key: cord-0968935-1igv8c8t
authors: Elhamzaoui, Hamza; Rebahi, Houssam; Hachimi, Abdelhamid
title: Coronavirus disease 2019 (COVID-19) pathogenesis: a concise narrative review
date: 2021-05-03
journal: Pan Afr Med J
DOI: 10.11604/pamj.2021.39.8.23546
sha: ca6f27b7077752a54176c271afb0d36659f3ff78
doc_id: 968935
cord_uid: 1igv8c8t

SARS-CoV-2 is the third zoonotic coronavirus. Since December 2019, it has spread through the globe and infects more than four million patients (as of May 10(th), 2020). The disease was named coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO). It involves many organs and systems in the human organism. We aimed to describe the pathogenesis of the COVID-19.

Of the coronaviridae family, human coronaviruses (HCoVs) include six strains. The first HCoV, named B814, was identified in 1965 in nasal swabs in patients with cold Since the first case, COVID-19 could be qualified as a "great imitator" because it is not a simple lung disease. It can cause more severe impairment such as heart rhythm problems, heart failure, acute kidney failure, hemorrhagic stroke, seizures, meningitis Guillain-Barre syndrome, or thromboembolic events [15, 16] . When the virus gains the body via eyes, nose, or mouth, it invades cells by connecting to ACE2 receptors, which are found in the organs. In this review, we aimed to set out SARS-CoV-2 pathogenesis.

We [28] , the infected ACE2 knockout mice are resistant to virus infection and the virus titers are 10 5 fold lower than those isolated from the lung of SARS-CoV-2 infected wild-type mice, without evidence of inflammation in the lung histology. Recently, Yan et al. [29] , Zhang et al. [30] and Wan et al. [31] stated that ACE2 is involved in the pathogenesis of SARS-CoV-2. To find out more about the genes that influence SARS-CoV-2 infection, some projects are underway [32, 33] .

Pulmonary involvement: angiotensin-converting enzyme 2 (ACE2) is the host receptor through which SARS-CoV-2 enters cells ( Figure 1 ) [34] . In normal lung tissue, ACE2 is mainly expressed by type I and type II alveolar epithelial cells. It was reported that 83% of type II alveolar cells expressed ACE2. Therefore, COVID-19 infection causes damages to most type II alveolar cells. After alveolar cell injury, transforming growth factor-β (TGF-β) is released in the tissue to promote lung repair. Virus infection often leads to excessive activation of the TGF-β pathway, which leads to the occurrence of pulmonary fibrosis [35, 36] . In the early phases of the lung pathology of COVID-19, Tian et al. described findings of edema, proteinaceous exudate, focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration and multinucleated giant cells in a pathologic examination of infected lungs [37] . Even though the COVID-19 meets the acute respiratory distress syndrome (ARDS) Berlin definition [38] , it is a disease with distinctive phenotypes and can even be part of the ARDS mimics described by Aublanc et al. [39] . Its main characteristic is the dissociation between the severity of the hypoxemia and the maintenance of relatively good respiratory mechanics [40] . To conceptualize this phenomenon, Gattinoni L et al. [41] hypothesized a sequence of events: SARS-CoV-2 infection causes a modest local subpleural interstitial edema located between lung structures with different elastic properties [42] . The normal response is to increase minute ventilation, by increasing the tidal volume [43] , which is associated with a more negative intrathoracic inspiratory pressure. However, the near-normal compliance explains why some of the patients present without dyspnea as the patient inhales the volume he expects.

Two peculiar phenotypes can be distinguished: type L, characterized by Low elastance (i.e. high compliance), low ventilation to perfusion ratio, low lung weight and low recruitability. These patients may remain unchanging for a period and then improve or worsen. The possible feature that can determine the evolution of the disease, other than severity, is the depth of the negative intrathoracic pressure associated with the increased tidal volume in spontaneous breathing. The increased lung permeability due to inflammation, associated with this negative intrathoracic pressure, causes interstitial lung edema. As the edema increases, the lung weight increases, until eventually the gas volume in the lung decreases and the tidal volumes decrease. This phenomenon leads to a transition from type L, to type H, which is characterized by high elastance, high right-to-left shunt, high lung weight and high recruitability. These patients likely develop self-inflicted ventilator-induced lung injury [40, 41] . These different COVID-19 patterns depend on the interaction between three factors [41] : 1) the severity of the infection, the host response, and comorbidities; 2) the ventilatory response to hypoxemia and 3) the time between the beginning of the disease and the hospitalization.

Hematological disorders: besides, in the early phases of infection, ACE-2 consumption by viral entry is predicted to increase local angiotensin II concentration. Among the known effects of angiotensin II are vasoconstriction, endothelial activation, and pro-inflammatory cytokine release [44] . Consequently, viral injury, disordered cytokine release and platelet activation by angiotensin II induce localized microvascular inflammation, which triggers endothelial activation, leading to vasodilation and prothrombotic conditions. The procoagulant state has also long been recognized as part of ARDS pathophysiology, demonstrated by the identification of diffuse pulmonary endothelial injury associated with platelets' activation, macroand micro-thrombi thought to be either embolic, formed in situ, or both [45] . Moreover, activated platelets, neutrophils, endothelial cells, neutrophil extracellular traps, microparticles, and coagulation proteases in ARDS have been associated with the process of deep vein thrombosis formation [46] . This explains the high prevalence of acute pulmonary embolism recently reported in COVID-19 patients admitted for hypoxemic acute respiratory failure [47] . Accumulating evidence suggests that SARS-CoV-2 might induce a cytokine storm ( Figure 2 ) [48] . Patients with severe pneumonia or ARDS develop systemic manifestations of hyper inflammation called secondary hemophagocytic lymphocytosis (sHLH), also called macrophage activation syndrome (MAS) [49] . This hyperinflammation is characterized by an increased release of cytokines, particularly interleukin (IL)-6, IL-1 by binding to ACE-2 in the lung tissue, IL-6, interferon-γ and tumor necrosis factor-α [50] . This exaggerated response is responsible for significant tissue damage that could lead to multiorgan failure. Multiple studies comparing severe and moderate forms of COVID-19 concluded that the cytokine storm is associated with the severity of the disease [51, 52] .

Many studies reported thrombocytopenia in patients with COVID-19, but its mechanism is still unclear. Xu et al. [53] described the hematological changes of thrombocytopenia in patients with COVID-19 and proposed three possible mechanisms (Figure 3 ) [53] by which SARS-CoV-2 can induce thrombocytopenia: a) SARS-CoV-2 can reduce platelet production by direct infection of bone marrow cells and therefore inhibit platelet synthesis. The virus can also do so through the cytokine storm that destroys bone marrow progenitor cells; b) COVID-19 infection can increase autoantibodies and immune complexes resulting in the specific destruction of platelets by the immune system; c) and damages of the lung tissues and pulmonary endothelial cells by the SARS-CoV-2 infection activate platelets in the lungs, resulting in aggregation and formation of microthrombi, which leads to an increase in platelet consumption.

Cardiovascular involvement: the cardiovascular (CV) system can be involved in different ways. The common mechanisms responsible for cardiovascular complications in COVID-19 are: a) direct myocardial injury [54] : SARS-CoV-2 enters human cells by binding to angiotensin-converting enzyme 2 (ACE2), a membrane-bound aminopeptidase that is highly expressed in the heart and lungs. ACE2 plays an important role in the neurohumoral regulation of the CV system under normal health conditions as well as in various diseases. Binding between the SARS-CoV-2 and ACE2 can lead to alterations in ACE2 signaling pathways, leading to acute damage to the myocardium and lungs; b) systemic inflammation [54] : the most severe forms of COVID-19 are characterized by an acute systemic inflammatory response and cytokine storm, which can lead to multi-organ injury, leading to organ failure. Studies have shown elevated circular levels of pro-inflammatory cytokines in patients with critical COVID-19; c) altered myocardial supplydemand relationship [55] : the increased metabolic demand associated with systemic infection coupled with hypoxia caused by the acute respiratory disease may alter the relationship between myocardial oxygen supply and demand and result in acute myocardial injury; d) plaque rupture and coronary thrombosis [56] : systemic inflammation and increased shear stress due to increased coronary blood flow may precipitate plaque rupture and result in acute myocardial infarction. The prothrombotic appearance created by systemic inflammation further increases the risk; e) adverse effects of various therapies [57] : various antiviral drugs, corticosteroids, and other therapies to treat the COVID-19 channel also have deleterious effects on the CV system. Electrolyte imbalances -electrolyte imbalances can occur in any critical systemic disease and precipitate arrhythmias, particularly in hospitalized patients with underlying heart disease. Of particular concern is the hypokalemia of COVID-19 due to the interaction of SARS-CoV-2 with the reninangiotensin-aldosterone system, which increases susceptibility to various cardiac arrhythmias.

Role of underlying CV co-morbidities patients with the pre-existing cardiovascular disease appear to have an increased susceptibility to the development of COVID-19 and tend to have more severe disease with poorer clinical outcomes. Although the prevalence of diabetes and hypertension in this cohort is the same as in the general Chinese population, the prevalence of the cardiovascular disease is significantly higher. More importantly, the presence of diabetes, CVD and hypertension were associated with a two-fold, three-fold and two-fold increased risk of serious illness or requiring admission to an intensive care unit (ICU), suggesting a prognostic impact of these co-morbidities [57] .

is an independent mortality factor, in SARS-CoV-2 infection, with an OR of 4.057 (95% CI 1.46-11.27; p<0.001) [58] . SARS-CoV-2-related AKI is a serious complication in 0.5 to 29% of hospitalized patients, particularly in the ICU setting [59] [60] [61] [62] , due to various etiology such as hemodynamic and cardiac disorders, invasive mechanical ventilation with impaired gas exchange, and occurrence of nosocomial sepsis; in addition to inflammatory substances release, microcirculatory alteration, and tubular injury [63] . Other factors are risks for AKI in acute respiratory distress syndrome (ARDS) including age, the severity of the illness, diabetes, obesity, and the history of heart failure [64]. Furthermore, the abundance, in the kidney tubular cells, of ACE2 as receptor facilitates the entry into target cells [26, 27] ; this infection participates in the worsening of the local inflammation, thus the incidence and the duration of AKI episodes [65] . In a postmortem renal histopathological analysis, Su et al. noted the invasion of SARS-CoV-2 into kidney parenchyma with diffuse proximal tubule injury, non-isometric vacuolar degeneration and even frank necrosis was observed, prominent erythrocyte aggregates obstructing the lumen of capillaries without platelet or fibrinoid material, without vasculitis, interstitial inflammation or hemorrhage, by light microscopy. The electron microscopic study described clusters of coronavirus in the tubular epithelium and podocytes. Additionally, ACE2 receptors were upregulated, and immunostaining with SARS-CoV-2 nucleoprotein antibody was positive in tubules [66] . Summarily, three mechanisms are involved in the SARS-CoV-2 associated AKI: cytokine damage, lung, and heart interactions and systemic effects [67] without forgetting direct lesions of the virus.

in the immunocompetent host, viral brain infections are rare, in general. But, neurotropic viruses can infect the central nervous system (CNS) (encephalitis, meningitis, myelitis, strokes) in the presence of temporary immunosuppression. The peripheral nervous system can be also affected (neuropathy, Guillain-Barré syndrome) [68] . The neurological complications during epidemic SARS-CoV-2 were not well studied. However, some case reports were presented with axonal peripheral neuropathy, myopathy with elevated creatinine kinase, or stroke [69] [70] [71] . For COVID-19, neurologic presentations were 36.4% of cases, more declared in severe patients (45.5% vs. 30.2% in non-severe patients). They can be subdivided into three groups: central nervous system manifestations (dizziness, headache, coma, acute cerebrovascular disease (intracerebral hemorrhage, hemorrhagic necrotizing encephalopathy, ischemic stroke), ataxia, acute myelitis, and seizure), peripheral nervous system manifestations (taste impairment, smell impairment, vision impairment, cranial neuropathies, Guillain-Barré Syndrome, and nerve pain) and skeletal muscle injury manifestations [72] [73] [74] [75] [76] [77] [78] .

It is known that SARS-CoV-2 can induce neurological disease [79] . Effectively, Xu et al. mentioned the evident presence of SARS-CoV-2 in the brain of infected patients from the culture of the brain suspension [80] . Moreover, ACE2 receptors exist in the brainstem and the regions responsible for the regulation of cardiovascular function and were found in both neurons and glia [81, 82] . Additionally, Yu et al. showed that SARS-CoV-2 belongs to the beta-coronavirus subgroup including MERS-CoV and SARS-CoV and has a high homological sequence with SARS-CoV-2 in the genomic analysis [83] . Given that, SARS-CoV-2 could have a potential neuroinvasion [84] .

Regarding the route of invasion, first, the hematological and the lymphatic appear to be implausible because of the absence of virus particles in the non-neuronal cells in the infected brain areas [80, 85, 86] . Second, the synapseconnected route is more pointed out as possible via peripheral nerve terminals [87] [88] [89] [90] . Third, since the last route has been described in other CoVs and avian bronchitis virus [87, [89] [90] [91] [92] , there are case reports about smell or taste disturbances in the early stage of the disease [72] . Fourth, systemic inflammatory storm damaged the bloodbrain-barrier and therefore sustained neuroinflammation [93] .

Hepatic damage: Huang et al. [35] announced that 62% of critically ill patients had elevated aspartate aminotransferase (AST). Moreover, in a cohort of 1099 patients, Guan et al. observed that severe patients had more abnormal aminotransferase levels compared to non-severe [59] . In patients with COVID-19, the virus can directly affect the liver because about 2-10% of patients with COVID-19 develop diarrhea with SARS-CoV-2 RNA in stool and blood [94] . Liver disease is likely to be multifactorial and requires close biological monitoring to anticipate any progression. First, given that ACE2 receptors are expressed in cholangiocytes, SARS-CoV-2 may fix directly to cholangiocytes [95] and causes abnormal liver tests. Second, immune-mediated inflammation such as cytokine storm and hypoxia may also contribute to liver damage in critically ill patients with COVID-19. Third, there is a possible role of hepatotoxic drugs, especially lopinavir and ritonavir. Fourth, ventilation of severe recruitable ARDS with high levels of positive expiratory pressure may contribute to hepatic congestion [96] . Finally, in the histological examination, Cai et al. showed vesicular steatosis and degeneration of hepatocytes in the interlobular region and the hepatic sinuses and inflammatory cells in the hepatic sinuses [97] . However, no viral inclusions have been detected [98] .

COVID-19 is a "great imitator". It primarily infects the lung and may invade the cardiovascular system, central and peripheral nervous systems, kidneys, and liver. Thus, the management is multidisciplinary including ventilator and hemodynamic supports, pharmacologic treatment, and specific technics such as plasma exchange, stem cells convalescent plasma.

• SARS-CoV-2 is an emerging infection;

• SARS-CoV-2 affects essentially the pulmonary tract;

• Other organs might be impaired.

• SARS-CoV-2 could cause multiorgan impairment; • The initial presentation is sometimes unusual; • The multiorgan involvement requires multidisciplinary management.

The authors declare no competing interests.

AH, HR and HE participated in the conceptualization of the study, sourced the materials, drafted the manuscript, read and approved the final version of the manuscript. 

A crucial role of angiotensin-converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus

COVID-19: several imagine teams mobilize. Institut Imagine

Rheumatologists' perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer

Acute respiratory distress syndrome: the Berlin Definition

Acute respiratory distress syndrome mimics: the role of lung biopsy

COVID-19 pneumonia: ARDS or not

COVID-19 pneumonia: different respiratory treatments for different phenotypes

Lung recruitment in patients with the acute respiratory distress syndrome

Lung inhomogeneity in patients with acute respiratory distress syndrome

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China

COVID-19: consider cytokine storm syndromes and immunosuppression

Haemophagocytic lymphohistiocytosis in COVID-19 cases?

Clinical and immunological features of severe and moderate coronavirus disease 2019

Cytokine release syndrome in severe COVID-19

Mechanism of thrombocytopenia in COVID-19 patients

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med

Analysis of myocardial in-jury in patients with COVID-19 and association between concomitant cardiovascular diseases and severity of COVID-19

Influenza infection and risk of acute myocardial infarction in England and Wales: a caliber self-controlled case series study

Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19)

Acute renal impairment in coronavirus-associated severe acute respiratory syndrome

Clinical characteristics of coronavirus disease 2019 in China

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Presenting characteristics, comorbidities and outcomes among 5700 patients hospitalized with COVID-19 in the NewYork City area

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centred, retrospective, observational study

Lung-kidney interactions in critically ill patients: consensus report of the Acute Disease Quality Initiative (ADQI) 21 Workgroup

Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B beta coronaviruses

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China

Kidney involvement in COVID-19 and rationale for extracorporeal therapies

Virusinduced neuronal dysfunction and degeneration

Neuromuscular disorders in severe acute respiratory syndrome

The clinical pathology of severe acute respiratory syndrome (SARS): a report from China

Olfactory neuropathy in severe acute respiratory syndrome: report of a case

Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China

Acute myelitis after SARS-CoV-2 infection: a case report

COVID-19 presenting with ophthalmoparesis from cranial nerve palsy

COVID-19-associated acute hemorrhagic necrotizing encephalopathy: imaging features

Guillain-Barré syndrome associated with SARS-CoV-2

Neurologic features in severe SARS-CoV-2 infection

Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV-2) pulmonary infection of mice

Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis

Angiotensin II regulation of angiotensin-converting enzymes in spontaneously hypertensive rat primary astrocyte cultures

Measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in Wuhan

The neuroinvasive potential of SARS-CoV-2 may play a role in the respiratory failure of COVID-19 patients

Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV-2) in SARS patients: implications for pathogenesis and virus transmission pathways

Multiple organ infection and the pathogenesis of SARS

Coronavirus infection of rat dorsal root ganglia: ultrastructural characterization of viral replication, transfer and the early response of satellite cells

Immunofluorescence studies on the pathogenesis of hemagglutinating encephalomyelitis virus infection in pigs after oronasal inoculation

The vagus nerve is one route of transneuronal invasion for intranasally inoculated influenza a virus in mice

Characteristics of a coronavirus (strain 67N) of pigs

Morphogenesis of avian infectious bronchitis virus in primary chick kidney cells

Systemic inflammation and the brain: novel roles of genetic, molecular and environmental cues as drivers of neurodegeneration. Front Cell Neurosci

Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection

Liver injury in COVID-19: management and challenges

COVID-19: abnormal liver function tests

Pathological findings of COVID-19 associated with acute respiratory distress syndrome