Chronic Immune Dysregulation as a Possible Cause of Post-Acute Sequelae of SARS-CoV-2: A Detailed Report
Introduction In early 2020, COVID-19 was recognized as a highly virulent and deadly infectious disease. However, it soon became apparent that a significant number of patients were experiencing persistent symptoms during convalescence, a phenomenon previously described in other viral infections such as influenza, chikungunya, SARS-CoV-1, and MERS-CoV. With COVID-19, this post-acute sequelae of SARS-CoV-2 (PASC) has become a significant burden on individuals’ quality of life and healthcare systems worldwide.
Definition of PASC The World Health Organization (WHO) defines PASC as symptoms that persist for at least two months and cannot be explained by an alternative diagnosis in patients with a history of SARS-CoV-2 infection, at least three months after COVID-19 onset, with impact on patient functionality. PASC is a multi-system disease with a wide variety of unspecific physical and mental symptoms that may vary in severity from mild to incapacitating.
Risk Factors for PASC Development While conflicting results exist, increased age and hospitalization, especially in Intensive Care Units (ICUs), are risk factors for the persistence of symptoms. However, young and non-hospitalized patients may also develop PASC. Some studies also suggest that women are more prone to specific manifestations of this syndrome.
Pathophysiological Hypotheses for PASC Onset Several pathophysiological hypotheses have been proposed to explain the onset of PASC.
Firstly, the extensive damage induced during acute disease by SARS-CoV-2 may drive long-term tissue repair.
Secondly, the persistence of SARS-CoV-2 in the human body, particularly in the gastrointestinal system, nervous system, and other ACE2-expressing tissues, may remain for more than four months after acute infection.
Thirdly, autoimmune phenomena have been reported in long-term recovered patients. Chronic immune dysregulation due to virus persistence, autoimmunity, or repair of damaged tissues has been linked to PASC.
Study on Chronic Immune Dysregulation in PASC In this study, the hypothesis that chronic immune dysregulation characterizes PASC is followed. The study performs CD4+ and CD8 + T cell immunophenotyping, quantifies the viral-specific antibody response, and determines the cytokine signature on groups of convalescent individuals who developed or did not develop PASC. The study observes immune CD8+ T-cell activation in convalescent patients, irrespective of developing PASC, in which the CD4/CD8 ratio remains low upon six months of infection.
The study also observes that patients show distinct profiles in type I and mucosal type III IFN compared to uninfected individuals. Higher levels of CD8+ T cells expressing the transcriptional factor Eomes are pinpointed in PASC patients. Furthermore, CD8+ T cells expressing the β7 mucosal homing receptor are low in the blood of PASC individuals.
Specific IgA directed to N and S proteins of SARS-CoV-2 in PASC individuals is detected, consistent with mucosal immune response. The study highlights a model in which the persistence of viral antigens in mucosa alters mucosal immune response.
A new study led by researcher from University of Minho, Braga-Portugal and Hospital of Braga-Portugal has found that diminished peripheral CD8+β7 integrin+ T cells and anti-SARS-CoV-2 IgA response characterizes Long COVID.
The study findings were published in the peer reviewed journal: Nature
Reference link : https://www.nature.com/articles/s41467-023-37368-1
The study compared the immune cell populations in the blood of asymptomatic convalescent individuals (who had recovered from COVID-19 without developing symptoms) and long COVID patients (who experienced symptoms lasting more than 12 weeks after initial infection). The authors used flow cytometry to analyze the expression of various immune cell markers, including those involved in mucosal immunity.
The study found that both asymptomatic convalescent individuals and long COVID patients had an increased percentage of CD8+ T cells, which are important for fighting viral infections. However, the proportion of blood CD8+ T cells expressing the mucosal homing receptor β7 was significantly lower in long COVID patients compared to convalescent individuals. This receptor is important for directing immune cells to the mucosal surfaces of the body, where they can provide protection against viral infections.
The study also found that long COVID patients had a lower frequency of circulating follicular T helper cells, which play an important role in the development of long-lasting antibody responses. This suggests that long COVID patients may have a weaker antibody response to the virus, which could potentially contribute to their prolonged symptoms.
These findings suggest that there may be differences in the immune response between asymptomatic convalescent individuals and long COVID patients. Further research will be needed to fully understand the implications of these findings and how they may inform the development of treatments or vaccines for COVID-19.
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