Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts

Introduction: It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations. Methods: Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course. Results: Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes. Conclusions: Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery

Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability

Risk Factors for Mortality in Dengue Shock Syndrome (DSS)

Background: Dengue shock syndrome (DSS) is the most severe form of dengue hemorrhagic fever (DHF) and has a high mortality. There are two major pathological changes in DHF determining the severity of disease, plasma leakage and bleeding. Cytokines released during the immune response to dengue virus have been thought to be mediators of the process. Methods: The study involved 50 children with DSS, of whom 13 (26%) died. We investigated which clinical signs and laboratory findings are related to mortality. Results: We found that gastrointestinal bleeding and bilateral pleural effusion were significantly more frequent in non-survivors than in survivors (p<0.02 and p=0.0006, respectively). Also, mean admission levels of thrombin-antithrombin complexes (TATc) and plasminogen activator inhibitor type 1 (PAI-1), activation markers of coagulation and fibrinolysis, respectively, were significantly higher in non-survivors (p=0.004 and p=0.0006, respectively). In regression analysis, bilateral pleural effusion and admission levels of TATc were significantly associated with mortality (p=0.007 and p=0.048, respectively). Conclusions: Our data provide evidence for a relationship of mortality with pleural effusion, a marker of plasma leakage, and coagulation activation, both characteristic pathological changes in dengue shock syndrome

Protective host defense against disseminated candidiasis is impaired in mice expressing human interleukin-37

The effect of the anti-inflammatory cytokine interleukin-37 (IL 37) on host defense against Candida infections remains unknown. We assessed the role of IL 37 in a murine model of disseminated candidiasis using mice transgenic for human IL 37 (hIL 37Tg). Upon exposure to C. albicans pseudohyphae, macrophages from hIL-37Tg mice release 39% less TNFα compared to cells from wild-type mice (P=0.01). In vivo, hIL 37Tg mice displayed a decreased capacity to recruit neutrophils to the site of infection. These defects were associated with increased mortality and organ fungal growth in hIL-37Tg compared to wild-type mice. We conclude that IL-37 interferes with the innate protective anti-Candida host response by reducing the production of proinflammatory cytokines and suppressing neutrophil recruitment in response to Candida, resulting in an increased susceptibility to disseminated candidiasis