Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches
Jasimuddin Ahamed, Jeffrey Laurence
Jasimuddin Ahamed, Jeffrey Laurence
Published August 1, 2022
Citation Information: J Clin Invest. 2022;132(15):e161167. https://doi.org/10.1172/JCI161167.
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Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches

Abstract

SARS-CoV-2–infected individuals may suffer a multi–organ system disorder known as “long COVID” or post-acute sequelae of SARS-CoV-2 infection (PASC). There are no standard treatments, the pathophysiology is unknown, and incidence varies by clinical phenotype. Acute COVID-19 correlates with biomarkers of systemic inflammation, hypercoagulability, and comorbidities that are less prominent in PASC. Macrovessel thrombosis, a hallmark of acute COVID-19, is less frequent in PASC. Female sex at birth is associated with reduced risk for acute COVID-19 progression, but with increased risk of PASC. Persistent microvascular endotheliopathy associated with cryptic SARS-CoV-2 tissue reservoirs has been implicated in PASC pathology. Autoantibodies, localized inflammation, and reactivation of latent pathogens may also be involved, potentially leading to microvascular thrombosis, as documented in multiple PASC tissues. Diagnostic assays illuminating possible therapeutic targets are discussed.

Authors

Jasimuddin Ahamed, Jeffrey Laurence

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Figure 2

Potential mechanisms underlying long COVID (PASC).

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Potential mechanisms underlying long COVID (PASC). Multiple factors may ...
Multiple factors may contribute to the pathophysiology of at least certain PASC phenotypes, either directly or via microvascular injury. This occurs in the absence of the hypercoagulable state and systemic immune activation that characterize acute COVID-19. It is proposed that cryptic reservoirs of SARS-CoV-2 in multiple tissues, acting via direct EC infection, release of soluble viral products, infection of monocytes adjacent to the vasculature, or activation of other viruses, such as EBV, which can transmit virus to microvascular ECs, lead to cytopathic effects in ECs. Specific evidence for this is outlined in Tables 1 and 2. Autoantibodies, particularly against IFN-I, leading to suppression of the antiviral MxA pathway shown in Figure 1B, or against ECs, may also be involved. Development of SARS-CoV-2 cryptic reservoirs may be facilitated by lower antiviral immunity. Vaccinated individuals have a much lower incidence of PASC than the unvaccinated.