Progress in the management of critical care syndromes such as sepsis, Acute Respiratory Distress Syndrome (ARDS), and trauma has slowed over the last two decades, limited by the inherent heterogeneity within syndromic illnesses. Numerous immune endotypes have been proposed in sepsis and critical care, however the overlap of the endotypes is unclear, limiting clinical translation. The SUBSPACE consortium is an international consortium that aims to advance precision medicine through the sharing of transcriptomic data. By evaluating the overlap of existing immune endotypes in sepsis across over 6,000 samples, we developed cell-type specific signatures to quantify dysregulation in these immune compartments. Myeloid and lymphoid dysregulation were associated with disease severity and mortality across all cohorts. This dysregulation was not only observed in sepsis but also in ARDS, trauma, and burn patients, indicating a conserved mechanism across various critical illness syndromes. Moreover, analysis of randomized controlled trial data revealed that myeloid and lymphoid dysregulation is linked to differential mortality in patients treated with anakinra or corticosteroids, underscoring its prognostic and therapeutic significance. In conclusion, this novel immunology-based framework for quantifying cellular compartment dysregulation offers a valuable tool for prognosis and therapeutic decision-making in critical illness.

Center for Biomedical Informatics Research Department of Medicine Stanford University Stanford CA

Center of Experimental and Molecular Medicine Amsterdam University Medical Centers University of Amsterdam the Netherlands

Department of Applied Biomedical Science University of Malta Malta

Department of Emergency Medicine Emory University Atlanta GA

Department of Emergency Medicine The Johns Hopkins University Baltimore MD

Department of Intensive Care Medicine Multidisciplinary Intensive Care Research Organization St James's Hospital Dublin Ireland

Department of Internal Medicine Faculty of Medicine Teaching Hospital and Biomedical Center in Pilsen Charles University Pilsen Czech Republic

Department of Internal Medicine National and Kapodistrian University of Athens Medical School Greece

Division of Critical Care Medicine Cincinnati Children's Hospital Medical Center Department of Pediatrics University of Cincinnati College of Medicine OH

Division of Infectious Diseases Amsterdam University Medical Centers University of Amsterdam the Netherlands

Division of Pulmonary Allergy and Critical Care Medicine Perelman School of Medicine University of Pennsylvania Philadelphia PA

Division of Pulmonary Allergy and Critical Care Medicine Stanford University Stanford CA

Hospital Clinic Universitat de Barcelona IDIBAPS CIBERES Barcelona Spain

Inflammatix Inc Sunnyvale CA

Institute for Immunity Transplantation and Infection Stanford University Stanford CA

Sepsis and Critical Illness Research Center and the SPIES Consortium University of Florida College of Medicine Gainesville FL

See more in PubMed

Berthelsen P. G. & Cronqvist M. The first intensive care unit in the world: Copenhagen 1953. Acta Anaesthesiol. Scand. 47, 1190–1195 (2003). PubMed

Zimmerman J. E., Kramer A. A. & Knaus W. A. Changes in hospital mortality for United States intensive care unit admissions from 1988 to 2012. Crit. Care 17, R81 (2013). PubMed PMC

Maslove D. M. et al. Redefining critical illness. Nat. Med. 28, 1141–1148 (2022). PubMed

Marshall J. C. Why have clinical trials in sepsis failed? Trends Mol. Med. 20, 195–203 (2014). PubMed

Antcliffe D. B. et al. Transcriptomic Signatures in Sepsis and a Differential Response to Steroids. From the VANISH Randomized Trial. Am. J. Respir. Crit. Care Med. 199, 980–986 (2019). PubMed PMC

Calfee C. S. et al. ARDS Subphenotypes and Differential Response to Simvastatin: Secondary Analysis of a Randomized Controlled Trial. Lancet Respir. Med. 6, 691–698 (2018). PubMed PMC

Famous K. R. et al. Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy. Am. J. Respir. Crit. Care Med. 195, 331–338 (2017). PubMed PMC

Sinha P. et al. Latent Class Analysis Reveals COVID-19-related Acute Respiratory Distress Syndrome Subgroups with Differential Responses to Corticosteroids. Am. J. Respir. Crit. Care Med. 204, 1274–1285 (2021). PubMed PMC

Meyer N. J. et al. Mortality Benefit of Recombinant Human Interleukin-1 Receptor Antagonist for Sepsis Varies by Initial Interleukin-1 Receptor Antagonist Plasma Concentration. Crit. Care Med. 46, 21–28 (2018). PubMed PMC

Stanski N. L. & Wong H. R. Prognostic and predictive enrichment in sepsis. Nat. Rev. Nephrol. 16, 20–31 (2020). PubMed PMC

Calfee C. S. et al. Latent Class Analysis of ARDS Subphenotypes: Analysis of Data From Two Randomized Controlled Trials. Lancet Respir. Med. 2, 611–620 (2014). PubMed PMC

Davenport E. E. et al. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir. Med. 4, 259–271 (2016). PubMed PMC

Sweeney T. E. et al. A community approach to mortality prediction in sepsis via gene expression analysis. Nat. Commun. 9, 694 (2018). PubMed PMC

Sweeney T. E. et al. Unsupervised Analysis of Transcriptomics in Bacterial Sepsis Across Multiple Datasets Reveals Three Robust Clusters. Crit. Care Med. 46, 915–925 (2018). PubMed PMC

Wong H. R. et al. Identification of pediatric septic shock subclasses based on genome-wide expression profiling. BMC Med. 7, 34 (2009). PubMed PMC

Raymond S. L. et al. Prospective Validation of a Transcriptomic Metric in Severe Trauma. Ann. Surg. 10.1097/SLA.0000000000003204 (2019) doi:10.1097/SLA.0000000000003204. PubMed DOI PMC

Cano-Gamez E. et al. An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression. Sci. Transl. Med. 14, eabq4433 (2022). PubMed PMC

Wong H. R. et al. Developing a Clinically Feasible Personalized Medicine Approach to Pediatric Septic Shock. Am. J. Respir. Crit. Care Med. 191, 309–315 (2015). PubMed PMC

Yao L. et al. Gene Expression Scoring of Immune Activity Levels for Precision Use of Hydrocortisone in Vasodilatory Shock. Shock Augusta Ga 57, 384–391 (2022). PubMed PMC

Zheng H. et al. Multi-cohort analysis of host immune response identifies conserved protective and detrimental modules associated with severity across viruses. Immunity 54, 753–768.e5 (2021). PubMed PMC

Scicluna B. P. et al. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir. Med. 5, 816–826 (2017). PubMed

Waddington C. S. et al. An outpatient, ambulant-design, controlled human infection model using escalating doses of Salmonella Typhi challenge delivered in sodium bicarbonate solution. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 58, 1230–1240 (2014). PubMed PMC

Tang B. M. et al. Neutrophils-related host factors associated with severe disease and fatality in patients with influenza infection. Nat. Commun. 10, 3422 (2019). PubMed PMC

Wallihan R. G. et al. Molecular Distance to Health Transcriptional Score and Disease Severity in Children Hospitalized With Community-Acquired Pneumonia. Front. Cell. Infect. Microbiol. 8, 382 (2018). PubMed PMC

Blohmke C. J. et al. Diagnostic host gene signature for distinguishing enteric fever from other febrile diseases. EMBO Mol. Med. 11, e10431 (2019). PubMed PMC

Yu J. et al. Host Gene Expression in Nose and Blood for the Diagnosis of Viral Respiratory Infection. J. Infect. Dis. 219, 1151–1161 (2019). PubMed PMC

Ambite I. et al. Fimbriae reprogram host gene expression - Divergent ejects of P and type 1 fimbriae. PLoS Pathog. 15, e1007671 (2019). PubMed PMC

Petzke M. M. et al. Global Transcriptome Analysis Identifies a Diagnostic Signature for Early Disseminated Lyme Disease and Its Resolution. mBio 11, e00047–20 (2020). PubMed PMC

Berdal J.-E. et al. Excessive innate immune response and mutant D222G/N in severe A (H1N1) pandemic influenza. J. Infect. 63, 308–316 (2011). PubMed

Banchereau R. et al. Host immune transcriptional profiles reflect the variability in clinical disease manifestations in patients with Staphylococcus aureus infections. PloS One 7, e34390 (2012). PubMed PMC

Mejias A. et al. Whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection. PLoS Med. 10, e1001549 (2013). PubMed PMC

Alder M. N., Opoka A. M., Lahni P., Hildeman D. A. & Wong H. R. Olfactomedin-4 Is a Candidate Marker for a Pathogenic Neutrophil Subset in Septic Shock. Crit. Care Med. 45, e426–e432 (2017). PubMed PMC

Heinonen S. et al. Rhinovirus Detection in Symptomatic and Asymptomatic Children: Value of Host Transcriptome Analysis. Am. J. Respir. Crit. Care Med. 193, 772–782 (2016). PubMed PMC

Jaggi P. et al. Whole blood transcriptional profiles as a prognostic tool in complete and incomplete Kawasaki Disease. PloS One 13, e0197858 (2018). PubMed PMC

Zhai Y. et al. Host Transcriptional Response to Influenza and Other Acute Respiratory Viral Infections--A Prospective Cohort Study. PLoS Pathog. 11, e1004869 (2015). PubMed PMC

Lindow J. C. et al. Cathelicidin Insufficiency in Patients with Fatal Leptospirosis. PLoS Pathog. 12, e1005943 (2016). PubMed PMC

de Steenhuijsen Piters W. A. A. et al. Nasopharyngeal Microbiota, Host Transcriptome, and Disease Severity in Children with Respiratory Syncytial Virus Infection. Am. J. Respir. Crit. Care Med. 194, 1104–1115 (2016). PubMed PMC

Thair S. A. et al. Transcriptomic similarities and differences in host response between SARS-CoV-2 and other viral infections. iScience 24, 101947 (2021). PubMed PMC

Soares-Schanoski A. et al. Systems analysis of subjects acutely infected with the Chikungunya virus. PLoS Pathog. 15, e1007880 (2019). PubMed PMC

Stevens J., Tezel O., Bonnefil V., Hapstack M. & Atreya M. R. Biological basis of critical illness subclasses: from the bedside to the bench and back again. Crit. Care 28, 186 (2024). PubMed PMC

Schulte-Schrepping J. et al. Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment. Cell 182, 1419–1440.e23 (2020). PubMed PMC

Wilk A. J. et al. Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19. J. Exp. Med. 218, e20210582 (2021). PubMed PMC

Combes A. J. et al. Global absence and targeting of protective immune states in severe COVID-19. Nature 591, 124–130 (2021). PubMed PMC

Sinha S. et al. Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19. Nat. Med. 28, 201–211 (2022). PubMed PMC

Seok J. et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl. Acad. Sci. U. S. A. 110, 3507–3512 (2013). PubMed PMC

Tompkins R. G. Genomics of Injury: The Glue Grant Experience. J. Trauma Acute Care Surg. 78, 671–686 (2015). PubMed PMC

Prozan L. et al. Prognostic value of neutrophil-to-lymphocyte ratio in COVID-19 compared with Influenza and respiratory syncytial virus infection. Sci. Rep. 11, 21519 (2021). PubMed PMC

Nahm C. H., Choi J. W. & Lee J. Delta Neutrophil Index in Automated Immature Granulocyte Counts for Assessing Disease Severity of Patients with Sepsis. Ann. Clin. Lab. Sci. 38, 241–246 (2008). PubMed

Park B. H. et al. Delta neutrophil index as an early marker of disease severity in critically ill patients with sepsis. BMC Infect. Dis. 11, 299 (2011). PubMed PMC

Kyriazopoulou E. et al. Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial. Nat. Med. 27, 1752–1760 (2021). PubMed PMC

Sevransky J. E. et al. Eject of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial. JAMA 325, 742–750 (2021). PubMed PMC

Gordon A. C. et al. Eject of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA 316, 509–518 (2016). PubMed

Kwok A. J. et al. Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis. Nat. Immunol. 24, 767–779 (2023). PubMed

Veglia F., Sanseviero E. & Gabrilovich D. I. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat. Rev. Immunol. 21, 485–498 (2021). PubMed PMC

de Pablo R., Monserrat J., Prieto A. & Alvarez-Mon M. Role of Circulating Lymphocytes in Patients with Sepsis. BioMed Res. Int. 2014, 671087 (2014). PubMed PMC

Varchetta S. et al. Unique immunological profile in patients with COVID-19. Cell. Mol. Immunol. 18, 604–612 (2021). PubMed PMC

Villanueva J. et al. Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res. Ther. 7, R30–37 (2005). PubMed PMC

Schulert G. S. & Grom A. A. MACROPHAGE ACTIVATION SYNDROME AND CYTOKINE DIRECTED THERAPIES. Best Pract. Res. Clin. Rheumatol. 28, 277 (2014). PubMed PMC

Sprung C. L. et al. Hydrocortisone Therapy for Patients with Septic Shock. N. Engl. J. Med. 358, 111–124 (2008). PubMed

Plassais J. et al. Transcriptome modulation by hydrocortisone in severe burn shock: ancillary analysis of a prospective randomized trial. Crit. Care Lond. Engl. 21, 158 (2017). PubMed PMC