Risk Factors and Multidimensional Assessment of Long Coronavirus Disease Fatigue: A Nested Case-Control Study

Ili Margalit*, Dana Yelin, Moshe Sagi, Maya Merav Rahat, Liron Sheena, Nadav Mizrahi, Yael Gordin, Hadar Agmon, Nitzan Karny Epstein, Alaa Atamna, Ori Tishler, Vered Daitch, Tanya Babich, Donna Abecasis, Yoni Yarom, Shirit Kazum, Dorit Shitenberg, Erik Baltaxe, Odelia Elkana, Irit Shapira-LichterLeonard Leibovici, Dafna Yahav

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background: Fatigue is the most prevalent and debilitating long-COVID (coronavirus disease) symptom; however, risk factors and pathophysiology of this condition remain unknown. We assessed risk factors for long-COVID fatigue and explored its possible pathophysiology. Methods: This was a nested case-control study in a COVID recovery clinic. Individuals with (cases) and without (controls) significant fatigue were included. We performed a multidimensional assessment evaluating various parameters, including pulmonary function tests and cardiopulmonary exercise testing, and implemented multivariable logistic regression to assess risk factors for significant long-COVID fatigue. Results: A total of 141 individuals were included. The mean age was 47 (SD: 13) years; 115 (82%) were recovering from mild coronavirus disease 2019 (COVID-19). Mean time for evaluation was 8 months following COVID-19. Sixty-six (47%) individuals were classified with significant long-COVID fatigue. They had a significantly higher number of children, lower proportion of hypothyroidism, higher proportion of sore throat during acute illness, higher proportions of long-COVID symptoms, and of physical limitation in daily activities. Individuals with long-COVID fatigue also had poorer sleep quality and higher degree of depression. They had significantly lower heart rate [153.52 (22.64) vs 163.52 (18.53); P =. 038] and oxygen consumption per kilogram [27.69 (7.52) vs 30.71 (7.52); P =. 036] at peak exercise. The 2 independent risk factors for fatigue identified in multivariable analysis were peak exercise heart rate (OR:. 79 per 10 beats/minute; 95% CI:. 65-.96; P =. 019) and long-COVID memory impairment (OR: 3.76; 95% CI: 1.57-9.01; P =. 003). Conclusions: Long-COVID fatigue may be related to autonomic dysfunction, impaired cognition, and decreased mood. This may suggest a limbic-vagal pathophysiology. Clinical Trials Registration: NCT04851561.

Original languageEnglish
Pages (from-to)1688-1697
Number of pages10
JournalClinical Infectious Diseases
Issue number10
StatePublished - 15 Nov 2022


  • post-COVID
  • post-viral fatigue


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