Severe fatigue in the first year following SARS-CoV-2 infection: A prospective cohort study 5 151 severe fatigue after COVID-19. In addition to ongoing efforts to prevent new SARS-CoV-2 infections, identifying effective interventions for persistent severe fatigue that can be readily scaled up should therefore be a research priority. We identified several risk factors for fatigue severity following SARS-CoV-2 infection, several of which are modifiable and provide scope for risk reduction. Firstly, having multiple comorbidities was an independent risk factor. Previous studies have also reported a relationship between comorbidities and post-infectious fatigue [26], with comorbidities probably both lying on the causal pathway and partly representing preexisting fatigue. These findings add to the multitude of reasons why prevention of non-communicable diseases, such as cardiovascular disease and diabetes, is crucial for public health worldwide, not only during a pandemic. Dyspnoea during the acute phase of infection was also independently associated with fatigue severity. Since many participants with acute dyspnoea experience persistent dyspnoea as part of PACS [17], the association between dyspnoea and fatigue may be a direct consequence of acute respiratory distress syndrome and ongoing reduced functional capacity due to lung tissue damage [27, 28]. Underlying contributing factors including lung pathology should be a focus of future research. Interestingly, reporting a high level of sadness was identified as an independent risk factor for fatigue severity over time. Explaining this finding is challenging, as fatigue is both a known symptom of depression and, in turn, depression can be a reaction to persistent fatigue [26]. Additionally, other symptoms of depression, such as sleep disorders and concentration problems, have been reported as long-term sequelae of COVID-19 disease [29, 30] and may be associated with severe fatigue. The association between sadness levels and fatigue severity following COVID-19 is not likely explained by pre-existing clinical depression as only 18/303 (6%) of our participants reported a previous psychiatric diagnosis. We did not explore the contribution of underlying biochemical, hormonal, or body system (e.g., lung, cardiac, neurological or psychological) abnormalities to fatigue in our study participants. To date, the pathogenesis of post-infectious fatigue is largely unknown. Several theories have been proposed, which include end-organ damage, ongoing inflammation, changes in skeletal muscle morphology and function, and neurological causes [31]. Others have also described psychological factors, such as the cognitive and behavioural responses to acute illness and cultural factors [31]. Regardless of its cause, persistent severe fatigue can have serious consequences for the individual as well as impact health care usage and the economic productivity of a population [32,
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