Long COVID: A proposed hypothesis-driven model of viral persistence for the pathophysiology of the syndrome

Abstract

Background: Long COVID (coronavirus disease 2019) syndrome includes a group of patients who, after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibit lingering mild-to-moderate symptoms and develop medical complications that can have lasting health problems. In this report, we propose a model for the pathophysiology of the long COVID presentation based on increased proinflammatory cytokine production that results from the persistence of the SARS-CoV-2 virus or one of its molecular components. Associated with this hyperproduction of inflammatory cytokines is a heightened activity of nuclear factor κ B (NF-κB) and p38 mitogen-activated protein kinase signaling pathways that regulate cytokine production. Objective: The purpose of the present report was to review the causes of long COVID syndrome and suggest ways that can provide a basis for a better understanding of the clinical symptomatology for the of improved diagnostic and therapeutic procedures for the condition. Methods: Extensive research was conducted in medical literature data bases by applying terms such as “long COVID” associated with “persistence of the SARS-CoV-2 virus” “spike protein' “COVID-19” and “biologic therapies.” Results and Conclusions: In this model of the long COVID syndrome, the persistence of SARS-CoV-2 is hypothesized to trigger a dysregulated immune system with subsequent heightened release of proinflammatory cytokines that lead to chronic low-grade inflammation and multiorgan symptomatology. The condition seems to have a genetic basis, which predisposes individuals to have a diminished immunologic capacity to completely clear the virus, with residual parts of the virus persisting. This persistence of virus and resultant hyperproduction of proinflammatory cytokines are proposed to form the basis of the syndrome.

Prevalence and clinical presentation of long COVID in children: a systematic review

“…The mechanisms underlying post COVID condition are not clearly defined; however, several pathogenesis models have been put forward. One of the most supported hypotheses is based on the persistence of the virus or a virus component [ 46 ]. Several studies have demonstrated a prolonged SARS-CoV-2 shedding in the respiratory tract, faeces, and intestinal biopsies, even in asymptomatic patients [ 47 , 48 ].…”

“…This could lead to an exacerbated immune response resulting in increased levels of proinflammatory cytokines, including interleukin (IL)-6, IL-1β, and TNF [ 49 , 50 ]. A persistent proinflammatory state could explain organ damage and prolonged symptoms, such as fatigue, headache, and smell impairment [ 46 , 48 ]. Moreover, several types of autoantibodies are produced during SARS-CoV-2 infection due to a molecular mimicry mechanism between self-antigens and spike epitopes [ 51 ].…”

Subtle structural differences of nucleotide analogs may impact SARS-CoV-2 RNA-dependent RNA polymerase and exoribonuclease activity

“…Long COVID, also known as Post COVID-19 condition, defined as the persistence of symptoms 12 weeks after the first acute SARS-CoV-2 infection, affects millions of individuals worldwide [60] and over 50 different symptoms have been associated with this condition [61] . The ultimate cause of this pathology remains an open issue, and different ideas have been posited as its main contributors, including the formation and deposition of blood clots, alterations in the immune system, the persistence of replicating virus in various tissues including the intestinal epithelium, or a combination of all of them [62] , [63] , [64] , [65] . A related, but slightly different scenario, is represented by immunocompromised patients, in which the virus continues its replication for months [66] , [67] .…”

Cytokine Hub Classification of PASC, ME-CFS and other PASC-like Conditions

“…We agree with the conclusions of Schett et al 1 that targeting of individual cytokines underlying the immunopathogenesis of these conditions may provide a powerful new tool in the treatment of these immunologically-mediated disorders using precision medicine. Further study may elucidate how pathogen or antigen persistence could contribute to these classi cations 12,13 .…”