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  • Molecular phenotypes of critical illness confer prognostic and biological enrichment in sub-Saharan Africa: a prospective cohort study from Uganda

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Critical care
Molecular phenotypes of critical illness confer prognostic and biological enrichment in sub-Saharan Africa: a prospective cohort study from Uganda
  1. Matthew J Cummings1,2,
  2. Julius J Lutwama3,
  3. Alin S Tomoiaga1,4,
  4. Nicholas Owor3,
  5. Xuan Lu1,
  6. Jesse E Ross1,
  7. Moses Muwanga5,
  8. Christopher Nsereko5,
  9. Irene Nayiga5,
  10. Kai Nie6,
  11. John Kayiwa3,
  12. Xiaoyu Che2,7,
  13. Misaki Wayengera3,8,
  14. Seunghee Kim-Schulze6,
  15. W Ian Lipkin2,9,10,
  16. Max R O’Donnell1,2,10,
  17. Barnabas Bakamutumaho3
  1. 1 Department of Medicine, Columbia University, New York, New York, USA
  2. 2 Center for Infection and Immunity, Columbia University, New York, New York, USA
  3. 3 Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
  4. 4 Department of Accounting, Business Analytics, Computer Information Systems, and Law, Manhattan College, Riverdale, New York, USA
  5. 5 Entebbe Regional Referral Hospital, Entebbe, Uganda
  6. 6 Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  7. 7 Department of Biostatistics, Columbia University, New York, New York, USA
  8. 8 Department of Immunology and Molecular Biology, Makerere University, Kampala, Uganda
  9. 9 Department of Pathology and Cell Biology, Columbia University, New York, New York, USA
  10. 10 Department of Epidemiology, Columbia University, New York, New York, USA
  1. Correspondence to Dr Matthew J Cummings; mjc2244{at}columbia.edu

Abstract

The generalisability of critical illness molecular phenotypes to low- and middle-income countries (LMICs) is unknown. We show that molecular phenotypes derived in high-income countries (hyperinflammatory and hypoinflammatory, reactive and uninflamed) stratify sepsis patients in Uganda by physiological severity, mortality risk and dysregulation of key pathobiological domains. A classifier model including data available at the LMIC bedside modestly discriminated phenotype assignment (area under the receiver operating characteristic curve (AUROC) 0.80, 95% CI 0.71 to 0.90 for hyperinflammatory vs hypoinflammatory; AUROC 0.74, 95% CI 0.65 to 0.83 for reactive vs uninflamed). Our findings highlight the potential for a globally relevant, clinicomolecular classification of critical illness and may support the inclusion of diverse populations in phenotype-targeted critical care trials. Improved laboratory capacity and access to rapid biomarker assays are likely necessary to optimise phenotype stratification in LMIC settings.

  • Critical Care
  • Cytokine Biology

https://doi.org/10.1136/thorax-2024-222412

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    Footnotes

    • MRO’D and BB are joint senior authors.

    • Contributors MJC, BB and MRO’D conceived the study and design. JJL, NO, MM, CN and IN collected, organised and entered clinical data and blood samples and contributed to pathogen diagnostics. SK-S and KN contributed to proteomic analyses. MJC, AST, JER and XL contributed to data cleaning, processing, verification and analysis. XC, WIL and MRO’D contributed to additional data analysis and interpretation. MJC developed the first draft of the manuscript. All authors reviewed, edited and approved the final version of the manuscript. MJC is the guarantor.

    • Funding This work was supported by the National Institute of Allergy and Infectious Diseases (K23AI163364 to MC), the National Center for Advancing Translational Sciences (UL1TR001873 to Columbia University, sub-award to MRO'D), and the MakCHS-Berkeley-Yale Pulmonary Complications of AIDS Research Training (PART) Program (D43TW009607, sub-award to BB) from the Fogarty International Center, National Institutes of Health. Additional support was provided by the Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene (MJC; no award/grant number).

    • Competing interests MJC and MRO’D were investigators for clinical trials evaluating the efficacy and safety of remdesivir, convalescent plasma, and anti-SARS-CoV-2 hyperimmune globulin in hospitalised patients with COVID-19, sponsored by Gilead Sciences, Amazon and the NIH, respectively. Compensation for this work was paid to Columbia University. MJC reports consulting fees from Vertex Pharmaceuticals and Veracyte unrelated to the submitted work. The remaining authors declare no conflicts of interest.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.