Long COVID: The Newest Post-Viral Syndrome

Written by: Parker Davis
Edited by: Esther Melamed

Post-viral syndromes have been well-documented for many prominent human viruses, including Influenza B virus (as far back as 1959), the coronaviruses that cause MERS and SARS, and coxsackieviruses, the agent that causes hand-foot-and-mouth disease (Adams, 1959; Calder et al., 1987). Though the symptoms are well characterized, the molecular and physiological processes that underlie post-viral syndromes are relatively poorly understood, as is the case with the post-COVID syndrome due to SARS-CoV-2 viral infection, also called “Long COVID” or post-acute sequelae SARS-CoV-2 infection (PASC).

Reports of persistent fatigue, brain fog, pain, and respiratory and cardiovascular complications arose in the first few months of the pandemic. These patients – many of whom only ever had a mild infection and were never admitted to the hospital – experienced infection-like symptoms weeks or months even after their system cleared the virus. This condition has perplexed physicians and researchers alike: its manifestations as different problems in different people made it hard to pin down, and as a result, those with persistent post-COVID complications found themselves without answers and without a community, trapped somewhere between illness and wellness. That is until a few enterprising individuals took to social media to spread their message. It has been said that the patients themselves made Long COVID; by piecing together bits of information from across the world, they created the mosaic of symptoms that they would come to call “Long COVID” (Callard, Perego, 2021), now also named PASC by Anthony Fauci in March 2021. It was indeed the patients’  call to action that helped raise initial awareness about this elusive disease.

The impact of Long COVID/PASC does tend to correlate with the severity of acute  COVID-19 infection: a study published in the British Journal of Medicine found that over 10% of individuals who experienced long-term symptoms and had previously been hospitalized due to COVID-19 died within a few months of discharge (Ayoubkhani et al., 2021). These individuals also tended to have a greater number of significant comorbidities, including cardiovascular, respiratory, and metabolic disorders. The same study found that almost 30% of those discharged are subsequently re-admitted for post-COVID symptoms.

The fragmented definitions, unclear physiology, and lack of awareness surrounding the issue mean that only now is Long COVID/PASC beginning to receive the attention necessary to fight back. But research in this area has hit snags: online COVID surveys reach only a small, unrepresentative proportion of those afflicted; and even if online analyses were sufficient, the lack of a unified definition prevents one from drawing conclusions across studies. The PHOSP-COVID and TLC studies out of the UK hope to address these issues by enrolling over 10,000 and 2,000, respectively, Long COVID/PASC patients along with matched controls. By greatly expanding the sample size and including controls, they hope to uncover clear correlations that may help answer some questions of definition, and even of the underlying biology.

Hypotheses about the mechanisms of Long COVID/PASC range from long-term cellular damage as a direct result of viral toxicity, to viral persistence in the body and potential integration into our DNA, to an autoimmune response that may follow clearance of the virus. Government agencies like the NIH have begun funding studies that may provide answers. Researchers are performing meta-analyses of biomarker data and are studying autopsy reports in attempts to identify the molecular, cellular, and macroscopic “damage signature” of SARS-CoV-2 infection. And newly funded animal studies will also help bring some of these mechanisms to light.

New trials are aimed at discovering drugs that specifically target and prevent the symptoms of Long COVID/PASC. The HEAL-COVID trial, for example, plans to enroll 2,000 COVID-19 patients and test the drugs Apixaban, an anticoagulant, and Atorvastatin, a cholesterol-lowering drug, two medications the researchers believe may have wide-spread off-label effects that provide protection from lingering disease. A similar trial, the NIH-sponsored ACTIV-6 trial, will reportedly test 7 drugs for beneficial effects, with plans to assess the impacts of these drugs on long-term COVID-19 symptoms at 90 days. Though results from these trials will not be available for some time, their large sample sizes and use of controls hopefully mean that the data collected will be incredibly robust. And researchers hope that these trials will help set the stage for a new era of digital research that will enable faster results while remaining as accurate and reliable as in-person studies.

The nature of Long COVID/PASC means that researchers will need to continuously change their approach to keep up with the shifting definitions, but as new research is performed and more data are collected, the hope is that scientists will be able to zero in on a common understanding of the disease. It is important to remember that though the end may be in sight, there are still thousands – perhaps millions – of people who remain devastated by COVID-19. For them, we must remain selfless and err on the side of caution until all is said and done.