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Although lymphopenia predicts mortality, functional lymphocyte thresholds and their coupling with inflammation are insufficiently defined. This retrospective study profiled 714 patients within 24 hours using lymphocyte subsets and inflammatory biomarkers to determine whether integrated immune-inflammation signals define sepsis endotypes with differential treatment responsiveness. Nonlinear count–mortality relationships and four endotypes with distinct 28-day survival were identified. Corticosteroid association improved survival in immunosuppressed/hypo-inflammatory but not hyperinflammatory endotypes, and multi-omics integration produced a validated T-cell dysfunction signature.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/sepsis-endotypes-defined-by-lymphocyte-thresholds-and-inflammation-inform-precision-immunomodulation/432998/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/sepsis-endotypes-defined-by-lymphocyte-thresholds-and-inflammation-inform-precision-immunomodulation/432998.png","ImageObject",300,407,{"name":92,"@type":93},"SANS","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",15,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What question does the study address about sepsis endotypes?","Question",{"text":113,"@type":114},"Whether combining lymphocyte status with systemic inflammation defines sepsis endotypes that respond differently to treatment.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How were endotypes identified in this work?",{"text":118,"@type":114},"The authors profiled 714 patients within 24 hours using lymphocyte subsets and inflammatory biomarkers, then used nonlinear modeling and principal component analysis to classify four discrete endotypes.",{"name":120,"@type":111,"acceptedAnswer":121},"How did corticosteroids relate to survival across the endotypes?",{"text":122,"@type":114},"Patients in the immunosuppressed/hypo-inflammatory endotype showed higher 28-day survival with corticosteroids, while hyperinflammatory endotypes did not show the same association.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},432998,1790765101,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},962090760505,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","MedComm  \nORIGINAL ARTICLE   \nSepsis Endotypes Defined by Lymphocyte Thresholds and Inflammation Inform Precision Immunomodulation  \nZhongyi Sun1  Li Li1  Wenkang Gao1  Han Gao2  Liangyu Guo3  Zhiyong Peng1  \n1 Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China  2 Department of Pulmonary Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China  3 Department of Orthopaedics, Renmin Hospital of Wuhan University, Wuhan, China  \nCorrespondence: Han Gao ([2022103030001@whu.edu.cn](2022103030001@whu.edu.cn))  Liangyu Guo (whicudrg@126.com)  Zhiyong Peng (Pengzy5@hotmail.com)  \nReceived: 27 August 2025  Revised: 4 December 2025  Accepted: 5 December 2025  \nKeywords: biomarker-guided therapy | corticosteroids | immunomodulation | lymphocyte dysfunction | sepsis endotypes  \nABSTRACT  \nImmunomodulatory therapies demonstrate variable efficacy in sepsis, suggesting biological heterogeneity inadequately captured by current stratification approaches. Although lymphopenia predicts mortality, functional thresholds and their interaction with inflammation remain poorly characterized. We investigated whether integrating lymphocyte status with systemic inflammation defines sepsis endotypes with differential treatment responsiveness. We retrospectively profiled 714 patients within 24 h using lymphocyte subsets and inflammatory biomarkers. Restricted cubic spline analysis revealed nonlinear associations between lymphocyte counts and mortality (p \u003C 0.01), with steep risk increases at lower counts. Risk optimization identified critical thresholds at 374 cells/µL (total T cells), 340 cells/µL (CD4+ ), and 157 cells/µL (CD8+ ) . Principal component analysis of inflammatory markers combined with lymphocyte stratification classified patients into four discrete endotypes with markedly divergent 28-day survival (55%–58% vs. 82–87%, p \u003C 0.001) . Patients with immunosuppressed/hypo-inflammatory endotype had higher survival among those who received corticosteroids (CD4+ -depleted: 84.4% vs. 75.6%, p \u003C 0.001; T-cell-depleted: 78.7% vs. 72.3%, p = 0.006), whereas hyperinflammatory endotypes showed no such association. Integration of publicly available single-cell (GSE167363) and bulk transcriptomics (GSE65682) datasets yielded a 15-gene T-cell dysfunction signature with external validation (CNP0004962, area under the curve [AUC] 0.76–0.85) . These observational findings suggest that immune-inflammatory coprofiling identifies biologically distinct sepsis subgroups with differential treatment associations, generating testable hypotheses for prospective validation through endotype-guided trials.  \n1  Introduction  \nSepsis affects more than 49 million people and causes approximately 11 million deaths annually worldwide [1] . Despite more than a hundred clinical trials evaluating immunomodulatory interventions, few have shown consistent benefit when applied uniformly to unselected populations [2, 3] . This failure reflects not inadequate pharmacology agents such as corticosteroids and  \ninterleukin-7 (IL-7) possess demonstrable biological activity but rather the profound heterogeneity of host immune responses [4, 5] . Sepsis triggers divergent immune trajectories: hyperinflammation characterized by excessive cytokine production and tissue injury in some patients, and immunosuppression marked by lymphocyte depletion and secondary infections in others [6, 7] . These opposing states impose different therapeutic requirements; administering immunosuppressive therapy to immunocompro-  \n\n| Zhongyi Sun and Li Li contributed equally to this work and shared first authorship.\u003Cbr>|\n| --- |\n| This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\u003Cbr>© 2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Austral","cbCaipKotg46wiKA","https://ap.wps.com/l/cbCaipKotg46wiKA","pdf",5832695,17,"English","# Introduction\n## Immunomodulatory trials and heterogeneity\n## Hyperinflammation vs immunosuppression in sepsis\n## Precision immunomodulation and need for quantifiable states","[{\"question\":\"What question does the study address about sepsis endotypes?\",\"answer\":\"Whether combining lymphocyte status with systemic inflammation defines sepsis endotypes that respond differently to treatment.\"},{\"question\":\"How were endotypes identified in this work?\",\"answer\":\"The authors profiled 714 patients within 24 hours using lymphocyte subsets and inflammatory biomarkers, then used nonlinear modeling and principal component analysis to classify four discrete endotypes.\"},{\"question\":\"How did corticosteroids relate to survival across the endotypes?\",\"answer\":\"Patients in the immunosuppressed/hypo-inflammatory endotype showed higher 28-day survival with corticosteroids, while hyperinflammatory endotypes did not show the same association.\"}]","Sepsis Endotypes Defined by Lymphocyte Thresholds and Inflammation Inform Precision Immunomodulation | PDF",1790662257,43]