Project Title

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Sequelae of COVID 19 Infection

Principal Investigator/Project Director

Nancy Klimas

Colleges / Centers

Dr. Kiran C. Patel College of Osteopathic Medicine


U.S. DHHS - Centers for Disease Control and Prevention

Start Date



As the rate of COVID-19 infection progresses in many regions of the United States, many patients, after experiencing an acute infection, continue to experience debilitating symptoms that result in a viral induced fatigue syndrome with similar symptomatology to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). It is well understood that viral or bacterial insult combined with other factors likely contribute to the onset of the ME/CFS. However, the rate of post-COVID-19 ME/CFS could drive these numbers up to staggering proportions, with one million ME/CFS cases in the U.S. today, prior to the pandemic, which could increase dramatically. Predicting risk from post-Epstein Barr virus (EBV) rates and post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rates suggest a range of 11 to 40 percent, perhaps higher with more severe infection. Early indications point to inflammation playing a key role in acute COVID-19 illness and severity, and may play a role in prolonged post-COVID- 19 infection symptom intolerance and long-term sequelae. Researchers have demonstrated the involvement of persistent inflammation, poor antiviral responses, and evidence of chronic viral reactivation. Viral infections of acute onset that are accompanied with systemic and brain inflammation are known to trigger ME/CFS (IOM report, 2015), a condition, commonly associated with viral or bacterial insult, which is characterized by persistent, unrelenting fatigue and known to impact one million people in the U.S. prior to the COVID-19 pandemic. The condition affects multiple organ systems including nervous, cardiovascular, respiratory, endocrine, muscular, and digestive. Researchers have demonstrated the involvement of persistent neuroinflammation and oxidative stress in central nervous system (CNS) and systemic studies, as well as a complex homeostatic imbalance of autonomic, neuroendocrine, and immune function (Craddock, et al 2014). Immune studies have demonstrated poor antiviral immune responses, and viral serology evidence of chronic viral reactivation of Herpes family viruses and GI biopsy evidence of Coxsackie virus reactivation (Institute of Medicine (IOM) report, 2015). Most recently, practicing ME/CFS clinicians are seeing COVID-19 cases with a similar presentation to ME/CFS symptomatology appearing in clinical practice post-COVID-19 infection (personal communication, ME/CFS Clinicians Summit dialogue June 2020). In addition, social media websites have support groups forming describing similar symptomatology. Editorials published in the New York Times and Washington Post have raised the same concern. An Australian group, working with the Centers for Disease Control and Prevention (CDC), showed the single best predictor of ME/CFS post-infection insult was the severity of the acute infection, no immune or psychological factors were predictive (Hickie et al, 2006). While ME/CFS researchers understand that viral or bacterial insult combined with other factors likely contribute to the onset of the condition, it is important to identify the risk of ME/CFS sequelae as early as possible, as few studies have been designed with prospectively collected data from early after onset, an issue emphasized as a research priority in the IOM report. Elevations in inflammatory cytokines distinguished individuals in the initial three years of illnesses when compared to more prolonged illness, suggesting important mechanisms and potential targets of intervention in preventing lifelong illness (Hornig et al. 2015). The urgency of capturing a population willing to participate in trajectory and phenotyping studies early in the post-COVID-19 illness progression not only assesses risk, but also could prove essential in providing targeted effective therapy and preventing decades of ME/CFS suffering in the post-COVID-19 infected population. It also provides an opportunity to help those already suffering with ME/CFS. Providing insight into the onset of the condition may help better understand the progression of the condition, potentially identifying prevention and targeted treatment strategies. As such, this study aims survey a community-based epidemiologic population in sufficient numbers to estimate risk of long-term sequelae post-COVID-19 acute infection. This part of the study will involve a large online survey component involving the study populations (Longitudinal Survey Population) and a smaller onsite component to phenotype the ME/CFS-like illness (Clinic-Based Assessment/Phenotyping Population). Two main cohorts will be used for recruitment including Florida Department of Health (FDOH) surveillance data and Community Health of South Florida (CHI), a Federally Qualified Health Center in Miami-Dade County, Florida, for broad demographic of the two counties (Broward and Miami-Dade Counties). The FDOH Bureau of Epidemiology disease surveillance data of COVID-19 positive tests in Broward County, Florida includes individuals aged 18 to 65 years. As of July 22, 2020, the n of this population is approximately 45,000 cases and is increasing rapidly. Our team will also work with CHI to enroll patients who have tested positive for COVID-19 infection through their testing sites. Utilizing these two recruitment approaches (and others outlined in the technical discussion, if needed) for the Longitudinal Survey Cohort, our aim is to recruit 2,000 persistently ill participants. These participants will complete a screening text based survey that will ask the individual if they have fully recovered from COVID-19, if they were hospitalized and, for those who have not fully recovered, ask if they are more tired, experiencing low energy and/or more fatigued now than they were before their COVID-19 diagnosis. In addition, they will be asked if they will participate in a research study that will include additional surveys. Among the first 2,000 individuals persistently ill individuals who complete this screening survey, the first 700 who agree to participate in future surveys and who meet inclusion criteria for possible ME/CFS will be invited to participate in the Longitudinal Survey Cohort. The Longitudinal Survey Cohort will be contacted at least four times a year for health and trajectory assessment over a three year period. They may be contacted via text or phone to support engagement. To address survey fatigue, we selected surveys on alternating quarters to assess the domains of ME/CFS longitudinally. We included a trajectory question to quickly assess self-reported health over the course of the study. The study team will evaluate reducing the number of surveys for participants who report no change in self-reported health in order to reduce survey fatigue. Of these 700 participants, 150 will be recruited for the clinical based assessment based on study inclusion criteria. In addition, another 200 participants who have fully recovered from COVID-19 infection will be recruited as a control cohort, surveyed annually for three years, from which 50 will be recruited into the Phenotyping Study. In the phenotyping/clinical assessment, a second group of survey questionnaires will be administered, along with physical examination, echocardiogram, spirometry, laboratory testing, and expert clinical examination. Overall, this study should be the first in a series designed to understand risk, mechanisms and identify targets for intervention. With the large size of the Longitudinal Survey Cohort, we aim to understand if potential sub-groups exist, the role of prior co-morbid conditions, and potential predictors of recovery or persistence, as well as the recovery and progression rates. Through phenotyping, we hope to understand the presentation, severity, and underlying mediators of illness persistence. Based on this overall assessment, it is our goal to understand the long term impact of acute COVID-19 infection on the risk of developing ME/CFS or ME/CFS-like symptomatology, and potentially lead to early intervention strategies and targeted approaches, the focus of much of our groups’ ongoing ME/CFS research and clinical practice efforts.

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