COVID-19 and post-infectious myalgic encephalomyelitis/chronic fatigue syndrome: a narrative review, by Sonia Poenaru, Sara J Abdallah, Vicente Corrales-Medina, Juthaporn Cowan in Therapeutic Advances in Infectious Disease. Jan 2021 [doi:10.1177/20499361211009385]

Bottom line

• Many post-acute COVID-19 symptoms resemble post-infectious ME/CFS
• Acute disease severity does not clearly correlate with persistent symptoms
• Long-term monitoring of post-acute COVID-19 symptoms and screening for common comorbid conditions is essential
• Further research is required to establish COVID-19 as an infectious trigger for ME/CFS as well as to define risk factors, prevalence, natural history, and possible interventional strategies to treat this condition

Review abstract:

Coronavirus disease 2019 (COVID-19) is a viral infection which can cause a variety of respiratory, gastrointestinal, and vascular symptoms. The acute illness phase generally lasts no more than 2–3 weeks. However, there is increasing evidence that a proportion of COVID-19 patients experience a prolonged convalescence and continue to have symptoms lasting several months after the initial infection.

A variety of chronic symptoms have been reported including fatigue, dyspnea, myalgia, exercise intolerance, sleep disturbances, difficulty concentrating, anxiety, fever, headache, malaise, and vertigo. These symptoms are similar to those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a chronic multi-system illness characterized by profound fatigue, sleep disturbances, neurocognitive changes, orthostatic intolerance, and post-exertional malaise. ME/CFS symptoms are exacerbated by exercise or stress and occur in the absence of any significant clinical or laboratory findings.

The pathology of ME/CFS is not known: it is thought to be multifactorial, resulting from the dysregulation of multiple systems in response to a particular trigger. Although not exclusively considered a post-infectious entity, ME/CFS has been associated with several infectious agents including Epstein–Barr Virus, Q fever, influenza, and other coronaviruses.

There are important similarities between post-acute COVID-19 symptoms and ME/CFS. However, there is currently insufficient evidence to establish COVID-19 as an infectious trigger for ME/CFS. Further research is required to determine the natural history of this condition, as well as to define risk factors, prevalence, and possible interventional strategies.

Discussion

The evidence for post-infectious ME/CFS following COVID-19 is not as strong as for other viruses such as EBV. Although persistent fatigue has been described extensively in post-acute COVID-19 symptom studies, no study has used ME/CSF criteria to characterize chronic fatigue in conjunction with other key symptoms and common disease manifestations.5,71,82,83 Another limitation is the degree of variability among different ME/CSF diagnostic criteria. Most post-infectious ME/CFS studies continue to use the 1994 CDC diagnostic criteria, which do not require the presence of other hallmark features of ME/CFS such as post-exertional malaise, cognitive changes, sleep disturbances, or orthostatic intolerance for diagnosis.7,8,16–19 This leads to difficulty interpreting the significance of individual chronic symptoms within the context of a post-infectious ME/CFS diagnosis.

Diagnosis of post-infectious ME/CFS in COVID-19 patients is further limited by its emerging infection status, as a duration of follow-up of at least 6 months is required to make this diagnosis.

Some symptoms seen in post-acute COVID-19 may occur as a consequence of critical illness or as a side effect of treatments such as steroids. For example, dyspnea is seen in up to 36% of people diagnosed with ME/CFS and is considered part of the broader category of orthostatic intolerance, along with postural tachycardia and hypotension.109 However, the dyspnea reported in post-COVID studies is not clearly described as a manifestation of orthostatic intolerance and may in fact represent fibrosis following inflammatory lung injury.76–78 This theory would be supported by the presence of clinically detectable abnormalities on imaging and pulmonary function testing in post-acute COVID-19 patients.73,74 Similar findings can be seen in survivors of acute respiratory distress syndrome, suggesting an organic cause for dyspnea.110–112

Other complications of critical illness and acute respiratory distress syndrome such as loss of muscle mass, deconditioning, steroid-induced myopathy, and multi-organ failure are correlated with poorer long-term health outcomes, chronic fatigue, and decreased functional capacity.111 There is some overlap between these outcomes and symptoms of ME/CFS. However, it is important to note that multiple post-acute COVID-19 studies have found no association between illness severity, presence of chronic symptoms, and objective measures of respiratory function, suggesting an alternate mechanism of pathogenesis.72,73,75,77,82

The importance of the higher rate of psychiatric comorbidities seen following epidemic outbreaks is similarly unclear. This association is likely caused by external stressors rather than due to the infection itself.11,35,42 While specific psychiatric conditions have not been consistently associated with increased risk of post-infectious ME/CFS, other psychosocial factors such as stressful life events, persistent high levels of anxiety, and reduced community support may play a role.7,17,28,29 Evidence from prior viral epidemics suggests that this period of multiple stressful life events may be an independent risk factor for developing ME/CFS; it will be difficult to separate the impact of pandemic-associated stress from the impact of the infection itself in defining COVID-19 as a risk factor for ME/CFS.

Although the symptom patterns seen in post-acute COVID-19 are similar to those seen in ME/CFS, further investigation with longer periods of follow-up and clearly defined diagnostic criteria will be required to establish COVID-19 as an infectious trigger for ME/CFS.