Associations Between Perceived Stress Levels and Post-Acute Fatigue Sequelae of COVID-19: Results From a Nested Case Control Study

Background: Continued COVID-19 symptoms past the typical illness period (≥30 days) are post-acute sequelae of COVID-19, or PASC. The most common PASC symptom is fatigue, which follow the post-viral symptoms reported by survivors of other infections. Stress has been shown to increase susceptibility to viruses and risk for chronic infectious outcomes. This study examined the relationship between perceived stress during illness onset and chronic PASC fatigue, as well as how gender, illness severity, and sleep duration affect this association. Methods: Arizona CoVHORT participants completed baseline and follow-up questionnaires about demographics, perceived stress, and sleep patterns. Cases had PASC and fatigue lasting for at least three months, and controls had PASC cases and no fatigue at three months or later. Multiple logistic regression estimated the odds ratios (OR) and 95% confidence intervals (CIs) of the relationship between perceived stress and chronic PASC fatigue. Models adjusted for age and pre-existing conditions and were fit with interaction terms for gender and illness severity to assess effect modification. A bootstrap mediation analysis determined the proportion mediated by sleep duration in this relationship. Results: Chronic PASC fatigue prevalence within this sample was 33%, with an average perceived stress score of 17.5±6.3. Odds of chronic PASC fatigue were 7% higher for every one unit increase in perceived stress after adjustment (95% CI: 0.99, 1.15). Women had 4% lower odds for chronic fatigue compared to men (adjOR: 0.96; 95% CI: 0.78, 1.18). Odds in those with moderate illness severity decreased compared to low illness severity (adjOR: 0.96; 95% CI: 0.78, 1.18), while high illness severity had 5% greater odds (adjOR: 1.05; 95% CI: 0.82, 1.36). 11.8% of stress’s effect on fatigue was attributed to sleep. Conclusions: Our results indicate a positive relationship between chronic PASC fatigue and perceived stress during COVID-19 onset, with marginal statistical significance after adjustment. Illness severity and gender did not significantly modify the effect of stress on fatigue, while sleep duration partially mediated this association. Further investigation of the relationship between chronic fatigue, perceived stress, and sleep is needed as PASC continues in COVID-19 survivors.Release after 05/16/202