There are a dizzying array of case definitions for long COVID that vary in terms of what to name this condition, the duration of symptoms, the types of symptoms, and the medical comorbidities. The field of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has encountered comparable problems as they developed case definitions over the past 3 decades. In this commentary, we will show how lessons learned from ME/CFS can help with identifying a variety of conceptually distinct medical comorbid conditions. This is a challenging task for those who are overseeing the large national COVID study, RECOVER, with over 8,500 participants currently enrolled and a goal of 40,000 participants by the end of the year.
Enrollees in the RECOVER study are asked hundreds of questions at each assessment over time, and one set of questions asks patients to indicate if participants have any comorbid conditions. RECOVER investigators want to learn if these comorbid conditions are due to either: 1) the SARS-CoV-2 infection itself, such as lung or other organ damage as a result of acute respiratory distress syndrome, or lingering symptoms consistent with a post-ICU syndrome; or 2) medical conditions that might have preceded the infection such as obesity and cerebrovascular disease. Both new and existing conditions might make recovery from COVID more difficult (and such premorbid conditions can also make one more susceptible to SARS-CoV-2 in the first place). RECOVER officials are now deliberating about whether to add to their list of illness comorbidities.
However, there is another issue that is just as important, but has been rarely discussed by RECOVER scientists or others. This issue is of critical importance in classifying long COVID patients, as some have “explained” and some have “unexplained” conditions contributing to the onset and persistence of symptoms.
From its earliest days, ME/CFS scientists have dealt with this issue of “explainable versus unexplainable” comorbidities, as many ME/CFS case definitions exclude a person from having ME/CFS if they had an explainable reason — i.e., a previously diagnosed medical condition whose resolution has not been documented beyond reasonable clinical doubt and whose continued activity may explain their chronic fatiguing illness. In other words, if cancer was causing their fatigue and other symptoms, they would have cancer fatigue but not ME/CFS, as ME/CFS is an illness that has unexplained symptoms.
In addition, ME/CFS researchers realized that the consequences of various medical conditions could also explain fatigue. For example, if the person with cancer had surgery or radiation which led to fatigue and other symptoms, researchers would not classify the person as having ME/CFS, as the person has another explained reason for their symptoms. However, if a person with core ME/CFS symptoms had cancer in the past, the cancer was successfully treated, and the cancer is no longer causing the symptoms, then the person would not have an exclusionary illness, and they would be eligible for an ME/CFS diagnosis.
It is critically important to identify those long COVID patients who might be classified as having unexplained persistent symptoms versus those that are explained, as these two groups might need to be differentiated when analyzing the long COVID data. To accomplish this, the RECOVER trial must gather sufficient information to determine if previous uncontrolled medical illnesses are present. We can learn from ME/CFS investigators how to collect adequate information to determine whether the patient’s persistent symptoms are due to an explained or unexplained cause. At minimum, physicians should determine whether the patients have other active and untreated disease processes that explain most of the major symptoms of post-exertional malaise, sleep disturbance, and cognitive impairment.
This explained/unexplained symptom information would also allow RECOVER investigators to determine whether their participants meet ME/CFS criteria, as there is growing evidence of multiple similarities between the two conditions. However, without this diagnostic information regarding explained or unexplained symptoms, it will not be possible to differentiate between those in the RECOVER trial who have versus those who do not have ME/CFS.
Leonard Jason, PhD, is a professor of psychology and director of the Center for Community Research at DePaul University. He is also chairperson of the Diagnostics Testing and Test Algorithms subcommittee of the NIH RECOVER Commonalities with Other Post Viral Syndromes Task Force, and serves as ME/CFS expert for ILLInet RECOVER. Ben Katz, MD, is a pediatric physician at the Ann & Robert H. Lurie Children’s Hospital of Chicago, and his research interest is the pathophysiology of viral infections in immunocompromised versus normal hosts. Benjamin Natelson, MD, is a neurologist at Mount Sinai in New York. He has been studying and caring for patients with ME/CFS for many years, and is now adding care of those with long COVID to his practice. Hector Fabio Bonilla, MD, is an infectious disease doctor and researcher at Stanford University in California, specializing in HIV/AIDS, hepatitis C, and ME/CFS. Suvetha Ravichandran is a research assistant at the DePaul Center for Community Research where she is developing a consensus statement on ME/CFS comorbid conditions.