An Observational Study of Sepsis in Takeo Province Cambodia: An in-depth examination of pathogens causing severe infections

Abstract

The world’s most consequential pathogens occur in regions with the fewest diagnostic resources, leaving the true burden of these diseases largely under-represented. During a prospective observational study of sepsis in Takeo Province Cambodia, we enrolled 200 patients over an 18-month period. By coupling traditional diagnostic methods such as culture, serology, and PCR to Next Generation Sequencing (NGS) and advanced statistical analyses, we successfully identified a pathogenic cause in 46.5% of our cohort. In all, we detected 25 infectious agents in 93 patients, including severe threat pathogens such as Burkholderia pseudomallei and viral pathogens such as Dengue virus. Approximately half of our cohort remained undiagnosed; however, an independent panel of clinical adjudicators determined that 81% of those patients had infectious causes of their hospitalization, further underscoring the difficulty of diagnosing severe infections in resource-limited settings. We garnered greater insight as to the clinical features of severe infection in Cambodia through analysis of a robust set of clinical data.

The performance of screening tools for predicting mortality across multi-site international sepsis cohorts

“…The most common positive microbiologic results overall included bacteraemia (N=83), respiratory culture growth (N=19), serum hepatitis B surface antigen (N=15), and malaria rapid diagnostic tests (N=11). A minority (121 of 567, 21.3%) of subjects had confirmed infections with complete adjudicator agreement using all available sources of clinical microbiologic results (with the notable addition of RNA sequencing of samples from Cambodia 14 ) including 90 (15.9%) bacterial, 17 viral (3.0%), 20 malarial (3.5%), and 2 (0.3%) fungal infections identified across all cohorts ( Supplementary Figure S1 ).…”

“…Microbiologic results were available if collected through routine clinical care across cohorts. Additional molecular testing and next generation sequencing for pathogens were also performed on blood samples in the Cambodia cohort as previously described 14 . Participants were followed throughout their hospitalization and a record review performed at discharge.…”

“…Responses were recorded on a standardized case report form and included demographics, medical history, physical exam findings, and admission diagnoses. Study specific procedures conducted in Cambodia were described in detail by Rozo et al 14 . Similar enrolment and study procedures were followed in Kumasi, Ghana and in Durham, North Carolina, USA.…”

A multipronged next‐generation sequencing metabarcoding approach unearths hyperdiverse and abundant dog pathogen communities in Cambodia

“…are important zoonotic pathogens with approximately 500,000 globally reported cases annually, with high lethality depending on species, strain, and case severity (Esson et al., 2019; Song et al., 2021). Exposure to Leptospira has been demonstrated in humans with unexplained sepsis in Cambodia and in people with undifferentiated febrile illness in Northern Thailand (Rozo et al., 2020; Takhampunya et al., 2019). Moreover, the latter study demonstrated the presence of Leptospira DNA in small mammal, vector, and human populations, highlighting the significance of vector species to provide a conduit for animal‐to‐human transmission in Southeast Asia (Takhampunya et al., 2019).…”

Topological data analysis identifies distinct biomarker phenotypes during the ‘inflammatory’ phase of COVID-19

“…The panel included: IL-6, CXCL10, IL-1RA, D-dimer, procalcitonin, ferritin, VEGF-A, IL-5, soluble receptor for advanced glycation end-product (RAGE), TNFR1, IFN-γ, and C-reactive protein (CRP). This panel was selected to include analytes in clinical use for prognostication (i.e., CRP, procalcitonin, ferritin, and D-dimer)(11), based on prior COVID-19 literature (i.e., IL-6, IFN-γ and CXCL10) (15), and identified to be representative of prior TDA-based non-COVID-19 sepsis clusters (i.e., IL-1RA, VEGF-A, IL-5, RAGE, and TNFR1) (10, 16). All protein concentrations were log 10 -transformed and normalized for site-to-site variation using the R package SVA ComBat (17).…”