E2 ModerateCohortPEM not requiredCase-ControlPeer-reviewed

Standard · 3 min

Persistent symptoms and clinical findings in adults with post-acute sequelae of COVID-19/post-COVID-19 syndrome in the second year after acute infection: A population-based, nested case-control study.

Peter, Raphael S, Nieters, Alexandra, Göpel, Siri et al. · PLoS medicine · 2025 · DOI

Quick Summary

This study followed nearly 1,000 people who had long-term COVID symptoms for over a year to see who improved and who stayed sick. Researchers found that about two-thirds of patients still had symptoms in the second year after infection, with fatigue, breathing problems, and thinking difficulties being the most common complaints. People who got better tended to have had milder initial infections and were more educated, while those who stayed sick were more likely to be overweight and have had specialist medical care or rehabilitation.

Why It Matters

This study provides crucial population-based evidence that post-COVID syndrome frequently persists into the second year in working-age adults, with objective evidence of reduced exercise capacity and cognitive dysfunction despite normal laboratory results. For ME/CFS research, the identification of post-exertional malaise (PEM) as a marker of greater disease severity aligns with ME/CFS diagnostic criteria and suggests PEM may be valuable for stratifying patient severity across post-viral conditions. The finding that standard medical investigations fail to identify pathology in persistent cases highlights the urgent need for novel biomarkers and mechanistic research in post-viral illnesses.

Observed Findings

67.6% of patients with post-COVID syndrome at baseline remained symptomatic at 8.5-month follow-up (second year post-infection), while 78.5% of initially recovered participants stayed symptom-free.
Patients with persistent symptoms had significantly lower maximal oxygen consumption (27.9 vs 31.0 ml/min/kg), reduced handgrip strength (40.2 vs 42.5 kg), and worse ventilatory efficiency compared to those with continued recovery.
35.6% of persistent PCS cases reported post-exertional malaise (PEM) lasting >14 hours; 11.6% met criteria for myalgic encephalomyelitis/chronic fatigue syndrome.
Persistent PCS was associated with higher obesity rates (30.2% vs 12.4%), higher mean BMI and body fat, and lower educational attainment compared to those who recovered.
No significant differences were found in laboratory markers including inflammatory markers, EBV reactivation, complement activity, cardiac function measures, natriuretic peptide levels, cortisol/ACTH/DHEA-S levels, or viral persistence (PCR/antigen testing).

Inferred Conclusions

The majority of working-age patients with post-COVID syndrome do not recover by the second year of illness, with symptoms remaining non-specific but dominated by fatigue, exercise intolerance, and cognitive complaints.
Objective physiological deficits in exercise capacity and neurocognition are present in persistent PCS despite absence of major laboratory pathology, suggesting mechanistic processes not captured by standard investigations.
History of post-exertional malaise (PEM) is a marker of more severe disease with greater symptom burden and objective physiological impairment, and may help stratify PCS cases for severity and prognosis.
Viral persistence, EBV reactivation, primary adrenal insufficiency, and abnormal complement turnover are unlikely to be major pathophysiological drivers of persistent PCS based on negative laboratory findings.

Remaining Questions

What mechanistic pathways drive the reduced exercise capacity, cognitive dysfunction, and dysautonomia observed in persistent PCS if standard laboratory investigations are negative?
Why are obesity, lower educational status, and prior specialist medical consultation associated with worse outcomes—are these risk factors, consequences of illness severity, or markers of healthcare-seeking behavior?
What differentiates the 67.6% of patients who remain symptomatic from the 32.4% who improve; are there biomarkers or early clinical features that predict recovery versus chronicity?
Do the objective neurocognitive deficits and reduced aerobic capacity persist beyond year 2, and what is the long-term functional and employment prognosis for patients with persistent PCS?

What This Study Does Not Prove

This study does not establish causality for the observed associations with PCS persistence (e.g., obesity, educational status, smoking) and cannot determine whether these are risk factors, consequences of illness, or confounders. The study cannot prove that the cognitive deficits or reduced exercise capacity existed before COVID infection, as there were no pre-infection baseline measurements, making pre-existing illness a potential confounder. The negative viral persistence and EBV reactivation findings do not exclude other potential mechanisms (mitochondrial dysfunction, autonomic dysfunction, microclotting, or other pathophysiology) in PCS/ME-CFS pathogenesis.

Topics

Post-Exertional Malaise

Metadata

DOI: 10.1371/journal.pmed.1004511
PMID: 39847575
Evidence level: Single-study or moderate support from human research
Last updated: 12 April 2026

Explore further

Explore Post-Exertional Malaise →Browse all studies →

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 →

Cite this study

The first block is for the primary paper and is the citation you should use in research work. The atlas-snapshot line only applies if you are specifically referring to this atlas’s reading of the paper on the date shown.

Primary citation

Peter, Raphael S, Nieters, Alexandra, Göpel, Siri, Merle, Uta, Steinacker, Jürgen M, Deibert, Peter, et al. (2025). Persistent symptoms and clinical findings in adults with post-acute sequelae of COVID-19/post-COVID-19 syndrome in the second year after acute infection: A population-based, nested case-control study.. PLoS medicine. https://doi.org/10.1371/journal.pmed.1004511

BibTeX

@article{mecfsatlas-peter-2025-persistent-symptoms,
  author  = {Peter, Raphael S and Nieters, Alexandra and Göpel, Siri and Merle, Uta and Steinacker, Jürgen M and Deibert, Peter and Friedmann-Bette, Birgit and Nieß, Andreas and Müller, Barbara and Schilling, Claudia and Erz, Gunnar and Giesen, Roland and Götz, Veronika and Keller, Karsten and Maier, Philipp and Matits, Lynn and Parthé, Sylvia and Rehm, Martin and Schellenberg, Jana and Schempf, Ulrike and Zhu, Mengyu and Kräusslich, Hans-Georg and Rothenbacher, Dietrich and Kern, Winfried V and EPILOC Phase 2 Study Group},
  title   = {Persistent symptoms and clinical findings in adults with post-acute sequelae of COVID-19/post-COVID-19 syndrome in the second year after acute infection: A population-based, nested case-control study.},
  journal = {PLoS medicine},
  year    = {2025},
  doi     = {10.1371/journal.pmed.1004511},
  note    = {PubMed: 39847575},
  url     = {https://www.mecfsatlas.com/evidence/peter-2025-persistent-symptoms},
}

Atlas snapshot reference

ME/CFS Atlas. Generator v1 / Scanner v1.4 / policy v0.1. Accessed 2026-05-30. https://www.mecfsatlas.com/evidence/peter-2025-persistent-symptoms

Contribute

Private, reviewed by a human. Not a public comment thread.

Report an error Suggest a source Ask a follow-up Request a guide

Persistent symptoms and clinical findings in adults with post-acute sequelae of COVID-19/post-COVID-19 syndrome in the second year after acute infection: A population-based, nested case-control study.

Quick Summary

Why It Matters

Observed Findings

Inferred Conclusions

Remaining Questions

What This Study Does Not Prove

Topics

Tags

Metadata

Explore further

Cite this study

Evidence Atlas

Persistent symptoms and clinical findings in adults with post-acute sequelae of COVID-19/post-COVID-19 syndrome in the second year after acute infection: A population-based, nested case-control study.

Quick Summary

Why It Matters

Observed Findings

Inferred Conclusions

Remaining Questions

What This Study Does Not Prove

Topics

Tags

Metadata

Explore further

Cite this study