Decoding COVID-19: phenotypes and the pursuit of precision medicine.

Background: The pursuit of personalized medicine has underscored the critical role of phenotypes and subphenotypes in biology and medicine. A growing body of literature has identified diverse phenotypic manifestations of SARS-CoV-2 influenced by host and viral factors.

Objectives: To assess and integrate current knowledge regarding the clinical, immunologic, and molecular phenotypes associated with COVID-19, highlighting their impact on disease management, the personalization of therapeutic strategies, and the advancement of clinical research.

Sources: We conducted a comprehensive literature search of PubMed, Medline, and Embase databases from 1 October 2024 to 5 August 2025 to identify relevant literature regarding phenotypes observed in SARS-CoV-2 infection.

Content: Clinical phenotypes involve various demographic factors and comorbidities, vital sign trajectories, patterns of acute organ dysfunction, and variations in biomarkers, which may differ among viral variants. Immunologic phenotypes involve dysregulated cytokine responses, altered immune cell functions, disruptions in key signalling pathways, and variations in white blood cell ratios, often reflecting a pattern of immune suppression. Molecular phenotypes reflect variations in host polymorphisms involving interleukin-18 secretion, inflammasome formation, and human leucocyte antigen-DR isotype expression and alterations in leukocyte function which may persist beyond the acute phase of infection. Viral protein expression influences infectivity and transmissibility as well as disease severity and progression.

Implications: Understanding the phenotypes associated with SARS-CoV-2 infection can assist in clinical management and prognostication, stratification of patient populations for clinical trials, and development of novel therapies targeting various immunologic and molecular factors to improve morbidity and mortality.