Guest article: Ph.D. Akiko Iwasaki

We can think of these possible root causes being triggered at the same time in a person or triggered sequentially. Some long COVID patients may suffer from one of these root causes, while others might have two or three or all. In order to provide effective treatment, we need to understand these underlying causes and test targeted therapies in randomized placebo-controlled clinical trials.   

We propose and investigate 4 root causes of long COVID.  

1. Persistent viral infection by SARS-CoV-2. There are a large number of reports showing the presence of viral antigen and RNA in various tissues months post-infection in people, as well as the presence of circulating spike protein. Based on this hypothesis, we and others are now doing randomized placebo-controlled clinical trials of long COVID patients with the antiviral agent Paxlovid. The Yale PaxLC trial hopes to understand who responds positively to Paxlovid and identify biomarkers of success so that people with such biomarkers can be treated in the future with Paxlovid.  
2. Autoimmunity. Viral infections are known to trigger various bystander and cross-reactive autoreactive lymphocytes, leading to autoimmune diseases. We examined the presence of autoantibodies to extracellular antigens in people with long COVID but did not find significant differences compared to convalescent controls. However, autoreactive T cells and antibodies to intracellular autoantigens can still be at play. 
3. Latent virus reactivation. We and others see evidence for a recent reactivation of herpesviruses including Epstein-Barr virus and varicella-zoster virus. These reactivated viruses themselves may be causing the symptoms of long COVID. We are also extending the analysis to see if endogenous retroviruses may also be aberrantly expressed and induce pathology.  
4. Chronic tissue dysfunction. We have shown that there is chronic damage in the brain of mice that had mild respiratory COVID seven weeks prior. In this study, inflammatory immune factors (cytokines and chemokines) accounted for some of the brain phenotypes. It is possible that inflammatory triggers caused by COVID can incite chronic dysfunction in a variety of tissues.  

In addition to these root causes, there are many downstream physiological changes that happen, including micro clot formation, platelet activation, reduction in tissue utilization of oxygen, mitochondrial dysfunction, and lower levels of cortisol. In our study, lower levels of cortisol in the blood were the most distinguishing feature of people with long COVID. Such hormonal imbalance can explain some of the symptoms reported.

COVID is not alone in causing chronic diseases after the acute phase. There are many other viral and non-viral pathogens that can also lead to post-acute infection syndrome (PAIS). Studying the disease pathogenesis of long COVID has the promise of providing insights into the mechanism of other PAIS, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).