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Pathologic basis of coronavirus disease 2019 (COVID-19) – An overview of cellular affinities, pathogenesis, clinical manifestations, autopsy findings and sequelae

The global terror instigated by coronavirus disease 2019 (COVID-19) cannot be underestimated and the need for drastic measures towards its control cannot be overemphasized. Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) following attachment of the virus to specifi c receptors in the body. The distribution of these specialized receptors in various organs and tissues of the body is responsible for the various clinical presentations associated with the disease after infection. Despite the higher risk of spread of the infection, autopsies have been carried out though with maximum precautionary measures and information provided to further elucidate the extent of damages caused by the disease. Pathologic mechanisms leading to death from COVID-19 include respiratory failure due to surfactant defi ciency and consequent alveolar collapse, cardiac syncope from direct damage to cardiac muscles, peripheral paralysis, cytokine storm and excessive haemorrhage from impaired coagulation. In patients that recover, potential outcomes which could be shortand/or long-term have been recognized. As a means to develop effective control, eradication and prevention strategies, a proper understanding of the mechanisms of SARS-CoV-2 infection will fully ensure a positive breakthrough. Hence, in this article, the pathologic basis of COVID-19 are provided based on extensive literature searches, and proposed mechanisms of pathogenesis, clinical manifestations, autopsy fi ndings and sequelae are being described. Review Article Pathologic basis of coronavirus disease 2019 (COVID-19) – An overview of cellular affi nities, pathogenesis, clinical manifestations, autopsy fi ndings and sequelae Ochuko Orakpoghenor1*, Talatu Patience Markus2, Jamila Abdulhamid Atata3, Juwon Pius Erin1, Olushola Samuel Olaolu2, Collins Chimezie Udechukwu4, Ngozi Ejum Ogbuagu5, Kelvin Olutimilehin Jolayemi6, Magdalene Ogbonneya Okoronkwo6 and Bala Ningi Umar2 1Department of Veterinary Pathology, Ahmadu Bello University, Zaria, Nigeria 2Department of Veterinary Microbiology, Ahmadu Bello University, Zaria, Nigeria 3Department of Veterinary Pathology, University of Ilorin, Ilorin, Nigeria 4Department of Veterinary Medicine, Ahmadu Bello University, Zaria, Nigeria 5Department of Veterinary Physiology, Ahmadu Bello University, Zaria, Nigeria 6Department of Veterinary Pharmacology and Toxicology, Ahmadu Bello University, Zaria, Nigeria Received: 28 September, 2020 Accepted: 22 October, 2020 Published: 23 October, 2020 *Corresponding author: Ochuko Orakpoghenor, Department of Veterinary Pathology, Ahmadu Bello University Zaria, Nigeria; Tel: +2347067522037; E-mail;


Introduction
Coronavirus disease 2019 (COVID-19) is a respiratory syndrome of humans caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initially referred to as 2019-nCoV, in the family Coronaviridae [1,2]. This causative virus SARS-CoV-2 belongs to the same group as the zoonotic Middle East respiratory syndrome coronavirus (MERS-CoV) [3,4]. Other coronaviruses reported to be responsible for mild respiratory diseases in humans include HCoV-229E, HCoV-NL63, HCoV-HKU1 and HCoV-OC43 [5]. Transmission of SARS-CoV-2 involves contact of oral, respiratory and ocular mucus membranes with respiratory droplets and excreta containing the live virus from patients [6,7]. Though the virus has been reported to be of zoonotic origin, animal coronaviruses do not spread among humans [8]. Clinical manifestations of COVID-19, not limited to these, include fever, dry cough, weakness, dyspnoea, aches, diarrhoea, conjunctivitis and loss of taste and/or smell [9,10]. Severity of the disease is common among middle-aged and elderly patients with underlying disease conditions such as tumours, cirrhosis, hypertension, coronary heart disease, diabetes, and Parkinson's disease [11,12]. There is recovery after 1 week in patient with mild symptoms but death does occur in severe cases resulting from respiratory failure [9,13]. As there are no effective treatments and vaccines against COVID-19, prevention is targeted at avoidance of exposure to the causal virus [14]. However, in this review, the pathologic basis of COVID-19 with focus on the receptor and cellular targets, pathogenesis, clinical manifestations, gross and histopathology, and sequelae are being described.

Receptors and cellular targets of SARS-CoV-2
The receptors reported to be attached by SARS-CoV-2 are angiotensin-converting enzyme-2 (ACE2) and transmembrane protease serine-2 (TMPRSS2) [15]. They are cell surface proteins which enhance virus entry into cells and spread to other cells, and are abundant in epithelial and endothelial cells of the respiratory tract, kidneys, intestines, arteries and heart [16,17].
However, these proteins have been documented to be abundant in certain cells of the respiratory conducting system (ciliated cells), lungs (alveolar type II cells) and intestines (enterocytes) evident by more RNA expression of these proteins than other cells [18]. Also, dendritic cell specifi c intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN or CD209) and lymphocytic cell-SIGN (L-SIGN or CD209L) could be other receptors that enhance SARS-CoV-2 entry into host cells.
These receptors are reported to be differentially expressed in epithelial and endothelial cells of the lungs and kidneys in humans [19,20].

Pathogenesis of SARS-CoV-2 infection
Following inhalation, ingestion or contact with ocular epithelium, there is attachment of SARS-CoV-2 to epithelial cells leading to an initial viral replication and infl ammatory cellular reactions with limited innate immune response [16,21,22]. The incubation period has been estimated to range from 2.1-11.1 days with an average of 6.4 days [23].
In respiratory infection, there is propagation and migration of the virus down the conducting airways to the gas exchange system with subsequent greater innate immune response trigger accompanied by increased expression of interferon -induced protein 10 (IP-10 or CXCL10) [18]. The IP-10 has been reported to show abundant expression in alveolar type II cells following infection by SARS-CoV-2 [18,24]. This is followed by apoptosis of infected cells leading to loss of majority of type II cells, release of greater amount of viral particles and infection of adjacent type II cells [25]. Alveolar type I cells function in the process of gas exchange between the alveoli and blood while type II cells play roles in surfactant protein secretion and are the precursor cells for type I cells, hence, this major loss of type II cells will then trigger epithelial regeneration via secondary pathways [18,26,27].
In oral infection, the virus attaches to epithelial cells of the esophagus and enterocytes of the ileum and colon via ACE-2 and TMPRSS2 receptors [28,29]. This leads to viral replication within infected cells, cellular apoptosis activation and release of viral particles which in turn infect adjacent epithelial cells and enterocytes [22]. Also, there is exaggerated infl ammatory response via chemokine and cytokine release with consequent aggregation of infl ammatory cells and damage to the epithelium [21,30].
In ocular infection, there could be initial virus replication in the epithelial cells of the eyes and possible migration of viral particles via the nasolacrimal duct into the nasal cavity [31][32][33]. However, expression of SARS-CoV-2 receptor ACE2 and TMPRSS2 genes in human primary conjunctival and pterygium cell lines and in mouse cornea have been documented [34]. The evidence of SARS-CoV-2 attachment to receptors and/or presence of ACE-2, TMPRSS2 and/or CD209L receptors in the ocular epithelia requires further investigation.
The pyrexia may be associated with direct interaction of SARS-CoV-2 with the organum vasculosum of the lamina terminalis (OVLT) and/or indirectly via the stimulation of cytokine release (such as interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-α) which then act on the OVLT to cause fever [36].
Respiratory manifestations include respiratory distress, nasal congestion and sore throat. The respiratory distress resulted from lung compensatory mechanism on the hypoxia induced by infl ammatory damages caused by SARS-CoV-2 infection of alveolar type II cells [18,37]. Nasal congestion and sore throat could be suggested to result from damages by SARS-CoV-2 infection of epithelia of the nasal cavity and nasopharynx respectively [38].
Gastrointestinal manifestations include diarrhoea, nausea, vomiting, abdominal pain and anorexia [39,40]. The possible Citation: Orakpoghenor  The direct/indirect destruction of intestinal epithelia due to infl ammatory responses to the virus as ACE-2 is an important regulator of intestinal infl ammation and intestinal fl ora disruption by the virus could possibly induce the diarrhoea [28,41]. In patients undergoing antibiotic and/or antiviral therapy, diarrhoea could result from dysbiosis in the intestine induced by these drugs [41]. Also, alterations in respiratory fl ora due to SARS-CoV-2 have been suggested to affect the digestive system via immune regulation thus leading to diarrhoea [30,42]. Nausea and vomiting may be suggested to result On haematology, the symptoms of SARS-CoV-2 infection documented include lymphopaenia, thrombocytopaenia, coagulation disorders and thrombotic complications such as venous thromboembolism, arterial thrombotic event, activated partial thromboplastin and prothrombin times [54,55]. The lymphopaenia could be due to active lymphocyte destruction by SARS-CoV-2, excessive apoptotic signal induction by the virus in infected lymphocytes and/or suppression of myeloid cells in the bone marrow directly by the virus or indirectly by secondary mediators. The thrombocytic disorders observed could be associated with direct viral destruction of the cells or indirectly through interference with thrombocyte formation, coagulation and/or destruction of endothelial cells [22].

Gross pathological Observations due to SARS-CoV-2 infection
Autopsy reports of patients that died of COVID-19 have been focused on the respiratory system but fi ndings on other organs are also documented. The nasal cavity down to the trachea revealed the presence of frothy exudates and hyperaemic epithelial surfaces [52]. These could result from possible excessive exudate production during the infl ammatory processes and/or aspiration of fl uid from the stomach. The lungs showed very large, extremely heavy and brittle appearance with evidence of hepatizations indicating pneumonia [58,59]. This pneumonia could be due to secondary bacterial infection resulting from immunosuppression caused by SARS-CoV-2. Also, deep vein thromboses and fatal pulmonary embolisms linked to coagulopathy resulting from the viral infection have been reported [55]. Patterned alternations of pale and hyperaemic areas resembling 'zebra stripes' on pleura and cut surfaces of the lungs have been documented and could be proposed to result from the destructive effects of SARS-CoV-2 on endothelial cells [60].
Autopsy fi ndings that could be observed in the GIT include erosions and ulcerations of oesophageal mucosal surface due to refl uxed gastric acid caused by vomiting; erosions and ulcerations of intestinal epithelial surfaces caused by the direct virus injury and/or action of secondary mediators. Also, haemorrhagic areas on the serosal surfaces of the intestines and mesenteric congestion are expected. The liver presents congestion with rough surfaces and could be cirrhotic. Enlarged kidneys (hydronephrosis) and haemorrhagic areas on the surfaces could be seen.
The heart is enlarged with ventricular hypertrophy and atrial dilatation; myocardium appeared pale and fl abby, with evidence of ischemic or infl ammatory changes and valvular calcifi cations; and endocardial petechial haemorrhages. The enlargement and hypertrophy resulted from compensatory mechanisms on the induced hypoxia due to reduced lung capacity. The haemorrhages resulted from SARS-CoV-2 damages to endothelial cells and thrombocytes [61].

Histopathological fi ndings due to SARS-CoV-2 infection
In the lung sections of patients that died of COVID 19, Citation: Orakpoghenor  lesions observed under light microscopy include exudative and proliferative phases of diffuse alveolar damage (DAD) and these comprise capillary congestion, desquamation and necrosis of pneumocytes, hyaline membranes, interstitial and intraalveolar oedema, hyperplasia of alveolar type 2 cells, atypical squamous metaplasia, and thrombi containing platelet-fi brin [52,59,62]. The interstitial infl ammatory infi ltrate consisted mainly of lymphocytes and multinucleated syncytial cells [58,59]. SARS-CoV-2 particles in the pneumocytes have been demonstrated using electron microscopy [52]. These fi ndings are associated with infl ammatory reactions triggered by the virus following infection and destruction of epithelial and endothelial cells [63]. Also, the release of secondary mediators and actions of macrophages could further exacerbate the lesions observed.
In the heart, there is hypertrophy of myocytes with focal necrosis, interstitial and vascular fi brosis, haemorrhages and mononuclear cells infi ltration of adventitia. Tubular-interstitial infl ammation, interstitial fi brosis and glomerular sclerosis are observed in the kidneys and in the liver, microvascular congestion, steatosis and necrosis of hepatocytes have been reported [61].

Sequelae of SARS-CoV-2 infection
The sequelae of SARS-CoV-2 infection include recovery or death. Recovery will only be achieved in the presence of robust immune responses (innate and acquired) and effective epithelial regeneration [18]. Due to the decreased immune competency, reduced mucociliary clearance and retarded epithelial regenerative capacity associated with increase in age, elderly patients present higher risk of contracting COVID-19 with imminent death. These could have resulted from uninterrupted virus replication and readily spread to the gas exchange units of the lung [18,64].
Following recovery from COVID-19, sequelae reported in the pulmonary system include pulmonary fi brosis resulting from abnormal wound healing and severe scarring [65]. Myocardial lesions such as infection-related myocarditis, reduced systolic function and cardiac arrhythmias have been documented as sequelae in the heart following COVID-19 [50,66]. Nervous sequelae include decline in short-and long-term cognition, cerebrospinal complications, encephalopathies, muscle injuries, depression, anxiety, psychotic disorders, anosmia and aguesia [67][68][69]. Other possible sequelae of COVID-19 include liver and kidney injuries depicted by abnormal liver and kidney function tests [52,70].