Infection with Burkholderia pseudomallei - immune correlates of survival in acute melioidosis.

Melioidosis, caused by Burkholderia pseudomallei, is a potentially lethal infection with no licensed vaccine. There is little understanding of why some exposed individuals have no symptoms, while others rapidly progress to sepsis and death, or why diabetes confers increased susceptibility. We prospectively recruited a cohort of 183 acute melioidosis patients and 21 control subjects from Northeast Thailand and studied immune parameters in the context of survival status and the presence or absence of diabetes. HLA-B*46 (one of the commonest HLA class I alleles in SE Asia) and HLA-C*01 were associated with an increased risk of death (odds ratio 2.8 and 3.1 respectively). Transcriptomic analysis during acute infection in diabetics indicated the importance of interplay between immune pathways including those involved in antigen presentation, chemotaxis, innate and adaptive immunity and their regulation. Survival was associated with enhanced T cell immunity to nine of fifteen immunodominant antigens analysed including AhpC (BPSL2096), BopE (BPSS1525), PilO (BPSS1599), ATP binding protein (BPSS1385) and an uncharacterised protein (BPSL2520). T cell immunity to GroEL (BPSL2697) was specifically impaired in diabetic individuals. This characterization of immunity associated with survival during acute infection offers insights into correlates of protection and a foundation for design of an effective multivalent vaccine.

Patient Characteristics, Management, and Predictors of Outcome from Severe Community-Onset Staphylococcal Sepsis in Northeast Thailand: A Prospective Multicenter Study.

AbstractStaphylococcus aureus infection is a persistent threat in resource-restricted settings in southeast Asia but informative data about this disease remain limited. We analyzed characteristics, management, and predictors of outcome in severely septic patients with community-onset S. aureus infection in northeast Thailand. We performed a prospective, multicenter observational cohort study of community-onset S. aureus sepsis in four referral hospitals recruiting patients at least 14 years of age admitted between March 2010 and December 2013. One hundred and nineteen patients with severe staphylococcal sepsis were enrolled. Diabetes was the most common underlying condition. Methicillin-resistant infection was rare. Twenty-eight-day mortality was 20%. Ninety-two percent of patients received appropriate antibiotic therapy and 82% were administered intravenous fluids on the first hospital day, although only 14% were managed in an intensive care unit (ICU). On univariable analysis, clinical variables at enrollment significantly associated with death at 28 days were coagulopathy or respiratory failure. Plasma interleukin (IL)-8 concentration alone accurately predicted mortality (area under the receiver operating curve = 0.82, 95% confidence interval = 0.73-0.90). In multivariable analysis, addition of IL-8 concentration to a mortality prediction model containing clinical variables further improved the predictive ability of the model. We conclude that severe staphylococcal sepsis in northeast Thailand causes significant mortality. Diabetes is a common preexisting condition and most patients are managed outside the ICU even if they receive vasoactive/inotropic agents or mechanical ventilation. While clinical factors apparent on presentation including coagulopathy and respiratory failure predict death, plasma IL-8 improves this prediction.

T-Cell Responses Are Associated with Survival in Acute Melioidosis Patients.

BACKGROUND: Melioidosis is an increasingly recognised cause of sepsis and death across South East Asia and Northern Australia, caused by the bacterium Burkholderia pseudomallei. Risk factors include diabetes, alcoholism and renal disease, and a vaccine targeting at-risk populations is urgently required. A better understanding of the protective immune response in naturally infected patients is essential for vaccine design. METHODS: We conducted a longitudinal clinical and immunological study of 200 patients with melioidosis on admission, 12 weeks (n = 113) and 52 weeks (n = 65) later. Responses to whole killed B. pseudomallei were measured in peripheral blood mononuclear cells (PBMC) by interferon-gamma (IFN-γ) ELIspot assay and flow cytometry and compared to those of control subjects in the region with diabetes (n = 45) and without diabetes (n = 43). RESULTS: We demonstrated strong CD4+ and CD8+ responses to B. pseudomallei during acute disease, 12 weeks and 52 weeks later. 28-day mortality was 26% for melioidosis patients, and B. pseudomallei-specific cellular responses in fatal cases (mean 98 IFN-γ cells per million PBMC) were significantly lower than those in the survivors (mean 142 IFN-γ cells per million PBMC) in a multivariable logistic regression model (P = 0.01). A J-shaped curve association between circulating neutrophil count and mortality was seen with an optimal count of 4000 to 8000 neutrophils/µl. Melioidosis patients with known diabetes had poor diabetic control (median glycated haemoglobin HbA1c 10.2%, interquartile range 9.2-13.1) and showed a stunted B. pseudomallei-specific cellular response during acute illness compared to those without diabetes. CONCLUSIONS: The results demonstrate the role of both CD4+ and CD8+ T-cells in protection against melioidosis, and an interaction between diabetes and cellular responses. This supports development of vaccine strategies that induce strong T-cell responses for the control of intracellular pathogens such as B. pseudomallei.

Prospective observational study of the frequency and features of intra-abdominal abscesses in patients with melioidosis in northeast Thailand.

Retrospective case series from Thailand have reported the presence of intra-abdominal abscesses in around half of patients with melioidosis, a much higher rate than our clinical experience would suggest. We performed a prospective, observational study of 230 adult patients with culture-confirmed melioidosis in which all patients underwent abdominal ultrasound. One or more abscesses were detected in the liver and/or spleen in 77 (33%) cases. These were often multiple (70%, 31/44 in hepatic abscesses and 88%, 50/57 in splenic abscesses) and clinically silent (27% of cases with abscesses presenting with abdominal pain). The mortality rate at 4 weeks post-discharge was lower in patients who were abscess-positive vs abscess-negative (10%, 8/77 vs 20%, 31/153).