Higher expression of the inflammopathic profile was associated with greater illness severity and mortality, according to a recent study.
The 4 endotypes—inflammopathic, coagulopathic, adaptive, and neutrophil-associated—appeared consistently across more than 7,074 blood samples from patients with bacterial sepsis, viral sepsis, and COVID-19. Among 2,212 patients with clinical phenotype data, higher myeloid dysregulation scores, which include the inflammopathic signature, correlated with increased severity and mortality. The same architecture extended to noninfectious critical illnesses, including acute respiratory distress syndrome, trauma, and burns, suggesting a conserved immune biology across syndromes.
Researchers conducted a large transcriptomic analysis across 37 independent cohorts, with conormalization performed using the COCONUT method. Unsupervised clustering of 4,106 samples from 3,380 patients using hierarchical clustering, principal component analysis, and network analysis consistently identified the four endotypes. Silhouette index analysis assessed cluster separation and internal consistency across analytic methods. This structure was validated in 1,460 additional samples from 19 public datasets. An independent analysis of 258 publicly available sepsis and COVID-19 samples demonstrated the same clustering pattern.
Single-cell RNA sequencing of 602,388 cells revealed the cellular underpinnings of these endotypes: detrimental myeloid signatures were dominated by immature neutrophils, while protective lymphoid signatures mapped to T and NK cells. No detrimental signatures originated from lymphoid cells. Fourteen immune cell populations were identified, enabling assignment of bulk gene expression signatures to specific cellular drivers.
Researchers then generated continuous human immune dysregulation evaluation framework (Hi-DEF) scores reflecting myeloid and lymphoid dysregulation. These scores independently predicted mortality beyond the neutrophil-to-lymphocyte ratio. Myeloid dysregulation was more prominent in bacterial infections, whereas lymphoid dysregulation dominated in viral infections. Patients with system-wide dysregulation—elevated scores on both axes—had the highest severity and mortality across cohorts.
The researchers noted that Hi-DEF represents an early framework built from previously published signatures, with continuous scores created as proof-of-concept using genes that may not fully capture cell-type or pathway-specific biology. Thresholds will require refinement across clinical settings. They also reported that the findings are preliminary because sample collection was concentrated early in hospitalization, most cohorts were from the US and Europe, gene expression data were available only for subsets of trial participants. Treatment-response analyses were exploratory and based on small groups, highlighting the need for prospective validation in broader populations.
“The convergence of results by these independent research groups on sepsis endotypes offers promise for advancing molecular endotyping,” noted lead author Andrew R. Moore, of the Division of Pulmonary, Allergy and Critical Care Medicine; the Institute for Immunity, Transplantation and Infection; and the Center for Biomedical Informatics Research, Department of Medicine, Stanford University, California, and colleagues.
Yehudit Hasin-Brumshtein, Purvesh Khatri, and Timothy E. Sweeney have professional roles with Inflammatix, Inc., which funded gene expression sequencing but did not participate in the study’s analysis; additional disclosures include consulting fees, honoraria, grants, or institutional funding reported by Nuala J. Meyer, Evangelos J. Giamarellos-Bourboulis, Hjalmar R. Bouma, and Jeremiah Hinson. All other researchers reported no competing interests.
Source: Nature Medicine
