Health outcomes up to 3 years and PEM in patients after hospitalization for COV-19: a multicentre prospective cohort study (CO-FLOW), 2025, Berentscho

Summary
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.
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Does this mean that 13.6 % (12 % / 88 %) completely recovered between 3 and 36 months?

 

So some returned to work while having more cognitive problems? That is weird.

 

Or the people that didn’t return to work developed more cognitive problems?

 

Maybe!

 

Research in context

Evidence before this study

We conducted a PubMed search for studies examining long-term health problems in patients previously hospitalized for COVID-19, including publications up to October 29, 2024, without language restrictions. The following search terms were used: (“COVID-19” OR “SARS-CoV-2” OR “Coronavirus disease 2019” or “long COVID”) AND “hospital∗” AND (“long-term∗” OR “follow∗” OR “recovery∗”) AND (“health outcomes” OR “patient-reported outcomes” OR “persistent” OR “sequelae”) AND (“2 year∗” OR “3 year∗”). Additionally, we searched PubMed for research articles on post-exertional malaise (PEM) in patients with long COVID using the terms: (“COVID-19” OR “SARS-CoV-2” OR “Coronavirus disease 2019” or “long COVID”) AND “post-exertional malaise”. The results indicated that only a limited number of studies have assessed health outcomes up to 3 years post-infection, reporting persistence of symptoms in most patients. Few studies have focused on PEM, but not in patients hospitalized for COVID-19, highlighting a notable gap in the current understanding of this condition within long COVID research.

Added value of this study

In this multicentre prospective cohort study with follow-up up to 3 years after hospitalization for COVID-19, the findings showed that patient experienced persisting and even worsening of several health issues up to 3 years. Specifically, while some health outcomes improved over time, self-reported fatigue and cognitive problems worsened between the second and third year. Similarly, joint pain, sleep disturbances, resuming work, and health-related quality of life (HRQoL) deteriorated during this period. Notably, only 24% of patients hospitalized for COVID-19 reported complete recovery at 3 years, underscoring the substantial health burden. This study also highlights post-exertional malaise (PEM), experienced by 36% of patients, with 98% of them also reporting co-occurring health issues. Patients with PEM showed significantly worse health outcomes throughout the 3-year follow-up period, suggesting that PEM may represent a more severe phenotype of long COVID. Risk factors for PEM included female sex, pre-existing pulmonary disease, and ICU admission, aligning with factors known to impact long-term COVID-19 recovery.

Implications of all the available evidence

The persistence and worsening of health problems in the third year after hospitalization for COVID-19 highlight the need for optimizing management strategies. The complexity and long-lasting health impact of COVID-19 remains poorly understood. PEM may serve as a marker for a more severe phenotype of long COVID. Early phenotyping of patients could improve risk stratification and enable more tailored aftercare, which may improve long-term outcomes. Additionally, our findings underscore the urgent need for research into the pathophysiology of long COVID and potential pharmacological treatments. Future studies should focus on identifying biomarkers and clinical tools to monitor symptom progression, ultimately enhancing management strategies and care for patients with long COVID.