“A journey of a thousand miles begins with a single step."
Chinese proverb, attributed to Laozi, 6th century BCE
“Progress toward preventing and curing long COVID and other infection-associated chronic conditions will require deep and sustained investment by funders and industry.”
Michael J. Peluso, MD, MHS, Assistant Professor of Medicine, University of California San Francisco, and Steven Deeks. MD, Professor of Medicine, University of California San Francisco
In March 2020, when the World Health Organization declared SARS-CoV-2 infection a “global health emergency,” nobody predicted that this virus would cause two pandemics. The first, the COVID-19 pandemic, was an acute multisystem disease that quickly spread around the world and by April 2024 claimed the lives of more than 7 million people. The second pandemic, a disabling chronic illness called long COVID, unfolded more slowly but by August 2024 afflicted over 400 million people worldwide.
As I spent over twelve years of my research career studying myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disabling disease that has marked similarities to long COVID, I am particularly interested in—my wife claims I am “obsessed” with—long COVID. The fact that this is my seventh post on the subject may prove her point. (The first appeared on August 5, 2020, “Post-COVID-19 Fatigue: The New Chronic Fatigue Syndrome?,” and the sixth a year ago, “The Long COVID Puzzle,” October 23, 2023.) In this week’s Germ Gems post, I provide an update on the funding and research aimed at finding a treatment or cure for long COVID-19.
Long COVID Synopsis. From the outset of the long COVID pandemic, debates about various aspects of the disease surfaced. These include: naming the disease; defining “long”; symptoms of the illness; and laboratory evidence requirement.
What’s in a name? Some researchers prefer post-acute sequelae of SARS-CoV-2 (PASC). Others prefer the name post-infection fatigue syndrome (PIFS) because a number of other infections, such as, Epstein Barr Virus (infectious mononucleosis), Coxiella burnetii (Q fever), and most recently added to the list, Babesia burgdorferi (Lyme disease), can trigger a similar illness. But the name “long COVID,” created in Spring 2020 by the people experiencing the illness, is simpler and to the point.
How long is long? Some authorities favor defining long COVID as an illness lasting at least 3 months after acute COVID-19; others prefer 6 months or longer. The Centers for Disease Control and Prevention, however, defines long COVID “as a chronic condition that occurs after SARS-CoV-2 infection and is present for at least 3 months.”
What is the nature of the syndrome (clinical illness)? Long COVID patients are plagued by a number of symptoms the most disabling of which are fatigue, post-exertional malaise, lack of refreshing sleep, and “brain fog” (memory and concentrating difficulty). These symptoms are similar to those reported by people with ME/CFS and other chronic illnesses that occur after other infections.
Is laboratory evidence required? No. There is no laboratory test that can determine whether the symptoms a patient is experiencing are due to long COVID. In fact, results of routine blood tests and X-rays are normal in patient with long COVID.
Funding of long COVID research. To date, the National Institutes of Health (NIH) has provided the lion’s share of funding for long COVID research. The precise amount of financial support the NIH has funneled into long COVID research programs is difficult to assess as the NIH is constantly increasing its support. (See, e.g., “NIH to bolster RECOVER Long COVID research efforts through infusion of $515 million,” February, 2024—this infusion was on top of the $1.15 billion in appropriations for RECOVER in 2021; and “NIH to open long COVID clinical trials to study sleep disturbances, exercise intolerance, and post exertional malaise,” August, 2024.)
Despite the NIH’s substantial financial investment, there is little evidence clinical outcomes have improved, let alone resulted in a cure of long COVID. This has raised the question in some minds, particularly those of long COVID patients and their loved ones, whether the long COVID patient community is getting its money’s worth.
What is the long COVID research strategy? The etiology of long COVID is known, that is, SARS-CoV-2, but the pathogenesis (the mechanisms underlying the disease) is not. Based on the presumption that establishing the mechanisms of pathogenesis of long COVID could lead to effective prevention and treatment measures, a very broad net has been cast encompassing a range of possible pathogenic mechanisms.
The review article “Mechanisms of long COVID and the path toward therapeutics,” in the October 3, 2024 issue of the journal Cell details much of the current scientific thinking about the pathogenesis of long COVID. The hypothetical mechanisms cited include biological drivers, such as, end-organ tissue damage, endotheliopathy, neuropathy, disruption of the gut-brain axis, virus persistence, autoimmunity, thrombosis, latent virus reactivation, gut microbiome dysbiosis, and mitochondrial dysfunction. This approach may seem like it’s missing the forest for the trees, but the good news is that it does reflect the high level of research interest in long COVID. While many questions remain, the main “take home” message of this review is quite simple: The best way to prevent long COVID is to do all that you can do to prevent the initial infection. In other words, get vaccinated.
My opinion. When we concluded our clinical- and laboratory-based research on the illness CFS in 2000, we were certain of only two things: (1) CFS is a “real” illness that can, in some cases, be very disabling; and (2) a new research paradigm was needed. As I’ve mentioned before, I believe the most promising research paradigm for long COVID is the so-called “persistent antigen hypothesis” advanced in 2018 by University of Minnesota neuroscientists Lisa James and Apostolos Georgopoulus. (See “Persistent Antigens Hypothesis: The Human Leukocyte Antigen (HLA) Connection,” Journal of Neurology and Neuromedicine, 2018).
In the past several years, evidence has continued to mount suggesting that a major pathogenic mechanism of long COVID is brain damage provoked by inflammatory mediators stirred up by SARS-CoV-2. If a consensus is reached that long COVID is primarily a neurologic disorder, this would help focus treatment on strategies that target the brain.
I am optimistic that given the sustained NIH funding, progress toward symptom relief, if not a cure, is likely to follow. But advancements in therapeutics are going to take time. Nonetheless, for those suffering with long COVID, it’s important to know there is light at the end of the tunnel.
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