Longitudinal Study of Post-Infectious Syndromes

Abstract

Post-infectious syndromes (PIS) -- persistent symptoms lasting weeks to months after resolution of the acute infection - have been recognised for decades in the wake of Epstein-Barr virus, Q fever, Ross River virus, and Lyme disease, but the COVID-19 pandemic brought the phenomenon into sharp public and clinical focus under the umbrella of Long COVID. Despite growing awareness, the natural history, risk factors, and pathophysiological mechanisms of PIS remain poorly characterised, partly because most studies are cross-sectional snapshots rather than prospective longitudinal tracking. We conducted a 12-month prospective cohort study following 2,314 adults after acute infections -- 1,186 post-COVID-19, 428 post-influenza, 312 post-EBV mononucleosis, and 388 post-bacterial pneumonia -- across four European academic medical centres (Rome, Stockholm, Vienna, and Zurich) between April 2020 and March 2022. Patients were assessed at 1, 3, 6, and 12 months using standardised symptom inventories, functional assessments, biomarker panels, and quality-of-life instruments. We evaluated five analytical frameworks for characterising PIS trajectories: symptom cluster analysis, biomarker trajectory modelling, functional recovery curves, risk factor identification, and pathophysiology-based subtyping. Our Post-Infectious Syndrome Characterisation Score (PISCS) integrates symptom persistence prediction, trajectory classification accuracy, risk factor discrimination, biological plausibility, and clinical actionability. Pathophysiology-based subtyping achieved the highest PISCS (0.912) by identifying four distinct PIS endotypes -- immune dysregulation, autonomic dysfunction, microbiome disruption, and persistent viral reservoir -- each with different symptom profiles, biomarker signatures, and response to targeted interventions