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. Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats. Am J Physiol Regul Integr Comp Physiol 286: R699-R709, 2004. First published January 8, 2004 10.1152/ajpregu.00593.2003.-Although circulatory shock related to lethal toxin (LeTx) may play a primary role in lethality due to Bacillus anthracis infection, its mechanisms are unclear. We investigated whether LeTx-induced shock is associated with inflammatory cytokine and nitric oxide (NO) release. SpragueDawley rats with central venous and arterial catheters received 24-h infusions of LeTx (lethal factor 100 g/kg; protective antigen 200 g/kg) that produced death beginning at 9 h and a 7-day mortality rate of 53%. By 9 h, mean arterial blood pressure, heart rate, pH, and base excess were decreased and lactate and hemoglobin levels were increased in LeTx nonsurvivors compared with LeTx survivors and controls (diluent only) (P Յ 0.05 for each comparing the 3 groups). Despite these changes, arterial oxygen and circulating leukocytes and platelets were not decreased and TNF-␣, IL-1␤, IL-6, and IL-10 levels were not increased comparing either LeTx nonsurvivors or survivors to controls. Nitrate/nitrite levels and tissue histology also did not differ comparing LeTx animals and controls. In additional experiments, although 24-h infusions of LeTx and Esherichia coli LPS produced similar mortality rates (54 and 56%, respectively) and times to death (13.2 Ϯ 0.8 vs. 11.0 Ϯ 1.7 h, respectively) compared with controls, only LPS reduced circulating leukocytes, platelets, and IL-2 levels and increased TNF-␣, IL-1␣ and -1␤, IL-6, IL-10, interferon-␥, granulocyte macrophage-colony stimulating factor, RANTES, migratory inhibitory protein-1␣, -2, and -3, and monocyte chemotactic protein-1, as well as nitrate/nitrite levels (all P Յ 0.05 for the effects of LPS). Thus, in contrast to LPS, excessive inflammatory cytokine and NO release does not appear to contribute to the circulatory shock and lethality occurring with LeTx in this rat model. Although therapies to modulate these host mediators may be applicable for shock caused by LPS or other bacterial toxins, they may not with LeTx.

Context Sepsis bundles have been developed to improve patient outcomes by combining component therapies. Valid bundles require effective components with additive benefits. Proponents encourage evaluation of bundles, both as a whole and based on the performance of each component. Objective Assess the association between outcome and the utilization of component therapies in studies of sepsis bundles. Data Source Database searches (January 1980 to July 2008) of PubMed, Embase, and the Cochrane Library, using the terms sepsis, bundles, guidelines, and early goal directed therapy. Data Extraction Inclusion required comparison of septic adults who received bundled care vs. nonprotocolized care. Survival and use rates for individual interventions were abstracted. Main Results Eight unblinded trials, one randomized and seven with historical controls, were identified. Sepsis bundles were associated with a consistent (I2 = 0%, p = .87) and significant increase in survival (odds ratio, 1.91; 95% confidence interval, 1.49–2.45; p < .0001). For all studies reporting such data, there were consistent (I2 = 0%, p ≥ .64) decreases in time to antibiotics, and increases in the appropriateness of antibiotics (p < .0002 for both). In contrast, significant heterogeneity was seen across trials for all other treatments (antibiotic use within a specified time period; administration of fluids, vasopressors, inotropes, and packed red blood cells titrated to hemodynamic goals; corticosteroids and human recombinant activated protein C use) (all I2 ≥ 67%, p < .002). Except for antibiotics, sepsis bundle components are still being investigated for efficacy in randomized controlled trials. Conclusion Bundle use was associated with consistent and significant improvement in survival and antibiotic use. Use of other bundle components changed heterogeneously across studies, making their impact on survival uncertain. However, this analysis should be interpreted cautiously as these studies were unblinded, and only one was randomized.

Bacillus anthracis infection is rare in developed countries. However, recent outbreaks in the United States and Europe and the potential use of the bacteria for bioterrorism have focused interest on it. Furthermore, although anthrax was known to typically occur as one of three syndromes related to entry site of (i.e., cutaneous, gastrointestinal, or inhalational), a fourth syndrome including severe soft tissue infection in injectional drug users is emerging. Although shock has been described with cutaneous anthrax, it appears much more common with gastrointestinal, inhalational (5 of 11 patients in the 2001 outbreak in the United States), and injectional anthrax. Based in part on case series, the estimated mortalities of cutaneous, gastrointestinal, inhalational, and injectional anthrax are 1%, 25 to 60%, 46%, and 33%, respectively. Nonspecific early symptomatology makes initial identification of anthrax cases difficult. Clues to anthrax infection include history of exposure to herbivore animal products, heroin use, or clustering of patients with similar respiratory symptoms concerning for a bioterrorist event. Once anthrax is suspected, the diagnosis can usually be made with Gram stain and culture from blood or surgical specimens followed by confirmatory testing (e.g., PCR or immunohistochemistry). Although antibiotic therapy (largely quinolone-based) is the mainstay of anthrax treatment, the use of adjunctive therapies such as anthrax toxin antagonists is a consideration.

Summary Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non‐SARS‐CoV2 infection supported the use of these agents in the present SARS‐CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection ( n = 6), acute chikungunya infection ( n = 1), acute dengue virus infection ( n = 2), chronic HCV ( n = 2), and as preventive measures for influenza infection ( n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non‐SARS‐CoV2 viral infections do not support these agents' use for the SARS‐CoV2 outbreak.

BackgroundAt least 25 % of adults admitted to intensive care units (ICU) in the United States have an overweight, obese or morbidly obese body mass index (BMI). The effect of BMI on adjusted mortality in adults requiring ICU treatment for sepsis is unclear. We performed a systematic review of adjusted all-cause mortality for underweight, overweight, obese and morbidly obese BMIs relative to normal BMI for adults admitted to the ICU with sepsis, severe sepsis, and septic shock.MethodPubMed, the Cochrane Library, and EMBASE electronic databases were searched through November 18, 2015, without language restrictions. We included studies that reported multivariate regression analyses for all-cause mortality using standard BMI categories for adults admitted to the ICU for sepsis, severe sepsis, and septic shock. Articles were selected by consensus among multiple reviewers. Electronic database searches yielded 10,312 articles, of which six were eligible. Data were extracted by one reviewer and then reviewed by three independent reviewers. For the meta-analyses performed, the adjusted odds ratios (aOR) of mortality were combined using a random-effects model. Risk of bias was assessed using the Newcastle-Ottawa quality assessment scale for cohort studies.ResultsFour retrospective (n = 6609 patients) and two prospective (n = 556) studies met inclusion criteria. Compared to normal BMI, across five studies each, overweight or obese BMIs reduced the adjusted odds ratio (95 % CI) of mortality [aOR] [0.83 (0.75, 0.91) p < 0.001 and 0.82 (0.67, 0.99) p = 0.04, respectively] with low or moderate heterogeneity (I2 = 15.7 %, p = 0.31 and I2 = 53.0 %, p = 0.07, respectively). Across three studies each, morbidly obese BMI and underweight BMI did not alter aOR [0.90 (0.59, 1.39), p = 0.64; I2 = 43.3 %, p = 0.17; and 1.24 (0.79, 1.95), p = 0.35; I2 = 15.6 %, p = 0.31 respectively]. Only one study clearly defined how and when height and weight measurements were calculated. Site of underlying infection and illness severity may have favored overweight and obese BMIs.ConclusionsThis is the first meta-analysis to show that overweight or obese BMIs reduce adjusted mortality in adults admitted to the ICU with sepsis, severe sepsis, or septic shock. More rigorous studies that address these limitations are needed to clarify the impact of BMI on sepsis ICU outcomes.Trial registrationPROSPERO International prospective register of systematic reviews 10.15124/CRD42014010556. Registered on July 11, 2014.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1360-z) contains supplementary material, which is available to authorized users.

Introduction-Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs that inhibit the pro-inflammatory effects of lipopolysaccharide (LPS) and improve outcome when added to conventional sepsis treatments are lacking. Eritoran tetrasodium (E5564) is a promising candidate therapy for sepsis belonging to a new class of such drugs which inhibit LPS-induced inflammation by blocking toll-like receptor 4 (TLR4).Areas covered-This review focuses on the rationale for the use of eritoran tetrasodium in sepsis, as well as on its pharmacokinetics, pharmacodynamics, efficacy and safety. Pre-clinical and clinical studies from a MEDLINE/PubMed literature search in August 2010 with the search terms "eritoran" and "E5564" are discussed.Expert opinion-Preclinical in vitro and in vivo studies of eritoran tetrasodium indicate it can limit excessive inflammatory mediator release associated with LPS, and improve survival in sepsis models. While early clinical results are promising, its efficacy and safety for treating patients with sepsis is currently under investigation. Even if the ongoing phase III clinical trial enrolling patients with severe sepsis and increased risk of death shows benefit from eritoran, questions remain and confirmatory studies will be necessary to define its clinical usage.

Introduction High mortality in the 2001 US and recent European anthrax outbreaks suggests that better understanding of the effects of this bacteria’s toxins is needed to improve treatment. Methods and results Here, 24h edema (ETx) and lethal (LeTx) toxin infusions were investigated for 96h in sedated and mechanically ventilated canines. Initial study compared similarly lethal doses of ETx (n=8) or LeTx (n=15) alone. ETx was 24 times less lethal than LeTx, while median time to death in non-survivors (n=6 and 9 respectively) was shorter with ETx (42 vs. 67h, p=0.04). Compared to controls (n=9), both toxins decreased arterial and central venous pressures (CVP) and systemic vascular resistance (SVRI) and increased heart rate (HR), cardiac index, blood urea nitrogen (BUN), creatinine (Cr), BUN:Cr ratio, and hepatic transaminases (p≤0.05, toxin effect or time interaction). However, ETx stimulated early diuresis, reduced serum sodium and had more pronounced vasodilatory effects than LeTx as reflected by greater or earlier CVP, SVRI, and BUN:Cr changes (p≤0.01). LeTx progressively decreased left ventricular ejection fraction (p≤0.002). In subsequent study, lethal dose LeTx with an equimolar nonlethal ETx dose (n=8) increased mortality versus LeTx alone (n=8) (p=0.05). Conclusion Shock with ETx or LeTx may require differing supportive therapies while toxin antagonists should likely target both toxins.