**1. 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 *CO*rona*VI*rus *D*isease 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

#### **Figure 1.**

*Global epidemiology of COVID-19. (a) Confirmed cases of coronavirus and (b) deaths from coronavirus. (source WHO live situation dashboard www.covid19.who.int).*

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*Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement…*

China by 31st January 2020 reached as staggering 32,642. 75% of these were in Hubei province. The incidence of the disease in mainland China had escalated to over 74,000 cases by 19th February 2020 along with 65 cases and 5 deaths in Hong

From mid to late January countries other than China began reporting COVID-19 cases. The first non-mainland case was a Chinese national from Wuhan who travelled to Thailand and tested positive for COVID-19 on the 13th January 2020. The first reported case outside of Asia was announced on the 21st January 2020 in the United States of America (USA). At the end of February, the WHO declared the epidemic as a 'Public Health Emergency of International Concern' with evidence of infected cases in South Korea (2,337), Japan (210), Italy (650), Iran (245), Singapore (96) and USA (59). The cases in Japan are of note as they are associated with a contained infection on the Diamond Princess cruise ship. The ship departed Japan on 20th January 2020. Five days later a passenger developed a fever and tested positive on 1st February 2020 in Hong Kong. The ship returned to Japan and was placed in quarantine. By 12th February 492 passengers were tested of which 174 were positive for COVID-19. By 19th February 2020, the number of passengers infected rose to 621 and 705 nine days later. On 11th March 2020, at the daily briefing by the director general, Dr. Tedros Adhanom Ghebreyesus, the WHO declared COVID-19 as an

It is now a year since the initial outbreak in China. In this short time the WHO report via their live situation dashboard [2] to date (5th January 2021) 84,233,579 confirmed cases globally of which 1,843,293 individuals have died (**Figure 1**). What is shocking and apparent is the upward escalation of these figures on a daily basis,

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

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

especially in the winter months in the Northern Hemisphere.

they do not increase the severity of COVID-19 infection [4].

and is likely to respond to the current vaccination programme [5].

Kong, 10 confirmed cases in Macao and 24 cases and one death in Taiwan.

*DOI: http://dx.doi.org/10.5772/intechopen.98210*

offically recognised pandemic [1].

**2. Novel SARS-CoV-2 variants**

*Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement… DOI: http://dx.doi.org/10.5772/intechopen.98210*

China by 31st January 2020 reached as staggering 32,642. 75% of these were in Hubei province. The incidence of the disease in mainland China had escalated to over 74,000 cases by 19th February 2020 along with 65 cases and 5 deaths in Hong Kong, 10 confirmed cases in Macao and 24 cases and one death in Taiwan.

From mid to late January countries other than China began reporting COVID-19 cases. The first non-mainland case was a Chinese national from Wuhan who travelled to Thailand and tested positive for COVID-19 on the 13th January 2020. The first reported case outside of Asia was announced on the 21st January 2020 in the United States of America (USA). At the end of February, the WHO declared the epidemic as a 'Public Health Emergency of International Concern' with evidence of infected cases in South Korea (2,337), Japan (210), Italy (650), Iran (245), Singapore (96) and USA (59). The cases in Japan are of note as they are associated with a contained infection on the Diamond Princess cruise ship. The ship departed Japan on 20th January 2020. Five days later a passenger developed a fever and tested positive on 1st February 2020 in Hong Kong. The ship returned to Japan and was placed in quarantine. By 12th February 492 passengers were tested of which 174 were positive for COVID-19. By 19th February 2020, the number of passengers infected rose to 621 and 705 nine days later. On 11th March 2020, at the daily briefing by the director general, Dr. Tedros Adhanom Ghebreyesus, the WHO declared COVID-19 as an offically recognised pandemic [1].

It is now a year since the initial outbreak in China. In this short time the WHO report via their live situation dashboard [2] to date (5th January 2021) 84,233,579 confirmed cases globally of which 1,843,293 individuals have died (**Figure 1**). What is shocking and apparent is the upward escalation of these figures on a daily basis, especially in the winter months in the Northern Hemisphere.

#### **2. 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].

*Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions*

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 *CO*rona*VI*rus *D*isease 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.

*Global epidemiology of COVID-19. (a) Confirmed cases of coronavirus and (b) deaths from coronavirus.* 

*(source WHO live situation dashboard www.covid19.who.int).*

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

**126**

**Figure 1.**

*Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions*

**Figure 2.**

*Distribution of confirmed sequenced cases of VOC202012/01 as of 6th January 2021. [source: https://beta. microreact.org/project/vVnFfZG7o3qYUJ6bnDs3Jo-cog-uk-2020-12-20-sars-cov-2-in-the-uk].*

## **3. Coronaviruses**

#### **3.1 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].

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**Figure 3.**

**Figure 4.**

**3.2 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

*(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].*

*Phylogenic tree of alpha and beta coronaviruses. MERS, Middle East respiratory syndrome; SARS, severe acute* 

*respiratory syndrome; SARS-COV-2, severe acute respiratory syndrome coronavirus 2.*

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

*Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement…*

*DOI: http://dx.doi.org/10.5772/intechopen.98210*

*Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement… DOI: http://dx.doi.org/10.5772/intechopen.98210*

#### **Figure 3.**

*Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions*

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

*Distribution of confirmed sequenced cases of VOC202012/01 as of 6th January 2021. [source: https://beta.*

*microreact.org/project/vVnFfZG7o3qYUJ6bnDs3Jo-cog-uk-2020-12-20-sars-cov-2-in-the-uk].*

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

developing associated with novel coronaviruses in humans.

**128**

diameter luminal space [7].

**3. Coronaviruses**

**Figure 2.**

**3.1 Taxonomy and morphology**

*Phylogenic tree of alpha and beta coronaviruses. MERS, Middle East respiratory syndrome; SARS, severe acute respiratory syndrome; SARS-COV-2, severe acute respiratory syndrome coronavirus 2.*

#### **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].*

#### **3.2 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].

#### **3.3 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

#### **Figure 5.**

*Viral entry of SARS-CoV-2 in host cells via the ACE2 surface protein. Following entry ACE2 is downregulated resulting in upregulation of angiotensin II (Ang II) which via its AT1R receptor induces NF-kB signalling pathways to increase expression of inflammatory cytokines such as interleukins (IL-1, IL1*β*, IL-6), matrixmtalloproteinases (MMP-1, MMP-3) and tumour necrosis factor alpha (TNF-*α*). [source: Banu et al. [14]].*

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**Figure 6.**

*Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement…*

persons 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

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.

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).

*Respiratory and systemic signs and symptoms associated with COVID-19 [source: Rothan and Byareddy [26]].*

*DOI: http://dx.doi.org/10.5772/intechopen.98210*

**4. General clinical presentation of COVID-19**

cancer screening [20].

*Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement… DOI: http://dx.doi.org/10.5772/intechopen.98210*

persons 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.
