A Case Definition for Long COVID

A National Academies of Sciences, Engineering, and Medicine committee is in the process of examining the working definition of Long COVID. Case definitions are sets of rules that allow patients, clinicians, and investigators to determine who has and who does not have an illness, and they are the foundations for studying any illness. If there are ambiguities with case definitions, samples of patients in various laboratories will be different on fundamental aspects of an illness. This would ultimately result in difficulties replicating findings across different laboratories, consistently identifying biomarkers, estimating the prevalence of an illness, and determining which treatments help patients.

Multiple lessons can be learned from progress made on case definitions from other post-viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). For example, with that illness, progress occurred in deciding which ME/CFS symptoms to include in the case definition, developing valid instruments to reliably assess agreed-upon symptoms, and specifying thresholds regarding whether or not a particular symptom is severe and frequent enough to meet criteria. Each of these issues is briefly explored below with their relevance to Long COVID, and we argue that not only does a case definition need to be accurate and reliable, but the ways it is implemented need to be precise and comprehensive.

Determining whether a person has an illness can be more complicated than it might initially appear. For example, community surveys have found from 90 to 95% of people with ME/CFS have not been diagnosed or do not even know they have this illness. Therefore, in addition to asking a patient whether or not they have ME/CFS, researchers in this area have also learned to determine whether patients experience key symptoms within the ME/CFS case definition. Some patients with at least six months of Long COVID can be diagnosed as having ME/CFS, but it simply is not enough to just ask patients whether or not they have ME/CFS. For example, in a recent study involving a sample of people with Long COVID, among those who said they did not have ME/CFS, 40% nevertheless met the ME/CFS criteria. Underdiagnosis of ME/CFS was evident in this study, and it is why with the development of a Long COVID case definition, it is critical to use a case definition to determine whether a person has the key symptoms of that case definition.

There are hundreds of symptoms of Long COVID and another core issue is deciding which symptoms should be included in the case definition. In the ME/CFS field, researchers found patients almost always had post-exertional malaise, cognitive impairment, and unrefreshing sleep; and these symptoms were subsequently included in the ME/CFS case definition. Therefore, a critical task is developing a list of symptoms that can be asked of patients with Long COVID. Symptoms following COVID-19 should probably be divided into those that are consequences of the acute infection versus those that are similar to ME/CFS. The former includes those with lung or other organ damage secondary to the acute respiratory symptoms of COVID-19, which causes secondary pulmonary vascular damage and fibrosis due either to the acute respiratory infection itself or post-intensive care syndrome. The latter involves those who experience ME/CFS symptoms such as post-exertional malaise and cognitive impairment.

Another critical task is to ask questions about symptoms in a structured way so that individuals in different settings are asked the questions the same way. The benefit of using similar questionnaires is that they ensure that patients in the same or different settings have data elicited similarly. Thus, structured questionnaires serve to remove as much as possible the unreliability in the resulting diagnosis introduced by differences in the way clinicians and scientists elicit clinical information. The reliability and validity of these instruments need to be established in the Long COVID area. This has occurred in the ME/CFS field where instruments such as the DePaul Symptom Questionnaire have been used in multiple settings with good reliability and validity.

Many of the questionnaires to assess Long COVID symptoms solely measure the occurrence of symptoms, but many of the symptoms, such as fatigue, are common among individuals even before they had COVID. So just indicating whether a patient has a symptom is insufficient for designating at a threshold the symptom needs to exist for it to be considered a problem. A very infrequent symptom might not be a problem for the person even if it is rather serious when it occurs. A migraine that only occurs once every few months might be painful when experienced, but its relative infrequency might not make it a burden to the person. Failing to document these types of frequency and severity differentiations in symptoms makes it considerably more difficult to assess the impact of symptoms and their burden. Cut-off points need to be developed and empirically evaluated, as they have in the ME/CFS field of study.

Finally, in developing case definitions, there should also be efforts to classify patients into broad (clinical) versus narrow (research) ME/CFS case definitions. Those with one to two months of symptoms could be clinical and those of three or more months being researched, and overall level of functional impairment could also be utilized in this differentiation. There is also a critical need to uncover subtypes using sophistical statistical techniques as this helps avoid the comparison of two subtype groups of patients within the same diagnostic category. Whether the symptoms are new or intensifications of prior symptoms also needs to be differentiated. Finally, there is a need to identify exclusionary conditions, as has been done with the ME/CFS field, as a person who has cancer that is not connected with COVID-19 might have some of the symptoms of Long COVID, such as fatigue and pain.

Research over four decades in the field of ME/CFS has uncovered lessons that may be instructive for those developing criteria to better understand Long COVID. As this post has demonstrated, there has been considerable work in the ME/CFS area involving defining classification systems, operationalizing methods, and developing instruments with proper thresholds, reliability, and validity. Insights from ME/CFS research could help in the development of the Long COVID case definition, as shown in chapters in the recent book titled: Understanding the Behavioral and Medical Impact of Long COVID, which would ultimately improve our efforts to understand its pathophysiology, early diagnosis, prognosis, as well as identifying effective treatments. Most importantly, we need to better understand not only the person-centered case definition but how it influences those parts of our healthcare system that continue to delegitimize and stigmatize those with Long COVID.