Article Category:
Research Article

Development of a Novel Clinicomolecular Risk Index to Enhance Mortality Prediction and Immunological Stratification of Adults Hospitalized with Sepsis in Sub-Saharan Africa: A Pilot Study from Uganda

Matthew J. Cummings Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York;
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York;

Search for other papers by Matthew J. Cummings in
Current site
Google Scholar
PubMed Close
,
Barnabas Bakamutumaho Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda;
Immunizable Diseases Unit, Uganda Virus Research Institute, Entebbe, Uganda;

Search for other papers by Barnabas Bakamutumaho in
Current site
Google Scholar
PubMed Close
,
Komal Jain Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York;

Search for other papers by Komal Jain in
Current site
Google Scholar
PubMed Close
,
Adam Price Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York;

Search for other papers by Adam Price in
Current site
Google Scholar
PubMed Close
,
Nicholas Owor Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda;

Search for other papers by Nicholas Owor in
Current site
Google Scholar
PubMed Close
,
John Kayiwa Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda;

Search for other papers by John Kayiwa in
Current site
Google Scholar
PubMed Close
,
Joyce Namulondo Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda;

Search for other papers by Joyce Namulondo in
Current site
Google Scholar
PubMed Close
,
Timothy Byaruhanga Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda;

Search for other papers by Timothy Byaruhanga in
Current site
Google Scholar
PubMed Close
,
Moses Muwanga Entebbe General Referral Hospital, Ministry of Health, Entebbe, Uganda;

Search for other papers by Moses Muwanga in
Current site
Google Scholar
PubMed Close
,
Christopher Nsereko Entebbe General Referral Hospital, Ministry of Health, Entebbe, Uganda;

Search for other papers by Christopher Nsereko in
Current site
Google Scholar
PubMed Close
,
Stephen Sameroff Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York;

Search for other papers by Stephen Sameroff in
Current site
Google Scholar
PubMed Close
,
W. Ian Lipkin Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York;
Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York;
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York

Search for other papers by W. Ian Lipkin in
Current site
Google Scholar
PubMed Close
,
Julius J. Lutwama Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda;

Search for other papers by Julius J. Lutwama in
Current site
Google Scholar
PubMed Close
, and
Max R. O’Donnell Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York;
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York;
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York

Search for other papers by Max R. O’Donnell in
Current site
Google Scholar
PubMed Close
DOI:
https://doi.org/10.4269/ajtmh.22-0483
Volume/Issue:
Volume 108: Issue 3
Page(s):
619–626
Restricted access
Get Permissions

ABSTRACT.

The global burden of sepsis is concentrated in sub-Saharan Africa (SSA), where epidemic HIV and unique pathogen diversity challenge the effective management of severe infections. In this context, patient stratification based on biomarkers of a dysregulated host response may identify subgroups more likely to respond to targeted immunomodulatory therapeutics. In a prospective cohort of adults hospitalized with suspected sepsis in Uganda, we applied machine learning methods to develop a prediction model for 30-day mortality that integrates physiology-based risk scores with soluble biomarkers reflective of key domains of sepsis immunopathology. After model evaluation and internal validation, whole-blood RNA sequencing data were analyzed to compare biological pathway enrichment and inferred immune cell profiles between patients assigned differential model-based risks of mortality. Of 260 eligible adults (median age, 32 years; interquartile range, 26–43 years; 59.2% female, 53.9% living with HIV), 62 (23.8%) died by 30 days after hospital discharge. Among 14 biomarkers, soluble tumor necrosis factor receptor 1 (sTNFR1) and angiopoietin 2 (Ang-2) demonstrated the greatest importance for mortality prediction in machine learning models. A clinicomolecular model integrating sTNFR1 and Ang-2 with the Universal Vital Assessment (UVA) risk score optimized 30-day mortality prediction across multiple performance metrics. Patients assigned to the high-risk, UVA-based clinicomolecular subgroup exhibited a transcriptional profile defined by proinflammatory innate immune and necroptotic pathway activation, T-cell exhaustion, and expansion of key immune cell subsets including regulatory and gamma-delta T cells. Clinicomolecular stratification of adults with suspected sepsis in Uganda enhanced 30-day mortality prediction and identified a high-risk subgroup with a therapeutically targetable immunological profile. Further studies are needed to advance pathobiologically informed sepsis management in SSA.

    • Supplemental Materials (PDF 135 KB)

Author Notes

Address correspondence to Matthew J. Cummings, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Irving Medical Center, 622 West 168th St., PH 8E-101, New York, NY 10032. E-mail: mjc2244@columbia.edu

Financial support: This work was supported by the National Center for Advancing Translational Sciences (UL1TR001873 to Columbia University, sub-award to M. R. O.), the National Institute of Allergy and Infectious Diseases (K23AI163364 to M. J. C.), and the MakCHS-Berkeley-Yale Pulmonary Complications of AIDS Research Training (PART) Program (D43TW009607, sub-award to B. B.) from the Fogarty International Center, National Institutes of Health. Additional support was provided by the Stony Wold-Herbert Fund (M. J. C.), the Potts Memorial Foundation (M. J. C.), the Thrasher Research Fund (M. J. C.), the Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene (M. J. C.), and the DELTAS Africa Initiative (sub-award to M. J. C. and B. B.; Grant no. 107743).

Disclaimer: The funders had no role in study design, data analysis or interpretation, manuscript preparation, or decision to publish. Each enrolled participant ≥ 18 years or their surrogate provided written informed consent. Study protocols were approved by ethics committees at Columbia University (AAAR1450), the Uganda Virus Research Institute (GC/127/17/02-06/582), and the Uganda National Council for Science and Technology (HS2308). RNA sequencing data analyzed in this study are available in the NIH National Center for Biotechnology Information Sequence Read Archive under BioProject accession no. PRJNA794277. Other de-identified data will be made available to researchers affiliated with an appropriate institution after mutual signing of a data access agreement and obtainment of necessary ethics approvals. All code is available on request from M. J. C., A. P., and K. J.

Authors’ addresses: Matthew J. Cummings, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, and Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, E-mail: mjc2244@columbia.edu. Barnabas Bakamutumaho, Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda, and Immunizable Diseases Unit, Uganda Virus Research Institute, Entebbe, Uganda, E-mail: bbarnabas2001@yahoo.com. Komal Jain, Adam Price, and Stephen Sameroff, Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, E-mails: komalj@gmail.com, price0416@gmail.com, and scs2178@cumc.columbia.edu. Nicholas Owor, John Kayiwa, Joyce Namulondo, Timothy Byaruhanga, and Julius J. Lutwama, Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda, E-mails: nicowor@gmail.com, jkayiwa@yahoo.com, jonacla.j@gmail.com, tssekandi@gmail.com, and jjlutwama03@yahoo.com. Moses Muwanga and Christopher Nsereko, Entebbe General Referral Hospital, Ministry of Health, Entebbe, Uganda, E-mails: docmuwanga@yahoo.com and chrisdoc23@yahoo.com. W. Ian Lipkin, Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, and Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, E-mail: wil2001@columbia.edu. Max R. O’Donnell, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, E-mail: mo2130@columbia.edu.

Copyright:
© The American Society of Tropical Medicine and Hygiene 2023
Received:
29 Jul 2022
|
Accepted:
16 Nov 2022
|
Published Online:
16 Jan 2023
Cover The American Journal of Tropical Medicine and Hygiene
The American Journal of Tropical Medicine and Hygiene
Print ISSN:
0002-9637
Online ISSN:
1476-1645
  • 1.

    Rudd KE et al., 2020. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet 395: 200–211.

    • Search Google Scholar
    • Export Citation
  • 2.

    Singer M et al., 2016. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315: 801–810.

  • 3.

    Vincent JL et al., 2009. International study of the prevalence and outcomes of infection in intensive care units. JAMA 302: 2323–2329.

  • 4.

    Lewis JM , Feasey NA , Rylance J , 2019. Aetiology and outcomes of sepsis in adults in sub-Saharan Africa: a systematic review and meta-analysis. Crit Care 23: 212.

    • Search Google Scholar
    • Export Citation
  • 5.

    Adegbite BR , Edoa JR , Ndzebe Ndoumba WF , Dimessa Mbadinga LB , Mombo-Ngoma G , Jacob ST , Rylance J , Hänscheid T , Adegnika AA , Grobusch MP , 2021. A comparison of different scores for diagnosis and mortality prediction of adults with sepsis in low-and-middle-income countries: a systematic review and meta-analysis. EClinicalMedicine 42: 101184.

    • Search Google Scholar
    • Export Citation
  • 6.

    Maitland K et al., 2011. Mortality after fluid bolus in African children with severe infection. N Engl J Med 364: 2483–2495.

  • 7.

    Andrews B , Muchemwa L , Kelly P , Lakhi S , Heimburger DC , Bernard GR , 2014. Simplified severe sepsis protocol: a randomized controlled trial of modified early goal-directed therapy in Zambia. Crit Care Med 42: 2315–2324.

    • Search Google Scholar
    • Export Citation
  • 8.

    Andrews B , Semler MW , Muchemwa L , Kelly P , Lakhi S , Heimburger DC , Mabula C , Bwalya M , Bernard GR , 2017. Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension: a randomized clinical trial. JAMA 318: 1233–1240.

    • Search Google Scholar
    • Export Citation
  • 9.

    Cummings MJ et al., 2021. Stratifying sepsis in Uganda using rapid pathogen diagnostics and clinical data: a prospective cohort study. Am J Trop Med Hyg 105: 517–524.

    • Search Google Scholar
    • Export Citation
  • 10.

    Cummings MJ et al., 2022. Multidimensional analysis of the host response reveals prognostic and pathogen-driven immune subtypes among adults with sepsis in Uganda. Crit Care 26: 36.

    • Search Google Scholar
    • Export Citation
  • 11.

    Bolger AM , Lohse M , Usadel B , 2014. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30: 2114–2120.

  • 12.

    Andrews S , 2010. FastQC: A Quality Control Tool for High Throughput Sequence Data. Available at: http://www.bioinformatics.babraham.ac.uk/projects/fastqc/. Accessed December 14, 2022.

  • 13.

    Dobin A , Davis CA , Schlesinger F , Drenkow J , Zaleski C , Jha S , Batut P , Chaisson M , Gingeras TR , 2013. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29: 15–21.

    • Search Google Scholar
    • Export Citation
  • 14.

    Liao Y , Smyth GK , Shi W , 2014. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30: 923–930.

    • Search Google Scholar
    • Export Citation
  • 15.

    Cook NR , 2018. Quantifying the added value of new biomarkers: how and how not. Diagn Progn Res 11: 14.

  • 16.

    Pencina MJ , D’Agostino RB Sr , D’Agostino RB Jr , Vasan RS , 2008. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 27: 157–172.

    • Search Google Scholar
    • Export Citation
  • 17.

    Harrell FE , 2015. Multivariable modeling strategies. Regression Modeling Strategies: With Applications to Linear Models, Logistic and Ordinal Regression, and Survival Analysis, 2nd edition. New York, NY: Springer Press, 63–102.

    • Search Google Scholar
    • Export Citation
  • 18.

    Pencina MJ , D’Agostino RB Sr , Steyerberg EW , 2011. Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Stat Med 30: 11–21.

    • Search Google Scholar
    • Export Citation
  • 19.

    Love MI , Huber W , Anders S , 2014. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15: 550.

  • 20.

    Newman AM et al., 2019. Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol 37: 773–782.

    • Search Google Scholar
    • Export Citation
  • 21.

    Collins GS , Reitsma JB , Altman DG , Moons KG , 2015. Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): the TRIPOD statement. Ann Intern Med 162: 55–63.

    • Search Google Scholar
    • Export Citation
  • 22.

    Barichello T , Generoso JS , Singer M , Dal-Pizzol F , 2022. Biomarkers for sepsis: more than just fever and leukocytosis: a narrative review. Crit Care 26: 14.

    • Search Google Scholar
    • Export Citation
  • 23.

    Reinhart K , Bauer M , Riedemann NC , Hartog CS , 2012. New approaches to sepsis: molecular diagnostics and biomarkers. Clin Microbiol Rev 25: 609–634.

    • Search Google Scholar
    • Export Citation
  • 24.

    Stanski NL , Wong HR , 2020. Prognostic and predictive enrichment in sepsis. Nat Rev Nephrol 16: 20–31.

  • 25.

    Prescott HC , Calfee CS , Thompson BT , Angus DC , Liu VX , 2016. Toward smarter lumping and smarter splitting: rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design. Am J Respir Crit Care Med 194: 147–155.

    • Search Google Scholar
    • Export Citation
  • 26.

    Reddy K , Sinha P , O’Kane CM , Gordon AC , Calfee CS , McAuley DF , 2020. Subphenotypes in critical care: translation into clinical practice. Lancet Respir Med 8: 631–643.

    • Search Google Scholar
    • Export Citation
  • 27.

    Maslove DM et al., 2022. Redefining critical illness. Nat Med 28: 1141–1148.

  • 28.

    van der Poll T , van de Veerdonk FL , Scicluna BP , Netea MG , 2017. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol 17: 407–420.

    • Search Google Scholar
    • Export Citation
  • 29.

    Brady J , Horie S , Laffey JG , 2020. Role of the adaptive immune response in sepsis. Intensive Care Med Exp 8 (Suppl 1): 20.

  • 30.

    Qu M , Wang Y , Qiu Z , Zhu S , Guo K , Chen W , Miao C , Zhang H , 2022. Necroptosis, pyroptosis, ferroptosis in sepsis and treatment. Shock 57: 161–171.

Past two years Past Year Past 30 Days
Abstract Views 792 792 44
Full Text Views 159 159 2
PDF Downloads 174 174 2
 
Membership Banner
 
 
 
Affiliate Membership Banner
 
 
Research for Health Information Banner
 
 
CLOCKSS
 
 
 
Society Publishers Coalition Banner
Save