E2 ModerateModerate confidencePEM ✓LongitudinalPeer-reviewedMachine draft
Health outcomes up to 3 years and post-exertional malaise in patients after hospitalization for COVID-19: a multicentre prospective cohort study (CO-FLOW).
Berentschot, Julia C, Bek, L Martine, Drost, Manon et al. · The Lancet regional health. Europe · 2025 · DOI
Quick Summary
This study followed 299 people hospitalized with COVID-19 for three years after discharge to track their recovery. While some improved over time, many people continued experiencing fatigue, memory problems, and cognitive difficulties—and these problems actually got worse between years 2 and 3. About one-third of patients developed post-exertional malaise (PEM), a condition where activity makes symptoms significantly worse, and these patients had more severe and persistent health problems throughout the study.
Why It Matters
This study provides crucial evidence that post-COVID conditions share features with ME/CFS, particularly the high prevalence of PEM and the pattern of symptom worsening over time despite initial expectations of recovery. The identification of PEM as a distinct phenotype with identifiable risk factors and worse outcomes supports arguments that PEM-positive patients require specialized management approaches. For ME/CFS researchers, the documented third-year deterioration and concurrent fatigue-cognition-dyspnea cluster offers insights into disease mechanisms relevant to understanding exertional intolerance.
Observed Findings
- At 3 years post-discharge: 66% reported fatigue, 63% impaired fitness, 59% memory problems, and 53% concentration problems
- Between years 2 and 3, fatigue scores worsened (mean difference +1.0), cognitive failures worsened (+2.2), and mental health summary scores declined (-2.2)
- Post-exertional malaise was reported by 36% (105/292) of patients at 3 years
- Patients with PEM had concurrent fatigue, cognitive failures, and dyspnea in 42% of cases versus only 6% in those without PEM
- Female sex (OR 3.4), pre-existing pulmonary disease (OR 3.0), pre-COVID physical inactivity (OR 2.3), and ICU treatment (OR 1.8) were significant risk factors for developing PEM
Inferred Conclusions
- Many health problems from COVID-19 hospitalization persist and worsen between years 2–3 despite general population-level improvement, suggesting a subgroup with progressive disease
- PEM represents a distinct and severe phenotype of long COVID, characterized by more concurrent symptoms and worse health trajectories
- Female patients, those with pre-existing lung disease, pre-COVID inactivity, and those requiring ICU care are at substantially elevated risk for developing PEM
- Current treatment approaches are insufficient; urgent investigation of underlying pathological mechanisms and optimized interventions are needed for PEM-positive patients
What This Study Does Not Prove
This study does not establish causality between identified risk factors and PEM—only associations. It cannot determine whether PEM in post-COVID patients represents the same pathophysiological mechanism as ME/CFS PEM, as no direct comparison group with ME/CFS was included. The reliance on patient-reported outcomes without objective biomarkers or exercise testing limits ability to distinguish subjective perception from actual physiological dysfunction.
Tags
Symptom:Post-Exertional MalaiseCognitive DysfunctionUnrefreshing SleepFatigue
Phenotype:Infection-TriggeredSevereLong COVID Overlap
Method Flag:Strong PhenotypingSevere ME IncludedSex-Stratified