Growing recognition of post-acute infection syndromes

This illness first attracted attention in the 1980s. Typically, people suffering from ME/CFS previously have been healthy, and then develop a flu-like illness. While that illness appears initially not unlike previous transient illnesses, and while the respiratory symptoms and fever usually improve, people are left with a severe, persisting fatigue, cognitive problems, worsened symptoms following physical or mental exertion or upright posture, as well as unrefreshing sleep, an illness that can last for years (3, 4). The symptoms are not relieved by rest, and greatly impair a person’s ability to function at work and at home. Some individuals are homebound, some largely bedbound. People with ME/CFS often say, in so many words, “I am no longer the person I was.”

In the 1980s, some scientists suspected that a novel human pathogen was causing the illness. Such speculation seemed reasonable, since a novel virus recently had been discovered to cause the AIDS. However, no single, novel pathogen has emerged as the cause of ME/CFS.

Moreover, the standard laboratory tests that were performed in the 1980s generally came back “normal,” leading some to believe there were no underlying biological abnormalities to explain the symptoms. However, over the past 40 y, thousands of studies have identified many underlying abnormalities involving the brain, immune system, energy metabolism, redox imbalance, vascular injury, and gut microbiota (4–9). The symptoms of the illness are, indeed, accompanied by objective abnormalities.

Despite the fact that—in the United States, alone—the illness is estimated to affect up to 3.1 million people, and to generate direct and indirect expenses of approximately $36 to 51 billion annually (3, 10), relatively few investigators have sought to study the illness: the initial skepticism about whether the illness had a biological basis may have created a lingering stigma. That skepticism faded, to some degree, following publication in 2015 of a report from the U.S. National Academies of Science, Engineering and Medicine highlighting the importance of the problem (3).

Then, along came the COVID-19 pandemic. It was predicted that the pandemic would greatly increase the number of people with an ME/CFS-like illness (11), and that has proved to be the case. Many who have “recovered” from acute COVID-19, even from mild cases, have developed a persisting illness (called “long COVID”) with symptoms much like ME/CFS. The cumulative global incidence of long COVID may be as high as 400 million individuals (5, 8), and the costs to the U.S. and global economy (not including the direct costs of healthcare) may be several trillion dollars in the next 5 to 10 y (8, 12).

The similarity of the symptoms seen in ME/CFS and long COVID is underscored by the report from Eckey et al. (1). The study involved a survey of nearly 4,000 people with these illnesses. Participants recorded the prevalence and severity of a large number of symptoms, comorbid illnesses, and responses to different treatments.

The authors recognize that such a survey has important limitations. The diagnoses of ME/CFS, long COVID, and comorbid illnesses were self-reported, and not determined by protocol-directed objective testing—although such testing often had been performed by their doctors. Likewise, the responses to different treatments were self-reported, not the results of randomized, placebo-controlled trials. Nevertheless, the large number of study subjects, and the consistency of their responses, suggests that their responses are valid.

Response to Therapies.

Patients with the two illnesses also responded similarly to specific treatments. Remarkably, even at the level of specific symptoms, responses were similar in people with the two illnesses, and the drugs most effective against particular symptoms would be expected to improve those symptoms, adding credibility to the self-reported improvement (1). Thus, the study is consistent with others in finding similar symptoms in people with the two illnesses and, additionally, finds similar comorbidities and responses to treatment.

PAIS

ME/CFS and long COVID are not the only two illnesses that share very similar symptoms. Over the past century, there have been many reports of an illness with very similar symptoms following multiple different acute bacterial, viral, fungal, and protozoal infections; hence, the proposal to call all of these illnesses PAIS (2). Long COVID surely is a PAIS (since the inciting infectious agent is known), and myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) likely often is (even though the inciting agents often have not been pursued by physicians).