Matthew J Cummings, Julius J Lutwama, Nicholas Owor, Alin S Tomoiaga, Jesse E Ross, Moses Muwanga, Christopher Nsereko, Irene Nayiga, Stephen Kyebambe, Joseph Shinyale, Thomas Ochar, Moses Kiwubeyi, Rittah Nankwanga, Kai Nie, Hui Xie, Sam Miake-Lye, Bryan Villagomez, Jingjing Qi, Steven J Reynolds, Martina Cathy Nakibuuka, Xuan Lu, John Kayiwa, Mercy Haumba, Joweria Nakaseegu, Xiaoyu Che, Misaki Wayengera, Sankar Ghosh, Seunghee Kim-Schulze, W Ian Lipkin, Barnabas Bakamutumaho, Max R O'Donnell
{"title":"Unsupervised Classification of the Host Response Identifies Dominant Pathobiological Signatures of Sepsis in Sub-Saharan Africa.","authors":"Matthew J Cummings, Julius J Lutwama, Nicholas Owor, Alin S Tomoiaga, Jesse E Ross, Moses Muwanga, Christopher Nsereko, Irene Nayiga, Stephen Kyebambe, Joseph Shinyale, Thomas Ochar, Moses Kiwubeyi, Rittah Nankwanga, Kai Nie, Hui Xie, Sam Miake-Lye, Bryan Villagomez, Jingjing Qi, Steven J Reynolds, Martina Cathy Nakibuuka, Xuan Lu, John Kayiwa, Mercy Haumba, Joweria Nakaseegu, Xiaoyu Che, Misaki Wayengera, Sankar Ghosh, Seunghee Kim-Schulze, W Ian Lipkin, Barnabas Bakamutumaho, Max R O'Donnell","doi":"10.1164/rccm.202407-1394OC","DOIUrl":null,"url":null,"abstract":"<p><strong>Rationale: </strong>The global burden of sepsis is concentrated in sub-Saharan Africa, where inciting pathogens are diverse and HIV co-infection is a major driver of poor outcomes. Biological heterogeneity inherent to sepsis in this setting is poorly defined.</p><p><strong>Objectives: </strong>To identify dominant pathobiological signatures of sepsis in sub-Saharan Africa and their relationship to clinical phenotypes, patient outcomes, and biological classifications of sepsis identified in high-income-countries (HICs).</p><p><strong>Methods: </strong>We analyzed two prospective cohorts of adults hospitalized with sepsis (severe infection with qSOFA score≥1) at disparate settings in Uganda (discovery cohort [Entebbe,urban], N=242; validation cohort [Tororo,rural], N=253). To identify pathobiological signatures in the discovery cohort, we applied unsupervised clustering to 173 soluble proteins reflecting key domains of the host response to severe infection. A random forest-derived classifier was used to predict signature assignment in the validation cohort.</p><p><strong>Measurements and main results: </strong>Two signatures (Uganda Sepsis Signature [USS]-1 and USS-2) were identified in the discovery cohort, distinguished by expression of proteins involved in myeloid cell and inflammasome activation, T cell co-stimulation and exhaustion, and endothelial barrier dysfunction. A five-protein classifier (AUROC 0.97) reproduced two signatures in the validation cohort with similar biological profiles. In both cohorts, USS-2 mapped to a more severe clinical phenotype associated with HIV and related immunosuppression, severe tuberculosis, and increased risk of 30-day mortality. Substantial biological overlap was observed between USS-2 and hyperinflammatory and reactive sepsis phenotypes identified in HICs.</p><p><strong>Conclusions: </strong>We identified prognostically-enriched pathobiological signatures among sepsis patients with diverse infections and high HIV prevalence in Uganda. Globally inclusive investigations are needed to define generalizable and context-specific mechanisms of sepsis pathobiology, with the goal of improving access to precision medicine treatment strategies.</p>","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":""},"PeriodicalIF":19.3000,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of respiratory and critical care medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1164/rccm.202407-1394OC","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CRITICAL CARE MEDICINE","Score":null,"Total":0}
引用次数: 0
Abstract
Rationale: The global burden of sepsis is concentrated in sub-Saharan Africa, where inciting pathogens are diverse and HIV co-infection is a major driver of poor outcomes. Biological heterogeneity inherent to sepsis in this setting is poorly defined.
Objectives: To identify dominant pathobiological signatures of sepsis in sub-Saharan Africa and their relationship to clinical phenotypes, patient outcomes, and biological classifications of sepsis identified in high-income-countries (HICs).
Methods: We analyzed two prospective cohorts of adults hospitalized with sepsis (severe infection with qSOFA score≥1) at disparate settings in Uganda (discovery cohort [Entebbe,urban], N=242; validation cohort [Tororo,rural], N=253). To identify pathobiological signatures in the discovery cohort, we applied unsupervised clustering to 173 soluble proteins reflecting key domains of the host response to severe infection. A random forest-derived classifier was used to predict signature assignment in the validation cohort.
Measurements and main results: Two signatures (Uganda Sepsis Signature [USS]-1 and USS-2) were identified in the discovery cohort, distinguished by expression of proteins involved in myeloid cell and inflammasome activation, T cell co-stimulation and exhaustion, and endothelial barrier dysfunction. A five-protein classifier (AUROC 0.97) reproduced two signatures in the validation cohort with similar biological profiles. In both cohorts, USS-2 mapped to a more severe clinical phenotype associated with HIV and related immunosuppression, severe tuberculosis, and increased risk of 30-day mortality. Substantial biological overlap was observed between USS-2 and hyperinflammatory and reactive sepsis phenotypes identified in HICs.
Conclusions: We identified prognostically-enriched pathobiological signatures among sepsis patients with diverse infections and high HIV prevalence in Uganda. Globally inclusive investigations are needed to define generalizable and context-specific mechanisms of sepsis pathobiology, with the goal of improving access to precision medicine treatment strategies.
期刊介绍：
The American Journal of Respiratory and Critical Care Medicine focuses on human biology and disease, as well as animal studies that contribute to the understanding of pathophysiology and treatment of diseases that affect the respiratory system and critically ill patients. Papers that are solely or predominantly based in cell and molecular biology are published in the companion journal, the American Journal of Respiratory Cell and Molecular Biology. The Journal also seeks to publish clinical trials and outstanding review articles on areas of interest in several forms. The State-of-the-Art review is a treatise usually covering a broad field that brings bench research to the bedside. Shorter reviews are published as Critical Care Perspectives or Pulmonary Perspectives. These are generally focused on a more limited area and advance a concerted opinion about care for a specific process. Concise Clinical Reviews provide an evidence-based synthesis of the literature pertaining to topics of fundamental importance to the practice of pulmonary, critical care, and sleep medicine. Images providing advances or unusual contributions to the field are published as Images in Pulmonary, Critical Care, Sleep Medicine and the Sciences.
A recent trend and future direction of the Journal has been to include debates of a topical nature on issues of importance in pulmonary and critical care medicine and to the membership of the American Thoracic Society. Other recent changes have included encompassing works from the field of critical care medicine and the extension of the editorial governing of journal policy to colleagues outside of the United States of America. The focus and direction of the Journal is to establish an international forum for state-of-the-art respiratory and critical care medicine.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
