Figure 2: Overlap of subphenotypes reported in sepsis.

Current sepsis subtyping is often done as a single-domain (clinical data or a single omics approach) focused analysis, which largely ignores the functional interconnections between different biological domains and is unlikely to capture the entire immunological complexity of sepsis biology. Hypothetical molecular and clinical subtypes are shown, with similar subphenotypes overlapping in the figure. Summary descriptors highlight apparent similarities between molecular subphenotypes and between clinical subphenotypes—for example, there are similarities between MARS-2, SRS-1, and inflammopathic molecular subphenotypes and between MARS-3, SRS-2, and adaptive molecular subphenotypes.^84–87 Subphenotypes are described relative to other subphenotypes within the same group. There are numerous challenges with the current approach to subphenotyping. These include (but are not limited to) differences in input data and analytical approaches for dimensionality reduction, limited use of integrated information from two or more biological data domains, and uncertainty around differential biological mechanisms linked to each subphenotype, probabilistic assignment of subphenotypes, unique targetable mechanisms with functional relevance in a subphenotype, relevant surrogate markers or endpoints, treatment response features at a biological level for each subphenotype, and the reproducibility of subphenotypes in multiple independent datasets. There is also uncertainty about the feasibility of implementation globally, including in resource-limited settings. See original studies^43,84–91 for more details on the different groups of subtypes, and elsewhere⁹² for additional information on the concepts included in the figure. ARDS=acute respiratory distress syndrome. ICU=intensive care unit. IL-6=interleukin 6. MARS=molecular diagnosis and risk stratification of sepsis. MODS=multiorgan dysfunction syndrome. NF-κB=nuclear factor κB. SOFA=Sequential Organ Failure Assessment. SRS=sepsis response signature.