Health outcomes up to 3 years and post-exertional malaise in patients after hospitalization for COVID-19: a multicentre prospective cohort study (CO-FLOW)

Background: Many patients experience long-lasting health problems after COVID-19. The study aimed to assess 3-year trajectories of a comprehensive set of patient-reported outcome measures (PROMs) in patients hospitalized for COVID-19, particularly focusing on the 2- to 3-year trajectory. Additionally, we evaluated prevalence of post-exertional malaise (PEM) at 3 years, its risk factors, co-occurring health problems, and the 3-year trajectories of patients with and without PEM. Methods: The CO-FLOW multicentre prospective cohort study followed up adults hospitalized for COVID-19 in 7 hospitals, located in the Netherlands. Study assessments were performed at 3, 6, 12, 24, and 36 months post-discharge, conducted between July 1, 2020, and May 22, 2024. PROMs on recovery, symptoms, fatigue, mental health, cognition, participation, sleep quality, work status, health-related quality of life (HRQoL), and PEM were collected. Generalized estimating equations were used to assess health trajectories and multivariable logistic regression to identify risk factors for PEM. Findings: In total, 299/344 (87%) patients completed the 3-year follow-up and were included in the analysis. Complete recovery rates increased (p < 0.001), from 12% at 3 months to 24% at 3 years. Symptoms of impaired fitness, fatigue, and muscle weakness (all p < 0.0019) and PROMs for fatigue score, participation, return to work, and HRQoL (all p < 0.005) improved significantly over time, while PROMs for cognitive failures worsened (p < 0.001). Between the 2- and 3-year visits, memory problems (OR 1.4 [1.1–1.7], p < 0.001), and scores of fatigue (MD +1.0 [0.4–1.6], p = 0.002), cognitive failures (MD +2.2 [0.9–3.4], p < 0.001), and SF-36 mental component summary (−2.2 [−3.1 to −1.3], p < 0.001) significantly worsened. At 3 years, 66% of patients experienced fatigue, 63% impaired fitness, 59% memory problems, and 53% concentration problems. PROMs showed that 62% reported poor sleep quality, 55% fatigue, and 28% cognitive failures. PEM was reported by 105/292 (36%) patients at 3 years; risk factors were female sex (OR 3.4 [95% CI 1.9–6.0], p < 0.001), pre-existing pulmonary disease (3.0 [1.7–5.6], p < 0.001), physical inactivity pre-COVID-19 (2.3 [1.2–4.1], p = 0.008), and ICU treatment for COVID-19 (1.8 [1.02–3.0], p = 0.04). Concurrent fatigue, cognitive failures, and dyspnea were more common in patients with (42%) than without (6%) PEM. Patients with PEM showed poor health outcomes throughout the entire follow-up period, including worsening fatigue and HRQoL during the third year. Interpretation: Many health problems persisted up to 3 years post-discharge, with self-reported fatigue and cognitive problems worsening in the third year. PEM was common, and linked to a more severe phenotype of long COVID. These findings highlight the urgent need to optimize treatment options and investigate underlying pathological mechanisms of COVID-19. Funding: The Netherlands Organisation for Health Research and Development (ZonMw); Rijndam Rehabilitation; Laurens.