Mortality In Melioidosis Research Articles

Dysregulated immunologic landscape of the early host response in melioidosis.

Melioidosis, a neglected tropical infection caused by Burkholderia pseudomallei, commonly presents as pneumonia or sepsis with mortality rates up to 50% despite appropriate treatment. A better understanding of the early host immune response to melioidosis may lead to new therapeutic interventions and prognostication strategies to reduce disease burden. Whole blood transcriptomic signatures in 164 patients with melioidosis and in 70 patients with other infections hospitalized in northeastern Thailand enrolled within 24 hours following hospital admission were studied. Key findings were validated in an independent melioidosis cohort. Melioidosis was characterized by upregulation of interferon (IFN) signaling responses compared with other infections. Mortality in melioidosis was associated with excessive inflammation, enrichment of type 2 immune responses, and a dramatic decrease in T cell-mediated immunity compared with survivors. We identified and independently confirmed a 5-gene predictive set classifying fatal melioidosis (validation cohort area under the receiver operating characteristic curve 0.83; 95% CI, 0.67-0.99). This study highlights the intricate balance between innate and adaptive immunity during fatal melioidosis and can inform future precision medicine strategies for targeted therapies and prognostication in this severe infection.

Dysfunctional host cellular immune responses are associated with mortality in melioidosis

ABSTRACT Melioidosis is a tropical infection caused by the intracellular pathogen Burkholderia pseudomallei, an underreported and emerging global threat. As melioidosis-associated mortality is frequently high despite antibiotics, novel management strategies are critically needed. Therefore, we sought to determine whether functional changes in the host innate and adaptive immune responses are induced during acute melioidosis and are associated with outcome. Using a unique whole blood stimulation assay developed for use in resource-limited settings, we examined induced cellular functional and phenotypic changes in a cohort of patients with bacteremic melioidosis prospectively enrolled within 24 h of positive blood culture and followed for 28 days. Compared to healthy controls, melioidosis survivors generated an IL-17 response mediated by Th17 cells and terminally-differentiated effector memory CD8+ T cells (P < .05, both), persisting to 28 days after enrolment. Furthermore, melioidosis survivors developed polyfunctional cytokine production in CD8+ T cells (P < .01). Conversely, a reduction in CCR6+ CD4+ T cells was associated with higher mortality, even after adjustments for severity of illness (P = 0.004). Acute melioidosis was also associated with a profound acute impairment in monocyte function as stimulated cytokine responses were reduced in classical, intermediate and non-classical monocytes. Impaired monocyte cytokine function improved by 28-days after enrolment. These data suggest that IL-17 mediated cellular responses may be contributors to host defense during acute melioidosis, and that innate immune function may be impaired. These insights could provide novel targets for the development of therapies and vaccine targets in this frequently lethal disease.

Plasma Metabolomics Reveals Distinct Biological and Diagnostic Signatures for Melioidosis.

Rationale: The global burden of sepsis is greatest in low-resource settings. Melioidosis, infection with the gram-negative bacterium Burkholderia pseudomallei, is a frequent cause of fatal sepsis in endemic tropical regions such as Southeast Asia. Objectives: To investigate whether plasma metabolomics would identify biological pathways specific to melioidosis and yield clinically meaningful biomarkers. Methods: Using a comprehensive approach, differential enrichment of plasma metabolites and pathways was systematically evaluated in individuals selected from a prospective cohort of patients hospitalized in rural Thailand with infection. Statistical and bioinformatics methods were used to distinguish metabolomic features and processes specific to patients with melioidosis and between fatal and nonfatal cases. Measurements and Main Results: Metabolomic profiling and pathway enrichment analysis of plasma samples from patients with melioidosis (n = 175) and nonmelioidosis infections (n = 75) revealed a distinct immuno-metabolic state among patients with melioidosis, as suggested by excessive tryptophan catabolism in the kynurenine pathway and significantly increased levels of sphingomyelins and ceramide species. We derived a 12-metabolite classifier to distinguish melioidosis from other infections, yielding an area under the receiver operating characteristic curve of 0.87 in a second validation set of patients. Melioidosis nonsurvivors (n = 94) had a significantly disturbed metabolome compared with survivors (n = 81), with increased leucine, isoleucine, and valine metabolism, and elevated circulating free fatty acids and acylcarnitines. A limited eight-metabolite panel showed promise as an early prognosticator of mortality in melioidosis. Conclusions: Melioidosis induces a distinct metabolomic state that can be examined to distinguish underlying pathophysiological mechanisms associated with death. A 12-metabolite signature accurately differentiates melioidosis from other infections and may have diagnostic applications.

Melioidosis Patient Survival Correlates With Strong IFN-γ Secreting T Cell Responses Against Hcp1 and TssM.

Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a serious infectious disease with diverse clinical manifestations. The morbidity and mortality of melioidosis is high in Southeast Asia and no licensed vaccines currently exist. This study was aimed at evaluating human cellular and humoral immune responses in Thai adults against four melioidosis vaccine candidate antigens. Blood samples from 91 melioidosis patients and 100 healthy donors from northeast Thailand were examined for immune responses against B. pseudomallei Hcp1, AhpC, TssM and LolC using a variety of cellular and humoral immune assays including IFN-γ ELISpot assays, flow cytometry and ELISA. PHA and a CPI peptide pool were also used as control stimuli in the ELISpot assays. Hcp1 and TssM stimulated strong IFN-γ secreting T cell responses in acute melioidosis patients which correlated with survival. High IFN-γ secreting CD4+ T cell responses were observed during acute melioidosis. Interestingly, while T cell responses of melioidosis patients against the CPI peptide pool were low at the time of enrollment, the levels increased to the same as in healthy donors by day 28. Although high IgG levels against Hcp1 and AhpC were detected in acute melioidosis patients, no significant differences between survivors and non-survivors were observed. Collectively, these studies help to further our understanding of immunity against disease following natural exposure of humans to B. pseudomallei as well as provide important insights for the selection of candidate antigens for use in the development of safe and effective melioidosis subunit vaccines.

Blood transcriptomics to characterize key biological pathways and identify biomarkers for predicting mortality in melioidosis

ABSTRACT Melioidosis is an often lethal tropical disease caused by the Gram-negative bacillus, Burkholderia pseudomallei. The study objective was to characterize transcriptomes in melioidosis patients and identify genes associated with outcome. Whole blood RNA-seq was performed in a discovery set of 29 melioidosis patients and 3 healthy controls. Transcriptomic profiles of patients who did not survive to 28 days were compared with patients who survived and healthy controls, showing 65 genes were significantly up-regulated and 218 were down-regulated in non-survivors compared to survivors. Up-regulated genes were involved in myeloid leukocyte activation, Toll-like receptor cascades and reactive oxygen species metabolic processes. Down-regulated genes were hematopoietic cell lineage, adaptive immune system and lymphocyte activation pathways. RT-qPCR was performed for 28 genes in a validation set of 60 melioidosis patients and 20 healthy controls, confirming differential expression. IL1R2, GAS7, S100A9, IRAK3, and NFKBIA were significantly higher in non-survivors compared with survivors (P < 0.005) and healthy controls (P < 0.0001). The AUROCC of these genes for mortality discrimination ranged from 0.80-0.88. In survivors, expression of IL1R2, S100A9 and IRAK3 genes decreased significantly over 28 days (P < 0.05). These findings augment our understanding of this severe infection, showing expression levels of specific genes are potential biomarkers to predict melioidosis outcomes.

Melioidosis presenting with periorbital cellulitis and rhinosinusitis

Melioidosis is an infectious disease caused by the bacteria Burkholderia pseudomallei. It has a variety of clinical manifestations ranging from localized abscess, to severe pneumonia to fatal septicaemia. Sinonasal and orbital manifestations of Melioidosis are rare [1]. This is the first reported case of Melioidosis presenting with orbital cellulitis and rhinosinusitis in Sri Lanka. A 42-year-old patient with diabetes mellitus presented with pyrexia of unknown origin, multiple abscesses in the leg, periorbital cellulitis and rhinosinusitis. Initial investigations did not reveal a diagnosis. Eventually it was diagnosed as Melioidosis with a positive blood culture and successfully managed with long term antibiotics. ConclusionEarly identification and aggressive management is needed to reduce the morbidity and mortality of Melioidosis. Awareness amongst clinicians of different specialties is important as this disease has variety of manifestations.

A 2-Biomarker Model Augments Clinical Prediction of Mortality in Melioidosis.

BackgroundMelioidosis, infection caused by Burkholderia pseudomallei, is a common cause of sepsis with high associated mortality in Southeast Asia. Identification of patients at high likelihood of clinical deterioration is important for guiding decisions about resource allocation and management. We sought to develop a biomarker-based model for 28-day mortality prediction in melioidosis.MethodsIn a derivation set (N = 113) of prospectively enrolled, hospitalized Thai patients with melioidosis, we measured concentrations of interferon-γ, interleukin-1β, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-ɑ, granulocyte-colony stimulating factor, and interleukin-17A. We used least absolute shrinkage and selection operator (LASSO) regression to identify a subset of predictive biomarkers and performed logistic regression and receiver operating characteristic curve analysis to evaluate biomarker-based prediction of 28-day mortality compared with clinical variables. We repeated select analyses in an internal validation set (N = 78) and in a prospectively enrolled external validation set (N = 161) of hospitalized adults with melioidosis.ResultsAll 8 cytokines were positively associated with 28-day mortality. Of these, interleukin-6 and interleukin-8 were selected by LASSO regression. A model consisting of interleukin-6, interleukin-8, and clinical variables significantly improved 28-day mortality prediction over a model of only clinical variables [AUC (95% confidence interval [CI]): 0.86 (.79–.92) vs 0.78 (.69–.87); P = .01]. In both the internal validation set (0.91 [0.84–0.97]) and the external validation set (0.81 [0.74–0.88]), the combined model including biomarkers significantly improved 28-day mortality prediction over a model limited to clinical variables.ConclusionsA 2-biomarker model augments clinical prediction of 28-day mortality in melioidosis.

Subcutaneous surprise

Melioidosis is a zoonosis caused by the accidental pathogen Burkholderia pseudomallei, which is endemic in Southeast Asia and northern Australia. The mortality of melioidosis is 20-50% even with treatment. Suppurative lymphadenitis caused by melioidosis has been rarely encountered by clinicians practicing in endemic areas. In the majority of previously described patients, the infected lymph nodes were in the head and neck region, except for four patients who presented with unilateral, inguinal lymphadenitis. Hence, we report a case of unilateral suppurative inguinal lymphadenitis caused by B. pseudomallei in a 48-year-old lady who presented with groin swelling of 2 months duration.

Glyburide Is Anti-inflammatory and Associated with Reduced Mortality in Melioidosis

Patients with diabetes mellitus are more prone to bacterial sepsis, but there are conflicting data on whether outcomes are worse in diabetics after presentation with sepsis. Glyburide is an oral hypoglycemic agent used to treat diabetes mellitus. This K(ATP)-channel blocker and broad-spectrum ATP-binding cassette (ABC) transporter inhibitor has broad-ranging effects on the immune system, including inhibition of inflammasome assembly and would be predicted to influence the host response to infection. We studied a cohort of 1160 patients with gram-negative sepsis caused by a single pathogen (Burkholderia pseudomallei), 410 (35%) of whom were known to have diabetes. We subsequently studied prospectively diabetics with B. pseudomallei infection (n = 20) to compare the gene expression profile of peripheral whole blood leukocytes in patients who were taking glyburide against those not taking any sulfonylurea. Survival was greater in diabetics than in nondiabetics (38% vs 45%, respectively, P = .04), but the survival benefit was confined to the patient group taking glyburide (adjusted odds ratio .47, 95% confidence interval .28-.74, P = .005). We identified differential expression of 63 immune-related genes (P = .001) in patients taking glyburide, the sum effect of which we predict to be antiinflammatory in the glyburide group. We present observational evidence for a glyburide-associated benefit during human melioidosis and correlate this with an anti-inflammatory effect of glyburide on the immune system.

Melioidosis: A Retrospective Review of Orthopaedic Manifestations

Melioidosis is an infectious disease which is associated with high rate of mortality. We reviewed 33 patients treated in our hospital over a period of 14 months. About half (55%) of these patient presented with one focus of infection while the rest had multifocal infections. 81% require drainage of abscess or arthrotomy. Four patients (12%) died as a result of septicaemia and the rate is lower than those reported in literature. We conclude that mortality of melioidosis can reduce with early diagnosis followed by appropriate and prolonged antibiotic therapy.

A proposed scoring system for predicting mortality in melioidosis

Melioidosis, due to infection with the environmental organism Burkholderia pseudomallei, continues to beassociated with high mortality despite improvements in antibiotic therapy. Using simple clinical findings and baseline laboratory tests available at the time of admission, we attempted to define those patients with acute melioidosis who were at higher risk of death. Using data, collected prospectively from the period October 1989 to June 2002, from patients with acute culture-confirmed melioidosis presenting at the Royal Darwin Hospital, Darwin, Australia, a number of variables were selected that were easily available at the time of admission and reflected organ dysfunction. Mortality was predicted in univariate logistic and multivariate models by the presence of pneumonia, age at diagnosis, serum urea, serum bilirubin, lymphocyte count, and serum bicarbonate. A score was assigned from 0 to 2, based on the degree of abnormality. A melioidosis score was formed from the sum of these scores, with a maximum score of 11. A score of3 (n = 140) was associated with a mortality of 8.6%, whereas a score of ⩾ 4 (n = 112) was associated with a mortality of 44.6%. Although this scoring system requires external validation, it may help identify a suitable target group of patients for intensive intervention such as early admission to an intensive care unit, the early use of meropenem, and goal-directed resuscitation therapies.