What is currently known about the mechanism and treatments of long COVID?

A recent feature published in PNAS discussed the current understanding of the mechanisms underlying long coronavirus disease (COVID) or post-acute sequelae of COVID (PASC) and potential treatment methods that show promise in long COVID management.

Study: Lots of long COVID treatment leads, but few are proven. Image Credit: Josie Elias/Shutterstock
Study: Lots of long COVID treatment leads, but few are proven. Image Credit: Josie Elias/Shutterstock


A worldwide effort to develop vaccines, combined with strictly enforced lockdowns and isolations, has resulted in some success in controlling the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. However, long COVID, formally known as PASC, continues to be an area of concern, along with newly emerging SARS-CoV-2 variants.

Manifesting 12 to 24 weeks after an acute or even a mild COVID-19 infection, PASC includes close to 200 different symptoms varying from one individual to the other. The commonly reported complaints include shortness of breath, fatigue, and anosmia. While the symptoms clear up for most people without intervention within six months, one study from China reports that over half of the COVID patients infected at the beginning of the pandemic still exhibit at least one PASC symptom two years later.

About the feature

The present piece reports the headway made in the two years since the onset of the COVID-19 pandemic in understanding the mechanisms of long COVID. Researchers investigating PASC believe it results from various COVID-19 complications, including tissue damage and lingering virus and viral particles that could trigger inflammatory and autoimmune responses. They have noted similarities between long COVID and other post-viral syndromes such as chronic fatigue syndrome or myalgic encephalomyelitis and believe that immune dysregulation is the main cause of PASC.

Doctors believe that treating PASC involves finding the right combination of antihistamines, antivirals, and anti-inflammatory treatments that can address tissue damage and microclots and restore homeostasis in the body. An increasing number of studies on PASC and information on other post-viral syndromes are providing leads for potential treatment avenues.

Major findings

Many researchers believe long COVID symptoms could be due to possible hidden reservoirs of viral particles in the body. Studies have now provided evidence of the viral presence in tissues outside the respiratory system. One study found that COVID-19-infected individuals shed SARS-CoV-2 ribonucleic acid (RNA) in their feces almost seven months after infection.

While hidden SARS-CoV-2 virus and viral particle reservoirs would explain many of the persistent and recurring symptoms of PASC, biopsies are necessary to test for the presence of viral RNA in tissues. This makes the hidden viral reserve hypothesis difficult to prove since biopsies are invasive and much more expensive than nasal swabs. However, anecdotal evidence from long COVID patients who have seen symptoms recede after treatment with antivirals lends credibility to this hypothesis.

The challenge, however, has been in using antivirals to treat long COVID since they have been in short supply until this year, and clinical trials are still being designed to test various antivirals to treat PASC symptoms. Currently, Remdesivir appears promising compared to other antivirals, such as Paxlovid, since it is less reactive to other drugs.

Hidden viral particles in the body could also result in inflamed blood vessels and microclots, which could manifest as various PASC symptoms. Researchers are exploring the role of activated endothelial cells and coagulation proteins in the various PASC manifestations.  They believe that symptoms like fatigue and muscle ache could result from oxygen deprivation which occurs when viral fragments trigger immune signaling that activates endothelial cells and inflames blood vessels, constricting blood flow.

PASC treatment using Pravastatin, which suppresses specific endothelial-cell transmembrane protein, and the HIV drug Maraviroc, which blocks inflammatory signaling, are being explored. Scientists are also trying to target the microclots directly by using an atherosclerosis treatment regimen consisting of anti-platelet drugs clopidogrel and aspirin along with the anticoagulant Apixiban. When this combination was used in 23 patients part of a small study, all participants showed recession of symptoms and restoration of pre-COVID-19 platelet levels.


Despite promising results from various treatment trials, the fact remains that these treatments might not have uniform results across long COVID patients. Researchers believe that with more information on the symptoms and mechanisms of PASC, it will eventually consist of sub-categories based on underlying mechanisms. Each sub-category would need a specifically tailored treatment regimen.

Currently, doctors are choosing a trial-and-error treatment method. Most patients are given short trials of a wide variety of drugs to explore their efficiency based on variability in patients. Many researchers believe that apart from increased funding and improved access to drugs, a central database on long COVID can help accelerate the research on long COVID treatment methods.

Journal reference:
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.


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