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  • Writer's pictureP.K. Peterson

The Long COVID Puzzle

“By challenging the long-held assumption that treating infectious disease is all about tackling acute infection, a moonshot initiative for long COVID could ultimately change the way all of us think about the effects of pathogens on our health.”

- Lisa McCorkell, co-founder, Patient-led Research Collaborative for Long COVID; Michael Peluso, M.D., Assistant Professor of Medicine, University of California San Francisco

“Make everything as simple as possible, but not simpler.”

- Albert Einstein

Long COVID is a puzzling disease. As I spent many years of my research career studying myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a similar and equally puzzling and disabling disease, I’ve read with intense curiosity the publications on Long COVID research. These publications show that we now have a clearer picture of Long COVID. In this Germ Gems post, I highlight new insights into the disorder that have emerged since I last wrote on Long COVID (May 24, 2023 Germ Gems post—my fourth on the topic) and provide an assessment of what the bigger picture is starting to look like.

Solving the Long Covid puzzle. Scientists and medical researchers seek to discover the pathogenesis of a disease, that is the biological mechanisms underpinning the development of the disease, with the hope that understanding the pathogenesis will lead to effective treatments. In some ways, they use the same reasoning that all of us use when solving puzzles.

If you do a Google search on “Basic Steps to Solve Puzzles in Reasoning,” this is what you’ll find:

  1. Go through the question—reading and understanding the question correctly is more important to get an accurate result;

  2. Focus on the required information needed and leave out unnecessary data;

  3. Problem-solving;

  4. Reasoning skill; and

  5. Thinking skills.

All of these basic steps can apply to solving the puzzle of Long COVID. But to me, framing the right questions tops the list. The following are what I believe to be the most important questions that need to be answered.

1.What is the definition of Long COVID? A universally accepted definition of Long COVID does not exist. This is surprising given the fact that in July 2021 Long COVID, also called post-acute sequelae SARS-CoV-2 infection (PASC), was recognized as a condition that could result in disability under the Americans with Disabilities Act.

Most researchers do agree that the main symptoms of the disorder are: a sense of profound fatigue; post-exercise malaise (exhaustion); unrefreshing sleep; and concentrating/memory difficulties (called “brain fog”). But a contentious issue is the duration of the symptoms. Some researchers use two months, others three, and some use six months. The Centers for Disease Control and Prevention (CDC) uses a three month duration.

2. How many people have long Covid? Many epidemiologists have been involved in Long COVID research. But it still isn’t clear how many people suffer from Long COVID. This is especially true if a 6-month duration is used. (The CDC recently provided an excellent review of its data in “Long COVID in Adults: United States, 2022.”)

According to the CDC’s 2022 National Health Interview Survey, 6.9% of American adults reported having had Long COVID, while 3.4% of adults were suffering from Long COVID at the time of the interview. This means that nearly 18 million adults had suffered from the condition at some point and that approximately 9 million where suffering from the disorder when surveyed. (Figures are based on U.S. census data.) It appears that Long COVID is rare in kids, and while older adults may have a lower risk of Long COVID, the disease poses special challenges in this age group.

3. What is the pathogenesis of long COVID?

a. Is SARS-CoV-2 the only etiology? SARS-CoV-2 –the virus that causes COVID-19—is the etiology (cause) of Long COVID. It is becoming increasingly clear, however, that Long COVID-like symptoms are not unique to COVID-19. Other pathogens and, on the rare occasion, some vaccines can trigger a similar, if not indistinguishable, illness. Some examples are: the Epstein-Barr virus (the cause of infectious mononucleosis); viruses that cause acute respiratory tract infections (the illness is called “Long Colds”); bacterial infections such as Borrelia burgdorferi, the cause of Lyme disease; the COVID-19 vaccine itself (referred to as “Long Vax”); and the anthrax vaccine (Gulf War Illness).

In my previous Germ Gems posts on Long COVID, I highlighted the article, “At the Root of 3 ‘Long’ Diseases: Persistent Antigens Inflicting Chronic Damage on the Brain and Other Organs in Gulf War Illness, Long-COVID-19, and Chronic Fatigue Syndrome.” In this article University of Minnesota neuroscientists proposed “the persistent antigen hypothesis.” This hypothesis holds that a variety of pathogens or bits of pathogens (”antigens”) can remain in the bodies of people after acute infections or immune stimulation that can provoke Long COVID or a Long COVID-like illness. Support for this “persistent antigen hypothesis” is now emerging in recent publications from other scientists.

b. What are the key pathological findings to date? A pathological finding means something that is the result of a disease or disorder or, to put it simply, an abnormal finding. Multiple studies of patients with Long COVID have shown the following consistent pathological findings.

The immune profile of Long COVID patients implicate persistent inflammation in the pathogenesis of the disorder. One of the more notable studies published in September 2023 in Nature, ”Distinguishing features of Long COVID identified through immune profiling,” describes distinct immune abnormalities and a low blood cortisol level in Long COVID patients versus controls.

Microclots (blood clots visible only under a microscope) have been found in the brain and other organs of patients with Long COVID. Damage to the vascular system by blood clotting proteins appears to be an underlying factor in the pathogenesis of “brain fog.” And recently, University of Pennsylvania researchers reported another factor involved in the pathogenesis of neurocognitive abnormalities. They found a reduction of the neurotransmitter serotonin triggered by remnants of SARS-CoV-2 in the gut. (It’s unclear whether this has any bearing on the distinct characteristics of the gut microbiota in Long COVID patients reported by some investigators.).

Finally, another consistent abnormality found in studies of Long COVID patients is that SARS-CoV-2 causes lasting damage to energy production by mitochondria in many organs of the body. (Mitochondria are the powerhouses of cells, producing much of the energy they need.) It’s suggested that stopping the virus from hijacking mitochondrial energy production would be a novel approach to treating Long COVID.

4. What treatments work for Long COVID? A goal of most studies of pathogenesis is to identify potential treatments of Long COVID. The U.S. Food and Drug Administration has not approved any medications for the treatment of Long COVID. But based on the findings given above and other studies, a number of drugs are currently being tested or considered for Randomized Clinical Trials. (As part of its Researching COVID to Enhance Recovery (RECOVER) Initiative, the National Institutes of Health (NIH) has opened enrollment for clinical trials at sites around the country that will test potential treatments for Long COVID. Treatments include drugs, biologics, medical devices, and other therapies.)

While there are no approved drugs to treat Long COVID, the results of a controlled trial in The Netherlands of Cognitive Behavioral Therapy (CBT), published in Clinical Infectious Disease in September 2023, showed that CBT was effective in reducing fatigue for at least 6-months.

5.How can Long COVID be prevented? The harsh reality is that only sure way to prevent Long COVID is not to get COVID in the first place. Results of several studies suggest that the COVID-19 vaccine reduces the risk not only of developing acute COVID-19 but also of Long COVID. So if you haven’t already done so, get jabbed with the most recent COVID-19 vaccine.

If you have acute COVID-19, treatment with Paxlovid may be beneficial. As reported in an October 16, 2023 MedPage Today article, the benefits of treatment with Paxlovid appear mixed. Paxlovid works in older adults but may increase the risk of Long COVID in adolescents.

Would a “moonshot” solve the Long COVID puzzle? The October 23, 2023 New York Times article “Long COVID research risks losing momentum—we need a moonshot,” provides an excellent overview of Long COVID and, more important, makes the case for a “moonshot”-like investment in research on Long COVID. (An investment akin to what the NIH, CDC, and other research and public health organizations pulled together in the field of HIV/AIDS several decades ago.) As a witness to the incredible accomplishments of the HIV/AIDS research programs, I agree that such a full-throated long-term investment would pay off. But the thorny question is, given all the other health and existential challenges we’re currently facing, is there a will and a way (funding) to mount such an ambitious endeavor?

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Main Page images courtesy of Shuxian Hu, MD. Dr. Hu is a scientist in the Neuroimmunology Research Laboratory at the University of Minnesota.

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