Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement of the Cardiovascular System

Since the emergence in China of coronavirus disease (COVID-19) in December 2019; the virus causing the pandemic has infected the human population in almost every country and territory on the globe. At the time of writing there are over 84 million confirmed cases of infection and over 1.8 million deaths globally. Rates of infection differ as does the number of severe cases and subsequent deaths between countries and continents. This is due in part to lockdown measures, social distancing and wearing of face coverings. It is also reflected by how healthcare systems record coronavirus deaths along with access to testing as well as tracking and tracing of infected individuals. Symptoms of COVID-19 include a novel persistent cough, fever and anosmia (loss of smell). In most cases, such symptoms are mild. A small proportion of those who become infected however, have a severe reaction to the disease affecting multiple organ systems and often require respiratory support in the intensive care setting. One such physiological system affected is the cardiovascular system. This is likely due to the increased number of ACE2 receptors in co-morbid cardiac pathologies. ACE2 receptors serve as the entry port for the coronavirus into human cells. Those individuals with underlying cardiovascular risk factors are therefore disproportionately at risk of COVID-19 infection. This chapter reviews the aetiology and epidemiology of the coronavirus infection; potential pathophysiological mechanisms of disease involving the cardiovascular system including the clinical utility of biomarkers, electrocardiography and echocardiography as well as autopsy cardiac pathology and histopathology.


Introduction
Coronavirus disease (COVID- 19) is an emerging viral disease affecting humans.In December 2019, a small series of cases of a pneumonia-like illness presented to a hospital in Wuhan, Hubei province in China.The patients displayed bilateral pulmonary infiltrative lesions on chest x-ray.The disease was initially named 'viral pneumonia of unknown cause' .Many of those presenting with similar symptoms had visited or been closely associated with a local wholesale seafood market which also sold exotic species such as civets, snakes, rats and bats.The Chinese Centre for Disease Control and Prevention (China CDC) identified the virus as a novel coronavirus (nCoV) on 7th January 2020 and renamed the disease 'pneumonia caused by a novel coronavirus.Subsequently on 30th January 2020, the World Health Organisation (WHO) referred to the disease as 2019-nCoV.The Coronaviridae study group of the International Committee on Taxonomy of Viruses (ICTV) officially named the virus Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) on 11th February 2020.The WHO also announced a name change to COronaVIrus Disease 2019 (COVID- 19).The change reflected the greater reporting of a wide range of clinical presentations and multiple organ system involvement in severe cases of the disease.At the same time, it became apparent the disease was spreading significantly in Hubei Province due to an increase in numbers of cases with no identifiable association to the seafood market, demonstrating community (person-to-person) transmission.
The rate of escalation of COVID-19 infection is alarming.This is detailed in the following statistics (provided by many resources online via China CDC, news outlets and social media coverage).A retrospective epidemiological analysis by China CDC indicated there were 104 symptomatic cases by 31st December 2019.All cases were contained in Hubei province.Between 1st and 10th January 2020, this had risen to 566 cases showing symptoms in Hubei, with a further 87 cases in 19 other provinces.On January 20th 2020, 5 cases were reported in Beijing and 2 in Shanghai.Further analysis demonstrates that the number of cases of COVID-19 present in

Novel SARS-CoV-2 variants
Late in 2020, two variants of the SARS-CoV-2 virus have been identified.The first was identified in September and sequenced in the United Kingdom [3].The 'UK Kent variant' as it is commonly known has spread rapidly both in the UK and internationally.Since 26th December 2020, cases of the new UK Kent Variant have also been reported in other EU/EEA countries (Belgium, Denmark, Finland, France, Germany, Iceland, Ireland, Italy, the Netherlands, Norway, Portugal, Spain and Sweden) and globally (Australia, Canada, Hong Kong SAR, India, Israel, Japan, Jordan, Lebanon, South Korea, Switzerland, Singapore).The second variant originated in South Africa and is due to the mutation E484K; known as 501.V2.This variant was first detected in October 2020 and is associated with over 300 cases as of 26th December 2020.Both variants are highly transmissible, but data suggest they do not increase the severity of COVID-19 infection [4].
The first variant was identified following a surge in positive cases in the County of Kent in South East England and has spread extensively into London and beyond (Figure 2).The variant was named as variant under investigation (VUI) followed by year, month and number; thus, the designation given was VUI-202012/01 which was changed to variant of concern (VOC-202012/01).The variant is defined by 23 novel mutations.13 of which are non-synonymous, 4 deletion and 6 synonymous.Of concern is nucleotide A23063T in the spike protein representing mutation N501Y.This mutation is located in the receptor-binding domain and is associated with increased binding affinity to ACE2; making viral entry into host cells easier than with the original strain, thus increasing transmissibility.Although more transmissible, recent data suggest this variant is less likely to cause severe infection and is likely to respond to the current vaccination programme [5].

Taxonomy and morphology
Coronaviruses are a large family of viruses found in animals such as camels, dogs, rats, cattle, mice, rats and bats; as well as several viruses known to infect humans.They were first discovered in 1968 and named Coronaviridae in 1975 by the ITCV.The viruses are positive-sense single stranded RNA viruses with 26 to 32 kb genomes and are classified into Alpha, Beta, Gamma and Delta genera (Figure 3).The viruses that infect mammals are Alpha and Betacoronaviruses.In humans, pathogenic coronaviruses include SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-HKU1, HCoV-229E, HCoV-NL63 HCoV-OC43.Most are inconspicuous and develop into common colds and mild-flu like symptoms, but recently since the emergence of SARS and MERS and now SARS-CoV-2, an increasing number of severe illnesses are developing associated with novel coronaviruses in humans.
Morphologically, the viral particle of coronaviruses are encased in a bilipid layer with three glycoproteins on the surface designated as membrane (M protein), envelope (E protein) and spike (S protein) proteins (Figure 4a).These give the virus the characteristic protrusions on the surface akin to a medieval European crown or 'corona' hence the name coronavirus.An electron micrograph of viral particles isolated in alveolar tissue from the first infected case in the United States is shown in Figure 4b.
Utilising cryptoelecton tomography (Cryo-ET), Yao and colleagues determined the detailed molecular structure of the novel SARS-CoV-2 enveloped virus and elucidated the mechanism of packing the ~30 kb long single RNA into the 80 nm diameter luminal space [7].

Cellular entry of SARS-CoV-2
The SARS-CoV-2 virus enters human cells via interaction of the spike protein with the Angiotensin Converting Enzyme 2 protein (ACE2) [8].ACE2 is integral to the renin-angiotensin-aldosterone (RAAS) system.Originally thought to have a systemic effect on maintenance of blood pressure and electrolyte balance, it has been found to be involved in inflammatory responses in many tissues including the cardiovascular system [9].Activation of the RASS system has been associated with the development of hypertension, myocardial infarction, chronic heart failure, diabetes and inflammatory processes in lung tissue [10].SARS-CoV-2 and ACE2 protein interaction is like the SARS-CoV virus responsible for the original SARS outbreak [11].
ACE2 is a metallopeptidase and is found in virtually all cell types.It is highly expressed on cell surfaces in lung alveolar epithelium, intestinal enterocytes as well  as on vascular endothelial cells [12].This is especially important in those individuals with underlying cardiovascular diseases as expression of ACE2 in the vasculature is altered [13].This will be detailed further in the chapter under cardiovascular involvement.Following internalisation via vesicle entry, the ACE2 surface proteins are downregulated, potentiating the increasing physiological effects of angiotensin II (Figure 5) via proinflammatory mediators [14].

Routes of transmission of SARS-CoV-2
The major route of transmission in the human population is from person-to-person via respiratory droplets when infected individuals cough, sneeze and talk when in close contact with another person [15].Susceptible individuals inhale droplets shed from an infected individual near one another.The risk of infection depends on the size of the particles and droplets, the extent of viral shedding from the infected individual, the force of expulsion of droplets from an infected individual, the proximity between infected and uninfected individuals as well as environmental factors such as air density, humidity and wind speed [16].Aerosol transmission is an alternative route of infectivity; however, this has been subject to significant debate and scientific study.
Aerosol transmission occurs when proteins and pathogens float in the form of aerosols after droplets dry out.This may be possible with SARS-CoV-2 in enclosed areas if individuals are exposed to high levels of infected aerosol material such as in care home settings and hospital wards; thus, pose a risk to healthcare workers and others in close contact with infected individuals over a long period of time.Aerosol transmission is often successful with particles with a diameter of 5-10 μm and can be carried over a large distance, whereas droplets are often larger than 10 μm and fall from the air within 1 metre hence the global adoption of spacing between individuals of 1-2 metres [17].
Oral-faecal transmission is another potential route of person-to-person transmission [18].SARS-CoV-2 has been detected in faecal material from known COVID-19 patients [15,19].This is unsurprising given the clinical gastrointestinal manifestations in some individuals.This poses as a rapid transmission route in
Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement… DOI: http://dx.doi.org/10.5772/intechopen.98210persons unable to maintain good hygiene such as neonates/infants, the infirm and the elderly with cognitive decline such as dementia.It is also a source of environmental viral transmission in developing countries with poor sanitation and no running clean water and soap for adequate hand washing.This has wider impact on those healthcare systems who provide screening of faecal material for colorectal cancer screening [20].
SARS-CoV-2 has not been detected in semen from individuals who have either recovered from or have active COVID-19 infections [21,22], suggesting sexual transmission is very unlikely.Maternal-fetal transmission however has been described in a small number of clinical cases.A neonate born in Wuhan to a COVID-19 positive woman tested positive for COVID-19 in a nasopharyngeal swab taken 2 days after birth, however this does not confirm maternal-fetal transmission.Oher studies refute vertical intrauterine transmission from mother to child [23,24] however a recent meta-analysis suggests vertical transmission is possible normally in the third trimester but the incidence is low at 2-3% [25].This is in part due to the ACE2 receptor portal of SARS-CoV-2 entry into cells being expressed in low concentrations at the maternal-fetal barrier, limiting the route of vertical transmission.

General clinical presentation of COVID-19
With the emergence of the pandemic in earnest at the beginning of 2020, the medical and scientific literature has been flooded with case reports and small clinical series often on a regional (district/country) basis.In general, the clinical presentation of patients with SARS-CoV-2 is very similar to that of other coronavirus infections in humans.For the majority of those infected, individuals are either asymptomatic or have a mild fever, novel dry cough or anosmia (loss of smell).In the small minority of those who are severely affected, the overriding clinical presentation is of respiratory distress however other symptoms are case-dependent.
The reported clinical characteristics and prognosis of COVID-19 patients varies greatly (Figure 6).A recent comprehensive meta-analysis has been performed of clinical characteristics, risk factors and outcomes by Li and colleagues [27].This vast analysis includes 212 studies from 11 countries involving 281,461 laboratory confirmed COVID-19 cases.The mean age of patients was 46.7y (95%CI 42.8y to 50.6y) with 51.9 (95%CI 50.4 to 53.2) males.The mean time of illness onset to hospital admission was 5.5 days (95%CI 4.6 to 6.4 days) with an incubation period of 5.3 days (95%CI 4.5 to 5.9 days).Clinical presentation characteristics and outcome are summarised in Table 1.79% of subjects were febrile and 53% developed a cough.Renal and hepatic injury occurred in 4% and 7% respectively but cardiac injury was higher at 9%.Overall mortality was reported to be 6% but this differed greatly by country.Mortality was significantly associated with age, male sex, the presence of hypertension or diabetes mellitus [27].faster alternative.CXR lacks sensitivity for diagnosis in the early presentation of COVID-19 being 55% within two days, increasing to 79% at 11 days from onset of symptoms.Specificity decreased over time from 83-70% at ≤2d and > 11d respectively [28].In approximately 60% of cases, CXR reveals interstitial and airspace opacities in an IA pattern.This increased over time from 51% at ≤2d vs. 73% at >11d [28].Normal and mild severity CXR findings were the largest factor behind false-negative CXR and often associated with young age and some ethnic groups.In a real-world reader performance study by Cozzi and colleagues [29], experienced radiologist (>10 y experience) reported CXR with higher specificity than less experienced (<10 y experience) radiologists.Comparative CXR images from different respiratory diseases and a normal CXR are shown in Figure 7.

Chest imaging
Computed tomography (CT) is the preferred radiological procedure for diagnosis.A Cochrane review of CT for diagnosis of COVID-19 found that in 84 studies with 8,279 participants; the pooled sensitivity for diagnosis was 86% (95%CI 90-95%) with a very low specificity of 18% (95%CI 4-56%) [31].A retrospective study of chest CT findings in 121 symptomatic patients in 4 centres in China has been reported [32].The classical findings were bilateral and peripheral ground-glass consolidative opacity.56% of subjects had normal CT images in the early phase (0 to 2 days) of the disease but more frequent in longer infections with consolidation, bilateral and peripheral and greater total lung involvement.Bilateral involvement occurred in 28%, 76% and 88% of early (0-2 days), intermediate (3-5 days) and late (6-12 days) infection times respectively.Further notable CT findings include linear opacity, crazy-paving patterns and reverse halo sign (Figure 8).
Following isolation and treatment, most COVID-19 patients stabilise and become well.Further CT imaging demonstrates regression of infection with absorbed lesions, and some cord-like shadows.

Gastrointestinal symptoms in COVID-19
Gastrointestinal (GI) symptoms are emerging in patients with COVID-19.This is due to the presence of the ACE2 receptor expressed in the GI tract [33,34].

Representative characteristic findings of COVID-19 infection on thoracic CT imaging: (a) axial CT image obtained without intravenous contrast. 36y male showing bilateral ground-glass opacities in upper lobes with rounded morphologies (arrows); (b) axial CT image. 65 y female, showing bilateral ground-glass and consolidative opacities with striking peripheral distribution (arrows); (c) axial CT image obtained without intravenous contrast material in a 43 y female, demonstrating crazy-paving pattern manifested by right lower lobe ground-glass opacification with interlobular septal thickening (arrows) with intralobular lines. (d) Axial CT image obtained in a 22y female, showing an area of faint ground-glass opacification in left upper lobe with a ring of denser consolidation or reverse halo sign (arrow). [source: Images modified from Bernheim et al. [32]].
Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement… DOI: http://dx.doi.org/10.5772/intechopen.98210

Cardiovascular findings in COVID-19
In addition to respiratory and gastrointestinal symptoms, cardiovascular involvement is also common amongst patients with COVID-19.The symptoms are wide-ranging in manifestation and severity and are more common in the elderly and those hospitalised with the infection.Previous influenza epidemics have been associated with an increased prevalence of myocardial infarction, myocarditis and chronic/congestive heart failure [37].Both SARS and MERS were associated with either bradycardia, tachycardia, cardiomegaly, diastolic impairments, cardiac arrest, cardiomegaly and acute cardiac failure [38][39][40].
Patients with cardiovascular risk factors or established cardiovascular disease disproportionately suffer with severe forms of the infection with worse clinical prognosis and outcome.In one of the earliest reports of clinical characteristics of COVID-19 from Wuhan China; 14% of 138 patients demonstrated baseline cardiovascular disease and 31% had hypertension [41].Similar data has been reported in other population studies from Wuhan, China [42][43][44]; Italy [45,46]; Iran [47], United Kingdom [48] and the USA [49] to varying cardiac involvement.
The pathophysiological mechanism of cardiac injury in COVID-19 infection are similar to those associated with other influenza pandemics and human coronavirus diseases (SARS and MERS).Although the pathophysiological mechanisms injury is not fully established in COVID-19 patients, it is likely that the elevation is related to  Haematological differentials along with abnormal clotting factors and elevated D-dimer result in haemostasis and thrombosis as evident of coronary microvascular disease.(3) Endothelial injury causing diffuse disruption to the vasculature in several organs including the heart.( 4) Down regulation of ACE2 expression in cardiomyocytes and loss of the protective signalling pathway (5) Inflammatory and stress response causing plaque rupture in those subjects with active coronary artery disease (Figure 9).
The evidence of cardiac injury in COVID-19 is wide ranging and its association with mortality differs between studies.Li and collages performed a metaanalysis of 28 studies involving 4,189 individuals with COVID-19.Elevated cardiac biomarkers (cTn, creatine kinase-MB, myoglobin and NTproBNP were associated with the severe forms of infection compared to subjects with mild forms of the disease (Figure 10).In addition, those with evidence of COVID-19 Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement… DOI: http://dx.doi.org/10.5772/intechopen.98210related cardiac injury was more likely to die than those without (summary risk ratio 3.85 (95%CI 2.13 to 6.96, p = <0.001)[53].
With the emergence of cTn elevation in severe COVID-19 disease, attention turned to its prognostic value.A study of 416 COVID-19 patients by Shi and colleagues found elevated cTnI in 1 in 5 presenting patients, and positive cTn patients were more likely to require non-invasive ventilation and develop acute respiratory distress syndrome or acute kidney injury.In addition, the mortality rate was 10-fold higher in those patients with evidence of myocardial injury [43].This is consistent with other studies.
Guo and colleagues reported 28% myocardial injury demonstrated by an elevated cTnT in 187 COVID-19 patients; with an in-hospital mortality of 60% and a higher incidence of mortality (69%) in those cTnT positive patients with underlying cardiovascular disease compared to 38% mortality in those without a cardiac history [55].Giustino and colleagues investigated 305 COVID-19 patients in 7 hospitals in New York City, USA and Milan, Italy.Patients exhibiting myocardial injury has elevated inflammatory markers, electrocardiographic abnormalities as well as transthoracic echocardiographic (TTE) evidence of left ventricular wall motion abnormalities, global left ventricular dysfunction, grade II or III left ventricular diastolic dysfunction, right ventricular dysfunction and pericardial effusion.In-hospital mortality was 32% in patients with myocardial damage and TT abnormalities, 19% with cTn positive myocardial injury only and 5% in those without evidence of cardiac involvement [56].
Lala and colleagues investigated the degree of myocardial injury in laboratoryconfirmed cases of COVID-19 and correlated findings with outcome [57].36% of 2,736 patients had an elevated cTnI (>0.03 ng/mL).

Electrocardiographic and echocardiographic changes in COVID-19
The cardiac involvement in COVID-19 is diverse and as such varying different findings have been observed with diagnostic tools such as the electrocardiogram (ECG) and echocardiography.ECG changes in COVID-19 represent both left and right-sided heart disease [65] and are associated with a higher risk of mortality.In a study of 756 patients, 90 (12%) of which died (Table 2); one or more atrial premature contractions right bundle or intraventricular block, ischemic T-wave inversion and nonspecific repolarisation were associated with death [65].These finding were  further supported by De Vita and colleagues [66] who observed the ECG on admission was a helpful tool to identify COVID-19 patients with increased risk of death.
In a retrospective analysis of 319 severe and critically severe COVID-19 cases, Wang and colleagues observed 118 (37%) with normal ECG and 201 (63%) abnormal ECG traces.Differences were observed in ST-T changes, sinus tachycardia, atrial fibrillation, and atrial tachycardia between the group severity.Sinus tachycardia and atrial fibrillation were the independent risk factors of in-hospital death and ventilator use and could be used as an independent predictor of poor outcome [67].
A caveat to ECG induced changes is due to drug therapies given in severe COVID-19 infections.Drug-induced changes associated with chloroquine, hydroxychloroquine and azithromycin can result in a prolonged corrected QT (QTc), however such elongations do not induce arrhythmia-related death [68].
Echocardiographic findings demonstrate Left and right ventricular abnormalities in 39% and 33% of COVID-19 patients respectively [69].severe ventricular dysfunction or tamponade is observed in approximately 15% of patients.In those without pre-existing cardiac disease the echocardiogram is abnormal in roughly half of COVID-19 patients with approximately 15% demonstrating severe disease.In a study of 90 hospitalised patients with severe (44, 49%) and non-severe (46, 51%) COVID-19; right ventricular (RV) and left ventricular (LV) functions were compared [70].The RV and LV diameters were larger in severe patients compared to non-severe.Left ventricular ejection fraction (LVEF) were significantly (p = <0.001)lower (54.0%±9.8%) in the severe-infections compared to the nonsevere (61.9 ± 4.8%).Furthermore, pericardial effusions were observed in 23% of the severe patients with no observed cases in the non-severe patients.
In a study of 749 known COVID-19 positive patients undergoing transthoracic echocardiography (TTE), 38% were found to have LVEF ≤50% and 14% had moderately reduced right ventricular function.Stress-induced cardiomyopathy as evident by wall motion abnormalities were observed in four patients.A significant inverse relationship between cTnT and LVEF was observed (P = −0.34,P = 0.006).On the basis of the clinical TTE findings, therapeutic management was altered in 24% due to concern for a major cardiac even and in 14% where haemodynamic instability warranted TTE [71].
Both ECG and echocardiography are useful tools in the identification of left and right-sided cardiac dysfunction in COVID-19.Abnormalities are more frequent as infection severity increases and are often associated with poor prognosis.
In nine community deaths with suspected COVID-19 infections, Youd and colleagues did not observe any cases of myocarditis, however one case of bacterial bronchopneumonia had associated myocarditis.Contraction band necrosis was observed in a 86y Caucasian Male who had an underlying history of hypertension and cardiovascular disease.Cardiac amyloidosis was evident in one case [79].
An Italian study of 22 autopsies (18 with comorbid conditions, 4 without) demonstrated significant pulmonary and cardiovascular pathologies.All 22 deaths were reported as cardiorespiratory failure [76].Cardiovascular pathologies are reported in Table 3.
A systematic review of histopathological findings by physiological system have identified cardiovascular findings such as focal lymphocytic inflammation, acute cardiomyocyte necrosis, presence of inflammatory cells and apoptotic bodies [74].
A multicentre study of 21 autopsy examinations by Basso and colleagues [73] examined cardiac tissue.Lymphocytic myocarditis was present in 3 (14%) cases, two of which were CD4 predominant T-cells, and one CD8 prominent.86% of cases demonstrated interstitial macrophage infiltration.Mild pericarditis was evident in 4 cases.Common histological findings from cardiac tissue are presented in Figure 13.
Although the underlying mechanisms of cardiac involvement in COVID-19 infection remain to be fully elucidated, cardiac fibrosis occurs in tandem with local and systemic inflammatory responses [84].Whilst these mechanisms are designed to facilitate healing following tissue damage, an excess of the inflammatory response along with the development of fibrotic tissue are pathological drivers for global organ damage.Overt inflammation and fibrosis in the heart can result in abnormal cardiac remodelling potentiating the development of acute and chronic heart failure.Anti-inflammatory and anti-fibrotic therapies are in general unsuccessful in improving damaged cardiac tissue function.With respect to COVID-19,

Conclusion
The novel Coronavirus disease, COVID-19 that emerged just over one year ago has caused substantial disruption to everyday life for every human on the   [Source: Adapted from Basso et al., [73]].

Figure 4 .
Figure 4. (a) Schematic structure of a coronavirus particle [source: Peiris et al., [6]] (b) transmission electron microscopy image of an isolate from the first case of COVID-19 in the USA.The spherical extracellular viral particles contain cross-sections through the viral genome seen as black dots [source: cdc.gov].

Figure 8 .
Figure 8.Representative characteristic findings of COVID-19 infection on thoracic CT imaging: (a) axial CT image obtained without intravenous contrast.36y male showing bilateral ground-glass opacities in upper lobes with rounded morphologies (arrows); (b) axial CT image.65 y female, showing bilateral ground-glass and consolidative opacities with striking peripheral distribution (arrows); (c) axial CT image obtained without intravenous contrast material in a 43 y female, demonstrating crazy-paving pattern manifested by right lower lobe ground-glass opacification with interlobular septal thickening (arrows) with intralobular lines.(d) Axial CT image obtained in a 22y female, showing an area of faint ground-glass opacification in left upper lobe with a ring of denser consolidation or reverse halo sign (arrow).[source:Images modified from Bernheim et al.[32]].

Figure 10 .
Figure 10.Forest plot of cardiac biomarker standard mean difference between severe and less severe cases [source, Li et al.[53]].