Focus on long-COVID: Perimenopause and post-COVID chronic fatigue

Chronic fatigue syndrome

Chronic fatigue syndrome: A large number of patients have “post-COVID conditions” affecting everyday function, including depression/anxiety, insomnia, and chronic fatigue (with a 3:1 female predominance)

Alexandra Kadl, MD

After 3 years battling acute COVID-19 infections, we encounter now a large number of patients with PASC— also known as “long COVID,” “COVID long-hauler syndrome,” and “post-COVID conditions”—a persistent multisystem syndrome that impacts everyday function.¹ As of October 2023, there are more than 100 million COVID-19 survivors reported in the United States; 10% to 85% of COVID survivors2-4 may show lingering, life-altering symptoms after recovery. Common reported symptoms include fatigue, depression/ anxiety, insomnia, and brain fog/difficulty concentrating, which are particularly high in women who often had experienced only mild acute COVID-19 disease and were not even hospitalized. More recently, chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been recognized as major component of PASC5 with a 3:1 female predominance.6 Up to 75% of patients with this diagnosis are not able to maintain their jobs and normal life, and up to 25% are so disabled that they are bedbound.⁶

Diagnosis

Although illnesses resembling CFS have been reported for more than 200 years,⁷ the diagnosis of CFS/ME remains difficult to make. There is a likely underreporting due to fear of being labeled as malingering when reaching out to health care providers, and there is a reporting bias toward higher socioeconomic groups due to better access to health care. The current criteria for the diagnosis of CFS/ME include the following 3 components⁸:

1. substantial impairment in the ability to function for more than 6 months, accompanied by profound fatigue, not alleviated by rest
2. post-exertional malaise (PEM; prolonged, disabling exacerbation of the patient’s baseline symptoms after exercise)
3. non-refreshing sleep, PLUS either cognitive impairment or orthostatic intolerance.

Pathophysiology

Originally found to evolve in a small patient population with Epstein-Barr virus infection and Lyme disease, CFS/ME has moved to centerstage after the COVID-19 pandemic. While the diagnosis of COVID-19–related CFS/ME has advanced in the field, a clear mechanistic explanation of why it occurs is still missing. Certain risk factors have been identified for the development of CFS/ME, including female sex, reactivation of herpesviruses, and presence of connective tissue disorders; however, about one-third of patients with CFS/ME do not have identifiable risk factors.^9,10 Persistence of viral particles¹¹ and prolonged inflammatory states are speculated to affect the nervous system and mitochondrial function and metabolism. Interestingly, there is no correlation between severity of initial COVID-19 illness and the development of CFS/ME, similar to observations in non–COVID-19–related CFS/ME.

Proposed therapy

There is currently no proven therapy for CFS/ME. At this time, several immunomodulatory, antiviral, and neuromodulator drugs are being tested in clinical trial networks around the world.¹² Usual physical therapy with near maximum intensity has been shown to exacerbate symptoms and often results in PEM, which is described as a “crash” or “full collapse” by patients. The time for recovery after such episodes can be several days.¹³

Instead, the focus should be on addressing “treatable” concomitant symptoms, such as sleep disorders, anxiety and depression, and chronic pain. Lifestyle changes, avoidance of triggers, and exercise without over exertion are currently recommended to avoid incapacitating PEM.

Gaps in knowledge

There is a large knowledge gap regarding the pathophysiology, prevention, and therapy for CFS/ME. Many health care practitioners are not familiar with the disease and have focused on measurable parameters of exercise limitations and fatigue, such as anemias and lung and cardiac impairments, thus treating CFS/ME as a form of deconditioning. Given the large number of patients who recovered from acute COVID-19 that are now disabled due to CFS/ME, a patient-centered research opportunity has arisen. Biomedical/mechanistic research is ongoing, and well-designed clinical trials evaluating pharmacologic intervention as well as tailored exercise programs are needed.

Conclusion

General practitioners and women’s health specialists need to be aware of CFS/ME, especially when managing patients with long COVID. They also need to know that typical physical therapy may worsen symptoms. Furthermore, clinicians should shy away from trial drugs with a theoretical benefit outside of a clinical trial. ●

References

1. Soriano JB, Murthy S, Marshall JC, et al. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22:e102-e107. doi: 10.1016 /S1473-3099(21)00703-9
2. Chen C, Haupert SR, Zimmermann L, et al. Global prevalence of post-coronavirus disease 2019 (COVID-19) condition or long COVID: a meta-analysis and systematic review. J Infect Dis. 2022;226:1593-1607. doi: 10.1093/infdis/jiac136
3. Davis HE, McCorkell L, Vogel JM, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133-146. doi: 10.1038/s41579-022 -00846-2
4. Pavli A, Theodoridou M, Maltezou HC. Post-COVID syndrome: incidence, clinical spectrum, and challenges for primary healthcare professionals. Arch Med Res. 2021;52:575-581. doi: 10.1016/j.arcmed.2021.03.010
5. Kedor C, Freitag H, Meyer-Arndt L, et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022;13:5104. doi: 10.1038/s41467-022-32507-6
6. Bateman L, Bested AC, Bonilla HF, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: essentials of diagnosis and management. Mayo Clin Proc. 2021;96:28612878. doi: 10.1016/j.mayocp.2021.07.004
7. Wessely S. History of postviral fatigue syndrome. Br Med Bull. 1991;47:919-941. doi: 10.1093/oxfordjournals.bmb.a072521
8. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. National Academies Press; 2015. doi: 10.17226/19012
9. Ceban F, Ling S, Lui LMW, et al. Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav Immun. 2022;101:93135. doi: 10.1016/j.bbi.2021.12.020
10. Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019. doi: 10.1016/j.eclinm.2021.101019
11. Hanson MR. The viral origin of myalgic encephalomyelitis/ chronic fatigue syndrome. PLoS Pathog. 2023;19:e1011523. doi: 10.1371/journal.ppat.1011523
12. Scheibenbogen C, Bellmann-Strobl JT, Heindrich C, et al. Fighting post-COVID and ME/CFS—development of curative therapies. Front Med (Lausanne). 2023;10:1194754. doi: 10.3389/fmed.2023.1194754
13. Stussman B, Williams A, Snow J, et al. Characterization of post-exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front Neurol. 2020;11:1025. doi: 10.3389/fneur.2020.01025