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, whether symptomatic or not, will go on to develop persisting symptoms that resemble those of myalgic encephalitis/chronic fatigue syndrome.

SOURCE: Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in adults at 6 months after Covid-19 infection. JAMA Netw Open 2021;4:e210830doi10.1001/jamanetworkopen.2021.0830.

Persistent disease after an acute illness is a fact of life. Some diseases, like myalgic encephalitis/chronic fatigue syndrome (ME/CFS), have 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. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the disease known as COVID-19, is producing a pandemic as it presents within a spectrum of symptoms from asymptomatic to mild to severe disease.

Early in 2020, at the outset of the pandemic, 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 very eager to record and understand the duration and progression of sequelae in post-COVID-19 illness in those who adopted the term long haulers.

Several early studies had followed COVID-19 patients for one or three months and found that the persistence of symptoms occurred in 4% to 10% of patients with symptomatic illness. Now comes a more recent report from Dr. Helen Y. Chu’s group from the division of allergy and infectious diseases at the University of Washington in Seattle. The 177 patients in the Seattle study were those who reported symptoms up to 110 days after illness as compared to the 21 healthy controls.

Participants were 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.

There were 177/224 COVID-19 patients who completed the survey, with 6% asymptomatic, 85% outpatients, and 9.0% hospitalized. Surveys were completed between 31 and 300 days. There were 82/177 (46%) who reported persistent symptoms. The most common persistent symptoms were fatigue (13.6%) and loss of taste and smell (13.6%); 23 patients (13.0%) reported other symptoms, including brain fog. Interestingly, of 51 outpatient and hospitalized patients, 30.7% reported a worse quality of life.


This University of Washington study is the first to extend a study period out to nine months following COVID-19 illness to determine persistent symptoms. The researchers found that about 30% fell into this category, many of whom had mild outpatient disease. Persistent symptoms tended to increase with age. Fatigue persisted in almost 14% (24/177) and, surprisingly, in this study there was persistence of cranial nerve I dysfunction, meaning abnormalities in smell and taste. A recent New England Journal of Medicine letter documented in a small number (five) of deceased COVID-19 patients that activated microglia, a type of viral footprint, was present 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 has some central nervous system dysfunction, COVID-19 can cause changes in the brain, meaning that for the first time, medicine has a definitive cause, a coronavirus, that causes brain abnormalities and persisting symptoms lasting up to nine months, as shown in this study. I have seen patients who have had persisting post-COVID-19 symptoms longer than nine months.

For years, researchers in ME/CFS have searched for a “stealth organism,” and despite many false starts, no culprit has been nailed down. Nevertheless, the search still pertains since many ME/CFS patients will have some inciting event, such as a mild upper respiratory infection, trauma, surgery, etc. Moreover, even though there are various eponyms for ME/CFS, it remains a disease with many symptoms involving many organs. Several studies have shown multi-organ dysfunction. Some younger patients with ME/CFS will have remission, but with age, the likelihood of remission decreases. I have followed many patients who have ME/CFS for 15 or more years. Logue et al concluded, “comprehensive long-term investigations will be necessary to fully understand the impact of this evolving viral pathogen.”1

If we assume that at least 100 million Americans have been infected with COVID-19, an estimation from the present 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 symptoms, help them adapt to their new malady, and assure them that several medications can reduce their symptoms. Patients with ME/CFS have been stigmatized for years as having somatization syndromes and silly ills like “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 and solve the enigma of the long hauler.


  1. Belluck P. Covid survivors with long-term symptoms need urgent attention, experts say. New York Times. Dec. 5, 2020.
  2. 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.