A Transcriptomic Classifier Model Identifies High-Risk Endotypes in a Prospective Study of Sepsis in Uganda

Area of Science:

• * Translational Medicine
• * Infectious Diseases
• * Genomics and Transcriptomics

Background:

• * Sepsis endotypes, defined by distinct biological mechanisms and treatment responses, have been identified in high-income countries (HICs) using blood transcriptomics.
• * The applicability of these HIC-derived endotypes to low- and middle-income countries (LMICs), where the majority of sepsis cases occur, remains largely unknown.
• * Understanding sepsis heterogeneity in LMICs is crucial for developing effective, context-specific treatment strategies.

Purpose of the Study:

• * To investigate the prevalence and prognostic significance of HIC-derived transcriptomic sepsis endotypes in sub-Saharan Africa.
• * To determine the immunopathological characteristics of these endotypes in a Ugandan cohort.
• * To assess the generalizability of sepsis endotyping across diverse healthcare settings.

Main Methods:

• * Prospective cohort study involving 128 adults hospitalized with suspected sepsis at a public referral hospital in Uganda.
• * Whole-blood RNA sequencing was performed to classify patients into sepsis response signatures (SRS) using 19-gene and 7-gene classifiers (SepstratifieR) previously validated in HICs.
• * Analysis included assessment of biological features, host-pathogen profiles, and 30-day mortality rates associated with each endotype.

Main Results:

• * The 19-gene classifier assigned patients to SRS-1 (23.4%), SRS-2 (71.9%), and SRS-3 (4.7%). SRS-1 was characterized by high inflammation and suppressed lymphocyte immunity, often seen in individuals with advanced HIV and tuberculosis.
• * Thirty-day mortality was significantly higher in SRS-1 (48.1%) compared to other groups.
• * Agreement between the 19-gene and 7-gene classifiers was poor, with the 7-gene classifier showing suboptimal patient stratification and higher mortality in the 'health-closest' group (SRS-3).

Conclusions:

• * Transcriptomic sepsis endotypes identified in HICs share conserved biological features with those in sub-Saharan Africa, but differ in host-pathogen interactions.
• * The findings underscore the importance of considering local context in sepsis endotyping and highlight conserved biological signatures of critical illness.
• * This research provides a foundation for developing more pathobiologically informed sepsis treatment strategies tailored for LMICs.