Unraveling Sepsis Epidemiology in a Low- and Middle-Income Intensive Care Setting Reveals the Alarming Burden of Tropical Infections and Antimicrobial Resistance: A Prospective Observational Study (MARS-India).

BACKGROUND: Our study addresses the sepsis research gap in lower middle-income countries, notably India. Here, we investigate community-acquired sepsis comprehensively and explore the impact of tropical microbiology on aetiology and outcomes. METHODS: MARS-India was a prospective observational study from Dec-2018 to Sep-2022 in a tertiary-care hospital in South India. Adult patients within 24hrs of ICU admission meeting the Sepsis 3.0 definition were enrolled, with 6-months follow-up (http://clinicaltrials.gov number NCT03727243). RESULTS: Over 4000 patients were screened on ICU admission, with 1000 unique patients meeting the inclusion criteria. Median age was 55 years (IQR: 44-65) with a male preponderance (66%). Almost half the cohort resided in villages (46.5%) and 74.6% worked in the primary sector. Mortality in-hospital was 24.1%. Overall, ∼54% had confirmed microbiological diagnosis. Over 18% had a viral cause of sepsis. Surprisingly, we identified leptospirosis (10.6%), scrub typhus (4.1%), dengue (3.7%) and Kyasanur forest disease (1.6%) as notables causes of sepsis. All these infections showed seasonal variation around the monsoon. In community-acquired infections we observed substantial resistance to 3rd generation cephalosporins and carbapenems. CONCLUSIONS: In India, sepsis disproportionally affects a younger and lower socio-economic demographic, yielding high mortality. Tropical and viral sepsis carry a significant burden. Analyzing local data, we pinpoint priorities for public health and resources, offering valuable insights for global sepsis research.

Dysregulation of Host-Pathogen Interactions in Sepsis: Host-Related Factors.

Sepsis stands as a prominent contributor to sickness and death on a global scale. The most current consensus definition characterizes sepsis as a life-threatening organ dysfunction stemming from an imbalanced host response to infection. This definition does not capture the intricate array of immune processes at play in sepsis, marked by simultaneous states of heightened inflammation and immune suppression. This overview delves into the immune-related processes of sepsis, elaborating about mechanisms involved in hyperinflammation and immune suppression. Moreover, we discuss stratification of patients with sepsis based on their immune profiles and how this could impact future sepsis management.

Burkholderia pseudomallei and melioidosis.

Burkholderia pseudomallei, the causative agent of melioidosis, is found in soil and water of tropical and subtropical regions globally. Modelled estimates of the global burden predict that melioidosis remains vastly under-reported, and a call has been made for it to be recognized as a neglected tropical disease by the World Health Organization. Severe weather events and environmental disturbance are associated with increased case numbers, and it is anticipated that, in some regions, cases will increase in association with climate change. Genomic epidemiological investigations have confirmed B. pseudomallei endemicity in newly recognized regions, including the southern United States. Melioidosis follows environmental exposure to B. pseudomallei and is associated with comorbidities that affect the immune response, such as diabetes, and with socioeconomic disadvantage. Several vaccine candidates are ready for phase I clinical trials. In this Review, we explore the global burden, epidemiology and pathophysiology of B. pseudomallei as well as current diagnostics, treatment recommendations and preventive measures, highlighting research needs and priorities.

The Intestinal Microbiome in Infectious Diseases: The Clinical Relevance of a Rapidly Emerging Field.

The field of infectious disease is undergoing a paradigm shift as the intestinal microbiome is becoming understood. The aim of this review is to inform infectious disease physicians of the potential relevance of the intestinal microbiome to their practice. We searched Medline using both index and text words relating to infectious diseases, microbiome, and probiotics. Relevant articles published up through 2017 were reviewed within Rayyan. The review illustrates pathophysiologic concepts linking the microbiome and infectious diseases; specifically, the intestinal microbiome's relevance to early immune development, the microbiome and enteric infections, the microbiome's relevance in compromised hosts, and antimicrobial resistance. Within each subject, there are specific examples of diseases and at-risk patient populations where a role for the microbiome has been strongly established. This provides an overview of the significance of the intestinal microbiome to microbiology, pediatric and adult infectious diseases with an underpinning of concepts useful for the practicing clinician.

Melioidosis in Africa: should we be looking more closely?

Melioidosis is a life-threatening infection caused by the Gram-negative bacterium Burkholderia pseudomallei, mainly found in Southeast Asia. Recently, African foci have been identified, although reports remain mostly anecdotal. In Africa, multiple febrile diseases have been erroneously attributed to malaria in the past, and many cases of fever remain mis- or undiagnosed. Vigilance for previously under-recognized pathogens may enhance our understanding of disease epidemiology and facilitate improvement of patient care. Melioidosis may be such a condition. We summarize data on melioidosis in Africa and discuss the future directions for epidemiological, clinical and bacteriological studies. We conclude that searching for old bugs in new places is no academic treasure hunt but a clinically relevant activity to pursue.

Diabetes does not influence activation of coagulation, fibrinolysis or anticoagulant pathways in Gram-negative sepsis (melioidosis).

Diabetes is associated with a disturbance of the haemostatic balance and is an important risk factor for sepsis, but the influence of diabetes on the pathogenesis of sepsis remains unclear. Melioidosis ( Burkholderia pseudomallei infection) is a common cause of community-acquired sepsis in Southeast Asia and northern Australia. We sought to investigate the impact of pre-existing diabetes on the coagulation and fibrinolytic systems during sepsis caused by B.pseudomallei . We recruited a cohort of 44 patients (34 with diabetes and 10 without diabetes) with culture-proven melioidosis. Diabetes was defined as a pre-admission diagnosis of diabetes or an HbA1c>7.8% at enrolment. Thirty healthy blood donors and 52 otherwise healthy diabetes patients served as controls. Citrated plasma was collected from all subjects; additionally in melioidosis patients follow-up specimens were collected seven and ≥ 28 days after enrolment where possible. Relative to uninfected healthy controls, diabetes per se (i.e. in the absence of infection) was characterised by a procoagulant effect. Melioidosis was associated with activation of coagulation (thrombin-antithrombin complexes (TAT), prothrombin fragment F1+2 and fibrinogen concentrations were elevated; PT and PTT prolonged), suppression of anti-coagulation (antithrombin, protein C, total and free protein S levels were depressed) and abnormalities of fibrinolysis (D-dimer and plasmin-antiplasmin complex [PAP] were elevated). Remarkably, none of these haemostatic alterations were influenced by pre-existing diabetes. In conclusion, although diabetes is associated with multiple abnormalities of coagulation, anticoagulation and fibrinolysis, these changes are not detectable when superimposed on the background of larger abnormalities attributable to B. pseudomallei sepsis.

Osteopontin is not crucial to protective immunity during murine tuberculosis.

Upon infection with Mycobacterium (M.) tuberculosis, the development of a strong T helper 1 (Th1)-mediated adaptive immune response is considered as being most important for containment of the infection. Osteopontin (OPN) is a phosphorylated glycoprotein that is chemotactic for inflammatory cells and has been implicated in the induction of Th1 responses and granulomatous disease. We tested the hypothesis that OPN facilitates protective immunity during M. tuberculosis infection using wild-type (WT) and OPN knockout (KO) mice in a model of pulmonary tuberculosis. OPN expression was up-regulated in alveolar macrophages and lymphoid cells during M. tuberculosis infection. There were no significant differences in bacterial outgrowth, inflammation or recruitment of lymphocytes, macrophages and polymorphonuclear cells in the lungs after 2 and 5 weeks of infection. However, the numbers of CD4(+) and CD8(+) T cells were reduced in the absence of OPN 5 weeks after infection. Similar concentrations of cytokine were observed in lungs from both WT mice and OPN KO mice; however, there was a trend towards decreased levels of interferon-gamma (IFN-gamma) in OPN KO mice 5 weeks after infection. Despite an unaltered immune response in the early phase of tuberculosis, OPN KO mice had a modest survival advantage. Of note, both pulmonary bacterial loads and lung inflammation were reduced in these mice 31 weeks after infection. These data suggest that OPN is not crucial for protective immunity upon M. tuberculosis infection and during the late phase of tuberculosis may even be detrimental for the host.

Immunity to Burkholderia pseudomallei.

PURPOSE OF REVIEW: Largely due to its recognition as a biological threat agent, current knowledge on melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, has increased tremendously over the last years. This review summarizes current understanding on the molecular characterization of B. pseudomallei and the immunology of melioidosis. RECENT FINDINGS: The genome of B. pseudomallei is composed of two chromosomes of which the largest part represents the B. pseudomallei core genome, whereas the remaining accessory genome has been associated with bacterial virulence. Virulence factors, most notably quorum sensing, type III secretion system, lipopolysaccharide and other surface polysaccharides, flagella and various factors essential for the intracellular life cycle of B. pseudomallei, have been further characterized. The neutrophils play a critical in host defense, which is initiated by the Toll-like receptors. The proinflammatory immune response--including the activation of coagulation-- and its regulation have been further dissected. SUMMARY: Severe melioidosis can probably be seen as the clinical manifestation of a pathogen recognition receptor mediated dysregulation of the immune response to invading B. pseudomallei. B. pseudomallei employs numerous tactics to evade the immune response. Studies on host-pathogen interactions in melioidosis have identified a whole range of potential new treatment targets.