Long COVID may be linked to the presence of active viral reservoirs in the intestine

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The diagnosis and management of post-acute sequelae of COVID-19 present a constant medical challenge. Identifying biomarkers associated with long COVID would improve patient classification and provide the means to evaluate treatment strategies. Currently, scientists are not unanimous as to the reasons for this persistence of symptoms after the acute phase of the disease, and some studies have pointed to the maintenance of the virus within the body, in “reservoir” pockets. Recently, researchers have demonstrated the persistence of the Spike protein of SARS-CoV-2 in the plasma of patients. It could be a new diagnostic tool for long Covid, thus allowing better care for these people. Additional research on these viral reservoirs within the body is becoming a key point in understanding long-term COVID, a real public health and economic issue.

The World Health Organization (WHO) reports that about a quarter of people with COVID-19 continue to have symptoms 4-5 weeks after testing positive and about 1 in 10 after 12 weeks. Although recent studies provide some clues, the underlying etiology of COVID remains obscure to scientists. This lack of clarity is partly due to inconsistencies in the definition of patients with long-term Covid, making it difficult to bring together the results of the different studies.

It is therefore essential to be able to define, clearly and unambiguously, which patients can be considered to be suffering from Covid for a long time, in order to make fundamental research more robust on the one hand and better care on the other. of these people. In this perspective, a team led by David R. Walt of the Harvard Medical School tried to provide some clarification through the analysis of blood samples from patients who contracted COVID-19, some of whom defined COVID long. Their results, which have yet to be reviewed by the pairs, are published in MedRxiv.

Presence of SARS-CoV-2 in the blood, well after infection

The study authors analyzed 63 plasma samples taken from a set of COVID-19 patients, 37 of whom received a long Covid diagnosis. Their goal was firstly to quantify circulating viral antigens (anti-Spike) as well as inflammatory markers (cytokines), and secondly to identify a blood biomarker appearing in the majority of long-term COVID patients.

For 31 long COVID patients, blood samples were taken two or more times up to 12 months after their first positive result with a PCR test. Moreover, 30 of these people were women, in line with other studies revealing that women are mainly affected by persistent symptoms after infection with SARS-CoV-2.

Graph showing SARS-CoV-2 antigen levels as a function of time in COVID-19 patients and long COVID patients (PASC), for Spike protein S1 subunit (A), for whole Spike protein (B) and for the nucleocapsid protein, commonly used in diagnostic tests (C). © Z. Swank et al., 2022

The researchers detected the circulating virus Spike protein in the majority of long COVID patients, but in none of the COVID-19 patients without persistent disease symptoms. They specify: Although our sample size is small, detection of the Spike protein at multiple time points 2-12 months after infection is elicited “.

Indeed, the presence of the Spike protein circulating in the plasma supports the hypothesis that a reservoir of active viruses persists in the body. Another preliminary study found SARS-CoV-2 RNA in multiple anatomical sites up to seven months after symptom onset, supporting viral antigen persistence.

A viral reservoir in the intestine

In a previous study by Dr. Walt’s colleagues, a SARS-CoV-2 replication reservoir was found to be present in the gastrointestinal tract of children who developed multisystem inflammatory syndrome (MISC). In their work, they detected elevated levels of the Spike protein, weeks after the initial SARS-CoV-2 infection. They would be due to a breach in the gastrointestinal barrier, dependent on zonulin – a protein that regulates intestinal permeability in a reversible manner –, obtaining in favor of the MISC and allowing the residual viral particles of SARS-CoV-2 to penetrate into blood flow.

Furthermore, in another research, analysis of the gut microbiota in adults revealed that SARS-CoV-2 antigens persist in the intestinal mucosa for up to six months after infection in the majority of patients with disease. inflammatory bowel disease (IBD), independent of immunosuppressive therapy or intestinal inflammation. Persistence of viral antigen is then associated with post-acute symptoms of COVID-19.

Moreover, a study from Stanford University supports this idea of ​​viral reservoirs associated with long COVID. The team, led by Ami Bhatt, believe that the prolonged presence of viral RNA in feces, but not in respiratory samples, as well as the association with gastrointestinal symptoms, provides evidence that SARS-CoV -2 infects the gastrointestinal tract and that this infection may persist.

Collectively, these results demonstrate that the persistence of the viral antigen within the body, in reservoirs in the intestine, is at the root of the post-acute sequelae of COVID-19.

In conclusion, the presence of the Spike protein circulating in long Covid patients up to 12 months after the first diagnosis strongly supports the hypothesis that viral reservoirs of SARS-CoV-2 persist in the body. Moreover, this direct measurement of the antigen in the majority of these individuals gives hope for its use as a reliable biomarker of this disease. If these patients can thus be identified on the basis of a simple assay, the evaluation of treatment strategies will become increasingly efficient.

Source: MedRxiv

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