“Communicate clearly things you know, but more importantly things you don’t know.”
Tassos Kyriakides, PhD, Assistant Professor of Biostatistics, Yale School of Public Health
“It’s important to move away from the idea that nothing can be done [for sufferers of Long COVID]. . .it’s simply not true. Even in pediatrics, we have numerous therapeutic options that may offer relief, from medication to psychosocial interventions.”
Uta Behrends, MD, head, Munich Chronic Fatigue Center, Center for Pediatric and Adolescent Medicine, Technical University of Munich, Munich, Germany
On March 11, 2020, the World Health Organization (WHO) declared that the COVID-19 outbreak was a global pandemic. By May 11, 2023, the U.S. proclaimed that the federal COVID-19 Public Health Emergency had ended. Nonetheless, acute SARS-CoV-2 infections continue to take a major toll around the globe. (According to the WHO, between December 9, 2024 and January 5, 2025 there were 147,000 new cases and more than 4,500 deaths.) In addition, the chronic disabling illness called “post-acute sequelae of SARS-CoV-2 infection” or Long COVID afflicts a large number of people. (An estimated 8% of American adults are victims.)
Fortunately, SARS-CoV-2 research is ongoing on a number of important issues such as the origin and nature of the virus, treatment, prevention (vaccines), and diagnostic tests. My goal in writing this week’s post is to highlight—albeit briefly—some of the recent findings of both acute SARS-CoV-2 infection and Long COVID and to identify the biggest challenges that confront the public health experts, physicians, and scientists who are grappling with them.
Acute SARS-CoV-2 infection. For the past five years, a large number of virologists from around the world have been studying SARS-CoV-2. This research is especially important as it bears on strategies to prevent future pandemics. (See, “Four ways COVID changed virology: lessons from the most sequenced virus of all time,” Nature, March 12, 2025, summarizing studies that have had the largest impact on the field of virology).
The virus. A controversy continues to rage over the origin of the pandemic. Was this a natural spillover from bats to raccoon dogs and then on to humans in the Wuhan Seafood Market or a modified virus created in the Wuhan Institute of Virology that inadvertently made its way to the market? In my opinion, we’ll never know for sure.
Treatment. Remdesivir was the very first antiviral drug approved for the treatment of acute SARS-CoV-2. Its effectiveness continues to hold up in subsequent studies. (Unfortunately, it is only available for parenteral administration.)
Most of the early evidence from randomized clinical trials, however, pointed to nirmatrelvir-ritonavir (Paxlovid) as the antiviral agent of choice for treatment of acute SARS-CoV-2 infection. Studies now indicate that Paxlovid is of little value in older adults that are vaccinated.
But, recent evidence from the Czech Republic suggests the antiviral drug molnupiravir is highly effective in older patients. And two new antiviral drugs, simnotrelvir and ensitrelvir, have shown promise in the treatment or prevention of household spread of SARS-CoV-2, respectively. (As yet, neither agent has been approved by the U.S. Food and Drug Administration.)
Prevention (vaccines): The effectiveness of mRNA vaccines in protection against SARS-CoV-2 infection has astounded most clinical researchers. Unfortunately, vaccines against all SARS-CoV-2 variants has not been as robust. For example, the vaccine against the XBB.1.5 Omicron variant proved ineffective. Moreover, as we all witnessed, the protection provided by mRNA vaccines typically wanes over time.
A potential reason behind waning benefit of the COVID mRNA vaccines is a lack of SARS-CoV-2 specific plasma cells (the cells that produce antibodies) in the bone marrow after mRNA vaccination. (See, Lee, H., et al., “SARS-CoV-2-specfic plasma cells are not durably established in bone marrow long-lived compartment after mRNA vaccination,” Nature Medicine, September 27, 2024). In an interview, Dr. Eun-Hyung Lee, one of the senior investigators of this Emory University study, suggested, “The holy grail of vaccine researchers is the generation of long-lived plasma cells.” Hence, additional research on mRNA vaccines is needed.
Diagnostic testing: COVID-19 and influenza A and B infections are usually clinically indistinguishable. But now, there are at-home tests available over-the-counter at most pharmacies that can distinguish between COVID-19 and influenza A and B infections. This is an important practical advance in the management of these infections.
Long COVID. People experiencing chronic illness after a bout of acute SARS-CoV-2 created the term “Long COVID” in the Spring of 2020. The National Institutes of Health (NIH) provided substantial funding for research into “Long COVID.” Despite this funding, clinical and basic researchers have not as yet agreed on many of the clinical and epidemiologic features of the illness and its pathogenesis (mechanisms underlying it). Two recent articles summarize the current understanding of the illness. (See, “Long COVID: a clinical update,” The Lancet, August 17, 2024 ; “Long Covid Defined” New England Journal of Medicine, November 7, 2024).
The main symptoms of Long COVID are debilitating fatigue that worsens with physical exertion, unrefreshing sleep, and “brain fog,” that is, the inability to concentrate, forgetfulness, mood swings, and impaired awareness of one’s surroundings. To date, the evidence suggests that the illness is more common in women and that it can occur in children and adolescents as well as adults. It can last three or more months and in some cases drags on for two or more years. It is important to stress, however, that in many patients, it eventually resolves.
A growing number of studies indicate that COVID-19 vaccination prevents development of Long COVID. (See, “Meta-analysis ties pre- and post-COVID-19 vaccinations to reduced long COVID risk,” Journal of Infection, December 9, 2024). And there are anecdotal reports that COVID-19 vaccination of patients with Long COVID can result in relief of some symptoms. Although promising evidence suggests that various medications (e.g., low-dose naltrexone, selective serotonin reuptake inhibitors, and metformin) as well as pulmonary therapy and cognitive behavioral therapy have modest benefits, it’s clear the search for an effective treatment remains a top priority.
Chronic Fatigue Syndrome. The features of Long COVID are similar to those of patients suffering from the idiopathic illness called chronic fatigue syndrome (CFS). As I suggested in my August 5, 2020 Germ Gems post, “Post-COVID-19 Fatigue: The New Chronic Fatigue Syndrome?,” mounting evidence supports the notion that Long COVID is a form of CFS with the difference being the etiology of Long COVID, that is SARS-CoV-2, is known whereas the etiology of CFS is not.
In previous posts, I endorsed the concept of pathogenesis proposed by neuroscientists at the University of Minnesota, Drs. Apostolos Georgopoulis and Lisa James. They suggest the development of Long COVID is due to persistent antigen(s) of SARS-CoV-2. Results of studies by other research groups support this idea. And some studies suggest that a similar pathogenic mechanism applies to other baffling post-infectious disease states, such as infectious mononucleosis, chronic Lyme disease, Q fever, and chronic brucellosis.
Future prospects for sufferers of chronic fatigue. I spent 12 years of my research career overseeing the University of Minnesota Chronic Fatigue Syndrome Research Program and, more recently, I’ve been following the results of research groups dedicated to trying to understand and find an effective treatment for patients with Long COVID. I am optimistic that we’re on the cusp of making real progress in helping not only Long COVID patients but also those suffering with chronic fatigue following many infectious disease insults. Unfortunately, there is a proverbial fly in the ointment of scientific progress: the current administration’s evisceration of U.S. scientific and medical research institutions.
A recent MedPage Today article suggested the NIH may lose 5,000 workers and may cut 1,000 grants. This is devastating news. The NIH is recognized as the leading medical research institution in the world. Historically, it’s been strongly supported by members of the U.S. Congress, Republicans and Democrats alike. And it’s been by far the leading supporter of research on Long COVID.
Alarmingly, the NIH isn’t the only research organization impacted by the current administration. The entire American Public Health system is affected, including the Centers for Disease Control and Prevention (CDC), a bastion of public health research.
As New York Times columnist, David Wallace-Wells pointed out, the future of American public health is at risk. (See, Wallace-Wells, D., “The Entire Future of American Public Health Is at Risk,” New York Times, March 19, 2025). This means YOUR health and mine are at risk. So when the article “Keep New Bat Coronavirus On the Radar, Researchers Say ” appeared on March 12, 2025 in Medscape Medical News shivers went up and down my spine.
