Four-Year Longitudinal Phenotyping of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC): A Single-Centre Cohort Study

Background: Although an increasing number of studies have reported 2- and 3-year outcomes of post-acute sequelae of SARS-CoV-2 infection (PASC), the long-term symptom patterns of and their clinical phenotypes beyond four years remains unknown. We aimed to characterize 48-month clinical outcomes and symptom profiles using hierarchical cluster analysis. Methods: We conducted a longitudinal cohort study of 79 patients with persistent PASC enrolled between March 2021 and March 2022. Of these, 77 patients completed the 48-month follow-up. Symptoms were assessed at 11 and 48 months post-infection. Hierarchical cluster analysis using Jaccard distance and Ward’s linkage identified symptom-based phenotypes at 48 months. Cluster membership was subsequently mapped back to 11-month symptom profiles to evaluate longitudinal trajectories. Results: Of the 77 patients completing the 48-month follow-up, symptom profiles at 48 months could be descriptively characterized into four exploratory, symptom-based profiles, which differed from the broader symptom patterns observed at month 11: Cluster 1 (cardiorespiratory and neurosensory symptoms; 16.9%, n = 13), characterized by persistent chest discomfort and palpitations; Cluster 2 (musculoskeletal/pain-predominant; 33.8%, n = 26), characterized by persistent myalgia and arthralgia. Cluster 3 (neurocognitive and mixed multisystem profile; 23.4%, n = 18), characterized by persistent cognitive impairment and musculoskeletal pain and Cluster 4 (minimal residual symptom burden; 26.0%, n = 20), demonstrating the lowest overall residual symptom burden at 48 months. Conclusions: At 48 months, PASC symptoms showed substantial heterogeneity, with four exploratory symptom-based profiles. In our cohort, over one-quarter of patients had the lowest observed residual symptom burden at 48 months; neurocognitive and musculoskeletal symptoms remained prominent in specific profiles, supporting the need for targeted multidisciplinary post-acute care.