Longitudinal Landscape of Long Flu and Long COVID

Influenza is typically framed as an acute respiratory infection, yet accumulating evidence suggests that—like SARS-CoV-2—it may trigger persistent, multi-organ morbidity consistent with a post-acute infection syndrome (“long flu”). Leveraging the nationwide FinnGen registry infrastructure, we conducted a temporally stratified disease-wide association study (DWAS) to map antecedent risk factors and long-term sequelae following clinically diagnosed influenza and COVID-19. We assembled an exposed cohort comprising 9204 individuals with influenza (ICD-10 J09–J11) and 4258 individuals with COVID-19 (ICD-10 U072) recorded in specialist inpatient/outpatient care between 1998 and 2021, and an unexposed comparator cohort of 420,005 individuals with no recorded influenza or pneumonia (J09–J18) across their available medical history. Across harmonized clinical endpoints, we fitted age- and sex-adjusted Cox proportional hazards models and controlled for multiple testing using a stringent false discovery rate threshold (FDR-adjusted p < 0.001), further interrogating temporal persistence within 1-, 5-, and 15-year windows. The DWAS revealed that both infections are associated with broad, system-spanning disease signatures extending beyond the respiratory tract, including circulatory, neurological, metabolic, musculoskeletal, digestive, mental/behavioural, ocular, and oncologic endpoints. Predisposition analyses demonstrated that infection risk is concentrated in individuals with substantial pre-existing multimorbidity, most prominently cardiovascular disease, alongside cardiometabolic, respiratory, renal, neuropsychiatric, and inflammatory conditions. Post-infection analyses identified a durable burden of incident multi-system morbidity after influenza, with particularly robust and persistent cardiovascular and neurological signatures—encompassing thromboembolic disease and major adverse cardiovascular outcomes, as well as migraine, neurodegenerative disorders, and depression—together with metabolic and renal sequelae that, in subsets, extended across multi-year horizons. Collectively, these longitudinal findings reframe influenza as a systemic event embedded within a chronic disease continuum, motivate recognition of “long flu” as a clinically meaningful post-viral risk landscape, and support intensified prevention and risk-stratified surveillance strategies alongside analogous efforts for long COVID.