PASC Update

Specializing in the diagnosis, treatment and monitoring of heart disorders

Long COVID or Post-acute Sequelae of COVID-19 (PASC):

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.

Introduction

The novel virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic of coronavirus disease 2019 (COVID-19) (Hiscott et al., 2020). Classic cases of acute COVID-19 are characterized by respiratory symptoms, fever, and gastrointestinal problems (Larsen et al., 2020). However, patients can present with a wide range of other symptoms, including neurological issues suggesting central nervous system (CNS) involvement (Harapan and Yoo, 2021).

Acute COVID-19 cases range in length and severity. Many patients are asymptomatic, while others require hospitalization and ventilation (Cunningham et al., 2021). Overall, an average case of COVID-19 lasts between 1 and 4 weeks. However, 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 (Carfì et al., 2020; Davis et al., 2020; Huang C. et al., 2021) (Figure 1). One study of COVID-19 patients who were followed for up to 9 months after illness found that approximately 30% reported persistent symptoms (Logue et al., 2021). These patients are being given the diagnosis Long COVID, post-acute COVID-19 syndrome (PACS), or post-acute sequelae of COVID-19 (PASC).

Acute COVID-19

In order to best understand persistent symptoms arising from SARS-CoV-2 infection we must first review major trends associated with SARS CoV-2 activity in patients with acute COVID-19. SARS-CoV-2 is a positive-sense single-stranded RNA virus (V’kovski et al., 2021). It is one of seven coronaviruses capable of infecting humans (Corman et al., 2018). Compared with other coronaviruses (e.g., HCoV-NL63, HCoV-229E, and HCoV-OC43) that are pathogenic to humans but generally drive only mild clinical symptoms, SARS-CoV-2 more closely resembles MERS-CoV or SARS-CoV (sometimes called SARS-CoV-1) in that it is capable of causing severe disease (Zhu et al., 2020).

Many COVID-19 patients are asymptomatic (∼40–45%) (Oran and Topol, 2020) or exhibit mild to moderate symptoms (Zheng P. et al., 2020). However, approximately 15% progress to severe pneumonia, with ∼5% eventually developing acute respiratory distress syndrome (ARDS), septic shock and/or multiple organ failure (Cao, 2020; Huang et al., 2020). The most common symptoms of acute COVID-19 are fever, fatigue, diarrhea, and respiratory symptoms such as cough, sore throat and shortness of breath (Larsen et al., 2020). However, some patients develop neurological manifestations ranging from mild symptoms such as anosmia, dizziness, and headache to more severe cerebrovascular disease, seizures, encephalitis, or the Guillain–Barré syndrome (Berlit et al., 2020). Other extrapulmonary manifestations of COVID-19 include acute kidney injury, hyperglycemia, thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, and hepatocellular injury (Gupta et al., 2020; Robba et al., 2020).

These diverse COVID-19 symptoms partially reflect the fact that SARS-CoV-2 can infect a wide range of human cell types. The spike subunit of SARS CoV-2 binds the human angiotensin-converting enzyme 2 (ACE2) receptor to infect and enter host cells (Hoffmann et al., 2020). Viral cell entry additionally requires priming of the spike protein by cellular serine proteases such as TMPRSS2 and TMPRSS4. ACE2 is expressed along the entire human respiratory system and in brain endothelium and vascular smooth muscle cells (Hamming et al., 2004). Single-cell RNA-sequencing studies have also confirmed expression of ACE2 and TMPRSS2 in a wide range of cell types including esophageal keratinocytes, renal proximal tubules, pancreatic β-cells, and gastrointestinal epithelial cells (Gupta et al., 2020; Puelles et al., 2020; Qi et al., 2020).

Recent work has further clarified CNS cellular expression of ACE2 and other genes that may contribute to COVID-19. For example, Matschke et al. (2020) performed an in silico analysis of publicly available datasets to determine which CNS cell types might be prone to SARS-CoV-2 infection. They analyzed genes that can contribute to viral entry into the cell and viral persistence, including ACE2, TMPRSS2, TMPRSS4, TPCN2, CTSL, and NRP1. They found that these genes are expressed in neurons, glial cells, and endothelial cells, suggesting their possible capacity to support SARS-CoV-2 infection.

Like all pathogens, SARS-CoV-2 employs a number of mechanisms to disable and evade the host immune response (Lucas et al., 2001; Bowie and Unterholzner, 2008; Taefehshokr et al., 2020). These include the ability to replicate within double-membrane vesicles that are not detected by host pathogen pattern recognition receptors (Taefehshokr et al., 2020). SARS-CoV-2 also dysregulates the host interferon response (Ribero et al., 2020). Interferons are cytokines secreted by host cells in response to viral infection. They bind to cell surface receptors and act as transcription factors, regulating the expression of hundreds of genes whose protein products target viruses at many levels (Acharya et al., 2020). SARS-CoV-2 expresses at least 10 proteins that allow it to either counteract the induction or escape the antiviral activity of interferons (Ribero et al., 2020), allowing the virus to better survive by rendering the host innate immune response inefficient.