The Prevalence, Severity, and Impact of Post-COVID Persistent Fatigue, Post-Exertional Malaise, and Chronic Fatigue Syndrome

Since March 2020, individuals tested for SARS-CoV-2 at the Geneva University Hospitals outpatient testing center benefit from remote ambulatory follow-up (COVICARE). This study included all individuals tested between March 2020 and December 2020 and whose follow-up was at 6 months or more after their test date. Follow-up included questions about the prevalence of symptoms (yes/no) and their severity using a Likert scale (mild, moderate, or severe). Fatigue was assessed using the Eastern Cooperative Oncology Group (ECOG) scale and the Chalder fatigue scale. The Chalder fatigue scale was scored using the 4-item Likert and the bimodal scoring schemes. A score of ≥ 4 on bimodal scoring indicated severe fatigue. The DePaul brief questionnaire was used to identify post-exertional malaise and criteria for chronic fatigue syndrome. The Sheehan Disability Scale was used to assess functional impairment. Reduced work capacity was defined as missing days off work or having a reduced productivity on the Sheehan disability scale. Comorbidities were considered present if preexisting prior to SARS-CoV-2 infection. Statistical analysis included descriptive comparisons of percentages using chi-square tests and Student’s t test. RESULTS


METHODS
Since March 2020, individuals tested for SARS-CoV-2 at the Geneva University Hospitals outpatient testing center benefit from remote ambulatory follow-up (COVICARE). 1 This study included all individuals tested between March 2020 and December 2020 and whose follow-up was at 6 months or more after their test date.
Follow-up included questions about the prevalence of symptoms (yes/no) and their severity using a Likert scale (mild, moderate, or severe). Fatigue was assessed using the Eastern Cooperative Oncology Group (ECOG) scale and the Chalder fatigue scale. 4 The Chalder fatigue scale was scored using the 4-item Likert and the bimodal scoring schemes. A score of ≥ 4 on bimodal scoring indicated severe fatigue. The DePaul brief questionnaire 5 was used to identify post-exertional malaise and criteria for chronic fatigue syndrome. The Sheehan Disability Scale was used to assess functional impairment. Reduced work capacity was defined as missing days off work or having a reduced productivity on the Sheehan disability scale. Comorbidities were considered present if preexisting prior to SARS-CoV-2 infection. Statistical analysis included descriptive comparisons of percentages using chi-square tests and Student's t test.

RESULTS
Overall, 5515 individuals participated in this study (response rate 70.7%), with 5406 participants at 6 months or more after their test date. A total of 1497 (27.7%) participants had a documented positive SARS-CoV-2 test and were ultimately included in the study. The median time for follow-up was 225 days (interquartile range 207-398). Respectively, fatigue was reported by 17.2%, post-exertional malaise by 8.2%, and the presence of criteria for chronic fatigue syndrome by 1.1% of SARS-CoV-2-positive individuals, compared to 8.9%, 3.5%, and 0.5% of SARS-CoV-2negative individuals. Characteristics are presented in Table 1.
Out of SARS-CoV-2-positive participants with fatigue (n = 258), 35.3% had moderate to severe limitations on the ECOG scale, and 83.0% had a score ≥ 4 on the Chalder fatigue scale. The Chalder fatigue scale revealed a mean score of 19 out of 33, SD 5.4, and a mean score of 6.7 out of 11, SD 3.3 using bimodal scoring. After adjusting for age and sex, 47.7% of SARS-CoV-2-positive individuals with fatigue at 6 months or more had the frequency and severity criteria for postexertional malaise, and 6.2% had criteria for chronic fatigue syndrome.
Individuals had a higher prevalence of insomnia, cognitive impairment, headaches, generalized pain, functional impairment, reduced work capacity, and decreased physical activity, after SARS-CoV-2 infection. The prevalence of these sequelae was adjusted for age and sex and was increasingly higher with severe fatigue, with post-exertional malaise, or when criteria for chronic fatigue syndrome were present ( Fig. 1).

DISCUSSION
Fatigue is the most common and persistent post-COVID symptom. The spectrum of fatigue severity in post-COVID individuals ranges from feeling tired to having severe fatigue, post-exertional malaise, or criteria for chronic fatigue syndrome with an increasing impact on health, functional capacity, and physical activity. Almost half of individuals experiencing fatigue at 6 months after the infection had post-exertional malaise, and 6.2% had criteria for chronic fatigue syndrome, prompting physicians to consider pacing as a management option, in the absence of other treatment options at this stage. SARS-CoV-2 infection was positively associated with fatigue and post-exertional malaise. Results showed that individuals with fatigue were more likely to be vaccinated. This was partially explained by the baseline distribution as older individuals and those with more comorbidities were more likely to get vaccinated.
Results compare to recent reviews showing an overlap between post-COVID condition and chronic fatigue syndrome. 6 Our study graded post-COVID fatigue by severity in correlation with functional capacity, and showed the high prevalence of post-exertional malaise.
Limitations include the self-reported nature of this followup with individuals infected in 2020 and follow-up in 2021, lacking comparisons to individuals infected with other variants. Additionally, this study considered having received at least 2 doses as full vaccination, a concept that continues to evolve with time.
Physicians, employers, and insurance companies should address fatigue on a spectrum, accounting for the correlated functional impairment, decreased activity levels, and potentially poorer quality of life.