Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms

Abstract

The novel virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of coronavirus disease 2019 (COVID-19). Across the globe, a subset of patients who sustain an acute SARS-CoV-2 infection are developing a wide range of persistent symptoms that do not resolve over the course of many months. These patients are being given the diagnosis Long COVID or Post-acute sequelae of COVID-19 (PASC). It is likely that individual patients with a PASC diagnosis have different underlying biological factors driving their symptoms, none of which are mutually exclusive. This paper details mechanisms by which RNA viruses beyond just SARS-CoV-2 have be connected to long-term health consequences. It also reviews literature on acute COVID-19 and other virus-initiated chronic syndromes such as post-Ebola syndrome or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to discuss different scenarios for PASC symptom development. Potential contributors to PASC symptoms include consequences from acute SARS-CoV-2 injury to one or multiple organs, persistent reservoirs of SARS-CoV-2 in certain tissues, re-activation of neurotrophic pathogens such as herpesviruses under conditions of COVID-19 immune dysregulation, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation issues, dysfunctional brainstem/vagus nerve signaling, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage care for specific patients with the diagnosis.

Post COVID-19 Syndrome (“Long COVID”) and Diabetes: Challenges in Diagnosis and Management

“…Commonly understood factors include organ damage, persistently dysregulated inflammatory and immune responses, and unrecognised microvascular thrombosis and endotheliitis [ 9 ]. Many other factors have been hypothesised; persistent tissue reservoirs of SARS-CoV-2, re-activation of other viruses, brainstem and/or vagus nerve dysfunctions and activation of autoimmunity due to molecular mimicry between pathogen and host proteins [ 10 ]. In addition, secondary infections (bacterial or fungal), effects of prolonged hospitalisation, sequelae of critical illness, post intensive care syndrome, drug side effects (e.g., corticosteroids), socioeconomic and psychological impact of the illness, may contribute [ 2 , 11 ].…”

COVID-19 Immunobiology: Lessons Learned, New Questions Arise

“…For example the time needed for the full panel of symptoms to arise (1-2 weeks), coincides with the time needed for the production of autoantibodies (220,221). Persistence of these autoantibodies and/or the accompanying inflammation after the resolution of the acute phase of COVID-19 has also been proposed as a possible mechanism leading to the so-called "long-COVID" (222)(223)(224). On the other hand, it is of interest, that, some of the main drugs used in patients hospitalized with COVID-19 (like corticosteroids, IL6 inhibitors, Jak inhibitors etc.)…”

Implications of Innate Immunity in Post-Acute Sequelae of Non-Persistent Viral Infections

“…While some of the post-acute sequelae may be transient, others are irreversible. In general, symptoms are diverse but often include chronic fatigue, decline in quality of life, neurological symptoms and auto-inflammatory/auto-immune diseases [22,23].…”

“…A recent study reported that about 30% of COVID-19 outpatients or hospitalized patients report persistent symptoms [89]. Among these are fatigue, abnormal thermoregulation, skin diseases, intestinal symptoms up to diabetes leading to significant symptom burden and failure to fully recover and return to previous work levels [22,23,[90][91][92][93][94]. Notably, the previously epidemic coronaviruses SARS-CoV-1 and MERS-CoV have induced a similar set of symptoms in their post-acute phase [97][98][99].…”