Phenotypic Evolution, Clinical Subtypes, and Independent Predictors of Long COVID: A Retrospective Cohort Study

Background: Post-acute sequelae of COVID-19 (PASC), commonly known as long COVID, affects an estimated 10-30% of SARS-CoV-2 non-hospitalised and 50-70% of hospitalised survivors. This condition remains clinically heterogeneous, and the specific mechanisms driving the transition from acute infection to chronic sequelae remain poorly understood. We assessed independent risk factors, tracked the evolution of clinical features, defined distinct symptom-based phenotypes, and assessed the impact of different pandemic waves on the likelihood of developing long COVID in hospitalised survivors. Methods: We conducted a single-centre, retrospective cohort study at a university hospital in London. The population comprised 627 adults hospitalised with acute COVID-19 between February 2020 and December 2022. Baseline characteristics and outcomes were compared between long COVID and resolved cases using appropriate statistical tests for continuous and categorical variables. Multivariable logistic regression identified risk factors. McNemar's test quantified the phenotypic shift from admission to follow-up. Latent Class Analysis (LCA) identified clinical subtypes based on symptom clusters. Results: Of 627 patients, 252 (40.2%) met long COVID criteria. Comorbidity burden was the strongest predictor; patients with a single condition had a 4-fold increase in odds (aOR 4.62, 95% CI 2.36-9.04). The ORs were also significantly elevated among patients with 2 (aOR 3.26), 3 (aOR 2.68), or 4 or more (aOR 3.24) comorbidities. Older age (aOR 1.04), acute disease severity (measured by length of hospital stay) (aOR 1.27 per log-day) and elevated admission fibrinogen (aOR 1.21 per g/L) were significant predictors. Temporal analysis revealed a precipitous decline in risk from Wild-type/Alpha (>50%) to Delta/Omicron (<21%). We observed a distinct phenotypic shift: while acute respiratory inflammation resolved, systemic fatigue increased fourfold (7.0% to 32.4%), and memory difficulties emerged in the post-acute phase. LCA identified two phenotypes: fatigue-dominant and multisystem phenotypes. Conclusions: Long COVID is a multifactorial syndrome driven by host susceptibility, acute severity, and persistent coagulopathy. Clinical management should move beyond a monolithic approach and favour phenotype-specific strategies.