E2 ModeratePreliminaryPEM not requiredObservationalPeer-reviewedMachine draft
Standard · 3 min
Neurological Involvement in COVID-19 Among Non-Hospitalized Adolescents and Young Adults.
Havdal, Lise Beier, Berven, Lise Lund, Selvakumar, Joel et al. · Frontiers in neurology · 2022 · DOI
Quick Summary
This study looked at young people (ages 12-25) who had COVID-19 but were not hospitalized, comparing them to people who didn't have COVID-19. Researchers found that COVID-19 patients reported more fatigue and post-exertional malaise (PEM)—a worsening of symptoms after physical activity—and had slightly elevated markers of brain injury in their blood. However, their thinking and memory abilities tested normally, and the blood markers didn't directly correlate with their symptoms.
Why It Matters
This study documents that non-severe COVID-19 can produce biomarkers of brain injury alongside fatigue and post-exertional malaise—symptoms central to ME/CFS—in young people, suggesting potential biological underpinnings for post-COVID conditions. Understanding whether and how COVID-19 causes ME/CFS-like illness requires identifying objective markers and mechanisms, which this work partially addresses. The findings may inform clinical recognition and investigation of post-COVID fatigue syndromes that resemble ME/CFS.
Observed Findings
Serum neurofilament light chain (NfL) was significantly elevated in COVID-19 cases versus controls (p=0.050)
Serum glial fibrillary acidic protein (GFAp) was significantly elevated in COVID-19 cases versus controls (p=0.014)
COVID-19 cases reported significantly more fatigue compared to non-COVID controls (p<0.001)
COVID-19 cases reported significantly more post-exertional malaise compared to non-COVID controls (p=0.001)
Cognitive test performance and clinical neurological examination showed no significant differences between COVID-19 and control groups
Inferred Conclusions
Non-hospitalized young people with COVID-19 exhibit subtle markers of brain injury despite normal cognitive testing and normal neurological examination.
Fatigue and post-exertional malaise are prominent neurological symptoms in mild-to-moderate COVID-19 in adolescents and young adults, with stronger associations to female sex and older age than to measured brain injury biomarkers.
The disconnect between elevated biomarkers and normal cognitive performance suggests that current cognitive testing may not capture the neural dysfunction underlying post-COVID fatigue symptoms.
Remaining Questions
Do elevated brain injury biomarkers at baseline predict persistence or worsening of fatigue and PEM at follow-up, and what is the natural history of these symptoms in non-hospitalized adolescents and young adults?
What This Study Does Not Prove
This study does not prove that elevated brain injury markers *cause* fatigue or PEM, nor does it demonstrate that post-COVID fatigue represents true ME/CFS or that it will persist long-term—these are baseline cross-sectional findings without longitudinal follow-up data. The absence of correlations between biomarkers and symptoms does not rule out pathological involvement; it may reflect measurement limitations or different temporal relationships between injury and symptoms. The study also does not establish diagnostic criteria for post-COVID ME/CFS or explain why only some individuals develop these symptoms.
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 →
Why are there no detectable associations between NfL/GFAp levels and symptom severity or cognitive performance, and could different biomarkers or more sensitive cognitive testing reveal such relationships?
Are the mechanisms driving fatigue and PEM in post-COVID illness the same as those in ME/CFS, and do longitudinal cognitive or neuroimaging findings emerge over time?
How do sex and age modify the relationship between viral infection, brain injury, and symptom development in young people?