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.

Keywords: COVID-19; SARS-CoV-2; brainstem; infection; long COVID; microbiome; vagus; virus.

FIGURE 1

Most common symptoms remaining after 7 months in 966 respondents from a cohort of suspected and confirmed COVID-19 cases. Results obtained via an international web-based survey. Image adapted with permission from Davis et al. (2020).

FIGURE 2

Enteroviral capsid protein 1 in the stomach biopsy of an ME/CFS patient by immunoperoxidase staining (100×) (Chia et al., 2015). This type of chronic viral infection is difficult to identify without the use of special techniques such as antibody staining or nucleic acid amplification of biopsies taken from symptomatic areas, since viral cultures are rarely positive. Original image courtesy of Dr. John Chia.

FIGURE 3

Murine embryonic fibroblasts, 6 h after infection with Toxoplasma gondii tachyzoites. Persistent pathogens such as Toxoplasma may reactivate during acute COVID-19. Original image courtesy of Dr. Lena Pernas.

FIGURE 4

Microclots are significantly increased in COVID-19 plasma as compared to controls. Fluorescence microscopy of COVID-19 and control platelet poor plasma incubated with the dye thioflavin (ThT), which detects spontaneously formed microclots. Original image courtesy of Dr. Resia Pretorius.

FIGURE 5

Several studies have shown that the dorsal brainstem can be affected or infected by SARS-CoV-2. This region is dense with nuclei that may be important for PASC. AP, area postrema, a circumventricular organ lacking a blood brain barrier, involved in nausea/vomiting; DRt, dorsal reticular nucleus, involved in inflammatory pain; DMV, dorsal motor nucleus of the vagus nerve, site of parasympathetic neurons and the main source of the vagal innervation of trunk organs; NAmb, nucleus ambiguus, contains soma of cholinergic preganglionic parasympathetic neurons that control heart rate; NTS, nucleus of the solitary tract, site of sensory vagus nerve soma that respond to detection of peripheral inflammation; VLM, ventrolateral medulla, involved in noradrenergic sympathetic nervous system signaling, autonomic control of blood pressure and breathing. Image adapted with permission from Sclocco et al. (2018). Original image courtesy of Dr. Zahra Mona Nasiriavanaki, Paulita Lara Mejia, and Dr. Roberta Sclocco.