of the appropriate spectrum is more than adequate to treat the great majority of septicemic patients. Double-drug therapy is recommended to treat febrile leukopenic compromised hosts, serious P. aeruginosa infections, and selected cases of intra-abdominal sepsis. At the present time, corticosteroids and mediator therapy have no place in the treatment of the septic patient. PMID:7752728
Cunha, B A
With the help of a surgical nurse and using data-processing techniques, a prospective clinical study was conducted to determine the wound infection rate in two hospitals in Calgary. The overall sepsis rate was 5.2% and the clean wound rate 3.5%. The latter is the more meaningful figure as it allows for comparison between hospitals, specialties and individuals and is a good guide for hospital morbidity reviews. The groundwork for succeeding wound infection is laid in the operating theatre, and it is believed that wound infection would be reduced more by attention to Halsted's principles than by more rigid aseptic techniques. It is estimated that wound sepsis costs the Province of Alberta 1.5 million dollars per year for hospitalization alone. This amounts to roughly $1 per person per year. The annual cost of a prospective study such as the present one is approximately $7000. This is equivalent to the cost of hospitalizing 24 patients with infected wounds for one week (at $300 per week). One dividend of a prospective study is an associated reduction in infection rate. This reduction more than pays for the cost of the program.
Cruse, P. J. E.
During sepsis, a complex network of cytokine, immune, and endothelial cell interactions occur and disturbances in the microcirculation cause organ dysfunction or even failure leading to high mortality in those patients. In this respect, numerous experimental and clinical studies indicate sex-specific differences in infectious diseases and sepsis. Female gender has been demonstrated to be protective under such conditions, whereas male gender may be deleterious due to a diminished cell-mediated immune response and cardiovascular functions. Male sex hormones, i.e., androgens, have been shown to be suppressive on cell-mediated immune responses. In contrast, female sex hormones exhibit protective effects which may contribute to the natural advantages of females under septic conditions. Thus, the hormonal status has to be considered when treating septic patients. Therefore, potential therapies could be derived from this knowledge. In this respect, administration of female sex hormones (estrogens and their precursors) may exert beneficial effects. Alternatively, blockade of male sex hormone receptors could result in maintained immune responses under adverse circulatory conditions. Finally, administration of agents that influence enzymes synthesizing female sex hormones which attenuate the levels of pro-inflammatory agents might exert salutary effects in septic patients. Prospective patient studies are required for transferring those important experimental findings into the clinical arena.
Angele, Martin K; Pratschke, Sebastian; Hubbard, William J; Chaudry, Irshad H
Abstract Question I have heard about children who have tic disorders that seem to be exacerbated by group A ?-hemolytic streptococcal infection. Should children presenting with this phenomenon receive treatment with antibiotics, receive prophylactic treatment, or use immunomodulators to treat the symptoms? Answer Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) constitute a condition that includes neuropsychiatric symptoms, mainly obsessive-compulsive disorder or tic disorders, temporally associated with an immune-mediated response to streptococcal infections. The actual existence of PANDAS as a unique clinical entity is still up for debate, as a temporal association between group A ?-hemolytic streptococcal infections and symptom exacerbations has been difficult to prove thus far. Based on only a few studies, positive results have been found using antibiotic prophylaxis and immunomodulatory therapy in children with PANDAS. At this time, however, evidence does not support a recommendation for long-term antibiotic prophylaxis or immunomodulatory therapy.
Tan, Jason; Smith, Christine H.; Goldman, Ran D.
We hereby present the first case report of a child with concomitant post-streptococcal glomerulonephritis (PSGN) and uveitis. Pediatricians should be familiar with this entity and recognize signs and symptoms of uveitis in children with PSGN. PMID:20517620
Feldon, Michal; Dorfman, Lev; Tauber, Tsivia; Morad, Yair; Bistritzer, Tzvy; Goldman, Michael
Severe meningococcal sepsis is still of high morbidity and mortality. Its management may be improved by an experimental model allowing better understanding of its pathophysiology. We developed an animal model of meningococcal sepsis in transgenic BALB/c mice expressing human transferrin. We studied experimental meningococcal sepsis in congenic transgenic BALB/c mice expressing human transferrin by transcriptional profiling using microarray analysis of blood and brain samples. Genes encoding acute phase proteins, chemokines and cytokines constituted the largest strongly regulated groups. Dynamic bioluminescence imaging further showed high blood bacterial loads that were further enhanced after a primary viral infection by influenza A virus. Moreover, IL-1 receptor–associated kinase–3 (IRAK-3) was induced in infected mice. IRAK-3 is a negative regulator of Toll-dependant signaling and its induction may impair innate immunity and hence result in an immunocompromised state allowing bacterial survival and systemic spread during sepsis. This new approach should enable detailed analysis of the pathophysiology of meningococcal sepsis and its relationships with flu infection.
Szatanik, Marek; Hong, Eva; Ruckly, Corinne; Ledroit, Morgan; Giorgini, Dario; Jopek, Katarzyna; Nicola, Marie-Anne; Deghmane, Ala-Eddine; Taha, Muhamed-Kheir
Sepsis is a potential life-threatening oncologic emergency. Early recognition and prompt intervention can decrease the morbidity and mortality associated with sepsis. The Surviving Sepsis Campaign Guidelines Committee updated its recommendations in 2012, outlining specific evidence-based interventions to manage sepsis. PMID:24867108
Objective To provide an update to the original Surviving Sepsis Campaign clinical management guidelines, “Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock,” published in 2004. Design Modified Delphi method with a consensus conference of 55 international experts, several subsequent meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. This process was conducted independently of any industry funding. Methods We used the GRADE system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations. A strong recommendation  indicates that an intervention's desirable effects clearly outweigh its undesirable effects (risk, burden, cost), or clearly do not. Weak recommendations  indicate that the tradeoff between desirable and undesirable effects is less clear. The grade of strong or weak is considered of greater clinical importance than a difference in letter level of quality of evidence. In areas without complete agreement, a formal process of resolution was developed and applied. Recommendations are grouped into those directly targeting severe sepsis, recommendations targeting general care of the critically ill patient that are considered high priority in severe sepsis, and pediatric considerations. Results Key recommendations, listed by category, include: early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures prior to antibiotic therapy (1C); imaging studies performed promptly to confirm potential source of infection (1C); administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D); reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate (1C); a usual 7–10 days of antibiotic therapy guided by clinical response (1D); source control with attention to the balance of risks and benefits of the chosen method (1C); administration of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore mean circulating filling pressure (1C); reduction in rate of fluid administration with rising filing pressures and no improvement in tissue perfusion (1D); vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure ? 65 mm Hg (1C); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy (1C); stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C); recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for post-operative patients). In the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of 7–9 g/dL (1B); a low tidal volume (1B) and limitation of inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in mechanically ventilated patients unless contraindicated (1B); avoiding routine use of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanical ventilation and ICU length of stay, a conservative fluid strategy for patients with established ALI/ARDS who are not in shock (1C); protocols for weaning and sedation/analgesia (1B); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening (1B); avoidance of neuromuscular blockers, if at all possible (1B); institution of glycemic control (1B) targeting a blood glucose < 150 mg/dL after initial stabilization ( 2C );
Levy, Mitchell M.; Carlet, Jean M.; Bion, Julian; Parker, Margaret M.; Jaeschke, Roman; Reinhart, Konrad; Angus, Derek C.; Brun-Buisson, Christian; Beale, Richard; Calandra, Thierry; Dhainaut, Jean-Francois; Gerlach, Herwig; Harvey, Maurene; Marini, John J.; Marshall, John; Ranieri, Marco; Ramsay, Graham; Sevransky, Jonathan; Thompson, B. Taylor; Townsend, Sean; Vender, Jeffrey S.; Zimmerman, Janice L.; Vincent, Jean-Louis
Although unusual in western countries and in Australia in general, post-streptococcal glomerulonephritis (PSGN) is still common in Australian Aboriginal children living in remote communities. Here, we evaluated whether episodes of acute PSGN increased the risk for chronic kidney disease in later life in 1519 residents of a remote Aboriginal community (85% of those age eligible), with high rates of renal and cardiovascular disease, who participated in a health screen over a 3-year period. Of these, 200 had had at least one episode of PSGN, with 27 having had multiple episodes, usually in childhood. High levels of albuminuria (albumin/creatinine ratio) with increasing age were confirmed. All PSGN episodes were associated with group A streptococcal skin infections, often related to scabies. In both genders, aged 10-39 years at screening, about one in five had such a history. Among them, PSGN (5 years or more earlier) was significantly associated with higher levels of albuminuria than those without. In women, aged 30-39 years, a history of PSGN was associated with a significantly higher frequency of estimated glomerular filtration rates <60 ml/min. The adjusted odds ratios for an albumin/creatinine ratio over 34 g/mol (overt albuminuria) in males and females with a history of PSGN were 4.6 and 3.1, respectively, compared with those without a history. Thus, PSGN contributes to the very serious burden of chronic kidney disease in this community. Rigorous strategies to prevent scabies and Group A streptococcal infections will reduce this burden. PMID:22297679
Hoy, Wendy E; White, Andrew V; Dowling, Alison; Sharma, Suresh K; Bloomfield, Hilary; Tipiloura, Bernard T; Swanson, Cheryl E; Mathews, John D; McCredie, David A
Introduction We conducted the present study to evaluate the changes in serum total antioxidant capacity (TAC) in patients with severe sepsis and to investigate the association between serum TAC and clinical severity. Method This was a prospective observational study involving a sample of patients who met established criteria for severe sepsis and were admitted to the emergency department of a university teaching hospital. Serum TAC was determined using the total radical-trapping antioxidant parameter method. The levels of TAC, uric acid, albumin, and bilirubin in sera were obtained in the emergency department and evaluated to determine whether there were any correlations between the major antioxidant biomarkers and clinical severity of sepsis. The Acute Physiology and Chronic Health Evaluation (APACHE) II score was used for clinical evaluation of the severity of sepsis. Results A total of 73 patients with sepsis, with a mean (± standard deviation) APACHE II score of 23.2 ± 8.2 and a mortality rate of 26.0%, were included. Seventy-six healthy individuals served as control individuals. Among the patients, serum TAC levels correlated significantly with APACHE II scores. Patients who died also had higher TAC than did those who survived. Serum uric acid levels correlated significantly with serum TAC and APACHE II scores in patients with severe sepsis. Conclusion Elevated serum TAC level may reflect clinical severity of sepsis. In addition, serum uric acid levels appear to contribute importantly to the higher TAC levels observed in patients with severe sepsis.
Chuang, Chia-Chang; Shiesh, Shu-Chu; Chi, Chih-Hsien; Tu, Yi-Fang; Hor, Lien-I; Shieh, Chi-Chang; Chen, Ming-Feng
The use of glucocorticoids (corticotherapy) in severe sepsis is one of the main controversial issues in critical care medicine. These agents were commonly used to treat sepsis until the end of the 1980s, when several randomized trials casted serious doubt on any benefit from high-dose glucocorticoids. Later, important progress in our understanding of the role played by the hypothalamic–pituitary–adrenal axis
Helene Prigent; Virginie Maxime; Djillali Annane
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.
Oda, Takashi; Yoshizawa, Nobuyuki; Yamakami, Kazuo; Sakurai, Yutaka; Takechi, Hanako; Yamamoto, Kojiro; Oshima, Naoki; Kumagai, Hiroo
The inflammatory and immune responses evoked in sepsis may create not only an acute brain dysfunction, which occurs in the majority of septic patients, but also long-term deficits such as memory impairment. In this context, we evaluated depressive-like parameters in sepsis survivor rats. For this purpose, male Wistar rats, weighing 300-350 g, underwent cecal ligation and perforation (CLP) (sepsis group) followed by "basic support", or were sham-operated (control group). After 3 days of the sepsis procedure, the animals were treated with imipramine at 10 mg/kg or saline during 14 days (days 3-17). The consumption of sweet food was measured for 7 days (days 10-17) and the body weight was measured before CLP, 10, and 17 days after CLP. Seventeen days after sepsis (immediately after sweet food consumption measurement), the animals were anesthetized and blood was withdrawn for the analyses of corticosterone and adrenocorticotropic hormone (ACTH) levels, and immediately killed by decapitation. The adrenal gland and hippocampus were immediately isolated and weighed, and the hippocampus was utilized for determining brain-derived neurotrophic factor (BDNF) levels. It was observed that animals subjected to CLP presented decreased sucrose intake. Septic rats did not increase body weight and presented an increase in the weight of adrenal gland. Both corticosterone and ACTH levels were increased, while hippocampus weight and BDNF levels in the hippocampus decreased. The treatment with imipramine reversed all the parameters described above. Our results supported the hypothesis that rats that survive sepsis show depressive-like behavior, alterations in the hypothalamus-pituitary-adrenal axis, and decreased BDNF levels in the hippocampus. PMID:19705213
Comim, Clarissa M; Cassol-Jr, Omar J; Constantino, Leandra C; Petronilho, Fabrícia; Constantino, Larissa S; Stertz, Laura; Kapczinski, Flávio; Barichello, Tatiana; Quevedo, João; Dal-Pizzol, Felipe
Group B streptococci (GBS) is a leading cause of sepsis and meningitis in neonates and immunocompromised adults in western countries. GBS do not bind to fibronectin (Fn) in solution, but will bind to Fn adsorbed onto a solid surface. The reason for the specificity of this binding is unknown. Single molecule force spectroscopy was used to test the hypothesis that GBS, through streptococcal C5a peptidase (ScpB) molecules present on the surface of the bacteria, binds to a motif created by the juxtaposition of multiple adjacent Fn molecules. Atomic force microscopy (AFM) topographical images of adsorbed Fn deposited from various Fn coating concentrations were used to determine the Fn surface concentration. ScpB was tethered to an AFM tip with all surface modifications characterized by X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry. At the lowest Fn coverages the probability of observing a ScpB–Fn binding event increased linearly with Fn surface coverage. As an Fn monolayer was reached the probability of a ScpB–Fn binding event occurring increased markedly (~50 fold), with a concomitant increase in the rupture force from 17 pN to 33 pN. These results are consistent with the hypothesis that ScpB binds to a motif created by the juxtaposition of multiple Fn molecules.
Hull, James R.; Tamura, Glen S.; Castner, David G.
Background. Group A streptococcal (GAS) meningitis is rarely seen in the antenatal period, but it is associated with significant mortality. We present a case of a mid-trimester woman who developed fulminant meningitis following a rapid onset atypical presentation of infection with this organism. Case. A multiparous 23+5-week woman presented with a 10-day history of a non-productive cough associated with pyrexia. Within minutes of her admission she collapsed and lost consciousness; sepsis was suspected and cross-specialty care was initiated. She was managed empirically in extremis with broad-spectrum antibiotics and mannitol with 3% hypertonic saline for suspected infection and raised intracranial pressure, respectively. Despite intensivist management, a CT head revealed diffuse oedema with coning of the cerebellar tonsils. Brainstem death was certified within 19 hours of admission and fetal death ensued. Postmortem bacteriology confirmed GAS meningitis. Conclusion. Through raising awareness of this patient and her disease course, we hope that future policy decisions, primary care, and hospital level management will be informed accordingly for treatment of pregnant women with suspected GAS infection.
Kamaledeen, Abderahman; Law, Penelope
Streptococcal toxic shock syndrome (STSS) is the most severe form of invasive infections caused by group A streptococci. In this report, a 36-years-old man who was admitted to our clinic with the complaints of fever, rash, skin lesions, abdominal pain, weakness and anuria for 2 days, has been presented. His body temperature was 39.5 degrees C and blood pressure was 50/20 mmHg. In physical examination, diffuse erythematous rash on the body, cellulitis on left leg and foot, fungal lesions on the toes, and abdominal tenderness were noted. Laboratory results revealed a dramatic increase in leukocyte count, increased sedimentation rate, elevated blood urea nitrogen, cretinine, liver enzymes and bilirubin levels. Group A streptococci were isolated from the blood culture of the patient. Despite supportive (intravenous saline, dopamine) and antibiotic (clindamycin-ceftriaxone combination) therapies, adult respiratory distress syndrome has developed in two days, and he died on the third day. This case was presented to draw attention to STSS, which was a rare clinical entity with rapid progression to mortality despite aggressive medical therapy. PMID:14748269
Ozkurt, Zülal; Erol, Serpil; Ertek, Mustafa; Altoparlak, Ulkü; Ta?yaran, Mehmet A
The filterability of the broth-grown stable L-form derived from Streptococcus faecium F24 was tested by filtration under the influence of varying amounts of applied pressure. A decrease in the pore size of the filter resulted in a corresponding decrease in viable count, but no major effect was noted due to the different pressures applied. Serial filtration of a deoxyribonuclease-treated L-form culture in the mid-logarithmic phase of growth resulted in recovery of viable L-forms from the 0.45-?m filtrate but not from the 0.22-?m filtrate. It is possible that disruption of the L-form bodies with release of small viable elements had occurred. Protoplasts, diluted in an osmotic stabilizer, were filtered similarly; L-forms could be grown from the filtrate passing through the filters of 0.45 ?m or greater. Filtration of the parent streptococci gave rise to streptococcal colonies from the 1.2-?m filtrate only.
Wyrick, Priscilla B.; Gooder, Harry
Introduction. Severe sepsis and septic shock are the primary causes of multiple organ dysfunction syndrome (MODS), which is the most frequent cause of death in intensive care unit patients. Many pro- and anti-inflammatory mediators, such as interleukin-6 (IL-6), play a strategic role in septic syndrome. Continuous renal replacement therapy (CRRT) removes in a nonselective way pro- and anti-inflammatory mediators. Objective. To investigate the effects of continuous venovenous hemofiltration (CVVH) as an immunomodulatory treatment of sepsis in a prospective clinical study. Methods. High flux hemofiltration (Qf?=?60?ml/Kg/hr) was performed for 72?hr in thirteen critically ill patients suffering from severe sepsis or septic shock with acute renal failure (ARF). IL-6 gene expression was measured by real-time PCR analysis on RNA extracted from peripheral blood mononuclear cell before beginning of treatment (T0) and after 12, 24, 48, and 72 hours (T1–4). Results. Real-time PCR analysis demonstrated in twelve patients IL-6 mRNA reduction after 12 hours of treatment and a progressive increase after 24, 48, and 72 hours. Conclusions. We suggest that an immunomodulatory effect might exist during CVVH performed in critically ill patients with severe sepsis and septic shock. Our data show that the transcriptional activity of IL-6 increases during CVVH.
Servillo, Giuseppe; Pastore, Antonio; Procino, Alfredo; Iannuzzi, Michele; Capuano, Alfredo; Memoli, Andrea; Memoli, Bruno
Septic shock is characterized by increased vascular permeability and hypotension despite increased cardiac output. Numerous vasoactive cytokines are upregulated during sepsis, including angiopoietin 2 (ANG2), which increases vascular permeability. Here we report that mice engineered to inducibly overexpress ANG2 in the endothelium developed sepsis-like hemodynamic alterations, including systemic hypotension, increased cardiac output, and dilatory cardiomyopathy. Conversely, mice with cardiomyocyte-restricted ANG2 overexpression failed to develop hemodynamic alterations. Interestingly, the hemodynamic alterations associated with endothelial-specific overexpression of ANG2 and the loss of capillary-associated pericytes were reversed by intravenous injections of adeno-associated viruses (AAVs) transducing cDNA for angiopoietin 1, a TIE2 ligand that antagonizes ANG2, or AAVs encoding PDGFB, a chemoattractant for pericytes. To confirm the role of ANG2 in sepsis, we i.p. injected LPS into C57BL/6J mice, which rapidly developed hypotension, acute pericyte loss, and increased vascular permeability. Importantly, ANG2 antibody treatment attenuated LPS-induced hemodynamic alterations and reduced the mortality rate at 36 hours from 95% to 61%. These data indicate that ANG2-mediated microvascular disintegration contributes to septic shock and that inhibition of the ANG2/TIE2 interaction during sepsis is a potential therapeutic target.
Ziegler, Tilman; Horstkotte, Jan; Schwab, Claudia; Pfetsch, Vanessa; Weinmann, Karolina; Dietzel, Steffen; Rohwedder, Ina; Hinkel, Rabea; Gross, Lisa; Lee, Seungmin; Hu, Junhao; Soehnlein, Oliver; Franz, Wolfgang M.; Sperandio, Markus; Pohl, Ulrich; Thomas, Markus; Weber, Christian; Augustin, Hellmut G.; Fassler, Reinhard; Deutsch, Urban; Kupatt, Christian
Sepsis is a complex condition that results from a dysregulated immune system in response to a systemic infection. Current treatments lack effectiveness in reducing the incidence and mortality associated with this disease. The endocannabinoid system offers great promise in managing sepsis pathogenesis due to its unique characteristics. The present study explored the effect of modulating the CB2 receptor pathway in an acute sepsis mouse model. Endotoxemia was induced by intravenous injection of lipopolysaccharide (LPS) in mice and intestinal microcirculation was assessed through intravital microscopy. We found that HU308 (CB2 receptor agonist) reduced the number of adherent leukocytes in submucosal venules but did not restore muscular and mucosal villi FCD in endotoxemic mice. AM630 (CB2 receptor antagonist) maintained the level of adherent leukocytes induced by LPS but further reduced muscular and mucosal villi FCD. URB597 (FAAH inhibitor) and JZL184 (MAGL inhibitor) both reduced the number of adherent leukocytes in submucosal venules but did not restore the mucosal villi FCD. Using various compounds we have shown different mechanisms of activating CB2 receptors to reduce leukocyte endothelial interactions in order to prevent further inflammatory damage during sepsis.
Sardinha, J.; Kelly, M. E. M.; Zhou, J.; Lehmann, C.
Sepsis is a significant health problem with an estimated 750,000 new cases in the USA annually. It is also the third leading cause of death in developed countries, equaling the number of fatalities from acute myocardial infarction. The high sepsis-related mortalities mean there is an urgent need to improve the diagnosis and management of sepsis patients. The aim of this study was the evaluation of fibronectin and C-reactive protein (CRP) plasma levels in patients with sepsis and other infectious diseases without sepsis. In a case-control study, 90 patients with sepsis and 90 patients with other infectious diseases without sepsis were studied. Serum levels of fibronectin and CRP were measured. The data were analyzed by SPSS version 15. The mean levels of fibronectin in the cases and controls were 288.97±89.10 mg/l and 341.24±110.53 mg/l respectively (P=0.001). The mean levels of CRP in the cases and controls were 89.42±54.05 µg/ml and 27.42±25.89 µg/ml respectively (P<0.001). Concerning the source of infection, the mean CRP levels were significantly higher in septic patients with urinary tract infection, pneumonia, and soft tissue infection (P<0.001). Decreased levels of fibronectin and increased levels of CRP may be considered as reliable diagnostic markers for sepsis. Also, CRP could be a better predictive factor for sepsis than fibronectin. PMID:22837119
Mamani, Mojgan; Hashemi, Seyyed Hamid; Hajilooi, Mehrdad; Saedi, Farnaz; Niayesh, Amin; Fallah, Mohammad
The pathophysiology of sepsis and its accompanying systemic inflammatory response syndrome (SIRS) and the events that lead to multiorgan failure and death are poorly understood. It is known that, in septic humans and rodents, the development of SIRS is associated with a loss of the redox balance, but SIRS can also develop in non-infectious states. In addition, a hyperinflammatory state develops, together with impaired innate immune functions of phagocytes, immunosuppression, and complement activation, collectively leading to septic shock and lethality. Here we discuss recent insights into the signaling pathways in immune and phagocytic cells that underlie sepsis and SIRS and consider how these might be targeted for therapeutic interventions to reverse or attenuate pathways that lead to lethality during sepsis.
Bosmann, Markus; Ward, Peter A.
Background: Anaesthesia with concurrent sepsis is risky, and involves consideration of possible organ dysfunctions—respiratory, cardiovascular, renal, and haematological—as well as ensuring that appropriate antibiotics are given after taking the necessary microbiological specimens. Because prompt attention needs to be paid to so many body systems, the place for a structured approach during anaesthesia for a septic patient was assessed. Objectives: To examine the role of a previously described core algorithm "COVER ABCD–A SWIFT CHECK", supplemented by a specific sub-algorithm for sepsis, in the management of sepsis occurring in association with anaesthesia. Methods: The potential performance of this structured approach for each of the relevant incidents among the first 4000 reported to the Australian Incident Monitoring Study (AIMS) was compared with the actual management as reported by the anaesthetists involved. Results: Sepsis was identified as the primary problem in 13 of the first 4000 reports (<1%) to AIMS. The incidents reported generally occurred in sick patients; 70% were ASA status III or worse. The COVER ABCD algorithm provided a diagnosis and corrective manoeuvre in only 15% (2/13) of reported incidents, and the sepsis sub-algorithm provided adequate therapeutic strategies in a further 38% (5/13) of the incidents. Eight cases required the use of additional sub-algorithms for desaturation (30%), cardiac arrest (15%), hypotension (8%), and aspiration (8%). Conclusion: Sepsis involves a serious physiological stress upon multiple organ systems. The use of a structured approach involving a core algorithm and additional sub-algorithms as required provides a series of checklists that can successfully deal with the complex multiple and interrelating problems that these patients present.
Myburgh, J; Chapman, M; Szekely, S; Osborne, G
Sepsis is defined as an acute inflammatory response syndrome secondary to an infectious focus. It has a high incidence, morbidity and mortality, causing substantial financial costs, especially due to complications such as septic shock and multiple organ dysfunction. The pathogen toxins associated with individual susceptibility culminate with cytokine release, which promotes a systemic inflammatory response that can progress to multiple organ dysfunction and eventual patient death. Specifically, sepsis incidence, morbidity and mortality are lower in pregnant women, as this group is typically younger with fewer comorbidities having a polymicrobial etiology resulting in sepsis. Pregnant women exhibit physiological characteristics that may confer specific clinical presentation and laboratory patterns during the sepsis course. Thus, a better understanding of these changes is critical for better identification and management of these patients. The presence of a fetus also requires unique approaches in a pregnant woman with sepsis. Sepsis treatment is based on certain guidelines that were established after major clinical trials, which, unfortunately, all classified pregnancy as a exclusion criteria. Thus, the treatment of sepsis in the general population has been extrapolated to the pregnant population, with the following main goals: maintenance of tissue perfusion with fluid replacement and vasoactive drugs (initial resuscitation), adequate oxygenation, control of the infection source and an early start of antibiotic therapy, corticosteroid infusion and blood transfusion when properly indicated, prophylaxis, and specifically monitoring and maintenance of fetal heath.
Cordioli, Ricardo Luiz; Cordioli, Eduardo; Negrini, Romulo; Silva, Eliezer
Sepsis is defined as an acute inflammatory response syndrome secondary to an infectious focus. It has a high incidence, morbidity and mortality, causing substantial financial costs, especially due to complications such as septic shock and multiple organ dysfunction. The pathogen toxins associated with individual susceptibility culminate with cytokine release, which promotes a systemic inflammatory response that can progress to multiple organ dysfunction and eventual patient death. Specifically, sepsis incidence, morbidity and mortality are lower in pregnant women, as this group is typically younger with fewer comorbidities having a polymicrobial etiology resulting in sepsis. Pregnant women exhibit physiological characteristics that may confer specific clinical presentation and laboratory patterns during the sepsis course. Thus, a better understanding of these changes is critical for better identification and management of these patients. The presence of a fetus also requires unique approaches in a pregnant woman with sepsis. Sepsis treatment is based on certain guidelines that were established after major clinical trials, which, unfortunately, all classified pregnancy as a exclusion criteria. Thus, the treatment of sepsis in the general population has been extrapolated to the pregnant population, with the following main goals: maintenance of tissue perfusion with fluid replacement and vasoactive drugs (initial resuscitation), adequate oxygenation, control of the infection source and an early start of antibiotic therapy, corticosteroid infusion and blood transfusion when properly indicated, prophylaxis, and specifically monitoring and maintenance of fetal heath. PMID:24553516
Cordioli, Ricardo Luiz; Cordioli, Eduardo; Negrini, Romulo; Silva, Eliezer
Sepsis is the complex syndrome characterized by an imbalance between proinflammatory and antiinflammatory response to infection. The brain may be affected during the sepsis, and acute and long-term brain dysfunctions have been observed in both animal models and septic patients. Oxidative stress and antioxidant systems may prove the basis underling brain dysfunction in sepsis. The antioxidant therapy may be theoretically achieved by the following strategies: restoring endogenous antioxidants and nutrients and supplementation with exogenous trace elements, vitamins, and nutrients with antioxidant proprieties; or administering drugs that reduce oxidative stress, such as N-acetylcysteine (NAC), vitamins and statins. In the review, we described below the involvement of oxidative stress and antioxidants defenses and potential utility of these strategies and present data regarding their use in sepsis. PMID:24329483
Steckert, Amanda Valnier; de Castro, Adalberto Alves; Quevedo, Joao; Dal-Pizzol, Felipe
Acute nephritic syndrome is clinically characterized by hematuria, proteinuria, oliguria, and volume overload with or without azotemia and histologically be acute proliferative glomerulonephritis. Acute post streptococcal glomerulonephritis is the commonest cause in children. There is a preceding infection prior to this condition in majority. This is one of the comonest causes of renal edema in children. Early recognition, prompt and aggressive therapy and adequate follow-up are mandatory. Prognosis is usually good unless associated with severe renal failure and crescentic glomerulonephritis where the outcome is relatively poor unless treatment is early and adequate. Pathologically acute proliferative nephritis is with diffuse proliferative glomerulonephritis with or without crescents. Immunosuppressive therapy is not needed in simple acute proliferative glomerulonephritis but is essential in modifying the outcome of crescentic glomerulonephritis. Delayed resolution, severe renal failure at onset, progressive renal failure and associated systemic features like skin rashes, joint pains, hepatosplenomegaly and persistent fever are the indications for biopsy. Overall the prognosis in classical post streptococcal acute proliferative glomerulonephritis is good. PMID:12557962
Background Sepsis- associated encephalopathy (SAE) is an early and common feature of severe infections. Oxidative stress is one of the mechanisms associated with the pathophysiology of SAE. The goal of this study was to investigate the involvement of NADPH oxidase in neuroinflammation and in the long-term cognitive impairment of sepsis survivors. Methods Sepsis was induced in WT and gp91phox knockout mice (gp91phox-/-) by cecal ligation and puncture (CLP) to induce fecal peritonitis. We measured oxidative stress, Nox2 and Nox4 gene expression and neuroinflammation in the hippocampus at six hours, twenty-four hours and five days post-sepsis. Mice were also treated with apocynin, a NADPH oxidase inhibitor. Behavioral outcomes were evaluated 15 days after sepsis with the inhibitory avoidance test and the Morris water maze in control and apocynin-treated WT mice. Results Acute oxidative damage to the hippocampus was identified by increased 4-HNE expression in parallel with an increase in Nox2 gene expression after sepsis. Pharmacological inhibition of Nox2 with apocynin completely inhibited hippocampal oxidative stress in septic animals. Pharmacologic inhibition or the absence of Nox2 in gp91phox-/- mice prevented glial cell activation, one of the central mechanisms associated with SAE. Finally, treatment with apocynin and inhibition of hippocampal oxidative stress in the acute phase of sepsis prevented the development of long-term cognitive impairment. Conclusions Our results demonstrate that Nox2 is the main source of reactive oxygen species (ROS) involved in the oxidative damage to the hippocampus in SAE and that Nox2-derived ROS are determining factors for cognitive impairments after sepsis. These findings highlight the importance of Nox2-derived ROS as a central mechanism in the development of neuroinflammation associated with SAE.
We address the identification of optimal biomarkers for the rapid diagnosis of neonatal sepsis. We employ both canonical correlation analysis (CCA) and sparse support vector machine (SSVM) classifiers to select the best subset of biomarkers from a large hematological data set collected from infants with suspected sepsis from Yale-New Haven Hospital's Neonatal Intensive Care Unit (NICU). CCA is used to select sets of biomarkers of increasing size that are most highly correlated with infection. The effectiveness of these biomarkers is then validated by constructing a sparse support vector machine diagnostic classifier. We find that the following set of five biomarkers capture the essential diagnostic information (in order of importance): Bands, Platelets, neutrophil CD64, White Blood Cells, and Segs. Further, the diagnostic performance of the optimal set of biomarkers is significantly higher than that of isolated individual biomarkers. These results suggest an enhanced sepsis scoring system for neonatal sepsis that includes these five biomarkers. We demonstrate the robustness of our analysis by comparing CCA with the Forward Selection method and SSVM with LASSO Logistic Regression.
Wang, Kun; Bhandari, Vineet; Chepustanova, Sofya; Huber, Greg; O?Hara, Stephen; O?Hern, Corey S.; Shattuck, Mark D.; Kirby, Michael
Sepsis is characterized by systemic biochemical alterations including the central nervous system in the early times and cognitive impairment at later times after sepsis induction in the animal model. Recent studies have shown that, besides its hematological activity, erythropoietin (EPO) has cytoprotective effects on various cells and tissues. In order to corroborate elucidating the effects of alternative drugs for sepsis treatment, we evaluated the effects of both acute and chronic EPO treatment on oxidative stress and energetic metabolism in the hippocampus, and cognitive impairment, respectively, after sepsis induction by cecal ligation and perforation (CLP). To this aim, male Wistar rats underwent CLP with "basic support" or sham operation. In the acute treatment, EPO was administered once immediately after CLP induction. The rats were then killed after 6 and 24 h, and the hippocampus was removed for analysis of oxidative stress and energetic metabolism, respectively. Regarding the chronic treatment, EPO was administered once daily until the 4th day after induction. Aversive memory was tested on the 10th day after surgery. It was observed that the acute use of EPO (a single dose) alters the oxidative parameters and energetic metabolism. Chronic use (4 days) reversed cognitive impairment in the sepsis animal model. Mortality rates were attenuated only during chronic treatment. PMID:22350588
Comim, Clarissa M; Cassol, Omar J; Abreu, Igor; Moraz, Thais; Constantino, Larissa S; Vuolo, Francieli; Galant, Letícia S; de Rochi, Natália; Dos Santos Morais, Meline O; Scaini, Giselli; Barichello, Tatiana; Streck, Emílio L; Quevedo, João; Dal-Pizzol, Felipe
Sepsis represents a major challenge in medicine. It begins as a systemic response to infection that can affect virtually any organ system, including the central and peripheral nervous systems. Akin to management of stroke, early recognition and treatment of sepsis are just as crucial to a successful outcome. Sepsis can precipitate myasthenic crisis and lead to encephalopathy and critical illness neuropathy. Stroke and traumatic brain injury can predispose a patient to develop sepsis, whereas Guillain-Barré syndrome is similarly not uncommon following infection. This review article will first describe the essential principles of sepsis recognition, pathophysiology, and management and will then briefly cover the neurologic aspects associated with sepsis. Vigilant awareness of the clinical features of sepsis and timeliness of intervention can help clinicians prevent progression of this disease to a multisystem organ failure, which can be difficult to reverse even after the original source of infection is under control. PMID:23983879
Karnatovskaia, Lioudmila V; Festic, Emir
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 how immune responses against group A streptococci influence autoimmunity and inflammatory responses in the heart and brain. PMID:24892819
Cunningham, Madeleine W
Clostridium perfringens sepsis with intravascular haemolysis is a catastrophic process with a reported mortality of between 90 to 100%. We successfully treated a case of severe clostridial infection with a liver abscess following laparoscopic cholecystectomy, the first to our knowledge. A 59-year-old man presented one week after an uneventful laparoscopic cholecystectomy with jaundice, peritonism, sepsis and acute renal failure. He was found to have a haemolytic anaemia, unconjugated hyperbilirubinemia and blood cultures grew Clostridium perfringens. A CT revealed a large gas forming abscess in the gallbladder fossa and right lobe of liver. He was treated with directed antibiotic therapy and underwent emergency laparotomy, drainage of the abscess and peritoneal washout. He required intensive care support, parenteral nutrition and inotropic support for a limited period. CT liver angiogram post op was normal. Continued renal dysfunction necessitated protracted haemofiltration. This resolved and the patient was discharged home at 2 months.
Qandeel, H; Abudeeb, H; Hammad, A; Ray, C; Sajid, M; Mahmud, S
Acute kidney injury (AKI) is a common complication of hospitalized patients, and clinical outcomes remain poor despite advances in renal replacement therapy. The accepted pathophysiology of AKI in the setting of sepsis has evolved from one of simple decreased renal blood flow to one that involves a more complex interaction of intra-glomerular microcirculatory vasodilation combined with the local release of inflammatory mediators and apoptosis. Evidence from pre-clinical AKI models suggests that crosstalk occurs between kidneys and other organ systems via soluble and cellular inflammatory mediators, and that this involves both the innate and adaptive immune systems. These interactions are reflected by genomic changes and abnormal rates of cellular apoptosis in distant organs including the lungs, heart, gut, liver, and central nervous system. The purpose of this article is to review the influence of AKI, particularly sepsis-associated AKI, on inter-organ crosstalk in the context of systemic inflammation and multiple organ failure (MOF).
White, Laura E.; Chaudhary, Rahul; Moore, Laura J.; Moore, Frederick A.; Hassoun, Heitham T.
Rationale: Hospitalizations for severe sepsis are common, and a growing number of patients survive to hospital discharge. Nonetheless, little is known about survivors' post-discharge healthcare use. Objectives: To measure inpatient healthcare use of severe sepsis survivors compared with patients' own presepsis resource use and the resource use of survivors of otherwise similar nonsepsis hospitalizations. Methods: This is an observational cohort study of survivors of severe sepsis and nonsepsis hospitalizations identified from participants in the Health and Retirement Study with linked Medicare claims, 1998-2005. We matched severe sepsis and nonsepsis hospitalizations by demographics, comorbidity burden, premorbid disability, hospitalization length, and intensive care use. Measurements and Main Results: Using Medicare claims, we measured patients' use of inpatient facilities (hospitals, long-term acute care hospitals, and skilled nursing facilities) in the 2 years surrounding hospitalization. Severe sepsis survivors spent more days (median, 16 [interquartile range, 3-45] vs. 7 [0-29]; P < 0.001) and a higher proportion of days alive (median, 9.6% [interquartile range, 1.4-33.8%] vs. 1.9% [0.0-7.9%]; P < 0.001) admitted to facilities in the year after hospitalization, compared with the year prior. The increase in facility-days was similar for nonsepsis hospitalizations. However, the severe sepsis cohort experienced greater post-discharge mortality (44.2% [95% confidence interval, 41.3-47.2%] vs. 31.4% [95% confidence interval, 28.6-34.2%] at 1 year), a steeper decline in days spent at home (difference-in-differences, -38.6 d [95% confidence interval, -50.9 to 26.3]; P < 0.001), and a greater increase in the proportion of days alive spent in a facility (difference-in-differences, 5.4% [95% confidence interval, 2.8-8.1%]; P < 0.001). Conclusions: Healthcare use is markedly elevated after severe sepsis, and post-discharge management may be an opportunity to reduce resource use. PMID:24872085
Prescott, Hallie C; Langa, Kenneth M; Liu, Vincent; Escobar, Gabriel J; Iwashyna, Theodore J
Von Willebrand factor (VWF)-cleaving protease (ADAMTS13) cleaves ultralarge VWF (ULVWF) secreted from endothelium and by which is regulating its physiologic function. An imbalance between ULVWF secretion and ADAMTS13 level occurs in sepsis and may cause multiple organ dysfunction. We evaluated the association between the VWF-propeptide (VWF-pp)/ADAMTS13 ratio and disease severity in patients with severe sepsis or septic shock. In 27 patients with severe sepsis or septic shock and platelet count less than 120,000/?L, we measured plasma VWF, VWF-pp, and ADAMTS13 levels on hospital days 1, 3, 5, and 7. The VWF-pp/ADAMTS13 ratio was increased greater than 12-fold in patients with severe sepsis or septic shock on day 1 and remained markedly high on days 3, 5, and 7 compared with normal control subjects. The VWF-pp/ADAMTS13 ratio significantly correlated with Acute Physiology and Chronic Health Evaluation II score on days 1 and 5; Sepsis-related Organ Failure Assessment score on days 1, 3, and 5; maximum Sepsis-related Organ Failure Assessment score and tumor necrosis factor ? level on days 1, 3, 5, and 7; and creatinine level on days 1, 5, and 7. Patients with greater than stage 1 acute kidney injury had significantly higher VWF-pp/ADAMTS13 ratio than patients without acute kidney injury. In summary, the VWF-pp/ADAMTS13 ratio was associated with disease severity in patients with severe sepsis or septic shock and may help identify patients at risk for multiple organ dysfunction by detecting severe imbalance between ULVWF secretion and ADAMTS13 level. PMID:23481506
Fukushima, Hidetada; Nishio, Kenji; Asai, Hideki; Watanabe, Tomoo; Seki, Tadahiko; Matsui, Hideto; Sugimoto, Mitsuhiko; Matsumoto, Masanori; Fujimura, Yoshihiro; Okuchi, Kazuo
Introduction Several observational studies suggest that statins modulate the pathophysiology of sepsis and may prevent its progression. The aim of this study was to determine if the acute administration of atorvastatin reduces sepsis progression in statin naïve patients hospitalized with sepsis. Methods A single centre phase II randomized double-blind placebo-controlled trial. Patients with sepsis were randomized to atorvastatin 40 mg daily or placebo for the duration of their hospital stay up to a maximum of 28-days. The primary end-point was the rate of sepsis progressing to severe sepsis during hospitalization. Results 100 patients were randomized, 49 to the treatment with atorvastatin and 51 to placebo. Patients in the atorvastatin group had a significantly lower conversion rate to severe sepsis compared to placebo (4% vs. 24% p = 0.007.), with a number needed to treat of 5. No significant difference in length of hospital stay, critical care unit admissions, 28-day and 12-month readmissions or mortality was observed. Plasma cholesterol and albumin creatinine ratios were significantly lower at day 4 in the atorvastatin group (p < 0.0001 and p = 0.049 respectively). No difference in adverse events between the two groups was observed (p = 0.238). Conclusions Acute administration of atorvastatin in patients with sepsis may prevent sepsis progression. Further multi-centre trials are required to verify these findings. Trial Registration International Standard Randomized Control Trial Registry ISRCTN64637517.
Dynamic changes in microvascular endothelial structure and function are pivotal in the acute inflammatory response, the body's rapid, coordinated effort to localize, sequester, and eliminate microbial invaders at their portal of entry. To achieve this, the endothelium becomes leaky and inflamed, providing innate immune cells and humoral effector molecules access to the site of infection. During sepsis this locally adaptive response becomes manifest throughout the body, leading to dangerous host consequences. Increased leakiness in the pulmonary circulation contributes to acute respiratory distress syndrome (ARDS), a complication of sepsis associated with 40% mortality. Understanding the molecular governance of vascular leak and inflammation has major diagnostic, prognostic, and potentially therapeutic implications for this common and pernicious disease. This review summarizes results from cell-based experiments, animal models, and observational human studies; together, these studies suggest that an endothelial receptor called Tie2 and its ligands, called angiopoietins, form a signaling axis key to the vascular dyshomeostasis that underlies sepsis. PMID:23652985
Parikh, Samir M
Acute post-streptococcal glomerulonephritis (PSGN) is characterized by an abrupt onset of edema, hypertension, and hematuria. Life-threatening diffuse alveolar hemorrhage (DAH) is rarely associated with acute PSGN. There have been only two reported cases worldwide, and no case has been reported previously in Korea. Here, we present a patient who clinically presented with pulmonary-renal syndrome; the renal histology revealed post-infectious glomerulonephritis of immune complex origin. A 59-yr-old woman was admitted with oliguria and hemoptysis two weeks after pharyngitis. Renal insufficiency rapidly progressed, and respiratory distress developed. Chest radiography showed acute progressive bilateral pulmonary infiltrates. The clinical presentation suggested DAH with PSGN. Three days after treatment with high-dose steroids, the respiratory distress and pulmonary infiltrates resolved. Electron microscopy of a renal biopsy specimen sample revealed diffuse proliferative glomerulonephritis with characteristic subendothelial deposits of immune complex (''hump''). The renal function of the patient was restored, and the serum creatinine level was normalized after treatment. PMID:18162726
Sung, Hye Young; Lim, Chang Hoon; Shin, Mi Jung; Kim, Byung Soo; Kim, Young Ok; Song, Ho Chul; Kim, Suk Young; Choi, Euy Jin; Chang, Yoon Sik; Bang, Byung Kee
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.
Shao, Yang; Wang, Xiang; Wu, Xi; Gao, Wei; He, Qing-hua; Cai, Shaoxi
At present, the only reasonable action which reduces the case fatality rate at patients with severe sepsis and septic shock is the early diagnosis of infection which allows to introduce effective therapy. Although sepsis is a typical clinical syndrome recognized in connection with infection, it should be remembered that infection does not reveal itself in each case. Also bacteriological blood culture does not confirm it in most cases. In view of few characteristic, especially in the initial phase of sepsis, clinical symptoms, laboratory investigations describing the present state of immune response of organism find a huge application. In our work we made an attempt to bring closer the latest markers of inflammatory reaction and infection such as acute phase proteins procalcytonin (PCT), proANP and lipopolisacharyde binding protein (LBP). PMID:17249188
Paradowski, Marek; Szablewski, Mariusz; Piatas, S?awomir; Urbaniak, Anna; Majda, Jacek
Patients with sepsis often require anaesthesia for surgical procedures. Anaesthesia can be unpredictable and the most haemodynamically\\u000a stable agents are used. No data are available for the minimum alveolar concentration (MAC) requirements in such patients or\\u000a in animal models of sepsis. We have characterized the effect of sepsis on the MAC of isoflurane in a normotensive rodent model\\u000a of sepsis.
Ravi Gill; Claudio Martin; Ted McKinnon; Calvin Lain; David Cunningham; William J. Sibbald
We describe a 15-year-old boy with acute transient encephalopathy complicating poststreptococcal glomerulonephritis. Based on advanced magnetic resonance imaging, cerebral alterations were related to cerebrovascular autoregulatory dysfunction (ie, a vasogenic edema) and vasculitis was excluded. These insights into the pathophysiology improve patient management and argue against the therapeutic immunosuppression postulated by some authors. PMID:16395114
Fux, Christoph A; Bianchetti, Mario G; Jakob, Stephan M; Remonda, Luca
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.
Lopez Sastre, Jose B; Solis, David Perez; Serradilla, Vicente Roques; Colomer, Belen Fernandez; Cotallo, Gil D Coto
Background Conventional C-reactive protein assays have been used to detect or guide the treatment of acute sepsis. The objective of this study was to determine the association between elevated baseline high-sensitivity C-reactive protein (hsCRP) and the risk of future sepsis events. Methods We studied data from 30,239 community dwelling, black and white individuals, age ?45 years old enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Baseline hsCRP and participant characteristics were determined at the start of the study. We identified sepsis events through review of hospital records. Elevated hsCRP was defined as values >3.0 mg/L. Using Cox regression, we determined the association between elevated hsCRP and first sepsis event, adjusting for sociodemographic factors (age, sex, race, region, education, income), health behaviors (tobacco and alcohol use), chronic medical conditions (coronary artery disease, diabetes, dyslipidemia, hypertension, chronic kidney disease, chronic lung disease) and statin use. Results Over the mean observation time of 5.7 years (IQR 4.5–7.1), 974 individuals experienced a sepsis event, and 11,447 (37.9%) had elevated baseline hsCRP (>3.0 mg/L). Elevated baseline hsCRP was independently associated with subsequent sepsis (adjusted HR 1.56; 95% CI 1.36–1.79), adjusted for sociodemographics, health behaviors, chronic medical conditions and statin use. Conclusion Elevated baseline hsCRP was associated with increased risk of future sepsis events. hsCRP may help to identify individuals at increased risk for sepsis.
Wang, Henry E.; Shapiro, Nathan I.; Safford, Monika M.; Griffin, Russell; Judd, Suzanne; Rodgers, Joel B.; Warnock, David G.; Cushman, Mary; Howard, George
Widespread vascular endothelial injury is the major mechanism for multiorgan dysfunction in sepsis. Following this process, the permeability of the alveolar capillaries is augmented with subsequent increase in water content and acute respiratory distress syndrome (ARDS). Nevertheless, the role of alveolar epithelium is less known. Therefore, we examined alveolar fluid clearance (AFC) using isolated perfused rat lung model in septic rats without ARDS. Sepsis was induced by ligating and puncturing the cecum with a 21-gauge needle. AFC was examined 24 and 48 h later. The expression of Na-K-ATPase proteins was examined in type II alveolar epithelial cells (ATII) and basolateral membrane (BLM). The rate of AFC in control rats was 0.51 ± 0.02 ml/h (means ± SE) and decreased to 0.3 ± 0.02 and 0.33 ± 0.03 ml/h in 24 and 48 h after sepsis induction, respectively (P < 0.0001). Amiloride, significantly decreased AFC in sepsis; conversely, isoproterenol reversed the inhibitory effect of sepsis. The alveolar-capillary barrier in septic rats was intact; therefore the finding of increased extravascular lung water in early sepsis could be attributed to accumulation of protein-poor fluid. The expression of epithelial sodium channel and Na-K-ATPase proteins in whole ATII cells was not different in both cecal ligation and puncture and control groups; however, the abundance of Na-K-ATPase proteins was significantly decreased in BLMs of ATII cells in sepsis. Early decrease in AFC in remote sepsis is probably related to endocytosis of the Na-K-ATPase proteins from the cell plasma membrane into intracellular pools, with resultant inhibition of active sodium transport in ATII cells. PMID:21478253
Berger, Gidon; Guetta, Julia; Klorin, Geula; Badarneh, Reem; Braun, Eyal; Brod, Vera; Saleh, Niroz Abu; Katz, Adriana; Bitterman, Haim; Azzam, Zaher S
Background and the purpose of the study Analysis of current immunomodulating strategies indicates that monovalent approaches are unlikely to restore immunostasis or achieve complete therapy of sepsis. Setarud (IMOD) as a mixture of urtica, carotenoids, urea, and selenium has been recently patented for its potential in reduction of Tumor Necrosis Factor alpha (TNF-?) and Interferon-? and Interleukin-2 levels. The aim of this study was to examine efficacy of IMOD in the management of patients with severe sepsis. Methods Twenty patients with severe sepsis and acute physiology and chronic health evaluation (APACHE) score of more than 20 were randomized to receive standard treatment of severe sepsis (control group) or standard treatment plus IMOD (IMOD group). The group treated with IMOD for 14 days was according to the pilot study and regarding the stability of patient's conditions in the ICU. Of course patients in both groups received standard treatment and all were monitored for 28 days. Blood samples were analyzed for interleukins (IL-1, IL-2, IL-6), plasminogen activator inhibitor (PAI-1), TNF-?, total thiol molecules (TTM), nitric oxide (NO), total antioxidant power (TAP), and lipid peroxidation (LPO). Daily APACHE, Sequential Organ Failure Assessment (SOFA), and Simplified Acute Physiology Score (SAPS) were calculated. Results and major conclusion Comparing with controls, IMOD was significantly effective in improving SAPS, SOFA, and APACHE scores, and reduction of mortality rate. Among tested inflammatory biomarkers, IMOD significantly improved TTM and TNF-? values. It is concluded that IMOD might be added as a safe adjutant to standard treatment of severe sepsis.
Mahmoodpoor, A.; Eslami, K.; Mojtahedzadeh, M.; Najafi, A.; Ahmadi, A.; Dehnadi-Moghadam, A.; Mohammadirad, A.; Baeeri, M.; Abdollahi, M.
Narcolepsy-cataplexy is an uncommon sleep disorder which may present in childhood. We report a case of an 8-year-old presenting with narcolepsy-cataplexy following a streptococcal infection. Autoimmune etiology for narcolepsy has been suggested. In our patient increased anti-streptolysin O and anti-DNAse B titers were noted. As suggested by recent cases, the streptococcal infection was likely a trigger for narcolepsy onset in this genetically predisposed child. The patient was initially diagnosed as having Sydenham chorea due to motor movements. However, these transient movements may be due to the narcolepsy onset. Narcolepsy in childhood may present with atypical symptoms; it might be difficult to obtain accurate history and can be misdiagnosed as in the reported case. A high index of clinical suspicion is needed to diagnose these patients. PMID:23493659
Natarajan, Niranjana; Jain, Sejal V; Chaudhry, Hina; Hallinan, Barbara E; Simakajornboon, Narong
M protein, the major virulence factor of group A streptococci, has antiopsonic activity in that it inhibits activation of the alternative complement pathway on the streptococcal surface. Two properties of M protein have been claimed to account for the inhibitory activity, namely, (i) its binding affinity for complement factor H, which is an inhibitor of alternative pathway activation, and (ii) its high binding affinity for fibrinogen. We have recently shown that fibrinogen, like M protein, inhibits alternative pathway activation by possessing binding affinity for factor H. Here we report that fibrinogen effectively competes with factor H for binding to M protein but retains its own binding affinity for factor H. The presence of fibrinogen did not significantly affect alternative pathway inhibition on the streptococcal surface. Images
Horstmann, R D; Sievertsen, H J; Leippe, M; Fischetti, V A
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
Johnston, Andrew McD; Easby, D; Ewington, I
Perianal streptococcal dermatitis is an infectious disease that predominantly affects younger children and is mostly caused\\u000a by Group A ?-hemolytic streptococci. Although patients are mostly seen primarily by their pediatrician or family physician,\\u000a the diagnosis is not infrequently established just after referral to a dermatologist or colorectal surgeon. We report a case\\u000a series of 124 children, aged 14 years or younger,
Johannes Jongen; Anne Eberstein; Hans-Günter Peleikis; Volker Kahlke; Rudolf A. Herbst
Expanded abstract Citation Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, Madsen KR, Møller MH, Elkjær JM, Poulsen LM, Bendtsen A, Winding R, Steensen M, Berezowicz P, Søe-Jensen P, Bestle M, Strand K, Wiis J, White JO, Thornberg KJ, Quist L, Nielsen J, Andersen LH, Holst LB, Thormar K, Kjældgaard AL, Fabritius ML, Mondrup F, Pott FC, Møller TP, Winkel P, Wetterslev J; 6S Trial Group; Scandinavian Critical Care Trials Group: Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012, 367:124-34. Background Hydroxyethyl starch (HES) is widely used for fluid resuscitation in ICUs, but its safety and efficacy have not been established in patients with severe sepsis. Methods Objective To assess the effects of HES 130/0.4 compared with a balanced crystalloid solution on mortality and end-stage kidney failure in patients with severe sepsis. Design Multicenter, parallel-group, blinded, randomized clinical trial, in patients with severe sepsis. Interventions Patients with severe sepsis admitted to the ICU received fluid resuscitation with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. Results Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval (CI), 1.01 to 1.36; P = 0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P = 0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P = 0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline. Conclusions Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal replacement therapy compared with those receiving Ringer's acetate.
EXPANDED ABSTRACT: CITATION: Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, Madsen KR, Møller MH, Elkjær JM, Poulsen LM, Bendtsen A, Winding R, Steensen M, Berezowicz P, Søe-Jensen P, Bestle M, Strand K, Wiis J, White JO, Thornberg KJ, Quist L, Nielsen J, Andersen LH, Holst LB, Thormar K, Kjældgaard AL, Fabritius ML, Mondrup F, Pott FC, Møller TP, Winkel P, Wetterslev J; 6S Trial Group; Scandinavian Critical Care Trials Group: Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012, 367:124-34. BACKGROUND: Hydroxyethyl starch (HES) is widely used for fluid resuscitation in ICUs, but its safety and efficacy have not been established in patients with severe sepsis. METHODS: OBJECTIVE: To assess the effects of HES 130/0.4 compared with a balanced crystalloid solution on mortality and end-stage kidney failure in patients with severe sepsis. DESIGN: Multicenter, parallel-group, blinded, randomized clinical trial, in patients with severe sepsis. INTERVENTIONS: Patients with severe sepsis admitted to the ICU received fluid resuscitation with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. RESULTS: Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval (CI), 1.01 to 1.36; P = 0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P = 0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P = 0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline. CONCLUSIONS: Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal replacement therapy compared with those receiving Ringer's acetate. PMID:23509901
Estrada, Carlos A; Murugan, Raghavan
Introduction Sepsis is still a leading cause of morbidity and mortality, even in modern times, and thrombocytopenia has been closely associated with unfavorable disease outcome. Decreases in mitochondrial membrane potential (depolarization) were found in different tissues during sepsis. Previous work suggests that mitochondrial dysfunction of platelets correlates with clinical disease activity in sepsis. However, platelet mitochondrial membrane potential (Mmp) has not been investigated in a clinical follow-up design and not with regard to disease outcome. Methods In this study, platelet mitochondrial membrane depolarization was assessed by means of a fluorescent Mmp-Index with flow cytometry in 26 patients with sepsis compared with control patients. Platelet Mmp-Index on admission was correlated with the clinical disease scores Acute Physiology and Chronic Health Evaluation Score II (APACHE II), Sequential Organ Failure Score (SOFA), and Simplified Acute Physiology Score II (SAPS II). Finally, platelet Mmp-Index on admission and follow-up were compared in the group of sepsis survivors and nonsurvivors. Expression of the prosurvival protein Bcl-xL in platelets was quantified by immunoblotting. Results Platelet mitochondrial membrane depolarization correlated significantly with the simultaneously assessed clinical disease severity by APACHE II (r?=?-0.867; P?0.0001), SOFA (r?=?-0.857; P <0.0001), and SAPS II score (r?=?-0.839; P?0.0001). Patients with severe sepsis showed a significant reduction in platelet Mmp-Index compared with sepsis without organ failure (0.18 (0.12 to 0.25) versus 0.79 (0.49 to 0.85), P?0.0006) or with the control group (0.18 (0.12 to 0.25) versus 0.89 (0.68 to 1.00), P?0.0001). Platelet Mmp-Index remained persistently low in sepsis nonsurvivors (0.269 (0.230 to 0.305)), whereas we observed recovery of platelet Mmp-Index in the survivor group (0.9 (0.713 to 1.017)). Furthermore, the level of prosurvival protein Bcl-xL decreased in platelets during severe sepsis. Conclusion In this study, we demonstrated that mitochondrial membrane depolarization in platelets correlates with clinical disease severity in patients with sepsis during the disease course and may be a valuable adjunct parameter to aid in the assessment of disease severity, risk stratification, and clinical outcome.
Accurate and timely diagnosis of early onset neonatal sepsis remains challenging to the clinician and the laboratory. A test with a rapid turnaround time with 100% sensitivity, rather than high specificity, which allows accurate diagnosis and appropriate antimicrobial treatment or which allows antibiotics to be safely withheld in non?infected infants, is desirable. Many potential markers (acute phase reactants, cell surface markers, cytokines) are not routinely available to the laboratory, and most likely combinations of markers will ensure greater diagnostic accuracy. In the future, molecular biology techniques offer the prospect of rapid identification of both pathogens and antimicrobial resistance markers.
Mishra, U K; Jacobs, S E; Doyle, L W; Garland, S M
Narcolepsy-cataplexy is an uncommon sleep disorder which may present in childhood. We report a case of an 8-year-old presenting with narcolepsy-cataplexy following a streptococcal infection. Autoimmune etiology for narcolepsy has been suggested. In our patient increased anti-streptolysin O and anti-DNAse B titers were noted. As suggested by recent cases, the streptococcal infection was likely a trigger for narcolepsy onset in this genetically predisposed child. The patient was initially diagnosed as having Sydenham chorea due to motor movements. However, these transient movements may be due to the narcolepsy onset. Narcolepsy in childhood may present with atypical symptoms; it might be difficult to obtain accurate history and can be misdiagnosed as in the reported case. A high index of clinical suspicion is needed to diagnose these patients. Citation: Natarajan N; Jain SV; Chaudhry H; Hallinan BE; Simakajornboon N. Narcolepsy-cataplexy: is streptococcal infection a trigger? J Clin Sleep Med 2013;9(3):269-270.
Natarajan, Niranjana; Jain, Sejal V.; Chaudhry, Hina; Hallinan, Barbara E.; Simakajornboon, Narong
Perianal streptococcal dermatitis (PSD) is a pediatric dermatologic infectious disease predominantly affecting children, particularly younger children, which is most commonly caused by group A beta-hemolytic streptococci (GABHS). Although the clinical picture of a sharply demarcated erythema is very characteristic, PSD is often misdiagnosed for long periods of time and patients are subjected to treatments for a variety of differential diagnoses. Vulvar and penile involvement with similar signs and symptoms have been documented in several patients with PSD. The diagnosis is made by either a swab of the affected region submitted for microbiological analysis with the specific question for GABHS, or a rapid strep test. Systemic antibiotics such as penicillin, erythromycin, newer macrolides, or others, probably augmented by topical antiseptic or antibiotic ointments are the treatment of choice. Treatment duration should be at least 14 days or, even better, 21 days, and be dictated by clinical and microbiological cure. Therefore treatment success should be investigated not only by clinical examination but also by post-treatment perineal swabs as well as a urine analysis to monitor for post-streptococcal glomerulonephritis. The author of this review supports the recent suggestion to summarize GABHS-induced vulvovaginal and penile infections together with PSD under the inclusive term 'perineal streptococcal disease' because these conditions coincide, share important clinical characteristics and, therefore, represent manifestations of the same disease. PMID:12862498
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 useful as part of a full sepsis evaluation.
Lopez Sastre, Jose B; Perez Solis, David; Roques Serradilla, Vicente; Fernandez Colomer, Belen; Coto Cotallo, Gil D; Krauel Vidal, Xavier; Narbona Lopez, Eduardo; Garcia del Rio, Manuel; Sanchez Luna, Manuel; Belaustegui Cueto, Antonio; Moro Serrano, Manuel; Urbon Artero, Alfonso; Alvaro Iglesias, Emilio; Cotero Lavin, Angel; Martinez Vilalta, Eduardo; Jimenez Cobos, Bartolome
Introduction Ultrasound measurements of brachial artery reactivity in response to stagnant ischemia provide estimates of microvascular function and conduit artery endothelial function. We hypothesized that brachial artery reactivity would independently predict severe sepsis and severe sepsis mortality. Methods This was a combined case-control and prospective cohort study. We measured brachial artery reactivity in 95 severe sepsis patients admitted to the medical and surgical intensive care units of an academic medical center and in 52 control subjects without acute illness. Measurements were compared in severe sepsis patients versus control subjects and in severe sepsis survivors versus nonsurvivors. Multivariable analyses were also conducted. Results Hyperemic velocity (centimeters per cardiac cycle) and flow-mediated dilation (percentage) were significantly lower in severe sepsis patients versus control subjects (hyperemic velocity: severe sepsis = 34 (25 to 48) versus controls = 63 (52 to 81), P < 0.001; flow-mediated dilation: severe sepsis = 2.65 (0.81 to 4.79) versus controls = 4.11 (3.06 to 6.78), P < 0.001; values expressed as median (interquartile range)). Hyperemic velocity, but not flow-mediated dilation, was significantly lower in hospital nonsurvivors versus survivors (hyperemic velocity: nonsurvivors = 25 (16 to 28) versus survivors = 39 (30 to 50), P < 0.001; flow-mediated dilation: nonsurvivors = 1.90 (0.68 to 3.41) versus survivors = 2.96 (0.91 to 4.86), P = 0.12). Lower hyperemic velocity was independently associated with hospital mortality in multivariable analysis (odds ratio = 1.11 (95% confidence interval = 1.04 to 1.19) per 1 cm/cardiac cycle decrease in hyperemic velocity; P = 0.003). Conclusions Brachial artery hyperemic blood velocity is a noninvasive index of microvascular function that independently predicts mortality in severe sepsis. In contrast, brachial artery flow-mediated dilation, reflecting conduit artery endothelial function, was not associated with mortality in our severe sepsis cohort. Brachial artery hyperemic velocity may be a useful measurement to identify patients who could benefit from novel therapies designed to reverse microvascular dysfunction in severe sepsis and to assess the physiologic efficacy of these treatments.
Sepsis is defined as the host's reaction to infection and characterised by a systemic inflammatory response with important clinical implications. Central nervous system dysfunction secondary to sepsis is associated with local generation of pro- and anti-inflammatory cytokines, impaired cerebral microcirculation, an imbalance of neurotransmitters, apoptosis and cognitive impairment. It's known that the IL-1? is one of the first cytokines to be altered. Thus, the objective of this study was to evaluate the role of IL-1? in cognitive parameters in brain tissue through the use of an IL-1? (IL-1ra) receptor antagonist up to 10 days and to assess blood-brain barrier permeability, cytokine levels, oxidative parameters and energetic metabolism up to 24 h, after sepsis induction. To this aim, we used sham-operated Wistar rats or submitted to the cecal ligation and perforation (CLP) procedure. Immediately after, the animals received one dose of 10 ?g of IL-1ra. After 24 h, the rats were killed and were evaluated for biochemical parameters in the pre-frontal cortex, hippocampus and striatum. After 10 days, the animals were submitted to the habituation to the open field and step-down inhibitory avoidance task. We observed that the use of IL-1ra reverted the increase of blood-brain barrier permeability in the pre-frontal cortex, hippocampus and striatum; the increase of IL-1?, IL1-6 and TNF-? levels in the pre-frontal cortex and striatum; the decrease of complex I activity in the pre-frontal, hippocampus and striatum; the increase of oxidative parameters in pre-frontal cortex, hippocampus and striatum; and cognitive impairment. In conclusion, the results observed in this study reinforce the role of acute brain inflammatory response, in particular, the IL1? response, in the cognitive impairment associated with sepsis. PMID:24234155
Mina, Francielle; Comim, Clarissa M; Dominguini, Diogo; Cassol-Jr, Omar J; Dall Igna, Dhébora M; Ferreira, Gabriela K; Silva, Milena C; Galant, Leticia S; Streck, Emílio L; Quevedo, João; Dal-Pizzol, Felipe
Oral administration of autoantigens can influence the outcome of experimental autoimmune diseases, yet little is known about nonself Ag-induced tolerance. In this study, we administered group A streptococcal cell wall (SCW) peptidoglycan-polysaccharide complexes orally and monitored the impact on SCW-induced erosive polyarthritis. Oral administration of low dose SCW (3 mg\\/day), initiated 7 days before an arthritogenic dose of systemic SCW,
Wanjun Chen; Wenwen Jin; Melissa Cook; Howard L. Weiner; Sharon M. Wahl
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
Zhang, Songen; Hwaiz, Rundk; Rahman, Milladur; Herwald, Heiko; Thorlacius, Henrik
After being notified that 2 high school football teammates were hospitalized with confirmed or suspected invasive group A streptococcal infections, we conducted an investigation of possible spread among other team members. This investigation highlights a need for guidelines on management of streptococcal and other infectious disease outbreaks in team sport settings.
Lee, Elsie; Bambino, Maribeth; Ackelsberg, Joel; Weiss, Don; Sathyakumar, Chiminyan; Kornblum, John; Barbot, Oxiris; Johnson, Dwight; Kaplan, Edward L.; Layton, Marcelle
INTRODUCTION: Streptococcal toxic shock syndrome is a complication of group A streptococcal infection, most often originating from the skin. The syndrome is characterized by fever, hypotension and multiple organ failure. Mortality rate may be as high as 80%. CASE PRESENTATION: A 25-year-old man of Indian origin presented with abdominal complaints, rash and fever after an episode of pharyngitis. The patient
Henrik Endeman; David A Ligtenstein; Heleen M Oudemans-van Straaten
We studied the effects of scrubbing with poloxamer 188 (SCR), irrigating with povidone iodine (PI), and scrubbing followed by irrigation (SCR-PI) on staphylococcal and streptococcal counts in inoculated guinea pig lacerations. PI irrigation and SCR-PI significantly lowered streptococcal counts (P < 0.05). Staphylococcal counts were not different from those in controls.
Howell, J M; Dhindsa, H S; Stair, T O; Edwards, B A
Clinically normal psoriatic skin (CNPS) and psoriatic lesions (PLs) were studied for mast cell degranulation (MCD) in patients with acute eruptive guttate psoriasis vulgaris (AEGP) following penicillin-treated acute streptococcal throat infection. The clinically manifest duration of psoriasis at the time of the biopsies was 2, 5, 10, 14, or 21 days. Two types of MCD were distinguished. Type I was
Changes in red blood cell (RBC) function can contribute to alterations in microcirculatory blood flow and cellular dysoxia in sepsis. Decreases in RBC and neutrophil deformability impair the passage of these cells through the microcirculation. While the role of leukocytes has been the focus of many studies in sepsis, the role of erythrocyte rheological alterations in this syndrome has only
M. Piagnerelli; K. Zouaoui Boudjeltia; M. Vanhaeverbeek; J.-L. Vincent
Prompt diagnosis and treatment with appropriate antimicrobial chemotherapy is of paramount importance to reduce morbidity and mortality associated with sepsis. Inflammatory markers currently in use, such as C-reactive protein (CRP) do not reliably differentiate between the systemic inflammatory response and sepsis. Procalcitonin (PCT), a precursor of calcitonin, is a 116 amino acid protein that has been proposed as a marker
E. D Carrol; A. P. J Thomson; C. A Hart
Clostridium perfringens sepsis is rare since the legalization of abortion in 1973. This is a 49 year old female who developed clostridial sepsis after suction dilation and curettage for a molar pregnancy. A hysterectomy was performed after prompt recognition, and the patient survived. PMID:24096275
Adams, Brandi N; Lekovic, Jovana P; Robinson, Suzzette
Group A Streptococcus is a leading human pathogen associated with a diverse array of mucosal and systemic infections. Cell wall anchored pili were recently described in several species of pathogenic streptococci, and in the case of GAS, these surface appendages were demonstrated to facilitate epithelial cell adherence. Here we use targeted mutagenesis to evaluate the contribution of pilus expression to virulence of the globally disseminated M1T1 GAS clone, the leading agent of both GAS pharyngitis and severe invasive infections. We confirm that pilus expression promotes GAS adherence to pharyngeal cells, keratinocytes, and skin. However, in contrast to findings reported for group B streptococcal and pneumococcal pili, we observe that pilus expression reduces GAS virulence in murine models of necrotizing fasciitis, pneumonia and sepsis, while decreasing GAS survival in human blood. Further analysis indicated the systemic virulence attenuation associated with pilus expression was not related to differences in phagocytic uptake, complement deposition or cathelicidin antimicrobial peptide sensitivity. Rather, GAS pili were found to induce neutrophil IL-8 production, promote neutrophil transcytosis of endothelial cells, and increase neutrophil release of DNA-based extracellular traps, ultimately promoting GAS entrapment and killing within these structures. PMID:19960175
Crotty Alexander, Laura E; Maisey, Heather C; Timmer, Anjuli M; Rooijakkers, Suzan H M; Gallo, Richard L; von Köckritz-Blickwede, Maren; Nizet, Victor
A 15-year-old male developed transient monocular visual loss secondary to retinal artery flow disturbance, vasospasm, and\\u000a possible microemboli associated with acute rheumatic heart disease. He had insufficiently treated streptococcal pharyngitis.\\u000a Inadequately treated rheumatic carditis should be considered among the causes of transient monocular visual loss in children.
Iason S. Mantagos; Jonathan Rhodes; Linda R. Dagi
Spreading odontogenic infections are a common source of hospital admissions to Oral and Maxillofacial Surgery (OMFS) units. This report describes an unusual reaction to routine treatment for a spreading odontogenic infection in a healthy male with no known allergies, requiring the patient to be managed supportively in the resuscitation room. The patient deteriorated rapidly after the administration of paracetamol, intravenous fluids, steroids and antibiotics, demonstrating delusional behaviour, fever, rigors, tachycardia and hypoxia. Fever associated with sepsis can lead to confusional states, but similar symptoms have been described in the literature as a reaction to antibiotic therapy known as Jarisch–Herxheimer (J-H) reaction. This is potentially the first time a J-H like reaction has been described in the context of dental sepsis. The authors feel that the OMFS team should be aware of possible sequelae of medical therapy in patients with acute dental sepsis and be confident in their management of these complications.
Moss, Helen; Collier, Jonathan Marc; Collier, Sophie
Sepsis is the main cause of acute kidney injury (AKI) among individuals hospitalized in intensive care units. Acute kidney injury is an independent risk factor for mortality, and its occurrence increases the complexity and cost of treatment. However, the pathophysiological mechanisms of AKI remain unclear. Hemodynamic, vascular, tubular, cellular, inflammatory, and oxidative processes are involved. Individuals with AKI generally have various comorbidities and are elderly and hypercatabolic and on vasopressors and mechanical ventilation. Dialysis is the main treatment for AKI. Although there is no clear benefit of any specific dialysis modality, these patients are initially instructed to use continuous dialysis methods, especially for the most severe cases with multiple organ system dysfunctions and for those who display signs of hemodynamic instability. Recent studies demonstrate that patients should receive a dialysis dose of at least 25 mL · kg · h. PMID:23481503
Filiponi, Thiago Corsi; de Souza Durão, Marcelino
Objective Prior studies have concentrated on the acute short-term outcomes of sepsis, with little focus on its long-term consequences. The objective of this study was to characterise long-term mortality following a sepsis event. Design Population-based data from the 30?239 community-dwelling individuals in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Setting USA. Participants Community-dwelling adults ?45?years of age. Sepsis was defined as hospitalisation or emergency department treatment for a serious infection with the presence of ?2 systemic inflammatory response syndrome criteria. Outcomes 6-year all-cause mortality. The analysis utilised a time-varying Cox model adjusted for participant's age, demographic factors, health behaviours and chronic medical conditions. Results The participants were observed for a median of 6.1?years (IQR 4.5–7.1). During this period, 975 individuals experienced a sepsis event. Sepsis hospital mortality was 8.9%. One-year, 2-year and 5-year all-cause mortality among individuals with sepsis were 23%, 28.8% and 43.8%, respectively, compared with death rates of 1%, 2.6% and 8.3% among those who never developed sepsis. On multivariable analysis, the association of sepsis with increased all-cause mortality persisted for up to 5?years, after adjustment for confounders; year 0.00–1.00, adjusted HR (aHR) 13.07 (95% CI 10.63 to 16.06); year 1.01–2.00 aHR 2.64 (1.85 to 3.77); year 2.01–3.00 aHR 2.18 (1.43 to 3.33); year 3.01–4.00 aHR 1.97 (1.19 to 3.25); year 4.01–5.00 aHR 2.08 (1.14 to 3.79); year 5.01+ aHR 1.41 (0.67 to 2.98). Conclusions Individuals with sepsis exhibited increased rates of death for up to 5?years after the illness event, even after accounting for comorbidities. Sepsis is independently associated with increased risk of mortality well after hospital treatment.
Wang, Henry E; Szychowski, Jeff M; Griffin, Russell; Safford, Monika M; Shapiro, Nathan I; Howard, George
Objective Arginine deficiency may contribute to microvascular dysfunction, but previous studies suggest that arginine supplementation may be harmful in sepsis. Systemic arginine availability can be estimated by measuring the ratio of arginine to its endogenous inhibitors, asymmetric and symmetric dimethylarginine. We hypothesized that the arginine to dimethylarginine (Arg/DMA) ratio is reduced in patients with severe sepsis and associated with severity of illness and outcomes. Design Case-control and prospective cohort study Setting Medical and surgical intensive care units of an academic medical center Patients and Subjects 109 severe sepsis and 50 control subjects Measurements and Main Results Plasma and urine were obtained in control subjects and within 48 hours of diagnosis in severe sepsis patients. The Arg/DMA ratio was higher in control subjects vs. sepsis patients ((median = 95 [inter-quartile range = 85 – 114]) vs. 34 [24 – 48], p < 0.001), and in hospital survivors vs. non-survivors ((39 [26 – 52]) vs. 27 [19 – 32], p = 0.004). The Arg/DMA ratio was correlated with Acute Physiology and Chronic Health Evaluation II score (Spearman’s correlation coefficient [rho] = ? 0.40, p < 0.001) and organ-failure free days (rho = 0.30, p = 0.001). A declining Arg/DMA ratio was independently associated with hospital mortality (odds ratio =1.63 per quartile, 95% confidence interval [CI] = 1.00 – 2.65, p = 0.048) and risk of death over 6 months (hazard ratio = 1.41 per quartile, 95% CI = 1.01 – 1.98, p = 0.043). The Arg/DMA ratio was correlated with the urinary nitrate to creatinine ratio (rho = 0.46, p < 0.001). Conclusions The Arg/DMA ratio is associated with severe sepsis, severity of illness, and clinical outcomes. The Arg/DMA ratio may be a useful biomarker, and interventions designed to augment systemic arginine availability in severe sepsis may still be worthy of investigation.
Gough, Michael S.; Morgan, Mary Anne M.; Mack, Cynthia M.; Darling, Denise C.; Frasier, Lauren M.; Doolin, Kathleen P.; Apostolakos, Michael J.; Stewart, Judith C.; Graves, Brian T.; Arning, Erland; Bottiglieri, Teodoro; Mooney, Robert A.; Frampton, Mark W.; Pietropaoli, Anthony P.
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.
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.
Acute kidney injury (AKI) is an independent risk factor for mortality in sepsis syndrome. Few Indian studies have focused on describing the epidemiology of sepsis with AKI. Adult patients with sepsis-induced AKI were evaluated for the clinical characteristics and outcome and to correlate various parameters associated with sepsis to the outcome of patients. This prospective study included 136 patients with sepsis-induced AKI between 2007 and 2009. All patients required renal replacement therapy. Males comprised 44% of the patients while 56% were females; their mean age was 38.6 years. When we compared the survivor and non-survivor groups, it was found that mortality was associated with delayed presentation (6.8 vs 9.4 days), presence of hypotension (132/80 vs 112/70 mmHg), oliguria (300 vs 130 mL), anemia (8 vs 9.3 gm/dL), prolonged prothrombin time (15 vs 29 s) and activated partial thrombin time (38 vs 46 s), creatinine (7.8 vs 6.4 mg/dL), blood urea (161 vs 135 mg/dL), higher D-dimer (1603 vs 2185), short hospital stay (27.9 vs 8.3 days), number of hemodialysis sessions (11.9 vs 6 times), need for vasopressors (14% vs 52%) and ventilator (7.2% vs 75%) and higher Sequential Organ Failure Assessment (SOFA) score (6.7 vs 11.4) (P <0.05). The most com-mon source of infection in this study was urogenital tract (34%). About 51.4% showed complete recovery of renal function. The overall hospital mortality rate was 38.9%. Less than 10% of the patients developed impaired renal function following septic AKI. In conclusion, the most common renal manifestation of sepsis was AKI, which is a risk factor for mortality in sepsis syndrome. SOFA score >11 and multi-organ dysfunction are the risk factors for mortality. PMID:23640650
Shah, Pankaj R; Gireesh, M S; Kute, Vivek B; Vanikar, Aruna V; Gumber, Manoj R; Patel, Himanshu V; Goplani, K R; Trivedi, Hargovind L
Introduction The pathophysiology of sepsis-associated delirium is not completely understood and the data on cerebral perfusion in sepsis are conflicting. We tested the hypothesis that cerebral perfusion and selected serum markers of inflammation and delirium differ in septic patients with and without sepsis-associated delirium. Methods We investigated 23 adult patients with sepsis, severe sepsis, or septic shock with an extracranial focus of infection and no history of intracranial pathology. Patients were investigated after stabilisation within 48 hours after admission to the intensive care unit. Sepsis-associated delirium was diagnosed using the confusion assessment method for the intensive care unit. Mean arterial pressure (MAP), blood flow velocity (FV) in the middle cerebral artery using transcranial Doppler, and cerebral tissue oxygenation using near-infrared spectroscopy were monitored for 1 hour. An index of cerebrovascular autoregulation was calculated from MAP and FV data. C-reactive protein (CRP), interleukin-6 (IL-6), S-100?, and cortisol were measured during each data acquisition. Results Data from 16 patients, of whom 12 had sepsis-associated delirium, were analysed. There were no significant correlations or associations between MAP, cerebral blood FV, or tissue oxygenation and sepsis-associated delirium. However, we found a significant association between sepsis-associated delirium and disturbed autoregulation (P = 0.015). IL-6 did not differ between patients with and without sepsis-associated delirium, but we found a significant association between elevated CRP (P = 0.008), S-100? (P = 0.029), and cortisol (P = 0.011) and sepsis-associated delirium. Elevated CRP was significantly correlated with disturbed autoregulation (Spearman rho = 0.62, P = 0.010). Conclusion In this small group of patients, cerebral perfusion assessed with transcranial Doppler and near-infrared spectroscopy did not differ between patients with and without sepsis-associated delirium. However, the state of autoregulation differed between the two groups. This may be due to inflammation impeding cerebrovascular endothelial function. Further investigations defining the role of S-100? and cortisol in the diagnosis of sepsis-associated delirium are warranted. Trial registration ClinicalTrials.gov NCT00410111.
Pfister, David; Siegemund, Martin; Dell-Kuster, Salome; Smielewski, Peter; Ruegg, Stephan; Strebel, Stephan P; Marsch, Stephan CU; Pargger, Hans; Steiner, Luzius A
Background Acute respiratory distress syndrome (ARDS) is a devastating complication of numerous underlying conditions, most notably sepsis. Although pathologic vascular leak has been implicated in the pathogenesis of ARDS and sepsis-associated lung injury, the mechanisms promoting leak are incompletely understood. Angiopoietin-2 (Ang-2), a known antagonist of the endothelial Tie-2 receptor, was originally described as a naturally occurring disruptor of normal embryonic vascular development otherwise mediated by the Tie-2 agonist angiopoietin-1 (Ang-1). We hypothesized that Ang-2 contributes to endothelial barrier disruption in sepsis-associated lung injury, a condition involving the mature vasculature. Methods and Findings We describe complementary human, murine, and in vitro investigations that implicate Ang-2 as a mediator of this process. We show that circulating Ang-2 is significantly elevated in humans with sepsis who have impaired oxygenation. We then show that serum from these patients disrupts endothelial architecture. This effect of sepsis serum from humans correlates with measured Ang-2, abates with clinical improvement, and is reversed by Ang-1. Next, we found that endothelial barrier disruption can be provoked by Ang-2 alone. This signal is transduced through myosin light chain phosphorylation. Last, we show that excess systemic Ang-2 provokes pulmonary leak and congestion in otherwise healthy adult mice. Conclusions Our results identify a critical role for Ang-2 in disrupting normal pulmonary endothelial function.
Schultz, Aylit; Yuan, Hai-Tao; Christiani, David; Karumanchi, S. Ananth; Sukhatme, Vikas P
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
Mascarenhas, Desmond D; Elayadi, Amina; Singh, Baljit K; Prasai, Anesh; Hegde, Sachin D; Herndon, David N; Finnerty, Celeste C
Infection is the most common and most serious complication of a major burn injury related to burn size. Despite improvements in antimicrobial therapies sepsis still accounts for 50–60% of deaths in burn patients. Given the acute onset and unpredictable nature of sepsis, primary prevention was rarely attempted in its management. However, recent studies have demonstrated that statin treatment can decrease mortality is a murine model of sepsis by preservation of cardiac function and reversal of inflammatory alterations. In addition, it has been shown that treatment with statins is associated with reduced incidence of sepsis in human patients. In the current study groups of CD1 male mice (n=12) were anesthetized and subjected to a dorsal 30% TBSA scald burn injury. Starting 2 hours post burn, the animals were divided into a treatment group receiving 0.2 µ/g simvastatin or a sham group receiving placebo. Simvastatin and placebo were administered by intraperitoneal injection with two dosing regimens; once daily and every 12 hours. On Post burn day 7 cecal ligation and puncture with a 21-gauge needle was performed under ketamine/xylazine anesthesia and the two different dosing schedules were continued. A simvastatin dose dependant improvement in survival was observed in the burn sepsis model.
Beffa, David C; Fischman, Alan J.; Fagan, Shawn P.; Hamrahi, Victoria F.; Kaneki, Masao; Yu, Yong-Ming; Tompkins, Ronald G.; Carter, Edward A.
Although the prevailing concept has been that mortality in sepsis results from an unbridled hyper-inflammatory cytokine-mediated response, the failure of more than 30 clinical trials to treat sepsis by controlling this cytokine response requires a 'rethink' of the molecular mechanism underpinning the development of sepsis. As we discuss here, remarkable new studies indicate that most deaths from sepsis are actually
Richard S. Hotchkiss; Donald W. Nicholson
Sepsis remains the leading cause of death in most intensive care units. Advances in understanding the immune response to sepsis provide the opportunity to develop more effective therapies. The immune response in sepsis can be characterized by a cytokine-mediated hyper-inflammatory phase, which most patients survive, and a subsequent immune-suppressive phase. Patients fail to eradicate invading pathogens and are susceptible to opportunistic organisms in the hypo-inflammatory phase. Many mechanisms are responsible for sepsis-induced immuno-suppression, including apoptotic depletion of immune cells, increased T regulatory and myeloid-derived suppressor cells, and cellular exhaustion. Currently in clinical trial for sepsis are granulocyte macrophage colony stimulating factor and interferon gamma, immune-therapeutic agents that boost patient immunity. Immuno-adjuvants with promise in clinically relevant animal models of sepsis include anti-programmed cell death-1 and interleukin-7. The future of immune therapy in sepsis will necessitate identification of the immunologic phase using clinical and laboratory parameters as well as biomarkers of innate and adaptive immunity.
Boomer, Jonathan S; Green, Jonathan M; Hotchkiss, Richard S
Intraperitoneal administration of group A streptococcal cell walls to rats induces an acute arthritis that resolves and is followed by a chronic lesion. The effect of low dose methotrexate, D-penicillamine and gold thioglucose has been investigated in this model. Whereas D-penicillamine and gold thioglucose had no effect on the hind paw inflammation and joint destruction (radiological assessment) associated with the lesion, methotrexate treatment suppressed both of these variables. Spleen cells derived from cell wall treated arthritic rats were hyporesponsive to concanavalin A (Con-A) and were deficient in the synthesis of interleukin 2 (IL-2). Spleen cells derived from methotrexate treated rats exhibited an improved response to Con-A and their ability to synthesize IL-2 was significantly enhanced. PMID:3102727
Ridge, S C; Rath, N; Galivan, J; Zabriske, J; Oronsky, A L; Kerwar, S S
Abstract A recent collecting trip to Vietnam yielded three new species and two new records of Sepsidae (Diptera) for the country. Here we describe two new species in the species-poor genus Perochaeta (Perochaeta cuirassa sp. n. andPerochaeta lobo sp. n.) and one to the largest sepsid genus Sepsis (Sepsis spura sp. n.) which is also found in Sumatra and Sulawesi. Two additional Sepsis species are new records for Vietnam (Sepsis sepsi Ozerov, 2003; Sepsis monostigma Thompson, 1869). We conclude with a discussion of the distribution of Perochaeta and the three Sepsis species.
Ang, Yuchen; Meier, Rudolf
Sepsis is the commonest cause of admission to medical ICUs across the world. Mortality from sepsis continues to be high. Besides shock and multi-organ dysfunction occurring following the intense inflammatory reaction to sepsis, complications arising from sepsis-related immunoparalysis contribute to the morbidity and mortality from sepsis. This review explores the basis for sepsis related immune dysfunction and discusses its clinical implications for the treating intensivist. Recent trends indicate that a significant proportion of septic patients succumb to the complications of secondary infections and chronic critical care illness from the initial bout of sepsis. Therefore care-givers in the ICU need to be aware of the impediments posed by sepsis-related immune dysfunction that can impair recovery in patients with sepsis and contribute to sepsis-related mortality.
Sundar, Krishna M.; Sires, Mazen
Objective Multiple biomarkers are used to assess sepsis severity and prognosis. Increased levels of the soluble receptor for advanced glycation end products (sRAGE) were previously observed in sepsis but also in end-organ injury without sepsis. We evaluated associations between sRAGE and (i) 28-day mortality, (ii) sepsis severity, and (iii) individual organ failure. Traditional biomarkers procalcitonin (PCT), C-reactive protein (CRP) and lactate served as controls. Methods sRAGE, PCT, CRP, and lactate levels were observed on days 1 (D1) and 3 (D3) in 54 septic patients. We also assessed the correlation between the biomarkers and acute respiratory distress syndrome (ARDS), acute kidney injury (AKI) and acute heart failure. Results There were 38 survivors and 16 non-survivors. On D1, non-survivors had higher sRAGE levels than survivors (p = 0.027). On D3, sRAGE further increased only in non-survivors (p < 0.0001) but remained unchanged in survivors. Unadjusted odds ratio (OR) for 28-day mortality was 8.2 (95% CI: 1.02–60.64) for sRAGE, p = 0.048. Receiver operating characteristic analysis determined strong correlation with outcome on D3 (AUC = 0.906, p < 0.001), superior to other studied biomarkers. sRAGE correlated with sepsis severity (p < 0.00001). sRAGE showed a significant positive correlation with PCT and CRP on D3. In patients without ARDS, sRAGE was significantly higher in non-survivors (p < 0.0001) on D3. Conclusion Increased sRAGE was associated with 28-day mortality in patients with sepsis, and was superior compared to PCT, CRP and lactate. sRAGE correlated with sepsis severity. sRAGE was increased in patients with individual organ failure. sRAGE could be used as an early biomarker in prognostication of outcome in septic patients.
BRODSKA, HELENA; MALICKOVA, KARIN; VALENTA, JIRI; FABIO, ANTHONY; DRABEK, TOMAS
The frequency and severity of streptococcal infections and their sequelae have declined dramatically in the past century, yet the prevalence of streptococcal infections is still high. The reasons for this decline must be intimately related to host resistance, virulence of the agent, and environmental factors, especially crowding. Close examination of these fundamental influences does not reveal any evidence that humans have become less resistant to streptococcal infections, but they react less violently. There is some evidence that the agent may have lost a degree of its virulence. The decline in morbidity and mortality due to streptococcal infections began long before antibiotics, especially penicillin, were available. However, penicillin has proved to be an important factor in prevention of streptococcal infections, especially in rheumatic fever prophylaxis. There are certain indications that repeated streptococcal infections due to similar M types, occurring in young children over the past several decades, have resulted in some degree of immunity as well as the possible evolution of less virulent, but not less infectious, strains of group A streptococci. Also, a decrease in crowding would be expected to result in fewer streptococcal infections. Although there are more people in the world than at any other time in the history of man, urban population density in the western world, at least, is less than in the late 1800s and early 1900s.
Quinn, R. W.
The frequency and severity of streptococcal infections and their sequelae have declined dramatically in the past century, yet the prevalence of streptococcal infections is still high. The reasons for this decline must be intimately related to host resistance, virulence of the agent, and environmental factors, especially crowding. Close examination of these fundamental influences does not reveal any evidence that humans have become less resistant to streptococcal infections, but they react less violently. There is some evidence that the agent may have lost a degree of its virulence. The decline in morbidity and mortality due to streptococcal infections began long before antibiotics, especially penicillin, were available. However, penicillin has proved to be an important factor in prevention of streptococcal infections, especially in rheumatic fever prophylaxis. There are certain indications that repeated streptococcal infections due to similar M types, occurring in young children over the past several decades, have resulted in some degree of immunity as well as the possible evolution of less virulent, but not less infectious, strains of group A streptococci. Also, a decrease in crowding would be expected to result in fewer streptococcal infections. Although there are more people in the world than at any other time in the history of man, urban population density in the western world, at least, is less than in the late 1800s and early 1900s. PMID:6758372
Quinn, R W
Patients with sepsis often require anaesthesia for surgical procedures. Anaesthesia can be unpredictable and the most haemodynamically stable agents are used. No data are available for the minimum alveolar concentration (MAC) requirements in such patients or in animal models of sepsis. We have characterized the effect of sepsis on the MAC of isoflurane in a normotensive rodent model of sepsis. The minimum inhibitory concentration (MIC) of isoflurane to an identical stimulus was determined for rodents subjected to caecal ligation and perforation (CLP n = 8), or sham laparotomy (n = 7). The calculated MAC of isoflurane was reduced in the septic animals compared with the sham animals (MAC of isoflurane, CLP = 0.8%, sham = 1.4% P < 0.003). No statistical differences were found in the haemodynamic variables measured in either group. Isoflurane leads to haemodynamic stability during anaesthesia in this animal model of sepsis. However, the MAC requirement for isoflurane is reduced by sepsis. PMID:7554004
Gill, R; Martin, C; McKinnon, T; Lam, C; Cunningham, D; Sibbald, W J
In a prospective study (400 patients, intensive care stay > 18 h) the following data were documented daily: Clinical sepsis, a modified sepsis score, Apache II-score, number of organ failure, Elastase-concentrations and injury severity score (ISS > or = 20 = polytrauma). On admission day a prognostic assessment for early diagnosis of septic complications during intensive care could be demonstrated by a combination of the modified sepsis score and the number of organ failures and the presence of polytrauma. All other parameters did not have any predictive value. PMID:9063920
Reist, K; Hilfiker, O; Stepniewski, M S; Heinzer, I; Berchtold, W; Reist, U; Bürgi, U; Aeberhard, P; Bürgi, W
We report 2 cases of children with group A streptococcus pyogenes pleuropneumonia, in one child associated with Kawasaki disease and in the other with streptococcal toxic shock syndrome. These 2 features, with theoretically well-defined clinical and biological criteria, are difficult to differentiate in clinical practice, however, likely due to their pathophysiological links. In case of clinical doubt, an echocardiography needs to be performed to search for coronary involvement and treatment including intravenous immunoglobulins, and an antibiotic with an anti-toxin effect such as clindamycin has to be started early. PMID:22041597
Bosland, A; Arlaud, K; Rousset-Rouvière, C; Fouilloux, V; Paut, O; Dubus, J-C; Bosdure, E
Background The greatest burden of Group A streptococcal (GAS) disease worldwide is due to acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Safe, effective and affordable vaccines designed to prevent GAS infections that trigger ARF could reduce the overall global morbidity and mortality from RHD. The current study evaluated the potential coverage of a new 30-valent M protein-based vaccine using GAS isolates from school children in Bamako, Mali, a population at high risk for the development of RHD. Methods The bactericidal activity of rabbit antisera against the 30-valent vaccine was assessed using a collection of GAS isolates recovered during a study of the epidemiology of pharyngitis in Bamako. Results Single isolates representing 42 of 67 emm-types, accounting for 85% of the GAS infections during the study, were evaluated. All (14/14) of the vaccine emm-types in the collection were opsonized (bactericidal killing >50%) and 26/28 non-vaccine types were opsonized. Bactericidal activity was observed against 60% of the total emm-types recovered in Bamako, which accounted for 81% of all infections. Conclusions Multivalent vaccines comprised of N-terminal M peptides elicit bactericidal antibodies against a broad range of GAS serotypes, indicating that their efficacy may extend beyond the emm-types included in the vaccine.
Dale, James B.; Penfound, Thomas A.; Tamboura, Boubou; Sow, Samba O.; Nataro, James P.; Tapia, Milagritos; Kotloff, Karen L.
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
Toufexis, Megan; Deoleo, Caroline; Elia, Josephine; Murphy, Tanya K
Two streptococcal extracellular antigens (X and Y), which are detectable with naturally occurring human antibodies, have been isolated and shown to represent entities distinct from previously described streptococcal enzymes, toxins, and antigens. They are each synthesized by both group C and group A streptococci and appear to be proteins. Both antigens were found to be nonhemolytic and nontoxic for human leucocytes as well as for isolated beating newborn rat heart cells in tissue culture. In addition to being distinct from known streptococcal enzymes, they were also shown to be devoid of several other enzymatic activities. Images
Kiefer, D; Halbert, S P
Identifying single nucleotide polymorphisms (SNPs) in the genes involved in sepsis may help to clarify the pathophysiology of neonatal sepsis. The aim of this study was to evaluate the relationships between sepsis in pre-term neonates and genes potentially involved in the response to invasion by infectious agents. The study involved 101 pre-term neonates born between June 2008 and May 2012 with a diagnosis of microbiologically confirmed sepsis, 98 pre-term neonates with clinical sepsis and 100 randomly selected, otherwise healthy pre-term neonates born during the study period. During the study, 47 SNPs in 18 candidate genes were genotyped on Guthrie cards using an ABI PRISM 7900 HT Fast real-time and MAssARRAY for nucleic acids instruments. Genotypes CT and TT of rs1143643 (the IL1? gene) and genotype GG of rs2664349GG (the MMP-16 gene) were associated with a significantly increased overall risk of developing sepsis (p?=?0.03, p?=?0.05 and p?=?0.03), whereas genotypes AG of rs4358188 (the BPI gene) and CT of rs1799946 (the DEF?1 gene) were associated with a significantly reduced risk of developing sepsis (p?=?0.05 for both). Among the patients with bacteriologically confirmed sepsis, only genotype GG of rs2664349 (the MMP-16 gene) showed a significant association with an increased risk (p?=?0.02). Genotypes GG of rs2569190 (the CD14 gene) and AT of rs4073 (the IL8 gene) were associated with a significantly increased risk of developing severe sepsis (p?=?0.05 and p?=?0.01). Genotype AG of rs1800629 (the LTA gene) and genotypes CC and CT of rs1341023 (the BPI gene) were associated with a significantly increased risk of developing Gram-negative sepsis (p?=?0.04, p?=?0.04 and p?=?0.03). These results show that genetic variability seems to play a role in sepsis in pre-term neonates by influencing susceptibility to and the severity of the disease, as well as the risk of having disease due to specific pathogens.
Esposito, Susanna; Zampiero, Alberto; Pugni, Lorenza; Tabano, Silvia; Pelucchi, Claudio; Ghirardi, Beatrice; Terranova, Leonardo; Miozzo, Monica; Mosca, Fabio; Principi, Nicola
Changes in red blood cell (RBC) function can contribute to alterations in microcirculatory blood flow and cellular dysoxia\\u000a in sepsis. Decreases in RBC and neutrophil deformability impair the passage of these cells through the microcirculation. While\\u000a the role of leukocytes has been the focus of many studies in sepsis, the role of erythrocyte rheological alterations in this\\u000a syndrome has only
M. Piagnerelli; K. Zouaoui Boudjeltia; M. Vanhaeverbeek; J.-L. Vincent
A hallmark of severe sepsis is systemic inflammation which activates leukocytes and can result in their misdirection. This leads to both impaired migration to the locus of infection and increased infiltration into healthy tissues. In order to better understand the pathophysiologic mechanisms involved, we developed a coarse-grained phenomenological model of the acute inflammatory response in CLP (cecal ligation and puncture)-induced sepsis in rats. This model incorporates distinct neutrophil kinetic responses to the inflammatory stimulus and the dynamic interactions between components of a compartmentalized inflammatory response. Ensembles of model parameter sets consistent with experimental observations were statistically generated using a Markov-Chain Monte Carlo sampling. Prediction uncertainty in the model states was quantified over the resulting ensemble parameter sets. Forward simulation of the parameter ensembles successfully captured experimental features and predicted that systemically activated circulating neutrophils display impaired migration to the tissue and neutrophil sequestration in the lung, consequently contributing to tissue damage and mortality. Principal component and multiple regression analyses of the parameter ensembles estimated from survivor and non-survivor cohorts provide insight into pathologic mechanisms dictating outcome in sepsis. Furthermore, the model was extended to incorporate hypothetical mechanisms by which immune modulation using extracorporeal blood purification results in improved outcome in septic rats. Simulations identified a sub-population (about of the treated population) that benefited from blood purification. Survivors displayed enhanced neutrophil migration to tissue and reduced sequestration of lung neutrophils, contributing to improved outcome. The model ensemble presented herein provides a platform for generating and testing hypotheses in silico, as well as motivating further experimental studies to advance understanding of the complex biological response to severe infection, a problem of growing magnitude in humans.
Song, Sang O. K.; Hogg, Justin; Peng, Zhi-Yong; Parker, Robert; Kellum, John A.; Clermont, Gilles
Objective:Prospective examination whether changes in interleukin (IL)-6, IL-10 or procalcitonin (PCT) concentrations correlate with poor outcome in patients with severe sepsis in comparison with APACHE III or SAPS II. Methods:33 patients who fulfilled the criteria for severe sepsis have been included in the study. Blood samples were collected for cytokine and PCT determinations. The Acute Physiology, Age and Chronic Health
C. Wunder; O. Eichelbrönner; N. Roewer
Raftlin is a major protein in lipid raft. The aim of this study was to evaluate blood levels of raftlin in septic patients. A prospective study of 82 patients with sepsis was conducted. Human umbilical vein endothelial cells (HUVECs) or mice were exposed to lipopolysaccharide (LPS, 100 ng/ml to HUVECs or 10 mg/kg to mice) or subjected to cecal ligation and puncture (CLP) surgery. Data showed that LPS induced upregulation of the synthesis and secretion of raftlin in LPS-treated HUVECs, and LPS-injected and CLP-mice. In patients admitted to the intensive care unit with sepsis, circulating levels of raftlin were significantly elevated, compared with control donors. Raftlin levels were higher in patients with septic shock, 891.6 (789.7-1,087.8, n?=?30) than in patients with severe sepsis, 681.6 (480.1-819.6, n?=?22) or sepsis, 496.1 (418.1-738.9, n?=?30), compared with healthy volunteers 364.9 (312.1-392.4, n?=?21). These results suggest that in septic patients, raftlin blood level is related to the severity of sepsis and the outcome of the patient and may represent a novel marker of endothelial cell dysfunction, and that raftlin can be used as a biomarker for determining the severity of sepsis. PMID:24317805
Lee, Wonhwa; Yoo, Hayoung; Ku, Sae-Kwang; Kim, Shin-Woo; Bae, Jong-Sup
A 3033g male infant was born to a healthy mother at 39 weeks gestation by normal vaginal delivery with Grade 1 meconium stained liquor. There was no prolonged rupture of membranes or any antenatal risk factors for sepsis. The immediate neonatal period was uneventful and the baby was discharged after two days. At 6 weeks of age the baby was
S K Shetty; D Hindley
Post-streptococcal glomerulonephritis (PSGN) is an immune-mediated disease in which an immune complex containing a streptococcal antigen are deposited in affected glomeruli. Strains of only some M types are known to be associated with PSGN. A secretory protein called SIC inhibits complement function. Whereas all M1 and M57 strains express closely related SIC (CRS), all M12 and M55 strains express distantly related SIC (DRS) proteins. Strains belonging to these four M types are historically associated with PSGN. This study used ELISA to analyse 112 sera from individuals with a recorded history of PSGN and 86 sera from individuals who had no such recorded history, all from a PSGN endemic region in tropical Australia. Antibody reactions to CRS, DRS and peptides corresponding to the N-termini of M1, M5, M12, M49, M55 and M57 antigens were assessed. A large proportion of the population showed reactions to each of these antigens and there was no correlation between CRS seropositivity and antibodies to CRS-positive M types. Likewise there was no correlation between DRS seropositivity and antibodies to DRS-positive M types. Interestingly, in this community endemic for PSGN a significantly higher proportion of DRS seropositive subjects had a recorded history of PSGN than did DRS seronegative subjects. DRS may have a predictive value for PSGN diagnosis or a role in PSGN pathogenesis. PMID:12132776
Sriprakash, K S; Hartas, Jon; White, Andrew
We describe a case in which a human immunodeficiency virus (HIV)-positive child presented in severe metabolic acidosis secondary to his candidal sepsis and T-cell lymphoma, a rare finding in pediatric AIDS. Significantly elevated levels of Interleukin-10 (IL-10) were found in the patient's serum, which may have played a role in acute demise. PMID:18812591
Lighter, Jennifer; Tse, Doris B; Kaul, Aditya; Borkowsky, William
Streptococcal infections were diagnosed in a group of strain 2 guinea-pigs. 10 of the animals had cervical lymphadenitis with abscess formation. Other lesions noted were: widespread lymphadenitis, pericarditis, myocardial degeneration, peritonitis, pleuri...
F. C. Fraunfelter F. M. Garner R. E. Schmidt R. J. Beattie
We report a case of post-streptococcal uveitis mainly presenting with bilateral recurrent retinal vasculitis in Korea. A 14-year-old Asian female presented with decreased visual acuity of 20 / 30 in the right eye and 20 / 25 in the left eye. The patient had a history of glomerulonephritis nine months before onset of uveitis. The manifestation of uveitis was predominantly retinal vasculitis. We presumed post-streptococcal uveitis because probable streptococcal infection was confirmed by anti-streptolysin O titer elevation. With topical and oral steroid treatments, the patient experienced complete vision recovery. Post-streptococcal uveitis occurs rarely and mostly involves young patients in the form of non-granulomatous anterior uveitis. However, as this case shows, it may primarily involve the posterior uvea without anterior inflammation and may recur.
Han, Jinu; Lee, Sung Chul
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 ?M) 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.
Pathak, Elina; MacMillan-Crow, Lee Ann
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 ?M) 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
Pathak, Elina; MacMillan-Crow, Lee Ann; Mayeux, Philip R
Acute kidney injury (AKI) contributes to the high morbidity and mortality of multi-system organ failure in sepsis. However, recovery of renal function after sepsis-induced AKI suggests active repair of energy-producing pathways. Here, we tested the hypothesis in mice that Staphyloccocus aureus sepsis damages mitochondrial DNA (mtDNA) in the kidney and activates mtDNA repair and mitochondrial biogenesis. Sepsis was induced in wild-type C57Bl/6J and Cox-8 Gfp-tagged mitochondrial-reporter mice via intraperitoneal fibrin clots embedded with S. aureus. Kidneys from surviving mice were harvested at time zero (control), 24, or 48 hours after infection and evaluated for renal inflammation, oxidative stress markers, mtDNA content, and mitochondrial biogenesis markers, and OGG1 and UDG mitochondrial DNA repair enzymes. We examined the kidneys of the mitochondrial reporter mice for changes in staining density and distribution. S. aureus sepsis induced sharp amplification of renal Tnf, Il-10, and Ngal mRNAs with decreased renal mtDNA content and increased tubular and glomerular cell death and accumulation of protein carbonyls and 8-OHdG. Subsequently, mtDNA repair and mitochondrial biogenesis was evidenced by elevated OGG1 levels and significant increases in NRF-1, NRF-2, and mtTFA expression. Overall, renal mitochondrial mass, tracked by citrate synthase mRNA and protein, increased in parallel with changes in mitochondrial GFP-fluorescence especially in proximal tubules in the renal cortex and medulla. Sub-lethal S. aureus sepsis thus induces widespread renal mitochondrial damage that triggers the induction of the renal mtDNA repair protein, OGG1, and mitochondrial biogenesis as a conspicuous resolution mechanism after systemic bacterial infection.
Bartz, Raquel R.; Fu, Ping; Suliman, Hagir B.; Crowley, Stephen D.; MacGarvey, Nancy Chou; Welty-Wolf, Karen; Piantadosi, Claude A.
The last 5 years have brought dramatic changes to the care of patients with severe sepsis. While early diagnosis remains a challenge and, regrettably, a rapid, sensitive, and specific diagnostic test is still lacking, the methods to identify those critically ill patients who are likely to die have become clearer. The presence of multiple organ failure, vasopressor-dependent shock, and high values in formalized scoring methods such as the APACHE (acute physiology and chronic health evaluation) and sequential organ failure assessment systems all have some utility for outcome prediction for groups of patients. Refinements in long-used supportive practices such as lower tidal volume ventilation and enhanced glucose control have improved outcomes. A growing appreciation of the importance of timely provision of antimicrobial therapy, circulatory resuscitation, and activated protein C administration have also improved survival. Optimal treatment candidates for, and the timing and dose of some treatments (eg, corticosteroids) remain controversial and are undergoing additional study. Perhaps the most important change in the care of patients with severe sepsis is awareness that the syndrome is more common, lethal, and expensive, than previously appreciated, and as such it warrants an organized approach to care provided by experts. Although there is still much to learn, numerous studies now indicate that improvements in outcomes are possible when treatment protocols that incorporate all known beneficial therapies are applied in a timely fashion. PMID:18079230
Wheeler, Arthur P
Sepsis is one of the main problems in medicine due to its complexity from pathophysiology, clinical, and therapeutic standpoints.\\u000a Although several definitions have been proposed for this syndrome, it can in general be assumed that it represents the clinical\\u000a manifestation of a system response of the body to infection or to an inflammatory-associated acute disease [1,2]. Despite advances in medical
A. Gullo; F. Iscra; F. Rubulotta
methods We randomly assigned adult patients with severe sepsis and a low risk of death (defined by an Acute Physiology and Chronic Health Evaluation (APACHE II) score <25 or single- organ failure) to receive an intravenous infusion of placebo or DrotAA (24 µ g per kilo- gram of body weight per hour) for 96 hours in a double-blind, placebo-controlled, mul-
Edward Abraham; Pierre-François Laterre; Rekha Garg; Howard Levy; Deepak Talwar; Benjamin L. Trzaskoma; Bruno François; Jeffrey S. Guy; Martina Brückmann; Álvaro Rea-Neto; Rolf Rossaint; Dominique Perrotin; Armin Sablotzki; Nancy Arkins; Barbara G. Utterback; William L. Macias
The diagnosis of disseminated intravascular coagulation (DIC) based on composite scoring systems using routinely available coagulation tests has been greatly facilitated. Such scoring instruments not only adequately assess the presence of DIC but also have strong prognostic power for morbidity and mortality. In this issue of Critical Care, Gando and colleagues report on the prospective validation of the Japanese Association of Acute Medicine score for DIC in patients with severe sepsis.
Background: Some children with obsessive-compulsive disorder (OCD) and tic disorders appear to have symptom exacerbations triggered by group A beta-hemolytic streptococcal infections in a manner that is similar to rheumatic fever and its neurologic variant, Sydenham’s chorea. Because penicillin prophylaxis has proven to be effective in preventing recurrences of rheumatic fever, it was postulated that it might also prevent streptococcal-triggered
Marjorie A. Garvey; Susan J. Perlmutter; Albert J. Allen; Susan Hamburger; Lorraine Lougee; Henrietta L. Leonard; M. Elizabeth Witowski; Billinda Dubbert; Susan E. Swedo
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
Piero Pavone; Enrico Parano; Renata Rizzo; Rosario R. Trifiletti
Protein G was solubilized from 31 human group C and G streptococcal strains with the muralytic enzyme mutanolysin. As judged by the mobility in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the binding patterns of the solubilized protein G molecules in Western blot experiments, the strains could be divided into three groups, represented by the group G streptococcal strains G148 and G43 and the group C streptococcal strain C40. The 65-kDa G148 protein G and the 58-kDa C40 protein G showed affinity for both immunoglobulin G (IgG) and human serum albumin (HSA), whereas the 40-kDa G43 protein G bound only IgG. Despite the different molecular patterns, the three protein G species had identical NH2-terminal amino acid sequences. Apart from the 65-kDa peptide, digestion of G148 streptococci with mutanolysin also produced a 52-kDa IgG- and HSA-binding peptide and a 14-kDa HSA-binding peptide. It was demonstrated that these peptides resulted from cleavage of 65-kDa protein G by proteolytic components in the mutanolysin preparation. The protein G genes of the C40 and G43 strains were cloned and sequenced, and their structure was compared to the previously published sequence of the G148 protein G gene. As compared to G148, both the C40 and G43 genes lacked a 210-base pair fragment in the IgG-binding region, accounting for the 10-fold lower affinity of these proteins for IgG. The G43 gene also lacked a 450-base pair fragment in the 5'-end of the gene, explaining why the G43 protein G did not bind HSA. The differences in protein G structure did not correlate with the clinical origin of the strains used in this study. The IgG-binding region of protein G was further mapped. Thus, a peptide corresponding to a single IgG-binding unit was obtained by the cloning and expression of a 303-base pair polymerase chain reaction-generated DNA fragment. The affinity of this 11.5-kDa peptide for human IgG was 8.0 x 10(7) M-1, as determined by Scatchard plots. Finally, a 55-amino acid-long synthetic peptide, corresponding to one of the three repeated domains in the COOH-terminal half of strain G148 protein G, effectively blocked binding of protein G to IgG. PMID:1985908
Sjöbring, U; Björck, L; Kastern, W
Sepsis, severe sepsis, and septic shock cause significant morbidity and mortality worldwide. Rapid diagnosis and therapeutic interventions are desirable to improve the overall mortality in patients with sepsis. However, gold standard laboratory diagnostic methods for sepsis, pose a significant challenge to rapid diagnosis of sepsis by physicians and laboratories. This article discusses the usefulness and potential of biomarkers and molecular test methods for a more rapid clinical and laboratory diagnosis of sepsis. Because new technologies are quickly emerging, physicians and laboratories must appreciate the key factors and characteristics that affect the clinical usefulness and diagnostic accuracy of these test methodologies. PMID:23931833
Riedel, Stefan; Carroll, Karen C
The goal of the present study was to identify novel protein biomarkers from the target genes of six serum miRNAs that we identified previously in patients with sepsis. The target genes were predicted by bioinformatics analysis; the levels of the respective proteins in the sera of patients with sepsis were detected by ELISA. ACVR2A (activin A receptor, type IIA), FOXO1 (forkhead box O1), IHH (Indian hedgehog), STK4 (serine/threonine kinase 4) and DUSP3 (dual specificity phosphatase 3) were predicted to be the targets of the six miRNAs, and their encoded proteins were used for biomarker identification. Levels of ACVR2A (P<0.01) and FOXO1 (P<0.01) were significantly different among normal controls, patients with sepsis, patients with severe sepsis and patients with septic shock. Furthermore, levels of ACVR2A (P=0.025), FOXO1 (P<0.001), IHH (P=0.001) and STK4 (P=0.001) were differentially expressed in survivors and non-survivors. DUSP3 levels were not significantly different between any groups. Conjoin analysis of the four differentially expressed proteins showed that the area under the curve of the predictive probabilities was 0.875 [95% CI (confidence interval): 0.785-0.965], which was higher than the SOFA (Sequential Organ Failure Assessment) and APACHE II (Acute Physiology and Chronic Health Evaluation II) scores. When the value of predictive probabilities was 0.449, the four proteins yielded a sensitivity of 68% and a specificity of 91%. Dynamic changes in ACVR2A, FOXO1 and IHH levels showed differential expression between survivors and non-survivors at all time points. On the basis of a combined analysis of the four identified proteins, their predictive value of 28-day mortality of patients with sepsis was better than the SOFA or APACHE II scores. PMID:24303815
Wang, Hui-juan; Wang, Bao-zeng; Zhang, Peng-jun; Deng, Jie; Zhao, Zhi-rui; Zhang, Xin; Xiao, Kun; Feng, Dan; Jia, Yan-hong; Liu, You-ning; Xie, Li-xin
Post-streptococcal autoimmunity affects millions worldwide, targeting multiple organs including the heart, brain, and kidneys. To explore the post-streptococcal autoimmunity spectrum, we used western blot analyses, to screen 310 sera from healthy subjects with (33%) and without (67%) markers of recent streptococcal infections [anti-Streptolysin O (ASLO) or anti-DNAse B (ADB)]. A 58 KDa protein, reacting strongly with post-streptococcal sera, was identified as Protein Disulfide Isomerase (PDI), an abundant protein with pleiotropic metabolic, immunologic, and thrombotic effects. Anti-PDI autoantibodies, purified from human sera, targeted similar epitopes in Streptolysin O (SLO, P51-61) and PDI (P328-338). The correlation between post-streptococcal status and anti-human PDI auto-immunity was further confirmed in a total of 2987 samples (13.6% in 530 ASLO positive versus 5.6% in 2457 ASLO negative samples, p<0.0001). Finally, anti-PDI auto-antibodies inhibited PDI-mediated insulin degradation in vitro (n?=?90, p<0.001), and correlated with higher serum insulin (14.1 iu/ml vs. 12.2 iu/ml, n?=?1215, p?=?0.039) and insulin resistance (Homeostatic Model Assessment (HOMA) 4.1 vs. 3.1, n?=?1215, p?=?0.004), in a population-based cohort. These results identify PDI as a major target of post-streptococcal autoimmunity, and establish a new link between infection, autoimmunity, and metabolic disturbances.
Aran, Adi; Weiner, Karin; Lin, Ling; Finn, Laurel Ann; Greco, Mary Ann; Peppard, Paul; Young, Terry; Ofran, Yanay; Mignot, Emmanuel
Background We sought to determine the associations between baseline chronic medical conditions and future risk of sepsis. Methods Longitudinal cohort study using the 30,239 community-dwelling participants of the REGARDS cohort. We determined associations between baseline chronic medical conditions and incident sepsis episodes, defined as hospitalization for an infection with the presence of infection plus two or more systemic inflammatory response syndrome criteria. Results Over the mean observation time of 4.6 years (February 5, 2003 through October 14, 2011), there were 975 incident cases of sepsis. Incident sepsis episodes were associated with older age (p<0.001), white race (HR 1.39; 95% CI: 1.22–1.59), lower education (p<0.001) and income (p<0.001), tobacco use (p<0.001), and alcohol use (p?=?0.02). Incident sepsis episodes were associated with baseline chronic lung disease (adjusted HR 2.43; 95% CI: 2.05–2.86), peripheral artery disease (2.16; 1.58–2.95), chronic kidney disease (1.99; 1.73–2.29), myocardial infarction 1.79 (1.49–2.15), diabetes 1.78 (1.53–2.07), stroke 1.67 (1.34–2.07), deep vein thrombosis 1.63 (1.29–2.06), coronary artery disease 1.61 (1.38–1.87), hypertension 1.49 (1.29–1.74), atrial fibrillation 1.48 (1.21–1.81) and dyslipidemia 1.16 (1.01–1.34). Sepsis risk increased with the number of chronic medical conditions (p<0.001). Conclusions Individuals with chronic medical conditions are at increased risk of future sepsis events.
Wang, Henry E.; Shapiro, Nathan I.; Griffin, Russell; Safford, Monika M.; Judd, Suzanne; Howard, George
Background: Sepsis is the commonest precipitating factor for acute kidney injury in hospitalised patients, and similarly patients with acute kidney injury are predisposed to sepsis. Mortality remains high despite improvements in supportive care. Methods: Literature search of Medline and Web of Science. Results: Above a threshold dialytic dose of 20 ml\\/kg\\/h for continuous renal replacement therapy and a sessional Kt\\/V
Identification to species level showed that Enterococcus faecalis and Ent. faecium largely dominated the enterococcal and streptococcal gut flora of 1-d-old chicks. Enterococcus faecalis was rare in 3- to 5-week-old broilers. Two species, Ent. faecium and Streptococcus alactolyticus, were isolated from nearly all broilers examined. Enterococcus hirae and Ent. durans were found in the small intestines of this category of poultry. In layers and parent stock of over 12 weeks of age, Ent. cecorum dominated with Strep. alactolyticus ranking next. Other species were isolated irregularly. Enterococcus avium and Ent. gallinarum, originally described from chickens, were rarely found. These species did not appear to belong to the normal intestinal flora of poultry. PMID:1910033
Devriese, L A; Hommez, J; Wijfels, R; Haesebrouck, F
Summary Background: Anaerobic bacterial meningitis is rare. It is extremely unusual without a portal of entry as most cases reported have been associated with trauma or neurosurgery. Case Report: We describe this rare case of clostridium meningitis and plesiomonas sepsis in an immunocompetent adult. A 71 year old man with diabetes presented with acute onset severe headaches, obtundation and signs of severe hemolysis following a 2 week game hunting trip in the Swiss Alps. His clinical status progressed rapidly; he died 3 hours after initial presentation. Post mortem lumbar puncture was performed with CSF analysis suggestive of bacterial meningitis. Clostridium perfringens was eventually recovered from the CSF as well as in the blood. Plesiomonas shigelloides was recovered from the blood as well. Conclusions: This is the first case of blood stream infection with these two organisms in a single patient without an obvious portal of entry.
Okon, Emmanuel; Bishburg, Eliahu; Ugras, Sandra; Chan, Trini; Wang, He
The current clinical management of surgical patients with sepsis is governed by two principles: control of the source of infection and supportive management of the patient until recovery. Recently, there has been renewed interest in the concept of source control-in particular, its importance for evaluating and comparing clinical trials. This brief review highlights some of the developments in the surgical literature. Important recent publications center on source control, the management of systemic inflammatory response syndrome, necrotizing pancreatitis, acute diverticulitis, gastrointestinal fistulas, and the role of laparoscopy in surgical infections. Novel interventions in supportive care are being developed, and their clinical applicability and effectiveness will be improved with increased understanding of the pathophysiology of systemic inflammation. PMID:11805535
Danielson, D; West, M A
Endothelial cells play a key role in initiating and propagating the inflammatory response seen in ischemia, infections and sepsis. Situated in a key position between the epithelial cells and white blood cells (WBC), they interact and respond to signals from both cell types. Microvascular endothelial cells within the kidney mediate coagulation, WBC attachment, WBC migration into the interstitium, microvascular flow rates and permeability. Low regeneration potential and endothelial-mesenchymal transformation lead to fibrosis and subsequent microvascular dropout. This last event is in large part responsible for a chronic reduction in regional perfusion, subsequent increased vulnerability to recurrent acute kidney injury, and acceleration of chronic kidney disease progression to end-stage renal disease. Glomerular endothelial dysfunction may lead to preglomerular shunting of blood flow allowing kidney blood flow to remain close to normal while resulting in a reduction in glomerular filtration rate. PMID:21921615
Molitoris, Bruce A; Sandoval, Ruben M
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.
Hendrix, Nancy W.; Mackeen, A. Dhanya; Weiner, Stuart
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
Hendrix, Nancy W; Mackeen, A Dhanya; Weiner, Stuart
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. Images
Soprey, Pandu; Slade, Hutton D.
Interleukin-1 (IL-1) is a polypeptide which possesses a broad spectrum of biological activities, many of which are associated with disease. It has been studied for its ability to induce fever, sleep and anorexia, elevate prostaglandins and nitric oxide, stimulate the release of pituitary hormones, elevate hepatic acute phase proteins, increase gene expression for other cytokines and augment the proliferation of
C. A. Dinarello
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-? (TNF-?)-dependent mechanisms. Glycocalyx degradation involved the specific loss of heparan sulfate and coincided with activation of endothelial heparanase, a TNF-?-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
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
Sepsis and septic shock are the most common causes of acute kidney injury (AKI) in the intensive care unit, and mortality remains high despite improvements in our ability to support vital organs. The lack of development of effective treatments is partly because there has been little advance in our understanding of the pathophysiology of septic AKI, owing to the difficulty in conducting experiments on critically ill patients and use of inappropriate experimental models. Recently, however, a number of new concepts have emerged that challenge existing dogma and give insights into the causes of AKI. Traditionally, renal ischaemia has been proposed as the main cause of AKI, but it is becoming apparent that in sepsis with a hyperdynamic circulation, the most common situation in septic patients, there is an increase or at least no decrease in renal blood flow. In this review, the possible role of changes in pre- and postglomerular resistance in setting the increased level of renal blood flow in the presence of a decreased glomerular filtration rate is discussed. New evidence also indicates that the increased sympathetic nerve activity that occurs in sepsis may contribute to the induction of organ failure. Experimental studies indicate that inhibition of central sympathetic outflow with ?(2)-adrenoceptor agonists or treatment with ?(1)-adrenoceptor antagonists might reduce mortality in experimental endotoxaemia and sepsis. The possibility that these beneficial actions are partly dependent on a reduction in the excessive cytokine release caused by marked and prolonged sympathetic activation is discussed. PMID:22689445
May, Clive N; Calzavacca, Paolo; Ishikawa, Ken; Langenberg, Christoph; Wan, Li; Ramchandra, Rohit; Bellomo, Rinaldo
Because of inadequate sample sizes of randomized controlled trials, few immunologic interventions to treat or prevent neonatal sepsis have been reliably evaluated. International collaboration is essential in achieving timely, adequate samples to assess effects on mortality or disability-free survival reliably. Promising or possible therapeutic interventions in severe or gram-negative sepsis include exchange transfusions, pentoxifylline, and IgM-enriched intravenous immunoglobulin. Promising or possible prophylactic interventions include lactoferrin, with or without a probiotic; selenium; early curtailment of antibiotics after sterile cultures; breast milk; and earlier initiation of colostrum in high risk preterm infants. Prophylactic oral probiotics are safe and effective (P<.00001) in reducing all-cause mortality and necrotizing enterocolitis in preterm infants by over half, but do not reduce sepsis. PMID:20569818
Tarnow-Mordi, William; Isaacs, David; Dutta, Sourabh
We assessed neutrophil CD64 as a diagnostic marker for neonatal sepsis. For early-onset sepsis, the CD64 index with a cut-point value of 2.38 had sensitivity, specificity and a negative predictive values of 100%, 68%, and 100%, respectively. For late-onset sepsis, the respective values were 3.62, 75%, 77%, and 96%. Neutrophil CD64 index can be incorporated as a valuable marker for excluding neonatal sepsis.
Streimish, Iris; Bizzarro, Matthew; Northrup, Veronika; Wang, Chao; Renna, Sara; Koval, Nancy; Li, Fang-Yong; Ehrenkranz, Richard; Rinder, Henry M.; Bhandari, Vineet
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.
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
Sartelli, Massimo; Catena, Fausto; Di Saverio, Salomone; Ansaloni, Luca; Malangoni, Mark; Moore, Ernest E; Moore, Frederick A; Ivatury, Rao; Coimbra, Raul; Leppaniemi, Ari; Biffl, Walter; Kluger, Yoram; Fraga, Gustavo P; Ordonez, Carlos A; Marwah, Sanjay; Gerych, Igor; Lee, Jae Gil; Tranà, Cristian; Coccolini, Federico; Corradetti, Francesco; Kirkby-Bott, James
Summary. Arginine (ARG) is an amino acid (AA) with unique properties and with a key-role in the metabolic, immune and reparative response\\u000a to trauma and sepsis. This study has been performed to characterize the correlations between plasma levels of ARG, of other\\u000a AA and of multiple metabolic variables in trauma and sepsis.\\u000a \\u000a Two-hundred and sixty-three plasma amino-acidograms with a large series
C. Chiarla; I. Giovannini; J. H. Siegel
Sepsis is a significant cause of morbidity and mortality in neonates. The most common pathogens of bacterial sepsis and antibiotic sensitivity patterns vary in different parts of the world. The aim of this study was to determine the most common pathogens and outcome of neonatal sepsis and also antibiotic sensitivity patterns of Klebsiella species. A retrospective descriptive study was carried
E Malakan Rad
Postoperative or posttraumatic sepsis remains one of the leading causes of morbidity and mortality in hospital populations, especially in populations in intensive care units (ICUs). Central to the successful control of sepsis-associated infections is the ability to rapidly diagnose and treat disease. The ability to identify sepsis patients before they show any symptoms would have major benefits for the health
R. A. Lukaszewski; A. M. Yates; M. C. Jackson; K. Swingler; J. M. Scherer; A. J. Simpson; P. Sadler; P. McQuillan; R. W. Titball; T. J. G. Brooks; M. J. Pearce
Introduction Inflammation and coagulation are closely interrelated pathophysiologic processes in the pathogenesis of sepsis. However, the diagnostic criteria of sepsis and disseminated intravascular coagulation (DIC) are different. This study aimed to define a biomarker panel to predict sepsis-induced DIC in emergency department patients. Methods Eighty-two patients who were admitted to the emergency department of a tertiary university hospital were included in this study. The inclusion criteria were as follows: (1) age >18 years; (2) ?1 systemic inflammatory response syndrome (SIRS) criteria. Patients were excluded if they lacked biomarker data or apparent clinical manifestations. Eleven biomarkers were assayed from blood drawn on ED admission. Receiver operating curve (ROC) analysis including the area under the ROC and multivariable logistic regression were used to identify an optimal combination of biomarkers to create a diagnostic panel. The derived formula for weighting biomarker values was used to determine the severity of sepsis-induced DIC, which was divided into three categories: mild, moderate, and severe. We also investigated the ability of this classification to predict secondary outcome measures of rates of sepsis and DIC, DIC score, acute physiology and chronic health evaluation (APACHE) II score, sequential organ failure score (SOFA) score, and 28-day all-cause mortality. Results Among the 11 biomarkers tested, the optimal 2-marker panel comprised presepsin and protein C. The area under the curve for the accuracies of predicting sepsis and DIC from these two biomarkers were 0.913 and 0.880, respectively. When patients were divided according to the severity of sepsis-induced DIC, all secondary outcomes except for mortality were significantly higher depending on the severity (P?.0001). The overall mortality rates of mild, moderate, and severe sepsis-induced DIC were 7.14%, 15.4%, and 28.6%, respectively (P?=?.0994). Conclusions A biomarker panel of presepsin and protein C is predictive of the severity of sepsis-induced DIC in suspected ED patients. These criteria for sepsis-induced DIC are very simple, easy to implement, and can be used in intensive care units as a point-of-care test.
Sepsis is characterised by a systemic dysregulated inflammatory response and oxidative stress, often leading to organ failure and death. Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. MitoQ is an antioxidant selectively targeted to mitochondria that protects mitochondria from oxidative damage and which has been shown to decrease mitochondrial damage in animal models of oxidative stress. We hypothesised that if oxidative damage to mitochondria does play a significant role in sepsis-induced organ failure, then MitoQ should modulate inflammatory responses, reduce mitochondrial oxidative damage, and thereby ameliorate organ damage. To assess this, we investigated the effects of MitoQ in vitro in an endothelial cell model of sepsis and in vivo in a rat model of sepsis. In vitro MitoQ decreased oxidative stress and protected mitochondria from damage as indicated by a lower rate of reactive oxygen species formation (P=0.01) and by maintenance of the mitochondrial membrane potential (P<0.005). MitoQ also suppressed proinflammatory cytokine release from the cells (P<0.05) while the production of the anti-inflammatory cytokine interleukin-10 was increased by MitoQ (P<0.001). In a lipopolysaccharide-peptidoglycan rat model of the organ dysfunction that occurs during sepsis, MitoQ treatment resulted in lower levels of biochemical markers of acute liver and renal dysfunction (P<0.05), and mitochondrial membrane potential was augmented (P<0.01) in most organs. These findings suggest that the use of mitochondria-targeted antioxidants such as MitoQ may be beneficial in sepsis. PMID:18845241
Lowes, Damon A; Thottakam, Bensita M V; Webster, Nigel R; Murphy, Michael P; Galley, Helen F
Introduction The incidence of death among patients admitted for severe sepsis or septic shock is high. Adrenomedullin (ADM) plays a central role in initiating the hyperdynamic response during the early stages of sepsis. Pilot studies indicate an association of plasma ADM with the severity of the disease. In the present study we utilized a novel sandwich immunoassay of bioactive plasma ADM in patients hospitalized with sepsis in order to assess the clinical utility. Methods We enrolled 101 consecutive patients admitted to the emergency department with suspected sepsis in this study. Sepsis was defined by fulfillment of at least two systemic inflammatory response syndrome (SIRS) criteria plus clinical suspicion of infection. Plasma samples for ADM measurement were obtained on admission and for the next four days. The 28-day mortality rate was recorded. Results ADM at admission was associated with severity of disease (correlation with Acute Physiology and Chronic Health Evaluation II (APACHE II) score: r?=?0.46; P <0.0001). ADM was also associated with 28-day mortality (ADM median (IQR): survivors: 50 (31 to 77) pg/mL; non-survivors: 84 (48 to 232) pg/mL; P <0.001) and was independent from and additive to APACHE II (P?=?0.02). Cox regression analysis revealed an additive value of serial measurement of ADM over baseline assessment for prediction of 28-day mortality (P?0.01). ADM was negatively correlated with mean arterial pressure (r?=?-0.39; P <0.0001), and it strongly discriminated those patients requiring vasopressor therapy from the others (ADM median (IQR): no vasopressors 48 (32 to 75) pg/mL; with vasopressors 129 (83 to 264) pg/mL, P <0.0001). Conclusions In patients admitted with sepsis, severe sepsis or septic shock plasma ADM is strongly associated with severity of disease, vasopressor requirement and 28-day mortality.
Sepsis remains one of the leading causes of mortality during pregnancy. Because of the inherent limitations of conducting scientific investigations during pregnancy, a great deal of clinical decision making is based on observational reports, an understanding of the physiologic changes of pregnancy, and consideration for risk to the fetus. We describe a 20-year-old pregnant woman at 20 weeks' gestation who was admitted to an obstetric ward for dehydration and a urinary tract infection. Approximately 36 hours later, the patient's clinical status deteriorated, with the development of mental status changes, acute respiratory failure, and renal failure. Drotrecogin alfa (activated) was started, as the patient's Acute Physiology and Chronic Health Evaluation II score was 27 (> 25 is the typical score required for drotrecogin alfa [activated] therapy); within 48 hours the patient's clinical status dramatically improved. The patient completed 96 uninterrupted hours of therapy and was subsequently discharged after a 15-day hospitalization, with no apparent sequelae. Approximately 17 weeks later, the patient gave birth to a 3.42-kg female infant with no congenital abnormalities. To our knowledge, this represents the second case report to describe the use of drotrecogin alfa (activated) along with the status of the mother and fetus both after completion of therapy and after subsequent delivery. Because of the threat of mortality from sepsis during pregnancy, combined with the inherent limitations associated with clinical research during pregnancy, further reports and investigation into the treatment of sepsis in the pregnant patient are warranted. PMID:21361743
Eppert, Heather D; Goddard, Kara B; King, Crystal L
Background Septimeb is a new herbal-derived remedy, recently approved for its potential immunomodulatory effects. Regarding the key role of immune system in the pathogenesis of severe sepsis and lack of any standard treatment for improving survival of these patients; we evaluated the effect of Septimeb -as an adjutant to standard treatment-on inflammatory biomarkers and mortality rates in patients with severe sepsis. Methods In this multicenter, randomized, single-blind trial, we assigned patients with severe sepsis and Acute Physiology and Chronic Health Evaluation (APACHE II) score of more than 20 to receive standard treatment of severe sepsis (control group) or standard treatment plus Septimeb. This group was treated with Septimeb for 14 days then followed up for another14 days. APACHE score, Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score (SAPS) were calculated daily. Blood samples were analyzed for interleukin 2 tumor necrosis factor-?, total antioxidant power, platelet growth factor and matrix metalloproteinase 2. Results A total of 29 patients underwent randomization (13 in control group and 16 in Septimeb group). There was significant difference between the Septimeb and control group in the 14 days mortality rate (18.8% vs. 53.85 respectively, P=0.048). Compared to control group, Septimeb was significantly effective in improving SAPS (P= 0.029), SOFA (P=0.003) and APACHE II (P=0.008) scores. Inflammatory biomarkers didn’t change significantly between the two groups (P>0.05). Conclusion Septimeb reduces mortality rates among patients with severe sepsis and it could be added as a safe adjutant to standard treatment of sepsis.
Objective: To determine the value of procalcitonin (PCT) in the early diagnosis (and differentiation) of patients with SIRS, sepsis, severe sepsis, and septic shock in comparison to C-reactive protein (CRP), white blood cell and thrombocyte count, and APACHE-II score (AP-II).¶Design: Prospective cohort study including all consecutive patients admitted to the ICU with the suspected diagnosis of infection over a 7-month
F. M. Brunkhorst; K. Wegscheider; Z. F. Forycki; R. Brunkhorst
Severe sepsis is traditionally associated with bacterial diseases. While fungi and parasites can also cause sepsis, they are significantly less common than bacterial causes. However, viruses are becoming a growing cause of severe sepsis worldwide. Among these viruses, influenza is crossing all geographic boundaries and is causing larger epidemics and pandemics. As a consequence, more critically ill patients with severe sepsis caused directly by influenza viruses, or indirectly by influenza-induced secondary bacterial infections are being admitted to hospitals worldwide. This manuscript aims to provide a pathophysiological and clinical update on the link between influenza and severe sepsis.
Florescu, Diana F; Kalil, Andre C
Streptococcus pyogenes sometimes induces invasive streptococcal infection, including streptococcal toxic shock syndrome (STSS). Muscular necrosis is one of the peculiar symptoms of invasive streptococcal infection and STSS. We inoculated S. pyogenes into the muscles of mice. To do so, 5 × 108 bacteria in 0·2 ml phosphate-buffered saline were injected into the right hind thigh. None of the mice injected with the bacteria showed muscular necrosis and none died. Tumour necrosis factor-? (TNF-?) and infiltration of leucocytes were detected in the muscles of infected sites, although the condition of the infected mice did not deteriorate after anti-TNF-? monoclonal antibody treatment. The infected mice treated intraperitoneally with Escherichia coli lipopolysaccharide (LPS) showed augmentation of bacterial growth, muscular necrosis and death. TNF-? was detected in the sera of the infected mice treated with LPS, but not in the muscles of the infected sites. Infiltration of leucocytes into the infected muscle was not observed in the infected mice treated with LPS. Anti-TNF-? monoclonal antibody treatment decreased mortality in the infected mice treated with LPS. Moreover, the infected mice treated with recombinant TNF-? showed augmentation of muscular necrosis and death. These results suggest that systemic production of TNF-? induced by stimulation with LPS inhibits infiltration of leucocytes into the infected site and exacerbates muscular infection, and that TNF-? produced in streptococcal infection is not a defence factor for the host. Invasive streptococcal infection and STSS appear to be induced by both S. pyogenes and the host's immune system.
Diao, Hongyan; Kohanawa, Masashi; Yimin; Nakajima, Hirofumi; Sato, Yuichiro; Minagawa, Tomonori; Nakane, Akio
Sepsis is the primary cause of death in the intensive care unit. Extracorporeal blood purification therapies have been proposed for patients with sepsis in order to improve outcomes since these therapies can alter the host inflammatory response by non-selective removal of inflammatory mediators or bacterial products or both. Recent technological progress has increased the number of techniques available for blood purification and their performance. In this overview, we report on the latest advances in blood purification for sepsis and how they relate to current concepts of disease, and we review the current evidence for high-volume hemofiltration, cascade hemofiltration, hemoadsorption, coupled plasma filtration adsorption, high-adsorption hemofiltration, and high-cutoff hemofiltration/hemodialysis. Promising results have been reported with all of these blood purification therapies, showing that they are well tolerated, effective in clearing inflammatory mediators or bacterial toxins (or both) from the plasma, and efficacious for improvement of various physiologic outcomes (for example, hemodynamics and oxygenation). However, numerous questions, including the timing, duration, and frequency of these therapies in the clinical setting, remain unanswered. Large multicenter trials evaluating the ability of these therapies to improve clinical outcomes (that is, mortality or organ failure), rather than surrogate markers such as plasma mediator clearance or transient improvement in physiologic variables, are required to define the precise role of blood purification in the management of sepsis.
Severe sepsis is a leading cause of morbidity and mortality in the intensive care unit (ICU). We conducted a prospective multicenter study to evaluate epidemiology and outcome of severe sepsis in Japanese ICUs. The patients were registered at 15 general critical care centers in Japanese tertiary care hospitals when diagnosed as having severe sepsis. Of 14,417 patients, 624 (4.3%) were diagnosed with severe sepsis. Demographic and clinical characteristics at enrollment (Day 1), physiologic and blood variables on Days 1 and 4, and mortality were evaluated. Mean age was 69.0 years, and initial mean Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were 23.4 and 8.6, respectively. The 28-day mortality was 23.1%, and overall hospital mortality was 29.5%. SOFA score and disseminated intravascular coagulation (DIC) score were consistently higher in nonsurvivors than survivors on Days 1 and 4. SOFA score, DIC score on Days 1 and 4, and hospital mortality were higher in patients with than without septic shock. SOFA score on Days 1 and 4 and hospital mortality were higher in patients with than without DIC. Logistic regression analyses showed age, presence of septic shock, DIC, and cardiovascular dysfunction at enrollment to be predictors of 28-day mortality and presence of comorbidity to be an additional predictor of hospital mortality. Presence of septic shock or DIC resulted in approximately twice the mortality of patients without each factor, whereas the presence of comorbidity may be a significant predictor of delayed mortality in severe sepsis. PMID:24530102
Ogura, Hiroshi; Gando, Satoshi; Saitoh, Daizoh; Takeyama, Naoshi; Kushimoto, Shigeki; Fujishima, Seitaro; Mayumi, Toshihiko; Araki, Tsunetoshi; Ikeda, Hiroto; Kotani, Joji; Miki, Yasuo; Shiraishi, Shin-Ichiro; Suzuki, Koichiro; Suzuki, Yasushi; Takuma, Kiyotsugu; Tsuruta, Ryosuke; Yamaguchi, Yoshihiro; Yamashita, Norio; Aikawa, Naoki
Severe sepsis has a high fatality rate, but no clinical indices for prognosis have been established. In recent years, the renin-angiotensin system (RAS) has received considerable attention. However, clinical data on RAS are inconsistent. Therefore, the aim of the present study was to assess the significance of RAS in the prognosis of sepsis. Blood samples were collected from patients, who met the diagnostic criteria of severe sepsis, on day 1 (D1) and 3 (D3). For each sample, the levels of angiotensin II (AngII), angiotensin-converting enzyme (ACE) and additional indices were measured. Patients were monitored for 28 days. On the D1 of inclusion, the average Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 22.2 and the Sepsis-related Organ Failure Assessment (SOFA) score was 6.1. Logistic regression analysis revealed that mortality-associated variables included the APACHE II score on D1, the SOFA score on D1, high lactic acid levels on D3 and low AngII and ACE levels on D1 and D3. AngII levels (<86.1 ng/ml) on D1 had a sensitivity of 88.2% and specificity of 77.3% for predicting mortality. ACE levels (<39.2 ng/ml) on D1 had a sensitivity of 88.2% and specificity of 72.7% for predicting mortality. These two indices were better than the APACHE II and SOFA scores. Therefore, low expression levels of AngII and ACE are valuable in predicting the mortality of patients with severe sepsis.
ZHANG, WEI; CHEN, XIAOWEI; HUANG, LING; LU, NING; ZHOU, LEI; WU, GUOJIE; CHEN, YUGUO
Pathogenesis of sepsis includes complex interaction between pathogen activities and host response, manifesting highly variable signs and symptoms, possibly delaying diagnosis and timely life-saving interventions. This study applies traditional Chinese medicine (TCM) Zheng diagnosis in patients with severe sepsis and septic shock to evaluate its adaptability and use as an early predictor of sepsis mortality. Three-year prospective observational study enrolled 126 septic patients. TCM Zheng diagnosis, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and blood samples for host response cytokines measurement (tumor necrosis factor-?, Interleukin-6, Interleukin-8, Interleukin-10, Interleukin-18) were collected within 24 hours after admission to Intensive Care Unit. Main outcome was 28-day mortality; multivariate logistic regression analysis served to determine predictive variables of the sepsis mortality. APACHE II score, frequency of Nutrient-phase heat, and Qi-Xu and Yang-Xu Zhengs were significantly higher in nonsurvivors. The multivariate logistic regression analysis identified Yang-Xu Zheng as the outcome predictor. APACHE II score and levels of five host response cytokines between patients with and without Yang-Xu Zheng revealed significant differences. Furthermore, cool extremities and weak pulse, both diagnostic signs of Yang-Xu Zheng, were also proven independent predictors of sepsis mortality. TCM diagnosis “Yang-Xu Zheng” may provide a new mortality predictor for septic patients.
Lin, Sunny Jui-Shan; Cheng, Yung-Yen; Chang, Chih-Hung; Huang, Yi-Chia; Su, Yi-Chang
The recognition, diagnosis, and management of sepsis remain among the greatest challenges in pediatric critical care medicine. Sepsis remains among the leading causes of death in both developed and underdeveloped countries and has an incidence that is predicted to increase each year. Unfortunately, promising therapies derived from preclinical models have universally failed to significantly reduce the substantial mortality and morbidity associated with sepsis. There are several key developmental differences in the host response to infection and therapy that clearly delineate pediatric sepsis as a separate, albeit related, entity from adult sepsis. Thus, there remains a critical need for well-designed epidemiologic and mechanistic studies of pediatric sepsis in order to gain a better understanding of these unique developmental differences so that we may provide the appropriate treatment. Herein, we will review the important differences in the pediatric host response to sepsis, highlighting key differences at the whole-organism level, organ system level, and cellular and molecular level.
Wheeler, Derek S.; Wong, Hector R.; Zingarelli, Basilia
Sepsis remains a major cause of admissions to Intensive Care Units (ICU) and has a high mortality rates and significant morbidity in survivors. There are physical, cognitive and psychological sequelae from severe sepsis that have a negative effect on the patients' health related quality of life in the longer term and a social care and humanitarian impact. Although muscle mass loss during the septic period happens very quickly, recovery takes a considerable time and requires the patient to commit to exercising and eating well to rebuild. Where cognitive impairment has resulted from the septic illness the patients' ability to look after themselves may be affected and this has financial and family implications for future care. Patients may also develop psychological problems such as anxiety, depression or post traumatic stress disorder (PTSD), which can have a profound effect on their everyday functioning and the possibility of returning to work. As yet there are no published studies of rehabilitation with patients surviving severe sepsis, although there is one in progress at the moment. The use of techniques such as ICU diaries to help patients to understand their illness and deal with delusional memories they may have from their ICU stay has been shown to aid psychological recovery in general ICU patients, a percentage of whom will have suffered from sepsis. The use of a self-guided manualised 6 week rehabilitation program, the ICU Recovery Manual, has been shown to accelerate physical recovery in general ICU patients. Considerable amounts of money are spent treating patients with severe sepsis in ICU and not completing the job of returning them to as close as possible to their normal functioning does not make financial sense. PMID:23857443
Jones, C; Griffiths, R D
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.
Fritzer, Andrea; Senn, Beatrice M.; Minh, Duc Bui; Hanner, Markus; Gelbmann, Dieter; Noiges, Birgit; Henics, Tamas; Schulze, Kai; Guzman, Carlos A.; Goodacre, John; von Gabain, Alexander; Nagy, Eszter; Meinke, Andreas L.
Introduction Although sepsis is the leading cause of death in noncoronary critically ill patients, identification of patients at high risk of death remains a challenge. In this study, we examined the incremental usefulness of adding multiple biomarkers to clinical scoring systems for predicting intensive care unit (ICU) mortality in patients with severe sepsis. Methods This retrospective observational study used stored plasma samples obtained from 80 severe sepsis patients recruited at three tertiary hospital ICUs in Hamilton, Ontario, Canada. Clinical data and plasma samples were obtained at study inclusion for all 80 patients, and then daily for 1 week, and weekly thereafter for a subset of 50 patients. Plasma levels of cell-free DNA (cfDNA), interleukin 6 (IL-6), thrombin, and protein C were measured and compared with clinical characteristics, including the primary outcome of ICU mortality and morbidity measured with the Multiple Organ Dysfunction (MODS) score and Acute Physiology and Chronic Health Evaluation (APACHE) II scores. Results The level of cfDNA in plasma at study inclusion had better prognostic utility than did MODS or APACHE II scores, or the biomarkers measured. The area under the receiver operating characteristic (ROC) curves for cfDNA to predict ICU mortality is 0.97 (95% CI, 0.93 to 1.00) and to predict hospital mortality is 0.84 (95% CI, 0.75 to 0.94). We found that a cfDNA cutoff value of 2.35 ng/?l had a sensitivity of 87.9% and specificity of 93.5% for predicting ICU mortality. Sequential measurements of cfDNA suggested that ICU mortality may be predicted within 24 hours of study inclusion, and that the predictive power of cfDNA may be enhanced by combining it with protein C levels or MODS scores. DNA-sequence analyses and studies with Toll-like receptor 9 (TLR9) reporter cells suggests that the cfDNA from sepsis patients is host derived. Conclusions These studies suggest that cfDNA provides high prognostic accuracy in patients with severe sepsis. The serial data suggest that the combination of cfDNA with protein C and MODS scores may yield even stronger predictive power. Incorporation of cfDNA in sepsis risk-stratification systems may be valuable for clinical decision making or for inclusion into sepsis trials.
In this study, we determined the function of a novel non-ribosomal peptide synthetase (NRPS) system carried by a streptococcal integrative conjugative element (ICE), ICESe2. The NRPS shares similarity with the yersiniabactin system found in the high-pathogenicity island of Yersinia sp. and is the first of its kind to be identified in streptococci. We named the NRPS product ‘equibactin’ and genes of this locus eqbA–N. ICESe2, although absolutely conserved in Streptococcus equi, the causative agent of equine strangles, was absent from all strains of the closely related opportunistic pathogen Streptococcus zooepidemicus. Binding of EqbA, a DtxR-like regulator, to the eqbB promoter was increased in the presence of cations. Deletion of eqbA resulted in a small-colony phenotype. Further deletion of the irp2 homologue eqbE, or the genes eqbH, eqbI and eqbJ encoding a putative ABC transporter, or addition of the iron chelator nitrilotriacetate, reversed this phenotype, implicating iron toxicity. Quantification of 55Fe accumulation and sensitivity to streptonigrin suggested that equibactin is secreted by S. equi and that the eqbH, eqbI and eqbJ genes are required for its associated iron import. In agreement with a structure-based model of equibactin synthesis, supplementation of chemically defined media with salicylate was required for equibactin production.
Heather, Zoe; Holden, Matthew T G; Steward, Karen F; Parkhill, Julian; Song, Lijiang; Challis, Gregory L; Robinson, Carl; Davis-Poynter, Nicholas; Waller, Andrew S
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
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
Hepatic granulomas are induced by intraperitoneal injection of streptococcal cell walls (SCW) into Lewis rats. Kupffer cells rapidly clear SCW from the blood, and the authors examined Kupffer cells further for a role in SCW-hepatic inflammation. Isolated Kupffer cells cultured with SCW secreted high levels of tumor necrosis factor alpha (TNF alpha), interleukin-1 (IL-1), transforming growth factor beta (TGF beta), and prostaglandin E2 (PGE2). SCW transiently induced increased steady-state levels of IL-1 beta and TNF alpha mRNA; in contrast, constitutive expression of TGF beta 1 mRNA in Kupffer cells was not affected by SCW. Low concentrations of SCW induced the accumulation of intracellular IL-1 and TGF beta bioactivity, with intracellular IL-1 bioactivity remaining high through at least 72 hours of culture. Kupffer cells isolated 1, 7, and 21 days after SCW injection did not express IL-1 beta or TNF alpha mRNA greater than control levels and exhibited marked hyporesponsiveness to secondary in vitro stimulation with SCW or LPS. SCW transiently induces Kupffer cells to secrete a variety of soluble mediators that contribute to hepatic inflammation by inducing leukocyte recruitment and activation and fibroproliferation. The transient nature of the Kupffer cell response and the hyporesponsiveness to secondary stimulation may be a mechanism by which the hepatic inflammation is negatively regulated. Images Figure 1 Figure 2 Figure 3 Figure 4
Manthey, C. L.; Kossmann, T.; Allen, J. B.; Corcoran, M. L.; Brandes, M. E.; Wahl, S. M.
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.
Erythrocytes have been long considered as “dead” cells with transport of oxygen (O2) as their only function. However, the ability of red blood cells (RBCs) to modulate the microcirculation is now recognized as an important additional function. This capacity is regulated by a key element in the rheologic process: the RBC membrane. This membrane is a complex unit with multiple interactions between the extracellular and intracellular compartments: blood stream, endothelium, and other blood cells on the one hand, and the intracytoplasmic compartment with possible rapid adaptation of erythrocyte metabolism on the other. In this paper, we review the alterations in the erythrocyte membrane observed in critically ill patients and the influence of these alterations on the microcirculatory abnormalities observed in such patients. An understanding of the mechanisms of RBC rheologic alterations in sepsis and their effects on blood flow and on oxygen transport may be important to help reduce morbidity and mortality from severe sepsis.
Serroukh, Yasmina; Djebara, Sarah; Lelubre, Christophe; Zouaoui Boudjeltia, Karim; Biston, Patrick; Piagnerelli, Michael
Erythrocytes have been long considered as "dead" cells with transport of oxygen (O(2)) as their only function. However, the ability of red blood cells (RBCs) to modulate the microcirculation is now recognized as an important additional function. This capacity is regulated by a key element in the rheologic process: the RBC membrane. This membrane is a complex unit with multiple interactions between the extracellular and intracellular compartments: blood stream, endothelium, and other blood cells on the one hand, and the intracytoplasmic compartment with possible rapid adaptation of erythrocyte metabolism on the other. In this paper, we review the alterations in the erythrocyte membrane observed in critically ill patients and the influence of these alterations on the microcirculatory abnormalities observed in such patients. An understanding of the mechanisms of RBC rheologic alterations in sepsis and their effects on blood flow and on oxygen transport may be important to help reduce morbidity and mortality from severe sepsis. PMID:22675622
Serroukh, Yasmina; Djebara, Sarah; Lelubre, Christophe; Zouaoui Boudjeltia, Karim; Biston, Patrick; Piagnerelli, Michael
Tension-free vaginal tape (TVT), is a commonly performed, low risk procedure for treatment of stress urinary incontinence (SUI). Severe complications are rare, but can be potentially life threatening. We present a case of 66 year old patient who sustained bladder perforation at the time of TVT procedure and subsequently developed sepsis rapidly leading to multi-organ failure and triggering sequence of serious complications. During her inpatient stay she required ITU admission, emergency laparotomy, TVT mesh removal, bowel resection due to ischemic colitis and anticoagulation for pulmonary embolism. Despite of clinical picture of sepsis her microbiology tests were almost consistently negative. This case emphasise importance of awareness and quick recognition of TVT related complications. Patient ultimately survived and recovered thanks to timely and coordinated management by the multidisciplinary team of doctors. PMID:24834712
Stec, Piotr; Connell, Rowan
Objective Human enteroviruses are the major cause of aseptic meningitis and also cause a wide range of other acute illnesses, including\\u000a neonatal sepsis like disease, meningitis, acute flaccid paralysis and acute hemorrhagic conjunctivitis. Infection in neonates\\u000a is particularly life threatening.Methods : Stool samples of 523 children (age < 4 years) showing symptoms of acute flaccid paralysis (AFP) were studied. National
Amit Kapoor; A. Ayyagari; T. N. Dhole
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.
Sepanski, Robert J.; Godambe, Sandip A.; Mangum, Christopher D.; Bovat, Christine S.; Zaritsky, Arno L.; Shah, Samir H.
The complement system is one of the key players in the defence against infections. Its activation during the innate immune response leads to the generation of several proteins that contribute to the lysis and opsonization of microorganisms, regulate inflammatory reactions and bridge innate immunity with the subsequent adaptive immune response. Complement is also activated in overwhelming bacterial infections that lead to sepsis, and its protective functions play a role in this frequently lethal disorder. However, despite its role in protection, complement can also contribute to the development of severe complications that significantly worsen the prognosis of septic patients. Therefore, an understanding of the mechanisms involved in the activation of complement during sepsis is essential to our efforts to introduce rational therapies targeting complement to the treatment of patients suffering from this condition. This review presents a current view of the mechanisms involved in the activation of complement in sepsis, in the context of the multiple interactions between complement and other biological systems that are involved in the pathogenesis of this disorder.
Markiewski, Maciej M.; DeAngelis, Robert A.; Lambris, John D.
The complement system is one of the key players in the defence against infections. Its activation during the innate immune response leads to the generation of several proteins that contribute to the lysis and opsonization of microorganisms, regulate inflammatory reactions and bridge innate immunity with the subsequent adaptive immune response. Complement is also activated in overwhelming bacterial infections that lead to sepsis, and its protective functions play a role in this frequently lethal disorder. However, despite its role in protection, complement can also contribute to the development of severe complications that significantly worsen the prognosis of septic patients. Therefore, an understanding of the mechanisms involved in the activation of complement during sepsis is essential to our efforts to introduce rational therapies targeting complement to the treatment of patients suffering from this condition. This review presents a current view of the mechanisms involved in the activation of complement in sepsis, in the context of the multiple interactions between complement and other biological systems that are involved in the pathogenesis of this disorder. PMID:18798865
Markiewski, Maciej M; DeAngelis, Robert A; Lambris, John D
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
Kleinpell, Ruth; Aitken, Leanne; Schorr, Christa A
Sepsis remains a major cause of morbidity and mortality in adult and pediatric intensive care units. Heterogeneity of demographics, comorbidities, biological mechanisms, and severity of illness leads to difficulty in determining which patients are at highest risk of mortality. Determining mortality risk is important for weighing the potential benefits of more aggressive interventions and for deciding whom to enroll in clinical trials. Biomarkers can be used to parse patients into different risk categories and can outperform current methods of patient risk stratification based on physiologic parameters. Here we review the Pediatric Sepsis Biomarker Risk Model that has also been modified and applied to estimate mortality risk in adult patients. We compare the two models and speculate on the biological implications of the biomarkers in patients with sepsis. PMID:24754535
Alder, Matthew N; Lindsell, Christopher J; Wong, Hector R
Background: Breakdown of microvascular endothelial barrier functions contributes to disturbed microcirculation, organ failure, and death in sepsis. Increased endothelial cAMP levels by systemic application of phosphodiesterase 4 inhibitors (PD-4-I) have previously been demonstrated to protect microvascular barrier properties in a model of systemic inflammation (systemic inflammatory response syndrome) suggesting a novel therapeutic option to overcome this problem. However, in a clinically relevant model of polymicrobial sepsis long-term effects, immunomodulatory effects and effectivity of PD-4-I to stabilize microvascular barrier functions and microcirculation remained unexplored. Methods: We induced polymicrobial sepsis using the colon ascendens stent peritonitis (CASP) model in which we performed macrohemodynamic and microhemodynamic monitoring with and without systemic intravenous application of different doses of PD-4-I rolipram in Sprague-Dawley rats over 26 h. Results: All animals with CASP showed clinical and laboratory signs of sepsis and peritonitis. Whereas macrohemodynamic adverse effects were not evident, application of PD-4-I led to stabilization of endothelial barrier properties as revealed by reduced extravasation of fluorescein isothiocyanate-albumin. However, only low-dose application of 1 mg/kg body weight per hour of PD-4-I improved microcirculatory flow in the CASP model, whereas high-dose therapy of 3 mg/kg BW per hour PDI-4-I had adverse effects. Accordingly, sepsis-induced acute kidney injury and lung edema were prevented by PD-4-I treatment. Furthermore, PD-4-I showed immunomodulatory effects as revealed by decreased interleukin 1? (IL-1?), IL-1?, IL-12, and tumor necrosis factor ? levels following PD-4-I treatment, which appeared not to correlate with barrier-stabilizing effects of rolipram. Conclusions: These data provide further evidence that systemic application of PD-4-I could be suitable for therapeutic microvascular barrier stabilization and improvement of microcirculatory flow in sepsis. PMID:24569506
Flemming, Sven; Schlegel, Nicolas; Wunder, Christian; Meir, Michael; Baar, Wolfgang; Wollborn, Jakob; Roewer, Norbert; Germer, Christoph-Thomas; Schick, Martin Alexander
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
Patil, Naeem K; Parajuli, Nirmala; MacMillan-Crow, Lee Ann; Mayeux, Philip R
Background The complement depletion commonly occurred during sepsis, but it was often underestimated compared with severe infection or coagulation dysfunction. Objective This study was designed to investigate the alteration of complement system in patients with severe abdominal sepsis and evaluate the role of complement depletion in prognosis of such patients. The relationship between complement depletion and infection or coagulopathy was also explored. Methods Forty-five patients with severe abdominal sepsis were prospectively conducted among individuals referral to SICU. Currently recommended treatments, such as early goal-directed resuscitation, source control and antibiotics therapy, were performed. Acute physiology and chronic health evaluation II (APACHE II) and sepsis related organ failure assessment (SOFA) scores were employed to evaluate severity. Plasma levels of C3, C4, CRP, PCT, D-dimer and other parameters were detected within eight times of observation. The 28-day mortality, length of stay, and postoperative complications were compared between complement depletion and non-complement depletion groups. Results Within the study period, eight (17.8%) patients died, five of them suffering from complement depletion. The overall incidence of complement depletion was 64.4%. At admission, mean complement C3 and C4 levels were 0.70 and 0.13 mg/mL, respectively. Using ROC analysis for mortality prediction, the area under the curve of C3 was 0.926 (95% CI, 0.845–0.998, P<0.001), with optimal cutpoint value of 0.578 mg/mL. Complement C3 depletion was shown to be no correlation to severity scores, however, strongly correlated with elevated D-dimer, PCT concentrations and increased postoperative complications. Conclusions Complement C3 depletion was found to be connected to poor prognosis in severe abdominal sepsis. This depletion seems to be associated with coagulopathy and aggravated infection during sepsis, which should be paid close attention in critical care. Trial Registration ClinicalTrials.gov NCT01568853
Zhao, Yunzhao; Han, Gang; Li, Weiqin; Huang, Qian; Tong, Zhihui; Li, Jieshou
Cardiac dysfunction is a well-recognized complication of severe sepsis and septic shock. Cardiac dysfunction in sepsis is\\u000a characterized by ventricular dilatation, reduction in ejection fraction and reduced contractility. Initially, cardiac dysfunction\\u000a was considered to occur only during the “hypodynamic” phase of shock. But we now know that it occurs very early in sepsis\\u000a even during the “hyperdynamic” phase of septic
Anthony Flynn; Bhalaghuru Chokkalingam Mani; Paul J. Mather
Sepsis is still a major burden for our society with high incidence of morbidity and mortality each year. Molecular mechanisms underlying the systemic inflammatory response syndrome (SIRS) associated with sepsis are still ill defined and most therapies developed to target the acute inflammatory component of the disease are insufficient. Recently the role of nuclear receptors (NRs) became a major topic of interest in transcriptional regulation of inflammatory processes. Nuclear receptors, such as the peroxisome proliferators-activated receptors (PPARs), have been demonstrated to exert anti-inflammatory properties by interfering with the NF?B pathway. We identified the nuclear envelope protein, interferon stimulated gene 12 (ISG12), which directly interacts with NRs. ISG12 is a co-factor stimulating nuclear export of NRs, thereby reducing the anti-inflammatory potential of NRs such as NR4A1. To examine the role of ISG12 in acute inflammatory processes we used recently generated ISG12 deficient mice. We can clearly demonstrate that lack of ISG12 prolongs survival in experimental sepsis and endotoxemia. Furthermore we can show that several acute inflammatory parameters, such as systemic IL6 cytokine levels, are downregulated in septic ISG12?/? animals. Consistently, similar results were obtained in in vitro experiments in peritoneal macrophages derived from ISG12 deficient mice. In contrast, mice deficient for the nuclear receptor NR4A1 exhibited an exacerbated innate immune response, and showed a significantly higher mortality after lethal endotoxemic challenge. This dramatic phenotype could be restored in ISG12/NR4A1 double deficient mice. We conclude from our data in vitro and in vivo that ISG12 is a novel modulator of innate immune responses regulating anti-inflammatory nuclear receptors such as NR4A1.
Uhrin, P.; Perkmann, T.; Binder, B.; Schabbauer, G.
Background: The relationship between childhood tic disorders and group A streptococcal (GAS) infections has been recently investigated by several research groups, but no systematic evaluation of laboratory indicators of GAS infections has been provided. Objective: The aim of our study was to seek clinical and laboratory evidence of GAS infections in a large population of children affected with tic disorders.
Francesco Cardona; Graziella Orefici
Antigenic variation allows pathogenic microorganisms to evade the immune system of the infected host. The variable structure must play an important role in pathogenesis, but its function is in most cases unknown. Here, we identify a function for the surface-exposed hypervariable region of streptococcal M5 protein, a virulence factor that inhibits phagocytosis. The hypervariable region of M5 was found to
Eskil Johnsson; Karin Berggård; Heike Kotarsky; Jens Hellwage; Peter F. Zipfel; Ulf Sjöbring; Gunnar Lindahl
The chromosomal region of Streptococcus agalactiae harboring the C5a peptidase and the lmb genes displays the structure of a composite transposon. Its presence in a streptococcal strain is associated with the origin of this strain from a human host. In S. agalactiae it is flanked by two copies of the insertion element ISSag2, and the nucleotide sequence for a third
Carmen Franken; Claudia Brandt; Gerd Bröker; Barbara Spellerberg
In this review we focus on three important families of LPxTG-anchored adhesins in the human pathogen Streptococcus pneumoniae, but also their homologues in related streptococci. We discuss the contribution of these streptococcal adhesins to host tropism, pathogenesis and their interactions with different host cell types. The first surface structures discussed are the heteropolymeric pili that have been found in important streptococcal pathogens such as S. pneumoniae, S. pyogenes, S. agalactiae and E. faecalis/faecium. Major and minor pilus subunit proteins are covalently joined and finally attached to the cell wall through the action of specific sortases. The role of pili and individual pilin subunits in adhesion and pathogenesis and their structure and assembly in different streptococcal species are being covered. Furthermore, we address recent findings regarding a family of large glycosylated serine-rich repeat (SRR) proteins that act as fibrillar adhesins for which homologues have been found in several streptococcal species including pneumococci. In the pneumococcal genome both pili and its giant SRR protein are encoded by accessory genes present in particular clonal lineages for which epidemiological information is available. Finally, we briefly discuss the role played by the pneumococcal neuraminidase NanA in adhesion and pathogenesis. PMID:21199258
Löfling, J; Vimberg, V; Battig, P; Henriques-Normark, B
We compared the performance of flocked swabs to that of traditional swabs for culture of beta-hemolytic streptococci in children with pharyngitis. Sensitivity was higher for flocked swabs, but this did not reach statistical significance. We conclude that flocked swabs can be used in place of traditional swabs for diagnosis of streptococcal pharyngitis. PMID:19605581
Goldfarb, David M; Slinger, Robert; Tam, Ron K; Barrowman, Nicholas; Chan, Francis
We compared the performance of flocked swabs to that of traditional swabs for culture of beta-hemolytic streptococci in children with pharyngitis. Sensitivity was higher for flocked swabs, but this did not reach statistical significance. We conclude that flocked swabs can be used in place of traditional swabs for diagnosis of streptococcal pharyngitis.
Goldfarb, David M.; Slinger, Robert; Tam, Ron K.; Barrowman, Nicholas; Chan, Francis
The development of cognitive impairment in sepsis is associated with neurotoxic effects caused by oxidative stress. We have assessed the effects of acute and extended administration of guanosine (GUA) on brain oxidative stress parameters and cognitive impairment in rats submitted to sepsis by cecal ligation and perforation (CLP). To achieve this goal, male Wistar rats underwent either sham operation or CLP with GUA. Rats subjected to CLP were treated with intraperitoneal injection of GUA (8 mg/kg after CLP) or vehicle. Twelve and 24 h after CLP, the rats were sacrificed, and samples from brain (hippocampus, striatum, cerebellum, prefrontal cortex and cortex) were obtained and assayed for thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. On the 10th day, another group of rats was submitted to the behavioral tasks. GUA administration reduced TBARS and carbonyl levels in some brain regions between 12 and 24 h after CLP, and ameliorated cognitive impairment evaluated 10 days after CLP. Our data provide the first experimental demonstration that GUA was able to reduce the consequences of CLP-induced sepsis in rats, by decreasing oxidative stress parameters in the brain and recovering the memory impairment. PMID:22497789
Petronilho, Fabricia; Périco, Susane Raquel; Vuolo, Francieli; Mina, Francielle; Constantino, Larissa; Comim, Clarissa M; Quevedo, João; Souza, Diogo Onofre; Dal-Pizzol, Felipe
Sepsis is associated with a high incidence of mortality and morbidity, however with appropriate strategies for monitoring and early targeted intervention mortality rates decline. This article examines the basic pathophysiology of the inflammatory response to tissue injury and the effects this has on circulation. A partnership of the Society of Critical Care Medicine, the European Society of Intensive Care Medicine and the International Sepsis Forum has developed the surviving sepsis strategy, which includes the sepsis six treatment pathway and early goal-directed therapy incorporating the six-hour care bundle. PMID:19753873
The cornerstones of therapy for sepsis and septic shock remain the prompt and adequate hemodynamic resuscitation, administration of antibiotics that target the pathogen, removal or drainage of an infected source and organ support. Despite adequate treatment and advanced life-support, the mortality remains high. However, the development of adjunctive anti-sepsis therapies has been challenging, with more than 30 unsuccessful drug trials. Fortunately, recent advances in our understanding of the sepsis pathophysiology revealed new pathogenic paradigms, and, thus, provided new exciting therapeutic concepts. In this review, we briefly discuss emerging pathogenesis-based strategies for treating severe sepsis and septic shock. PMID:24564778
Ledvinová, Lenka; Danihel, Vojt?ch; Mat?jovi?, Martin
Background and Objectives. Visceral leishmaniasis (VL) is one of the neglected diseases affecting the poorest segment of world populations. Sepsis is one of the predictors for death of patients with VL. This study aimed to assess the prevalence and factors associated with bacterial sepsis, causative agents, and their antimicrobial susceptibility patterns among patients with VL. Methods. A cross-sectional study was conducted among parasitologically confirmed VL patients suspected of sepsis admitted to the University of Gondar Hospital, Northwest Ethiopia, from February 2012 to May 2012. Blood cultures and other clinical samples were collected and cultured following the standard procedures. Results. Among 83 sepsis suspected VL patients 16 (19.3%) had culture confirmed bacterial sepsis. The most frequently isolated organism was Staphylococcus aureus (68.8%; 11/16), including two methicillin-resistant isolates (MRSA). Patients with focal bacterial infection were more likely to have bacterial sepsis (P < 0.001). Conclusions. The prevalence of culture confirmed bacterial sepsis was high, predominantly due to S. aureus. Concurrent focal bacterial infection was associated with bacterial sepsis, suggesting that focal infections could serve as sources for bacterial sepsis among VL patients. Careful clinical evaluation for focal infections and prompt initiation of empiric antibiotic treatment appears warranted in VL patients.
Takele, Yegnasew; Woldeyohannes, Desalegn; Tiruneh, Moges; Mohammed, Rezika; Lynen, Lutgarde; van Griensven, Johan
There is no systematic examination of affinity tag utility in Gram-positive bacteria, which limits the investigation of protein function in this important group of bacteria as specific antibodies for many of native proteins are generally not available. In this study, we utilized an E. coli-streptococcal shuttle vector pVT1666 and constructed two sets of expression plasmids pVPT-CTag and pVPT-NTag, with each set containing five affinity tags (GST, GFP, HSV, T7 and Nano) that can be fused to either the C- or N-terminus of a target protein. A putative glycosyltransferase (Gtf2) essential for Fap1 glycosylation was used to demonstrate the utility of the cassettes in detection of Gtf2 fusion proteins, and the biological relevance of the proteins in our working strain Streptococcus parasanguinis. GFP and T7 tags were readily expressed in S. parasanguinis as either an N- or C-terminal fusion to Gtf2. Only the C- terminal fusion of GST and HSV were able to be identified in S. parasanguinis. The Nano tag was not detected in either E. coli or S. parasanguinis. Genetic complementation experiments indicated that all the tagged Gtf2 fusion proteins could restore the Gtf2 function in the null mutant except for the Nano-tagged Gtf2 at its N-terminal fusion. Using a T7-tagged Gtf2 fusion construct, we demonstrated that the fusion cassette is also useful in detection of the fusion tag expression in other streptococci including S. mutans, S. pneumoniae and S. sanguinis. Therefore, the expression cassettes we constructed will be a useful tool not only to investigate protein-protein interactions in Fap1 biogenesis in S. parasanguinis, but also to study protein functions in other gram-positive bacteria in which pVT1666 replicates.
Zhou, Meixian; Fives-Taylor, Paula; Wu, Hui
We report a case of a 25-year-old woman presented with neutropenic fever after chemotherapy for the relapse of acute biphenotypic leukemia. Gallium-67 scintigraphy for the detection of infectious foci demonstrated a unique pattern of numerous foci with intense and varying-sized radioactivity spreading throughout the body. The subsequent skin biopsy and culture proved Pseudomonas infection. Therefore, this unique image, in combination with clinical information, was compatible with cutaneous manifestations of Pseudomonas sepsis. Eventually, the patient died of uncontrolled systemic infection despite the aggressive antibiotic treatment. This case reminded clinicians and nuclear medicine physicians to notice the potentially fatal finding on gallium-67 scan. PMID:21716010
Wu, Yu-Chin; Hsieh, Te-Chun; Sun, Shung-Shung; Lo, Woei-Chung; Yen, Kuo-Yang; Kao, Chia-Hung
Acute perturbations in the hemostatic balance of anticoagulation and procoagulation antecede the manifestation of purpura fulminans, a rare syndrome of intravascular thrombosis and hemorrhagic infarction of the skin. Hallmarks include small vessel thrombosis, tissue necrosis and disseminated intravascular thrombosis. The course may be rapidly fulminant resulting in multiorgan failure with thrombotic occlusion of the vasculature, leading to distal extremity ischemia and necrosis. Depletion of protein C (PC) has been emphasized in the pathogenesis. Early intravenous antibiotic administration and hemodynamic support are cornerstones in management. Herein, we report a case of pneumococcal sepsis-induced purpura fulminans limited to the skin in an asplenic adult patient without the development disseminated intravascular coagulation. PMID:24185261
Saraceni, Christine; Schwed-Lustgarten, Daniel
Co-infection with falciparum malaria and leptospirosis is uncommon. The aim of this study is to report a case of severe sepsis secondary to dual infection with falciparum malaria and leptospirosis. The literature is also reviewed on the clinical course of such co-infections, and the possible mechanisms and treatment of patients with life-threatening malaria and leptospirosis with activated protein C. The patient was a 25-year old male admitted in the Respiratory Intensive Care Unit (RICU) with fever, haemolysis, acute renal failure, hepatitis, acute lung injury (ALI) and altered sensorium. A syndromic evaluation was done and investigations revealed falciparum parasitaemia. He was treated with parenteral artesunate, ceftriaxone and doxycycline, and adjunctive therapies as for severe sepsis. Infusion of activated protein C was started 20 hours after onset of organ dysfunction, and intensive haemodialysis was instituted. Over the next four days the patient became afebrile with progressive resolution of ALI, renal failure and hepatitis. His Leptospira serology (requested as part of the evaluation) was reported positive on day 5. Dual infections are common and under-recognized in the tropics. Failure to treat potential co-infections may lead to poor outcomes. Acute lung injury in falciparum malaria has high mortality rates and therapy as for severe sepsis may improve survival. Adjunctive therapies, including activated protein C, cannot replace source eradication.
Srinivas, Rajagopala; Agarwal, Ritesh; Gupta, Dheeraj
Background Acute paraesophageal hernia is a surgical emergency presenting with sudden chest or abdominal pain, dysphagia, vomiting, retching\\u000a or significant anemia. Severe cases can present with respiratory failure or systemic sepsis. This can be due to gastric volvulus,\\u000a incarceration, strangulation, severe bleeding or perforation. Traditionally this has been treated with an open surgery. The\\u000a purpose of this study is to develop
Mohammed Bawahab; Philip Mitchell; Neal Church; Estifanos Debru
INTRODUCTION: The purpose of the present study was to evaluate the effects of intravenous lornoxicam on haemodynamic and biochemical parameters, serum cytokine levels and patient outcomes in severe sepsis. METHODS: A total of 40 patients with severe sepsis were included, and were randomly assigned (20 per group) to receive either lornoxicam (8 mg administered intravenously every 12 hours for six
Dilek Memi?; Beyhan Karamanl?o?lu; Alparslan Turan; Onur Koyuncu; Zafer Pamukçu
Procalcitonin (PCT) levels increase in patients with systemic infections; the highest levels have been found in sepsis. This study tested whether plasma procalcitonin level was related to sepsis, CRP, burn size, inhalation injury or mortality in severely burned patients over the entire clinical course.In 27 patients with 51 (20–91)% TBSA, PCT was measured three times weekly from admission over the
D von Heimburg; W Stieghorst; R Khorram-Sefat; N Pallua
Summary High serum levels of procalcitonin (PCT) are observed in patients with sepsis or severe infection. In a prospective study of 122 hospitalised adult medical patients with sepsis, serum PCT was determined on admission and for 9 days thereafter. Patients with no alteration in their immune system showed high PCT values up to day 5, decreasing to normal levels by
B. Al-Nawas; P. M. Shah
Sympathetic and parasympathetic activity was evaluated on 39 occasions in 17 patients with the sepsis syndrome, by measurement of the variation in resting heart rate using frequency spectrum analysis. Heart rate was recorded by electrocardiography and respiratory rate by impedance plethysmography. The sepsis syndrome was established on the basis of established clinical and physiological criteria. Subjects were studied, whenever possible,
Christopher S. Garrard; Dimitrios A. Kontoyannis; Massimo Piepoli
Rationale: The extent, timing, and significance of mitochondrial injury and recovery in bacterial sepsis are poorly characterized, although oxidative and nitrosative mitochondrial damage have been implicated in the development of organ failure. Objectives: To define the relationships between mitochondrial bio- genesis, oxidative metabolism, and recovery from Staphylococcus aureus sepsis. Methods: We developed a murine model of fibrin clot peritonitis, using
Douglas W. Haden; Hagir B. Suliman; Martha Sue Carraway; Karen E. Welty-Wolf; Abdelwahid S. Ali; Hiroshi Shitara; Hiromichi Yonekawa; Claude A. Piantadosi
Nosocomial sepsis is a serious problem for neonates who are admitted for intensive care. It is associated with an increase in mortality, morbidity, and prolonged length of hospital stay. Thus, both the human and fiscal costs of these infections are high. Although the rate of nosocomial sepsis increases with the degree of both prematurity and low birth weight, no specific
Reese Clark; Richard Powers; Robert White; Barry Bloom; Pablo Sanchez; Daniel K Benjamin
Objective. To compare the mortality of critically ill patients given either enteral feeding with an immune-enhancing formula or parenteral nutrition (PN). We report the results of a planned interim analysis on patients with severe sepsis which was undertaken earlier than planned once a meta-analysis suggested excess mortality in patients with severe sepsis given enteral immunonutrition. Design. Randomised multicentre unblinded controlled
Guido Bertolini; Gaetano Iapichino; Danilo Radrizzani; Rebecca Facchini; Bruno Simini; Paola Bruzzone; Giancarlo Zanforlin; Gianni Tognoni
Acute respiratory distress syndrome (ARDS) is commonly associated with severe sepsis. While the criteria for diagnosis have evolved since the first description in 1967, the characteristics of hypoxemia, tachypnea, rapidly progressing acute respiratory failure, and poor lung compliance continue. Scoring systems have been developed in an effort to quantify the severity of lung injury, with the most recent being the Berlin Definition. This system attempts to define acute lung injury (ALI) and ARDS with more precision in terms of timing of disease onset, severity of disease, and chest radiograph findings. The number of reported cases of ALI/ARDS per year is lower in pediatric patients vs. adults; however, mortality rates continue to be high. Sepsis-related ARDS has a generally higher disease severity and poorer recovery period from lung injury with an increased mortality rate. ARDS results from an initial insult (direct and/or indirect) which triggers a series of cell-mediated responses leading to damage to the capillary endothelium, alveolar epithelium, and impaired fluid removal from the alveolar space. There is, however, gradual resolution of hypoxemia, lung function, and radiographic abnormalities in survivors of ARDS. Management of ARDS is mainly supportive with specific mechanical ventilation strategies and goal-directed therapies. Prevention of ventilator-induced lung injury (VILI) has been demonstrated to have a positive impact on outcomes in patients with ARDS. PMID:24295609
Monahan, Laura J
Protein toxins are important virulence factors contributing to neonatal sepsis. The major pathogens of neonatal sepsis, group B Streptococci, Escherichia coli, Listeria monocytogenes, and Staphylococcus aureus, secrete toxins of different molecular nature, which are key for defining the disease. Amongst these toxins are pore-forming exotoxins that are expressed as soluble monomers prior to engagement of the target cell membrane with subsequent formation of an aqueous membrane pore. Membrane pore formation is not only a means for immediate lysis of the targeted cell but also a general mechanism that contributes to penetration of epithelial barriers and evasion of the immune system, thus creating survival niches for the pathogens. Pore-forming toxins, however, can also contribute to the induction of inflammation and hence to the manifestation of sepsis. Clearly, pore-forming toxins are not the sole factors that drive sepsis progression, but they often act in concert with other bacterial effectors, especially in the initial stages of neonatal sepsis manifestation.
Sonnen, Andreas F.-P.
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.
Starr, Marlene E; Saito, Hiroshi
Rheumatic fever (RF)/rheumatic heart disease (RHD) and post-streptococcal glomerulonephritis are thought to be autoimmune diseases, and follow group A streptococcal (GAS) infection. Different GAS M types have been associated with rheumatogenicity or nephritogenicity and categorized into either of two distinct classes (I or II) based on amino acid sequences present within the repeat region ('C' repeats) of the M protein. Sera from ARF patients have previously been shown to contain elevated levels of antibodies to the class I-specific epitope and myosin with the class I-specific antibodies also being cross-reactive to myosin, suggesting a disease association. This study shows that immunoreactivity of the class I-specific peptide and myosin does not differ between controls and acute RF (ARF)/RHD in populations that are highly endemic for GAS, raising the possibility that the association is related to GAS exposure, not the presence of ARF/RHD. Peptide inhibition studies suggest that the class I epitope may be conformational and residue 10 of the peptide is critical for antibody binding. We demonstrate that correlation of antibody levels between the class I and II epitope is due to class II-specific antibodies recognizing a common epitope with class I which is contained within the sequence RDL-ASRE. Our results suggest that antibody prevalence to class I and II epitopes and myosin is associated with GAS exposure, and that antibodies to these epitopes are not an indicator of disease nor a pathogenic factor in endemic populations. PMID:11581178
Brandt, E R; Yarwood, P J; McMillan, D J; Vohra, H; Currie, B; Mammo, L; Pruksakorn, S; Saour, J; Good, M F
It has been shown by agar precipitin tests (Ouchterlony and Oakley) that human sera may contain from 0 to 5 antibodies against antigens present in a partially purified streptolysin O preparation, and from 0 to 7 antibodies against antigens in a crude ammonium sulfate concentrate of the streptococcal culture supernate used. These antigens were prepared from a Group A hemolytic streptococcus (strain C203S). Strong evidence was presented suggesting that some of the bands seen with streptolysin O concentrate represented antibody reponses to streptococcal antigens heretofore undescribed. Tests were also carried out with other streptococcal antigens, including streptokinase-desoxyribonuclease mixture from Group C streptococci (varidase-Lederle), crystalline proteinase, proteinase precursor, C carbohydrate, and sonic vibrated streptococcal cell extracts (group A, C203S). Fewer bands were seen with these preparations, and with some they were quite uncommon. The observations indicated that the predominating antibody responses in human streptococcal infections were to extracellular products of the micro-organisms, and only very slightly and infrequently to intracellular antigens. The human sera studied included sera from patients with active or convalescent rheumatic fever, and non-rheumatic subjects suffering from a variety of illnesses. As was expected, the rheumatic subjects showed antibody responses to many more of the antigens present in these preparations than did the nonrheumatic group. Pooled normal human gamma globulin was found to contain many of the antibodies found in potent human sera. This finding confirmed the antigen-antibody nature of the bands seen with individual sera. The epidemiological significance of these findings with gamma, globulin was briefly discussed. It was found that rabbit, guinea pig, and human antibody precipitin bands join quite readily in the Ouchterlony tests. This finding adds another tool for the identification of the precipitin bands found with human sera. Evidence was obtained which indicated differing immunological specificities of two samples of streptococcal desoxyribonuclease, one from Group A, the other from a Group C streptococcus. The value of these technics as representing a new approach to the study of human infectious disease was discussed.
Halbert, Seymour P.; Swick, Lois; Sonn, Constance
The authors report 4 children and adolescents who had the acute onset of a movement and psychiatric disorder after a febrile illness. The differential diagnosis includes poststreptococcal syndromes (Sydenham chorea, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection [PANDAS], acute disseminated encephalomyelitis) and other postinfectious conditions. Their cases illustrate difficulties in making an accurate diagnosis and determining proper therapy and they recomme