“Unfortunately, current numbers and trends indicate that ‘long-haul Covid’ (or ‘long Covid’) is our next public health disaster in the making.”
- Steven Phillips, M.D., and Michelle A. Williams, Sc.D., COVID Collaborative, Washington, D.C. and the Harvard T.H. Chan School of Public Health
“Long Covid is just the latest example of a pathogen causing surprising persistent effects.”
- Roxanne Khamsi, New York Times science writer and editor
According to researchers at Penn State College of Medicine, more than half of the 236 million people who have been diagnosed with COVID-19 worldwide since December 2019 will experience post-COVID symptoms—more commonly known as “long Covid.” We know the etiology (cause) of long Covid—the wily coronavirus, SARS-CoV-2, but the pathogenesis (biological mechanisms underlying a disease) remains elusive. And understanding the pathogenesis of long Covid is key to finding effective treatments and preventative measures.
As an infectious disease physician and research scientist, I spent many years investigating chronic fatigue syndrome (CFS), an enigmatic disease. In the late 1980s, the Center for Disease Control and Prevention convened a group of researchers who developed a case definition for CFS. Nonetheless, many physicians dismissed CFS patients as “crocks,” a slang medical term meaning a patient whose illness is largely imaginary or psychosomatic. CFS is, however, real and it is disabling. Yet, no pathogen has been established as the cause of this idiopathic disorder.
At this point there is no approved treatment for either long Covid or CFS. I believe, however, that these disorders share some striking similarities. Based on my years investigating CFS (also called Myalgic Encephomyelitis/Chronic Fatigue Syndrome [ME/CFS]), in this Germ Gems post I share my views about what I believe are the most promising leads in determining the pathogenesis of long Covid.
What is long Covid? The illness that plagues many COVID-19 patients long after the acute phase of their disease has been called “long Covid,” “long-haul Covid,” “post-acute sequelae of COVID-19 (PASC)”, or “Brain Fog.” But don’t be confused by the terminology. All of these terms refer to the same thing: long Covid.
While the COVID-19 pandemic is barely over two years old, it became apparent early on that many patients continued to suffer from a variety of bothersome, and in some cases disabling, symptoms after their recovery from acute illness. In one of the first comprehensive studies, published last July in Lancet’s EClinicalMedicine, a research team led by University College London scientists analyzed survey responses from 3,762 patients from 56 countries with a history of COVID-19.
Six months after the acute phase of their illness, the most common symptoms patients experienced were fatigue, malaise after exertion, and cognitive problems, or “brain fog.” Insomnia and other sleep problems, heart palpitations, muscle aches and joint pains, and shortness of breath were also common. The most debilitating symptoms were fatigue, breathing problems, and cognitive issues. Except for shortness of breath, which might be explained by lung damage inflicted by SARS-CoV-2, this six-month symptom complex is very close to meeting the diagnostic criteria for CFS.
Subsequent studies have suggested that long Covid is more common after severe disease, but it also occurs after mild SARS-CoV-2 infections. The exact incidence of long Covid is unknown, but studies to date estimate that somewhere between 31% to 69% of COVID-19 patients develop this complication. When you consider that the number of COVID-19 cases in the U.S. now exceeds 75 million, it’s easy to understand why the impact of long Covid disability is so alarming.
In a recent article in the journal Cell, investigators at the Institute for Systems Biology at the University of Washington in Seattle reported that the following four factors increase the risk of developing long Covid: (1) the amount of SARS-CoV-2 in the blood in the early stage of infection; (2) autoantibodies (pathological antibodies aimed at normal host proteins [antigens]); (3) reactivation of Epstein Barr Virus; and (4) type 2 diabetes. Taken together with reports of other investigators, these findings point to involvement of a dysregulated immune response in the pathogenesis of long Covid.
Long Covid is a neurological disease, a tenable hypothesis. While there are numerous theories about the pathogenesis of long Covid, many of which were also postulated for CFS, I believe the most tenable is that long Covid is a neurological (brain) disorder. A growing number of recent studies support this hypothesis. (The best review of these studies can be found in the January 20, 2022 issue of Science, “Nervous system consequences of COVID-19.”)
The hypothesis that appears to best explain the pathogenesis of long Covid is that SARS-CoV-2 activates cells of the immune system which in turn produce mediators that damage the brain. Consistent with viewing long Covid as a neurological disorder is that one of the most striking symptoms is “brain fog.” People who have brain fog describe it as “the inability to concentrate or to think clearly, as well as trouble remembering things.”
In support of this hypothesis, a recent study by University of California researchers found abnormalities in the cerebrospinal fluid of a majority of long Covid patients who complained of brain fog. These abnormalities were similar to those found in patients with other infectious diseases involving the brain, including “the presence of unexpected antibodies found in an activated immune system.”
On a related note, in the 1980s and 1990s, investigators in our “University of Minnesota Neuroimmunolgy Research Laboratory” were particularly interested in the role of microglia (a type of immune cell that populates the brain), in neuropathogenesis, including potentially in CFS. These brain macrophages are known to produce mediators that can damage neurons, the cells responsible for cognition. Thus, I was intrigued by an article in February 2022 in Science News, titled “A faulty immune response may be behind lingering brain trouble after COVID-19,” reporting that postmortem tissue from people who died with COVID-19, as well as brain samples from mice infected with SARS-CoV-2, demonstrated the presence of activated microglia.
The bottom line. It’s clearly premature to conclude that an activated immune system, including activated microglia within the brain, plays a neuropathogenic role in brain fog or for that matter in long Covid. Nonetheless, it’s becoming increasingly clear that long Covid is in fact a neurological disorder and that an activated immune system is involved in the neuropathogenesis of long Covid.
Given the growing problem of long Covid, the U.S. National Institutes of Health allocated $1.15 billion for long Covid research. My hope is that a substantial amount of this research funding will be earmarked for studies of the neuropathogenesis of long Covid. Who knows, this funding may someday even help explain the neuropathogenesis of the symptom of debilitating fatigue in the estimated 836,000 to 2.5 million Americans who suffer from ME/CFS.
