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

Evidence Atlas

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.

Metadata

DOI: 10.1016/j.lanepe.2025.101290
PMID: 40636057
Review status: Editor reviewed
Evidence level: Single-study or moderate support from human research
Last updated: 12 April 2026

About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →

Evidence Atlas

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

Quick Summary

Why It Matters

Observed Findings

Inferred Conclusions

What This Study Does Not Prove

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