severe COVID-19

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:

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

Throughout the current pandemic, there has been a lot of talk about T cells and their role in protecting against SARS-CoV-2 infection and disease. Some data suggest that 20-50% of people with no prior exposure to SARS-CoV-2 have T cells that recognize SARS-CoV-2 peptides, and that these T cells may be a result of recent infections with one or more of the seasonal human coronaviruses. However, it is unclear whether these “cross-reactive” T cells actually protect from SARS-CoV-2 infection and disease.

T cells are an important part of the adaptive immune response, which initiates during a first exposure to a pathogen and protects from re-infection and disease upon a second exposure to the same pathogen. During that first exposure, T helper cells sense the presence of one or more proteins (i.e., antigens) on the surface of the invading pathogen and release a variety of signals that ultimately stimulate B cells to secrete antibodies to those antigens, white blood cells to destroy ingested microbes, and cytotoxic T cells to directly kill infected target cells (see schematic). Before T cells encounter their first antigen, they are considered to be “naïve.” Upon their first contact with an antigen, they begin to mature and differentiate into either cytotoxic T cells or memory T cells. As we age and encounter more and more pathogens, the ratio of our memory T cells to our naïve T cells increases – a phenomenon sometimes referred to as “immunological age.”

Based on evidence from several labs, some have suggested that pre-existing cross-reactive memory T cells in people with no prior exposure to SARS-CoV-2 may have a protective effect. However, recent findings indicate that this may not be the case.

Several research groups from the U.S. and Australia analyzed blood samples from individuals with no prior SARS-CoV-2 exposure with the intent of better defining the range of T helper cells that can recognize antigenic portions known as epitopes in the SARS-CoV-2 genome. To ensure that the blood donors had never been infected with SARS-CoV-2, the researchers used stored samples that had been collected between 2015 and 2018. The authors found that the blood samples contained T cells that can recognize SARS-CoV-2 sequences that have at least 67% similarity to seasonal coronavirus sequences. However, the authors also found that people who had experienced a previous infection with SARS-CoV-2 had stronger and more specific (i.e., higher avidity) memory T cell responses to SARS-CoV-2 peptides than people with no prior exposure, and more than half of these responses were directed to epitopes in the spike protein. This suggests that SARS-CoV-2 memory T helper cells preferentially target viral proteins that are made in abundance during infection.

The authors conclude that an infection with a seasonal coronavirus may induce a range of memory T cells that have substantial cross-reactivity to SARS-CoV-2. However, they are careful to note that the clinical relevance of these data remains unclear and that there is no evidence that these memory T cells have any functional role in protecting from infection or disease.

Based on these findings, several groups of investigators in Germany wanted to determine whether the observed pre-existing T cell memory response in people with no prior SARS-CoV-2 exposure is protective against COVID-19. They first tested T cell activity in the blood of donors with and without prior exposure to SARS-CoV-2 by exposing their blood to highly immunogenic SARS-CoV-2 peptides. Blood from donors with a prior exposure contained memory T cells that recognized SARS-CoV-2 peptides very well, especially peptides derived from the spike, membrane, and nucleocapsid proteins. Blood from donors with no prior exposure also contained low levels of SARS-CoV-2-reactive memory T cells, but this reaction was more scattered and directed against multiple viral proteins.

To further characterize the pre-existing cross-reactive T cells in blood samples from people with no prior SARS-CoV-2 exposure, the authors compared the numbers of memory T cells and naïve T cells in the blood samples by analyzing them for the presence of protein markers that are characteristic for each type of cell. A substantial portion of SARS-CoV-2-reactive T cells from donors with no prior exposure were naïve T cells, whereas from COVID-19 patients most were mature memory T cells. Because memory T cells are more easily activated following an infection than naïve T cells, the authors speculate that deficient, low avidity memory T cells in people with no prior SARS-CoV-2 exposure may compete with naïve T cells and prevent their activation and maturation into highly specific memory T cells upon infection with SARS-CoV-2. This could potentially lead to an inferior immune response in people with no prior SARS-CoV-2 exposure.

Some have suggested that young patients and children may be particularly well protected from SARS-CoV-2 infection and/or disease because they are frequently infected with seasonal coronaviruses and thus presumably have high levels of pre-existing memory T cells. However, the authors found that compared to young people, older people with no prior SARS-CoV-2 exposure actually had higher numbers of SARS-CoV-2 cross-reactive memory T cells, but these T cells had a decreased avidity to SARS-CoV-2 epitopes compared to memory T cells from people with prior SARS-CoV-2 exposure.

A further comparison of T cell responses in patients with mild or severe COVID-19 revealed that although the latter had high numbers of SARS-CoV-2 specific T cells, these T cells had reduced target specificity and avidity compared to T cells from patients with moderate disease. The authors conclude that this unfocused response may result from recruitment of a broad range of pre-existing memory T cells in people with increased immunological age and may contribute to development of severe COVID-19 in the elderly.

The initial discovery of SARS-CoV-2-specific memory T cells in individuals with no prior exposure to SARS-CoV-2 had inspired the hypothesis that these T cells could possibly protect these individuals from disease and might partially explain why children are less susceptible to COVID-19. However, in light of these new findings it is likely that pre-existing SARS-CoV-2-specific memory T cells may contribute to the wide spectrum of disease severity among the general population and may actually be partially responsible for severe COVID-19 in the elderly.

[For an in-depth discussion of these two papers, I recommend TWiV 657 and Christian Drosten’s “Das Coronavirus Update,” episodes 58 and 60.]

Why do Some People Develop Long COVID?

T Cell Responses to Coronavirus Infection are Complicated