Life after Coronavirus – Potential complications following recovery

COVID-19 primary lung infection and potential complications. Adapted from Journal of Medical Virology, July 2020 https://onlinelibrary.wiley.com/doi/10.1002/jmv.26294) 

To date there have been over 39 million cases of COVID 19 and greater than 1.1 million deaths reported globally [1]. The overwhelming majority of morbidity in COVID-19 disease is associated with pulmonary pathology; however, COVID-19 presents a complex array of pathologies. Symptoms of acute infection by SARS-CoV-2, the causative agent of COVID-19, can include fever, body aches, dry cough, sore throat, gastrointestinal distress, fatigue, loss of sense of smell and/or taste, and shortness of breath. Infection can also lead to “non-flu-like” complications such as hair loss, multisystem inflammatory syndrome in children (MIS-C), and coagulopathy resulting in blood clots in the veins and arteries of the lungs, heart, legs, kidneys, or brain. It remains to be seen if complications from non-fatal acute SARS-CoV-2 infection will result in long term chronic conditions or what the prognosis will be following recovery from COVID-19 disease. In some patients that recover, infection has resulted in the manifestation of lingering post-COVID-19 complications. Three independent studies that surveyed hospitalized COVID-19 patients for persistent symptoms following hospital discharge, found that the majority of patients had lingering symptoms, the most common of which were fatigue and shortness of breath but also included loss of memory, concentration and sleep disorders and loss of hair [2-4]. Whether these persistent symptoms are a direct result of virus infection and replication in tissue associated cells or a dysfunctional immune response, or both, has not been determined.  

Distribution of ACE-2 receptor 

The systemic distribution Angiotensin I Converting Enzyme- 2 (ACE-2), the functional receptor for SARS-CoV-2, raises the possibility that SARS-CoV-2 can infect multiple organs that are associated with non-pulmonary disease complications [5]. Within the group of non-pulmonary tissues and organs, cells within the gastrointestinal tract, kidney, and heart are high expressers of ACE2.  COVID19 associated complications in various non-pulmonary organs are as follows. 

Gastrointestinal (GI) tract: The presence of viral RNA and infectious virus in the feces and viral nucleocapsid in gastrointestinal tissues supports the hypothesis that the virus can infect and replicate in these cells [6-8]. Approximately 50% of COVID-19 patients have reported one or more GI symptoms during the acute phase [9]; however, published data regarding COVID19 associated GI inflammation is limited and long-term complications have not been reported. 

Kidney: A retrospective study found a 31.8% higher incidence of acute kidney injury (AKI) among patients hospitalized with COVID-19 compared with an historical non-COVID-19 hospitalized cohort. Patients with AKI and COVID-19 were more likely than those without COVID-19 to require kidney transplantations and were less likely to recover kidney function [10]. Data supporting the direct impact of virus infection as a cause of kidney damage are the presence of SARS-CoV-2 RNA and infectious virus in the urine of a COVID-19 patient [11], and detection of SARS-CoV-2 nucleocapsid protein (NP) and SARS-CoV-2 RNA in autopsy specimens of COVID-19 patients [12-14]. However, a survey of specimens collected from 74 hospitalized patients diagnosed with COVID-19 found that only 0.8% of the urine specimens were positive for presence of SARS-CoV-2 RNA, suggesting that the kidneys were not a location for high levels of viral replication and shedding [14].  

Heart: A prospective study of 100 patients recently recovered from COVID-19 revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), that was independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis [15]. Autopsy of cardiac tissue  from COVID-19 patients demonstrated SARS-CoV-2 viral RNA in the myocardium and evidence of viral replication in the autopsy tissue with high viral RNA loads; however, the analysis suggested that the most likely localization of SARS-CoV-2 was in interstitial cells or macrophages invading the myocardial tissue and not in the cardiomyocytes themselves [16].  

CNS: Numerous neurological complications involving the central and peripheral nervous system have been reported in patients with COVID-19. The severity of these range from mild to fatal symptoms and can occur in patients with severe or otherwise asymptomatic SARS-CoV-2 infection. In patients with mild COVID-19, neurological symptoms are mostly confined to nonspecific abnormalities such as malaise, dizziness, headache, loss of smell and taste and brain fog [17, 18]. All suggesting that SARS-CoV-2 infection and COVID-19 disease can damage the CNS. The expression of ACE2 in the human brain is not well established [5] although ACE2 expression and SARS-CoV-2 infection and replication has been reported in an in vitro neuronal tissue culture model [19]. Several mechanisms have been proposed as a means for viral access to the CNS including retrograde dissemination through the olfactory neurons [20]. Arguments against direct infection of neuronal tissues as a causative force behind CNS involvement in COVID-19 disease complications include the lack of SARS-CoV-2 in CSF of most COVID-19 patients with neurological abnormalities [17] and data which suggest that the virus is not detectable in human brain tissue from autopsies of COVID-19 patients [21, 22].  

Conclusion 

Whether systemic and extra-pulmonary complications are the result of direct infection and replication of SARS-CoV-2 in ACE2 bearing tissues and cells or the consequences of pulmonary viral infection leading to systemic inflammatory response syndrome, immune-mediated complications, or a combination of factors, remains to be elucidated. The expression and presence of ACE2 on a given cell makes it a candidate for infection by SARS-CoV-2; however, multiple co-factors such as cellular transmembrane protease serine 2 (TMPRSS2) or intercellular components, likely need to be present to make a cell fully susceptible to viral infection. Isolation of infectious virus from gastrointestinal tissue and kidneys indicates that virus can infect and replicate in these tissues, albeit at low incidence relative to lung infection. Productive viral replication in CNS and cardiac tissues has yet to be fully evidenced, indicating that pathologies associated with brain and heart functions are a consequence of the systemic inflammatory response to infection of other tissues or cells. Further research is necessary to determine the mechanisms leading to the numerous COVID-19 pathologies associated with specific organs and whether the complications are reversible or will be long-term chronic conditions.  

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