Study suggests patients with severe long COVID present with variable symptoms, do not cluster in relation to organs affected or immunological states

By Dr. Liji Thomas, MDReviewed by Danielle Ellis, B.Sc.Feb 16 2024

A new preprint, recently uploaded to the medRxiv* preprint server, reports significantly associated findings that may help predict severe long COVID and understand what causes it.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

SARS-CoV-2 infection causes protean manifestations extending over a wide range of severity. In the most severe cases, multiorgan failure and death supervene, with underlying coagulation failure and hyperinflammation. The key factor is the occurrence of an antiviral type-1 interferon (IFN-1) response to infection of respiratory epithelial cells and antigen-presenting dendritic cells, as this is responsible for further events that limit viral replication. In addition, it allows immune clearance of the virus.

A type of post-COVID sequel among children has been termed the Multisystem Inflammatory Syndrome in Children (MIS-C). The occurrence of this condition is associated with the persistence of the virus in the gut, perhaps linked to chronic T cell activation.

The resemblance to superantigen-induced T cell activation did not escape notice, especially as a superantigen-like motif had already been reported in the SARS-CoV-2 spike protein with similarity to staphylococcal enterotoxin B. Coupled with potential genetic defects associated with MIS-C, the authors speculate a common origin for both long COVID and MIS-C.

According to them, “disease tolerance, restrained antiviral T cell responses and viral persistence” comprise one such possibility. They believe that in select groups, such as children and women of reproductive age, efficient antiviral responses ensure mild infections by limiting systemic inflammation and T cell responses. On the flip side, this increases the odds of viral persistence and, thus of long COVID.

Evidence for viral persistence is scanty, including the presence of viral antigens in blood and tissue samples and imaging reports, as well as finding continued somatic hypermutation in B cells specific to this virus. Again, vaccination against COVID-19 reduces the risk of long COVID, as does early antiviral therapy, supporting the hypothesis that this sequel results from viral persistence.

The current report centers on patients who had mild to moderate COVID-19 and later developed severe long COVID.  

What did the study show?

 The scientists examined only patients with documented mild to moderate SARS-CoV-2 infection who had not been hospitalized over a thousand of them. From these, they selected those who had evidence of organ damage to the heart, blood vessels, autonomic nervous system, hyperventilation, or changes in computerized tomography (CT) of the lungs.

These were chosen since they provided objective proof of organ damage, supporting the diagnosis of severe long COVID. They found ~120 cases, almost 90% being females with the mean age being 48 years.

They found that there is no common set of symptoms, signs of organ damage, or characteristic immunological profile in patients who develop long COVID. However, serum antibody responses were markedly higher in these patients compared to those who recovered rapidly. This is a sign of persistent antigen stimulation, especially as these cases were sampled long after the acute infection.

When viral RNA and protein antigens were looked for in plasma samples, using an array of independent testing methods, the researchers found that only a subset of patients were positive for viral antigens by any of the methods used. There was little overlap in the results between different assays. This indicates that blood tests for viral persistence may not yield uniform results, and the finding of elevated antibody levels is a more sensitive marker of long COVID.

The failure to detect antigens by all assays could either reflect the decreased sensitivity of the tests or the fact that the virus harbored in the tissue reservoirs may not leak the antigens into the bloodstream. It is unlikely that failure of viral persistence is the reason, given the persistent increase in anti-SARS-CoV-2 IgG responses observed in multiple cohorts.

They also found certain monocyte subsets and plasma proteins associated with an ongoing innate immune response at elevated levels. Such elevations were in proportion to increased immunoglobulin G (IgG) antibody titers, a marker of persistent inflammation.

In contrast, there was a failure of expansion of cytotoxic memory CD8+ T cells targeting SARS-CoV-2. The frequency of such clones decreases as antibody levels rise.

“This suggests that individuals who fail to mount a clonally expanded memory CD8+ T cell response to SARS-CoV-2 develop a viral reservoir with persistent antigen.”

The researchers did not find autoantibodies to IFN-1 in these patients. However, these have been found in life-threatening COVID-19-associated pneumonia and account at least in part for one in five deaths due to COVID-19 by inhibiting IFN-1-mediated suppression of viral replication.

This indicates that the underlying mechanism of long COVID is viral persistence, with impaired CD8+ T cell responses being the norm, rather than T cell exhaustion, as some scientists have suggested earlier to be characteristic of severe long COVID.

What are the implications?

The study suggests that the finding of elevated SARS-CoV-2-specific IgG sensitively identifies long COVID mounted against the spike antigen. Secondly, this is likely to be the result of viral persistence with chronic antigen stimulation.

Those patients who respond strongly to the initial infection via an adaptive immune response likely clear the virus rapidly and have a lower chance of long COVID. In contrast, if a viral reservoir is established, chronic stimulation by viral antigens leads to a long-term elevation of anti-SARS-CoV-2 IgG.

The researchers continue to seek the reason for the failure of viral clearance in some patients leading to long COVID. Until then, prolonged administration of antivirals may be the best way to treat these patients by removing the viral reservoir.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.