Why do Some People Develop Long COVID?

by Gertrud U. Rey

Long COVID is a chronic manifestation of SARS-CoV-2 infection, and it is most commonly characterized by lingering fatigue, brain fog, memory impairment, and confusion. Although it is unclear how the viral infection leads to long COVID, experts speculate that one or more of the following factors may contribute: an inability to successfully clear virus, a reactivation of latent viruses, a disturbance of the gut microbiome, continuing inflammation, and/or autoimmunity.

Yale University researcher Akiko Iwasaki and colleagues recently explored some of these hypotheses in an attempt to identify diagnostic biomarkers associated with long COVID. The study involved four groups of participants, with the experimental group consisting of both vaccinated and unvaccinated individuals with long COVID. The other three groups served as three separate types of controls:

1. healthy, vaccinated, uninfected individuals;
2. healthy, unvaccinated, previously infected individuals without long COVID; and
3. healthy, vaccinated, previously infected individuals without long COVID.

The investigators obtained blood samples from all participants and analyzed the samples for the presence of specific immune cells. They found that compared to control groups, long COVID participants had lower levels of conventional dendritic cells and memory T helper cells. Conventional dendritic cells typically activate cytotoxic T cells, which in turn kill infected cells. Memory T helper cells are a central element of the adaptive immune response, where they help orchestrate downstream immune functions upon recognition of antigen. Long COVID participants also had increased numbers of “exhausted” T cells, which are no longer functional or capable of eliminating virus. These results suggested that people with long COVID may have insufficient numbers of immune cells able to inactivate virus, thus allowing viruses to linger and continue replicating and circulating. Whether this assumption is true, and whether long COVID participants do indeed have persistently circulating virus, is subject to ongoing analysis.

Previous studies have shown that patients with severe COVID-19 can have increased levels of functional antibodies directed against self antigens that circulate outside of cells (i.e., extracellular autoantibodies), suggesting that SARS-CoV-2 infection can cause autoimmune disorders. To identify a possible connection between autoimmunity and long COVID, the authors screened the collected blood samples for autoantibodies using a technique called Rapid Extracellular Antigen Profiling (REAP). Among other applications, REAP allows one to assess antibody reactivity against a panel of extracellular human proteins known to contribute to well-studied autoimmune disorders. Interestingly, long COVID participants did not have increased levels of autoantibodies compared to control groups, suggesting that the autoantibodies detected in patients with severe COVID-19 may only be present during the acute phase of disease. However, REAP only assesses antibodies directed to extracellular self proteins and does not provide any information regarding intracellular or non-protein-specific autoantibodies. Therefore, one cannot rule out a role for autoimmunity in long COVID.  

The authors also used REAP to detect antibodies against various viruses. They found that long COVID participants had antibodies against several other viruses in addition to SARS-CoV-2, including Epstein-Barr virus (EBV), a herpesvirus that is well known for causing infectious mononucleosis (i.e., “mono”), a condition that is often compared to encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. However, because most adults have antibodies against EBV and there was no significant difference in the percentage of EBV antibody-positive participants between experimental and control groups, it is unlikely that a positive EBV antibody status contributes to the risk of developing long COVID.

The most interesting observation in this study was that compared to control groups, long COVID participants had about 50% lower levels of the steroid hormone cortisol. Because cortisol is a potent anti-inflammatory agent, it is feasible that a shortage of cortisol would lead to persistent inflammation and the long-term tissue damage associated with inflammation. In line with this reasoning, cortisol levels were highest in healthy, vaccinated, uninfected controls (group 1 controls); lower in healthy, unvaccinated, previously infected individuals without persistent symptoms (group 2 controls); and lowest in long COVID participants. Using machine learning methods, the authors determined that cortisol deficiency was the single most significant predictor of a long COVID diagnosis. Low cortisol has also been implicated in ME/CFS, and treatment with hydrocortisone can provide some relief from symptoms. 

The authors are careful to note that the small sample size of 215 participants is a considerable limitation of this study. Nevertheless, the results offer some valuable insight that may apply to other chronic conditions. In contrast to public perception, long-term symptoms following an acute viral infection are not unique to COVID-19. Unexplained chronic syndromes involving similar symptoms to long COVID have also been reported after dengue virus, poliovirus, SARS-CoV, Chikungunya virus, West Nile virus, Ross River virus, Coxsackie virus, and influenza virus infections. Because these syndromes are associated with high public health and economic burdens, more work needs to be done to clarify their underlying mechanisms.