Chapter 5 150 COVID-19 clinical severity defined as follows: mild disease as having a RR <20/min and SpO2 >94% on room air at both D0 and D7 study visits; moderate disease as having a RR20–30/min and SpO2 90–94% or receiving oxygen therapy at D0 and/or D7 study visits; severe disease as having a RR >30/ min and SpO2 <90% or receiving oxygen therapy at D0 and/or D7 study visits; critical disease as requiring ICU admission as a result of COVID-19 at any point. Highest baseline sadness score defined as the highest reported level of sadness at D0 or D7, subjectively reported on a scale from 0 to 10. Abbreviation: aOR, adjusted odds ratio. Results were comparable when restricting the analyses to prospectively-enrolled participants (Supplementary Table S3a). When redefining the outcome to having chronic fatigue, the effect size of severe/critical COVID-19 became stronger (aOR 5.18 [95%CI 1.73-15.5] from aOR 3.51 [95%CI 1.37-8.96] in Model 2; aOR 5.22 [95%CI 1.68-16.2] from aOR 3.37 [95%CI 1.28-8.93] in Model 3) with minimal change in the effect size of other covariates (Supplementary Table S3b). DISCUSSION This is the first prospective cohort study on clinically severe fatigue (measured using a validated instrument) up to 12 months after illness onset in COVID-19 patients across the full spectrum of COVID-19 severity. The occurrence of severe fatigue in our cohort was high, particularly during the first six months after infection. Even after one year from COVID-19 disease onset, severe fatigue was reported by 17%, 22% and 45% of participants with initially mild, moderate and severe/critical COVID-19 illness, respectively. As these individuals were significantly more likely to take long-term leave compared to those without severe fatigue at month 12, the socio-economic consequences of persistent fatigue following COVID-19 could be substantial. Risk factors for higher fatigue severity during the first year included having multiple comorbidities, more severe COVID-19, acute dyspnoea and a high level of baseline sadness. Owing to its prospective longitudinal design, our study provides valuable insight into temporal changes in post-COVID-19 fatigue. The proportion of participants with severe fatigue was highest in the moderate and severe/critical groups at all time-points. Although a significant decline in fatigue severity was observed between 0 and 6 after illness onset, measurements stabilised between month 6 and 12, also for those with initially mild COVID-19, suggesting poor prognosis beyond this point. Indeed, among those with mild COVID-19, approximately one-fifth developed persistent severe fatigue. It is not evident whether this proportion differs from the general Dutch population as we lacked an appropriate comparison group [26]. However, as those with mild disease represent the largest proportion of COVID-19 patients globally, millions worldwide may be experiencing
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