Post-COVID-19 Condition Fatigue Outcomes Among Danish Residents

Abstract

Importance: Fatigue remains one of the most common and debilitating symptoms of post-COVID-19 condition; however, existing studies are limited to select populations and often lack noninfected controls. It also remains unclear to what extent severity of infection and psychiatric conditions, which are often linked to chronic fatigue, modify the risk of post-COVID-19 condition fatigue symptoms.

Objective: To evaluate the impact of SARS-CoV-2 infection on self-reported fatigue and postexertional malaise over time and to explore possible risk factors, such as the impact of acute SARS-CoV-2 hospitalization and preexisting psychiatric conditions on postacute fatigue.

Design, setting, and participants: In this cohort study, Danish residents aged 15 years and older were invited to participate in the EFTER-COVID survey, which used repeated, self-reported online questionnaires that collected information on fatigue (Fatigue Assessment Scale) and postexertional malaise scores (DePaul Symptom Questionnaire) after individuals' index SARS-CoV-2 polymerase chain reaction test. Participants were included if they completed a baseline and at least 1 follow-up questionnaire 2 to 18 months after testing for SARS-CoV-2.

Exposure: Testing for SARS-CoV-2 infection.

Main outcomes and measures: The primary outcomes were fatigue and postexertional malaise 2 to 18 months after testing. Mixed-effects models were used to compare scores between SARS-CoV-2 test-positive and test-negative individuals (testing period April 2021 to February 2023).

Results: Of a total of 50 115 participants (median [IQR] age at test date, 57 [46-67] years; 29 774 female [59.4%]), 25 249 were test positive and 24 866 were test negative. Most participants were vaccinated with at least 2 doses (21 164 test-negative participants [85.1%] and 22 120 test-positive participants [87.6%]) before their SARS-CoV-2 index test and fatigue reporting. In the period 2 to 18 months after testing, SARS-CoV-2 infection was associated with a small but significant 3% increase in self-reported fatigue scores (score ratio [SR], 1.03; 95% CI, 1.03-1.04) and higher odds of self-reported postexertional malaise (odds ratio, 2.04; 95% CI, 1.81-2.30), compared with test-negative participants. In the same period, hospitalization with SARS-CoV-2 increased fatigue scores by 23% (SR, 1.23; 95% CI, 1.20-1.26) compared with test-negative participants. Preexisting psychiatric conditions did not significantly modify postacute fatigue scores.

Conclusions and relevance: In this cohort study, SARS-CoV-2 infection was associated with a subtle increase in self-reported fatigue and postexertional malaise symptoms 2 to 18 months after mild infection. In contrast, individuals hospitalized with acute SARS-CoV-2 experienced a more substantial increase in postacute symptoms. Preexisting psychiatric conditions did not significantly modify the risk of postacute fatigue symptoms. The findings largely captured symptoms following first-time infections in a population where most had been vaccinated. Persons who experienced severe acute infection may benefit from clinical follow-up for fatigue.

Figure 1.. Prevalence of Fatigue and Postexertional Malaise Among Participants

Graphs show number of study participants contributing with a questionnaire response at each time point divided on test result (bars, left y-axis) and prevalence of severe fatigue (defined as a score of 35-50 on the Fatigue Assessment Scale [FAS]), mild-to-moderate and severe fatigue (score of 22-50 on FAS), and postexertional malaise (both a frequency and severity score of at least 2 on any of the same items from 1-5) over time and by SARS-CoV-2 test result (lines and points, right y-axis; error bars denote 95% CIs). DSQ indicates DePaul Symptom Questionnaire.

Figure 2.. Score Ratios and 95% CIs for Fatigue Assessment Scale (FAS) Scores Between Test-Positive and Test-Negative Individuals

Estimates are presented for pretest scores (ie, 6 months before the index test), each follow-up point, and the combined 2 to 18 months after testing. Poisson mixed-effects models took the following fixed effects into account: age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared; defined as with obesity [≥30], without obesity [<30], and unknown or missing), Charlson Comorbidity Index score (0, 1, or ≥2), health care occupation, SARS-CoV-2 variant (Alpha, Delta, Omicron, or Transition), vaccination status (unvaccinated and 1, 2, or 3 doses), employment, and education level. The individual identifier was included as a random effect. Diamond denotes score ratio and 95% CI over the combined 2- to 18-month period.

Figure 3.. Score Ratios and 95% CIs for Fatigue Assessment Scale (FAS) Scores Between Nonhospitalized (NH) and Acutely Hospitalized (H) Test-Positive and Test-Negative Individuals

Estimates are presented for pretest scores (ie, 6 months before the index test), each follow-up point, and the combined 2-18 months after testing. Poisson mixed-effects models took the following fixed effects into account: age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared; defined as with obesity [≥30], without obesity [<30], and unknown or missing), Charlson Comorbidity Index score (0, 1, or ≥2), health care occupation, SARS-CoV-2 variant (Alpha, Delta, Omicron, or Transition), vaccination status (unvaccinated and 1, 2, or 3 doses), employment, and education level. The individual identifier was included as a random effect. Thirty-two individuals who tested positive more than 2 days after hospitalization based on other reasons were excluded. Diamond denotes score ratio and 95% CI over the combined 2- to 18-month period.

Figure 4.. Score Ratios and 95% CIs for Fatigue Assessment Scale (FAS) Scores 2 to 18 Months After Testing Between Test-Positive and Test-Negative Patients, Stratified by Psychiatric Conditions

Poisson mixed-effects models took the following fixed effects into account: age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared; defined as with obesity [≥30], without obesity [<30], and unknown or missing), Charlson Comorbidity Index score (0, 1, or ≥2), health care occupation, SARS-CoV-2 variant (Alpha, Delta, Omicron, or Transition), vaccination status (unvaccinated and 1, 2, and 3 doses), employment, and education level. The individual identifier was included as a random effect. DNPR indicates Danish National Patient Register; EFTER COVID, AFTER COVID; and PTSD, posttraumatic stress disorder. Diamond denotes score ratio and 95% CI over the combined 2- to 18-month period in the overall study population.