By Joseph F. John, Jr., MD, FACP, FIDSA, FSHEA

Clinical Professor of Medicine and Microbiology, Medical University of South Carolina and Lowcountry Infectious Diseases, Charleston

SYNOPSIS: Many patients with COVID-19 will go on to develop persisting symptoms that resemble those of myalgic encephalitis/chronic fatigue syndrome, regardless of symptoms experienced at viral onset.

SOURCE: Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in adults at 6 months after COVID-19 infection. JAMA Netw Open 2021;4:e210830.

Persistent disease after an acute illness is a fact of life. Some diseases, such as myalgic encephalitis/chronic fatigue syndrome (ME/CFS), feature a well-known profile but an unknown specific trigger. ME/CFS may persist for years, carrying with it social stigma, financial ruin, and personal loss.

COVID-19 presents within a spectrum of symptoms from asymptomatic to mild to severe disease. Early in 2020, a certain percentage of COVID-19-infected patients began complaining of persistent symptoms, particularly fatigue, brain fog, low-grade fever, chest pain, muscle discomfort, sweats, persisting anosmia and dysgeusia, and more.1 These post-viral sequelae of COVID-19 resembled the disease ME/CFS, so researchers were eager to record and understand the duration and progression of sequelae in post-COVID-19 illness in those who have become known as “long-haulers.”

The authors of earlier studies had followed COVID-19 patients for one to three months, observing the persistence of symptoms occurred in 4% to 10% of patients with symptomatic illness. In the Logue et al study, patients reported experiencing symptoms many months later. Logue et al examined 234 patients with COVID-19 between August and November 2020 who completed subsequent questionnaires between three and nine months after their COVID-19 illness. Data analysis used R Project for Statistical Computing, version 4.0.2. A total of 177 patients completed the survey: 6% were asymptomatic, 85% were outpatients, and 9% were hospitalized. Surveys were completed between 31 and 300 days. There were 82 patients who reported persistent symptoms. The most common persistent symptoms were fatigue (13.6%) and loss of taste and smell (13.6%). Twenty-three patients reported other symptoms, including brain fog. Interestingly, of 51 outpatient and hospitalized patients, 30.7% reported a worse quality of life.


The Logue et al study is the first to extend a study period to nine months following COVID-19 illness to determine persistent symptoms. The researchers found about 30% fell into this category, many of whom had mild outpatient disease. Persistent symptoms tended to be worse with age. Fatigue persisted in 24 of 177 patients. The authors also observed persistent cranial nerve I dysfunction, meaning abnormalities in smell and taste. In a recent research letter, Lee et al observed activated microglia, a type of viral footprint, in the olfactory bulb, substantia nigra, dorsal motor nucleus of the vagal nerve, and the pre-Bötzinger complex in the medulla, related to spontaneous rhythmic breathing.2 Thus, like ME/CFS, which produces some central nervous system dysfunction, COVID-19 can cause changes in the brain.

For years, researchers in ME/CFS have searched for a “stealth organism.” Despite many false starts, no culprit has been identified. Nevertheless, the search still pertains since many ME/CFS patients will experience some inciting event (e.g., mild upper respiratory infection, trauma, or surgery). Moreover, even though there are various eponyms for ME/CFS, it remains a disease with many symptoms involving several organs. For some younger patients with ME/CFS, the disease will recede (as one ages, the likelihood of remission decreases).

If we assume that at least 100 million Americans have been infected with COVID-19, an estimation from the Logue et al study predicts that at least 14 million Americans may emerge with fatigue plus other chronic symptoms. As a clinician who follows many patients with ME/CFS, my immediate advice is to offer these post-COVID-19 patients hope, listen to all their symptom descriptions, help them adapt to their new malady, and assure them that several medications can alleviate their symptoms. Patients with ME/CFS have been stigmatized for years as having somatization syndromes and silly ills such as “yuppie flu.” Ironically, the historic plight of the ME/CFS patient likely will be targeted with new COVID-19 clinics (several of which already are established across the United States) and intense laboratory studies.

ME/CFS is a terrible disease, and medical science, now confronted with a known viral culprit as a trigger for chronic post-COVID-19 disease, must respond with a cadre of specialized medical scientists who can solve the enigma of the long-hauler. 


  1. Belluck P. Covid survivors with long-term symptoms need urgent attention, experts say. The New York Times. Dec. 5, 2020.
  1. Lee MH, Perl DP, Nair G, et al. Microvascular injury in the brains of patients with Covid-19. N Engl J Med 2021;384:481-483.