BACKGROUND
Fatigue is common after viral infections, including SARS-CoV-2.1 Our purpose was to report the prevalence and impact of persistent fatigue 6 months after SARS-CoV-2 infection, considering post-exertional malaise2 and criteria for chronic fatigue syndrome.3
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 questionnaire5 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 pre-existing 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-2-negative individuals. Characteristics are presented in Table 1.
Table 1.
Baseline Characteristics of SARS-CoV-2-Positive Participants at 6 Months or More After Their Infection (n = 1497)
| No fatigue (n = 1239) | Fatigue (n = 258) | Total (n = 1497) | P value | |
|---|---|---|---|---|
| n (%) | n (%) | n (%) | ||
| Age categories | 0.271 | |||
| Below 40 | 505 (40.8) | 102 (39.5) | 607 (40.5) | |
| 40–59 | 565 (45.6) | 129 (50.0) | 694 (46.4) | |
| 60 and above | 169 (13.6) | 27 (10.5) | 196 (13.1) | |
| Sex | < 0.001 | |||
| Male | 566 (45.6) | 82 (31.8) | 645 (43.2) | |
| Female | 673 (54.4) | 176 (68.2) | 847 (56.8) | |
| Education | 0.124 | |||
| Primary | 47 (4.7) | 10 (4.9) | 57 (4.8) | |
| Apprenticeship | 108 (10.9) | 20 (9.9) | 128 (10.7) | |
| Secondary | 125 (12.6) | 35 (17.2) | 160 (13.4) | |
| Tertiary | 643 (64.9) | 117 (57.6) | 760 (63.7) | |
| Other | 55 (5.6) | 15 (7.4) | 70 (5.9) | |
| Prefer not to answer | 12 (1.2) | 6 (3.0) | 18 (1.5) | |
| Profession | 0.588 | |||
| None | 88 (8.9) | 15 (7.4) | 103 (8.6) | |
| Unskilled workers | 39 (3.9) | 5 (2.5) | 44 (3.7) | |
| Skilled workers | 153 (15.5) | 40 (19.7) | 193 (16.2) | |
| High-grade skilled workers | 255 (25.8) | 58 (28.6) | 313 (26.2) | |
| Professional managers | 284 (28.7) | 52 (25.6) | 336 (28.2) | |
| Other | 159 (16.1) | 30 (14.8) | 189 (15.8) | |
| Prefer not to answer | 12 (1.2) | 3 (1.5) | 15 (1.3) | |
| Civil status | 0.151 | |||
| Single | 200 (17.9) | 47 (18.2) | 247 (18) | |
| In couple, not married | 258 (23.1) | 73 (28.3) | 331 (24.1) | |
| Married or registered partnership | 546 (48.9) | 107 (41.5) | 653 (47.5) | |
| Divorced or separated | 98 (8.8) | 28 (10.9) | 126 (9.2) | |
| Widowed | 11 (1.0) | 1 (0.4) | 12 (0.9) | |
| Other | 3 (0.3) | 2 (0.8) | 5 (0.4) | |
| Have children | 704 (63.1) | 157 (60.9) | 861 (62.7) | 0.505 |
| Living status | 0.023 | |||
| Alone | 195 (17.5) | 52 (20.2) | 247 (18.0) | |
| Single parent with children | 55 (4.9) | 21 (8.1) | 76 (5.5) | |
| In couple, without children | 258 (23.1) | 56 (21.7) | 314 (22.9) | |
| In couple, with children | 503 (45.1) | 95 (36.8) | 598 (43.6) | |
| Cohabitation with other people | 104 (9.3) | 34 (13.2) | 138 (10.1) | |
| Work situation | 0.002 | |||
| Salaried | 815 (73.2) | 186 (72.1) | 1,001 (73) | |
| Retired | 86 (7.7) | 11 (4.3) | 97 (7.1) | |
| Student or training | 80 (7.2) | 19 (7.4) | 99 (7.2) | |
| Independent worker | 52 (4.7) | 11 (4.3) | 63 (4.6) | |
| Homemaker | 23 (2.1) | 5 (1.9) | 28 (2) | |
| Unemployed | 25 (2.2) | 15 (5.8) | 40 (2.9) | |
| Disability | 7 (0.6) | 7 (2.7) | 14 (1.0) | |
| Other | 25 (2.2) | 4 (1.6) | 29 (2.1) | |
| Contract situation | < 0.001 | |||
| Short-term contract | 85 (9.2) | 26 (12.4) | 111 (9.8) | |
| Long-term contract | 655 (71.2) | 167 (79.9) | 822 (72.8) | |
| Subsidized contract | 1 (0.1) | 1 (0.5) | 2 (0.2) | |
| Training | 19 (2.1) | 2 (1.0) | 21 (1.9) | |
| Not concerned | 40 (4.3) | 9 (4.3) | 49 (4.3) | |
| Other | 120 (13.0) | 4 (1.9) | 124 (11.0) | |
| Work activity | 0.047 | |||
| Not working | 21 (2.2) | 4 (1.8) | 25 (2.1) | |
| Less than 30% | 22 (2.3) | 4 (1.8) | 26 (2.2) | |
| 30–49% | 33 (3.4) | 7 (3.2) | 40 (3.4) | |
| 50–79% | 103 (10.6) | 38 (17.3) | 141 (11.9) | |
| 80–99% | 172 (17.8) | 48 (21.8) | 220 (18.5) | |
| 100% | 608 (62.7) | 115 (52.3) | 723 (60.8) | |
| Prefer not to answer | 10 (1.0) | 4 (1.8) | 14 (1.2) | |
| Smoking status | 0.142 | |||
| Non-smoker | 715 (59.6) | 145 (56.2) | 860 (59.0) | |
| Ex-smoker | 315 (26.3) | 68 (26.4) | 383 (26.3) | |
| Current smoker | 141 (11.8) | 36 (14.0) | 177 (12.1) | |
| Prefer not to answer | 28 (2.3) | 9 (3.5) | 37(2.5) | |
| Activity level | < 0.001 | |||
| None | 143 (11.9) | 58 (22.5) | 201 (13.8) | |
| Partial | 605 (50.5) | 145 (56.2) | 750 (51.5) | |
| Full physical activity | 438 (36.5) | 51 (19.8) | 489 (33.6) | |
| Prefer not to answer | 13 (1.1) | 4 (1.6) | 17 (1.2) | |
| Vaccination status | 0.001 | |||
| No vaccination | 171 (14.6) | 19 (7.4) | 190 (13.3) | |
| Partially vaccinated (1 dose) | 212 (18.1) | 60 (23.3) | 272 (19.0) | |
| Fully vaccinated (at least 2 doses) | 782 (63.1) | 177 (68.6) | 959 (64.1) | |
| Prefer not to answer | 8 (0.7) | 2 (0.8) | 10 (0.7) | |
| Hospitalization | 62 (5.3) | 22 (8.8) | 84 (5.9) | 0.086 |
| Reinfection | 120 (9.7) | 29 (11.2) | 149 (10.0) | 0.448 |
| BMI (kg/m2) | 0.063 | |||
| Below 18.5 | 33 (3.0) | 7 (2.9) | 40 (3.0) | |
| 18.5–24.9 | 579 (53.5) | 132 (53.9) | 711 (53.6) | |
| 25–29.9 | 265 (24.5) | 74 (30.2) | 339 (25.5) | |
| 30–34.9 | 183 (16.9) | 25 (10.2) | 208 (15.7) | |
| 35 and above | 22 (2.0) | 7 (2.9) | 29 (2.2) | |
| Symptoms at testing | 0.002 | |||
| Pauci-symptomatic | 219 (23.7) | 26 (13.5) | 245 (21.9) | |
| Have several symptoms | 707 (76.3) | 167 (86.5) | 874 (78.1) | |
| Comorbidities | ||||
| None | 665 (53.7) | 115 (44.6) | 780 (52.1) | 0.012 |
| Obesity or overweight | 159 (12.8) | 32 (12.4) | 191 (12.8) | 0.504 |
| Hypertension | 81 (6.5) | 16 (6.2) | 97 (6.5) | 0.168 |
| Diabetes | 18 (1.5) | 7 (2.7) | 25 (1.7) | 0.164 |
| Respiratory disease | 31 (2.5) | 9 (3.5) | 40 (2.7) | 0.455 |
| Cardiovascular disease | 24 (1.9) | 6 (2.3) | 30 (2.0) | 0.540 |
| Headache disorders | 107 (8.6) | 30 (11.6) | 137 (9.2) | < 0.001 |
| Chronic pain or fibromyalgia | 5 (0.4) | 4 (1.6) | 9 (0.6) | 0.028 |
| Hyperthyroidism | 5 (0.4) | 3 (1.2) | 8 (0.5) | 0.054 |
| Hypothyroidism | 22 (1.8) | 8 (3.1) | 30 (2.0) | 0.029 |
| Anemia | 18 (1.5) | 8 (3.1) | 26 (1.7) | 0.020 |
| Chronic fatigue | 13 (1.0) | 6 (2.3) | 19 (1.3) | 0.046 |
| Cognitive disorders | 25 (2.0) | 3 (1.2) | 28 (1.9) | 0.395 |
| Sleep disorders | 78 (6.3) | 20 (7.8) | 98 (6.5) | 0.361 |
| Depression | 29 (2.3) | 9 (3.5) | 38 (2.5) | 0.542 |
| Anxiety | 41 (3.3) | 12 (4.7) | 53 (3.5) | 0.990 |
| Irritable bowel syndrome | 40 (3.2) | 9 (3.5) | 49 (3.3) | 0.309 |
| Rheumatologic disorders | 49 (4.0) | 6 (2.3) | 55 (3.7) | 0.727 |
| Tendinitis | 25 (2.0) | 8 (3.1) | 33 (2.2) | 0.022 |
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 post-exertional 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).
Figure 1.
The prevalence of newly developed insomnia, cognitive impairment, headache, generalized pain, and functional and physical impairment stratified by fatigue severity including post-exertional malaise and criteria for chronic fatigue syndrome in SARS-CoV-2-positive individuals at 6 months or more after their infection (n = 1497)*. Prevalence is adjusted for age and sex. Only newly reported symptoms and sequelae after SARS-CoV-2 infection were included in this analysis. Severe fatigue is defined as a Chalder fatigue scale score ≥ 4. The DePaul brief questionnaire evaluated the frequency and severity of symptoms characterizing post-exertional malaise including heaviness or drowsiness after exercise, pain, fatigue, and exhaustion after minimal effort, as well as the time required for recovery. Using a Likert scale, a score of 2 or more on the frequency (5 questions) and severity (5 questions) of symptoms indicated post-exertional malaise. If recovery required more than 14 h after minimal physical or mental activity, the questionnaire was positive for chronic fatigue syndrome.
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 follow-up 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.
Acknowledgements
We would like to thank the CoviCare study team for their ongoing contribution to the research and clinical work of post-COVID patients at the Geneva University Hospitals: Delphine S. Courvoisier, Frederic Lador, Lamyae Benzakour, Matteo Coen, Ivan Guerreiro, Gilles Allali, Christophe Graf, Jean-Luc Reny, Silvia Stringhini, Hervé Spechbach, Frederique Jacquerioz, Julien Salamun, Guido Bondolfi, Dina Zekry, Paola M. Soccal, Riccardo Favale, Stéphane Genevay, Kim Lauper, Philippe Meyer, Nana Kwabena Poku, Agathe Py, Basile N. Landis, Thomas Agoritsas, Marwène Grira, José Sandoval, Julien Ehrsam, Simon Regard, Camille Genecand, and Aglaé Tardin.
Funding
Private Foundation of the Geneva University Hospitals, Leenaards foundation
Declarations
Conflict of Interest
The authors declare that they do not have a conflict of interest.
Statement
We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that this work has been conducted with the ethical approval of the Cantonal Research Ethics Commission of Geneva, Switzerland, and that the approvals are acknowledged within the manuscript.
Footnotes
Publisher’s Note
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