Chapter 5 152 33]. Unsurprisingly, the predictors of persistent severe fatigue largely matched the factors associated with fatigue severity over time. Future studies should further elucidate predictors of persistent severe fatigue post-COVID-19 to target active prevention against SARS-CoV-2 infection for those at highest risk for post-COVID-19 fatigue. Our study has several strengths. Our prospective cohort study follows individuals from disease onset, minimising selection bias resulting from individuals self-referring after the onset of persistent fatigue. Furthermore, by including both hospitalised and nonhospitalised patients, we captured the entire spectrum of severity of COVID-19. Another strength is our long follow-up length and use of a validated instrument to assess fatigue [21, 34]. An important limitation of our study is that levels of fatigue pre-COVID-19, for example due to other chronic illnesses, were unknown. In addition, due to a lack of COVIDnegative controls, we cannot infer what proportion of fatigue was directly attributable to SARS-CoV-2 infection, as opposed to a result of lockdown restrictions, coined ‘pandemic fatigue’ [35]. Another limitation is that analysis of the prevalence of, and risk factors for, severe fatigue may be influenced by differential LTFU of participants and missing survey data. The direction of bias in prevalence estimates depends on whether fatigue severity influenced the likelihood to drop out or skip surveys. When comparing the sex, number of comorbidities, clinical severity and proportion of participants reporting severe fatigue in their earliest completed survey, no difference was found between those who were later lost to follow-up and those who remained in the study. However, those who were LTFU were generally younger than those who remained in active follow-up. Although we cannot rule out that attrition of these younger participants may have resulted in an over-exaggeration of severe fatigue prevalence estimates, the lack of difference observed in other baseline variables, notably initial fatigue prevalence, suggests that this retention bias is unlikely to be substantial. Finally, within our cohort, those who did not complete the Month 6 survey were more likely to be of non-Dutch than Dutch origin (p=0.005; Supplementary Table S1b), and therefore migrant groups were underrepresented in the persistent fatigue analysis. The occurrence of severe fatigue in our cohort was high, particularly among participants with severe/critical COVID-19. Although a decline in fatigue severity was observed in the first 6 months after illness onset, fatigue severity subsequently stabilized, indicating poor prognosis beyond this point. Participants with severe/critical COVID-19, multiple comorbidities, and high baseline sadness levels are at increased risk of persistent severe fatigue, a condition which may have substantial socio-economic implications. Our findings highlight an urgent need for improved understanding of the causes of persistent severe fatigue following COVID-19 in order to develop effective strategies for prevention.
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