Group A beta-hemolytic streptococci cause a wide range of infectious diseases such as pharyngitis impetigo, rheumatic fever, and even septic shock. Group A streptococcal puerperal sepsis is uncommon today, but recent reports indicate a reemergence of viru...
K. Okumura R. Schroff R. Campbell L. Nishioka E. Elster
Marginal zone macrophages in the murine spleen play an important role in the capture of blood-borne pathogens and are viewed as an essential component of host defense against the development of pneumococcal sepsis. However, we and others have previously described the loss of marginal zone macrophages associated with the splenomegaly that follows a variety of viral and protozoal infections; this finding raises the question of whether these infected mice would become more susceptible to secondary pneumococcal infection. Contrary to expectations, we found that mice lacking marginal zone macrophages resulting from Leishmania donovani infection have increased resistance to Streptococcus pneumoniae type 3 and do not develop sepsis. Using biophotonic imaging, we observed that pneumococci are rapidly trapped in the spleens of L. donovani-infected mice. By selective depletion studies using clodronate liposomes, depleting monoclonal antibodies specific for Ly6C/G and Ly6G, and CD11c-DTR mice, we show that the enhanced early resistance in L. donovani-infected mice is entirely due to the activity of SIGNR1(-) red pulp macrophages. Our data demonstrate, therefore, that the normal requirement for SIGNR1(+) marginal zone macrophages to protect against a primary pneumococcal infection can, under conditions of splenomegaly, be readily compensated for by activated red pulp macrophages. PMID:19644016
Kirby, Alun C; Beattie, Lynette; Maroof, Asher; van Rooijen, Nico; Kaye, Paul M
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
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
Striking individual differences in severity of group A streptococcal (GAS) sepsis have been noted, even among patients infected with the same bacterial strain. We had provided evidence that HLA class II allelic variation contributes significantly to differences in systemic disease severity by modulating host responses to streptococcal superantigens. Inasmuch as the bacteria produce additional virulence factors that participate in the pathogenesis of this complex disease, we sought to identify additional gene networks modulating GAS sepsis. Accordingly, we applied a systems genetics approach using a panel of advanced recombinant inbred mice. By analyzing disease phenotypes in the context of mice genotypes we identified a highly significant quantitative trait locus (QTL) on Chromosome 2 between 22 and 34 Mb that strongly predicts disease severity, accounting for 25%–30% of variance. This QTL harbors several polymorphic genes known to regulate immune responses to bacterial infections. We evaluated candidate genes within this QTL using multiple parameters that included linkage, gene ontology, variation in gene expression, cocitation networks, and biological relevance, and identified interleukin1 alpha and prostaglandin E synthases pathways as key networks involved in modulating GAS sepsis severity. The association of GAS sepsis with multiple pathways underscores the complexity of traits modulating GAS sepsis and provides a powerful approach for analyzing interactive traits affecting outcomes of other infectious diseases.
Abdeltawab, Nourtan F.; Aziz, Ramy K.; Kansal, Rita; Rowe, Sarah L.; Su, Yin; Gardner, Lidia; Brannen, Charity; Nooh, Mohammed M.; Attia, Ramy R.; Abdelsamed, Hossam A.; Taylor, William L.; Lu, Lu; Williams, Robert W.; Kotb, Malak
The group G streptococcus (GGS) is a rare cause of deep soft-tissue infection. We report that we believe is the first case of acute diffuse GGS myositis in association with toxic shock. Although the causative organism did not contain the genes for group A streptococcal pyrogenic exotoxins (SPEs) or make SPEs, the organism produced at least one new toxin that shared the biologic properties of the SPEs. PMID:8922817
Wagner, J G; Schlievert, P M; Assimacopoulos, A P; Stoehr, J A; Carson, P J; Komadina, K
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
Fluorescein-labeled immunoglobulin G fractions from serums of patients with acute glomerulonephritis and from many normal serums stained the glomerular basement membrane and mesangium of renal tissue from patients with early acute glomerulonephritis; these serums did not stain the corresponding tissues from patients with any other kidney disease. Previous absorption of the serum fraction with frozen and thawed nephritogenic beta hemolytic
Gerhard Treser; Martin Semar; Melinda McVicar; Maxine Franklin; Antonia Ty; Inge Sagel; Kurt Lange
BACKGROUND: Guidelines for prevention of group B streptococcal (GBS) infection have successfully reduced early onset (EO) GBS disease. Study results suggest that Escherichia coli is an important EO pathogen. OBJECTIVE: To determine EO infection rates, pathogens, morbidity, and mortality in a national network of neonatal centers. METHODS: Infants with EO infection were identified by prospective surveillance at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Network centers. Infection was defined by positive culture results for blood and cerebrospinal fluid obtained from infants aged ?72 hours plus treatment with antibiotic therapy for ?5 days. Mother and infant characteristics, treatments, and outcomes were studied. Numbers of cases and total live births (LBs) were used to calculate incidence. RESULTS: Among 396 586 LBs (2006–2009), 389 infants developed EO infection (0.98 cases per 1000 LBs). Infection rates increased with decreasing birth weight. GBS (43%, 0.41 per 1000 LBs) and E coli (29%, 0.28 per 1000 LBs) were most frequently isolated. Most infants with GBS were term (73%); 81% with E coli were preterm. Mothers of 67% of infected term and 58% of infected preterm infants were screened for GBS, and results were positive for 25% of those mothers. Only 76% of mothers with GBS colonization received intrapartum chemoprophylaxis. Although 77% of infected infants required intensive care, 20% of term infants were treated in the normal newborn nursery. Sixteen percent of infected infants died, most commonly with E coli infection (33%). CONCLUSION: In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease. GBS remains the most frequent pathogen in term infants, and E coli the most significant pathogen in preterm infants. Missed opportunities for GBS prevention continue. Prevention of E coli sepsis, especially among preterm infants, remains a challenge.
Hansen, Nellie I.; Sanchez, Pablo J.; Faix, Roger G.; Poindexter, Brenda B.; Van Meurs, Krisa P.; Bizzarro, Matthew J.; Goldberg, Ronald N.; Frantz, Ivan D.; Hale, Ellen C.; Shankaran, Seetha; Kennedy, Kathleen; Carlo, Waldemar A.; Watterberg, Kristi L.; Bell, Edward F.; Walsh, Michele C.; Schibler, Kurt; Laptook, Abbot R.; Shane, Andi L.; Schrag, Stephanie J.; Das, Abhik; Higgins, Rosemary D.
Development of acute renal failure during sepsis syndrome is common and portends a poor outcome. The interplay between systemic\\u000a host responses, local insults in the kidney, vascular bed, and immune system, all play a role in the development of sepsis-induced\\u000a acute renal failure. Despite advances in critical care, mortality rates have remained high for sepsis-associated acute renal\\u000a failure. This may
M. Raghavan; R. Venkataraman; J. A. Kellum
Group A streptococci (GAS) are ubiquitous human pathogens that cause a wide spectrum of clinical syndromes. The acute infections\\u000a range from uncomplicated pharyngitis, cellulitis, and pyoderma to necrotizing fasciitis, sepsis, pneumonia, and streptococcal\\u000a toxic shock syndrome. The non-suppurative sequelae that may follow GAS infections are acute rheumatic fever (ARF) and post-streptococcal\\u000a glomerulonephritis (PSGN). The burden of disease caused by GAS
James B. Dale
BACKGROUND: The bacterium Streptococcus pyogenes causes a variety of human diseases that range from relatively mild skin infections to severe invasive diseases, such as acute rheumatic fever, glomerulonephritis, puerperal sepsis, necrotizing fasciitis, meningitis, and streptococcal toxic shock syndrome. Accurate identification and typing of group A hemolytic streptococci (GAS) is essential for epidemiological and pathogenetic studies of streptococcal diseases. For this
Mubarak S Alfaresi
Group B streptococci (GBS) cause fatal sepsis in newborns. Strong activation of thromboxane synthesis is assumed to correlate with severe pulmonary hypertension. In this study we compared the impact of indomethacin versus parecoxib on hemodynamics and outcome and investigated the pharmacological effects on thromboxane synthesis and EP-3 receptor gene expression. Whereas both parecoxib and indometacin reduced expression of thromboxane synthase and EP-3 receptor in infected lung tissue, parecoxib did not suppress urine levels of thromboxane like indometacin. We presume that COX-2 inhibition in GBS sepsis is associated with enhanced thrombogenicity. PMID:19527795
Nögel, Stephanie C; Chada, Martin; Schmidt, Ana-Marija; Bosselmann, Stephan; Kandler, Michael; Schweer, Horst; Watzer, Bernhard; Schneider, Holm; Gessner, Andre; Rascher, Wolfgang
Late infection of devitalized pancreatic and peripancreatic tissue has become the major cause of morbidity in severe acute pancreatitis. Previous experience found that peritoneal lavage for periods of 48 to 96 hours may reduce early systemic complications but did not decrease late pancreatic sepsis. A fortunate observation led to the present study of the influence of a longer period of lavage on late sepsis. Twenty-nine patients receiving primary nonoperative treatment for severe acute pancreatitis (three or more positive prognostic signs) were randomly assigned to short peritoneal lavage (SPL) for 2 days (15 patients) or to long peritoneal lavage (LPL) for 7 days (14 patients). Positive prognostic signs averaged 5 in both groups but the frequency of five or more signs was higher in LPL (71%) than in SPL (47%). Eleven patients in each group had early computed tomographic (CT) scans. Peripancreatic fluid collections were shown more commonly in LPL (82%) than in SPL (54%) patients. Longer lavage dramatically reduced the frequency of both pancreatic sepsis (22% LPL versus 40% SPL) and death from sepsis (0% LPL versus 20% SPL). Among patients with fluid collections on early CT scan, LPL led to a more marked reduction in both pancreatic sepsis (33% LPL versus 83% SPL) and death from sepsis (0% LPL versus 33% SPL). The differences were even more striking among 17 patients with five or more positive prognostic signs. In this group the incidence of pancreatic sepsis was 30% LPL versus 57% SPL and of death from sepsis 0% (LPL) versus 43% (SPL) (p = 0.05). In these patients, overall mortality was also reduced (20% LPL versus 43% SPL). When 20 patients treated by LPL were compared with 91 other patients with three or more positive prognostic signs who were treated without lavage or by lavage for periods of 2 to 4 days, the frequency of death from pancreatic sepsis was reduced from 13% to 5%. In those with five or more signs, the incidence of sepsis was reduced from 40% to 27% (p = 0.03) and of death for sepsis from 30% to 7% (p = 0.08). These findings indicate that lavage of the peritoneal cavity for 7 days may significantly reduce both the frequency and mortality rate of pancreatic sepsis in severe acute pancreatitis.
Ranson, J H; Berman, R S
Objective Sepsis and acute lung injury continue to be major causes of morbidity and mortality worldwide despite advances in our understanding of pathophysiology and the discovery of new management strategies. Recent investigations show that stem cells may be beneficial as prognostic biomarkers and novel therapeutic strategies in these syndromes. This article reviews the potential use of endogenous adult tissue-derived stem cells in sepsis and acute lung injury as prognostic markers and also as exogenous cell-based therapy. Data Sources A directed systematic search of the medical literature using PubMed and OVID, with particular emphasis on the time period after 2002, was done to evaluate topics related to 1) the epidemiology and pathophysiology of sepsis and acute lung injury; and 2) the definition, characterization, and potential use of stem cells in these diseases. Data Synthesis and Findings When available, preferential consideration was given to prospective nonrandomized clinical and preclinical studies. Conclusions Stem cells have shown significant promise in the field of critical care both for 1) prognostic value and 2) treatment strategies. Although several recent studies have identified the potential benefit of stem cells in sepsis and acute lung injury, further investigations are needed to more completely understand stem cells and their potential prognostic and therapeutic value.
Cribbs, Sushma K.; Matthay, Michael A.; Martin, Greg S.
Acute inflammatory response is a complex process associ- ated with the production of both pro- and anti-inflammatory mediators. Although it is generally considered to be a sin- gle homeostatic mechanism, there are differences associated with the nature and the site of inflammation. We examined the changes of N-linked glycans released from the serum of a patient with sepsis and a
Olga Gornik; Louise Royle; David J Harvey; Catherine M Radcliffe; Radka Saldova; Raymond A Dwek; Pauline Rudd; Gordan Lauc
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
T. Devasena; S. Lalitha; K. Padma
Introduction Apoptosis of neutrophils (polymorphonuclear neutrophils [PMNs]) may limit inflammatory injury in sepsis and acute respiratory distress syndrome (ARDS), but the relationship between the severity of sepsis and extent of PMN apoptosis and the effect of superimposed ARDS is unknown. The objective of this study was to correlate neutrophil apoptosis with the severity of sepsis and sepsis-induced ARDS. Methods A prospective cohort study was conducted in intensive care units of three tertiary hospitals in Porto Alegre, southern Brazil. Fifty-seven patients with sepsis (uncomplicated sepsis, septic shock, and sepsis-induced ARDS) and 64 controls were enrolled. Venous peripheral blood was collected from patients with sepsis within 24 hours of diagnosis. All surgical groups, including controls, had their blood drawn 24 hours after surgery. Control patients on mechanical ventilation had blood collected within 24 hours of initiation of mechanical ventilation. Healthy controls were blood donors. Neutrophils were isolated, and incubated ex vivo, and apoptosis was determined by light microscopy on cytospun preparations. The differences among groups were assessed by analysis of variance with Tukeys. Results In medical patients, the mean percentage of neutrophil apoptosis (± standard error of the mean [SEM]) was lower in sepsis-induced ARDS (28% ± 3.3%; n = 9) when compared with uncomplicated sepsis (57% ± 3.2%; n = 8; p < 0.001), mechanical ventilation without infection, sepsis, or ARDS (53% ± 3.0%; n = 11; p < 0.001) and healthy controls (69% ± 1.1%; n = 33; p < 0.001) but did not differ from septic shock (38% ± 3.7%; n = 12; p = 0.13). In surgical patients with sepsis, the percentage of neutrophil apoptosis was lower for all groups when compared with surgical controls (52% ± 3.6%; n = 11; p < 0.001). Conclusion In medical patients with sepsis, neutrophil apoptosis is inversely proportional to the severity of sepsis and thus may be a marker of the severity of sepsis in this population.
Fialkow, Lea; Fochesatto Filho, Luciano; Bozzetti, Mary C; Milani, Adriana R; Rodrigues Filho, Edison M; Ladniuk, Roberta M; Pierozan, Paula; de Moura, Rafaela M; Prolla, Joao C; Vachon, Eric; Downey, Gregory P
Nitric oxide (NO), an important vasodilatory modulator of systemic and pulmonary vascular tone, is synthesized from L-arginine by the enzyme NO synthase in vascular endothelial and smooth muscle cells. L-Arginine analogs, such as N omega-nitro-L-arginine methyl ester (L-NAME), are competitive antagonists of NO synthase and inhibit NO synthesis. Group B streptococcus (GBS) causes pulmonary hypertension, hypoxemia, lung vascular injury, and reduced cardiac output in both human newborns and neonatal piglets. Lung vascular injury associated with prolonged GBS infusion in piglets may attenuate NO production and thus promote severe pulmonary hypertension. We studied the effect of the NOS inhibitor, L-NAME and the precursor of NO, L-arginine, on pulmonary and systemic hemodynamics during late-phase GBS sepsis in the piglet model. Neonatal piglets were anesthetized, ventilated with room air, and randomized to receive a continuous infusion of saline (n = 5) or GBS (n = 5) for 4 h. After 3 h of infusion, both groups received a bolus of L-NAME (3 mg/kg). Hemodynamic and gas exchange indices were measured at baseline, 30 min, and 3 h of infusion, and 30 min and 1 h after L-NAME treatment. L-NAME treatment caused 1) significant increases in mean pulmonary arterial pressure, pulmonary vascular resistance, mean systemic arterial pressure, and systemic vascular resistance for both groups; 2) a similar percentage of increase in pulmonary vascular resistance for the two groups; 3) greater reduction in cardiac output and SV in the GBS compared with the control group; and 4) no significant alterations in arterial partial pressure of oxygen or the difference between alveolar and arterial partial pressure of oxygen for either group.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7534903
Gibson, R L; Berger, J I; Redding, G J; Standaert, T A; Mayock, D E; Truog, W E
Acute kidney injury (AKI), or acute renal failure, is associated with hospital stays, increased economic costs, and significant mortality, particularly in the context of critically ill patients in the intensive care setting. Numerous factors contribute to the development of AKI, including reductions in renal blood flow, actions of nephrotoxic drugs, cellular injury or death of proximal tubular cells, and the proinflammatory responses of renal cells. Sepsis and septic shock are the dominant causes of AKI due to impairments in the microcirculation. Dysfunction of the microcirculation subsequently causes blood flow disruption and obstruction in the microcirculation, as well as ensuing ischemia. Prompt recognition and treatment of sepsis may decrease the incidence of AKI mortality and its effects on other organ systems. PMID:23767336
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.
Karnatovskaia, Lioudmila V.; Festic, Emir
We have shown that folate-induced kidney dysfunction and interstitial fibrosis predisposes mice to sepsis mortality. Agents that increase survival in normal septic mice were ineffective in a two-stage kidney disease model. Here we used the 5/6 nephrectomy mouse model of progressive chronic kidney disease (CKD) to study how CKD affects acute kidney injury (AKI) induced by sepsis. We induced sepsis using cecal ligation and puncture and found that the presence of CKD intensified the severity of kidney and liver injury, cytokine release, and splenic apoptosis. Accumulation of High Mobility Group Box Protein-1 (HMGB1; a late proinflammatory cytokine released from apoptotic cells), vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-?, interleukin (IL)-6, or IL-10 was increased in CKD or sepsis alone and to a greater extent in CKD-sepsis. Only part of the increase was explained by decreased renal clearance. Surprisingly, we found splenic apoptosis in CKD, even in the absence of sepsis. Although VEGF neutralization with soluble fms-like tyrosine kinase 1 (sFLT-1) (a soluble VEGF receptor) effectively treated sepsis, it was ineffective against CKD-sepsis. A single dose of HMGB1-neutralizing antiserum administered 6?h after sepsis alone was ineffective; however, CKD-sepsis was attenuated by anti-HMGB1. Splenectomy transiently decreased circulating HMGB1 levels, reversing the effectiveness of anti-HMGB1 treatment on CKD-sepsis. Thus, progressive CKD increases the severity of sepsis, in part, by reducing the renal clearance of several cytokines. CKD-induced splenic apoptosis and HMGB1 release could be important common mediators for both CKD and sepsis. PMID:21832986
Leelahavanichkul, Asada; Huang, Yuning; Hu, Xuzhen; Zhou, Hua; Tsuji, Takayuki; Chen, Richard; Kopp, Jeffrey B; Schnermann, Jürgen; Yuen, Peter S T; Star, Robert A
Septic complications owing to infection of necrotic areas are the main cause of mortality during severe acute pancreatitis. The necrotic tissue, originally sterile, constitutes an ideal pabulum for several bacterial species, translocated from the colon or originating from distant septic foci. The most important predisposing factor to infection is the extent of pancreatic necrosis, which correlates significantly with the risk
C. Bassi; M. Falconi; A. Bonora; R. Salvia; E. Caldiron; L. De Santis; N. Sartori; G. Butturini; G. Talamini; P. Pederzoli
Introduction We conducted a study to evaluate the incidence, risk factors and outcomes associated with early acute kidney injury (AKI)\\u000a in sepsis.\\u000a \\u000a \\u000a \\u000a \\u000a Methods The study was a retrospective interrogation of prospectively collected data from the Australian New Zealand Intensive Care\\u000a Society Adult Patient Database. Data were collected from 57 intensive care units (ICUs) across Australia. In total, 120,123\\u000a patients admitted to ICU
Sean M Bagshaw; Carol George; Rinaldo Bellomo
Sepsis is an often deadly systemic inflammatory response to infection that occurs frequently among older patients due to multiple\\u000a risk factors, including immunosenescence, comorbid illness, institutionalization, and instrumentation.\\u000a \\u000a Nonspecific or atypical symptoms are common among older patients with sepsis, and clinicians must have a high index of suspicion\\u000a for sepsis when patients present with such symptoms.\\u000a \\u000a \\u000a \\u000a The diagnostic approach to
Timothy D. Girard
Introduction Critical illnesses continue to be major causes of morbidity and mortality worldwide. Recent investigations show that stem cells may be beneficial as prognostic biomarkers and novel therapeutic strategies in these syndromes. This article reviews the use of stem cells in sepsis and acute lung injury as prognostic biomarkers and also as a potential for exogenous cell-based therapy. Methods A directed search of the medical literature was done using PubMed and OVID to evaluate topics related to pathophysiology of sepsis and acute lung injury, in addition to the characterization and utilization of stem cells in these diseases. Conclusions Stem cells have shown significant promise in the field of critical care medicine both for prognostication and treatment strategies. Although recent studies have been done to describe the mechanistic pathways of stem cells in critical illness, further investigation is necessary to fully delineate the mechanisms behind a stem cell’s immunomodulatory characteristics and its ability to mobilize and engraft in tissues.
Cribbs, Sushma K.; Martin, Greg S.
BACKGROUND: The gram-positive bacterium Streptococcus pyogenes is a common pathogen of humans that causes invasive infections, toxic-shock syndrome, rheumatic fever, necrotizing fasciitis and other diseases. Detection of antibiotic resistance in clinical isolates has renewed interest in development of new vaccine approaches for control S. pyogenes sepsis. In the study presented, a novel protein vaccine was examined. The vaccine was based
Robert G Ulrich
Tumor necrosis factor-? during continuous high-flux hemodialysis in sepsis with acute renal failure. Suppressed ex vivo endotoxin (ET)-induced production of the proinflammatory cytokine, tumor necrosis factor-? (TNF-?), in isolated mononuclear cells (PBMCs) is associated with fatal outcome in severe sepsis. PBMCs from surviving patients, but not those from nonsurviving patients, recover their capacity to produce normal amounts of TNF-?. We
Gerhard Lonnemann; Mikko Bechstein; Silvia Linnenweber; Michael Burg; Karl Martin Koch
Dendrimer-enhanced MRI as a diagnostic and prognostic biomarker of sepsis-induced acute renal failure in aged mice.BackgroundAcute renal failure (ARF) induced by sepsis has a high mortality. In an aged mouse model of sepsis-induced ARF we have previously shown that renal injury occurs before serum creatinine is elevated. Development of a noninvasive biomarker that could diagnose renal dysfunction early in sepsis
James W. Dear; HISATAKA KOBAYASHI; SANG-KYUNG JO; Mikaela K. Holly; XUZHEN HU; Peter S. T. Yuen; Martin W. Brechbiel; Robert A. Star
OBJECTIVE: The aim of this study was to determine the prevalence of clinical risk factors (CRF) for neonatal sepsis in laboring women and to evaluate clinician compliance with a CRF-based protocol for intrapartum antibiotic prophylaxis (IAP). METHODS: A retrospective chart audit was undertaken at a district hospital (A) and a tertiary obstetric hospital (B) in Sydney, Australia between 1996 and 1998, to determine compliance with IAP in women with defined CRF. RESULTS: Eighty-five (12%) women at Hospital A and 117 (19%) at Hospital B had one or more CRF. Overall compliance rates with the IAP protocols were 65 and 50% at Hospitals A and B respectively, but varied according to maternal, obstetric and sepsis-related risk factors. We postulate that differences between the hospitals were related to protocol implementation. CONCLUSIONS: Compliance with a CRF-based protocol was lower than previously reported. Improvements in protocol development, implementation and maintenance are required to enhance compliance with IAP based on CRF.
Sanders, Toni R; Roberts, Christine L; Gilbert, Gwendolyn L
Cell walls from M+ and M- protein variants of group A streptococci were examined for their arthritogenicity in female Lewis rats. Intraperitoneal administration of both of these sonicated cell wall preparations caused a severe acute and chronic arthritis in recipient rats. Histological evaluation of the hind paw of these rats indicated synovial lining hyperplasia, cell infiltration in the subsynovial space, pannus formation, and erosions of bone and cartilage. Joint pathology was similar in the hind paws of rats immunized with cell walls prepared from either the M+ or the M- protein variants. Cell-mediated immunity was also similar when lymph nodes were exposed to cell walls derived from these two preparations. A recombinant M6 protein from streptococci did not elicit a proliferative response from lymph nodes prepared from arthritic rats. These observations indicate that the M protein that has previously been implicated in auto-immunity does not have a critical role in the pathogenesis of streptococcal cell wall arthritis in rats. PMID:2297798
DeJoy, S Q; Ferguson-Chanowitz, K M; Sapp, T M; Oronsky, A L; Lapierre, L A; Zabriskie, J B; Kerwar, S S
Two outbreaks of group A streptococcal colonization of newborn infants over a 3-year period were observed. Manifestations of the outbreak included indolent oomphalitis in most infants, but two babies developed sepsis. Transmission to family members occurr...
C. C. Geil E. A. Mortimer W. K. Castle
Cellulomonas denverensis is a small and thin gram-positive rod-shaped bacterium that was proposed as a new species in 2005. Here we report a female case of acute cholecystitis and sepsis in which C. denverensis was determined to be causative. PMID:19656981
Ohtaki, Hirofumi; Ohkusu, Kiyofumi; Sawamura, Haruki; Ohta, Hirotoshi; Inoue, Rina; Iwasa, Junpei; Ito, Hiroyasu; Murakami, Nobuo; Ezaki, Takayuki; Moriwaki, Hisataka; Seishima, Mitsuru
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
otic use, in 38% of patients with streptococcal pharyn- gitis. Systematic RSAT led to nearly optimal treatment (94%) and antibiotic prescription (37%), with minimal antibiotic overuse (3%) and underuse (3%). Empirical antibiotictreatmentinpatientswith3or4clinicalsymp- toms or signs resulted in a lower rate of appropriate therapy (59%) but higher rates of antibiotic use (60%), overuse(32%),andunderuse(9%).SystematicRSATwas more cost-effective than strategies based on empirical treatment
Jean-Paul Humair; Sylvie Antonini Revaz; Patrick Bovier; Hans Stalder
BACKGROUND: Successful anal fistula care in complex cases can be assisted by specialized imaging which accurately defines the site of the internal fistula opening and the fistula type. There are currently limited data concerning the clinical indications for and accuracy of transperineal ultrasound (TP-US) in acute perianal sepsis. The aims of this study were to compare the anatomical interpretation of TP-US images with magnetic resonance imaging (MRI) and surgical findings in an unselected patient cohort presenting with acute perianal sepsis. METHODS: Sixty-seven consecutive patients with acute anorectal sepsis referred from the surgical department were examined using TP-US and Gadolinium-enhanced MRI with both examiners blinded to the surgical results. Fistulae were categorized by the Parks' classification of fistula type. RESULTS: Thirty-six abscesses were detected by MRI, 38 by TP-US and 30 by surgical examination. Operatively discordant cases showed only ischiorectal panniculitis. TP-US was more accurate in the diagnosis of superficial sepsis and MRI in the diagnosis of deep-seated perirectal infection. TP-US and MRI show concordance with operative findings in fistula diagnosis with a tendency for TP-US to overdiagnose trans-sphincteric fistulae and MRI to over diagnose extra-sphincteric fistulae. Comparison of TP-US with MRI showed good agreement for perianal abscess diagnosis (? = 0.82) and for fistula diagnosis (? = 0.68). For fistulae, TP-US showed moderate agreement with surgery (? = 0.43) with only fair agreement between MRI and surgery (? = 0.29). CONCLUSIONS: Transperineal ultrasound complements other imaging modalities in the anatomical diagnosis of acute perianal abscesses and fistulae. It has specific advantages over other techniques and is accurate in the detection of superficially located perirectal sepsis showing concordance with MRI and surgical findings. PMID:23681302
Plaikner, M; Loizides, A; Peer, S; Aigner, F; Pecival, D; Zbar, A; Kremser, C; Gruber, H
Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Abdominal peritonitis often results in acute lung injury (ALI). Recent reports demonstrate a potential benefit of parenteral vitamin C [ascorbic acid (AscA)] in the pathogenesis of sepsis. Therefore we examined the mechanisms of vitamin C supplementation in the setting of abdominal peritonitis-mediated ALI. We hypothesized that vitamin C supplementation would protect lungs by restoring alveolar epithelial barrier integrity and preventing sepsis-associated coagulopathy. Male C57BL/6 mice were intraperitoneally injected with a fecal stem solution to induce abdominal peritonitis (FIP) 30 min prior to receiving either AscA (200 mg/kg) or dehydroascorbic acid (200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers (myeloperoxidase, chemokines), bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression (aquaporin 5, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and Na(+)-K(+)-ATPase), tight junction protein expression (claudins, occludins, zona occludens), cytoskeletal rearrangements (F-actin polymerization), and coagulation parameters (thromboelastography, pro- and anticoagulants, fibrinolysis mediators) of septic blood. FIP-mediated ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, coagulation abnormalities, and increased mortality. Parenteral vitamin C infusion protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the proinflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities. Parenteral vitamin C may potentially have a role in the management of sepsis and ALI associated with sepsis. PMID:22523283
Fisher, Bernard J; Kraskauskas, Donatas; Martin, Erika J; Farkas, Daniela; Wegelin, Jacob A; Brophy, Donald; Ward, Kevin R; Voelkel, Norbert F; Fowler, Alpha A; Natarajan, Ramesh
The syndrome of sepsis-associated severe acute renal failure is a frequent component of sepsis-induced multiorgan failure. Continuous hemofiltration techniques are often used in its dialytic management but little is known about their impact. The aim of this study is to define the biochemical and clinical impact of continuous hemodiafiltration (CHD) in the management of this syndrome and to retrospectively compare
Rinaldo Bellomo; Michael Farmer; Christopher Wright; Geoffrey Parkin; Neil Boyce
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.
Patients with intra-abdominal processes that require prompt surgical intervention, including appendicitis, perforated viscus, ischemic bowel, volvulus, and bowel obstruction, often present with signs and symptoms of an acute abdomen. Several medical problems can mimic an acute abdomen. Overwhelming postsplenectomy infection is a life-threatening condition that can present with acute abdominal symptoms. The incidence of overwhelming postsplenectomy infection ranges from 1% to 25%, and is caused by Streptococcus pneumoniae in 50% of cases. Capnocytophaga canimorsus, a bacteria commonly found in dog saliva, accounts for less than 1% of cases. Overwhelming postsplenectomy infection has a rapidly deteriorating course that progresses to respiratory and renal failure, cardiovascular collapse, and death. The mortality associated with overwhelming postsplenectomy infection is 60% to 80%. Early diagnosis and institution of appropriate antibiotic therapy and supportive care is essential to improve patient outcome. A previously healthy woman who had undergone splenectomy secondary to trauma 11 years earlier presented with symptoms of an acute abdomen. A diagnosis of overwhelming postsplenectomy infection due to C canimorsus was made based on her peripheral blood smear and blood culture findings. Early aggressive care and antibiotic treatment resulted in a successful outcome for this patient with no long-term morbidity. This patient's clinical course demonstrates the importance of early diagnosis and treatment of overwhelming postsplenectomy infection. PMID:9865657
Sawmiller, C J; Dudrick, S J; Hamzi, M
Body temperature is precisely regulated to maintain homeostasis in homeothermic animals. Although it remains unproved whether change of body temperature constitutes a beneficial or a detrimental component of the septic response, temperature control should be an important entity in septic experiments. We investigated the effect of body temperature control on the lipopolysaccharide (LPS)-induced lung injury. Acute lung injury in rats
Giueng-Chueng Wang; Wei-Ming Chi; Wan-Cherng Perng; Kun-Lun Huang
Acute kidney injury (AKI) occurs in about half of patients in septic shock and the mortality of AKI with sepsis is extremely high. An effective therapeutic intervention is urgently required. Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors that also have pleiotropic actions. They have been reported to increase the survival of septic or infectious patients. But the effect of simvastatin, a widely used statin, on sepsis-induced AKI is unknown. The effects of simvastatin and tumor necrosis factor (TNF)-alpha neutralizing antibody were studied in a clinically relevant model of sepsis-induced AKI using cecal ligation and puncture (CLP) in elderly mice. Simvastatin significantly improved CLP-induced mortality and AKI. Simvastatin attenuated CLP-induced tubular damage and reversed CLP-induced reduction of intrarenal microvascular perfusion and renal tubular hypoxia at 24 h. Simvastatin also restored towards normal CLP-induced renal vascular protein leak and serum TNF-alpha. Neither delayed simvastatin therapy nor TNF-alpha neutralizing antibody improved CLP-induced AKI. Simvastatin improved sepsis-induced AKI by direct effects on the renal vasculature, reversal of tubular hypoxia, and had a systemic anti-inflammatory effect. PMID:16557230
Yasuda, H; Yuen, P S T; Hu, X; Zhou, H; Star, R A
Acute abdominal symptoms are frequently caused by surgical intra-abdominal problems. However, the differential diagnosis also includes several internal diseases. Overwhelming infections may present with acute abdominal signs, particularly in the immunocompromised host. Asplenic patients are highly susceptible to infections with encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. Severe infections due to Capnocytophaga canimorsus (DF2), are also common in this group. C. canimorsus is a Gram-negative rod, present as a commensal organism in cat and dog saliva. We describe the atypical presentation of a fatal C. canimorsus-sepsis in a 46-year-old man, who underwent traumatic splenectomy two decades earlier. PMID:11705640
Deprés-Brummer, P; Buijs, J; van Engelenburg, K C; Oosten, H R
PRImary care Streptococcal Management (PRISM) study: identifying clinical variables associated with Lancefield group A ?-haemolytic streptococci and Lancefield non-Group A streptococcal throat infections from two cohorts of patients presenting with an acute sore throat
Objective To assess the association between features of acute sore throat and the growth of streptococci from culturing a throat swab. Design Diagnostic cohort. Setting UK general practices. Participants Patients aged 5 or over presenting with an acute sore throat. Patients were recruited for a second cohort (cohort 2, n=517) consecutively after the first (cohort 1, n=606) from similar practices. Main outcome Predictors of the presence of Lancefield A/C/G streptococci. Results The clinical score developed from cohort 1 had poor discrimination in cohort 2 (bootstrapped estimate of area under the receiver operator characteristic (ROC) curve (0.65), due to the poor validity of the individual items in the second data set. Variables significant in multivariate analysis in both cohorts were rapid attendance (prior duration 3?days or less; multivariate adjusted OR 1.92 cohort, 1.67 cohort 2); fever in the last 24?h (1.69, 2.40); and doctor assessment of severity (severely inflamed pharynx/tonsils (2.28, 2.29)). The absence of coryza or cough and purulent tonsils were significant in univariate analysis in both cohorts and in multivariate analysis in one cohort. A five-item score based on Fever, Purulence, Attend rapidly (3?days or less), severely Inflamed tonsils and No cough or coryza (FeverPAIN) had moderate predictive value (bootstrapped area under the ROC curve 0.73 cohort 1, 0.71 cohort 2) and identified a substantial number of participants at low risk of streptococcal infection (38% in cohort 1, 36% in cohort 2 scored ?1, associated with a streptococcal percentage of 13% and 18%, respectively). A Centor score of ?1 identified 23% and 26% of participants with streptococcal percentages of 10% and 28%, respectively. Conclusions Items widely used to help identify streptococcal sore throat may not be the most consistent. A modified clinical scoring system (FeverPAIN) which requires further validation may be clinically helpful in identifying individuals who are unlikely to have major pathogenic streptococci.
Little, Paul; Moore, Michael; Hobbs, F D R; Mant, David; McNulty, Cliodna; Williamson, Ian; Cheng, Edith; Stuart, Beth; Kelly, Joanne; Barnett, Jane; Mullee, Mark
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
Background The efficacy of sivelestat in the treatment of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has not been established. In part, this is due to the wide variety of factors involved in the etiology of ALI/ARDS. In this study, we examined the efficacy of sivelestat in patients with ALI/ARDS associated with abdominal sepsis. Methods The subjects were 49 patients with ALI/ARDS after surgery for abdominal sepsis. The efficacy of sivelestat was retrospectively assessed in two treatment groups, ie, a sivelestat group (n = 34) and a non-sivelestat group (n = 15). Results The sivelestat group showed significant improvements in oxygenation, thrombocytopenia, and multiple organ dysfunction score. The number of ventilator days (6.6 ± 6.1 versus 11.1 ± 8.4 days; P = 0.034) and length of stay in the intensive care unit (8.5 ± 6.2 versus 13.3 ± 9.5 days; P = 0.036) were significantly lower in the sivelestat group. The hospital mortality rate decreased by half in the sivelestat group, but was not significantly different between the two groups. Conclusion Administration of sivelestat to patients with ALI/ARDS following surgery for abdominal sepsis resulted in early improvements of oxygenation and multiple organ dysfunction score, early ventilator weaning, and early discharge from the intensive care unit.
Tsuboko, Yoshiaki; Takeda, Shinhiro; Mii, Seiji; Nakazato, Keiko; Tanaka, Keiji; Uchida, Eiji; Sakamoto, Atsuhiro
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
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.
Endogenous Interleukin11 (IL11) Expression Is Increased and Prophylactic Use of Exogenous IL11 Enhances Platelet Recovery and Improves Survival During Thrombocytopenia Associated With Experimental Group B Streptococcal Sepsis in Neonatal Rats
Future preventive and\\/or concurrent therapy of neonatal sepsis may require the use of adjuvant immunohematopoietic therapy. In the present study, using reverse transcription-polymerase chain reaction, we demonstrated a significant increase in IL-11 mRNA extracted from the femurs of group B streptococcus (GBS)-infected rats during acute thrombocytopenia (platelet count: 65.8 ± 19.3 K\\/mm , n=5) compared to that 3 of uninfected
Mei Chang; Angela Williams; Lori Ishizawa; Annika Knoppel; Carmella van de Ven; Mitchell S. Cairo
Endogenous Interleukin11 (IL11) Expression Is Increased and Prophylactic Use of Exogenous IL11 Enhances Platelet Recovery and Improves Survival During Thrombocytopenia Associated With Experimental Group B Streptococcal Sepsis in Neonatal Rats
ABSTRACTFuture preventive and\\/or concurrent therapy of neonatal sepsis may require the use of adjuvant immunohematopoietic therapy. In the present study, using reverse transcription-polymerase chain reaction, we demonstrated a significant increase in IL-11 mRNA extracted from the femurs of group B streptococcus (GBS)-infected rats during acute thrombocytopenia (platelet count: 65.8 ± 19.3 K\\/mm3, n=5) compared to that of uninfected neonatal rats
Mei Chang; Angela Williams; Lori Ishizawa; Annika Knoppel; Carmella van de Ven; Mitchell S. Cairo
Background: Acute respiratory distress syndrome (ARDS) is a serious complication of sepsis, and sepsis-associated ARDS is associated with significant morbidity and mortality. To date, no study has directly examined the epidemiology of ARDS in severe sepsis from the earliest presentation to the health care system, the emergency department (ED). Methods: This was a single-center retrospective, observational cohort study of 778 adults with severe sepsis presenting to the ED. The primary outcome was the development of ARDS requiring mechanical ventilation during the first 5 hospital days. Acute respiratory distress syndrome was defined using the Berlin definition. We used multivariable logistic regression to identify risk factors associated independently with ARDS development. Results: The incidence of ARDS was 6.2% (48/778 patients) in the entire cohort. Acute respiratory distress syndrome development varied across the continuum of care: 0.9% of patients fulfilled criteria for ARDS in the ED, 1.4% admitted to the ward developed ARDS, and 8.9% admitted to the intensive care unit developed ARDS. Acute respiratory distress syndrome developed a median of 1 day after admission and was associated with a 4-fold higher risk of in-hospital mortality (14% vs. 60%, P < 0.001). Independent risk factors associated with increased risk of ARDS development included intermediate (2-3.9 mmol/L) (P = 0.04) and high (?4) serum lactate levels (P = 0.008), Lung Injury Prediction score (P < 0.001), and microbiologically proven infection (P = 0.01). Conclusions: In patients presenting to the ED with severe sepsis, the rate of sepsis-associated ARDS development varied across the continuum of care. Acute respiratory distress syndrome developed rapidly and was associated with significant mortality. Elevated serum lactate levels in the ED and a recently validated clinical prediction score were independently associated with the development of ARDS in severe sepsis. PMID:23903852
Mikkelsen, Mark E; Shah, Chirag V; Meyer, Nuala J; Gaieski, David F; Lyon, Sarah; Miltiades, Andrea N; Goyal, Munish; Fuchs, Barry D; Bellamy, Scarlett L; Christie, Jason D
The genus Streptococcus consists of large number of species many of which are pathogenic to humans and animals. Although streptococci have long been considered as extracellular pathogens, they are capable of causing serious invasive infections such as necrotizing fasciitis and meningitis. Streptococcal invasion, therefore, has been a focus of many studies in recent years. Streptococci are efficiently internalized by nonprofessional phagocytes and the current research interest has shifted to determine the role of this invasion in the natural infection process. Moreover, characterization of bacterial and eukaryotic components involved in the uptake process might be useful in developing new strategies for combating streptococcal infections. PMID:10047553
Molinari, G; Chhatwal, G S
Introduction In this study, we sought to determine the association between red blood cell (RBC) transfusion and outcomes in patients with acute lung injury (ALI), sepsis and shock. Methods We performed a secondary analysis of new-onset ALI patients enrolled in the Acute Respiratory Distress Syndrome Network Fluid and Catheter Treatment Trial (2000 to 2005) who had a documented ALI risk factor of sepsis or pneumonia and met shock criteria (mean arterial pressure (MAP) < 60 mmHg or vasopressor use) within 24 hours of randomization. Using multivariable logistic regression, we examined the association between RBC transfusion and 28-day mortality after adjustment for age, sex, race, randomization arm and Acute Physiology and Chronic Health Evaluation III score. Secondary end points included 90-day mortality and ventilator-free days (VFDs). Finally, we examined these end points among the subset of subjects meeting prespecified transfusion criteria defined by five simultaneous indicators: hemoglobin < 10.2 g/dL, central or mixed venous oxygen saturation < 70%, central venous pressure ? 8 mmHg, MAP ? 65 mmHg, and vasopressor use. Results We identified 285 subjects with ALI, sepsis, shock and transfusion data. Of these, 85 also met the above prespecified transfusion criteria. Fifty-three (19%) of the two hundred eighty-five subjects with shock and twenty (24%) of the subset meeting the transfusion criteria received RBC transfusion within twenty-four hours of randomization. We found no independent association between RBC transfusion and 28-day mortality (odds ratio = 1.49, 95% CI (95% confidence interval) = 0.77 to 2.90; P = 0.23) or VFDs (mean difference = -0.35, 95% CI = -4.03 to 3.32; P = 0.85). Likewise, 90-day mortality and VFDs did not differ by transfusion status. Among the subset of patients meeting the transfusion criteria, we found no independent association between transfusion and mortality or VFDs. Conclusions In patients with new-onset ALI, sepsis and shock, we found no independent association between RBC transfusion and mortality or VFDs. The physiological criteria did not identify patients more likely to be transfused or to benefit from transfusion.
The genus Streptococcus consists of large number of species many of which are pathogenic to humans and animals. Although streptococci have long been considered as extracellular pathogens, they are capable of causing serious invasive infections such as necrotizing fasciitis and meningitis. Streptococcal invasion, therefore, has been a focus of many studies in recent years. Streptococci are efficiently internalized by nonprofessional
Gabriella Molinari; Gursharan S Chhatwal
Background: Pre-B-cell colony-enhancing factor (PBEF) is a potential biomarker for acute lung injury (ALI) in sepsis. We aimed to determine the clinical correlates for elevated plasma PBEF upon ICU admission for severe sepsis and the usefulness of PBEF to predict ALI development and sepsis mortality. Methods: This is a prospective cohort of patients admitted to the medical ICU with severe sepsis. Patients without available blood samples or who were not enrolled within 24 h of admission were excluded. Plasma collected within 24 h of ICU admission was measured for PBEF concentrations by enzyme-linked immunosorbent assay. Patients were followed for ALI development as defined by the American-European Consensus Conference and for all-cause hospital mortality. Results: Between September 30, 2008, and March 10, 2009, 113 patients were enrolled, and 50 (44%) developed ALI. Elevated PBEF levels significantly correlated with higher APACHE (Acute Physiology and Chronic Health Evaluation) III scores (R2 = 0.08, P = .003) and failure to reach early sepsis goals within 6 h of severe sepsis (P = .003). PBEF did not differ by ALI status (P = .58). The mortality rate was 46%. Nonsurvivors had higher PBEF levels than survivors (2.53 ng/mL; interquartile range [IQR], 1.07-8.16 vs 1.44 ng/mL; IQR, 0.84-2.81; P = .02). After adjusting for severity of illness, PBEF levels were no longer significantly associated with mortality (OR, 1.44 per 10-fold increase; 95% CI, 0.69-3.03, P = .34). Conclusions: In this study, elevated PBEF did not correlate with lung injury in sepsis. However, it was associated with sepsis mortality mainly due to its association with greater severity of illness on ICU admission.
Lee, Kathleen A.
Sepsis remains a serious problem in critically ill patients with the mortality increasing to over half when there is attendant acute kidney injury. alpha-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 alpha-melanocyte-stimulating hormone analogue (AP214), which has increased binding affinity to melanocortin receptors, improves sepsis-induced kidney injury and mortality using a cecal ligation and puncture mouse model. In the lethal cecal ligation-puncture model of sepsis, severe hypotension and bradycardia resulted and AP214 attenuated acute kidney injury of the lethal model with a bell-shaped dose-response curve. An optimum AP214 dose reduced acute kidney injury even when it was administered 6 h after surgery and it significantly improved blood pressure and heart rate. AP214 reduced serum TNF-alpha and IL-10 levels with a bell-shaped dose-response curve. Additionally; NF-kappaB activation in the kidney and spleen, and splenocyte apoptosis were decreased by the treatment. AP214 significantly improved survival in both lethal and sublethal models. We have shown that AP214 improves hemodynamic failure, acute kidney injury, mortality and splenocyte apoptosis attenuating pro- and anti-inflammatory actions due to sepsis. PMID:18354376
Doi, K; Hu, X; Yuen, P S T; Leelahavanichkul, A; Yasuda, H; Kim, S M; Schnermann, J; Jonassen, T E N; Frøkiaer, J; Nielsen, S; Star, R A
The ?-common receptor (?cR) plays a pivotal role in the nonhematopoietic tissue-protective effects of erythropoietin (EPO). Here we determined whether EPO reduces the acute kidney injury (AKI) caused by sepsis and whether this effect is mediated by the ?cR. In young (2 months old) C57BL/6 wild-type and ?cR knockout mice, lipopolysaccharide caused a significant increase in serum urea and creatinine, hence AKI. This AKI was not associated with any overt morphological alterations in the kidney and was attenuated by EPO given 1?h after lipopolysaccharide in wild-type but not in ?cR knockout mice. In the kidneys of endotoxemic wild-type mice, EPO enhanced the phosphorylation of Akt, glycogen synthase kinase-3?, and endothelial nitric oxide synthase, and inhibited the activation of nuclear factor-?B. All these effects of EPO were lost in ?cR knockout mice. Since sepsis is more severe in older animals or patients, we tested whether EPO was renoprotective in 8-month-old wild-type and ?cR knockout mice that underwent cecal ligation and puncture. These older mice developed AKI at 24?h, which was attenuated by EPO treatment 1?h post cecal ligation and puncture in wild-type mice but not in ?cR knockout mice. Thus, activation of the ?cR by EPO is essential for the observed reduction in AKI in either endotoxemic young mice or older mice with polymicrobial sepsis, and for the activation of well-known signaling pathways by EPO. PMID:23594675
Coldewey, Sina M; Khan, Areeg I; Kapoor, Amar; Collino, Massimo; Rogazzo, Mara; Brines, Michael; Cerami, Anthony; Hall, Peter; Sheaff, Michael; Kieswich, Julius E; Yaqoob, Muhammed M; Patel, Nimesh S A; Thiemermann, Christoph
The paper shows the results of a study evaluating the impact of impulse magnetic fields on the blood of patients with acute lung injury concurrent with sepsis. Extracorporeal autohemomagnetic therapy has been ascertained to reduce blood and tissue hypoxia. Thus it normalizes basic oxygen homeostasis more effectively than do traditional methods. PMID:16076048
Iakubtsevich, R E; Spas, V V; Pletnev, S V; Plisiuk, N I; Kuznetsov, O E
Patients with acute group A- strepotococcal pharyngotonsillitis were randomly assigned to treatment for 10 d with either phenoxymethylpenicillin (PcV), loracarbef or clindamycin. The concentrations of the drugs, respectively, were determined in tonsillar surface fluid (TSF), serum and the saliva in each patient on altogether 5 occasions; before, during and 4 d after end of therapy. On the same occasions blood was drawn for analysis of C-reactive protein (CRP) and orosomucoid. On the last d of treatment PcV could be detected in TSF in 1 of 6 patients only. Loracarbef had a slower decrease in TSF during therapy and measurable levels did occur 2 d after end of therapy corresponding to MIC 100 for GAS. This may be related to the somewhat better clinical results of the cephalosporins than of PcV, and possibly indicates that an extended therapy with these drugs in primary GAS pharyngotonsillitis for more than the arbitrarily chosen 10 d could reduce the number of recurrent episodes. PcV and loracarbef were not detected in serum after the end of treatment. The concentration of clindamycin in both TSF and the saliva was fairly longstanding during therapy and reached levels exceeding MIC 100 for GAS, in both TSF and serum 2 d after the end of treatment. Several investigations have shown that GAS, especially in the stationary phase may invade respiratory epithelial cells and are present intracellularly in patients with acute pharyngotonsillitis as well as in asymptomatic carriers. The same T-type, identical DNA fingerprints and arbitrarily primed patterns are found in GAS before and after treatment failure indicating that the primary episode and the failures are caused by the same strain. The longstanding concentrations of clindamycin in TSF, roughly independent of the degree of the local inflammation combined with its intracellular accumulation and activity against resting GAS seem to explain the efficiency of the drug in recurrent GAS pharyngotonsillitis. CRP and orosomucoid were of limited value in differing between bacterial and viral pharyngtonsillitis and a correlation between antibiotic concentration and CRP/orosomucoid levels was not found. PMID:16012002
Orrling, Arne; Kamme, Carl; Stjernquist-Desatnik, Anna
The role of thyroid hormone metabolism in clinical outcomes of the critically ill remains unclear. Using preclinical models of acute lung injury (ALI), we assessed the gene and protein expression of type 2 deiodinase (DIO2), a key driver for synthesis of biologically active triiodothyronine, and addressed potential association of DIO2 genetic variants with ALI in a multiethnic cohort. DIO2 gene and protein expression levels in murine lung were validated by microarrays and immunoblotting. Lung injury was assessed by levels of bronchoalveolar lavage protein and leukocytes. Single-nucleotide polymorphisms were genotyped and ALI susceptibility association assessed. Significant increases in both DIO2 gene and D2 protein expression were observed in lung tissues from murine ALI models (LPS- and ventilator-induced lung injury), with expression directly increasing with the extent of lung injury. Mice with reduced levels of DIO2 expression (by silencing RNA) demonstrated reduced thyroxine levels in plasma and increased lung injury (increased bronchoalveolar lavage protein and leukocytes), suggesting a protective role for DIO2 in ALI. The G (Ala) allele of the Thr92Ala coding single-nucleotide polymorphism (rs225014) was protective in severe sepsis and severe sepsis–associated ALI after adjustments for age, sex, and genetic ancestry in a logistic regression model in European Americans. Our studies indicate that DIO2 is a novel ALI candidate gene, the nonsynonymous Thr92Ala coding variant of which confers ALI protection. Increased DIO2 expression may dampen the ALI inflammatory response, thereby strengthening the premise that thyroid hormone metabolism is intimately linked to the integrated response to inflammatory injury in critically ill patients.
Ma, Shwu-Fan; Xie, Lishi; Pino-Yanes, Maria; Sammani, Saad; Wade, Michael S.; Letsiou, Eleftheria; Siegler, Jessica; Wang, Ting; Infusino, Giovanni; Kittles, Rick A.; Flores, Carlos; Zhou, Tong; Prabhakar, Bellur S.; Moreno-Vinasco, Liliana; Villar, Jesus; Jacobson, Jeffrey R.; Dudek, Steven M.
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
Sepsis is a major cause of death worldwide. The associated risks and mortality are known to significantly increase on exposure to alcohol (chronic or acute). The underlying mechanisms of the association of acute ethanol ingestion and poor prognosis of sepsis are largely unknown. The study described here was designed to determine in detail the role of ethanol and TLR4 in the pathogenesis of the sepsis syndrome. The effects of acute ethanol exposure and TLR4 on bacterial clearance, spleen cell numbers, peritoneal macrophage numbers, and cytokine production were evaluated using wild type and TLR4 hypo-responsive mice treated with ethanol and then challenged with a non pathogenic strain of Escherichia. coli (E. coli). Ethanol treated mice exhibited a decreased clearance of bacteria and produced lesser amounts of most pro-inflammatory cytokines in both strains of mice at two hours after challenge. Neither ethanol treatment nor a hypo-responsive TLR4 had significant effects on the cell numbers in the peritoneal cavity and spleen 2 hours post infection. The suppressive effect of acute ethanol exposure on cytokine and chemokine production was more pronounced in the wild type mice, but the untreated hyporesponsive mice produced less of most cytokines than untreated wild type mice. The major conclusion of this study is that acute ethanol exposure suppresses pro-inflammatory cytokine production and that a hypo-responsive TLR4 (in C3H/HeJ mice) decreases pro-inflammatory cytokine levels but the cytokines and other mediators induced through other receptors are sufficient to ultimately clear the infection but not enough to induce lethal septic shock. In addition, results reported here demonstrate previously unknown effects of acute ethanol exposure on LIF (leukemia inhibitory factor) and eotaxin and provide the first evidence that IL-9 is induced through TLR4 in vivo.
Bhatty, Minny; Jan, Basit L; Tan, Wei; Pruett, Stephen B; Nanduri, Bindu
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
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
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.
Objective: Maternal vaccination may become a central strategy in the prevention of early-onset group B Streptococcal sepsis. Unlike earlier group B streptococcal polysaccharide vaccines that were poorly immunogenic, newer vaccines conjugated to tetanus toxoid have been developed and have improved immunogenicity. We sought to evaluate a conjugated vaccine using our rabbit model of ascending infection. Study Design: Rabbit does were
Jill K. Davies; Lawrence C. Paoletti; Robert S. McDuffie; Lawrence C. Madoff; Scott Lee; Joan Eskens; Ronald S. Gibbs
The reduction of circulating neutrophil migration to infection sites is associated with a poor outcome of severe sepsis. ?-1-Acid glycoprotein (AGP) was isolated from the sera of severely septic patients by HPLC and acrylamide gel electrophoresis and identified by mass spectrometry. Both the isolated protein and commercial AGP inhibited carrageenin-induced neutrophil migration into the rat peritoneal cavity when administered i.v. at a dose of 4.0 ?g per rat (95 pmol per rat). Analysis by intravital microscopy demonstrated that both proteins inhibited the rolling and adhesion of leukocytes in the mesenteric microcirculation. The inhibitory activity was blocked by 50 mg/kg aminoguanidine, s.c., and was not demonstrable in inducible nitric oxide synthase (iNOS) knockout mice. Incubation of AGP with neutrophils from healthy subjects induced the production of NO and inhibited the neutrophil chemotaxis by an iNOS/NO/cyclic guanosine 3,5-monophosphate-dependent pathway. In addition, AGP induced the l-selectin shedding by neutrophils. The administration of AGP to rats with mild cecal ligation puncture sepsis inhibited neutrophil migration and reduced 7-day survival from ?80% to 20%. These data demonstrate that AGP, an acute-phase protein, inhibits neutrophil migration by an NO-dependent process and suggest that AGP also participates in human sepsis.
Mestriner, F. L. A. C.; Spiller, F.; Laure, H. J.; Souto, F. O.; Tavares-Murta, B. M.; Rosa, J. C.; Basile-Filho, A.; Ferreira, S. H.; Greene, L. J.; Cunha, F. Q.
An open, comparative multicenter study was performed to evaluate the efficacy and safety of azithromycin (10 mg/kg) given once daily for three days in comparison with cefaclor (30 mg/kg) divided into three daily doses and given for a period of ten days. One hundred and twenty-two children aged 1-12 years with clinical symptoms of group A beta-hemolytic streptococcal tonsillopharyngitis and a positive throat culture were randomly allocated to the treatment groups. Overall, the clinical success (cure or improvement) of both regimens was identical in the evaluable patients (86.3%, 44 of 51 patients in either treatment group). In contrast, bacterial eradication after completion of treatment was lower with azithromycin than with cefaclor. Possible reasons for this discrepancy between clinical success and eradication rates could be antibiotic resistance, pre-disease carriage or insufficient dosage. Both agents were well tolerated; only mild or moderate side effects most frequently involving the gastrointestinal tract, were recorded in either therapy group. PMID:9707305
Cremer, J; Wallrauch, C; Milatovic, D; Braveny, I
Streptococci express arrays of adhesins on their cell surfaces that facilitate adherence to substrates present in their natural environment within the mammalian host. A consequence of such promiscuous binding ability is that streptococcal cells may adhere simultaneously to a spectrum of substrates, including salivary glycoproteins, extracellular matrix and serum components, host cells, and other microbial cells. The multiplicity of streptococcal
H. F. Jenkinson; R. J. Lamont
Background Sepsis is one of the common causes of acute renal failure (ARF). The objective of this study was to identify new biomarkers and therapeutic targets. We present a new rat model of sepsis-induced ARF based on cecal ligation and puncture (CLP). We used this model to find urinary proteins which may be potential biomarkers and/or drug targets. Methods Aged rats were treated with fluids and antibiotics after CLP. Urinary proteins from septic rats without ARF and urinary proteins from septic rats with ARF were compared by difference in-gel electrophoresis (DIGE). Results CLP surgery elevated IL-6 and IL-10 serum cytokines and blood nitrite compared with sham-operated rats. However there was a range of serum creatinine values at 24 hrs (0.4–2.3 mg/dL) and only 24% developed ARF. Histology confirmed renal injury in these rats. 49% of rats did not develop ARF. Rats without ARF also had less liver injury. The mortality rate at 24 hrs was 27% but was increased by housing the post-surgery rats in metabolic cages. Creatinine clearance and urine output 2–8 hours after CLP was significantly reduced in rats which died within 24 hours. Using DIGE we identified changes in a number of urinary proteins including albumin, brush-border enzymes (eg., meprin-1-alpha) and serine protease inhibitors. The meprin-1-alpha inhibitor actinonin prevented ARF in aged mice. Conclusion In summary we describe a new rat model of sepsis-induced ARF which has a heterogeneous response similar to humans. This model allowed us to use DIGE to find changes in urinary proteins and this approach identified a potential biomarker and drug target – meprin-1-alpha.
Holly, Mikaela K.; Dear, James W.; Hu, Xuzhen; Schechter, Alan N.; Gladwin, Mark T.; Hewitt, Stephen M.; Yuen, Peter S.T.; Star, Robert A.
Sepsis is a disease process that has humbled the medical profession for centuries with its resistance to therapy, relentless mortality, and pathophysiologic complexity. Despite 30 years of aggressive, concerted, well-resourced efforts the biomedical community has been unable to reduce the mortality of sepsis from 30%, nor the mortality of septic shock from greater than 50%. In the last decade only one new drug for sepsis has been brought to the market, drotrecogin alfa-activated (Xigris™), and the success of this drug has been limited by patient safety issues. Clearly a new agent is desperately needed. The advent of recombinant human immune modulators held promise but the outcomes of clinical trials using biologics that target single immune mediators have been disappointing. The complex pathophysiology of the systemic inflammatory response syndrome (SIRS) is self-amplifying and redundant at multiple levels. In this review we argue that perhaps pharmacologic therapy for sepsis will only be successful if it addresses this pathophysiologic complexity; the drug would have to be pleiotropic, working on many components of the inflammatory cascade at once. In this context, therapy that targets any single inflammatory mediator will not adequately address the complexity of SIRS. We propose that Chemically Modified Tetracycline-3, CMT-3 (or COL-3), a non-antimicrobial modified tetracycline with pleiotropic anti-inflammatory properties, is an excellent agent for the management of sepsis and its associated complication of the Acute Respiratory Distress Syndrome (ARDS). The purpose of this review is threefold: 1) to examine the shortcomings of current approaches to treatment of sepsis and ARDS in light of their pathophysiology, 2) to explore the application of COL-3 in ARDS and sepsis, and finally 3) to elucidate the mechanisms of COL-3 that may have potential therapeutic benefit in ARDS and sepsis.
Roy, Shreyas K.; Kendrick, Daniel; Sadowitz, Benjamin D.; Gatto, Louis; Snyder, Kathleen; Satalin, Joshua M.; Golub, Lorne M.; Nieman, Gary
Hydrogen sulfide (H(2)S) has been shown to promote transient receptor potential vanilloid type 1 (TRPV1)-mediated neurogenic inflammation in sepsis and its associated multiple organ failure, including acute lung injury (ALI). Accumulating evidence suggests that the cyclooxygenase-2 (COX-2)/PGE(2) pathway plays an important role in augmenting inflammatory immune response in sepsis and respiratory diseases. However, the interactions among H(2)S, COX-2, and PGE(2) in inciting sepsis-evoked ALI remain unknown. Therefore, the aim of this study was to investigate whether H(2)S would upregulate COX-2 and work in conjunction with it to instigate ALI in a murine model of polymicrobial sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in male Swiss mice. dl-propargylglycine, an inhibitor of H(2)S formation, was administrated 1 h before or 1 h after CLP, whereas sodium hydrosulfide, an H(2)S donor, was given during CLP. Mice were treated with TRPV1 antagonist capsazepine 30 min before CLP, followed by assessment of lung COX-2 and PGE(2) metabolite (PGEM) levels. Additionally, septic mice were administrated with parecoxib, a selective COX-2 inhibitor, 20 min post-CLP and subjected to ALI and survival analysis. H(2)S augmented COX-2 and PGEM production in sepsis-evoked ALI by a TRPV1 channel-dependent mechanism. COX-2 inhibition with parecoxib attenuated H(2)S-augmented lung PGEM production, neutrophil infiltration, edema, proinflammatory cytokines, chemokines, and adhesion molecules levels, restored lung histoarchitecture, and protected against CLP-induced lethality. The strong anti-inflammatory and antiseptic actions of selective COX-2 inhibitor may provide a potential therapeutic approach for the management of sepsis and sepsis-associated ALI. PMID:21957141
Ang, Seah-Fang; Sio, Selena W S; Moochhala, Shabbir M; MacAry, Paul A; Bhatia, Madhav
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.
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
M. J. A. M. Trijbels-Smeulders; G. A. de Jonge; P. C. M. Pasker-de Jong; L. J. Gerards; A. H. Adriaanse; R. A. van Lingen; L A A Kolle?e
Introduction Lung protective ventilation (LPV) has been shown to improve survival and the duration of mechanical ventilation in acute lung injury (ALI) patients. Mortality of ALI may vary by gender, which could result from treatment variability. Whether gender is associated with the use of LPV is not known. Methods A total of 421 severe sepsis-related ALI subjects in the Consortium to Evaluate Lung Edema Genetics from seven teaching hospitals between 2002 and 2008 were included in our study. We evaluated patients' tidal volume, plateau pressure and arterial pH to determine whether patients received LPV during the first two days after developing ALI. The odds ratio of receiving LPV was estimated by a logistic regression model with robust and cluster options. Results Women had similar characteristics as men with the exception of lower height and higher illness severity, as measured by Acute Physiology and Chronic Health Evaluation (APACHE) II score. 225 (53%) of the subjects received LPV during the first two days after ALI onset; women received LPV less frequently than men (46% versus 59%, P < 0.001). However, after adjustment for height and severity of illness (APACHE II), there was no difference in exposure to LPV between men and women (P = 0.262). Conclusions Short people are less likely to receive LPV, which seems to explain the tendency of clinicians to adhere to LPV less strictly in women. Strategies to standardize application of LPV, independent of differences in height and severity of illness, are necessary.
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
Summary We reviewed 55 cases of streptococcal bacteremia in adult patients who received cytotoxic chemotherapy for treatment of acute leukemia. Viridans group streptococci were the most frequent species isolated (45 isolates). Hemolytic streptococci (four isolates), pneumococci (three isolates), and enterococci (three isolates) were infrequent. Clinical features of streptococcal bacteremia included fever, upper and lower respiratory infection, respiratory distress syndrome, soft
W. Kern; E. Kurrle; T. Schmeiser
Recently, fluconazole (FLZ) has been shown to improve survival and reduce multiorgan failure in experimental and clinical septic shock. The mechanism by which FLZ affords protection against sepsis remains obscure. This study examines the effect of FLZ on phagocytic activity of polymorphonuclear leukocytes (PMNs) in a rat model of septic shock by inducing fecal peritonitis in male Wistar rats using intraperitoneal instillation (1?mL/kg) of fecal suspension in saline (1:1?w/v). Sham control rats received sterile fecal suspension and vehicle treatment. FLZ was administered in the doses of 0, 3, 10, and 30?mg/kg by gavage 30?minutes before fecal instillation. The samples of peritoneal fluid were collected 8?hours following fecal inoculation for the evaluation of phagocytic response of PMNs using zymosan-induced luminol-dependent chemiluminescence (CL). Fecal peritonitis caused massive infiltration of PMNs in the peritoneal cavity (ANOVA F4.45 = 6.322, P < .001). Although FLZ reduced the infiltration of PMNs, this effect was neither significant nor dose dependent. The actual CL response was significantly higher in the peritoneal fluid of rats subjected to peritonitis, which was significantly and dose-dependently attenuated by FLZ treatment (ANOVA F4.45 = 11.048, P < .001). Normalization of CL response for 1000?PMNs revealed that FLZ dose-dependently albeit insignificantly reduced the activity of PMNs. The high dose of FLZ caused 2.29-fold decrement in the area under curve (AUC) pertaining to cumulative CL response. The findings of this study suggest that FLZ protects rats against septic shock by inhibiting PMN-mediated inflammatory cascade without compromising their phagocytic activity.
Khan, Haseeb Ahmad
Aims: To assess changes in renal vascular resistance (RVR) in human and experimental sepsis and to identify determinants of RVR. Methods: We performed a systematic interrogation of two electronic reference libraries using specific search terms. Subjects were animals and patients involved in experimental and human studies of sepsis and septic acute renal failure, in which the RVR was assessed. We
Christoph Langenberg; Rinaldo Bellomo; Clive N. May; Moritoki Egi; Li Wan; Stanislao Morgera
Background To investigate the association between severity of acute kidney injury (AKI) and outcome, systemic inflammatory phenotype and HLA genotype in severe sepsis. Methodology/Principal Findings Prospective multicenter observational study done in 4 intensive care units in two university hospitals. Severe sepsis and septic shock patients with at least 2 organ failures based on the SOFA score were classified: 1) "no AKI", 2) "mild AKI" (grouping stage 1 and 2 of AKIN score) and 3) "severe AKI" (stage 3 of AKIN score). Sequential measurements: The vasopressor dependency index (VDI; dose and types of drugs) to evaluate the association between hemodynamic status and the development of early AKI; plasma levels of IL-10, macrophage migration inhibitory factor (MIF), IL-6 and HLA-DR monocyte expression. Genotyping of the 13 HLA-DRB1 alleles with deduction of presence of HLA-DRB3, -DRB4 and -DRB5 genes. We used multivariate analysis with competitive risk model to study associations. Overall, 176 study patients (146 with septic shock) were classified from AKIN score as "no AKI" (n?=?43), "mild AKI" (n?=?74) or "severe AKI" (n?=?59). The VDI did not differ between groups of AKI. After adjustment, "mild and severe AKI" were an independent risk factor for mortality (HR 2.42 95%CI[1.01-5.83], p?=?0.048 and HR 1.99 95%CI[1.30-3.03], p?=?0.001 respectively). "Severe AKI" had higher levels of plasma IL-10, MIF and IL-6 compared to “no AKI” and mild AKI (p<0.05 for each), with no difference in mHLA-DR at day 0. HLA-DRB genotyping showed a significantly lower proportion of 4 HLA-DRB alleles among patients requiring renal replacement therapy (RRT) (58%) than in patients with severe AKI who did not receive RRT (84%) (p?=?0.004). Conclusions AKI severity is independently associated with mortality and plasma IL-10, MIF or IL-6 levels. Presence of 4 alleles of HLA-DRB in severe AKI patients seems associated with a lower need of RRT.
Legrand, Matthieu; Gayat, Etienne; Faivre, Valerie; Megarbane, Bruno; Azoulay, Elie; Fieux, Fabienne; Charron, Dominique; Loiseau, Pascale; Busson, Marc
Streptococcal toxic shock syndrome (STSS) is a highly lethal, acute-onset illness that is a subset of invasive streptococcal disease. The majority of clinical STSS cases have been associated with the pyrogenic toxin superantigens (PTSAgs) streptococcal pyrogenic exotoxin A or C (SPE A or C), although cases have been reported that are not associated with either of these exotoxins. Recent genome sequencing projects have revealed a number of open reading frames that potentially encode proteins with similarity to SPEs A and C and to other PTSAgs. Here, we describe the cloning, expression, purification, and functional characterization of a novel exotoxin termed streptococcal pyrogenic exotoxin J (SPE J). Purified recombinant SPE J (rSPE J) expressed from Escherichia coli stimulated the expansion of both rabbit splenocytes and human peripheral blood lymphocytes, preferentially expanded human T cells displaying V?2, -3, -12, -14, and -17 on their T-cell receptors, and was active at concentrations as low as 5 × 10?6 ?g/ml. Furthermore, rSPE J induced fevers in rabbits and was lethal in two models of STSS. Biochemically, SPE J had a predicted molecular weight of 24,444 and an isoelectric point of 7.7 and lacked the ability to form the cystine loop structure characteristic of many PTSAgs. SPE J shared 19.6, 47.1, 38.8, 18.1, 19.6, and 24.4% identity with SPEs A, C, G, and H, streptococcal superantigen, and streptococcal mitogenic exotoxin Z-2, respectively, and was immunologically cross-reactive with SPE C. The characterization of a seventh functional streptococcal PTSAg raises important questions relating to the evolution of the streptococcal superantigens.
McCormick, John K.; Pragman, Alexa A.; Stolpa, John C.; Leung, Donald Y. M.; Schlievert, Patrick M.
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.
Gadolinium chloride (GdCl3), a Kupffer cells inhibitor, attenuates acute lung injury; however, the mechanisms behind this effect are not completely elucidated. We tested the hypothesis that GdCl3 acts through the inhibition of lung parenchymal cellular apoptosis. Two groups of rats were injected intraperitoneally with saline or E. coli lipopolysaccharide. In two additional groups, rats were injected with GdCl3 24?hrs prior to saline or LPS administration. At 12?hrs, lung injury, inflammation, and apoptosis were studied. Lung water content, myeloperoxidase activity, pulmonary apoptosis and mRNA levels of interleukin-1?, -2, -5, -6, -10 and TNF-? rose significantly in LPS-injected animals. Pretreatment with GdCl3 significantly reduced LPS-induced elevation of pulmonary water content, myeloperoxidase activity, cleaved caspase-3 intensity, and attenuated pulmonary TUNEL-positive cells. GdCl3 pre-treatment upregulated IL-1?, -2 and -10 pulmonary gene expression without significantly affecting the others. These results suggest that GdCl3 attenuates acute lung injury through its effects on pulmonary parenchymal apoptosis.
Kishta, Osama A.; Goldberg, Peter; Husain, Sabah N. A.
The coagulase-negative bacterial species Staphylococcus sciuri is widely distributed in the natural environment. Although principally found in animals, S. sciuri is occasionally isolated from human samples. In this paper, S. sciuri bacteremia which was associated with an indwelling catheter of a patient with acute myeloid leukemia (AML) and neutropenia was presented. An empirical intravenous antibiotic therapy (meropenem, vancomycin) was initiated with the preliminary diagnosis of febrile neutropenia and catheter infection. The catalase and oxidase positive, tube coagulase negative strain isolated from three of the concurrent blood cultures and intravenous catheter culture has been identified as S. sciuri. The isolate was found resistant to penicilin and oxacilline. This case has emphasized the importance of identification of coagulase-negative staphylococci isolated from the cultures of patients with haematological malignancy. PMID:17205699
Koço?lu, Esra; Karabay, O?uz
Catastrophic antiphospholipid antibody syndrome (CAPS) resembles severe sepsis in its acute presentation, with features of systemic inflammatory response syndrome (SIRS) leading to multiple organ dysfunction. Infections are the best known triggers of CAPS. This emphasizes the need for early diagnosis and aggressive treatment as the mortality is as high as 50%. We present a 42-year-old woman who developed SIRS postoperatively and was eventually diagnosed as CAPS. PMID:24082618
Guleria, Vivek S; Chauhan, Prabhat; Shankar, Subramanian; Nair, Velu
Catastrophic antiphospholipid antibody syndrome (CAPS) resembles severe sepsis in its acute presentation, with features of systemic inflammatory response syndrome (SIRS) leading to multiple organ dysfunction. Infections are the best known triggers of CAPS. This emphasizes the need for early diagnosis and aggressive treatment as the mortality is as high as 50%. We present a 42-year-old woman who developed SIRS postoperatively and was eventually diagnosed as CAPS.
Guleria, Vivek S.; Chauhan, Prabhat; Shankar, Subramanian; Nair, Velu
Although activation of the ?7 nicotinic acetylcholine receptor (?7 nAChR) modulates the response to sepsis, the role of this pathway in the development of sepsis-induced acute lung injury (ALI) is not known. In this study, we addressed the contribution of ?7 nAChR in mediating endotoxin- and live Escherichia coli–induced ALI in mice. Because we found that ?7 nAChR+ alveolar macrophages and neutrophils were present in bronchoalveolar lavage and injured lungs of mice, we tested whether acetylcholine released by lung vagal innervation stimulated these effector cells and thereby down-regulated proinflammatory chemokine/cytokine generation. Administration of ?7 nAChR agonists reduced bronchoalveolar lavage MIP-2 production and transalveolar neutrophil migration and reduced mortality in E. coli pneumonia mice, whereas vagal denervation increased MIP-2 production and airway neutrophil accumulation and increased mortality. In addition, ?7 nAChR?/? mice developed severe lung injury and had higher mortality compared with ?7 nAChR+/+ mice. The immunomodulatory cholinergic ?7 nAChR pathway of alveolar macrophages and neutrophils blocked LPS- and E. coli–induced ALI by reducing chemokine production and transalveolar neutrophil migration, suggesting that activation of ?7 nAChR may be a promising strategy for treatment of sepsis-induced ALI.
Su, Xiao; Matthay, Michael A.; Malik, Asrar B.
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.
We hypothesized that the time from sepsis to inception of continuous renal replacement therapy (CRRT) can be used to predict survival rates in patients with septic acute kidney injury (AKI). The survival predictability of CRRT inception time was compared with that of RIFLE criteria, which were previously used in clinical practice. We retrospectively analyzed outcomes in 55 patients with septic AKI admitted to the medical intensive care unit at Asan Medical Center (Seoul, Korea) between April 2009 and October 2010. These patients were stratified by the time of inception of CRRT from sepsis (early: ? 24 h and late: >24 h) and also by the RIFLE criteria (RIFLE-I and RIFLE-F). The primary outcome was 28-day mortality. Of the 55 patients, 38 (69.1%) were male. Patients' mean age was 62.6 years, the most common infection site was the lung (32, 58.2%), and 47 patients (85.5%) were on mechanical ventilation. Thirty patients (54.5%) were in the RIFLE-I, and the others were in the RIFLE-F. Twenty-eight-day mortality rates were lower in the early group than in the late group (19.4% vs. 47.4%; P = 0.03), but did not differ between RIFLE-I and RIFLE-F. Ventilator-free day at day 28 was longer in the early group than that in the late group (7.5 vs. 0 d; P = 0.033). After adjustment for covariates, we found that the late group (hazard ratio, 3.106; 95% confidence interval, 1.066-9.047) and Sequential Organ Failure Assessment at sepsis (hazard ratio, 1.410; 95% confidence interval, 1.108-1.796) were independent factors associated with 28-day mortality. This study suggests that the time interval from sepsis to CRRT inception may be a more useful predictor of 28-day mortality than RIFLE criteria in patients with septic AKI. PMID:22706021
Chon, Gyu Rak; Chang, Jai Won; Huh, Jin Won; Lim, Chae-Man; Koh, Younsuck; Park, Su Kil; Park, Jung Sik; Hong, Sang-Bum
Sepsis is characterized by a severe inflammatory response to infection, and its complications, including acute kidney injury, can be fatal. Animal models that correctly mimic human disease are extremely valuable because they hasten the development of clinically useful therapeutics. Too often, however, animal models do not properly mimic human disease. In this Review, we outline a bedside-to-bench-to-bedside approach that has resulted in improved animal models for the study of sepsis — a complex disease for which preventive and therapeutic strategies are unfortunately lacking. We also highlight a few of the promising avenues for therapeutic advances and biomarkers for sepsis and sepsis-induced acute kidney injury. Finally, we review how the study of drug targets and biomarkers are affected by and in turn have influenced these evolving animal models.
Doi, Kent; Leelahavanichkul, Asada; Yuen, Peter S.T.; Star, Robert A.
Definitions have been considered important in all fields of medicine, both at a patient level to facilitate accurate diagnosis and treatment, and at a research level to clarify patient inclusion criteria and interpretation of study results. Although there is agreement that sepsis refers to the host response to infection, the complexity of this response and of the patient groups affected, however, has meant that establishing accepted definitions of sepsis has been difficult. Recent consensus has provided global definitions of sepsis and infection, but further work is necessary to provide a means of more completely characterizing the sepsis response in individual patients, such that new interventions can be targeted better as physicians strive to decrease the still high mortality rates associated with this condition. PMID:18954694
Vincent, Jean-Louis; Korkut, Hakan Atalan
Optical immunoassay for streptococcal pharyngitis: evaluation of accuracy with routine and mucoid strains associated with acute rheumatic fever outbreak in the intermountain area of the United States.
The Strep A OIA (BioStar, Inc., Boulder, Colo.) rapid detection system is an intriguing technology that utilizes an immunoassay relying on changes in reflected light to directly detect group A streptococcal antigen from specimens. In this evaluation, 424 routine pediatric throat specimens and 20 simulated oropharyngeal specimens with added mucoid (M type 3, 18) strains were cultured and tested by the Strep A OIA. The respective sensitivities and specificities were as follows: Strep A OIA versus enhanced broth culturing, 84.2 and 95.7%; and streptococcus-SXT agar (BBL Microbiology Systems, Cockeysville, Md.) culturing versus enhanced broth culturing, 82.9 and 98.6%. The Strep A OIA is an 8-min, technologist-friendly, accurate technique with an 89.4% agreement with traditional culturing. PMID:8150968
Daly, J A; Korgenski, E K; Munson, A C; Llausas-Magana, E
Introduction To evaluate whether alkaline phosphatase (AP) treatment improves renal function in sepsis-induced acute kidney injury (AKI), a prospective, double-blind, randomized, placebo-controlled study in critically ill patients with severe sepsis or septic shock with evidence of AKI was performed. Methods Thirty-six adult patients with severe sepsis or septic shock according to Systemic Inflammatory Response Syndrome criteria and renal injury defined according to the AKI Network criteria were included. Dialysis intervention was standardized according to Acute Dialysis Quality Initiative consensus. Intravenous infusion of alkaline phosphatase (bolus injection of 67.5 U/kg body weight followed by continuous infusion of 132.5 U/kg/24 h for 48 hours, or placebo) starting within 48 hours of AKI onset and followed up to 28 days post-treatment. The primary outcome variable was progress in renal function variables (endogenous creatinine clearance, requirement and duration of renal replacement therapy, RRT) after 28 days. The secondary outcome variables included changes in circulating inflammatory mediators, urinary excretion of biomarkers of tubular injury, and safety. Results There was a significant (P = 0.02) difference in favor of AP treatment relative to controls for the primary outcome variable. Individual renal parameters showed that endogenous creatinine clearance (baseline to Day 28) was significantly higher in the treated group relative to placebo (from 50 ± 27 to 108 ± 73 mL/minute (mean ± SEM) for the AP group; and from 40 ± 37 to 65 ± 30 mL/minute for placebo; P = 0.01). Reductions in RRT requirement and duration did not reach significance. The results in renal parameters were supported by significantly more pronounced reductions in the systemic markers C-reactive protein, Interleukin-6, LPS-binding protein and in the urinary excretion of Kidney Injury Molecule-1 and Interleukin-18 in AP-treated patients relative to placebo. The Drug Safety Monitoring Board did not raise any issues throughout the trial. Conclusions The improvements in renal function suggest alkaline phosphatase is a promising new treatment for patients with severe sepsis or septic shock with AKI. Trial Registration www.clinicaltrials.gov: NCTNCT00511186
Purpose: To review the literature on group A streptococcal toxic shock syndrome, (STSS).\\u000a \\u000a \\u000a Data source: Medline and EMBASE searches were conducted using the key words group A streptococcal toxic shock syndrome, alone and in combination\\u000a with anesthesia; and septic shock, combined with anesthesia. Medline was also searched using key words intravenous immunoglobulin,\\u000a (IVIG) and group A streptococcus, (GAS); and group
Fred Baxter; Jim McChesney
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.
Class B scavenger receptors (SR-Bs), such as SR-BI/II or CD36, bind lipoproteins but also mediate bacterial recognition and phagocytosis. In evaluating whether blocking receptors can prevent intracellular bacterial proliferation, phagocyte cytotoxicity, and proinflammatory signaling in bacterial infection/sepsis, we found that SR-BI/II- or CD36-deficient phagocytes are characterized by a reduced intracellular bacterial survival and a lower cytokine response and were protected from bacterial cytotoxicity in the presence of antibiotics. Mice deficient in either SR-BI/II or CD36 are protected from antibiotic-treated cecal ligation and puncture (CLP)-induced sepsis, with greatly increased peritoneal granulocytic phagocyte survival (8-fold), a drastic diminution in peritoneal bacteria counts, and a 50-70% reduction in systemic inflammation (serum levels of IL-6, TNF-?, and IL-10) and organ damage relative to CLP in wild-type mice. The survival rate of CD36-deficient mice after CLP was 58% compared with 17% in control mice. When compensated for mineralocorticoid and glucocorticoid deficiency, SR-BI/II-deficient mice had nearly a 50% survival rate versus 5% in mineralo-/glucocorticoid-treated controls. Targeting SR-B receptors with L-37pA, a peptide that functions as an antagonist of SR-BI/II and CD36 receptors, also increased peritoneal granulocyte counts, as well as reduced peritoneal bacteria and bacterium-induced cytokine secretion. In the CLP mouse sepsis model, L-37pA improved survival from 6 to 27%, reduced multiple organ damage, and improved kidney function. These results demonstrate that the reduction of both SR-BI/II- and CD36-dependent bacterial invasion and inflammatory response in the presence of antibiotic treatment results in granulocyte survival and local bacterial containment, as well as reduces systemic inflammation and organ damage and improves animal survival during severe infections. PMID:22327076
Leelahavanichkul, Asada; Bocharov, Alexander V; Kurlander, Roger; Baranova, Irina N; Vishnyakova, Tatyana G; Souza, Ana C P; Hu, Xuzhen; Doi, Kent; Vaisman, Boris; Amar, Marcelo; Sviridov, Denis; Chen, Zhigang; Remaley, Alan T; Csako, Gyorgy; Patterson, Amy P; Yuen, Peter S T; Star, Robert A; Eggerman, Thomas L
While a definitive link between group A streptococcal (GAS) pharyngitis and the pathogenesis of acute rheumatic fever (ARF) is still largely undetermined, early studies have pointed to serological cross-reactions between streptococcal antigens and cardiac tissue as a possible connection (3, 6, 24-28, 46, 48, 49). M protein, the primary virulence factor for GAS (32), has received the most scrutiny in
KEVIN F. JONES; STEPHEN S. WHITEHEAD; MADELEINE W. CUNNINGHAM; V. A. Fischetti
SUMMARY This review begins with a discussion of the large family of Staphylococcus aureus and beta-hemolytic streptococcal pyrogenic toxin T lymphocyte superantigens from structural and immunobiological perspectives. With this as background, the review then discusses the major known and possible human disease associations with superantigens, including associations with toxic shock syndromes, atopic dermatitis, pneumonia, infective endocarditis, and autoimmune sequelae to streptococcal illnesses. Finally, the review addresses current and possible novel strategies to prevent superantigen production and passive and active immunization strategies. PMID:23824366
Spaulding, Adam R; Salgado-Pabón, Wilmara; Kohler, Petra L; Horswill, Alexander R; Leung, Donald Y M; Schlievert, Patrick M
Group B streptococcal (GBS) infections are the leading bacterial cause of disease and deaths among newborns in the United States. In 1993, the annual cost of caring for newborns with sepsis caused by group B Streptococcus was an estimated $294 million. A ...
Group A streptococcal pharyngitis remains the most important bacterial pharyngitis because of its frequency and potential complications. Group A streptococcal pharyngitis is most common in children 5-11 years of age in winter-spring, and a rapid test or culture is necessary for accurate diagnosis. We propose a management strategy for those geographic areas with very low acute rheumatic fever rates, emphasizing selective testing that avoids testing those patients with viral-like features (e.g., rhinorrhea and cough). Acute rheumatic fever is the most important immune-mediated sequela and has become rare in most areas of the USA and Western Europe, most probably due to decreased circulation of highly rheumatogenic group A streptococcal strains. PMID:20109044
Shulman, Stanford T; Tanz, Robert R
Context: Rapid treatment of sepsis is of crucial importance for survival of patients. Specific and rapid markers of bacterial infection have been sought for early diagnosis of sepsis. One such measurement, Procalcitonin (PCT), has recently become of interest as a possible marker of the systemic inflammatory response to infection. Aims: This study was done to find out the common sources of sepsis and to evaluate the diagnostic value of PCT, its predictive value and its relation with Sepsis-related Organ Failure Assessment (SOFA) scores and mortality in various stages of sepsis. Settings and Design: The prospective study was conducted at our tertiary care center from October 2006 to December 2008. A total of 100 patients were included in the study. The study sample included all patients aged above 18 years presenting consecutively to our center during the study period with acute sepsis. They were divided into three groups: sepsis, severe sepsis and septic shockbased on standardized criteria. Materials and Methods: PCT and various other relevant factors were measured in all study subjects. These parameters were compared among the three study groups. The statistical analyses were done using Student “t” test and two-way analysis of variance (ANOVA). Results: Respiratory tract infection was the most common source of sepsis. PCT proved to be an excellent indicator of sepsis with sensitivity of 94%. There was a significant association between serum PCT and SOFA scores (P < 0.05). Serum PCT levels did not predict mortality in the present study. Conclusions: PCT is among the most promising sepsis markers, capable of complementing clinical signs and routine lab parameters suggestive of severe infection.
Sudhir, Uchil; Venkatachalaiah, Ravi Kumar; Kumar, Thimmaiah Anil; Rao, Medha Yogesh; Kempegowda, Punith
The treatment of severe sepsis includes three essential principles: eradication of the inciting infection using source control\\u000a measures and empiric antibiotics, hemodynamic resuscitation of hypoperfusion to avoid acute life-threatening organ dysfunction,\\u000a and sustained support of organ system dysfunction using interventions that minimize organ injury. Therapy can be divided into\\u000a immediate steps taken to stabilize the patient, followed by more definitive
Ismail Cinel; R. Phillip Dellinger
The first 25 BMTs at the Royal Liverpool Children's Hospital (Alder Hey) were performed between April 1987 and July 1991. The aim of this report is to evaluate selective decontamination of the digestive tract (SDD) during the first post-BMT month in this series of 14 allografts and 11 autografts. SDD is a method used to abolish carriage of potentially pathogenic microorganisms including yeasts, Staphylococcus aureus and Gram-negative bacilli (GNB). Chlorhexidine mouth wash was used to decontaminate the oropharynx, and neomycin, colistin (polymyxin E) and nystatin (NEOCON) were given to eradicate gut carriage. Oropharyngeal decontamination was successful in 48% of patients, gut carriage was abolished in 60%, and eradication of the carrier state at both sites was achieved in 33%. A septic response was seen in 76% of children and 36% developed septicaemia (indigenous Gram-positive cocci only). A low carriage index for the target microorganisms during the study manoeuvre of SDD was associated with negative blood cultures (p < 0.01). Acute GVHD occurred in 28% of allografts, but was seen in none of the successfully decontaminated children (p < 0.05). It is concluded that septicaemia from yeasts and GNB, but not the septic response, were successfully prevented by SDD. PMID:8485474
Rhodes, L E; van Saene, H K; White, S; Fairclough, S; Ball, L M; Martin, J
We compared the test characteristics of interleukin (IL)-1 beta, IL-6, IL-8, IL-10, IL-12(p-70), tumor necrosis factor-alpha (TNF-alpha), procalcitonin (PCT), C-reactive protein (CRP), and full blood count (FBC) in the diagnosis of neonatal sepsis. This prospective cohort study in the Neonatal Intensive Care Unit of Dunedin hospital of patients between July 1, 2002 and February 28, 2007 included 117 neonates commenced on antibiotics for 164 episodes of suspected sepsis. Blood cultures, FBC, CRP, IL-1 beta, IL-6, IL-8, IL-10, IL-12(p-70), TNF-alpha, and PCT were obtained at the time sepsis was first suspected and for the following 3 days. Receiver operator characteristics (ROC) plots and test characteristics were determined using culture-positive sepsis as the gold standard. At the time sepsis was first suspected, the most promising individual test was IL-12(p70) with an area under the curve (95% confidence interval [CI]) for the ROC of 0.74 (0.63 to 0.86), which (with a cutoff at 75 pg/mL) had a sensitivity (95% CI) of 28% (20 to 36%) and a specificity of 98% (96 to 100%). IL-10 had a sensitivity of 17% (10 to 23%) and a specificity of 99% (97 to 100%). IL-10 and IL-12(p70) are promising diagnostic tests that can be used to confirm sepsis in neonates. PMID:18850512
Sherwin, Catherine; Broadbent, Roland; Young, Sarah; Worth, Janie; McCaffrey, Frances; Medlicott, Natalie J; Reith, David
We have previously shown that deferoxamine (DFO) infusion protected myocardium against reperfusion injury in patients undergoing open heart surgery, and reduced brain edema, intracranial pressure, and lung injury in pigs with acute hepatic ischemia (AHI). The purpose of this research was to study if DFO could attenuate sepsis inflammatory response syndrome (SIRS) and confer renoprotection in the same model of AHI in anesthetized pigs. Fourteen animals were randomly allocated to two groups. In the Group DFO (n=7), 150mg/kg of DFO dissolved in normal saline was continuously infused in animals undergoing hepatic devascularization and portacaval anastomosis. The control group (Group C, n=7) underwent the same surgical procedure and received the same volume of normal saline infusion. Animals were euthanized after 24h. Hematological, biochemical parameters, malondialdehyde (MDA), and cytokines (interleukin [IL]-1?, IL-6, IL-8, IL-10, and tumor necrosis factor-?) were determined from sera obtained at baseline, at 12h, and after euthanasia. Hematoxylin-eosin and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling were used to evaluate necrosis and apoptosis, respectively, in kidney sections obtained after euthanasia. A rapid and substantial elevation (more than 100-fold) of serum IL-6 levels was observed in Group C reaching peak at the end of the experiment, associated with increased production of oxygen free radicals and lipid peroxidation (MDA 3.2±0.1nmol/mL at baseline and 5.5±0.9nmol/mL at the end of the experiment, P<0.05) and various manifestations of SIRS and multiple organ dysfunction (MOD), including elevation of high-sensitivity C-reactive protein, severe hypotension, leukocytosis, thrombocytopenia, hypoproteinemia, and increased serum levels of lactate dehydrogenase (fourfold), alkaline phosphatase (fourfold), alanine aminotransferase (14-fold), and ammonia (sevenfold). In sharp contrast, IL-6 production and lipid peroxidation were completely blocked in DFO-treated animals offering remarkable resistance to the development of SIRS and MOD. Profound proteinuria, strips of extensive necrosis of tubular epithelial cells, and occasional apoptotic tubular epithelial cells were already present in Group C, but not in Group DFO animals at the time of euthanasia. DFO infusion attenuated lipid peroxidation, blocked IL-6 production, and substantially diminished SIRS and MOD, including tubulointerstitial damage in pigs after acute ischemic hepatic failure. This finding shows that iron, IL-6, and lipid peroxidation are important participants in the pathophysiology of renal injury in the course of generalized inflammation and provides novel pathways of therapeutic interventions for renal protection. PMID:22187937
Vlahakos, Demetrios; Arkadopoulos, Nikolaos; Kostopanagiotou, Georgia; Siasiakou, Sofia; Kaklamanis, Loukas; Degiannis, Dimitrios; Demonakou, Maria; Smyrniotis, Vassilios
Possibilities of timely diagnosis of sepsis were discussed. Informativity of its clinical symptoms, laboratory and instrumental data was studied. Diagnostic criteria were formulated, the programme of complex diagnosis of sepsis was suggested. PMID:18020296
Shapoval, S D; Datsenko, B M; Martyniuk, V B; Iakunich, A N; Maksimova, o O
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
The inflammatory and immune responses evoked in sepsis may create not only an acute brain dysfunction, which occurs in the\\u000a majority of septic patients, but also long-term deficits such as memory impairment. In this context, we evaluated depressive-like\\u000a parameters in sepsis survivor rats. For this purpose, male Wistar rats, weighing 300–350 g, underwent cecal ligation and perforation\\u000a (CLP) (sepsis group) followed
Clarissa M. Comim; Omar J. Cassol-Jr; Leandra C. Constantino; Fabrícia Petronilho; Larissa S. Constantino; Laura Stertz; Flávio Kapczinski; Tatiana Barichello; João Quevedo; Felipe Dal-Pizzol
Sepsis is a condition that results from a harmful or damaging host response to infection. Many of the components of the innate immune response that are normally concerned with host defences against infection can, under some circumstances, cause cell and tissue damage and hence multiple organ failure, the clinical hallmark of sepsis. Because of the high mortality of sepsis in
Background: ARDS may occur after either septic or nonseptic injuries. Sepsis is the major cause of ARDS, but little is known about the differences between sepsis-related and non-sepsis-related ARDS. Methods: A total of 2,786 patients with ARDS-predisposing conditions were enrolled consecutively into a prospective cohort, of which 736 patients developed ARDS. We defined sepsis-related ARDS as ARDS developing in patients with sepsis and non-sepsis-related ARDS as ARDS developing after nonseptic injuries, such as trauma, aspiration, and multiple transfusions. Patients with both septic and nonseptic risks were excluded from analysis. Results: Compared with patients with non-sepsis-related ARDS (n = 62), patients with sepsis-related ARDS (n = 524) were more likely to be women and to have diabetes, less likely to have preceding surgery, and had longer pre-ICU hospital stays and higher APACHE III (Acute Physiology and Chronic Health Evaluation III) scores (median, 78 vs 65, P < .0001). There were no differences in lung injury score, blood pH, Pao2/Fio2 ratio, and Paco2 on ARDS diagnosis. However, patients with sepsis-related ARDS had significantly lower Pao2/Fio2 ratios than patients with non-sepsis-related ARDS patients on ARDS day 3 (P = .018), day 7 (P = .004), and day 14 (P = .004) (repeated-measures analysis, P = .011). Compared with patients with non-sepsis-related ARDS, those with sepsis-related had a higher 60-day mortality (38.2% vs 22.6%; P = .016), a lower successful extubation rate (53.6% vs 72.6%; P = .005), and fewer ICU-free days (P = .0001) and ventilator-free days (P = .003). In multivariate analysis, age, APACHE III score, liver cirrhosis, metastatic cancer, admission serum bilirubin and glucose levels, and treatment with activated protein C were independently associated with 60-day ARDS mortality. After adjustment, sepsis-related ARDS was no longer associated with higher 60-day mortality (hazard ratio, 1.26; 95% CI, 0.71-2.22). Conclusion: Sepsis-related ARDS has a higher overall disease severity, poorer recovery from lung injury, lower successful extubation rate, and higher mortality than non-sepsis-related ARDS. Worse clinical outcomes in sepsis-related ARDS appear to be driven by disease severity and comorbidities.
Sheu, Chau-Chyun; Gong, Michelle N.; Zhai, Rihong; Chen, Feng; Bajwa, Ednan K.; Clardy, Peter F.; Gallagher, Diana C.; Thompson, B. Taylor
Group G streptococci which have been isolated from the oral flora of rats are also normal inhabitants of the human skin, oropharynx, gastrointestinal tract, and female genital tract. This group of streptococci can cause a wide variety of clinical diseases in humans, including septicemia, pharyngitis, endocarditis, pneumonia, and meningitis. Ten days after oral gavage with 7,12-dimethylbenz[a]anthracene, 12 of 22 two-month-old, female, outbred, viral-antibody-free rats presented with red ocular and nasal discharges and marked swelling of the cervical region. Various degrees of firm, nonpitting edema in the region of the cervical lymph nodes and salivary glands as well as pale mucous membranes and dehydration were observed. Pure cultures of beta-hemolytic streptococci were obtained from the cervical lymph nodes of three rats that were necropsied. A rapid latex test system identified the isolates to have group G-specific antigen. These streptococcal isolates fermented trehalose and lactose but not sorbitol and inulin and did not hydrolize sodium hippurate or bile esculin. A Voges-Proskauer test was negative for all six isolates. Serologic tests to detect the presence of immunoglobulin G antibody to rat viral pathogens and Mycoplasma pulmonis were negative. Histopathologic changes included acute necrotizing inflammation of the cervical lymph nodes with multiple large colonies of coccoid bacteria at the perimeter of the necrotiz zone. To our knowledge, this is the first report of naturally occurring disease attributed to group G streptococci in rats. Images
Corning, B F; Murphy, J C; Fox, J G
Introduction Henoch-Schönlein purpura is a systemic disease with frequent renal involvement, characterized by IgA mesangial deposits. Streptococcal infection can induce an abnormal IgA immune response like Henoch-Schönlein purpura, quite similar to typical acute post-infectious glomerulonephritis. Indeed, hypocomplementemia that is typical of acute glomerulonephritis has also been described in Henoch-Schönlein purpura. Case presentation We describe a 14-year-old Caucasian Spanish girl who developed urinary abnormalities and cutaneous purpura after streptococcal infection. Renal biopsy showed typical findings from Henoch-Schönlein purpura nephritis. In addition, she had low serum levels of complement (C4 fraction) that persisted during follow-up, in spite of her clinical evolution. She responded to treatment with enalapril and steroids. Conclusion The case described has, at least, three points of interest in Henoch-Schönlein purpura: 1) Initial presentation was preceded by streptococcal infection; 2) There was a persistence of low serum levels of complement; and 3) There was response to steroids and angiotensin-converting enzyme inhibitor in the presence of nephrotic syndrome. There are not many cases described in the literature with these characteristics. We conclude that Henoch-Schönlein purpura could appear after streptococcal infection in patients with abnormal complement levels, and that steroids and angiotensin-converting enzyme inhibitor could be successful treatment for the disease.
TREM-1 (triggering receptor expressed on myeloid cells) is a surface molecule expressed on neutrophils and macrophages which has been implicated in the amplification of inflammatory responses triggered during infection. In the present study, we have investigated the clinical significance of TREM-1 in Streptococcus pyogenes-induced severe sepsis in both experimentally infected mice as well as in patients with streptococcal toxic shock. We found that S. pyogenes induced a dose-dependent upregulation of TREM-1 in in vitro cultured phagocytic cells and in the organs of S. pyogenes-infected mice. Furthermore, we reported a positive correlation between serum levels of soluble TREM-1 (sTREM-1) and disease severity in infected patients as well as in experimentally infected mice. Hence, sTREM-1 may represent a useful surrogate marker for streptococcal sepsis. We found that modulation of TREM-1 by administration of the TREM-1 decoy receptor rTREM-1/Fc substantially attenuated the synthesis of inflammatory cytokines. More importantly, treatment of S. pyogenes-infected septic mice with rTREM-1/Fc or the synthetically produced conserved extracellular domain LP17 significantly improved disease outcome. In summary, our data suggest that TREM-1 may not only represent a valuable marker for S. pyogenes infection severity but it may also be an attractive target for the treatment of streptococcal sepsis. PMID:23571837
Horst, Sarah A; Linnér, Anna; Beineke, Andreas; Lehne, Sabine; Höltje, Claudia; Hecht, Alexander; Norrby-Teglund, Anna; Medina, Eva; Goldmann, Oliver
Forty patients with a history of recurrent non-beta-hemolytic streptococcal tonsillitis (RNST) participated in a prospective randomized study comparing penicillin and clindamycin in the treatment of acute non-group A streptococcal infection. The efficiency of each antibiotic was evaluated according to its ability to alleviate acute infection and prevent recurrence. Surface tonsillar cultures were obtained both before and ten days after the termination of therapy, and specimens were processed for aerobic and anaerobic bacteria. Beta-lactamase-producing bacteria (BLPB) were present in 36 (90%) tonsillar cultures. Thirty-one BLPB were isolated in 17 patients before penicillin therapy and 42 BLPB were recovered from 19 after such treatment. Thirty-three BLPB were recovered in 19 patients before clindamycin therapy, after which four BLPB were isolated in three patients (P less than .05). From the second day posttherapy onward, significantly fewer patients who received clindamycin had fever, pharyngeal injection, and sore throat. In a 1-year follow-up period, recurrent tonsillitis was noted in 13 of the patients who received penicillin and in two treated with clindamycin (P less than .001). The data clearly demonstrate the superiority of clindamycin therapy over penicillin in patients with RNST. PMID:2764234
Group B streptococcus is the leading cause of early-onset neonatal sepsis in the United States. Universal screening is recommended for pregnant women at 35 to 37 weeks' gestation. The Centers for Disease Control and Prevention recently updated its guideline for the prevention of early-onset neonatal group B streptococcal disease. The new guideline contains six important changes. First, there is a recommendation to consider using sensitive nucleic acid amplification tests, rather than just routine cultures, for detection of group B streptococcus in rectal and vaginal specimens. Second, the colony count required to consider a urine specimen positive is at least 104 colony-forming units per mL. Third, the new guideline presents separate algorithms for management of preterm labor and preterm premature rupture of membranes, rather than a single algorithm for both conditions. Fourth, there are minor changes in the recommended dose of penicillin G for intrapartum chemoprophylaxis. Fifth, the guideline provides new recommendations about antibiotic regimens for women with penicillin allergy. Cefazolin is recommended for women with minor allergies. For those at serious risk of anaphylaxis, clindamycin is recommended if the organism is susceptible [corrected] and vancomycin is recommended if there is clindamycin resistance or if susceptibility is unknown. [corrected]. Finally, the new algorithm for secondary prevention of early-onset group B streptococcal disease in newborns should be applied to all infants, not only those at high risk of infection. The algorithm clarifies the extent of evaluation and duration of observation required for infants in different risk categories. PMID:22962913
Cagno, Colleen K; Pettit, Jessie M; Weiss, Barry D
Severe sepsis, a syndrome that complicates infection and injury, affects 750,000 annually in the United States. The acute mortality rate is approximately 30%, but, strikingly, sepsis survivors have a significant disability burden: up to 25% of survivors are cognitively and physically impaired. To investigate the mechanisms underlying persistent cognitive impairment in sepsis survivors, here we developed a murine model of severe sepsis survivors following cecal ligation and puncture (CLP) to study cognitive impairments. We observed that serum levels of high mobility group box 1 (HMGB1), a critical mediator of acute sepsis pathophysiology, are increased in sepsis survivors. Significantly, these levels remain elevated for at least 4 wks after CLP. Sepsis survivors develop significant, persistent impairments in learning and memory, and anatomic changes in the hippocampus associated with a loss of synaptic plasticity. Administration of neutralizing anti-HMGB1 antibody to survivors, beginning 1 wk after onset of peritonitis, significantly improved memory impairments and brain pathology. Administration of recombinant HMGB1 to naïve mice recapitulated the memory impairments. Together, these findings indicate that elevated HMGB1 levels mediate cognitive decline in sepsis survivors, and suggest that it may be possible to prevent or reverse cognitive impairments in sepsis survivors by administration of anti-HMGB1 antibodies.
Chavan, Sangeeta S; Huerta, Patricio T; Robbiati, Sergio; Valdes-Ferrer, SI; Ochani, Mahendar; Dancho, Meghan; Frankfurt, Maya; Volpe, Bruce T; Tracey, Kevin J; Diamond, Betty
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.
Investigations of novel sepsis treatments have proven ineffective in the past. Despite advances in overall care of critically\\u000a ill patients, therapies specifically designated for sepsis were lacking. However, research unveiled a complex interaction\\u000a between the coagulation and inflammation systems, which has served as an impetus for innovative pharmacologic therapies in\\u000a the treatment of patients with sepsis. This article summarizes the
Todd W. Rice; Gordon R. Bernard
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.
The diagnosis of group A streptococcal disease still relies on isolation on sheep blood agar followed by presumptive identification of group A streptococcal strains by using bacitracin sensitivity or the more precise sero-grouping methods such as the Lanc...
E. A. Edwards I. A. Phillips W. C. Suiter
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
The histone-like protein (HlpA) is highly conserved among streptococci. After lysis of streptococci in infected tissues, HlpA can enter the bloodstream and bind to proteoglycans in the glomerular capillaries of kidneys, where it can react with antibodies or stimulate host cell receptors. Deposits of streptococcal antigens in tissues have been associated with localized acute inflammation. In this study, we measured
LIPING ZHANG; TRACEY A. IGNATOWSKI; ROBERT N. SPENGLER; BERNICE NOBLE; MURRAY W. STINSON
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.
Systemic sepsis continues to be the most-difficult management problem in caring for the combat casualty. The complications of sepsis pervade all areas of injury to soldiers in the field, whether it is mechanical (missiles), thermal (burns), chemical, biological, or radiation injury. With the advent of tactical nuclear weapons, the problem of sepsis will be much higher in future wars than has previously been experienced through the world. The purpose of this chapter is a) to review the data suggesting pharmacological agents that may benefit the septic patient, and b) to emphasize the adjunctive therapies that should be explored in clinical trials. The pharmacological management of sepsis remains controversial. Most of the drugs utilized clinically treat the symptoms of the disease and are not necessarily directed at fundamental mechanisms that are known to be present in sepsis. A broad data base is emerging, indicating that NSAID should be used in human clinical trials. Prostaglandins are sensitive indicators of cellular injury and may be mediators for a number of vasoactive chemicals. Opiate antagonists and calcium channel blockers require more in-depth data; however, recent studies generate excitement for their potential use in the critically ill patient. Pharmacological effects of antibiotics, in concert with other drugs, suggest an entirely new approach to pharmacological treatment in sepsis. There is no doubt that new treatment modalities or adjunctive therapies must be utilized to alter the poor prognosis of severe sepsis that we have observed in the past 4 decades.
There is much enthusiasm and interest in sepsis biomarkers, particularly because sepsis is a highly lethal condition, its diagnosis is challenging, and even simple treatment with antibiotics has led to serious adverse consequences such as emergence of resistant pathogens. Yet development of a sepsis biomarker requires many more steps than simply finding an association between a particular molecule and a clinical state or outcome. Demonstration of improvement of therapeutic practice using receiver-operating characteristic and other analyses is important. Validation in independent, prospective and, preferably, multicenter trials is essential. Many promising candidate sepsis biomarkers have recently been proposed. While procalcitonin (PCT) is currently the most studied sepsis biomarker, evidence of potential value has been found for a wide array of blood biomarkers including proteins, mRNA expression in whole blood or leukocytes, micro-RNAs (miRNA), pathogen and host DNA, pathogen and host genetic variants and metabolomic panels, and even in the novel use of currently available clinical data. While the most common early reports link putative sepsis biomarker levels to severity of illness and outcome (prognostic), this is not anticipated to be their primary use. More important is the distinction between infection and noninfectious inflammatory responses (diagnostic) and the use of sepsis biomarkers to direct therapy (predictive). PMID:23975686
Walley, Keith R
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
Vitamin D insufficiency and sepsis are both highly prevalent worldwide problems and this article reviews the emerging science that is defining the intersections of these conditions. The importance of vitamin D’s role in skeletal health has long been understood but recent evidence is beginning to highlight its role in the functioning of other physiologic systems of the body. Basic science data reveal its integral role in local immune responses to pathogens and the systemic inflammatory pathways of sepsis. Furthermore, clinical scientists have found associations with respiratory infections, critical illness and sepsis but the causal relationship and its clinical impact have yet to be clearly defined. The article ends with speculations on the connections between racial disparities and seasonal differences in sepsis and vitamin D insufficiency.
Kempker, Jordan A.; Han, Jenny E.; Tangpricha, Vin; Ziegler, Thomas R.; Martin, Greg S.
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.
\\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
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
Sepsis is often associated with haemostatic changes ranging from subclinical activation of blood coagulation (hypercoagulability), which may contribute to localized venous thromboembolism, to acute disseminated intravascular coagulation (DIC), characterized by widespread microvascular thrombosis and subsequent consumption of platelets and coagulation proteins, eventually causing bleeding manifestations. The key event underlying this life-threatening complication is the overwhelming inflammatory host response to the infectious agent leading to the overexpression of inflammatory mediators. The latter, along with the micro-organism and its derivatives are now believed to drive the major changes responsible for massive thrombin formation and fibrin deposition, namely 1) the aberrant expression of the TF by different cells (especially monocytes-macrophages), 2) the impairment of physiological anticoagulant pathways, orchestrated mainly by dysfunctional endothelial cells (ECs) and 3) the suppression of fibrinolysis due to overproduction of plasminogen activator inhibitor-1 (PAI-1) by ECs and likely also to thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor (TAFI). The ensuing microvascular thrombosis and ischemia are thought to contribute to tissue injury and multiple organ dysfunction syndrome (MODS). Recent evidence indicates that extracellular nuclear materials released from activated and especially apoptotic or necrotic cells, e.g. High Mobility Group Box-1 (HMGB-1) and histones, are endowed with cell toxicity, proinflammatory and clot-promoting properties and thus, during sepsis, they may represent late mediators that propagate further inflammation, coagulation, cell death and MODS. These insights into the pathogenesis of DIC and MODS may have implications for the development of new therapeutic agents potentially useful for the management of severe sepsis. PMID:22061311
Semeraro, Nicola; Ammollo, Concetta T; Semeraro, Fabrizio; Colucci, Mario
Enamel cylinders prepared from a pool of extracted teeth, were placed in Howley appliances. The appliance was then worn for 2 days by the 2 subjects to study 'in vivo' plaque development. Results have shown that percentages of streptococcal species in the...
A. Gross N. Tinanoff
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
Anne Matlow; Hillar Vellend
An in vivo model for group A streptococcal (GAS) impetigo was developed, whereby human neonatal foreskin engrafted onto SCID mice was superficially damaged and bacteria were topically applied. Severe infection, indicated by a purulent exudate, could be induced with as few as 1,000 CFU of a virulent strain. Early findings (48 h) showed a loss of stratum corneum and adherence
DOMINICK A. SCARAMUZZINO; JENNIFER M. MCNIFF; DEBRA E. BESSEN
In an incomplete study in 1965 microscopic haematuria in the second or third week after acute pharyngitis was found four times more often in patients with either microbiological or clinical evidence of dual infection with both group A streptococci and a virus than in patients with evidence only of infection with group A streptococci. Prospective studies of the role of viruses in the aetiology of transient haematuria and of acute post streptococcal glomerulonephritis are feasible in general practice and would be most productive if concentrated in children 5-9 years of age.
Higgins, P. M.
Group A streptococci can cause a variety of diseases ranging from uncomplicated superficial infections to severe systemic infections associated with high morbidity and mortality. Since the late 1980s a drastic resurgence of highly aggressive invasive streptococcal infections, including streptococcal toxic shock syndrome and necrotizing fasciitis, have been noted worldwide. This has prompted intense research in the field and important new information has been gained regarding the pathogenesis and treatment of life-threatening invasive group A streptococcal infections. Exotoxins with superantigenic activities have been identified as central mediators of the systemic effects seen in streptococcal toxic shock syndrome. Novel therapeutic strategies include agents that can inhibit these superantigens, and one promising candidate is intravenous polyspecific immunoglobulin that contains neutralizing antibodies against a wide spectrum of streptococcal superantigens. Intravenous immunoglobulin adjunctive therapy was shown in a case-control study to reduce mortality in patients with streptococcal toxic shock syndrome. PMID:12525288
Norrby-Teglund, Anna; Norrby, S. Ragnar; Low, Donald E.
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
Sepsis is a syndrome produced by the accelerated activity of the inflammatory immune response, the clotting cascade, and endothelial damage. It is a systematic process that can progress easily into septic shock and MODS. The chemical mediators or cytokines produce a complex self-perpetuating process that impacts all body systems. It is critical for the nurse first to identify patients at risk for developing sepsis and to assess patients who have SIRS and sepsis continually for signs and symptoms of organ involvement and organ dysfunction. Once sepsis has been diagnosed, evidence-based practice indicates initiation of fluid resuscitation. Vasopressor therapy, positive inotropic support, and appropriate antibiotic therapy should be started within the first hour. Within a 6-hour timeframe the goal is stabilization of the CVP, MAP, and UOP to prevent further organ damage. The challenge for nurses caring for septic patients is to support the treatment goals, to prevent added complications including stress ulcers, DVTs, aspiration pneumonia, and the progression to MODS, and to address the patient's and the family's psychosocial needs. As complex as the pathophysiology of sepsis is, the nursing care is equally complex but also rewarding. Patients who previously might have died now recover as vigilant nursing care combines forces with new drug therapies and evidence-based practice guidelines. PMID:17338953
King, Joan E
Bacteremia and sepsis are common problems in clinical practice. Bacteremia is the presence of bacteria in the blood, hence a microbiological finding. Sepsis is a clinical diagnosis needing further specification regarding focus of infection and etiologic pathogen, whereupon clinicians, epidemiologists and microbiologists apply different definitions and terminology. Knowing these differences is important when reading and interpreting the literature. Studies show a pan-European increase in the rate of bacteremia, both Gram-negative and Gram-positive. Reasons for this are an increase in invasive diagnostics and therapy, going along with increasing age of patients. Bacteremic infections are frequently healthcare related. This article illustrates recent aspects in diagnosis and therapy of sepsis and bacteremia. PMID:23478795
Hagel, S; Pletz, M W; Brunkhorst, F M; Seifert, H; Kern, W V
Sepsis and sepsis-associated multi-organ failure are major challenges for scientists and clinicians and are a tremendous burden for health-care systems. Despite extensive basic research and clinical studies, the pathophysiology of sepsis is still poorly understood. We are now beginning to understand that sepsis is a heterogeneous, dynamic syndrome caused by imbalances in the 'inflammatory network'. In this Review, we highlight
Daniel Rittirsch; Michael A. Flierl; Peter A. Ward
Introduction: Neonatal Sepsis is a major cause of mortality and morbidity in newborns both in developed and developing countries. Objective: This study was to analyse the symptoms and sign of Neonatal Sepsis. Materials and Methods: Retrospective hospital based study the date was collected from patient record files of two years (Jan. 2001-Dec.2002). Result: 106 Neonates with suspected sepsis were studied
Jain NK; Jain VM; Maheshwari S
The authors present clinical, microbiological and scintigraphic findings in eight children with poststreptococcal reactive arthritis, hospitalized in the Zadar General Hospital from 1990 to 1992. In all patients an antecedent throat infection was noticed, 7-10 days before the first symptoms and signs of arthritis developed. Antistreptolysin O microtitration and/or throat culture revealed streptococcal infection in all patients. Scintigraphic examination with Te-99m yielded four positive (50%) results. In the follow-up one of the positive scans was later suggestive of tumorous process. The authors conclude that accurate diagnosis of poststreptococcal reactive arthritis depends on microbiological identification of streptococcal infection and longitudinal clinical follow-up in which scintigraphy may be of differential diagnostic benefit. PMID:8965607
Skitareli?, N; Morovi?, M; Beli?, V; Mokovi?, I; Gili?, V; Kuzemenska, P
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
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.
The treatment of sepsis is an ongoing challenge for clinicians; despite the wide choice of effective antibiotics to treat infection, sepsis remains the leading cause of morbidity and mortality for patients admitted to an intensive care unit. Dysregulation of the immune response is now recognized to be a key factor in multiple organ dysfunction, yet our therapy for inflammation remains ineffective. It has been advocated for more than a decade that cytokine reduction in blood compartment could lead to a reduction in mortality in sepsis. Over the years, multiple extracorporeal techniques have evolved, with the intent of influencing the circulating levels of inflammatory mediators like cytokines and chemokines, the complement system, as well as factors of the coagulation system. These include high-volume hemofiltration, use of high cutoff membranes, and systems based on adsorption, such as coupled plasma filtration adsorption and the polymyxin-B column. In addition, new experimental systems that utilize human phagocytic cells and immobilized antibodies for targeted immunomodulation have emerged. In the context of limited resources and growing expansion in the availability of technologies, a better understanding of these therapies is required before they can be properly integrated into standard clinical practice in the hope of influencing major clinical outcomes. In this article, we will provide a concise overview of selected extracorporeal modalities currently in clinical use and briefly introduce some new promising techniques for sepsis. PMID:22027760
Panagiotou, Anthi; Gaiao, Sérgio; Cruz, Dinna N
Coagulation abnormalities, ranging from a simple fall in platelet count to full-blown disseminated intravascular coagulation, are a common occurrence in critically ill patients and have been associated with increased mortality. In sepsis, activation of the extrinsic coagulation pathway by tissue factor induces increased coagulation, and simultaneous depression of the inhibitory mechanisms of coagulation, and suppression of the fibrinolytic system results
André Amaral; Steven M. Opal; Jean-Louis Vincent
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
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
Streptococcal myositis is a very rare bacterial infection of muscle with a high mortality. Diagnosis is difficult because of the paucity of clinical signs and symptoms at the onset. However, presentation of the disease appears to have changed over the last 50 years. A case of streptococcal myositis is presented (misdiagnosed as hamstring injury), which more closely reflects the current
N Kang; D Antonopoulos; A Khanna
Puerperal group A streptococcal infections, a major postpartum killer during the late 19th and early 20th centuries, have become (fortunately) rare. We describe a cluster of 4 serious peripartum group A streptococcal infections occurring within the past five years at a single medical center. These cases were not epidemiologically linked and serve to illustrate the continuing risk of these potentially fulminant infections.
Busowski, Mary T.; Lee, Melissa; Busowski, John D.; Akhter, Kauser; Wallace, Mark R.
Invasive group A streptococcal infections, including strepto- coccal toxic shock syndrome and necrotizing fasciitis, are as- sociated with considerable morbidity and mortality despite the use of appropriate antibiotics (2, 3, 7, 9). The microbial diag- nosis of streptococcal necrotizing fasciitis is generally based on the isolation of group A streptococcus from either soft tissue or blood cultures. However, only about
LISA LOUIE; ANDREW E. SIMOR; MARIE LOUIE; ALLISON MCGEER; DONALD E. LOW; Mount Sinai; Princess Margaret
Introduction Complications associated to group-A streptococcal pharyingitis include non-suppurative complications such as acute rheumatic fever and glomerulonephritis and suppurative complications such as peritonsillar or retropharyngeal abscess, sinusitis, mastoiditis, otitis media, meningitis, brain abscess, or thrombosis of the intracranial venous sinuses. Case presentation We described a case of a 15-year-old patient with a history of acute pharyngodinia early followed by improvise fever and a progressive formation of a diffuse orbital edema, corneal hyperaemia, diplopia and severe decrease of visual acuity. The patient was surgically treated with functional endoscopic sinus surgery (FESS) after the response of a maxillofacial computed tomography scans that showed a pansinusitis complicated by a left orbital cellulites. Numerous colonies of Streptococcus pyogenes were found in the samples of pus and an antibiotic therapy with meropenem was initiated on the basis of the sensitivity test to antibiotics. The patient was finally discharged with diagnosis of left orbital cellulites with periorbital abscess, endophtalmitis and acute pansinusitis as a consequence of streptococcal pharyngitis. Conclusion The case highlights the possible unusual complication of a group-A streptococcal pharyingitis in a immunocompetent child and the needing of a prompt surgical and medical approach toward the maxillofacial complications associated to the infection.
Myocardial dysfunction is one of the main predictors of poor outcome in septic patients, with mortality rates next to 70%. During the sepsis-induced myocardial dysfunction, both ventricles can dilate and diminish its ejection fraction, having less response to fluid resuscitation and catecholamines, but typically is assumed to be reversible within 7-10 days. In the last 30 years, It´s being subject of substantial research; however no explanation of its etiopathogenesis or effective treatment have been proved yet. The aim of this manuscript is to review on the most relevant aspects of the sepsis-induced myocardial dysfunction, discuss its clinical presentation, pathophysiology, etiopathogenesis, diagnostic tools and therapeutic strategies proposed in recent years.
Romero-Bermejo, Francisco J; Ruiz-Bailen, Manuel; Gil-Cebrian, Julian; Huertos-Ranchal, Maria J
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
The serogroups A (Streptococcus pyogenes), B (Streptococcus agalactiae) and S. dysgalactiae subsp. equisimilis (group C and G) are generally defined as beta-hemolytic streptococci. Beta-hemolytic streptococci cause a variety of infections ranging from skin and soft-tissue infections to severe invasive infections such as necrotizing fasciitis (NF) and streptococcal toxic shock syndrome (STSS). The case fatality rate due to bacteremias caused by beta-hemolytic streptococci is 15%. The use of clindamycin in combination with benzylpenicillin has been shown to be of benefit. The use of intravenous immunoglobulin is suggested in STSS in combination with antibiotics and surgery. PMID:23961606
Antisera to streptococcal groups A through G containing 4% polyethylene glycol 6000 were prepared and evaluated. Seventy strains of homologous and heterologous beta- and non-beta-hemolytic streptococci were included in the evaluation. Homologous reactions were determined against extracts prepared by four extraction methods: hot hydrochloric acid (Lancefield) extraction, autoclave extraction, hot formamide extraction, and nitrous acid extraction. Enhancement of the precipitin reaction in the presence of polyethylene glycol 6000 permitted a fourfold dilution of all antisera for use in the capillary precipitin test. At this dilution, the potency of the antisera exceeded requirements established for these reagents. PMID:7026609
George, J R; Ashworth, H; Facklam, R R; Harrell, W K; Palmer, D F
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
U K Mishra; S E Jacobs; L W Doyle; S M Garland
In North America, approximately 700,000 cases of sepsis occur each year, with mortality ranging between 30% and 50%. The American Journal of Pathology has featured numerous articles on the topic, revealing mechanistic insights gleaned from both experimental rodent models and human sepsis. Nonetheless, there remains urgent need to determine the basis for sepsis-related complications and how they can be avoided, as well as how they can be most effectively treated once recognized. This historical perspective reviews what we currently understand about the mechanisms of sepsis, as well as the barriers that remain in our treatment strategies.
Ward, Peter A.; Bosmann, Markus
In order to study the effects of a severe bacterial infection on thyroid function rats were subjected to group A streptococcal pneumonia, and thyroid activity determined by measurement of the rate of discharge of I131 from the thyroid gland. Decreased thyroid activity of moderate to marked degree was observed in the majority of infected animals. Infected animals ate less than normal animals. Since fasting leads to decreased thyroid function, I131 release rates were measured in control animals pair-fed with infected animals and in control and infected animals force-fed a normal intake. The reduction in thyroid activity seen in acute infection was found to be partly but not entirely due to the associated voluntary food restriction. Although the adrenal glands of rats dying of pneumonia were very large, the thyroid inhibition occurring during the course of experimental pneumonia was not secondary to increased adrenocortical function since infected, adrenalectomized animals, receiving injections of cortisone, showed thyroid inhibition comparable to that observed in intact infected animals. The possible influence of the level of thyroid activity on resistance was evaluated. In two experiments a total of 80 rats in 3 groups was pretreated with propylthiouracil and injected daily with 3 dosage levels of 7-thyroxine for 3 weeks prior to inoculation. Under these conditions mortality rates in infected animals fell with decreasing levels of thyroid function. However, induced hypothyroidism was found to afford no protective effect in comparison with untreated infected animals.
Reichlin, Seymour; Glaser, Robert J.
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.
Twenty-eight pigs died in an outbreak of streptococcal meningitis in an East Anglian herd. Most were 10-14 weeks old. The outbreak lasted from January to April and was finally controlled by antibiotic therapy. A similar number of losses had occurred in the previous year though no diagnosis had then been made. The causal agent appeared to be a haemolytic streptococcus belonging to group D and provisionally designated Streptococcus suis type 2. It is probably identical with de Moor's group R streptococcus which causes a similar disease in the Netherlands. It is serologically distinct from Streptococcus suis type 1 which causes meningitis in piglets. Type 2 infection in pigs appears to be widespread in England and Wales and to occur in animals up to the age of at least 14 weeks. A comparison is drawn between Str. suis meningitis in pigs and group B streptococcal meningitis in human infants.
Windsor, R. S.; Elliott, S. D.
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.
Objective. To determine whether intra- partum antibiotic prophylaxis for neonatal group B strep- tococcal (GBS) disease has resulted in an increased rate of non-GBS or antibiotic-resistant early-onset invasive neonatal disease. Methods. Maternal and infant chart review of all in- fants with bacteria other than GBS isolated from blood or spinal fluid in 1996 through 1999 in 19 hospitals (repre- senting
Robert S. Baltimore; Sharon M. Huie; James I. Meek; Anne Schuchat; Katherine L. O'Brien
Sepsis is one of the leading causes of death in the critically ill. Early diagnosis is important to avoid delay in instituting appropriate treatment. However, diagnosis can be delayed because of difficulty in interpreting clinical features. Sepsis biomarkers can aid early diagnosis. This article reviews the application of readily available biomarkers for diagnosis of sepsis, for predicting prognosis, and for antibiotic stewardship. 178 biomarkers are described in the literature--ranging from specimen cultures, which lack sensitivity and specificity for early diagnosis of sepsis, to biomarkers such as C-reactive protein, procalcitonin, and genetic biomarkers, which have their own limitations. Future research will mainly focus on use of more than one biomarker, but the main problem in sepsis biomarker research seems to be a lack of a recommended biomarker. PMID:23108494
Sankar, Vinoth; Webster, Nigel R
Sepsis progresses from an early/acute hyperinflammatory to a late/chronic hypoinflammatory phase with immunosuppression. As a result of this phenotypic switch, mortality in late sepsis from persistent primary infection or opportunistic new infection often exceeds that in acute sepsis. Emerging data support that persistence of the hypoinflammatory (hyporesponsive) effector immune cells during late sepsis might involve alterations in myeloid differentiation/maturation that generate circulating repressor macrophages that do not readily clear active infection. Here, we used a cecal ligation and puncture (CLP) murine model of prolonged sepsis to show that adoptive transfer of CD34+ hematopoietic stem-progenitor cells after CLP improves long-term survival by 65%. CD34+ cell transfer corrected the immunosuppression of late sepsis by (i) producing significantly higher levels of proinflammatory mediators upon ex vivo stimulation with the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide, (ii) enhancing phagocytic activity of peritoneal macrophages, and (iii) clearing bacterial peritonitis. Improved immunity by CD34+ cell transfer decreased inflammatory peritoneal exudate of surviving late-sepsis mice. Cell tracking experiments showed that the transferred CD34+ cells first appeared in the bone marrow and then homed to the spleen and peritoneum. Because CD34+ cells did not affect the early-phase hyperinflammatory response, it is likely that the newly incorporated pluripotent CD34+ cells differentiated into competent immune cells in blood and tissue, thereby reversing or replacing the hyporesponsive endotoxin-tolerant cells that occur and persist after the initiation of early sepsis.
Brudecki, Laura; Ferguson, Donald A.; Yin, Deling; Lesage, Gene D.; McCall, Charles E.
Recent news in the field of bloodstream infection and sepsis relevant for the practitioner include the recommendation in the newly revised German sepsis guideline to introduce selective intestinal decontamination with non-absorbable antimicrobial substances for the prevention of secondary infections in ventilated patients. This intervention, however, remains controversial because there are indications of unfavourable effects (increased development of resistance), and because the effect size has been rather low. Other news indicate not only that procalcitonin can be reasonably used as an aid to determine the duration of antibiotic treatment in community-acquired respiratory infection and pneumonia. A procalcitonin-based algorithm can also be used in critical care patients to shorten the duration of antibiotic administration without worsening outcomes. Recent data indicate that E. coli and S. aureus continue to be the most frequent pathogens isolated in bloodstream infection. The proportion of E. coli strains producing extended-spectrum beta lactamase (ESBL) is increasing. New epidemiologic evidence shows that infections with this pathogen, resistant to many standard antibiotics, are associated with an increased mortality rate, similar to infections due to methicillin-resistant Staphylococcus aureus (MSRA). The incidence of MRSA bacteraemia in Germany can now be estimated better as it has become a notifiable infection. PMID:21271477
Kern, W V
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.
OBJECTIVE--To evaluate treatment of group A beta haemolytic streptococcal pharyngitis with amoxycillin once daily compared with phenoxymethylpenicillin three or four times a day. DESIGN--Randomised controlled study of consecutive patients presenting with symptoms suggestive of group A beta haemolytic streptococcal pharyngitis in whom culture of a throat swab yielded positive results. SETTING--Five family medicine practices. SUBJECTS--157 patients aged over 3 years
P Shvartzman; H Tabenkin; A Rosentzwaig; F Dolginov
Group A streptococci can cause a variety of diseases ranging from uncomplicated superficial infections to severe systemic\\u000a infections associated with high morbidity and mortality. Since the late 1980s a drastic resurgence of highly aggressive invasive\\u000a streptococcal infections, including streptococcal toxic shock syndrome and necrotizing fasciitis, have been noted worldwide.\\u000a This has prompted intense research in the field and important new
Anna Norrby-Teglund; S. Ragnar Norrby; Donald E. Low
Background Streptococcus pyogenes (GAS) harbors several superantigens (SAgs) in the prophage region of its genome, although speG and smez are not located in this region. The diversity of SAgs is thought to arise during horizontal transfer, but their evolutionary pathways have not yet been determined. We recently completed sequencing the entire genome of S. dysgalactiae subsp. equisimilis (SDSE), the closest relative of GAS. Although speG is the only SAg gene of SDSE, speG was present in only 50% of clinical SDSE strains and smez in none. In this study, we analyzed the evolutionary paths of streptococcal and staphylococcal SAgs. Results We compared the sequences of the 12–60 kb speG regions of nine SDSE strains, five speG+ and four speG–. We found that the synteny of this region was highly conserved, whether or not the speG gene was present. Synteny analyses based on genome-wide comparisons of GAS and SDSE indicated that speG is the direct descendant of a common ancestor of streptococcal SAgs, whereas smez was deleted from SDSE after SDSE and GAS split from a common ancestor. Cumulative nucleotide skew analysis of SDSE genomes suggested that speG was located outside segments of steeper slopes than the stable region in the genome, whereas the region flanking smez was unstable, as expected from the results of GAS. We also detected a previously undescribed staphylococcal SAg gene, selW, and a staphylococcal SAg -like gene, ssl, in the core genomes of all Staphylococcus aureus strains sequenced. Amino acid substitution analyses, based on dN/dS window analysis of the products encoded by speG, selW and ssl suggested that all three genes have been subjected to strong positive selection. Evolutionary analysis based on the Bayesian Markov chain Monte Carlo method showed that each clade included at least one direct descendant. Conclusions Our findings reveal a plausible model for the comprehensive evolutionary pathway of streptococcal and staphylococcal SAgs.
Streptococcal toxic shock syndrome (STSS) is an increasingly common disease entity but has rarely been described in the plastic surgery literature. We present the first known case of STSS associated with a reconstructive procedure. Two weeks postoperatively from a transverse rectus abdominis musculocutaneous flap for breast reconstruction, our patient presented with flulike symptoms and progressed rapidly to multiorgan failure. Though initially no nidus for infection was evident, the abdominal donor site was surgically debrided and found to contain group A Streptococcus. Following aggressive rehydration and antibiotic therapy, the patient gradually made a full recovery. In this case report, we review the presentation and epidemiology of STSS and compare it to the more common staphylococcal toxic shock syndrome. In addition, we discuss the management and outcomes of STSS, with an emphasis on raising clinical suspicion for this rare but dangerous entity. PMID:15838219
Agerson, Ashley N; Wilkins, Edwin G
Streptococcus pyogenes is an important human pathogen that can cause a variety of diseases in immunocompetent individuals ranging from uncomplicated superficial infections to severe life-threatening infections including rapidly progressing deep tissue infections, such as necrotizing fasciitis (NF) and severe cellulitis. The pathogenesis of these infections is complex and multifactorial involving numerous virulence factors expressed by the bacteria. Here, we review data from epidemiologic, pathogenomic, and pathogenesis studies that have provided insight into the host-pathogen interactions that contribute to S. pyogenes tissue infections. The role of tissue-specific streptococcal types, intracellular bacterial persistence, and other immune evasion strategies resulting in massive bacterial load at the tissue site, as well as virulence factors contributing to a local hyperinflammatory response are highlighted. A particular focus is on in vivo findings in patients that provide insight into host and bacterial factors that are expressed at the infected tissue site, and the mechanisms underlying tissue pathology. PMID:23224738
Johansson, Linda; Norrby-Teglund, Anna
1. Streptococcal proteinase is derived from an inactive precursor found in culture filtrates of proteinase-producing streptococci. 2. The precursor can be converted into the proteinase by low concentrations of trypsin but not by chymotrypsin. 3. In cultures grown in suitable media the conversion of precursor to proteinase is effected autocatalytically. This reaction occurs under reducing conditions and is initiated by active proteinase present in low concentrations with the precursor. 4. The autocatalytic reaction is suppressed or retarded by conditions which decrease the activity of the proteinase, e.g. by growing cultures at 22°C. instead of at 37°C. or by growing them under markedly aerobic conditions. It is also retarded in the presence of casein.
Elliott, Stuart D.; Dole, Vincent P.
Rarely taught in medical schools, clinical reasoning is the ability to discern the important from the unimportant and to arrive at accurate and efficient clinical conclusions. Identifying errors in reasoning is difficult; however, undetected clinical reasoning errors can have exponential consequences. As quality and patient safety come into focus, identifying and preventing clinical reasoning errors have become imperative. The authors present a case of a man sent for admission from a subspecialty clinic diagnosed with infliximab-induced serum sickness. Not countering the expert's diagnosis, initial workup failed to diagnose joint abscess and sepsis. Heuristics are mental shortcuts used to make decision making more efficient but can lead to error. The anchoring heuristic, premature closure, confirmation bias and the blind obedience heuristic are examples. Introspective surveillance and interactive hypothesis testing defend against heuristics. The authors conclude by discussing 4 types of hypersensitivity reactions, serum sickness in particular, and the chimeric nature of infliximab. PMID:21273840
Guidry, Michelle M; Drennan, Robert H; Weise, Jeff; Hamm, L Lee
Sepsis has continuously been a leading cause of neonatal morbidity and mortality despite current advances in chemotherapy and patient intensive care facilities. Neonates are at high risk for developing bacterial infections due to quantitative and qualitative insufficiencies of innate immunity, particularly granulocyte lineage development and response to infection. Although antibiotics remain the mainstay of treatment, adjuvant therapies enhancing immune function have shown promise in treating sepsis in neonates. This chapter reviews current strategies for the clinical management of neonatal sepsis and analyzes mechanisms underlying insufficiencies of neutrophil defense in neonates with emphasis on new directions for adjuvant therapy development.
Melvan, John Nicholas; Bagby, Gregory J.; Welsh, David A.; Nelson, Steve; Zhang, Ping
were analyzed. Baseline characteristics of the patients are summarized in Table 1. Sixty-eight patients (37.4%) had ARF. By multivariate analysis, age more than 60 years (odds ratio (OR) 0.39, 95% confidence interval (CI) 0.17 to 0.87, P = 0.002), male (OR 5.5, 95% CI 2.2 to 13.5, P < 0.0001), chronic kidney disease (OR 0.2, 95% CI 0.06 to 0.79,
José António Lopes; Sofia Jorge; Cristina Resina; Carla Santos; Álvaro Pereira; José Neves; Francisco Antunes; Mateus Martins Prata
We investigated the relationship between illness severity and accuracy of neonatal sepsis screen. Consecutive neonates with clinically suspected early onset sepsis (EOS) were enrolled and blood culture and sepsis screen [C-reactive protein, absolute neutrophil count, immature to total ratio (ITR) and microerythrocyte sedimentation rate] were performed. Exclusion criteria were prior antibiotic exposure, nonavailable reports, and contaminated cultures. Score for Neonatal Acute Physiology Perinatal Extension (SNAPPE-II) was used to categorize neonates into "mild to moderate" (score
Mahale, Ramanath; Dutta, Sourabh; Ahluwalia, Jasmina; Kishore, Sunil Sai; Narang, Anil
Objectives:To evaluate the accuracy of serum amyloid A (SAA), an acute phase protein in the detection of neonatal early-onset sepsis, by means of a fast automated SAA kit.Study Design:Full-term infants <72 h of age, who had risk factors and\\/or were suspected of having sepsis, were eligible for study. The levels of SAA were taken at 0, 24 and 48 h
S Arnon; I Litmanovitz; R H Regev; S Bauer; R Shainkin-Kestenbaum; T Dolfin
Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS) originated from the observational work of Swedo and collaborators, who formalized their definition in 1998 in a set of operational criteria. The application of these criteria, which focuses on tics and obsessive-compulsive symptoms as core symptoms, has encountered difficulties, eventually leading to a high rate of misdiagnosis. In particular, the core feature represented by the association between newly diagnosed infections and neuropsychiatric symptom relapses in youths with this diagnosis could not be demonstrated by longitudinal studies. Exploratory studies aiming to identify clinical or cognitive features that could discriminate PANDAS from other pediatric obsessive-compulsive and tic disorders present methodological limitations, and therefore are not conclusive. Other behavioral features, in addition to obsessive-compulsive symptoms and tics, have been included in pediatric acute-onset neuropsychiatric syndromes (PANS) and childhood acute neuropsychiatric syndromes (CANS), two new concepts recently proposed in order to define a much broader clinical spectrum encompassing etiologically diverse entities. Given the uncertainties on the clinical definition of PANDAS, it is not surprising that evidence in support of a post-infectious, immune-mediated pathophysiology is also insufficient. Anti-dopamine receptor antibodies might be relevant to both Sydenham’s chorea (SC)—the prototypical post-streptococcal neuropsychiatric disorder—and some rare forms of encephalitis targeting the basal ganglia specifically, but studies exploring their association with children fulfilling Swedo’s criteria for PANDAS have been inconclusive. Moreover, we lack evidence in favor of the efficacy of antibiotic prophylaxis or tonsillectomy in patients fulfilling Swedo’s criteria for PANDAS, whereas a response to immune-mediated treatments like intravenous immunoglobulins has been documented by one study, but needs replication in larger trials. Overall, the available evidence does not convincingly support the concept that PANDAS are a well-defined, isolated clinical entity subdued by definite pathophysiological mechanisms; larger, prospective studies are necessary to reshape the nosography and disease mechanisms of post-streptococcal acute neuropsychiatric disorders other than SC. Research is also under way to shed further light on a possible relationship between streptococcal infections, other biological and psychosocial stressors, and the complex pathobiology of chronic tic disorders.
Macerollo, Antonella; Martino, Davide
Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS) originated from the observational work of Swedo and collaborators, who formalized their definition in 1998 in a set of operational criteria. The application of these criteria, which focuses on tics and obsessive-compulsive symptoms as core symptoms, has encountered difficulties, eventually leading to a high rate of misdiagnosis. In particular, the core feature represented by the association between newly diagnosed infections and neuropsychiatric symptom relapses in youths with this diagnosis could not be demonstrated by longitudinal studies. Exploratory studies aiming to identify clinical or cognitive features that could discriminate PANDAS from other pediatric obsessive-compulsive and tic disorders present methodological limitations, and therefore are not conclusive. Other behavioral features, in addition to obsessive-compulsive symptoms and tics, have been included in pediatric acute-onset neuropsychiatric syndromes (PANS) and childhood acute neuropsychiatric syndromes (CANS), two new concepts recently proposed in order to define a much broader clinical spectrum encompassing etiologically diverse entities. Given the uncertainties on the clinical definition of PANDAS, it is not surprising that evidence in support of a post-infectious, immune-mediated pathophysiology is also insufficient. Anti-dopamine receptor antibodies might be relevant to both Sydenham's chorea (SC)-the prototypical post-streptococcal neuropsychiatric disorder-and some rare forms of encephalitis targeting the basal ganglia specifically, but studies exploring their association with children fulfilling Swedo's criteria for PANDAS have been inconclusive. Moreover, we lack evidence in favor of the efficacy of antibiotic prophylaxis or tonsillectomy in patients fulfilling Swedo's criteria for PANDAS, whereas a response to immune-mediated treatments like intravenous immunoglobulins has been documented by one study, but needs replication in larger trials. Overall, the available evidence does not convincingly support the concept that PANDAS are a well-defined, isolated clinical entity subdued by definite pathophysiological mechanisms; larger, prospective studies are necessary to reshape the nosography and disease mechanisms of post-streptococcal acute neuropsychiatric disorders other than SC. Research is also under way to shed further light on a possible relationship between streptococcal infections, other biological and psychosocial stressors, and the complex pathobiology of chronic tic disorders. PMID:24106651
Macerollo, Antonella; Martino, Davide
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.
Intravenous inoculation of a group A hemolytic streptococcus caused lethal infections in all of 11 untreated monkeys. Daily intragastric administration of either 25 or 50 mg per kg per day, given in two equal morning and afternoon doses, yielded similar results in monkeys treated with cephalexin, penicillin V, and ampicillin; all eight monkeys in each therapy group survived. At dose levels of 12.5 mg per kg per day, six of eight, four of eight, and one of eight receiving cephalexin, penicillin V, and ampicillin, respectively, died. The differences observed at the lower dose level between cephalexin and ampicillin could be attributed, in part, to differences in the minimal inhibitory concentrations (MIC) of cephalexin (MIC = 0.24 ?g/ml) and ampicillin (MIC = 0.01 ?g/ml). The differences in results between penicillin V, which had the same MIC as ampicillin, could perhaps be attributed, in part, to shorter duration of antibacterial activity and higher protein binding of penicillin V. These studies support previous observations that cephalexin at 25 to 50 mg/kg doses is effective in severe streptococcal sepsis in monkeys.
Saslaw, Samuel; Carlisle, Harold N.
Streptococcus equi subspecies zooepidemicus infection is rare in humans, but a well-known cause of pyogenic disease in cows and horses. S. zooepidemicus uncommonly causes post-strep glomerulonephritis (PSGN) in humans via epidemic outbreaks. We present a sporadic case of post S. zooepidemicus glomerulonephritis in a child most probably contracted from a horse. The 14-year-old girl presented with the typical signs of PSGN, with S. equi zooepidemicus isolated from a blood culture, together with a low C3 and raised anti-DNAse B. This is the first known report of a sporadic case of PSGN in a child caused by this organism. PMID:17109135
Thorley, Anna M; Campbell, David; Moghal, Nadeem E; Hudson, Sue
Sepsis has been around since the dawn of time, having been described for more than 2000 years, although clinical definitions are recent. The consensus sepsis definitions have permitted worldwide epidemiological studies of sepsis to be conducted. We now recognize the common nature of sepsis and the consistency of its disease – particularly severe sepsis and septic shock. The incidence of sepsis, severe sepsis and septic shock continues to increase, and although Gram-positive bacterial pathogens remain the most common cause of sepsis, fungal organisms are increasing rapidly. We have made progress over the past half-century in identifying and treating patients with sepsis, and decreasing fatality rates reflect this progress. However, owing to the increasing incidence of sepsis, the number of people who die each year continues to increase. The mortality with sepsis, particularly related to treating organ dysfunction, remains a priority to clinicians worldwide and is deserving of greater public health attention.
Martin, Greg S
Purified pyrogenic exotoxin from Group A streptococcal filtrates (Streptococcus pyogenes, type 10, strain NY-5) has been characterized primarily as a protein complexed with hyaluronic acid. Amino acid composition and analysis revealed a typical acidic protein with an average molecular weight of 29,000. The purified exotoxin was free of streptolysins O and S, nicotinamide adenine dinucleotidases (NADases), deoxyribonucleases (DNases), mucopeptide, and endotoxins. The biological activity was destroyed when the exotoxin was heated at 65°C for 30 min or boiled for 2 min. The biological activities investigated were pyrogenicity in rabbits (minimal pyrogenic dose-3 hr, 0.07 µg/kg), lethality in rabbits (LD50, 3500 µg/kg), skin test dose in human skin (> 109 skin test doses, per mg toxin), cytotoxicity of rabbit spleen macrophage (Cytotoxic Index 0.5–10 µg/ml), enhancement of susceptibility to endotoxin shock (in rabbits > 100,000-fold), and antigenic analysis (A-type toxin). The exotoxin was immunogenic and it was possible, therefore, to immunize animals against the various toxic activities. The immunity was specific for the A-type toxin. The clinical implications of the highly significant enhancement effect of these exotoxins are discussed. It is suggested that clinical or subclinical infection with Group A streptococci could prepare the host for fatal shock from Gram-negative infections or the inadvertent injection of small amounts of Gram-negative bacterial endotoxins.
Kim, Yoon Berm; Watson, Dennis W.
The M1 serotype of Streptococcus pyogenes plays an important role in streptococcal toxic shock syndrome. Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to inhibit streptococcal M1 protein-induced acute lung damage, although downstream mechanisms remain elusive. Protein isoprenylation, such as farnesylation and geranylgeranylation, has been suggested to regulate anti-inflammatory effects exerted by statins. Here, we examined the effect of a farnesyltransferase inhibitor (FTI-277) on M1 protein-triggered lung inflammation. Male C57BL/6 mice were treated with FTI-277 prior to M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema, and CXC chemokine formation. Flow cytometry was used to determine Mac-1 expression on neutrophils. The gene expression of CXC chemokines was determined in alveolar macrophages by using quantitative reverse transcription (RT)-PCR. We found that the administration of FTI-277 markedly decreased M1 protein-induced accumulation of neutrophils, edema formation, and tissue damage in the lung. Notably, inhibition of farnesyltransferase abolished M1 protein-evoked production of CXC chemokines in the lung and gene expression of CXC chemokines in alveolar macrophages. Moreover, FTI-277 completely inhibited chemokine-induced neutrophil migration in vitro. However, farnesyltransferase inhibition had no effect on M1 protein-induced expression of Mac-1 on neutrophils. Our findings suggest that farnesyltransferase is a potent regulator of CXC chemokine formation in alveolar macrophages and that inhibition of farnesyltransferase not only reduces neutrophil recruitment but also attenuates acute lung injury provoked by streptococcal M1 protein. We conclude that farnesyltransferase activity is a potential target in order to attenuate acute lung damage in streptococcal infections.
Zhang, Songen; Rahman, Milladur; Zhang, Su; Jeppsson, Bengt; Herwald, Heiko
There are several diseases associated with group A beta hemolytic streptococcal infection; the two most common are acute rheumatic fever (ARF) and poststreptococcal reactive arthritis (PsRA). Epidemiological and clinical data for both diseases are described, as well as current recommendations for treatment and prevention. There is an ongoing debate as to whether these two are different diseases or are parts of the spectrum of the same disease. There are some reports of carditis developing after PsRA, suggesting that PsRA may be part of the spectrum of ARF. However, since there are substantial clinical, immunological, and genetic differences between PsRA and ARF, we believe PsRA to be a distinct entity. PMID:23568568
The incidence of sepsis caused by transfusion of bacterially contaminated blood components is similar to or less than that of transfusion-transmitted hepatitis C virus infection, yet significantly exceeds those currently estimated for transfusion-associated human immunodeficiency and hepatitis B viruses. Outcomes are serious and may be fatal. In addition, transfusion of sterile allogenic blood can have generalized immunosuppressive effects on recipients, resulting in increased susceptibility to postoperative infection. This review examines the frequency of occurrence of transfusion-associated sepsis, the organisms implicated, and potential sources of bacteria. Approaches to minimize the frequency of sepsis are discussed, including the benefits and disadvantages of altering the storage conditions for blood. In addition, the impact of high levels of bacteria on the gross characteristics of erythrocyte and platelet concentrates is described. The potentials and limitations of current tests for detecting bacteria in blood are also discussed.
Wagner, S J; Friedman, L I; Dodd, R Y
The application of methycycline in treatment of the experimental models of acute streptococcal sepsis and acute staphylococcal penumonia gives good results. A new water-soluble tetracycline derivative was obtainted - methycycline. Methycycline was effecti...
A. V. Guzeeva M. D. Paikin
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. PMID:23971020
Servillo, Giuseppe; Vargas, Maria; Pastore, Antonio; Procino, Alfredo; Iannuzzi, Michele; Capuano, Alfredo; Memoli, Andrea; Riccio, Eleonora; 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
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
The histone-like protein (HlpA) is highly conserved among streptococci. After lysis of streptococci in infected tissues, HlpA can enter the bloodstream and bind to proteoglycans in the glomerular capillaries of kidneys, where it can react with antibodies or stimulate host cell receptors. Deposits of streptococcal antigens in tissues have been associated with localized acute inflammation. In this study, we measured the ability of purified HlpA (5 to 100 ?g/ml), from Streptococcus mitis, to induce the production of proinflammatory cytokines by cultured, murine peritoneal macrophages. The release of tumor necrosis factor alpha (TNF-?) and interleukin-1 (IL-1) was time and concentration dependent and was not diminished by the presence of polymyxin B. Exposure of macrophages to a mixture of HlpA and lipoteichoic acid resulted in a synergistic response in the production of both TNF-? and IL-1. Stimulation with a mixture of HlpA and heparin resulted in reduced cytokine production (50% less IL-1 and 76% less TNF-?) compared to that by cells incubated with HlpA alone. The inclusion of antibodies specific to HlpA in macrophage cultures during stimulation with HlpA did not affect the quantity of TNF-? or IL-1 produced. These observations suggest that streptococcal histone may contribute to tissue injury at infection sites by promoting monocytes/macrophages to synthesize and release cytokines that initiate and exacerbate inflammation. Streptococcus pyogenes, which can infect tissues in enormous numbers, may release sufficient amounts of HlpA to reach the kidneys and cause acute poststreptococcal glomerulonephritis.
Zhang, Liping; Ignatowski, Tracey A.; Spengler, Robert N.; Noble, Bernice; Stinson, Murray W.
Sepsis is a common complication of gastric operations, particularly in hypochlorhydric patients such as those with gastroesophageal carcinoma, gastric ulcer, or if revision gastric surgery is required for bile gastritis. By contrast, the risks of sepsis are small for patients with a duodenal ulcer having a proximal gastric vagotomy. The risks of endogenous sepsis are determined by the preoperative bacterial
T. J. Muscroft; S. A. Deane
INTRODUCTION: Angiotensin II (Ang II) is a potential vasopressor treatment for hypotensive hyperdynamic sepsis. However, unlike other vasopressors, its systemic, regional blood flow and renal functional effects in hypotensive hyperdynamic sepsis have not been investigated. METHODS: We performed an experimental randomised placebo-controlled animal study. We induced hyperdynamic sepsis by the intravenous administration of live E. coli in conscious ewes after
Li Wan; Christoph Langenberg; Rinaldo Bellomo; Clive N May
Interactions between complementary protein and carbohydrate structures on different genera of human oral bacteria have been implicated in the formation of dental plaque. The carbohydrate receptor on Streptococcus sanguis H1 that is specific for the adhesion on Capnocytophaga ochracea ATCC 33596 has been isolated from the streptococcal cell wall, purified, and structurally characterized. The hexasaccharide repeating unit of the polysaccharide was purified by reverse-phase, amino-bonded silica, and gel permeation high performance liquid chromatography. Earlier studies established that the repeating unit was a hexasaccharide composed of rhamnose, galactose, and glucose in the ration of 2:3:1, respectively. In the present study, determination of absolute configuration by gas chromatography of the trimethylsilyl (+)-2-butyl glycosides revealed that the rhamnose residues were of the L configuration while the hexoses were all D. 252Californium plasma desorption mass spectrometry of the native, the acetylated and the reduced and acetylated hexasaccharide determined that the molecular mass of the native hexasaccharide was 959, and that the 2 rhamnose residues were linked to each other at the nonreducing terminus of the linear molecule. Methylation analysis revealed the positions of the glycosidic linkages in the hexasaccharide and showed that a galactose residue was present at the reducing end. The structural characterization of the hexasaccharide was completed by one and two dimensional 1H and 13C NMR spectroscopy. Complete 1H and 13C assignments for each glycosyl residue were established by two-dimensional (1H,1H) correlation spectroscopy, homonuclear Hartmann-Hahn, and (13C,1H) correlation experiments. The configurations of the glycosidic linkages were inferred from the chemical shifts and coupling constants of the anomeric 1H and 13C resonances.
Cassels, F.J.; Fales, H.M.; London, J.; Carlson, R.W.; van Halbeek, H. (National Institute of Dental Research, Bethesda, MD (USA))
Streptococcal evolution has been shaped by human history, social change and microbial selection. Streptococci with pathogenicity for people likely diversified within the last 5–10,000 years, jumping from animal hosts to infect the larger aggregations of people seen in towns and cities following the rise of agriculture. Streptococci are subject to continuing selection through changes in population immunity, hygiene, living conditions,
John D. Mathews
Rabbit antibodies to streptococcal polysaccharide are described which show selectivity of expression of the allotypic specificities on both the heavy (H) and light (L) chains. One of these antibodies binds weakly to Sephadex. A purification method based on this binding has yielded antibody completely lacking any group a allotypic marker on its H chains.
Kindt, Thomas J.; Todd, Charles W.; Eichmann, Klaus; Krause, Richard M.
One of the major obstacles to the development of group A streptococcal M protein vaccines is the multiplicity of M serotypes expressed by these organisms. In this study, we have constructed a recombinant, hybrid M protein that contains type-specific aminoterminal fragments of eight different M proteins. We show that the purified hybrid recombinant protein is immunogenic in rabbits and evokes
James B. Dale; Matthew Simmons; Elbert C. Chiang; Edna Y. Chiang
Premature triplets each developed late onset group B streptococcal disease over a period of nine weeks. The source of the organism appeared to be expressed maternal breast milk, in the absence of clinical mastitis. Asymptomatic excretion of group B streptococcus in breast milk may be an under-recognised cause of neonatal infection.??
Olver, W.; Bond, D.; Boswell, T.; Watkin, S.
Objective. To determine the clinical epidemiology of invasive group A streptococcal disease (IGASD) and identify predictors of admissions into an intensive care unit (ICU). Design. A cross-sectional study. Setting. Retrospective review of data. Patients. A total of 204 patients hospitalized throughout the state of Florida, United States, between August 1996 and August 2000 for IGASD. Intervention. None. Measurements and results.
Zuber D. Mulla
More than one million neonatal deaths every year in the world are attributable to infection. In nurseries, infections occur with a reported incidence of 0.3-3%; in Neonatal Intensive Care Units (NICUs) the reported incidence is 7-24.5%, and up to 40% in newborns with birth weight less than 1000 g or gestational age at birth <28 weeks. Sepsis is the most severe and frequent infection, accounting for 45-55% of all infections. Several practices have been demonstrated to be effective in reducing the incidence of infection in NICUs, including hand hygiene practices, correct management of central venous catheters (CVC), accurate diagnostic strategies and correct use of antimicrobial drugs. Despite the reduction in the incidence of infection after implementation of these practices, nosocomial infections are still a relevant problem, with high mortality and morbidity rates in hospitalized newborns, especially preterm newborns. Searching for new strategies to further reduce the incidence of nosocomial sepsis in NICUs is a priority of clinical research. New and promising strategies for the prevention of nosocomial infection in NICU include: lactoferrin administration, early identification of infants at risk of infection by means of specific markers (e.g. mannose binding lectin), heparin use for the prevention of CVC-related infections, judicious use of antibiotics, and prevention of fungal sepsis with antifungal agents. On the contrary, recent studies demonstrated that the use of specific immunoglobulins directed against different staphylococcal antigens is not effective in preventing neonatal sepsis. PMID:23422580
Stronati, M; Bollani, L; Maragliano, R; Ruffinazzi, G; Manzoni, P; Borghesi, A
In this article, the mechanism of technetium, gallium, and indium-labeled white blood cell localization in septic processes is detailed, and the method of interpretation of these three isotopes with relationship to musculoskeletal infection is outlined. Specific clinical application of technetium, gallium, and indium-labeled white blood cell imaging for musculoskeletal sepsis is reviewed.
Merkel, K.D.; Fitzgerald, R.H. Jr.; Brown, M.L.
Sepsis continues to pose a clear challenge as one of the most difficult and costly problems to treat and prevent. Sepsis is caused by systemic or localized infections that damage the integrity of microcirculation in multiple organs. The challenge of sepsis and its long-term sequelae was addressed by the National Institutes of Health National Heart Lung and Blood Institute Division of Blood Diseases and Resources. Defining sepsis as severe endothelial dysfunction syndrome that causes multiorgan failure in response to intravascular or extravascular microbial agents, the National Heart Lung and Blood Institute panel proposed the concept of genome wars as a platform for new diagnostic, therapeutic, and preventive approaches to sepsis.
Background: The use of invasive devices and broad spectrum antibiotics has increased the rate of candidal superinfections.Candida sepsis associated with pregnancy is rare. Candida sepsis following chorionic villi sampling (CVS) has never been reported. Case: A 31-year-old pregnant woman presented with signs of sepsis one day after undergoing transcervical CVS. Blood culture and curettage material yielded C. albicans. She was treated with 400 mg of fluconazole daily for 4 weeks and completely recovered. Conclusion: Candida sepsis should be considered in the differential diagnosis of sepsis following CVS.
Paz, Alona; Gonen, Roni
Severe sepsis and septic shock have long been a challenge in intensive care because of their common occurrence, high associated costs of care, and significant mortality. The Surviving Sepsis Campaign (SSC) was developed in an attempt to address clinical inertia in the adoption of evidence-based strategies. The campaign relies on worldwide support from professional societies and has gained consensus on the management of patients with severe sepsis. The guidelines have subsequently been deployed into two bundles, with each bundle component sharing a common relationship in time. The widespread adoption of such evidence-based practice in clinical care has been disappointingly slow despite the quantifiable benefits regarding mortality. In Brazil, a country of continental dimensions with a heterogeneous population and unequal access to health services, this reality is no different. From 2004 to 2007, four prospective studies were published describing the country's reality. In the multicenter Promoting Global Research Excellence in Severe Sepsis (PROGRESS) Study, the in-hospital mortality rate was higher in Brazil when compared with other countries: 56% against 30% in developed countries and 45% in other developing countries. During these 2.5 years of the campaign in Brazil, 43 hospitals have been receiving the necessary training to put in practice the recommended measures in all Brazilian regions, except for the North. The idea of the campaign is based on a 25% reduction in the relative risk of death from severe sepsis and septic shock within 5 years in the SSC-participating Brazilian hospitals. Ideally, the mortality rate should come to a 41.2% level subject to the 2009 deadline. This article aims to describe the actual scenario of the SSC implementation in Brazilian institutions and to report on some initiatives that have been used to overcome barriers. PMID:18704009
Teles, José Mário Meira; Silva, Eliezer; Westphal, Glauco; Filho, Rubens Costa; Machado, Flavia Ribeiro
Models of sepsis have been instructive in understanding the sequence of events in animals and, to an extent, in humans with sepsis. Events developing early in sepsis suggest that a hyperinflammatory state exists, accompanied by a buildup of oxidants in tissues reflective of a redox imbalance. Development of immunosuppression and degraded innate and adaptive immune responses are well-established complications of sepsis. In addition, there is robust activation of the complement system, which contributes to the harmful effects of sepsis. These events appear to be associated with development of multiorgan failure. The relevance of animal models of sepsis to human sepsis and the failure of human clinical trials are discussed, together with suggestions as to how clinical trial design might be improved.
Ward, Peter A
Background The major virulence factors determining the pathogenicity of streptococcal strains include M protein encoded by emm and emm-like (emmL) genes and superantigens. In this study, the distribution of emm, emmL and superantigen genes was analyzed among the streptococcal strains isolated from the patients of acute pharyngitis. Methods The streptococcal strains were isolated from the throat swabs of 1040 patients of acute pharyngitis. The emm and emmL genes were PCR amplified from each strain and sequenced to determine the emm types. The dot-blot hybridization was performed to confirm the pathogens as true emm nontypeable strains. The presence of eleven currently known superantigens was determined in all the strains by multiplex PCR. Results Totally, 124 beta-hemolytic streptococcal strains were isolated and they were classified as group A streptococcus (GAS) [15.3% (19/124)], group C streptococcus (GCS) [59.7% (74/124)] and group G streptococcus (GGS) [25.0% (31/124)]. Among 124 strains, only 35 strains were emm typeable and the remaining 89 strains were emm nontypeable. All GAS isolates were typeable, whereas most of the GCS and GGS strains were nontypeable. These nontypeable strains belong to S. anginosus [75.3% (67/89)] and S. dysgalactiae subsp. equisimilis [24.7% (22/89)]. The emm and emmL types identified in this study include emm12.0 (28.6%), stG643.0 (28.6%), stC46.0 (17.0%), emm30.11 (8.5%), emm3.0 (2.9%), emm48.0 (5.7%), st3343.0 (2.9%), emm107.0 (2.9%) and stS104.2 (2.9%). Various superantigen profiles were observed in typeable as well as nontypeable strains. Conclusions Multiplex PCR analysis revealed the presence of superantigens in all the typeable strains irrespective of their emm types. However, the presence of superantigen genes in emm and emmL nontypeable strains has not been previously reported. In this study, presence of at least one or a combination of superantigen coding genes was identified in all the emm and emmL nontypeable strains. Thus, the superantigens may inevitably play an important role in the pathogenesis of these nontypeable strains in the absence of the primary virulence factor, M protein.
Severe sepsis is associated with early release of inflammatory mediators that contribute to the morbidity and mortality observed during the first stages of this syndrome. Although sepsis is a deadly, acute disease, high mortality rates have been observed in patients displaying evidence of sepsis-induced immune deactivation. Although the contribution of experimental models to the knowledge of pathophysiological and therapeutic aspects of human sepsis is undeniable, most of the current studies using animal models have focused on the acute, proinflammatory phase. We developed a murine model that reproduces the early acute phases but also the long-term consequences of human sepsis. We induced polymicrobial acute peritonitis (AP) by establishing a surgical connection between the cecum and the peritoneum, allowing the exit of intestinal bacteria. Using this model, we observed an acute phase with high mortality, leukopenia, increased interleukin-6 levels, bacteremia, and neutrophil activation. A peak of leukocytosis on day 9 or 10 revealed the persistence of the infection within the lung and liver, with inflammatory hepatic damage being shown by histological examination. Long-term (20 days) derangements in both innate and adaptive immune responses were found, as demonstrated by impaired systemic tumor necrosis factor alpha production in response to an inflammatory stimulus; a decreased primary humoral immune response and T cell proliferation, associated with an increased number of myeloid suppressor cells (Gr-1+ CD11b+) in the spleen; and a low clearance capacity. This model provides a good approach to attempt novel therapeutic interventions directed to augmenting host immunity during late sepsis.
Barrera, Gabriela; Landoni, Veronica; Martire-Greco, Daiana; Chiarella, Paula; Meiss, Roberto; Gomez, Sonia A.; Alves-Rosa, Fernanda; Rearte, Barbara; Isturiz, Martin; Palermo, Marina S.; Fernandez, Gabriela C.
Chromobacterium violaceum sepsis is extremely rare and usually fatal. A very few cases of C. violaceum infection have been reported from Africa, but never from South Africa. As far as could be ascertained, this infection has never been reported in a patient with leukaemia. We describe what we believe to be the first such case of C. violaceum sepsis, in a 16-year-old female patient with acute biphenotypic leukaemia, which developed during the neutropenic phase after intensive chemotherapy. The infection was due to a non-pigmented strain of C. violaceum and was associated with a co-infection with Candida parapsilosis; both were successfully treated using broad-spectrum antibiotics, antifungals and removal of a Hickman line. PMID:18809561
Bosch, F J; Badenhorst, L; Le Roux, J A; Louw, V J
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
Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction due to a systemic response to infection. We report the case of a 4-year-old girl with fever and vomiting for 48h, brought to the university hospital of Grenoble because of vigilance disorders, loss of verbal fluency, and a cerebellar syndrome. She had a biological infectious syndrome. Infectious encephalitis was suggested first, but the cerebral scan and the lumbar punction were normal. Magnetic resonance imaging (MRI) showed a diffuse brain edema with extended involvement of cortical and basal ganglia. The electroencephalogram was globally slow. The infectious syndrome was explained by perforated appendicitis with peritonitis, treated by surgery and antibiotic therapy. Other infectious explorations were negative. No metabolic or autoimmune diseases were found. Hence, our final diagnosis was sepsis-associated encephalopathy. After 1 year of follow-up care, her clinical exam, MRI, and EEG were normal. Sepsis-associated encephalopathy has been increasingly described in the adult population, but until today only three pediatric cases have been published. It is diagnosed when the patient has a severe infectious syndrome associated with neurologic symptoms, mostly vigilance or consciousness disorders, no signs of shock, and only when other potential reasons have been ruled out. The MRI shows non-specific diffuse lesions with vasogenic edema on the subcortical substance or on the basal ganglia and the thalami. The electroencephalogram is slowed down on the whole. The main differential diagnoses are infectious encephalitis, acute disseminated encephalomyelitis, and cerebral vasculitis. Posterior reversible encephalopathy syndrome is an MRI diagnosis that presents characteristics similar to SAE. In the future, it could be discovered that it is the same physiopathology. At the moment, we only treat the symptoms and the causative infection. Most of the time, patients have neurologic sequelae that affect their verbal fluency. It can persist from a few months up to 6yrs. Although quite slow, the neurologic progression is good. The mechanisms are studied and there are hopes for specific treatments. The main explanation seems to be immune with alterations of the blood-brain barrier. Cytokines and activated leukocytes may attack the cerebral substance. PMID:23953625
Chacqueneau, A-L; Desrumaux-Becquet, A; Debillon, T; Nguyen, M-A; Bessaguet, S; Bost-Bru, C; Leroy, P; Wroblewski, I
Objective To evaluate whether a relation exists between volume and outcome for admissions with severe sepsis to adult general critical care units in the United Kingdom. Design Retrospective cohort study using data from a pooled case mix and outcome database. Setting Adult general critical care units participating in the case mix programme. Participants Consecutive admissions to participating units for the years 2008-09 meeting objective, standardised criteria for severe sepsis. Main outcome measures Mortality at ultimate discharge from acute hospital. Results The primary exposure was volume of admissions with severe sepsis per unit per year. A multivariable logistic regression analysis, using generalised estimating equations, was used to assess the association between volume, modelled using fractional polynomials, and ultimate acute hospital mortality while adjusting for potential confounders. No relation was seen between volume and outcome for admissions with severe sepsis to adult, general critical care units in the UK. Subgroup analyses tested for interactions between the effect of volume and acute severity of illness or receipt of mechanical ventilation. No significant interactions were found. Conclusions This study showed no relation between volume and outcome in admissions with severe sepsis treated in adult general critical care units in the UK.
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
Absence of the spleen or splenic function predisposes individuals to risk of overwhelming infection. These infections are most often due to encapsulated organisms, especially pneumococcus, Haemophilus influenzae type b, and meningococcus, but any bacterial agent may cause the rapid onset of septicemia, meningitis, pneumonia, and shock characteristic of the asplenic-hyposplenic condition. The risk is greatest in infants and young children, but asplenic-hyposplenic adults also have an increased risk of infection. Prophylactic antibiotics and immunization with polyvalent pneumococcal, H. influenzae type b, and meningococcal vaccines have reduced the incidence of infections in asplenic-hyposplenic individuals, but even these measures have not eliminated the risk. Surgeons have adopted techniques to save as much splenic tissue as possible and some splenic functions, such as pitting red cells, have been preserved, but conservative surgery has not provided total protection against overwhelming infection. Therapies designed to interrupt the cascade of overwhelming sepsis have not yet been successful. In those cases in which the spleen is surgically removed, the underlying disease or condition leading to splenectomy influences the risk of sepsis. Splenectomy incidental to other operations, such as gastrectomy, results in the lowest risk for overwhelming infection, but this is still some 35-fold greater than the risk for overwhelming infections in the general population. In increasing order of risk, the other main indications for surgical removal of the spleen are idiopathic thrombocytopenia purpura, trauma, transplantation procedures, hereditary spherocytosis, staging Hodgkin's disease, portal hypertension with hypersplenism, and thalassemia. Pathologists should comment on the risk of overwhelming sepsis when spleens are processed as surgical specimens, and should carefully weigh all splenic tissue, including accessory spleens and splenic implants (splenosis), in autopsy cases with and without overwhelming sepsis. PMID:11178626
Hansen, K; Singer, D B
Intravenous immunoglobulins (IVIG) use in the management of streptococcal toxic shock syndrome remains highly controversial. To evaluate the current management of severe group A streptococcal infections and the feasibility of a randomized controlled trial comparing immunoglobulins versus placebo for streptococcal toxic shock syndrome and/or necrotizing fasciitis, a 32-question mail and web-based survey of Canadian infectious disease specialists was conducted between December 2003 and February 2004. Overall, 172 respondents (90.5%) recommended immunoglobulins as adjunctive treatment of streptococcal toxic shock compared to 67 (35.3%) for fasciitis without toxic shock and 93 (48.9%) for invasive group A streptococcal infections with hypotension. A considerable proportion of respondents agreed that a randomized clinical trial in streptococcal toxic shock (70.1%, 131/187) and necrotizing fasciitis without toxic shock (88.2%, 162/186) would be ethical. From these, a great majority would be willing to enroll patients in a trial comparing IVIG to placebo for streptococcal toxic shock (125/131, 95.4%) and necrotizing fasciitis without shock (152/162, 93.8%). These initial results clearly demonstrate ambivalence in the utilization of intravenous immunoglobulins (IVIG) in invasive group A streptococcal infections in Canada and emphasize the need for further clinical data on immunoglobulin use in streptococcal toxic shock syndrome. They also demonstrate that, although the majority of physicians recommend immunoglobulins, there is important variability between physician recommendations with regard to the indications of use, dose, and time of administration. PMID:17148064
Valiquette, L; Low, D E; Chow, R; McGeer, A J
Advances in intensive care and antibiotics have prevented the spread of some infections, though sepsis mortality rates remain high. With failure of over thirty clinical trials, sepsis remains a scientific and clinical challenge in modern medicine. Sepsis is defined by the clinical signs of a systemic inflammatory response to infection. “Severe sepsis” is when these symptoms are associated with multiple organ dysfunction. These definitions of sepsis may be too broad and common to heterogeneous groups of patients who do not necessarily have the same disorder. This consideration has become especially evident in the clinical trials that have failed to obtain consistent results in similar studies of patients diagnosed with severe sepsis. In these trials, patients with infections caused by different microorganisms, and affecting different organs, have been combined under the general diagnosis of severe sepsis. The situation is analogous to attempting a clinical trial based on the general definition of cancer, combining all patients with tumor independent of the type of malignancy. In this consideration, it would not be very surprising that activated protein C, the only treatment in sepsis approved by the Food and Drug Administration, is projected for use in only a small subset of patients with severe sepsis. This article reviews novel inflammatory molecular aspects and the experimental anti-inflammatory strategies for sepsis, as they may represent particular pathological processes in specific subsets of patients.
Ulloa, Luis; Brunner, Michael; Ramos, Laura; Deitch, Edwin A.
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 lung injury (ALI) and the acute respiratory distress syndrome (ARDS) remain common complications of sepsis. Unfortunately, development of effective pharmacologic and ventilatory treatment strategies for sepsis-induced ALI/ARDS has not made significant progress over the past several decades. One of the major reasons for this conundrum involves the animal models used as platforms for testing new treatment strategies. High-fidelity, clinically translational, large animal models are essential for developing treatments that will ultimately be successful in human clinical trials. Additionally, treatment strategies purely based on pharmacologic intervention are largely destined for failure as the redundancies in the systemic inflammatory response largely negate the effectiveness of a single-action drug. Conversely, a treatment strategy based on the appropriate use of mechanical ventilation affects lung physiology on a breath-to-breath basis and has the potential to treat, and even prevent, the ALI/ARDS associated with sepsis. PMID:22114967
Sadowitz, Benjamin; Roy, Shreyas; Gatto, Louis A; Habashi, Nader; Nieman, Gary
Bacterial infections and sepsis remain major causes of morbidity and mortality in intensive care units. The normal host response to infection is a complex process that serves to localise and control the invasion of microbes and to repair injured tissue. Local inflammatory processes are regulated through the production of cytokines by macrophages. In some cases, mediator release exceeds the boundaries of the local environment and results in the development of sepsis. It is well known that the innate immune system plays a crucial role in preventing microbial invasion. The human innate immune system consists of genetically programmed defence mechanisms that are directed against molecular components found only in microorganisms. Understanding the complexity of early response to infection with respect to innate immune response is required for the future development of drugs that will effectively control infectious diseases. PMID:23348491
Jedynak, Monika; Siemi?tkowski, Andrzej; Rygasiewicz, Karolina
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.
Actinomyces neuii belongs to the coryneform bacteria. In the case presented here this gram-positive rod had to be considered the pathogen causing\\u000a not only the chorioamnionitis but also the neonatal sepsis.\\u000a \\u000a \\u000a \\u000a Conventional therapeutic regimes are effective due to the high sensitivity of A. neuii to ?-lactam antibiotics.
C. Mann; S. Dertinger; G. Hartmann; R. Schurz; B. Simma
Purpose of the review Non-invasiveness and instantaneous diagnostic capability are prominent features of the use of echocardiography in critical\\u000a care. Sepsis and septic shock represent complex situations where early hemodynamic assessment and support are among the keys\\u000a to therapeutic success. In this review, we discuss the range of applications of echocardiography in the management of the\\u000a septic patient, and propose an
Gabriele Via; Susanna Price; Enrico Storti
Stapled hemorrhoidopexy is a surgical procedure used worldwide for the treatment of grade III and IV hemorrhoids in all age groups. However, life-threatening complications occur occasionally. The following case report describes the development of pelvic sepsis after stapled hemorrhoidopexy. A literature review of techniques used to manage major septic complications after stapled hemorrhoidopexy was performed. There is no standardized treatment currently available. Stapled hemorrhoidopexy is a safe, effective and time-efficient procedure in the hands of experienced colorectal surgeons.
van Wensen, Remco JA; van Leuken, Maarten H; Bosscha, Koop
Lemierre syndrome, otherwise known as postanginal sepsis or necrobacillosis, is an illness that originates as an acute pharyngitis or tonsillitis which progresses to sepsis, usually fusobacterial, due to suppurative thrombophlebitis of the internal jugular vein. Septic thromboemboli then seed various organs, resulting in multiple organ system pathology, most commonly affecting pulmonary and hepatic systems and joints. Although rare in the
Andrea Williams; Mark Nagy; Jennifer Wingate; Luna Bailey; Mark Wax
Sepsis is a syndrome related to severe infections. It is defined as the systemic host response to microorganisms in previously sterile tissues and is characterized by end-organ dysfunction away from the primary site of infection. The normal host response to infection is complex and aims to identify and control pathogen invasion, as well as to start immediate tissue repair. Both the cellular and humoral immune systems are activated, giving rise to both anti-inflammatory and proinflammatory responses. The chain of events that leads to sepsis is derived from the exacerbation of these mechanisms, promoting massive liberation of mediators and the progression of multiple organ dysfunction. Despite increasing knowledge about the pathophysiological pathways and processes involved in sepsis, morbidity and mortality remain unacceptably high. A large number of immunomodulatory agents have been studied in experimental and clinical settings in an attempt to find an efficacious anti-inflammatory drug that reduces mortality. Even though preclinical results had been promising, the vast majority of these trials actually showed little success in reducing the overwhelmingly high mortality rate of septic shock patients as compared with that of other critically ill intensive care unit patients. Clinical management usually begins with prompt recognition, determination of the probable infection site, early administration of antibiotics, and resuscitation protocols based on “early-goal” directed therapy. In this review, we address the research efforts that have been targeting risk factor identification, including genetics, pathophysiological mechanisms and strategies to recognize and treat these patients as early as possible.
Silva, Eliezer; Passos, Rogerio Da Hora; Ferri, Mauricio Beller; de Figueiredo, Luiz Francisco Poli
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
A throat culture is necessary for accurate diagnosis of group A beta-hemolytic streptococcal tonsillopharyngitis. The use of penicillin therapy in every patient with sore throat results in overtreatment of 85 percent of children and 95 percent of adults presenting to family physicians with the complaint of sore throat. Indiscriminate use of penicillin also increases the risk of drug side effects and subjects some patients to unnecessary alterations of microbial ecology. The signs and symptoms of group A beta-hemolytic streptococcal tonsillopharyngitis are nonspecific, and reliable clinical diagnosis is difficult. Throat culture is cost-effective and, if properly obtained and processed, more than 95 percent accurate. Antigen detection tests (rapid strep tests) are a viable laboratory alternative to throat cultures if these tests are properly performed and if negative test results are confirmed with traditional throat culture. PMID:1728090
Pichichero, M E
The Surviving Sepsis Campaign is a global effort to improve the care of patients with severe sepsis and septic shock. The first Surviving Sepsis Campaign Guidelines were published in 2004 with an updated version published in 2008. These guidelines have been endorsed by many professional organizations throughout the world and come regarded as the standard of care for the management of patients with severe sepsis. Unfortunately, most of the recommendations of these guidelines are not evidence-based. Furthermore, the major components of the 6-hour bundle are based on a single-center study whose validity has been recently under increasing scrutiny. This paper reviews the validity of the Surviving Sepsis Campaign 6-hour bundle and provides a more evidence-based approach to the initial resuscitation of patients with severe sepsis.
Streptococcal impetigo associated with atopic dermatitis has dramatically increased from 1989 to 1994 in outpatients visiting our hospital, totalling 174 cases. The most frequent causative agents were group A streptococci (Streptococcus pyogenes, 70.7%) followed by group G (19.5%) and group B (9.8%). Streptococcus was isolated singly in 28.2% of cases and in concomitant with Staphylococcus aureus (S. aureus) in 71.8%.
Jun Adachi; Kaoru Endo; Takayuki Fukuzumi; Nobuko Tanigawa; Toshiyuki Aoki
Single-dose trovafloxacin (15 mg\\/kg given intravenously (i.v.)) and ampicillin (40 mg\\/kg given i.v.) protected 38 and 33% of animals challenged with an ampicillin-tolerant strain of Streptococcus oralis, respectively. As a double-dose regimen, trovafloxacin afforded total protection (100%; P < 0.001 versus controls). Trovafloxacin is the first fluoroquinolone effective in preventing experimental streptococcal endocarditis. Trovafloxacin is highly active in vitro against
I. Katsarolis; A. Pefanis; D. Iliopoulos; P. Siaperas; P. Karayiannakos; H. Giamarellou
Streptococcus pyogenes is also known as group A Streptococcus (GAS) and is an important human pathogen that causes considerable morbidity and mortality worldwide. The GAS serotype M1T1 clone is the most frequently isolated serotype from life-threatening invasive (at a sterile site) infections, such as streptococcal toxic shock-like syndrome and necrotizing fasciitis. Here, we describe the virulence factors and newly discovered
Jason N. Cole; Timothy C. Barnett; Victor Nizet; Mark J. Walker
To evaluate the effect of genetic background and toll-like receptor 2 on antibacterial defense to streptococcal infection, eight genetically diverse strains of mice (A/J, DBA/2J, CAST/Ei, FVB/NJ, BALB/cJ, C57BL/6J, 129/SvImJ, and C3H/HeJ) and tlr2-deficient mice (C57BL/6...
Abstract Background: The aim of the study was to identify the diagnostic significance of presepsin in acute abdominal conditions and also to examine the correlation between presepsin, procalcitonin (PCT) and other parameters. Methods: To detect presepsin we used a new rapid method based on a chemiluminescent enzyme immunoassay. The clinical usefulness of presepsin to differentiate bacterial and non-bacterial infection [including systemic inflammation response syndrome (SIRS)] was studied and compared with PCT, C-reactive protein (CRP) and white blood cells (WBC). Results: The presepsin values in different conditions were (mean±standard deviation): healthy group (n=70) 258.7±92.53 pg/mL; SIRS (n=30) 430.0±141.33 pg/mL; sepsis (n=30) 1508.3±866.6 pg/mL. The presepsin values were significantly higher in patients with sepsis than the SIRS group (p<0.0001, Mann-Whitney U-test). The area under the receiver operating characteristics (ROC) curve (AUC) for discriminating of the SIRS from the sepsis patients was 0.996 for presepsin and it was greater than the AUC of PCT (0.912), CRP (0.857) or WBC (0.777). Conclusions: The ROC curve of the SIRS patient without infection and the sepsis patient showed that the presepsin concentration was a significantly sensitive indicator of sepsis and useful marker for the rapid diagnosis of sepsis. PMID:23740685
Vodnik, Tatjana; Kaljevic, Goran; Tadic, Tanja; Majkic-Singh, Nada
The authors report a 29-year-old kidney transplant patient who presented, four episodes of severe hyponatraemia associated with sepsis from 2006 to 2010. He was a long-term user of marijuana. The association between severe recurrent hyponatraemia during sepsis and marijuana addiction might not be casual, since experimental data show that vasopressin release induced by sepsis is modulated by the endocannabinoid system.
Concetta Catalano; Sidy Seck; Giuseppe Enia
Streptococcus pyogenes adheres to human epithelial cells in vitro and in vivo. To identify adhesins, cell wall components were extracted from S. pyogenes M6 with alkali or by treatment with mutanolysin and lysozyme. HEp-2 cells were incubated with extracts of S. pyogenes M6 and then analyzed by Western blot (immunoblot) assays, using antibodies to S. pyogenes. Only one streptococcal component (62 kDa) was bound to HEp-2 cells and was identified serologically as M6 protein. Experiments with pepsin-cleaved fragments of M protein indicated that the binding site was located at the N-terminal half of the molecule. M protein was bound selectively to two trypsin-sensitive surface components, 97 and 205 kDa, of HEp-2 cells on nitrocellulose blots of sodium dodecyl sulfate-polyacrylamide gels. Tritium-labeled lipoteichoic acid bound to different HEp-2 cell components, 34 and 35 kDa, in a parallel experiment, indicating that lipoteichoic acid was not complexed with M protein and does not mediate M-protein binding. The four HEp-2 components were unrelated to fibronectin since they did not react with specific antibodies. An M-protein-deficient (M-) strain of streptococcus (JRS75), grown in chemically defined medium, showed 73% less adhesion activity to HEp-2 monolayers than an M+ strain (JRS4). Streptococcal adhesion was insensitive to competitive inhibition by selected monosaccharides. These results indicate that M protein binds directly to certain HEp-2 cell membrane components and mediates streptococcal adhesion. Images
Wang, J R; Stinson, M W
Streptococcal pyrogenic exotoxin type B purified from culture filtrates of either the NY-5 or T-19 strain of group A streptococcus was found to be heterogeneous in charge. Three protein fractions with isoelectric points of 8.0, 8.4, and 9.0 were isolated by differential solubility in ethanol and acetate-buffered saline followed by isoelectric focusing and shown to be antigenically identical to streptococcal pyrogenic exotoxin type B. The molecular weights of all three fractions were approximately 17,500, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, with aggregates forming in the presence of hyaluronic acid. Only the pI 8.4 fraction showed the characteristic activities of streptococcal pyrogenic exotoxin in rabbits: pyrogenicity and ability to enhance susceptibility to lethal endotoxin shock. The pI 8.0 and pI 9.0 fractions were not pyrogenic, but could be used to immunize against pyrogenicity. These two fractions failed either to enhance lethal endotoxin shock or to immunize against enhancement activity. When the isolated fractions were electrofocused again they appeared heterogeneous, suggesting an instability of the B toxin molecular forms. Images
Barsumian, E L; Cunningham, C M; Schlievert, P M; Watson, D W
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
INTRODUCTION: Infection is an important complication in cancer patients, which frequently leads to or prolongs hospitalization, and can also lead to acute organ dysfunction (severe sepsis) and eventually death. While cancer patients are known to be at higher risk for infection and subsequent complications, there is no national estimate of the magnitude of this problem. Our objective was to identify
Mark D Williams; Lee Ann Braun; Liesl M Cooper; Joseph Johnston; Richard V Weiss; Rebecca L Qualy; Walter Linde-Zwirble
The objective was to determine the efficacy of a prostaglandin B1 oligomer 16,16-dimethyl-15-dehydro-PGB1, (PGB1)3 in preventing cellular acute injury and energy failure after tissue ischemia or chronic sepsis. An additional goal was to characterize the m...
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
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.
Acute postinfectious glomerulonephritis are defined by an acute nonsuppurative inflammatory insult predominantly glomerular. Its current incidence is uncertain because of the frequency of subclinical forms. The most common infectious agent involved is beta hemolytic streptococcus group A. Acute postinfectious glomerulonephritis is uncommon in adults, and its incidence is progressively declining in developed countries. Humoral immunity plays a key role in the pathogenesis of kidney damage. Complement activation by the alternative pathway is the dominant mechanism, but a third way (lectin pathway) has been recently identified. The classic clinical presentation is sudden onset of acute nephritic syndrome after a free interval from a streptococcal infection. Treatment is essentially symptomatic and prevention is possible through improved hygiene and early treatment of infections. PMID:22483748
Ramdani, Benyounès; Zamd, Mohamed; Hachim, Khadija; Soulami, Kenza; Ezzahidy, Madiha; Souiri, Malika; Fadili, Wafaa; Lahboub, Assia; Hanafi, Leila; Boujida, Meryem; Squalli, Saida; Benkirane, Amal; Benghanem, Mohamed Gharbi; Medkouri, Ghizlane
M proteins, the major virulence factor of group A streptococci, have been implicated in the pathogenesis of acute rheumatic fever (ARF) and other streptococcal related autoimmune diseases. A 22-kD fragment of M type 5 protein is a potent stimulant of human T cells and has recently been shown by our laboratory to belong to the newly designated family of superantigens. Using flow cytometry and the polymerase chain reaction, we demonstrate that this molecule reacts with subsets of human T cells expressing specific T cell receptor (TCR) V beta elements, namely V beta 2, 4, and 8. We employed similar techniques to analyze the TCR V alpha usage of pep M5-stimulated T cells. These studies revealed that the preferential usage of particular V alpha elements is not specific for the superantigen; rather, it may reflect the repertoire of the individual being tested. The expansion of a large number of T cells bearing specific TCR V beta sequences by M protein may account for its role in mediating the pathogenesis of post- streptococcal diseases. Furthermore, the preferential usage of TCR V alpha elements in certain individuals may be an important factor that predisposes them to development of self-reactivity.
Coagglutination after enzymatic digestion is a widely used, rapid procedure for serogrouping isolated colonies of beta-hemolytic streptococci. We tried to determine whether the same procedure could be used for the detection of group A streptococcal antigen directly from swabs used to take throat samples. This was achieved by incubating the swabs immersed in a small quantity of lytic extract obtained from cultures of the Maxted strain of Streptomyces griseus and testing the supernatant fluid by coagglutination. Of 538 throat swabs tested, blindly comparing the results of conventional cultures and rapid antigen detection, both tests were negative in 480 and both were positive in 49 swabs. In six cases, culture was positive and the rapid test was negative, but only one swab was from a patient with acute pharyngitis. In three cases, cultures were negative but the rapid test showed a strongly positive reaction. No special instructions were given to the physicians taking the samples. We conclude that this rapid antigen detection test, giving results in approximately 1 h, is an economic and reliable procedure for the detection of group A streptococcal antigen directly from throat samples.
Otero, J R; Reyes, S; Noriega, A R
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
An impressive change in the epidemiology and severity of invasive group A streptococcal infections occurred in the 1980s, and the incidence of streptococcal toxic shock syndrome cases continues to rise. The reason for the resurgence of severe invasive cases remains a mystery—has there been a change in the pathogen or in host protective immunity? To address these questions, we have
HESHAM BASMA; ANNA NORRBY-TEGLUND; YAJAIRA GUEDEZ; ALLISON MCGEER; DONALD E. LOW; OMAR EL-AHMEDY; BENJAMIN SCHWARTZ; MALAK KOTB
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
Since the 1980s there has been a marked increase in the recognition and reporting of highly invasive group A streptococcal infections with or without necrotizing fasciitis associated with shock and organ failure. Such dramatic cases have been defined as streptococcal toxic-shock syndrome. Strains of group A streptococci isolated from patients with invasive disease have been predominantly M types 1 and
Dennis L. Stevens
Delayed presentation of right-sided congenital diaphragmatic hernia in association with neonatal group B streptococcal pneumonia is a recently recognized entity. Its diagnosis is based on characteristic yet nonspecific chest X-ray findings, frequently supplemented by a variety of other imaging techniques. We describe two cases in which the diagnosis was reached by ultrasound examination. In the presence of nonresolving neonatal streptococcal
D. Poenaru; J.-M. Laberge; S. Jéquier; P. W. Blanchard; D. P. Doody
Primary lymph node cells derived from streptococcal cell wall arthritic rats or those derived from adjuvant arthritic rats proliferated in response to cell wall antigens derived from either streptococcal cell walls or those from M. tuberculosis. In addition, two T cell lines have been isolated from lymph nodes of rats during the chronic phase of streptococcal cell wall arthritis. These T cell lines transfered clinical disease to naive syngeneic irradiated recipients, and they proliferated in the presence of cell wall antigens derived from streptococci or antigens derived from Mycobacterium but failed to proliferate in the presence of the 65-kD antigen (containing the sequence TFGLQLELT) derived from Mycobacterium. These observations indicate that T cells play a crucial role in the pathogenesis of streptococcal cell wall arthritis and suggest that antigenic crossreactivity exists between cell walls of group A streptococci and antigens derived from Mycobacterium. The 65-kD Mycobacterium protein is not involved in the observed antigenic crossreactivity.
Primary lymph node cells derived from streptococcal cell wall arthritic rats or those derived from adjuvant arthritic rats proliferated in response to cell wall antigens derived from either streptococcal cell walls or those from M. tuberculosis. In addition, two T cell lines have been isolated from lymph nodes of rats during the chronic phase of streptococcal cell wall arthritis. These T cell lines transfered clinical disease to naive syngeneic irradiated recipients, and they proliferated in the presence of cell wall antigens derived from streptococci or antigens derived from Mycobacterium but failed to proliferate in the presence of the 65-kD antigen (containing the sequence TFGLQLELT) derived from Mycobacterium. These observations indicate that T cells play a crucial role in the pathogenesis of streptococcal cell wall arthritis and suggest that antigenic crossreactivity exists between cell walls of group A streptococci and antigens derived from Mycobacterium. The 65-kD Mycobacterium protein is not involved in the observed antigenic crossreactivity. PMID:2502600
DeJoy, S Q; Ferguson, K M; Sapp, T M; Zabriskie, J B; Oronsky, A L; Kerwar, S S
INTRODUCTION: Consistent data about the incidence and outcome of sepsis in Latin American intensive care units (ICUs), including Brazil, are lacking. This study was designed to verify the actual incidence density and outcome of sepsis in Brazilian ICUs. We also assessed the association between the Consensus Conference criteria and outcome METHODS: This is a multicenter observational cohort study performed in
Eliézer Silva; Marcelo de Almeida Pedro; Ana Cristina Beltrami Sogayar; Tatiana Mohovic; Carla Silva; Mariano Janiszewski; Ruy Guilherme Rodrigues Cal; Érica de Sousa; Thereza Phitoe Abe; Joel de Andrade; Jorge Dias de Matos; Ederlon Rezende; Murillo Assunção; Álvaro Avezum; Patrícia CS Rocha; Gustavo Faissol Janot de Matos; André Moreira Bento; Alice Corrêa; Paulo Cesar Bastos Vieira; Elias Knobel
The microcirculatory disturbances in sepsis have prompted micropore bulk-filtration studies of red blood cell (RBC) mechanical behavior (i.e., deformability). However, these prior reports may not solely reflect RBC behavior because of possible white blood cell (WBC) occlusion of the filter pores. The present study was designed to examine RBC mechanical alterations in human and experimental sepsis using techniques that are
OGUZ K. BASKURT; DAVID GELMONT; HERBERT J. MEISELMAN
The prevention of catheter sepsis lies in a sound understanding of the routes through which catheters get contaminated. The catheter hub has been recognized as a portal for microorganisms causing catheter sepsis, particularly in central venous catheters inserted for >1 wk. Bacteria and fungi may reach the internal surface of the catheter connector during manipulation by hospital staff and then
Antonio Sitges-Serra; R. Hernández; S. Maestro; T. Pi-Suñer; José M. Garcés; M. Segura
The history of therapeutic interventions in clinical trials for sepsis has been referred to as the “graveyard for pharmaceutical companies.” That is now set to change, as research provides hope for new approaches that will be therapeutically effective in humans with sepsis.
Niels C. Riedemann; Ren-Feng Guo; Peter A. Ward
Sepsis and sepsis syndrome are leading causes of mortality throughout the world. It is widely held that sepsis represents a dysregulated innate immune response to an offending pathogen. This immune response is often initiated via microbial products signaling through TLRs expressed on host immune cells. There is increasing evidence that this innate response can be dramatically influenced by the cellular redox state, and thus a better understanding of oxidative regulation of innate immunity could lead to new treatments for sepsis. In this issue of the JCI, Thimmulappa et al. show that nuclear factor-erythroid 2-related factor 2 (Nrf2), a member of the "cap'n'collar" family of basic region-leucine zipper transcription factors, which has previously been shown to be involved in the transcription of antioxidant gene expression in response to xenobiotic stress, is also a critical regulator of cellular oxidative stress in sepsis (see the related article beginning on page 984). PMID:16585954
Kolls, Jay K
Sepsis is difficult to diagnose and remains a common mortality cause worldwide in both humans and animals. The uterine infection pyometra causes sepsis in more than half of affected dogs and therefore allows the natural physiological development of sepsis to be studied. To find a sepsis-specific biochemical marker that could be combined with conventional clinical criteria for a more robust and quick diagnosis of sepsis, we measured systemic concentrations of high-mobility group box 1 (HMGB1) in 23 healthy control dogs and in 27 dogs with pyometra, 74% of which had sepsis. We also measured concentrations of the major acute phase protein C-reactive protein (CRP) and an indicator for endotoxaemia, prostaglandin F2? metabolite (PGM) to assess the relative contribution of HMGB1 to the detection of systemic inflammation and endotoxaemia. We found that HMGB1 concentrations, in line with concentrations of CRP and PGM, were significantly increased in dogs with pyometra, and that concentrations of CRP, but not HMGB1, were significantly higher in dogs with sepsis compared to dogs without sepsis. Although serum HMGB1 did not differ between dogs with or without sepsis and was not correlated with either CRP or PGM concentrations, HMGB1 was correlated with the total white blood cell counts, suggesting an independent regulation and involvement in inflammation. PMID:24120445
Karlsson, I; Wernersson, S; Ambrosen, A; Kindahl, H; Södersten, F; Wang, L; Hagman, R
FCT region genes of Streptococcus pyogenes encode surface proteins that include fibronectin- and collagen-binding proteins and the serological markers known as T antigens, some of which give rise to pilus-like appendages. It remains to be established whether FCT region surface proteins contribute to virulence by in vivo models of infection. In this study, a highly sensitive and ecologically relevant humanized mouse model was used to measure superficial skin infection. Three genes encoding FCT region surface proteins essential for T-serotype specificity were inactivated. Both the ?cpa and ?prtF2 mutants were highly attenuated for virulence when topically applied to the skin following exponential growth but were fully virulent when delivered in stationary phase. In contrast, the ?fctA mutant was virulent at the skin, regardless of its initial growth state. Immunoblots of cell extracts revealed anti-FctA-reactive, ladder-like polymers characteristic of streptococcal pili. In addition, FctA formed a heteropolymer with the putative collagen-binding protein Cpa. The ?fctA mutant showed a loss in anti-Cpa-reactive polymers, whereas anti-FctA-reactive polymers were reduced in the ?cpa mutant. The findings suggest that both FctA and Cpa are required for pilus formation, but importantly, an intact pilus is not essential for Cpa-mediated virulence. Although it is an integral part of the T-antigen complex, the fibronectin-binding protein PrtF2 is not covalently linked to the FctA- and Cpa-containing heteropolymer derived from cell extracts. The data provide direct evidence that streptococcal T antigens function as virulence factors in vivo, but they also reveal that a pilus-like structure is not essential for the most common form of streptococcal skin disease.
Lizano, Sergio; Luo, Feng; Bessen, Debra E.
FCT region genes of Streptococcus pyogenes encode surface proteins that include fibronectin- and collagen-binding proteins and the serological markers known as T antigens, some of which give rise to pilus-like appendages. It remains to be established whether FCT region surface proteins contribute to virulence by in vivo models of infection. In this study, a highly sensitive and ecologically relevant humanized mouse model was used to measure superficial skin infection. Three genes encoding FCT region surface proteins essential for T-serotype specificity were inactivated. Both the Deltacpa and DeltaprtF2 mutants were highly attenuated for virulence when topically applied to the skin following exponential growth but were fully virulent when delivered in stationary phase. In contrast, the DeltafctA mutant was virulent at the skin, regardless of its initial growth state. Immunoblots of cell extracts revealed anti-FctA-reactive, ladder-like polymers characteristic of streptococcal pili. In addition, FctA formed a heteropolymer with the putative collagen-binding protein Cpa. The DeltafctA mutant showed a loss in anti-Cpa-reactive polymers, whereas anti-FctA-reactive polymers were reduced in the Deltacpa mutant. The findings suggest that both FctA and Cpa are required for pilus formation, but importantly, an intact pilus is not essential for Cpa-mediated virulence. Although it is an integral part of the T-antigen complex, the fibronectin-binding protein PrtF2 is not covalently linked to the FctA- and Cpa-containing heteropolymer derived from cell extracts. The data provide direct evidence that streptococcal T antigens function as virulence factors in vivo, but they also reveal that a pilus-like structure is not essential for the most common form of streptococcal skin disease. PMID:17012387
Lizano, Sergio; Luo, Feng; Bessen, Debra E
The factors present in streptococcal lesion extracts (SLE) which enhanced the lethal and tissue-damaging properties of Gram-negative bacterial endotoxins and streptolysin O were identified with the scarlet fever group of toxins. Toxic manifestations attributed to this group of toxins included lethality, cardiotoxic and other tissue damage, enhancement of toxicity, and pyrogenicity. Of these, the measurement of febrile response in American Dutch rabbits was the most useful parameter of toxicity. In rabbits, repeated daily intravenous injections of 0.125 Lf of a purified erythrogenic toxin immunizes specifically against the pyrogenic activity; this technique was used to type the toxins and to distinguish them from exogenous and endogenous pyrogens; non-specific pyrogens, such as streptococcal endotoxin, were not found in SLE. All types of the Lancefield Group A streptococci tested produced one or or more immunologically distinct toxins in vivo in contrast to Groups B and C which did not produce them; toxins A and B, previously distinguished by neutralization of rash-inducing activity in the skin, were produced in vivo. The A toxin was the most common, as indicated by its presence in extracts prepared with Types 28, 12, 17, and 10 (NY-5); B toxin was found in 10 (NY-5) and 19. A new toxin, designated C, was obtained from a Type 18. In American Dutch rabbits, purified toxin at a concentration of 15 Lf (900,000 STD) neither gave a Dick test nor prepared the skin for the local Shwartzman reaction; by this route, however, in contrast to classical endotoxins, they enhance the lethal and tissue-damaging properties of sublethal doses of these and other toxins. These properties of the immunologic distinct exotoxins as demonstrated in American Dutch rabbits suggest by analogy their importance in the pathogenesis of streptococcal disease in man. Evidence that might implicate them in sequelae, in addition to scarlet fever, is discussed.
Watson, Dennis W.
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. PMID:22707695
Moss, Helen; Collier, Jonathan Marc; Collier, Sophie
The pathogenic, diagnostic and therapeutic landscape of sepsis is no longer confined to the intensive care unit: many patients from other portals of entry to care, both outside and within the hospital, progress to severe disease. Approaches that have led to improved outcomes with other diseases (e.g., acute myocardial infarction, stroke and trauma) can now be similarly applied to sepsis. Improved understanding of the pathogenesis of severe sepsis and septic shock has led to the development of new therapies that place importance on early identification and aggressive management. This review emphasizes approaches to the early recognition, diagnosis and therapeutic management of sepsis, giving the clinician the most contemporary and practical approaches with which to treat these patients.
Rivers, Emanuel P.; McIntyre, Lauralyn; Morro, David C.; Rivers, Kandis K.
Between 1994 and 1997, sixteen patients suffering from necrotising soft tissue infection were treated at the burn centre of the Division of Reconstructive Surgery, University of Zurich. The case of a 47 year old man is presented: He suffered from a necrotising fasciitis caused by Streptococcal induced Toxic Shock Syndrome (STSS). This example emphasizes the necessity of early diagnosis, priority of surgical intervention, and the antibiotic strategy. Necrotising fasciitis is a serious disease, caused by a variety of bacteria, which shows a high mortality rate, and its frequency was increasing over the last years. PMID:12073187
Wedler, V; Meuli-Simmen, C; Künzi, W; Giovanoli, P; Meyer, V E
To evaluate the effect of genetic background on antibacterial defense to streptococcal infection, eight genetically diverse\\u000a strains of mice (A\\/J, DBA\\/2J, CAST\\/Ei, FVB\\/NJ, BALB\\/cJ, C57BL\\/6J, 129\\/SvImJ, and C3H\\/HeJ) and tlr2-deficient mice (C57BL\\/6tlr2?\\/?) were infected with three doses of Streptococcus zooepidemicus (500, 5,000, or 50,000 colony-forming units) by alveolar challenge. There was a range of susceptibility between the strains\\u000a at each dose
John W. Hollingsworth; Gregory Whitehead; Katherine Gray Berman; Erin McElvania Tekippe; M. Ian Gilmour; Jennie E. Larkin; John Quackenbush; David A. Schwartz
The aim of this study was to set accurate and reliable methods in the identification of streptococcal, enterococcal and staphylococcal species. Micro CSB Strep and Staph system consists each of a strip with cupules containing dehydrated substrates for biochemical identification of bacterial species. Baye's theorem was used to validate tests. Reactions from micromethods were clear and easily read. Identification of 229 strains of streptococci and enterococci was correct for most species with 98.7% species with 99.3% sensitivity. 41 strains of staphylococci were also correctly identified with 85.2% of specificity and 97.68% of sensitivity. PMID:10797992
Gassama, A; Boye, C S; Ndao, S K; Kairé, O; Coly, I; Macondo, E A; Sow, A I; Diaw, L; Diop-Diop, M; Mboup, S
Can C-reactive protein, procalcitonin and mid-regional pro-atrial natriuretic peptide measurements guide choice of in-patient or out-patient care in acute pyelonephritis? Biomarkers In Sepsis (BIS) multicentre study.
Whereas C-reactive protein (CRP), procalcitonin (PCT) and mid-regional pro-atrial natriuretic peptide (ANP) may be of use at the bedside in the management of adult patients with infectious disorders, their usefulness has not been established in the setting of acute pyelonephritis. To assess the effectiveness of CRP, PCT and ANP measurements in guiding emergency physicians' decisions whether to admit to hospital patients with acute pyelonephritis, we conducted a multicentre, prospective, observational study in 12 emergency departments in France; 582 consecutive patients were included. The reference standard for admission was defined by experts' advice combined with necessity of admission or death during the 28-day follow-up. Baseline CRP, PCT and ANP were measured and their accuracy in identifying the necessity of admission was analysed using area under curves (AUC) of receiver-operating characteristic (ROC) plots. According to the reference standard, 126 (22%) patients required admission. ANP (AUC 0.75, 95% CI 0.69-0.80) and PCT (AUC 0.75, 95% CI 0.71-0.80) more accurately predicted this than did CRP (AUC 0.69, 95% CI 0.64-0.74). The positive and negative likelihood ratios for each biomarker remained clinically irrelevant whatever the threshold. Our results did not support the use of these markers to help physicians in deciding about admission of patients experiencing acute pyelonephritis in daily practice. PMID:19747215
Claessens, Y-E; Schmidt, J; Batard, E; Grabar, S; Jegou, D; Hausfater, P; Kierzek, G; Guérin, S; Pourriat, J-L; Dhainaut, J-F; Ginsburg, C
Puerperal infections are an important cause of maternal morbidity and mortality in developing nations. Investigators have noted several risk factors for developing puerperal sepsis. However, the relative importance of these risk factors varies and has to be determined for each setting. Therefore the aim of the present work was to determine the risk factors for puerperal sepsis in Alexandria, Egypt. A case-control design was used to study the risk factors of puerperal sepsis in Alexandria. The study included 160 puerperal sepsis cases and 160 controls. Puerperal sepsis cases were recruited from the fever hospital as well as from 3 rural health units and three urban health offices in Alexandria. A pre-designed interviewing questionnaire was used to collect data about risk factors of puerperal sepsis. Logistic regression analysis indicated that very low socio-economic score (OR = 6.4), no ANC (OR = 4.5), delivery at a governmental maternity hospital (OR = 203.4), frequent vaginal examinations (OR = 5.1), anemia during puerperium (OR = 4.3), unsanitary vaginal douching during puerperium (OR = 19.9) and unhygienic preparation of diapers used immediately after delivery (OR = 12.1) were significantly related to the occurrence of puerperal sepsis. Improving infection control measures during delivery, limiting the frequency of vaginal examinations, and avoiding all unhygienic practices related to delivery are strongly recommended. PMID:16918152
El-Mahally, Azza A; Kharboush, Ibrahim F; Amer, Naila H; Hussein, Mohamed; Abdel Salam, Tawfik; Youssef, Adel A
Introduction Apolipoprotein M (apoM) is present in 5% of high-density lipoprotein (HDL) particles in plasma. It is a carrier of sphingosine-1-phosphate (S1P), which is important for vascular barrier protection. The aim was to determine the plasma concentrations of apoM during sepsis and systemic inflammatory response syndrome (SIRS) and correlate them to levels of apolipoprotein A-I (apoA1), apolipoprotein B (apoB), HDL-, and low-density lipoprotein (LDL)-cholesterol. Methods Plasma samples from patients with (1), severe sepsis with shock (n = 26); (2), severe sepsis without shock (n = 44); (3), sepsis (n = 100); (4), infections without SIRS (n = 43); and (5) SIRS without infection (n = 20) were analyzed. The concentrations of apoM, apoA1, and apoB were measured with enzyme-linked immunosorbent assays (ELISAs). Total, HDL-, and LDL-cholesterol concentrations were measured with a commercial HDL/LDL cholesterol test. Results ApoM concentrations correlated negatively to acute-phase markers. Thus, apoM behaved as a negative acute-phase protein. Decreased values were observed in all patient groups (P < 0.0001), with the most drastic decreases observed in the severely sick patients. ApoM levels correlated strongly to those of apoA1, apoB, HDL, and LDL cholesterol. The HDL and LDL cholesterol levels were low in all patient groups, as compared with controls (P < 0.0001), in particular, HDL cholesterol. ApoA1 and apoB concentrations were low only in the more severely affected patients. Conclusions During sepsis and SIRS, the plasma concentrations of apoM decrease dramatically, the degree of decrease reflecting the severity of the disease. As a carrier for barrier-protective S1P in HDL, the decrease in apoM could contribute to the increased vascular leakage observed in sepsis and SIRS.
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
Purpose: Changes of B-type natriuretic peptide (BNP) in sepsis and its utility in predicting intensive care unit outcomes remains a conflicting issue. To investigate the changes in plasma levels of BNP in patients with severe sepsis/septic shock and to study the association of BNP levels with the severity of the disease and prognosis of those patients. Methods: Thirty patients with severe sepsis or septic shock were enrolled in our study. BNP measurements and echocardiography were carried out on admission and on 4th and 7th days. Blood concentrations of BNP were measured by commercially available assays (Abbott methods). In-hospital mortality and length of stay were recorded multivariate analyses adjusted for acute physiology and chronic health evaluation score II (APACHE II score) was used for mortality prediction. Results: Twenty patients admitted with the diagnosis of severe sepsis and 10 patients with septic shock. The in-hospital mortality was 23.3% (7 patients). Admission BNP was significantly higher in the non-survivors 1123±236.08 versus 592.7±347.1 (P<0.001). By doing multivariate logestic regression, the predicatable variables for mortality was APACHE II score, BNP, and then EF. Conclusion: BNP concentrations were increased in patients with severe sepsis or septic shock and poor outcome was associated with high BNP levels; thus, it may serve as a useful laboratory marker to predict survival in these patients.
Omar, Amr S.; ur Rahman, Masood; Dhatt, Gurdeep S.; Salami, Gubril O.; Abuhasna, Said
In a randomized multicenter study, the efficacy and safety of cefprozil were compared with those of penicillin in the treatment of group A streptococcal tonsillopharyngitis in children. Of the 409 patients enrolled, 323 were evaluable for their clinical and bacteriological responses; of these 323 children, 172 received cefprozil and 151 received penicillin V. The clinical responses in patients treated with cefprozil were significantly better than those in patients who received penicillin (95.3 versus 88.1%; P = 0.023). Eradication of the original serotype of group A streptococci was achieved in 91.3% of patients treated with cefprozil and 87.4% of patients treated with penicillin, the difference not being statistically significant (P = 0.125). However, there were significantly more symptomatic patients among the bacteriological failures in the penicillin group (68.4%) than in the cefprozil group (26.7%). beta-Lactamase-producing Staphylococcus aureus was more frequently isolated from the throat flora during penicillin therapy than during cefprozil treatment. No difference in the incidence of adverse events probably related or of unknown relationship to the study drugs was observed in the two treatment groups (5.2% of those treated with cefprozil and 6.0% of those treated with penicillin). Cefprozil can be considered a safe and reliable drug for the treatment of streptococcal pharyngitis in children.
Milatovic, D; Adam, D; Hamilton, H; Materman, E
Sepsis remains one of the leading causes of death in intensive care units. Progressive cardiovascular failure is an important cause of the mortality. Septic patients with myocardial dysfunction have significantly higher mortality compared with patients without cardiovascular impairment. Myocardial dysfunction in sepsis is characterized by decreased contractility and impaired myocardial compliance. Experimental studies of sepsis showed heterogeneity of microvascular perfusion, as well as impaired myocardial oxygen extraction. The underlying cellular mechanisms include increased neutrophil adhesion to the endothelium, production of reactive free radicals and oxidants, and endothelial dysfunction. Superoxide, nitric oxide and peroxynitrite cardiac formation has been demonstrated in septic hearts, which has been implicated in the pathogenesis of the myocardial depression and cell death in sepsis. Nitric oxide, carbon monoxide and hydrogen sulfide are gaseotransmitters that may exert protective effects in the septic heart. PMID:20509838
Lorigados, Clara Batista; Soriano, Francisco Garcia; Szabo, Csaba
... Public Health Advisory: Sepsis and Medical Abortion. ... The approved Mifeprex regimen for a medical abortion through 49 days' pregnancy is: ... More results from www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders
Neuro-oxidative-nitrosative stress may prove the molecular basis underlying brain dysfunction in sepsis. In the current review, we describe how sepsis-induced reactive oxygen and nitrogen species (ROS/RNS) trigger lipid peroxidation chain reactions throughout the cerebrovasculature and surrounding brain parenchyma, due to failure of the local antioxidant systems. ROS/RNS cause structural membrane damage, induce inflammation, and scavenge nitric oxide (NO) to yield peroxynitrite (ONOO?). This activates the inducible NO synthase, which further compounds ONOO? formation. ROS/RNS cause mitochondrial dysfunction by inhibiting the mitochondrial electron transport chain and uncoupling oxidative phosphorylation, which ultimately leads to neuronal bioenergetic failure. Furthermore, in certain ‘at risk' areas of the brain, free radicals may induce neuronal apoptosis. In the present review, we define a role for ROS/RNS-mediated neuronal bioenergetic failure and apoptosis as a primary mechanism underlying sepsis-associated encephalopathy and, in sepsis survivors, permanent cognitive deficits.
Berg, Ronan M G; M?ller, Kirsten; Bailey, Damian M
\\u000a Severe sepsis is a major cause of morbidity and mortality worldwide. Recent advances in our understanding of the pathophysiology\\u000a of sepsis have emphasized the pivotal role of the innate immune system in the development of a deleterious host response to\\u000a bacterial infection. It is now recognized that the endothelium is an important effector cell of the innate immune system.\\u000a This
John M. Harlan
Sepsis (blood poisoning) is a severe infectious disease with high mortality, and no effective therapy is actually known. In\\u000a the case of Gram-negative bacteria, endotoxins (lipopolysaccharides) are known to be responsible for the strong inflammation\\u000a reaction leading to the systemic infection. Peptides based on endotoxin-binding domains of human or animal proteins represent\\u000a a promising approach in sepsis research. Although so
Klaus Brandenburg; Jörg Andrä; Patrick Garidel; Thomas Gutsmann
We show here that heterologous expression of a single group B streptococcal (GBS) surface-anchored protein, sapB, is sufficient to render the nonpathogenic bacterium Lactococcus lactis resistant to innate immune clearance and highly virulent upon animal challenge.
H. C. Maisey; M. E. Hensler; A. Khosravi; G. Y. Liu; V. Nizet; K. S. Doran
Children with obsessive compulsive disorder or tic disorders that are associated with streptococcal infections (Group A beta-hemolytic) in the oro-pharyngeal region are given the diagnosis of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Tonsillectomy has been reported to resolve the neuro-psychiatric symptoms in these children. We have a case of a 9-year-old boy who was seen in our clinic with multiple recurrent streptococcal infections of the oro-pharyngeal cavity. He also exhibited neuro-psychiatric symptoms including agitation, hyperactivity, and tics. These symptoms followed his recurrent infections. Tonsillectomy was performed and in one year follow-up the patient did not have any recurrent streptococcal infections, and his neuro-psychiatric symptoms resolved completely. Guidelines for medical and surgical management of recurrent strep infections in the face of PANDAS are reviewed. PMID:21466900
Alexander, Alan A Z; Patel, Nitin J; Southammakosane, Cathy A; Mortensen, Melissa M
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
The influence of mutationally induced changes in protein folding on development of effective neutralizing antibodies during vaccination remains largely unexplored. In this study, we probed how mutational substitutions of streptococcal pyrogenic exotoxin A...
J. H. Carra B. C. Welcher R. D. Schokman C. S. David S. Bavari
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
An unusual case of group B streptococcal meningitis in an adult is described. The evidence presented suggests that early vascular involvement during the meningitic process resulted in cerebral infarction, thereby explaining the patient's sudden deterioration and atypical presentation.
Klassen, H.; Klassen, M. K.; Huncharek, M.
The structural gene encoding streptococcal pyrogenic exotoxin type B, designated speB, was cloned in Escherichia coli and localized onto a 4.5-kilobase BamHI-BglII DNA fragment. Streptococcal pyrogenic exotoxin type B, partially purified from E. coli clones, was immunologically related to streptococcus-derived toxin. Also, toxin derived from either E. coli or Streptococcus pyogenes had similar lymphocyte mitogenic activity and molecular weight (29,300) and displayed comparable microheterogeneity when evaluated by isoelectric focusing. Images
Bohach, G A; Hauser, A R; Schlievert, P M
Interaction of Porphyromonas gingivalis with plaque-forming bacteria is necessary for its colonization in periodontal pockets. Participation of Streptococcus oralis glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and P. gingivalis fimbriae in this interaction has been reported. In this investigation, the contribution of various oral streptococcal GAPDHs to interaction with P. gingivalis fimbriae was examined. Streptococcal cell surface GAPDH activity was measured by incubation of a constant
Kazuhiko Maeda; Hideki Nagata; Aya Nonaka; Kosuke Kataoka; Muneo Tanaka; Satoshi Shizukuishi
OBJECTIVE:To investigate whether specimens obtained from the perianal area have a Group B streptococcal culture detection rate similar to anorectal specimens.METHODS:This is a prospective cohort study at a tertiary care university-affiliated teaching hospital. A total of 136 pregnant women between 33 and 40 weeks’ gestation were recruited. Three samples for Group B streptococcal culture detection were obtained from each subject
Chinyere Orafu; Prabhcharan Gill; Karl Nelson; Bryan Hecht; Michael Hopkins
OBJECTIVE: To identify limitations of current strategies for intrapartum prophylaxis of neonatal early-onset group B streptococcal infection.METHODS: Retrospective review of infants with culture-proven early-onset group B streptococcal infection admitted to two nurseries and their mothers from July 1992, when ACOG and AAP guidelines for intrapartum prophylaxis were first issued, through December 2001. Information was recorded regarding clinical risk factors for
Nelangi M Pinto; Errol I Soskolne; Mark D Pearlman; Roger G Faix
ABSTRACT: The clinical, human and economic burden associated with sepsis is huge. Initiatives such as the Surviving Sepsis Campaign aim to effectively reduce risk of death from severe sepsis and septic shock. Nonetheless, although substantial benefits raised from the implementation of this campaign have been obtained, much work remains if we are to realise the full potential promised by this strategy. A deeper understanding of the processes leading to sepsis is necessary before we can design an effective suite of interventions. Dysregulation of the immune response to infection is acknowledged to contribute to the pathogenesis of the disease. Production of both proinflammatory and immunosuppressive cytokines is observed from the very first hours following diagnosis. In addition, hypogammaglobulinemia is often present in patients with septic shock. Moreover, levels of IgG, IgM and IgA at diagnosis correlate directly with survival. In turn, nonsurvivors have lower levels of C4 (a protein of the complement system) than the survivors. Natural killer cell counts and function also seem to have an important role in this disease. HLA-DR in the surface of monocytes and counts of CD4+CD25+ T-regulatory cells in blood could also be useful biomarkers for sepsis. At the genomic level, repression of networks corresponding to major histocompatibility complex antigen presentation is observed in septic shock. In consequence, cumulative evidence supports the potential role of immunological monitoring to guide measures to prevent or treat sepsis in a personalised and timely manner (early antibiotic administration, immunoglobulin replacement, immunomodulation). In conclusion, although diffuse and limited, current available information supports the development of large comprehensive studies aimed to urgently evaluate immunological monitoring as a tool to prevent sepsis, guide its treatment and, as a consequence, diminish the morbidity and mortality associated with this severe condition. PMID:23351425
Almansa, Raquel; Wain, John; Tamayo, Eduardo; Andaluz-Ojeda, David; Martin-Loeches, Ignacio; Ramirez, Paula; Bermejo-Martin, Jesús F
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
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
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 tissue binding properties of streptococcal lipoteichoic acid (LTA) were studied using normal and passively immunized BALB/c mice. After intraperitoneal injection in non-immunized mice, 3H-LTA concentrations in blood, heart, kidney and liver were highest between 24 and 30 h post-injection. LTA deposits in heart remained high for the next 24 h, whereas other tissue levels decreased. Constant amounts of 3H-LTA were detected in urine throughout the 48 h period. In passively immunized mice, the amount of tissue deposition of 3H-LTA was inversely proportional to the ratio of antibodies to LTA. Autoradiography revealed focal deposits of 3H-LTA in heart, kidney and liver. These observations indicate that LTA, released by streptococci growing at remote body sites, can be carried by the blood to internal organs where it can accumulate and participate in pathogenesis. PMID:1453925
Hyzy, J; Sciotti, V; Albini, B; Stinson, M
Conditions for the release of streptococcal type 12 M protein from whole cells by cyanogen bromide are described; they demonstrated that methionine is not essential to the structural arrangements which account for some of its immunological and biological properties. The released M protein was separated from other proteins by column chromatography with hydroxylapatite. The type-specific molecules which reacted with precipitating antibodies were found only in the 0.3 M eluate, formed zones with mobilities less than 12% of that of the dye front on electrophoresis in the standard acrylamide disc gel system, formed at least four bands in sodium dodecyl sulfate-acrylamide disc gels with molecular weights ranging from 12,000 to 23,000, and stimulated the formation of opsonic antibodies in rabbits. Cyanogen bromide provides a highly specific method for the release of M proteins which should prove particularly useful in analyses of structural-functional relationships among different M proteins. Images
Vosti, K L; Williams, W K
In this paper we present a prospective evaluation of 100 patients with Group A Streptococcal (GAS) bacteremia evaluated in our hospital over a 10-year period. Sixty-two patients were intravenous drug users (IVDU); all but 1 of these had an obvious cutaneous portal of entry related to the injection of illicit drugs. Twenty-seven patients had infectious metastasis, and the presence of septic pulmonary embolism was associated with suppurative phlebitis. Four of these patients had endocarditis. In the non-IVDU group, 24 patients had an underlying disease, and 12 were immunosuppressed. In 14 cases the infection was of hospital acquisition; in 35% infection was related to medical manipulations. Comparing the IVDU and non-IVDU groups, GAS bacteremia in IVDU patients is associated with a more benign outcome, a longer time of evolution before diagnosis, and a lower frequency of septic shock and mortality than in non-IVDU patients. Although in the univariate analysis GAS bacteremia was associated with several variables, in the multivariate analysis only the presence of shock and nosocomial acquisition of the infection were independently associated with a fatal outcome. Fifty-two patients were infected with human immunodeficiency virus (HIV); 5 of these were in the non-IVDU group. During the last 5 years of study, GAS bacteremia in our hospital was 39 times more frequent in HIV-infected patients than in patients without HIV. Nine patients presented clinical criteria corresponding to Streptococcal toxic shock syndrome (STSS), although its incidence was lower in the IVDU group. In the non-IVDU group, STSS was more frequent in patients with a necrotizing portal of entry, an age between 20 and 40 years, women, and when the origin of the infection was the skin or soft tissue. Six patients with STSS died, and death was associated with the presence of necrotizing lesions and lower counts of white cells, platelets, or hemoglobin. PMID:9279330
Bernaldo de Quirós, J C; Moreno, S; Cercenado, E; Diaz, D; Berenguer, J; Miralles, P; Catalán, P; Bouza, E
Microcirculatory dysfunction is correlated with increased mortality among septic patients and is believed to be a major contributor to the development of acute kidney injury (AKI). Rolipram, a selective phosphodiesterase 4 (PDE4) inhibitor, has been shown to reduce microvascular permeability and in the kidney, increase renal blood flow (RBF). This led us to investigate its potential to improve the renal microcirculation and preserve renal function during sepsis using a murine cecal ligation and puncture (CLP) model to induce sepsis. Rolipram, tested at doses of 0.3-10 mg/kg i.p., acutely restored capillary perfusion in a bell-shaped dose-response effect with 1 mg/kg being the lowest most efficacious dose. This dose also acutely increased RBF despite transiently decreasing mean arterial pressure. Rolipram also reduced renal microvascular permeability. It is noteworthy that delayed treatment with rolipram at 6 hours after CLP restored the renal microcirculation, reduced blood urea nitrogen and serum creatinine, and increased glomerular filtration rate at 18 hours. However, delayed treatment with rolipram did not reduce serum nitrate/nitrite levels, a marker of nitric oxide production, nor reactive nitrogen species generation in renal tubules. These data show that restoring the microcirculation with rolipram, even with delayed treatment, is enough to improve renal function during sepsis despite the generation of oxidants and suggest that PDE4 inhibitors should be evaluated further for their ability to treat septic-induced AKI. PMID:24018639
Holthoff, Joseph H; Wang, Zhen; Patil, Naeem K; Gokden, Neriman; Mayeux, Philip R
GM-CSF plays a critical role in innate immunity by stimulating the differentiation of tissue macrophages via the transcription factor PU.1. Previous studies showed that GM-CSF deficient (GM-CSF?/?) mice had susceptibility to and impaired clearance of group B streptococcal bacteria by macrophages. For these studies, we hypothesized that GM-CSF?/? mice have increased susceptibility to peritonitis caused by immune dysfunction of peritoneal macrophages. We examined the role of peritoneal macrophages in pathogen clearance, cytokine responses, and survival in a murine cecal ligation and puncture (CLP) model of peritonitis/sepsis. Surprisingly, CLP minimally affected survival in GM-CSF?/? mice while markedly reducing survival in wild type mice. This was not explained by differences in the composition of microbial flora, rates of bacterial peritonitis or sepsis, all of which were similar in GM-CSF?/? and wild type mice. However, survival correlated with peritoneal and serum TNF-? and IL-6 levels which were significantly lower in GM-CSF?/? than control mice. Following peritoneal LPS instillation, GM-CSF?/? mice also had improved survival and reduced TNF-? and IL-6 responses. In vitro studies demonstrated reduced secretion of TNF-? and IL-6 by peritoneal macrophages isolated from sham GM-CSF?/? mice as compared to macrophages from sham control mice. Peritoneal instillation of GM-CSF?/?/PU.1Positive macrophages, but not GM-CSF?/?/PU.1Negative macrophages into GM-CSF?/? mice conferred susceptibility to death following CLP or peritoneal LPS exposure. These results demonstrate that GM-CSF/PU.1-dependent peritoneal macrophage responses are a critical determinant of survival following experimentally induced peritonitis/sepsis or exposure to LPS and have implications for therapies to treat such infections.
Spight, Donn; Trapnell, Bruce; Zhao, Bin; Berclaz, Pierre; Shanley, Thomas P.
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
Background Sepsis has several clinical stages, and mortality rates are different for each stage. Our goal was to establish the evolution and the determinants of the progression of clinical stages, from infection to septic shock, over the first week, as well as their relationship to 7-day and 28-day mortality. Methods This is a secondary analysis of a multicenter cohort of inpatients hospitalized in general wards or intensive care units (ICUs). The general estimating equations (GEE) model was used to estimate the risk of progression and the determinants of stages of infection over the first week. Cox regression with time-dependent covariates and fixed covariates was used to determine the factors related with 7-day and 28-day mortality, respectively. Results In 2681 patients we show that progression to severe sepsis and septic shock increases with intraabdominal and respiratory sources of infection [OR?=?1,32; 95%IC?=?1,20-1,46 and OR?=?1.21, 95%CI?=?1,11-1,33 respectively], as well as according to Acute Physiology and Chronic Health Evaluation II (APACHE II) [OR?=?1,03; 95%CI?=?1,02-1,03] and Sequential Organ Failure Assessment (SOFA) [OR?=?1,16; 95%CI?=?1,14-1,17] scores. The variables related with first-week mortality were progression to severe sepsis [HR?=?2,13; 95%CI?=?1,13-4,03] and septic shock [HR?=?3,00; 95%CI?=?1,50-5.98], respiratory source of infection [HR?=?1,76; 95%IC?=?1,12-2,77], APACHE II [HR?=?1,07; 95% CI?=?1,04-1,10] and SOFA [HR?=?1,09; 95%IC?=?1,04-1,15] scores. Conclusions Intraabdominal and respiratory sources of infection, independently of SOFA and APACHE II scores, increase the risk of clinical progression to more severe stages of sepsis; and these factors, together with progression of the infection itself, are the main determinants of 7-day and 28-day mortality.
Streptococcal infection is believed to have an intimate relationship with psoriasis, although the pathogenic role of streptococcal DNA is not fully understood. To gain a clearer understanding of these dynamics, we investigated the effect of streptococcal DNA on lymphocyte proliferation and activation as well as cytokine secretion in psoriasis. Peripheral blood mononuclear cells (PBMCs) from psoriatic patients had higher proliferative
Yi-Hua Cai; Zhi-Yong Lu; Ruo-Fei Shi; Feng Xue; Xiao-Ying Chen; Meng Pan; Wei-Ru Yuan; Han Xu; Wei-Ping Li; Jie Zheng
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
During sepsis, the liver plays a key role. It is implicated in the host response, participating in the clearance of the infectious agents/products. Sepsis also induces liver damage through hemodynamic alterations or through direct or indirect assault on the hepatocytes or through both. Accordingly, liver dysfunction induced by sepsis is recognized as one of the components that contribute to the severity of the disease. Nevertheless, the incidence of liver dysfunction remains imprecise, probably because current diagnostic tools are lacking, notably those that can detect the early liver insult. In this review, we discuss the epidemiology, diagnostic tools, and impact on outcome as well as the pathophysiological aspects, including the cellular events and clinical picture leading to liver dysfunction. Finally, therapeutic considerations with regard to the weakness of the pertinent specific approach are examined.
For more than 30 years, intravenously administered immunoglobulins (ivIG) have been used to treat primary and secondary syndromes of immune deficiency. Increasing insight into pathomechanisms of severe sepsis and septic shock have led to the implementation of ivIG therapy in the strategies for adjunctive therapy in sepsis in both adults and children. Direct antitoxic effects, as well as indirect immunomodulatory mechanisms of ivIG have been described in the literature and were the basis for the rationale to use these substances in life-threatening infections and hyperinflammatory states. Several clinical trials have been performed, most of them as minor, investigator-initiated protocols. This review summarizes the results of clinical investigations and systematic meta-analyses that have implications for the development of therapeutic strategies, and international guidelines for the management of severe sepsis and septic shock in adult patients. PMID:22886554
Toussaint, Susanne; Gerlach, Herwig
The immune response to sepsis can be seen as a pattern recognition receptor-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital. Invasive infection triggers both proinflammatory and anti-inflammatory host responses, the magnitude of which depends on multiple factors, including pathogen virulence, site of infection, host genetics, and comorbidities. Toll-like receptors, the inflammasomes, and other pattern recognition receptors initiate the immune response after recognition of danger signals derived from microorganisms, so called pathogen-associated molecular patterns or derived from the host, so called danger-associated molecular patterns. Further dissection of the role of host-pathogen interactions, the cytokine response, the coagulation cascade and their multidirectional interactions in sepsis should lead toward the development of new therapeutic strategies in sepsis. PMID:23774844
Wiersinga, Willem Joost; Leopold, Stije J; Cranendonk, Duncan R; van der Poll, Tom
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.
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
Background Elevated cardiac troponin I (cTnI) is frequently observed in patients with severe sepsis and septic shock. However, the mechanisms underlying cTnI release in these patients are still unknown. To date no data regarding coagulation disturbances as a possible mechanism for cTnI release during sepsis are available. Methodology/Principal Findings Consecutive patients with systemic inflammatory response syndrome (SIRS), sepsis or septic shock without evidence of an acute coronary syndrome were analyzed. Coagulation parameters (clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), ?-angle) were assessed in native whole blood samples, and using specific activators to evaluate the extrinsic and intrinsic as well as the fibrin component of the coagulation pathway with the use of rotational thrombelastometry (ROTEM). Thirty-eight patients were included and 22 (58%) were cTnI-positive. Baseline characteristics between TnI-positive and -negative patients were similar. The CT, CFT, MCF and the ?-angle were similar between the groups with trends towards shorter CT in the extrinsic and fibrin activation. Conclusions/Significance We found no differences in coagulation parameters analyzed with rotational thrombelastometry between cTnI-positive and -negative patients with SIRS, severe sepsis, and septic shock. These findings suggest that pathophysiological mechanisms other than thrombus-associated myocardial damage might play a major role, including reversible myocardial membrane leakage and/or cytokine mediated apoptosis in these patients.
Altmann, David R.; Korte, Wolfgang; Maeder, Micha T.; Fehr, Thomas; Haager, Philipp; Rickli, Hans; Kleger, Gian-Reto; Rodriguez, Regulo; Ammann, Peter
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
Severe sepsis is a major challenge for clinicians caring for acutely ill patients. For many years, several biomarkers have been tested and proposed to improve the ability not only to diagnose but also to anticipate clinical response to antibiotics. Despite the availability of many sophisticated and novel biomarkers, current evidence demonstrates that C-reactive protein (CRP), a well-known and relatively inexpensive biomarker, is useful in the clinical setting. The sequential evaluation of plasma CRP concentrations in patients with severe sepsis and the interpretation of its patterns may allow assessments of individual prognosis and response to treatment.
Objective A lack of published pharmacokinetic data on statins in sepsis has prompted concerns about their safety and toxicity. This\\u000a study determined single dose pharmacokinetics of Atorvastatin administered orally to acutely ill patients.\\u000a \\u000a \\u000a \\u000a Design, setting and participants A prospective open label study conducted in a tertiary referral centre on 5 healthy volunteers, 5 acutely ill patients admitted\\u000a to the medical ward and
Peter S. Kruger; Noelle M. Freir; Bala Venkatesh; Thomas A. Robertson; Michael S. Roberts; Mark Jones
Background Carbon dioxide (CO2) pneumoperitoneum has been shown to attenuate the inflammatory response after laparoscopy. This study tested the hypothesis\\u000a that abdominal insufflation with CO2 improves survival in an animal model of sepsis and investigated the associated mechanism.\\u000a \\u000a \\u000a \\u000a Methods The effect of CO2, helium, and air pneumoperitoneum on mortality was studied by inducing sepsis in 143 rats via intravenous injection of lipopolysaccharide
E. J. Hanly; J. M. Fuentes; A. R. Aurora; S. L. Bachman; A. De Maio; M. R. Marohn; M. A. Talamini
Fungal sepsis is an important cause of fever resistant to antibiotic therapy that is very often taken into marginal account. It should instead be particularly considered in patients with a long history of immune depression such as diabetes or chronic and debilitating diseases. Blood cultures are essential for diagnostic purposes, preferably performed in antibiotic wash-out, since they may allow identification of pathogenic (or opportunistic) fungi responsible for episodes of fungal sepsis. The case described illustrates an episode of systemic infection by Rhodotorula glutinis correlated with the presence of CVC. PMID:20610937
Pulvirenti, Fabrizio; Pasqua, Paolo; Falzone, Elio; Maffeo, Federico; Gugliara, Carmelo; Guarneri, Luigi
The purpose of this study was to compare the bacteriologic and clinical efficacy of oral penicillin versus amoxicillin as first-line therapy for group A beta-hemolytic streptococcal (GABHS) tonsillopharyngitis. The prospective observational study was conducted over 18 months (January 2000-June 2001). Children enrolled had acute onset of symptoms and signs and a laboratory-documented GABHS tonsillopharyngitis illness. Follow-up examination and laboratory testing occurred 10 +/- 4 days following completion of treatment. In total, 389 patients were enrolled (intent-to-treat group): 195 received penicillin V and 194 received amoxicillin. Fifty-six of the penicillin-treated and 57 amoxicillin-treated patients refused to take the drug, or were noncompliant, or did not return for the follow-up visit, leaving 276 patients in the per-protocol group: 139 penicillin-treated and 137 amoxicillin-treated. Bacteriologic cure for amoxicillin-treated children occurred in 76% versus 64% in the penicillin-treated children (p = 0.04). The clinical cure rate for amoxicillin-treated children was 84% compared to 73% in the penicillin-treated children (p = 0.03). Since treatment allocation was not randomized, logistic regression analysis was used to adjust for treatment group differences. The odds ratio (OR) estimate for cure for patients in the amoxicillin versus penicillin V treatment group remained significant (OR = 1.84, 95% confidence interval 1.02-3.29); the same was true for dinical cure (OR = 1.99, 95% CI = 1.02-3.87). Amoxicillin may be superior to penicillin for bacteriologic and clinical cure of GABHS tonsillopharyngitis. PMID:12739920
Curtin-Wirt, Correne; Casey, Janet R; Murray, Patrick C; Cleary, Carolyn T; Hoeger, William J; Marsocci, Steven M; Murphy, Marie Lynd; Francis, Anne B; Pichichero, Michael E
Objectives: We determined whether initial antithrombin (AT) levels help in diagnosis and prognosis of neonatal sepsis. Methods: Sepsis was diagnosed according to clinical and laboratory findings and positive culture results in 34 of the 54 newborns who presented to the hospital with suspected sepsis. Between AT levels and hematological parameters (fibrinogen levels, prothrombin time (PT), activated partial thromboplastin time (aPTT)
Betul Ersoy; Hakan Nehir; Serdar Altinoz; Ozge Yilmaz; Aysel Aydogan
On one side, brain dysfunction is a poorly explored complication of sepsis. On the other side, brain dysfunction may actively contribute to the pathogenesis of sepsis. The current review aimed at summarizing the current knowledge about the reciprocal interaction between the immune and central nervous systems during sepsis. The immune-brain cross talk takes part in circumventricular organs that, being free
Tarek Sharshar; Nicholas S Hopkinson; David Orlikowski; Djillali Annane
Chronic sepsis promotes a stable increase in pyruvate dehydrogenase kinase (PDHK) activity in skeletal muscle. PDHK is found tightly bound to the pyruvate dehydrogenase (PDH) complex and as free kinase. We investigated the ability of sepsis to modify the activity of the PDHK intrinsic to the PDH and free PDHK. Sepsis was induced by the intraabdominal introduction of a fecal-agar
Thomas C. Vary; Stacy Hazen
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
BACKGROUND: Most patients with sepsis develop potentially irreversible cerebral dysfunctions. It is yet not clear whether cerebral haemodynamics are altered in these sepsis patients at all, and to what extent. We hypothesized that cerebral haemodynamics and carbon dioxide reactivity would be impaired in patients with sepsis syndrome and pathological electroencephalogram patterns. METHODS: After approval of the institutional ethics committee, 10
Christof Thees; Markus Kaiser; Martin Scholz; Alexander Semmler; Michael T Heneka; Georg Baumgarten; Andreas Hoeft; Christian Putensen
The outcome of cephalosporin versus penicillin treatment of group A streptococcal tonsillopharyngitis may differ between Europe and the USA. In the present study, Medline, Embase, reference lists, and abstract searches were used to identify randomized, controlled trials of cephalosporin versus penicillin treatment of group A streptococcal (GAS) tonsillopharyngitis. The outcomes of interest were bacteriologic and clinical cure rates from investigations
M. Pichichero; J. Casey
The majority of group A streptococcal (GAS) isolates from patients with streptococcal toxic shock syndrome (STSS) and necrotizing fasciitis (NF) express numerous virulence factors, including several superantigens (SAgs). Purified SAgs are potent inducers of inflammatory (Th1) cytokines that contribute to the pathogenesis of severe infections. However, GAS-infected individuals are likely to be exposed to a mixture of GAS SAgs as
ANNA NORRBY-TEGLUND; ROBERT LUSTIG; MALAK KOTB
International guidelines concerning the management of patients with sepsis, septic shock and multiple organ failure make no reference to the nature of the infecting organism. Indeed, most clinical signs of sepsis are nonspecific. In contrast, in vitro data suggest that there are mechanistic differences between bacterial, viral and fungal sepsis, and imply that pathogenetic differences may exist between subclasses such
Hongmei Gao; Timothy W Evans; Simon J Finney
While heart rate variability has been measured in many clinical settings and has offered insights into how HR is controlled, rarely has it offered unique information that has led to changes in patient management. We review our experience in developing continuous HR characteristics monitoring to aid in the early diagnosis of sepsis in premature infants in the neonatal intensive care
J. Randall Moorman; Douglas E. Lake; M. Pamela Griffin
Sepsis is one of the leading causes of mortality and morbidity, even with the current availability of extended-spectrum antibiotics and advanced medical care. Biomarkers offer a tool in facilitating early diagnosis, in identifying patient populations at high risk of complications, and in monitoring progression of the disease, which are critical assessments for appropriate therapy and improvement in patient outcomes. Several biomarkers are already available for clinical use in sepsis; however, their effectiveness in many instances is limited by the lack of specificity and sensitivity to characterize the presence of an infection and the complexity of the inflammatory and immune processes and to stratify patients into homogenous groups for specific treatments. Current advances in molecular techniques have provided new tools facilitating the discovery of novel biomarkers, which can vary from metabolites and chemical products present in body fluids to genes and proteins in circulating blood cells. The purpose of this review was to examine the current status of sepsis biomarkers, with special emphasis on emerging markers, which are undergoing validation and may transition into clinical practice for their informative value in diagnosis, prognosis, or response to therapy. We will also discuss the new concept of combination biomarkers and biomarker risk models, their existing challenges, and their potential use in the daily management of patients with sepsis. PMID:24088989
Samraj, Ravi S; Zingarelli, Basilia; Wong, Hector R
Bacillus licheniformis is recognized as a human pathogen causing infections, mainly in immunocompromised patients. We present a case of sepsis in an immunocompetent patient, caused by B. licheniformis. This case is of particular interest because the patient had no history of any immune deficiency and the disease did not respond to antibiotic treatment.
Haydushka, Irina A; Markova, Nadya; Kirina, Vesselina; Atanassova, Maria
Teicoplanin is a less toxic replacement for vancomycin in most situations where resistant organisms are encountered, and is therefore the drug of choice. As a commonly used drug in cardiac surgery, we treated a case of presumptive endocarditis with teicoplanin that caused neutropenic sepsis, unmasked on withdrawal of treatment. PMID:22879557
Booth, Karen; Parissis, Haralambos
This study evaluated the accuracy and utility of the In-111 labeled WBC imaging in a series of patients who were suspected of having musculoskeletal sepsis. The labeling of the WBCs was patterned after a method previously described, in which the WBCs are labeled with In-111 oxine in plasma. The WBCs from 100 ml of blood are separated and incubated with
L. Thompson; T. J. Ouzounian; M. M. Webber; H. C. Amstutz
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.
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
Background Mitochondrial injury develops in skeletal muscles during the course of severe sepsis. Autophagy is a protein and organelle recycling pathway which functions to degrade or recycle unnecessary, redundant, or inefficient cellular components. No information is available regarding the degree of sepsis-induced mitochondrial injury and autophagy in the ventilatory and locomotor muscles. This study tests the hypotheses that the locomotor muscles are more prone to sepsis-induced mitochondrial injury, depressed biogenesis and autophagy induction compared with the ventilatory muscles. Methodology/Principal Findings Adult male C57/Bl6 mice were injected with i.p. phosphate buffered saline (PBS) or E. coli lipopolysaccharide (LPS, 20 mg/kg) and sacrificed 24 h later. The tibialis anterior (TA), soleus (SOLD) and diaphragm (DIA) muscles were quickly excised and examined for mitochondrial morphological injury, Ca++ retention capacity and biogenesis. Autophagy was detected with electron microscopy, lipidation of Lc3b proteins and by measuring gene expression of several autophagy-related genes. Electron microscopy revealed ultrastructural injuries in the mitochondria of each muscle, however, injuries were more severe in the TA and SOL muscles than they were in the DIA. Gene expressions of nuclear and mitochondrial DNA transcription factors and co-activators (indicators of biogenesis) were significantly depressed in all treated muscles, although to a greater extent in the TA and SOL muscles. Significant autophagosome formation, Lc3b protein lipidation and upregulation of autophagy-related proteins were detected to a greater extent in the TA and SOL muscles and less so in the DIA. Lipidation of Lc3b and the degree of induction of autophagy-related proteins were significantly blunted in mice expressing a muscle-specific I?B? superrepresor. Conclusion/Significance We conclude that locomotor muscles are more prone to sepsis-induced mitochondrial injury, decreased biogenesis and increased autophagy compared with the ventilatory muscles and that autophagy in skeletal muscles during sepsis is regulated in part through the NF?B transcription factor.
Mofarrahi, Mahroo; Sigala, Ioanna; Guo, Yeting; Godin, Richard; Davis, Elaine C.; Petrof, Basil; Sandri, Marco
Streptococcus pyogenes is an important pathogen that causes pharyngitis, scarlet fever, rheumatic fever, and streptococcal toxic shock syndrome. To survive within its host, S. pyogenes has developed several immune evasion mechanisms. Here, we identified a novel gene encoding a 66-kDa protein with many leucine zipper motifs, that we call streptococcal leucine zipper protein (Lzp). Lzp was expressed on the bacterial cell surface, and some was detected in the culture medium. Lzp was expressed by all the S. pyogenes strains we tested, but not by group B streptococcal strains. Western blotting and Biacore assay demonstrated that recombinant Lzp bound to human IgA, IgG, IgM, and Lzp. In addition, native-PAGE analysis suggested that the Lzp molecule formed dimer and trimer conformations. Thus, Lzp is a novel immunoglobulin-binding protein that may play a role in helping S. pyogenes escape detection by the host immune system. PMID:18983979
Okamoto, Shigefumi; Terao, Yutaka; Hasuike, Kohei; Hamada, Shigeyuki; Kawabata, Shigetada
The resistance of native and trypsin-treated [14C] glucose-labeled cell walls to degradation by lysozyme and human lysosomal enzymes was confirmed. In contrast, chemically N-acetylated cell walls undergo significant degradation by these enzymes in the pH range of 4.5 to 5.5 without prior removal of the group-specific carbohydrate. N-acetylation after removal of the group A carbohydrate by formamide extraction renders the cell walls considerably more susceptible to these enzymes than by formamaide extraction alone. It appears, therefore, that unless N-acetylation can occur in vivo, streptococcal cell walls are minimally degraded, if at all, by human peripheral blood leukocytes or lysozyme. Examination of leukocyte extracts from normal subjects and patients with post-streptococcal syndromes revealed no qualitative differences in ability to dissolve streptococcal cell walls. Images
Gallis, H A; Miller, S E; Wheat, R W
Activation of the alternate complement pathway in human serum by several bacterial components was compared. Peptidoglycan from group A streptococcal cell walls was the most active material, on a weight basis, followed by cell walls, protoplast membranes, and whole cells. The group-specific carbohydrate was inactive. Treatment of peptidoglycan with low concentrations of lysozyme or short periods of sonic treatment enhanced complement activation. High concentrations of lysozyme or extended sonic treatment of peptidoglycan destroyed or greatly reduced the capacity to activate complement. Lysozyme treatment of group A streptococcal cell walls or lipopolysaccharide had no measurable effect. Activation of the alternate complement pathway by group D streptococcal cell walls was destroyed by lysozyme. Activity of peptidoglycan was not inhibited by N-acetyl glucosamine, N-acetyl muramic acid, or D-alanine-D-alanine. Conversion of C3 and factored B by peptidoglycan was shown to occur by immunoelectrophoresis and crossed immunoelectrophoresis. Images
Greenblatt, J; Boackle, R J; Schwab, J H
Background The aim of this study was to evaluate the clinical usefulness of a semiquantitative procalcitonin kit for assessing severity of sepsis and early determination of mortality in affected patients. Methods This was a prospective, observational study including 206 septic patients enrolled between June 2008 and August 2009. Disseminated intravascular coagulation (DIC), Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE) II scores were measured, along with semiquantitative procalcitonin concentrations. Patients were divided into three groups based on their semiquantitative procalcitonin concentrations (group A, <2 ng/mL; group B ? 2 ng/mL < 10 ng/mL; group C ? 10 ng/mL). Results A significant difference in DIC, SOFA, and APACHE II scores was found between group A and group C and between group B and group C (P < 0.01). Patients with severe sepsis and septic shock had significantly higher procalcitonin concentrations than did patients with less severe disease. The rate of patients with septic shock with high procalcitonin concentrations showed an upward trend. There was a significant (P < 0.01) difference between the three groups with regard to numbers of patients and rates of severe sepsis, septic shock, DIC, and mortality. Conclusion Semiquantitative procalcitonin concentration testing can be helpful for early assessment of disease severity in patients with sepsis. Furthermore, it may also help in predicting early mortality in septic patients. Based on the level of semiquantitative procalcitonin measured in patients with suspected sepsis, a timely decision can be reliably made to transfer them to a tertiary hospital with an intensive care unit for optimal care.
Kenzaka, Tsuneaki; Okayama, Masanobu; Kuroki, Shigehiro; Fukui, Miho; Yahata, Shinsuke; Hayashi, Hiroki; Kitao, Akihito; Kajii, Eiji; Hashimoto, Masayoshi
Introduction The effect of sepsis on epidermal wound healing has not been previously studied. It was hypothesised that epidermal wound healing is disturbed in severe sepsis. Methods Blister wounds were induced in 35 patients with severe sepsis and in 15 healthy controls. The healing of the wounds was followed up by measuring transepidermal water loss and blood flow in the wound, reflecting the restoration of the epidermal barrier function and inflammation, respectively. The first set of suction blisters (early wound) was made within 48 hours of the first sepsis-induced organ failure and the second set (late wound) four days after the first wound. In addition, measurements were made on the intact skin. Results The average age of the whole study population was 62 years (standard deviation [SD] 12). The mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score on admission was 25 (SD 8). The two most common causes of infections were peritonitis and pneumonia. Sixty-six percent of the patients developed multiple organ failure. The decrease in water evaporation from the wound during the first four days was lower in septic patients than in the control subjects (56 g/m2 per hour versus 124 g/m2 per hour, P = 0.004). On the fourth day, septic patients had significantly higher blood flow in the wound compared with the control subjects (septic patients 110 units versus control subjects 47 units, P = 0.001). No difference in transepidermal water loss from the intact skin was found between septic patients and controls. Septic patients had higher blood flow in the intact skin on the fourth and on the eighth day of study compared with the controls. Conclusions The restoration of the epidermal barrier function is delayed and wound blood flow is increased in patients with severe sepsis.
Koskela, Marjo; Gaddnas, Fiia; Ala-Kokko, Tero I; Laurila, Jouko J; Saarnio, Juha; Oikarinen, Aarne; Koivukangas, Vesa
Neonatal sepsis can be classified into two subtypes depending upon whether the onset of symptoms is before 72 hours of life (early-onset neonatal sepsis-EONS) or later (late-onset neonatal sepsis-LONS). These definitions have contributed greatly to diagnosis and treatment by identifying which microorganisms are likely to be responsible for sepsis during these periods and the expected outcomes of infection. This paper focuses on the tools that microbiologist can offer to diagnose and eventually prevent neonatal sepsis. Here, we discuss the advantages and limitation of the blood culture, the actual gold standard for sepsis diagnosis. In addition, we examine the utility of molecular techniques in the diagnosis and management of neonatal sepsis. PMID:22319539
Paolucci, Michela; Landini, Maria Paola; Sambri, Vittorio
This is a large cohort analysis in severely burned pediatric children to determine whether C-reactive protein (CRP) can be used as a predictor for severe infection or sepsis. Nine-hundred eighteen pediatric burn patients were enrolled in this study. CRP values were measured throughout acute hospitalization and for up to 6 months postburn. Demographic data, incidence of infection, surgical interventions and other relevant clinical information was compiled from medical records. We performed an extensive literature search to identify models that other groups have developed to determine the effects of CRP levels postburn to assess the value of these parameters as predictors of sepsis or severe infection. Statistical analysis was performed using ANOVA and regression analysis where appropriate. Three-hundred fifteen female and 603 male pediatric patients were enrolled in this study. Average total body surface area (TBSA) burn was 45±23%, with full thickness burn over 32±27% TBSA, and patients were 7±6 years old. CRP values significantly correlated with burn size, survival and gender. Significantly higher levels of CRP were found in large burns, in non-survivors, and in females, p<0.05. Using various described models to determine whether CRP levels change before and after an event can predict sepsis or severe infection, we found that CRP cannot predict severe infection or sepsis. Although CRP is a marker of the inflammatory response postburn, CRP fails to predict infection or sepsis in severely burn patients.
Jeschke, Marc G; Finnerty, Celeste C; Kulp, Gabriela A; Kraft, Robert; Herndon, David N
The structure of a cell surface enzyme from a Gram-positive pathogen has been determined to 2-Å resolution. Gram-positive pathogens have a thick cell wall to which proteins and carbohydrate are covalently attached. Streptococcal C5a peptidase (SCP), is a highly specific protease and adhesin/invasin. Structural analysis of a 949-residue fragment of the [D130A,S512A] mutant of SCP from group B Streptococcus (S. agalactiae, SCPB) revealed SCPB is composed of five distinct domains. The N-terminal subtilisin-like protease domain has a 134-residue protease-associated domain inserted into a loop between two ?-strands. This domain also contains one of two Arg-Gly-Asp (RGD) sequences found in SCPB. At the C terminus are three fibronectin type III (Fn) domains. The second RGD sequence is located between Fn1 and Fn2. Our analysis suggests that SCP binding to integrins by the RGD motifs may stabilize conformational changes required for substrate binding.
Brown, C. Kent; Gu, Zu-Yi; Matsuka, Yury V.; Purushothaman, Sai S.; Winter, Laurie A.; Cleary, P. Patrick; Olmsted, Stephen B.; Ohlendorf, Douglas H.; Earhart, Cathleen A.
Development of a group B streptococcal vaccine (GBS) vaccine is the most promising approach for the prevention of GBS infections in babies, given the potential adverse effects of intrapartum antibiotic prophylaxis as well as the need for effective prevention of both adult and late perinatal disease. There are numerous prevention strategies at this time but none are 100% effective in the eradication of neonatal early onset GBS disease and there are no preventative strategies for late onset disease. The need for a GBS vaccine is therefore, of utmost importance. Efforts applying genomics to GBS vaccine development have led to the identification of novel vaccine candidates. The publication of GBS whole genomes coupled with new technologies including multigenome screening and bioinformatics has also allowed researchers to overcome the serotype limitation of earlier vaccine preparations in the search of a universal effective vaccine against GBS. This review brings together the key arguments concerning the potential need of a GBS vaccine in developed countries and describes the current status with GBS epidemiology and microbiology in these countries. PMID:23973345
Melin, Pierrette; Efstratiou, Androulla
The structure of a cell surface enzyme from a gram-positive pathogen has been determined to 2-A resolution. Gram-positive pathogens have a thick cell wall to which proteins and carbohydrate are covalently attached. Streptococcal C5a peptidase (SCP), is a highly specific protease and adhesin/invasin. Structural analysis of a 949-residue fragment of the [D130A,S512A] mutant of SCP from group B Streptococcus (S. agalactiae, SCPB) revealed SCPB is composed of five distinct domains. The N-terminal subtilisin-like protease domain has a 134-residue protease-associated domain inserted into a loop between two beta-strands. This domain also contains one of two Arg-Gly-Asp (RGD) sequences found in SCPB. At the C terminus are three fibronectin type III (Fn) domains. The second RGD sequence is located between Fn1 and Fn2. Our analysis suggests that SCP binding to integrins by the RGD motifs may stabilize conformational changes required for substrate binding. PMID:16344483
Brown, C Kent; Gu, Zu-Yi; Matsuka, Yury V; Purushothaman, Sai S; Winter, Laurie A; Cleary, P Patrick; Olmsted, Stephen B; Ohlendorf, Douglas H; Earhart, Cathleen A
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 (55)Fe 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. PMID:18990191
Heather, Zoe; Holden, Matthew T G; Steward, Karen F; Parkhill, Julian; Song, Lijiang; Challis, Gregory L; Robinson, Carl; Davis-Poynter, Nicholas; Waller, Andrew S
To describe the clinical features of individuals hospitalized for postpartum invasive group A Streptococcus (GAS) infection, a retrospective, population-based study of hospitalized patients in the state of Florida was conducted. Cases of postpartum invasive GAS infection (occurring within 42 days of delivery) were compared to women with other manifestations of invasive GAS disease with respect to their age at the time of admission. Four cases of postpartum invasive GAS infection were detected in this population, yielding a prevalence of 1.6% (4/257) of postpartum disease in this invasive GAS infection database. Patients presented a median of 4 days (mean of 9 days) after delivery with signs and symptoms of infection. Three cases were complicated by bacteremia and one patient had streptococcal toxic shock syndrome. Each patient received multiple antibiotics and survived. No patients received intravenous immunoglobulin. For comparison, a secondary retrospective investigation of a large hospital discharge dataset obtained from the Florida Agency for Health Care Administration was assessed for patients with puerperal GAS infections. This method yielded an additional three cases, whose clinical and demographic characteristics were summarized. These data highlight that postpartum invasive GAS infection continues to complicate pregnancy, though the frequency has decreased markedly over the past century.
Aronoff, David M.; Mulla, Zuber D.
ABSTRACT: 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. PMID:22889177
Dwivedi, Dhruva J; Toltl, Lisa J; Swystun, Laura L; Pogue, Janice; Liaw, Kao-Lee; Weitz, Jeffrey I; Cook, Deborah J; Fox-Robichaud, Alison E; Liaw, Patricia C
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.
Because of reported differences in the production of streptococcal pyrogenic exotoxins by group A strains associated with severe streptococcal infections, the stability of exotoxin production by specific strains was examined by passing group A streptococci on blood agar culture plates daily for 20 days. No changes were detected in either exotoxin genes or in exotoxin production during this time, suggesting that these reported differences are due to other explanations such as differences in the strains collected from various geographic areas or to laboratory methodologic differences. PMID:1955721
Kaplan, E L; Johnson, D R; Wlazlo, A; Kim, M H; Schlievert, P M
The present invention provides a group B streptococcal (GBS) surface antigen, designated epsilon antigen, that is co-expressed with the delta antigen on a subset of serotype III GBS. Epsilon is expressed on more pathogenic Restriction Digest Pattern (RDP) III-3 GBS, but not on RDP types 1, 2, or 4. Accordingly, the present invention provides compositions and methods for detecting a group B streptococcus serotype III, RDP III-3 strain. Vaccines and methods of identifying agents which inhibit adhesion of a group B streptococcal cell to a host cell are also provided.
Brady, Linda Jeannine (Gainesville, FL); Seifert, Kyle N. (Harrisonburg, VA); Adderson, Elisabeth E. (Memphis, TN); Bohnsack, John F. (Salt Lake City, UT)
The frequency of symptomatic relapses following various antibiotic treatments for group A beta-hemolytic streptococcal tonsillopharyngitis was evaluated in 1080 pediatric patients. Within 5 days of completing therapy, the rank-order frequency of treatment failures was (1) penicillin, (2) amoxicillin, (3) first-generation cephalosporins, (4) beta-lactamase stable cephalosporins and amoxicillin-clavulanate ( P = .005). Retreatment of symptomatic failures resulted in another symptomatic relapse more often with penicillin than with cephalosporins (P = .02). Clinicians should be aware that the rate of symptomatic failures after antibiotic therapy for group A beta-hemolytic streptococcal tonsillopharyngitis differs by drug and is not an uncommon event. PMID:17475987
Casey, Janet R; Pichichero, Michael E
OBJECTIVES: A study was made of the epidemiological data of sepsis requiring admission to the ICU in patients over 65 years of age, with an evaluation of independent predictors of survival at 2 years. DESIGN: A prospective cohort study was made. PATIENTS: Patients meeting criteria for sepsis upon admission to the ICU. SETTING: A 40-bed ICU in a tertiary hospital. RESULTS: The study group included 237 elderly patients (?65 years of age) and 281 controls (<65 years of age) (n=518). At least one chronic comorbid condition was present in 70% of the elderly patients as compared to only 56.1% of patients under age 65 (P<.01). There were several epidemiological differences between the groups: the prevalence of chronic diseases (diabetes, chronic obstructive pulmonary disease, and chronic heart failure), presentation as septic shock (52.3% vs 42%; P<.05), and the abdomen as the source of sepsis (52% vs 36%; P<.01) were all more frequent in elderly patients. Nine percent of the global patients discharged from hospital died in the 2-year follow-up period, but this rate reached 20% among the elderly. Independent predictors of 2-year mortality in the elderly were: chronic heart failure (adjusted hazard ratio [aHR] 2.24, 95% confidence interval [CI 95%] 1.28-3.94; P<.01), acute renal failure (aHR 3.64, 95%CI 2.10-6.23; P<.01), acute respiratory failure (aHR 3.67, 95%CI 2.31-5.86; P<.01), and inappropriate empirical antimicrobial therapy (aHR 2.19, 95%CI 1.32-3.62; P<.01). CONCLUSIONS: Sepsis showed different demographic characteristics and clinical presentations in the elderly. In the aging cohort, after adjusting for potential confounders, inadequate empirical antimicrobial therapy was associated to a 2-fold decrease in survival at two years. PMID:23462427
Carbajal-Guerrero, J; Cayuela-Domínguez, A; Fernández-García, E; Aldabó-Pallás, T; Márquez-Vácaro, J A; Ortiz-Leyba, C; Garnacho-Montero, J
A new phenomenon of synergistic hemolysis by Clostridium perfringens alpha-toxin and the streptococcal CAMP factor on human and guinea pig erythrocytes is described. A possible mode of action of the CAMP factors is suggested. On human blood agar all of the tested isolates of group B streptococci gave an arrowhead-shaped zone of hemolysis; 74% of group A gave a crescent-shaped lytic zone, whereas all isolates of groups C and G and the remaining 26% of group A streptococci gave a bullet-shaped lytic zone. By comparison, in the CAMP test incubated aerobically and anaerobically, 70 and 91%, respectively, of streptococci other than group B gave positive, arrowhead-shaped lytic zones. If all intermediate positive reactions in the CAMP tests were read as negative after aerobic incubation, only 89% of group B streptococci would be properly identified. The synergistic hemolysis phenomenon, using an alpha-toxin-producing C. perfringens and human blood agar, provided a reliable test for presumptive identification of group B streptococci, with promising potential to differentiate in the same test group A streptococci from other groups. PMID:215600
Gubash, S M
Objective To determine the effect of clinical scores that predict streptococcal infection or rapid streptococcal antigen detection tests compared with delayed antibiotic prescribing. Design Open adaptive pragmatic parallel group randomised controlled trial. Setting Primary care in United Kingdom. Patients Patients aged ?3 with acute sore throat. Intervention An internet programme randomised patients to targeted antibiotic use according to: delayed antibiotics (the comparator group for analyses), clinical score, or antigen test used according to clinical score. During the trial a preliminary streptococcal score (score 1, n=1129) was replaced by a more consistent score (score 2, n=631; features: fever during previous 24 hours; purulence; attends rapidly (within three days after onset of symptoms); inflamed tonsils; no cough/coryza (acronym FeverPAIN). Outcomes Symptom severity reported by patients on a 7 point Likert scale (mean severity of sore throat/difficulty swallowing for days two to four after the consultation (primary outcome)), duration of symptoms, use of antibiotics. Results For score 1 there were no significant differences between groups. For score 2, symptom severity was documented in 80% (168/207 (81%) in delayed antibiotics group; 168/211 (80%) in clinical score group; 166/213 (78%) in antigen test group). Reported severity of symptoms was lower in the clinical score group (?0.33, 95% confidence interval ?0.64 to ?0.02; P=0.04), equivalent to one in three rating sore throat a slight versus moderate problem, with a similar reduction for the antigen test group (?0.30, ?0.61 to ?0.00; P=0.05). Symptoms rated moderately bad or worse resolved significantly faster in the clinical score group (hazard ratio 1.30, 95% confidence interval 1.03 to 1.63) but not the antigen test group (1.11, 0.88 to 1.40). In the delayed antibiotics group, 75/164 (46%) used antibiotics. Use of antibiotics in the clinical score group (60/161) was 29% lower (adjusted risk ratio 0.71, 95% confidence interval 0.50 to 0.95; P=0.02) and in the antigen test group (58/164) was 27% lower (0.73, 0.52 to 0.98; P=0.03). There were no significant differences in complications or reconsultations. Conclusion Targeted use of antibiotics for acute sore throat with a clinical score improves reported symptoms and reduces antibiotic use. Antigen tests used according to a clinical score provide similar benefits but with no clear advantages over a clinical score alone. Trial registration ISRCTN32027234
Oxidative stress (OS) and monocyte HLA-DR expression are known to be predictive of mortality in sepsis; nevertheless, limited information exists regarding sepsis with acute kidney injury (AKI). The aim of the study was to correlate these markers with outcome in septic patients with AKI requiring continuous renal replacement therapy (CRRT). Advanced oxidation protein products (AOPP) were measured in 32 patients
Sandra Silva; Massimo de Cal; Dinna Cruz; Paolo Lentini; Valentina Corradi; Giampiero Gallo; Gabriella Salvatori; Anton Verbine; Lusine Pogoshyan; Federico Nalesso; Alessandra Brendolan; Pasquale Piccinni; Claudio Ronco
Acute Lung Injury (ALI) carries about 50 percent mortality and is frequently associated with an infection (sepsis). Life-support treatment with mechanical ventilation rescues many patients, although superimposed infection or multiple organ failure can result in death. The outcome of a patient developing sepsis depends on two factors: the infection and the pre-existing inflammation. In this study, we described each stage
Isabelle Lesur; Julien Textoris; Béatrice Loriod; Cécile Courbon; Stéphane Garcia; Marc Leone; Catherine Nguyen; Carol Feghali-Bostwick
Objective To explore patient and healthcare professionals’ (HCP) views of clinical scores and rapid streptococcal antigen detection tests (RADTs) for acute sore throat. Design Qualitative semistructured interview study. Setting UK primary care. Participants General practitioners (GPs), nurse practitioners (NPs) and patients from general practices across Hampshire, Oxfordshire and the West Midlands who were participating in the Primary Care Streptococcal Management (PRISM) study. Method Semistructured, face-to-face and phone interviews were conducted with GPs, NPs and patients from general practices across Hampshire, Oxfordshire and the West Midlands. Results 51 participants took part in the study. Of these, 42 were HCPs (29 GPs and 13 NPs) and 9 were patients. HCPs could see a positive role for RADTs in terms of reassurance, as an educational tool for patients, and for aiding inexperienced practitioners, but also had major concerns about RADT use in clinical practice. Particular concerns included the validity of the tests (the role of other bacteria, and carrier states), the tension and possible disconnect with clinical assessment and intuition, the issues of time and resource use and the potential for medicalisation of self-limiting illness. In contrast, however, experience of using RADTs over time seemed to make some participants more positive about using the tests. Moreover, patients were much more positive about the place of RADTs in providing reassurance and in limiting their antibiotic use. Conclusions It is unlikely that RADTs will have a (comfortable) place in clinical practice in the near future until health professionals’ concerns are met, and they have direct experience of using them. The routine use of clinical scoring systems for acute upper respiratory illness also face important barriers related to clinicians’ perceptions of their utility in the face of clinician experience and intuition.
Leydon, Gerry M; McDermott, Lisa; Moore, Mike; Williamson, Ian; Hobbs, F D Richard; Lambton, Tessa; Cooper, Rebecca; Henderson, Hugo; Little, Paul
AIM: A nationwide 24-month study was conducted (2007-2009), via the New Zealand Paediatric Surveillance Unit to define epidemiology and clinical features of acute poststreptococcal glomerulonephritis (APSGN) in children hospitalised with the illness. METHODS: Paediatricians (n = 215) were requested to report new hospitalised cases fulfilling a case definition of definite (haematuria with low C3 and high streptococcal titres or biopsy proven APSGN) or probable (haematuria with low C3 or high streptococcal titres). RESULTS:?: A total of 176 cases were identified (definite: n = 138, probable: n = 38) with 63% residing in the Auckland metropolitan region. Sixty-seven percent were in the most deprived quintile. Annual incidence (0-14 years) was 9.7/100?000 (Pacific 45.5, Maori 15.7, European/other 2.6 and Asian 2.1/100?000). Annual incidence was highest in the South Auckland Metropolitan region (31/100?000), Central Auckland 14.9, West/North Auckland metropolitan region 5.9 and for the remainder of New Zealand 5.5/100?000. Age-specific incidence was highest in age 5-9 years (15.1/100?000). Reduced serum complement C3, gross haematuria, hypertension, impairment of renal function and heavy proteinuria were present in 93%, 87%, 72%, 67% and 44% of patients, respectively. Severe hypertension was closely associated with either symptoms of an acute encephalopathy or congestive heart failure. CONCLUSIONS: New Zealand children carry a significant disease burden of hospitalised APSGN with socio-economically deprived; Pacific and Maori children are being over-represented. Significant short-term complications were observed in hospitalised children with APSGN. Persistently very low rates in European/other suggest a preventable disease. PMID:23782011
Wong, William; Lennon, Diana R; Crone, Sonja; Neutze, Jocelyn M; Reed, Peter W
The mortality induced by severe sepsis and septic shock remains very elevated despite progress in diagnosis and treatment. All the experts in the field consider that further progress is possible with better and more prompt use of the treatments now available. The "Surviving Sepsis" campaign reviews the diverse treatments that can be used and the best ways to prescribe them. It also proposes two bundles of objectives to be completed systematically for all patients: the first within the first 6 hours, the second between the sixth and 24th hour. Encouraging results show that applying these therapeutic principles can reduce mortality by 30% (relative percentage) compared with a treatment without specific objectives. PMID:16550156
Leone, Marc; Vallet, Benoît; Martin, Claude
We compared six inflammatory mediators (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumour necrosis factor receptors (p55 and p75) and soluble adhesion molecules (ICAM-1, E-selectin)) as early diagnostic tests for neonatal sepsis, and studied the possible benefit of combining parameters. Blood samples were obtained from 166 consecutively admitted neonates, who were suspected to suffer from infection within the first week of
Henrik Døllner; Lars Vatten; Rigmor Austgulen
Myocardial dysfunction is an important component in the hemodynamic collapse induced by sepsis and septic shock. A series\\u000a of inflammatory cascades triggered by the inciting infection generate circulatory myocardial depressant substances, including\\u000a TNF-?, IL-1?, PAF and lysozyme. Current evidence suggests that septic myocardial depression in humans is characterized by\\u000a reversible biventricular dilatation, decreased systolic contractile function, and decreased response to
A. Kumar; J. E. Parrillo
Neisseria meningitidis (meningococcus), an exclusive pathogen of humans, is the cause of sepsis (meningococcemia) and meningitis, often in otherwise\\u000a healthy individuals. Several hundred thousand cases of meningococcal disease occur worldwide each year, a number that is frequently\\u000a accentuated by epidemic outbreaks. In recent years, significant advances, fueled by new molecular approaches and genome sequencing\\u000a projects, have improved our understanding of
David S. Stephens; Shanta M. Zimmer
Group A streptococcus (GAS) or Streptococcus pyogenes has been recognised as an important human pathogen since early days of modern microbiology, and it remains among the top ten causes of mortality from an infectious disease. Clinical manifestations attributable to this organism are perhaps the most diverse of any single human pathogen. These encompass invasive GAS infections, with high mortality rates despite effective antimicrobials, toxin-mediated diseases including scarlet fever and streptococcal toxic shock syndrome, the autoimmune sequelae of rheumatic fever and glomerulonephritis with potential for long-term disability, and nuisance manifestations of superficial skin and pharyngeal infection, which continue to consume a sizable proportion of healthcare resources. Although an historical perspective indicates major overall reductions in GAS infection rates in the modern era, chiefly as a result of widespread improvements in socioeconomic circumstances, this pathogen remains as a leading infectious cause of global morbidity and mortality. More than 18 million people globally are estimated to suffer from serious GAS disease. This burden disproportionally affects least affluent populations, and is a major cause of illness and death among children and young adults, including pregnant women, in low-resource settings. We review GAS transmission characteristics and prevention strategies, historical and geographical trends and report on the estimated global burden disease attributable to GAS. The lack of systematic reporting makes accurate estimation of rates difficult. This highlights the need to support improved surveillance and epidemiological research in low-resource settings, in order to enable better assessment of national and global disease burdens, target control strategies appropriately and assess the success of control interventions. PMID:23242849
Ralph, Anna P; Carapetis, Jonathan R
Serotypes of group A streptococci are still a major cause of pharyngitis and some post-infectious sequelae such as rheumatic fever. As part of the worldwide effort to clarify the epidemiological pattern of group A streptococci in different countries, the present study was conducted to assess the prevalence of Streptococcus pyogenes serotypes in Iran. A total of 1588 throat swabs were taken from healthy school children in the city of Gorgan during February and March 1999. Of those isolates, 175 resulted positive for group A streptococci. The distribution pattern was similar for girls and boys, with 10.8% and 11.2%, respectively. Urban school children showed a higher rate of colonization compared to those in rural areas. Serotyping was performed on 65 of the positive isolates using standard techniques, and only 21 (32%) were M-type isolates. Their profiles fell into four types with M1 predominating, which could reflect the presence of rheumatic fever in the region. However, when isolates were challenged for T-antigen types, nearly all were positive (94%). The pattern of T types was diverse (18 types), with the most common T types being T1 (26%), TB3264 (15%), TB\\1-19 & B\\25\\1-19 (9.2%) and T2 & 2\\28 (7.7%). When isolates were tested for opacity factor, only 23 (35%) were positive while 34 (52%) responded to the serum opacity reaction test. Although the number of isolates in this study was not sufficient to make any epidemiological conclusions, the scarcity of serotyping studies in Iran could render these data useful for future attempts to develop a streptococcal vaccine. PMID:12884067
Fazeli, M R; Ghaemi, E; Tabarraei, A; Kaplan, E L; Johnson, D R; Vakili, M A; Khodabakhshi, B
The immune response of nine inbred and one outbred strain of mice to the streptococcal group A polysaccharide was investigated with respect to magnitude and restriction. Analytical isoelectric focusing served as a tool to estimate the degree of restriction of Group A polysaccharide-specific antibodies. It proved feasible to distinguish low and intermediate from high responder strains, and to delineate strain-specificity of isoelectric focusing spectra of the immune sera. For example, immune sera of BALB/c mice, restricted high responders, and of C57BL/6 mice, heterogeneous low responders, had distinct focusing properties. Responsiveness was a dominant autosomal genetic trait in C57BL/6 x BALB/c F1 hybrid mice, irrespective of the maternal and the paternal genotype; the immune sera of these mice had their own, rather uniform isoelectric focusing spectra whereby structural genes of the low responder strain were expressed to predominant levels in 81% of the hybrids. Responsiveness in C57BL/6 x BALB/c F2 progeny segregated into 79% high and 21% low responders, and showed no genetic linkage to the following characteristics: hair color, sex, H-2 type, and Ig allotype of the heavy chain. The isoelectric focusing properties of these immune sera indicated segregation into patterns like BALB/c mice (40%), F1 hybrids (48%), and C57BL/6 mice (12%). Since this segregation is independent of any of the above criteria in these F2 mice a regulatory gene(s) is postulated that controls the clonal pattern of the immune response.
Cramer, Matthias; Braun, Dietmar G.
Low plasma levels of the opsonic glycoprotein fibronectin (Fn) have been suggested to imply an impaired host defense against sepsis. However, the mechanism(s) behind Fn depletion in sepsis are obscure. We measured the Fn plasma concentration in 32 patients 12 to 24 h after the diagnosis of septic shock. Although the average plasma level was low (214 +/- 80 [SD] mg/L) compared to that of a reference material (p less than .001), the range was great (60 to 403 mg/L). A multivariate analysis of some possible influencing factors showed significant (p less than .01) positive correlations to the prothrombin level (r = .62) and the amount of insulin infused per 24 h (r = .63). The relationships to disseminated intravascular coagulation-related variables, hemodilution, and outcome were weak. Cryoprecipitate was infused into 16 patients; Fn levels increased by 52 +/- 18% of the expected increase. The most severely ill patients displayed the lowest rates of increase. The postinfusion decrease in Fn plasma concentration indicated that the plasma half-life of cryoprecipitate Fn was about 25 h. The results support the concept that decreased Fn synthesis, probably in the liver, is the major reason for Fn depletion in sepsis, rather than an increased rate of consumption. PMID:3677761
Hesselvik, J F
Sepsis in humans is a major problem involving many individuals and with a high death rate. Except for a single drug (recombinant activated protein C) that has been approved for treatment of septic patients, supportive measures represent the main clinical approach. There are many models of experimental sepsis, mostly in rodents. A commonly used model is cecal ligation and puncture (CLP). In this model, robust activation of complement occurs together with upregulation of C5a receptors (C5aR, C5L2) in a variety of different organs (lungs, kidneys, liver, heart). In septic humans there is abundant evidence for complement activation. Interception of C5a or its receptors in the CLP model greatly improves survival in septic rodents. There is compelling evidence that CLP causes an intense proinflammatory state and that C5a interaction with its receptors can be linked to apoptosis of the lymphoid system and cells of the adrenal medulla, loss of innate immune functions of blood neutrophils, consumptive coagulopathy, and cardiac dysfunction. These findings may have implications for therapeutic interventions in humans with sepsis.
Ward, Peter A.; Gao, Hongwei
Severe sepsis and septic shock are lethal complications of infection, characterised by dysregulated inflammatory and immune responses. Our understanding of the pathogenesis of sepsis has improved markedly in recent years, but unfortunately has not been translated into efficient treatment strategies. Epigenetic mechanisms such as covalent modification of histones by acetylation are master regulators of gene expression under physiological and pathological conditions, and strongly impact on inflammatory and host defence responses. Histone acetylation is controlled by histone acetyltransferases and histone deacetylases (HDACs), which affect gene expression also by targeting non-histone transcriptional regulators. Numerous HDAC inhibitors (HDACi) are being tested in clinical trials, primarily for the treatment of cancer. We performed the first comprehensive study of the impact of HDACi on innate immune responses in vitro and in vivo. We showed that HDACi act essentially as negative regulators of the expression of critical immune receptors and antimicrobial pathways in innate immune cells. In agreement, HDACi impaired phagocytosis and killing of bacteria by macrophages, and increased susceptibility to non-severe bacterial and fungal infections. Strikingly, proof-of-principle studies demonstrated that HDACi protect from lethal toxic shock and septic shock. Overall, our observations argue for a close monitoring of the immunological and infection status of patients treated with HDACi, especially immunocompromised cancer patients. They also support the concept of pharmacological inhibitors of HDACs as promising drugs to treat inflammatory diseases, including sepsis. PMID:23664675
Ciarlo, Eleonora; Savva, Athina; Roger, Thierry
Sepsis is characterised by a hyper-inflammatory response due to microbial infection. We here review our current understanding of host mechanisms employed to mediate this hyper-inflammatory response, drawing together current knowledge pertaining to pathogen recognition and host pro-inflammatory response. Recognition of microbial derived ligands by pattern recognition receptors (PRRs) is a key step in initiating pro-inflammatory signalling pathways. Examples of PRRs linked to the aetiology of sepsis include Toll-like, C-type lectin, RIG-1-like and also Nod-like receptors, which are involved in the formation of the inflammasome, crucial for the maturation of some pro-inflammatory cytokines. Bacterial superantigens have evolved to exploit host MHC class II and T cell receptors (normally considered part of the adaptive immune response) as innate PRRs to propagate a so-called 'cytokine storm', while synergy between different microbial ligands and host-derived alarmins can augment the inflammatory response still further through as yet poorly understood interactions. The host pro-inflammatory response results in the characteristic features of inflammation: rubor, calor, dolor, and tumor. We will review herein the key mediators of inflammation in sepsis, identifying their overlapping and intersecting roles in vascular changes in tone, endothelial permeability, coagulation and contact activation, leukocyte mobilisation and activation. PMID:21659748
Chong, Deborah L W; Sriskandan, Shiranee
Nursing home residents are at high risk for invasive group A streptococcal (GAS) disease, and clusters of cases in nursing homes are common.To characterize the epidemi- ologic features of invasive GAS disease in nursing homes, we conducted active, statewide, population- and laboratory- based surveillance in Minnesota from April 1995 through 2006. Of 1,858 invasive GAS disease cases, 134 (7%) oc-
Jean Rainbow; Brenda Jewell; Richard N. Danila; David Boxrud; Bernard Beall; Chris Van Beneden; Ruth Lynfi
Two outbreaks of group A streptococcal abscesses following receipt of diphtheria-tetanus toxoid-pertussis (DTP) vaccine from different manufacturers were reported to the Centers for Disease Control (CDC) in 1982. The clustering of the immunization times of cases, the isolation of the same serotype of Streptococcus from all cases in each outbreak, and the absence of reported abscesses associated with receipt of
Harrison C. Stetler; Paul L. Garbe; Diane M. Dwyer; Richard R. Facklam; Walter A. Orenstein; Gary R. West; K. Joyce Dudley; Alan B. Bloch
The value of cooperation between clinicians and laboratorians is scarcely controversial, yet failure to assure adequate laboratory participation in implementing new programs can have serious clinical consequences. The recent example of preventing group B streptococcal (GBS) disease in newborns is illustrative. Neonatal GBS infection can lead to death, long term disability, and substantial direct and indirect health care costs, while
The nucleotide sequence of the gene encoding group A streptococcal pyrogenic exotoxin type A (SPE A) was determined by the dideoxy chain termination method. The first 30 residues of the translation product represented a hydrophobic signal peptide. The mature protein was 220 amino acids in length and had a molecular weight of 25,805. It has significant protein sequence homology with
James J. L'Italien; Patrick M. Schlievert
OBJECTIVE: To evaluate the utility of rapid antigen detection testing (RADT) for the diagnosis of group A beta-hemolytic streptococcal tonsillopharyngitis in children, and to detect the sensitivity and specificity of rapid antigen detection of group A beta-hemolytic streptococci from throat specimen compared with throat culture. METHODS: Rapid antigen detection and throat culture results for group A beta-hemolytic streptococci from outpatients attending university hospital between 1st January 2011 and 31st of December 2011 were evaluated retrospectively. The antigen test negative-throat culture positive patients were investigated for streptococcal carriage. For this purpose, the throat culture results taken from these patients were reviewed after treatment. RESULTS: Eighthundred and ninetytwo children were included in the studywith a mean age of 5.34 y. There were 639 and 253 children in two groups with age of 0-6 and 7-17 y, RADT sensitivity and specificity were found to be 59.5 % and 97.2 %, respectively. The positive predictive value was 87.1 %, whereas negative predictive value was 88.4 %. After treatment of 74 patients with throat culture positive and antigen test negative. Group A beta-hemolytic streptococci were isolated in 12 of them (16.2 %) and accepted as a carrier. CONCLUSIONS: The low sensitivity of the RADT may be related to streptococcal carriage in some patients. The throat culture should be repeated after treatment to detect streptococcal carriage. PMID:23749414
Küçük, Oznur; Biçer, Suat; Giray, Tuba; Cöl, Defne; Erda?, Gülay Ciler; Gürol, Ye?im; Kaspar, Ci?dem E; Vitrinel, Ayça
Streptococcal pyrogenic exotoxin B (SPE B), a cysteine protease, is an important virulence factor in group A streptococcus (GAS) infection. The inhibition of phagocytic activity by SPE B may help prevent bacteria from being ingested. In this study, we examined the mechanism SPE B uses to enable bacteria to resist opsono- phagocytosis. Using an enzyme-linked immunosorbent assay, we found that
Chih-Feng Kuo; Yee-Shin Lin; Woei-Jer Chuang; Jiunn-Jong Wu; Nina Tsao
We report a case of group A streptococcal meningitis in an infant resulting from an infected capillary haemangioma. The child suffered significant morbidity including cerebral infarction, epilepsy, and developmental delay. Treatment of infected capillary haemangiomas remains controversial and inconsistent. Conclusion: Our experience of this infant, resulting in profound neurological morbidity suggests that group A Streptococcus can be a virulent organism
Massoud Rezvani; Jerome Y. Yager; Dawn S. Hartfield
We identified seven novel variants of streptococcal pyrogenic exotoxin G (SPEGG), a superantigen, in Streptococcus dysgalactiae subsp. dysgalactiae or equisimilis isolates from clinical cases of infection in humans and animals. Phylogenetic analysis of the SPEGG variants indicated two clades in the dendrogram: one composed of variants derived from the bacteria isolated from the humans and the other composed of variants
Jizi Zhao; Tomohito Hayashi; Susanna Saarinen; Anastassios C. Papageorgiou; Hidehito Kato; K. Imanishi; T. Kirikae; R. Abe; T. Uchiyama; T. Miyoshi-Akiyama
Objectives: In the United States, universal screening for group B streptococcal (GBS) colonization is recommended at 35 to 37 weeks' gestation. Previous studies have shown equivalent detection rates for GBS when women receive uniform instruction about specimen collection. It is unclear if these results would hold among patients with limited education given minimal, nonuniform instruction about collec- tion technique. Methods:
Paul Hicks; Maria J. Diaz-Perez
Infection of the skin or throat by Streptococcus dysgalactiae subspecies equisimilis (SDSE) may result in a number of human diseases. To understand mechanisms that give rise to new genetic variants in this species, we used multi-locus sequence typing (MLST) to characterise relationships in the SDSE population from India, a country where streptococcal disease is endemic. The study revealed Indian SDSE
David J. McMillan; Santosh Y. Kaul; P. V. Bramhachari; Pierre R. Smeesters; Therese Vu; M. G. Karmarkar; Melkote S. Shaila; Kadaba S. Sriprakash
Background Adult opsoclonus?myoclonus (OM), a disorder of eye movements accompanied by myoclonus affecting the trunk, limbs, or head, is commonly associated with an underlying malignancy or precipitated by viral infection. Methods We present the first two reports of post?streptococcal OM associated with antibodies against a 56?kDa protein. Two young girls presented with opsoclonus and myoclonus following a febrile illness and pharyngitis. Protein purification techniques were employed. Amino acid sequences of human neuroleukin (NLK) and streptococcal proteins were compared using the protein?protein BLAST application. Results The antigen was identified as NLK (glucose?6?phosphate isomerase, GPI). GPI is present on the cell surface of streptococcus making the protein a candidate target for molecular mimicry. Conclusions We have identified NLK as an antigenic target in two patients with post?streptococcal OM. The pathogenicity of the antibodies is uncertain. The potential role of anti?neuroleukin antibodies in the pathogenesis of OM is discussed. We propose that OM may represent a further syndrome in the growing spectrum of post?streptococcal neurological disorders. The role of streptococcus in OM and the frequency with which anti?NLK responses occur in both post?infectious and paraneoplastic OM should be investigated further.
Candler, P M; Dale, R C; Griffin, S; Church, A J; Wait, R; Chapman, M D; Keir, G; Giovannoni, G; Rees, J H
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 is a very heterogeneous clinical syndrome broadly defined as the systemic host response to an infection. Until very recently, the prevailing concept of the pathogenesis of sepsis was that mortality is the consequence of an uncontrolled hyperinf lammatory response of the host. The disappointing results of nearly 40 years of anti-inflammatory strategies and the development of animal models that more closely mimic clinical sepsis have led to the reconsideration of the pathophysiology of sepsis. Sepsis is now considered a misbalance between proinflammatory reactions (designed to kill invading pathogens but at the same time responsible for tissue damage) and anti-inflammatory responses (designed to limit excessive inflammation, but at the same time making the host more vulnerable for secondary infections). This review discusses key components of the pro- and anti-inflammatory response to sepsis, listing potential novel interventional strategies along the way. PMID:20421654
Anas, A A; Wiersinga, W J; de Vos, A F; van der Poll, T
Introduction Sepsis-associated delirium (SAD) increases morbidity in septic patients and, therefore, factors contributing to SAD should be further characterized. One possible mechanism might be the impairment of cerebrovascular autoregulation (AR) by sepsis, leading to cerebral hypo- or hyperperfusion in these haemodynamically unstable patients. Therefore, the present study investigates the relationship between the incidence of SAD and the status of AR during sepsis. Methods Cerebral blood flow velocity was measured using transcranial Doppler sonography and was correlated with the invasive arterial blood pressure curve to calculate the index of AR Mx (Mx>0.3 indicates impaired AR). Mx was measured daily during the first 4 days of sepsis. Diagnosis of a SAD was performed using the confusion assessment method for ICU (CAM-ICU) and, furthermore the predominant brain electrical activity in electroencephalogram (EEG) both at day 4 after reduction of sedation to RASS >-2. Results 30 critically ill adult patients with severe sepsis or septic shock (APACHE II 32 ± 6) were included. AR was impaired at day 1 in 60%, day 2 in 59%, day 3 in 41% and day 4 in 46% of patients; SAD detected by CAM-ICU was present in 76 % of patients. Impaired AR at day 1 was associated with the incidence of SAD at day 4 (p = 0.035). Conclusions AR is impaired in the great majority of patients with severe sepsis during the first two days. Impaired AR is associated with SAD, suggesting that dysfunction of AR is one of the trigger mechanisms contributing to the development of SAD. Trial registration clinicalTrials.gov ID NCT01029080
Sepsis is associated with an initial hyperinflammatory state; however, therapeutic trials targeting the inflammatory response have yielded disappointing results. It is now appreciated that septic patients often undergo a period of relative immunosuppression, rendering them susceptible to secondary infections. Interest in this phenomenon has led to the development of animal models to study the immune dysfunction of sepsis. In this review, we analyze the available models of sepsis-induced immunosuppression.
Hu, Scott B.; Zider, Alexander; Deng, Jane C.
Septic syndromes induce immune alterations that have long been considered solely an overwhelming pro-inflammatory response. Increasing evidence now suggests that, after the first pro-inflammatory hours, sepsis is accompanied by the occurrence of a systemic immune failure. Here, novel perspectives regarding sepsis-induced lymphocyte alterations will be discussed in the context of a recently published study investigating overtime evolution of co-inhibitory lymphocyte receptor expressions in patients with severe sepsis.
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 x 10(8) 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-alpha (TNF-alpha) 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-alpha monoclonal antibody treatment. The infected mice treated intraperitoneally with Escherichia coli lipopolysaccharide (LPS) showed augmentation of bacterial growth, muscular necrosis and death. TNF-alpha 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-alpha monoclonal antibody treatment decreased mortality in the infected mice treated with LPS. Moreover, the infected mice treated with recombinant TNF-alpha showed augmentation of muscular necrosis and death. These results suggest that systemic production of TNF-alpha induced by stimulation with LPS inhibits infiltration of leucocytes into the infected site and exacerbates muscular infection, and that TNF-alpha 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. PMID:11918696
Diao, Hongyan; Kohanawa, Masashi; Yimin; Nakajima, Hirofumi; Sato, Yuichiro; Minagawa, Tomonori; Nakane, Akio
Background and Objectives Rhabdomyolysis is often associated with sepsis and gram positive bacterial pathogens are reported to be the most frequent cause of sepsis induced rhabdomyolysis. We report the pattern of infecting bacterial pathogens and associated causal factors in a South-Indian cohort. Design, Setting, Participants & Measurements Retrospective cohort study of adult patients with community acquired bacterial sepsis complicated by rhabdomyolysis from March 2003 - August 2008. Rhabdomyolysis was defined as serum creatine kinase >2000 IU/L. The study population was divided into group-I (sepsis with gram positive pathogens), group–II (sepsis with gram negative pathogens) and group-III (culture negative sepsis). Results 103 patients (group I -15, group II- 34 and group III- 54) formed the study cohort. Mean age was 55 years and two-third had diabetes. Mean creatine kinase was 7114 IU/L and mean serum creatinine on admission was 2.4 mg/dl. Causative pathogen of sepsis was identified in 47.5%. Gram negative pathogens were more frequently (33%) associated with rhabdomyolysis than gram positive pathogens (14.5%). Lung was the commonest foci of sepsis (38.8%). 78.6% of the study population had one or more additional causal factor for rhabdomyolysis like statin intake, chronic alcoholism, hypokalemia, hypernatremia and hypophosphatemia. Mortality was 59%. Conclusions Gram negative bacterial pathogens were more frequently associated with rhabdomyolysis than gram positive pathogens. Rhabdomyolysis in patients with sepsis is multifactorial and is associated with high mortality.
Kumar, Anita A.; Bhaskar, Emmanuel; Palamaner Subash Shantha, Ghanshyam; Swaminathan, Porchelvan; Abraham, Georgi
Background Patients with cirrhosis and sepsis had increased mortality.\\u000a \\u000a \\u000a \\u000a Aim Determine factors associated with increased in-hospital mortality in cirrhotic patients admitted for sepsis.\\u000a \\u000a \\u000a \\u000a Methods All cirrhotic patients admitted from 2004 to 2007 for sepsis were identified from hospital electronic database. Patients were\\u000a included if they had liver cirrhosis and sepsis, defined as identified sources of infection, and at least one of fever, altered
Lee-Guan Lim; Xiang-Xuan Eunice Tan; Shu-Jeng Woo; Yock-Young Dan; Yin-Mei Lee; Vincent Lai; Seng-Gee Lim
Background: Few studies demonstrated that serum amyloid A (SAA), a non-specific acute-phase reactant, could be used as a reliable early marker for the diagnosis of late-onset sepsis (LOS). Objectives: To evaluate the diagnostic value and the dynamics of SAA levels during the course of LOS and to compare it to those of other inflammatory markers. Methods: Levels of SAA, C-reactive
Shmuel Arnon; Ita Litmanovitz; Rivka Regev; Sofia Bauer; Monica Lis; Ruth Shainkin-Kestenbaum; Tzipora Dolfin
The streptococcal cysteine protease (SpeB) is one of the major virulence factors produced by group A streptococci (GAS). In this study we investigated if differences exist in SpeB production by clonally related M1T1 clinical isolates derived from patients with invasive infections. Twenty-nine of these isolates were from nonsevere cases and 48 were from severe cases, including streptococcal toxic shock syndrome
RITA G. KANSAL; ALLISON MCGEER; DONALD E. LOW; ANNA NORRBY-TEGLUND; MALAK KOTB
Klebsiella (K.) pneumoniae is a common cause of pneumonia-derived sepsis. Myeloid related protein 8 (MRP8, S100A8) and MRP14 (S100A9) are the most abundant cytoplasmic proteins in neutrophils. They can form MRP8/14 heterodimers that are released upon cell stress stimuli. MRP8/14 reportedly exerts antimicrobial activity, but in acute fulminant sepsis models MRP8/14 has been found to contribute to organ damage and death. We here determined the role of MRP8/14 in K. pneumoniae sepsis originating from the lungs, using an established model characterized by gradual growth of bacteria with subsequent dissemination. Infection resulted in gradually increasing MRP8/14 levels in lungs and plasma. Mrp14 deficient (mrp14?/?) mice, unable to form MRP8/14 heterodimers, showed enhanced bacterial dissemination accompanied by increased organ damage and a reduced survival. Mrp14?/? macrophages were reduced in their capacity to phagocytose Klebsiella. In addition, recombinant MRP8/14 heterodimers, but not MRP8 or MRP14 alone, prevented growth of Klebsiella in vitro through chelation of divalent cations. Neutrophil extracellular traps (NETs) prepared from wildtype but not from mrp14?/? neutrophils inhibited Klebsiella growth; in accordance, the capacity of human NETs to kill Klebsiella was strongly impaired by an anti-MRP14 antibody or the addition of zinc. These results identify MRP8/14 as key player in protective innate immunity during Klebsiella pneumonia.
Achouiti, Ahmed; Vogl, Thomas; Urban, Constantin F.; Rohm, Marc; Hommes, Tijmen J.; van Zoelen, Marieke A. D.; Florquin, Sandrine; Roth, Johannes; van 't Veer, Cornelis; de Vos, Alex F.; van der Poll, Tom
Tissue factor expression in sepsis activates coagulation in the lung, which potentiates inflammation and leads to fibrin deposition. We hypothesized that blockade of factor X binding to the tissue factor-factor VIIa complex would prevent sepsis-induced damage to the lungs and other organs. Acute lung injury was produced in 15 adult baboons primed with killed Escherichia coli [1 x 10(9) colony-forming units (CFU)/kg], and then 12 h later, they were given 1 x 10(10) CFU/kg live E. coli by infusion. Two hours after live E. coli, animals received antibiotics with or without monoclonal antibody to tissue factor intravenously to block tissue factor-factor X binding. The animals were monitored physiologically for 34 h before being killed and their tissue harvested. The antibody treatment attenuated abnormalities in gas exchange and lung compliance, preserved renal function, and prevented tissue neutrophil influx and bowel edema relative to antibiotics alone (all P < 0.05). It also attenuated fibrinogen depletion (P < 0.01) and decreased proinflammatory cytokines, e.g., IL-6 and -8 (P < 0.01), in systemic and alveolar compartments. Similar protective effects of the antibody on IL-6 and -8 expression and permeability were found in lipopolysaccharide-stimulated endothelial cells. Blockade of factor X binding to the tissue factor-factor VIIa complex attenuates lung and organ injuries in established E. coli sepsis by attenuating the neutrophilic response and inflammatory pathways. PMID:16100288
Welty-Wolf, Karen E; Carraway, Martha S; Ortel, Thomas L; Ghio, Andrew J; Idell, Steven; Egan, Jack; Zhu, Xiaoyun; Jiao, Jin-an; Wong, Hing C; Piantadosi, Claude A
Klebsiella (K.) pneumoniae is a common cause of pneumonia-derived sepsis. Myeloid related protein 8 (MRP8, S100A8) and MRP14 (S100A9) are the most abundant cytoplasmic proteins in neutrophils. They can form MRP8/14 heterodimers that are released upon cell stress stimuli. MRP8/14 reportedly exerts antimicrobial activity, but in acute fulminant sepsis models MRP8/14 has been found to contribute to organ damage and death. We here determined the role of MRP8/14 in K. pneumoniae sepsis originating from the lungs, using an established model characterized by gradual growth of bacteria with subsequent dissemination. Infection resulted in gradually increasing MRP8/14 levels in lungs and plasma. Mrp14 deficient (mrp14(-/-)) mice, unable to form MRP8/14 heterodimers, showed enhanced bacterial dissemination accompanied by increased organ damage and a reduced survival. Mrp14(-/-) macrophages were reduced in their capacity to phagocytose Klebsiella. In addition, recombinant MRP8/14 heterodimers, but not MRP8 or MRP14 alone, prevented growth of Klebsiella in vitro through chelation of divalent cations. Neutrophil extracellular traps (NETs) prepared from wildtype but not from mrp14(-/-) neutrophils inhibited Klebsiella growth; in accordance, the capacity of human NETs to kill Klebsiella was strongly impaired by an anti-MRP14 antibody or the addition of zinc. These results identify MRP8/14 as key player in protective innate immunity during Klebsiella pneumonia. PMID:23133376
Achouiti, Ahmed; Vogl, Thomas; Urban, Constantin F; Röhm, Marc; Hommes, Tijmen J; van Zoelen, Marieke A D; Florquin, Sandrine; Roth, Johannes; van 't Veer, Cornelis; de Vos, Alex F; van der Poll, Tom
Sepsis and septic shock lead to considerable morbidity and mortality in developed and developing countries. Despite advances in understanding the innate immune events that lead to septic shock, molecular therapies based on these advances have failed to improve sepsis mortality. The clinical failure of laboratory-derived therapies may be, in part, due to the pleiotropic consequences of the acute inflammatory response, which is the focus of this review. A brisk response to infecting organism is essential for pathogen containment and eradication. However, systemic spread of inflammation beyond a single focus leads to organ injury and higher mortality. The primary goal of this article is to discuss recent animal- and human-based scientific advances in understanding the host response to infection and to highlight how these defense mechanisms can be locally beneficial but systemically detrimental. There are other factors that determine the severity of sepsis that are beyond the scope of this review, including the virulence of the pathogen and regulation by Toll-like receptors. Specifically, this review focuses on how the effector mechanisms of platelets, mast cells, neutrophil extracellular traps (NETs), and the endothelium participate in combating local infections yet can induce organ injury during systemic infection.
Matthay, Michael A.; Wolters, Paul J.
Apoptosis(programmed cell death) is induced in pulmonary cells and contributes to the pathogenesis of acute lung injury in septic humans. Previous studies have shown that nitric oxide (NO) is an important modulator of apoptosis; however, the functional role of NO derived from inducible NO synthase (iNOS) in sepsis-induced pulmonary apoptosis remains unknown. We measured pulmonary apoptosis in a rat model of Escherichia coli lipopolysaccharide (LPS)-induced sepsis in the absence and presence of the selective iNOS inhibitor 1400W. Four groups were studied 24 h after saline (control) or LPS injection in the absence and presence of 1400W pretreatment. Apoptosis was evaluated using DNA fragmentation, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and caspase activation. LPS administration significantly augmented pulmonary cell apoptosis and caspase-3 activity in airway and alveolar epithelial cells. Pretreatment with 1400W significantly enhanced LPS-induced pulmonary apoptosis and increased caspase-3 and -7 activation. The antiapoptotic effect of iNOS was confirmed in iNOS-/- mice, which developed a greater degree of pulmonary apoptosis both under control conditions and in response to LPS compared with wild-type mice. By comparison, genetic deletion of the neuronal NOS had no effect on LPS-induced pulmonary apoptosis. We conclude that NO derived from iNOS plays an important protective role against sepsis-induced pulmonary apoptosis. PMID:14660484
Rudkowski, Jill C; Barreiro, Esther; Harfouche, Rania; Goldberg, Peter; Kishta, Osama; D'Orleans-Juste, Pedro; Labonte, Julie; Lesur, Olivier; Hussain, Sabah N A
During the report period, we studied sepsis-associated acute lung injury using a porcine model. In multiple protocols we found that deletion of certain proinflammatory mediators or disruption of neutrophil - endothelial cellular adhesion molecules effecti...
H. J. Sugerman A. A. Fowler
This review summarizes new insights in the pathophysiologic implications of inflammation and microvascular alterations in organ dysfunction, as well as genetic factor contribution, from clinical and experimental studies that were published in 2010 in Critical Care in the fields of multiple organ dysfunction and sepsis. New diagnostic and prognostic markers of organ dysfunction are presented. Evaluations of novel therapeutic strategies, including implementation of international guidelines, modulation of inflammation and coagulation, and prevention of ventilator-induced lung injury and acute kidney injury, are reported. The results of these experimental studies and clinical trials are discussed in the context of the current relevant scientific and clinical background.
Lemierre’s syndrome is a rare clinical syndrome defined as oropharyngeal sepsis, thrombophlebitis of the internal jugular vein and septic thombo-emboli. It is typically encountered in young, immunocompetent individuals, with a mean incident age of 20 years. The organism that is most commonly associated is an anaerobic Gram-negative bacterium: Fusobacterium species. The defined treatment course is at least six weeks of antibiotics, with the role of anticoagulation being unclear. The present article documents a case of Lemierre’s syndrome complicated by acute renal failure and loculated pleural effusion in an otherwise healthy 16-year-old patient.
Dirks, Jacquelyn; Bowie, Dennis
A 79-year-old man with a 3-month history of lymphedema of the lower limbs, and diabetes mellitus, was admitted to our hospital for suspected deep venous thrombosis. Several hours after admission, leg pain and purpura-like skin color appeared. On the 2nd hospital day, he was referred to our department for possible acute occlusive peripheral artery disease (PAD) and skin necrosis with blisters; however, computed tomography with contrast showed no occlusive lesions. He had already developed shock and necrotizing deep soft-tissue infections of the left lower leg. Laboratory findings revealed renal dysfunction and coagulation system collapse. Soon after PAD was ruled out, clinical findings suggested necrotizing deep soft-tissue infections, shock state, disseminated intravascular coagulation, and multiple organ failure. These symptoms led to a high suspicion of the well-recognized streptococcal toxic shock syndrome (STSS). With a high suspicion of STSS, we detected Group G ?-hemolytic streptococci (GGS) from samples aspirated from the leg bullae, and the species was identified as Streptococcus dysgalactiae subsp. equisimilis (SDSE) by 16S-ribosomal RNA sequencing. However, unfortunately, surgical debridement was impossible due to the broad area of skin change. Despite adequate antimicrobial therapy and intensive care, the patient died on the 3rd hospital day. The M-protein gene (emm) typing of the isolated SDSE was revealed to be stG6792. This type of SDSE is the most frequent cause of STSS due to GGS in Japan. We consider it to be crucial to rapidly distinguish STSS from acute occlusive PAD to achieve life-saving interventions in patients with severe soft-tissue infections. PMID:22327489
Nei, Takahito; Akutsu, Koichi; Shima, Ayaka; Tsuboi, Ippei; Suzuki, Hiroomi; Yamamoto, Takeshi; Tanaka, Keiji; Shinoyama, Akihiro; Kojima, Yoshiko; Washio, Yohei; Okawa, Sakina; Sonobe, Kazunari; Norose, Yoshihiko; Saito, Ryoichi
phi 227, a temperate phage from a group H streptococcus (Streptococcus sanguis), was propagated vegetatively in group H strain Wicky 4-EryR, and its characteristics were determined. A procedure dependent on multiplicity of infection, incubation time, and treatment of crude lysates with diatomaceous earth was found to optimize phage yield, resulting in titers of 1 X 10(10) to 2 X 10(10) PFU/ml. Without prior treatment with diatomaceous earth, subsequent purification procedures (methanol, ammonium sulfate, polyethylene glycol) gave recoveries of less than 1% of crude lysate titers. Adsorption of phi227 to host cells was relatively unaffected by the medium, but calcium (not substituted by magnesium) was required for formation of infectious centers. The phage receptor was present on purified cell walls, resisted trypsin and heat, and was removed ty hydrochloric acid, trichloracetic acid, and hot formamide: however, formamide-extracted material failed to inactivate phage, and the nature of the receptor is unknown. Single-step growth experiments showed a latent period of 39 min and a burst size of 100 PFU/infectious center; results were unaffected by omission of supplemental Ca2+, by supplementation with Mg2, addition of glucose, or changes of pH between 6.35 and 8.0; but increased temperature (40 to 43 degrees C) shortened the latent period and decreased the burst size. The latent period was prolonged in genetically competent host cells and in chemically defined medium; and in the latter, the burst size was smaller. Phage replication was sensitive to those metabolic inhibitors which inhibited the host streptococcus: these included rifampin, fluorodeoxyuridine, hydroxyurea, dihydrostreptomycin, and 6-P-hydroxyphenylazouracil. The data suggest that phi227 does not code for a rifampin-resistant RNA polymerase. However, in a rifampin-resistant host strain, phage replication and lysogen formation were both decreased suggesting that altered host core polymerase had less affinity for (some) promotors on the phi227 template. In transfection, a Ca2+-dependent stabilization step that was inhibited by Mg2+ was demonstrated; transformation was not affected by either Ca2+ or Mg2+, and the site and nature of the stabilization are unknown. More than one molecule of DNA was required for plaque formation. Biophysical characterization showed a type B phage of buoyant density (CsCl) 1.50, containing five proteins and 54.8% DNA. The duplex linear DNA had a molecular weight (calculated from contour length) of 23.2 X 10(6) and a guanine plus cytosine content (calculated from melting point) of 42.3 mol%. Similar characterizations of streptococcal phages, including biophysical data, have not been previously available. Images
Nugent, K M; Cole, R M
Background Emergency medical services (EMS) personnel commonly encounter sepsis, yet little is known about their understanding of sepsis. Study Objectives To determine the awareness, knowledge, current practice, and attitudes about sepsis among EMS personnel. Methods We performed an anonymous, multi-agency, online survey of emergency medical technicians (EMTs), firefighter-emergency medical technicians (FF-EMTs), and paramedics in a metropolitan, 2-tier EMS system. We compared responses according to the level of EMS training, and used multivariable logistic regression to determine the odds of correctly identifying the definition of sepsis, independent of demographic and professional factors. Results Overall response rate of study participants was 57% (786/1390), and greatest among EMTs (78%; 276/350). A total of 761 respondents (96%) had heard of the term sepsis. EMTs and FF-EMTs were at significantly reduced odds of correctly defining sepsis compared to paramedics, independent of age, sex, and years of experience (EMTs, OR=0.44, 95%CI:0.3,0.8; FF-EMTs, OR=0.32, 95%CI:0.2,0.6,). Overall, knowledge of the clinical signs and symptoms and recommended treatments for sepsis was typically greater than 75%, though best among paramedics than EMTs or FF-EMTs (p<0.01). The majority of respondents believed sepsis is not recognized by EMS “some” or “a lot” of the time (76%, 596/786). Conclusions EMS personnel demonstrated an overall sound awarenessof sepsis. Knowledge of sepsis was less among firefighter-EMTs and EMTs compared to paramedics. These results suggest that paramedics could be integrated into strategies of early identification and treatment of sepsis while EMTs may benefit from focused education and training.
Seymour, Christopher W.; Carlbom, David; Engelberg, Ruth A.; Larsen, Jonathan; Bulger, Eileen M.; Copass, Michael K.; Rea, Thomas D.
Infection in neonates is difficult to identify solely on the basis of physical findings, because signs are not specific. C reactive protein (CRP) is an acute phase reactant which has been used in diagnosis of bacterial infection in neonates. IL-6 is a proinflammatory cytokine produced by monocytes and macrophages activated by bacterial infection. IL-6 can be detected in blood earlier than CRP during the course of bacterial infection. The objective of this study was to compare the usefulness of the level of interleukin-6 with CRP as early markers of neonatal sepsis. This was a queasy experimental study carried out in neonatal unit, Department of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU) during the period of September 2005 to February 2006. Forty five cases of suspected septicemia were enrolled in the study and thirty healthy newborns were taken for comparison. On the 1st day of symptoms and 1st day of admission, complete blood count, blood for culture and sensitivity and interleukin-6 (IL-6) estimation were done. After 48-72 hours CRP was estimated. In suspected septic babies with high leukocyte count, IL-6 level was found to be raised with high sensitivity (85.71%), negative predictive value (95%). IL-6 was found to have high sensitivity (76.9%), specificity (73.68%), positive predictive value (80%) and negative predictive value (70%) in CRP positive suspected sepsis cases. So, the conclusion was that IL-6 is a very early marker of neonatal infection. IL-6 was mostly positive within 24 hours of onset of sepsis in comparison with other tests. So IL-6 is more useful than other markers for early detection of neonatal sepsis. PMID:18946456
Noor, M K; Shahidullah, M; Mutanabbi, M; Barua, C; Mannan, M A; Afroza, S
A prospective controlled study of the safety of various catheter dressing protocols was carried out in 168 patients receiving parenteral nutrition via an infraclavicular central venous catheter. Four protocols were compared: 36 patients received gauze dressings changed three times per week; 31 received OpSite dressings changed every 7th day (OpS-7), 32 received OpSite changed every 10th day (OpS-10), and 69 received OpSite changed twice weekly (OpS-ICU). Mean duration of parenteral nutrition was approximately 2 weeks and all groups were well matched except that OpS-ICU patients suffered more frequently from an acute illness. Catheter-related sepsis was identified by clinical signs of systemic sepsis, positive peripheral venous blood and catheter-tip cultures and/or defervescence of fever after catheter removal. Catheter-related sepsis rates were low in all groups: 1/36 for Gauze, 0/31 for OpS-7, 1/32 for OpS-10, and 2/69 for OpS-ICU. Septicemia attributable to causes apart from catheter sepsis occurred in two, two, three, and four patients, respectively. Bacterial colonization of skin beneath OpSite was no more common in the OpS-10 than in the other groups. Signs of inflammation at catheter insertion sites were common in all groups but did not relate closely to skin colonization. OpSite can be safely applied to central venous catheters inserted under strict aseptic conditions, even in patients with open septic drainage. Dressings can be left in place for 7 days with a margin of safety lasting to 10 days, thus saving on cost of materials and nursing time. PMID:3138446
Young, G P; Alexeyeff, M; Russell, D M; Thomas, R J
Left ventricular function and B-type natriuretic peptide (BNP) assessments are used to predict mortality in septic patients. Left atrial function has never been used to prognosticate outcome in septic patients. Objectives: To assess if deterioration of left atrial function in patients with severe sepsis and septic shock could predict mortality. Methods: We studied 30 patients with severe sepsis or septic shock with a mean age of 49.8±16.17. Echocardiographic parameters were measured on admission, Day 4, and Day 7, which comprised left ventricular ejection fraction (EF), and atrial function that is expressed as atrial ejection force (AEF). All patients were subjected to BNP assay as well. Multivariate analyses adjusted for APACHE II score was used for mortality prediction. Results: The underlying source for sepsis was lung in 10 patients (33%), blood in 7 patients (23.3%), abdomen in 7 patients (23.7%), and 3 patients (10%) had UTI as a cause of sepsis. Only one patient had CNS infection. In-hospital mortality was 23.3% (7 patients). Admission EF showed a significant difference between survivors and non survivors, 49.01±6.51 vs.. 56.44±6.93% (P<0.01). On the other hand, admission AEF showed insignificant changes between the same groups, 10.9±2.81 vs. 9.41±2.4 k/dynes P=0.21, while BNP was significantly higher in the non survivors, 1123±236.08 vs. 592.7±347.1 pg/ml (P<0.001). The predicatable variables for mortality was Acute Physiology and Chronic Health Evaluation II score, BNP, then EF. Conclusion: In septic patients, left atrial function unlike the ventricular function and BNP levels can not be used as an independent predictor of mortality.
Omar, Amr S.; ur Rahman, Masood; Abuhasna, Said
The streptococcal pyrogenic exotoxins (Spes) play a central role in the pathogenesis of invasive group A streptococcal (GAS) infections. The majority of recent invasive GAS infections have been caused by an M1T1 strain that harbors the genes for several streptococcal superantigens, including speA, speB, speF, speG, and smeZ. However, considerable variation in the expression of Spe proteins among clonal M1
SHAHANA U. KAZMI; RITA KANSAL; RAMY K. AZIZ; MASSOUMEH HOOSHDARAN; ANNA NORRBY-TEGLUND; D. E. Low; ABDEL-BASET HALIM; MALAK KOTB
PURPOSE: To determine the incidence of group A streptococcal necrotizing fasciitis in Ontario, Canada, and to describe the clinical features, outcome, and microbiologic characteristics of this infection.PATIENTS AND METHODS: Prospective, population-based surveillance for invasive group A streptococcal infections was conducted in Ontario from November 1991 to May 1995. All 77 patients meeting clinical and\\/or histopathologic criteria for streptococcal necrotizing fasciitis
Patients with sepsis may require mechanical ventilation due to the acute respiratory distress syndrome (ARDS). It has become increasingly accepted that mechanical ventilation can contribute to lung injury in these patients. The modern concept of ventilator-induced lung injury is described in the context of alveolar over-distention (volutrauma), alveolar de-recruitment (atelectrauma), and biochemical injury and inflammation to the lung parenchyma (biotrauma). To avoid over-distention lung injury, the tidal volume should be set at 6 mL/kg predicted body weight and plateau pressure should be limited to 30 cm H2O. This has been shown to afford a survival benefit. Although setting positive end-expiratory pressure (PEEP) to zero is likely harmful during mechanical ventilation of patients with ARDS, evidence is lacking for a survival benefit if a high PEEP level is set compared with a modest level of PEEP. Although adjunctive measures such as recruitment maneuvers, prone position, and inhaled nitric oxide may improve oxygenation, evidence is lacking that these measures improve survival. PMID:16107230
Hess, Dean R; Thompson, B Taylor
This is a rare case of broncho-pleuropericardial fistula in a 12-year-old female who presented with fever, painful joint swelling, and pleural and pericardial effusion secondary to disseminated methicillin-sensitive Staphylococcus aureus infection. The pleural and pericardial effusion were drained, however, air leak was observed from both tubes and was synchronous with mechanical inspiration. A broncho-pleuropericardial fistula was suspected and confirmed with computed tomography. This case report demonstrated that disseminated S. aureus bacteremia could result in broncho-pleuropericardial fistula. The ability of disseminated staphylococcal infection to produce pnemopericardium should be added to the list of other complications associated with disseminated staphylococcal sepsis.
Arab, Abeer A.; Kattan, Maan A.; Alyafi, Walid A.; Alhashemi, Jamal A.
An intact hypothalamic-pituitary-adrenal (HPA) axis with effective intracellular glucocorticoid anti-inflammatory activity is essential for host survival following exposure to an infectious agent. Glucocorticoids play a major role in regulating the activity of nuclear factor-kappa- B, which has a crucial and generalized role in inducing cytokine gene transcription after exposure to an invading pathogen. Severe sepsis is, however, associated with complex alterations of the HPA axis, which may result in decreased production of cortisol as well as glucocorticoid tissue resistance. PMID:21586102
Marik, Paul E
Antibodies against the group polysaccharide of group A streptococci were estimated by means of a haemagglutination reaction. In this reaction human erythrocytes of blood group O were sensitized with polysaccharide esterified with myristoylchloride. The optimal conditions of the reactions were determined by varying the ester group content in the antigen and the amount of ester used for sensitization. The specificity of the reaction could be established by reacting sensitized erythrocytes with homologous and heterologous sera and by absorption experiments. Antistreptococcal group A polysaccharide titres (ASPAT) and antibody levels to streptolysine O and DNase-B were compared in a group of 52 children with proved streptococcal infection and in 52 age- and season-matched controls. Antibody levels were significantly higher in the patient group than in the controls. In the ASPAT there was clearly less overlap between patients and controls than in both other reactions. In the patient group the ASO titres were raised above normal in 27 cases (51·9%), anti-DNase-B titres in 18 (34·6%), and ASPAT in 40 (76·9%). Taken together the three reactions gave a positive score in 51 cases (98·1%) in the patient group against 17 cases (32·7%) in the controls. A positive antibody response is usually defined as a rise of two dilution increments between the acute and convalescent sera. According to this definition the ASPAT showed a response in 42%, ASO and/or DNase-B in 42%, and the three reactions taken together in 68% of paired sera from patients. It is believed the ASPAT will prove a welcome addition to the diagnostic outfit when the presence of streptococcal infection in children is considered.
Groot, L. E. Goedvolk-De; Michel-Bensink, N.; Van Es-Boon, M. M.; Van Vonno, A. H.; Michel, M. F.
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
ABSTRACT. Objective. The evaluation of an infant for suspected sepsis often includes obtaining blood for laboratory tests. The shortcomings of the current practice are that the infant has to appear clinically ill for the diagnosis to be entertained, and the conventional labo- ratory tests are invasive. We have found that the clinical diagnosis of neonatal sepsis is preceded by abnormal
M. Pamela Griffin; Douglas E. Lake; J. Randall Moorman
Sepsis and multiple organ failure con- tinue to be significant problems among trauma, burn, and the critically ill patient population. Thus, a num- ber of laboratories have focused on understanding the role of altered apoptotic cell death in contributing to immune and organ dysfunction seen in sepsis and shock. Immune cells that undergo altered apoptotic changes include neutrophils, macrophages, dendritic
Doreen E. Wesche; Joanne L. Lomas-Neira; Mario Perl; Chun-Shiang Chung; Alfred Ayala
Thalidomide, an agent which inhibits biosynthesis of tumor necrosis factor alpha (TNF-) and which is used to treat a variety of chronic inflammatory conditions, was investigated as therapy for experimental sepsis. Sepsis was induced by intraperitoneal injection of 107 CFU of Escherichia coli per kg of body weight to 80 Wistar rats divided into four groups. Group A consisted of
Evangelos J. Giamarellos-Bourboulis; Helen Poulaki; Nikolaos Kostomitsopoulos; Ismene Dontas; Despina Perrea; Panayotis E. Karayannacos; Helen Giamarellou
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
We investigated inflammatory and physiologic parameters in sepsis models of increasing lethality induced by cecal ligation and puncture (CLP). Mice received imipenem for antibiotic therapy, and groups were sacrificed at 2, 4, 8, 12, 16, 20, and 24 h after CLP. The severity of sepsis increased with needle puncture size (lethality with 18-gauge puncture (18G), 100%; 21G, 50%; 25G, 5%;
SAMUEL EBONG; DOUGLAS CALL; JEAN NEMZEK; GERALD BOLGOS; DAVID NEWCOMB; DANIEL REMICK
Sepsis is a major clinical problem for which therapeutic interventions have been largely unsuccessful, in spite of promising strategies that were successful in animals, especially rodents. There is new evidence that sepsis causes excessive activation of the complement system and that this induces paralysis of innate immune functions in phagocytic cells due to effects of the powerful complement-activation product, C5a.
Peter A. Ward
Statins have a variety of properties that are independent of their lipid lowering ability. These anti-inflammatory, antioxidant, immunomodulatory, and antiapoptotic features have been collectively referred to as pleiotropic effects. Severe sepsis is an intense infection-induced inflammatory syndrome that ultimately results in organ dysfunction. Because so many cascades are triggered during sepsis, merely blocking a single component may be insufficient to
Victor Novack; Marius Terblanch