Emerging Biomarkers Across the Clinical Spectrum of SARS-CoV-2 Infection and Long COVID

Long COVID, also referred to in the literature as postacute sequelae of SARS-CoV-2 infection (PASC) or postacute COVID-19 syndrome (PACS), is a chronic and heterogeneous multisystem condition persisting beyond acute COVID-19. For consistency, this review uses the term “Long COVID” throughout; PASC and PACS are noted only where they reflect the terminology used by a specific cited study. The absence of validated, clinically actionable biomarkers remains a major barrier to diagnosis, risk stratification, and targeted intervention. This narrative review synthesizes evidence on candidate biomarkers relevant to SARS-CoV-2 infection, with particular attention to their mechanistic, clinical and translational relevance to long COVID specifically. Reflecting the fact that many candidate markers have been characterised primarily in acute or severe COVID-19, we explicitly indicate, for each biomarker domain, the strength and directness of the evidence linking it to long COVID as opposed to acute disease severity alone, and we distinguish exploratory candidates from those with more established clinical utility. Biomarkers are organised by domain virological, immunological/inflammatory, hematological/vascular, cardiovascular, metabolic/neuroendocrine, neurocognitive, and genetic/epigenetic beginning with virological and host-response markers, which we consider the most biologically direct evidence of ongoing SARS-CoV-2-related pathology, and closing with an integrative discussion of multiomics approaches. We also address biomarker overlap with other postinfectious and chronic inflammatory conditions, notably myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and the specific contribution of host genetic variation, including HLA haplotypes, to long COVID susceptibility. Relative to prior systematic reviews of long COVID biomarkers, this review’s distinguishing contribution is its explicit separation of acute-phase from chronic-phase evidence, its integration of genetic, epigenetic, and multiomics data within a single mechanistic framework, and its tiered classification of biomarkers by clinical readiness. Clinically, biomarker signatures are linked to core symptom clusters spanning respiratory, cardiovascular, neurological, metabolic and neuropsychiatric domains, underlining the potential for biomarker-informed patient classification, monitoring and targeted therapy, while emphasizing that most candidates currently remain exploratory and require validation in large, prospective, multicenter cohorts before clinical adoption.