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## Meet the editor

Prof. Dr. Öner Özdemir graduated from İstanbul Medical School, İstanbul University, Türkiye, and became a medical doctor in 1989. He completed his pediatric residency in the Department of Pediatrics, Children's Hospital, İstanbul Medical School, Türkiye. He completed his clinical fellowship training at the Pediatric Allergy/Immunology Division, Louisiana State University, Health Sciences Centre, USA. Some part of his clin-

ical fellowship training was done at the Pediatric Allergy/Immunology program, Cincinnati Children's Hospital Medical Center, USA. Dr. Özdemir was the firstplace winner of the 2005 Clemens Von Pirquet Award from the American College of Allergy, Asthma and Immunology (ACAAI) for the best research on allergy/ asthma/immunology by a fellow in training. Dr. Özdemir has more than 250 national and international publications, more than 400 national and international presentations, and more than 20 book chapters to his credit. Dr. Özdemir has also edited seven books.

### Contents



Preface

This book includes six chapters organized into four sections: "Introduction", "Ethio-

In Section 1, Chapter 1 discusses the importance of COVID-19 epidemiology in children. Knowing the factors that play a role in the epidemiology of this disease will help us to develop measures against them in possible future endemics and/or pandemic

In Section 2, Chapter 2 examines the role of angiotensin-converting enzyme 2 (ACE2) receptor expression in SARS-CoV-2 and its effects on COVID-19 epidemiology in children. The role and importance of ACE2 expression in the involvement of SARS-CoV-2 infection and COVID-19 disease has always been a point of discussion since the

In Section 3, Chapters 3–5 investigate the prevalence of COVID-19 in South Africa, Mexico, and Türkiye compared to other countries in the world, risk factors and changes in the care/treatment of the disease, and innovations and country-dependent approaches. The chapters give examples of pandemic prevention studies, treatment modalities, and vaccination studies developed according to the conditions of the

In Section 4, Chapter 6 discusses the link between 4-hydroxynonenal (HNE) and sleep and cognitive disturbances in children with COVID-19. Protein adducts of 4-hydroxynonenaline, a product of lipid peroxidation, have recently been investigated in studies of fatality in patients with COVID-19. Due to its relevance to the oxidant–antioxidant system, it can vary dynamically in the body in cases such as

I would like to thank Publishing Process Manager Karla Skuliber and the staff at IntechOpen for their assistance throughout the publication process. I would also like to thank my wife Seval Hülya Özdemir and my daughter Berrin Nikame Özdemir for

**Öner Özdemir, MD**

Department of Pediatrics,

Division of Allergy and Immunology,

 Sakarya University Medical Faculty, Research and Training Hospital, Adapazarı, Sakarya, Türkiye

Pathogenetic Factors", "Epidemiology," and "Clinico-Pathological Factors".

conditions.

beginning of the pandemic.

severe infection and chronic inflammation.

their support during the preparation of this book.

regions discussed.

## Preface

This book includes six chapters organized into four sections: "Introduction", "Ethio-Pathogenetic Factors", "Epidemiology," and "Clinico-Pathological Factors".

In Section 1, Chapter 1 discusses the importance of COVID-19 epidemiology in children. Knowing the factors that play a role in the epidemiology of this disease will help us to develop measures against them in possible future endemics and/or pandemic conditions.

In Section 2, Chapter 2 examines the role of angiotensin-converting enzyme 2 (ACE2) receptor expression in SARS-CoV-2 and its effects on COVID-19 epidemiology in children. The role and importance of ACE2 expression in the involvement of SARS-CoV-2 infection and COVID-19 disease has always been a point of discussion since the beginning of the pandemic.

In Section 3, Chapters 3–5 investigate the prevalence of COVID-19 in South Africa, Mexico, and Türkiye compared to other countries in the world, risk factors and changes in the care/treatment of the disease, and innovations and country-dependent approaches. The chapters give examples of pandemic prevention studies, treatment modalities, and vaccination studies developed according to the conditions of the regions discussed.

In Section 4, Chapter 6 discusses the link between 4-hydroxynonenal (HNE) and sleep and cognitive disturbances in children with COVID-19. Protein adducts of 4-hydroxynonenaline, a product of lipid peroxidation, have recently been investigated in studies of fatality in patients with COVID-19. Due to its relevance to the oxidant–antioxidant system, it can vary dynamically in the body in cases such as severe infection and chronic inflammation.

I would like to thank Publishing Process Manager Karla Skuliber and the staff at IntechOpen for their assistance throughout the publication process. I would also like to thank my wife Seval Hülya Özdemir and my daughter Berrin Nikame Özdemir for their support during the preparation of this book.

#### **Öner Özdemir, MD**

Division of Allergy and Immunology, Department of Pediatrics, Sakarya University Medical Faculty, Research and Training Hospital, Adapazarı, Sakarya, Türkiye

**1**

Section 1

Introduction

Section 1 Introduction

#### **Chapter 1**

## Introductory Chapter: The Importance of COVID-19 Epidemiology in Children

*Öner Özdemir*

#### **1. Introduction**

In this book, apart from the section on the pathogenesis of COVID-19 disease, the factors that play a role in the etiology of the disease in different countries will be evaluated.

#### **2. Discussion**

The role of the renin-angiotensin system (RAS) in the pathogenesis of COVID-19 has been known from the beginning. The disproportion between angiotensin II (Ang II) and angiotensin1–7 (Ang1,7) occurred by the interplay between SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) receptors is very important on the clinical table and prognosis. Other angiotensinases such as PRCP (prolyl carboxypeptidases) and POP (prolyl oligopeptidase) can lessen the deleterious effects of interplays between ACE2 and spike proteins of SARS-CoV-2. The deficiency of counter-regulatory RAS mechanisms in the acute phase of COVID-19 is presented by a decline in ACE2 expression due to unaffected activity of other angiotensinases and cannot prevent Ang II accumulation. Again, COVID-19 vaccines augment the endogenous synthesis of SARS-CoV-2 spike proteins. Therefore, unwanted effects of COVID-19 vaccination linked with Ang II buildup occur. Comprehension of the associations between the diverse mechanisms of Ang II degradation and buildup provides a chance to understand the pathophysiological cycle between the risk of development to severe types of COVID-19 disease and the possible unwanted effects of COVID-19 vaccination [1].

A zoonotic virus that causes severe respiratory diseases, three major outbreaks of the coronavirus including SARS-CoV, MERS-CoV, and most lately SARS-CoV-2, has been reported since 2002. Over the past few decades, the virus has been capable of mutating and changing, causing it to bypass the animal-to-human species barricade and infect humans. The appearance of SARS-CoV-2 created a serious global public health threat and caused major pandemic outbreaks. The latest pandemic of COVID-19, a disorder produced by SARS-CoV-2, in Wuhan, China's Hubei Province, has diseased more than 690 million people worldwide and caused fatality more than 6.8 million lives as of June 18, 2023. It has infected 213 other countries/regions worldwide. The virus constantly evolves and changes and spreads through asymptomatic carriers [2].

Epidemiologically, elderly individuals and people with predominant comorbidities are highly susceptible to grave health effects of COVID-19, comprising of cytokine upregulation and acute respiratory distress syndrome (ARDS) [3].

Multiple variants of the SARS-CoV-2 are known worldwide. This book discusses the overall picture of the pandemic in Latin America and several other countries, including its most common variants, how they affect surveillance at the genomic level, and the epidemiology of the disease. Again, the effect of COVID-19 vaccinations in Latin America and other countries on the epidemiology of the disease and how it can help alleviate the pandemic were also evaluated [4].

On March 5, 2020, South Africa registered its first imported patient of COVID-19. Since then, patients in South Africa have augmented exponentially with noteworthy communal spread. The situation in South Africa is also discussed in detail in our book [5].

A chapter in our book deals with the link of 4-hydroxynonenal (HNE) with sleep and cognitive disorders due to COVID-19 in children. As is known, protein adducts of the lipid peroxidation produce HNE was also found to be greater in the plasma of cases who died from the disease, while the total antioxidant capability was lower than the detection limit for most of the serum specimens. This suggests that the patients have active oxidative stress reaction mechanisms that respond to COVID-19 aggression. This may enable options to use antioxidants with a tailored, integrative biomedicine method to avert the initiation of a vicious cycle of HNE-mediated lipid peroxidation in cases with aggressive inflammatory disorders such as COVID-19 [6].

#### **3. Conclusion**

We hope that this book will help to understand the effects of lipid peroxidation elements such as HNE, which are little known, on the clinical picture, as well as their effects on the etiopathogenesis *via* the ACE-2 receptor, which is well known about COVID-19 disease.

#### **Author details**

Öner Özdemir

Division of Allergy and Immunology, Department of Pediatrics, Sakarya University Medical Faculty, Research and Training Hospital, Adapazarı, Sakarya, Türkiye

\*Address all correspondence to: ozdemir\_oner@hotmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Angeli F, Reboldi G, Trapasso M, Zappa M, Spanevello A, Verdecchia P. COVID-19, vaccines and deficiency of ACE2 and other angiotensinases. Closing the loop on the "Spike effect". European Journal of Internal Medicine. 2022;**103**:23-28. DOI: 10.1016/j. ejim.2022.06.015

[2] Sharma A, Ahmad Farouk I, Lal SK. COVID-19: A review on the novel coronavirus disease evolution, transmission, detection, control and prevention. Viruses. 2021;**13**(2):202. DOI: 10.3390/v13020202

[3] Muralidar S, Ambi SV, Sekaran S, Krishnan UM. The emergence of COVID-19 as a global pandemic: Understanding the epidemiology, immune response and potential therapeutic targets of SARS-CoV-2. Biochimie. 2020;**179**:85-100. DOI: 10.1016/j.biochi.2020.09.018

[4] García-López R, Laresgoiti-Servitje E, Lemus-Martin R, Sanchez-Flores A, Sanders-Velez C. The new SARS-CoV-2 variants and their epidemiological impact in Mexico. MBio. 2022;**13**(5):e0106021. DOI: 10.1128/mbio.01060-21

[5] Moonasar D, Pillay A, Leonard E, Naidoo R, Mngemane S, Ramkrishna W, et al. COVID-19: lessons and experiences from South Africa's first surge. BMJ Global Health. 2021;**6**(2):e004393. DOI: 10.1136/bmjgh-2020-004393

[6] Žarković N, Orehovec B, Milković L, Baršić B, Tatzber F, Wonisch W, et al. Preliminary findings on the association of the lipid peroxidation product 4-hydroxynonenal with the lethal outcome of aggressive COVID-19. Antioxidants (Basel). 2021;**10**(9):1341. DOI: 10.3390/antiox10091341

Section 2

## Ethio-Pathogenetic Factors

### **Chapter 2**

## SARS-CoV-2 Angiotensin Converting Enzyme 2 (ACE2) Receptor Expression and Its Effects on COVID-19 Epidemiology in Children

*Kevin M. Kover*

#### **Abstract**

Children account for less than 2% of COVID-19 cases around the globe, and children experience relatively minor symptoms compared to the adult population. Various theories have been proposed to explain this phenomenon. One such theory is the involvement of angiotensin converting enzyme 2 (ACE2) in the pathogenesis of COVID-19. Previous studies have found a direct relationship between the abundance of pulmonary ACE2 receptors and the age of patients. Since Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) binds to the ACE2 receptor to infect a patient, it is hypothesized that the low abundance of pulmonary ACE2 receptors in children relative to adults accounts for both the mild symptoms experienced as well as the difference in the number of identified cases.

**Keywords:** COVID-19, ACE2, RAAS, SARS, children, epidemiology, cases

#### **1. Introduction**

The World Health Organization (WHO) declared a global pandemic in March 2020 as COVID-19, an illness caused by SARS-CoV-2, was spreading rapidly around the globe, causing severe illness and death. There are numerous theories regarding the pathogenesis of COVID-19; however, it's pathogenesis is not completely understood due to the novelty of SARS-CoV-2. Various studies have been performed to determine how SARS-CoV-2 infects human cells so we can better understand its pathogenesis and, therefore, potential targets for medications and effective immunizations. COVID-19 is less prevalent in children than adults, accounting for less than 2% of cases. A few studies have demonstrated the potential involvement of ACE2, a component of the renin-angiotensin-aldosterone system (RAAS), as an explanation for the drastic difference between the number of COVID-19 cases in children versus adults. Multiple studies confirm that SARS-CoV-2 binds to ACE2, and there is a higher abundance of pulmonary ACE2 receptors in adults compared to children. These two conclusions together could provide insight into the lower number of COVID-19 cases and the lower severity of symptoms in children.

#### **2. The coronavirus disease (COVID-19)**

In December 2019, pneumonia of an unknown origin was linked to a seafood wholesale market in Wuhan, Hubei Province, China. Scientists isolated a novel coronavirus related to SARS-CoV. Therefore, it was named SARS-CoV-2, and the disease that it causes was named coronavirus disease 2019 (COVID-19). This novel disease began to spread globally due to its high rate of infectivity. Because of the high rate of mortality caused by COVID-19, the WHO declared a global pandemic in March 2020 [1, 2]. As of November 2022, the total number of cases in the United States was 98,481,551 including 305,082 new cases. The total number of deaths due to COVID-19 was 1,075,779 as of November of 2022, including 2,644 new deaths, and the number of hospitalizations was 25,224 with an average of 3,915 new admissions daily [3].

On December 14, 2020, the U.S. COVID Vaccination Program began where vaccines from Pfizer, Moderna, and Johnson & Johnson were administered around the globe [4]. Pfizer and Moderna each initially required 2 shots to be fully immunized, whereas Johnson & Johnson required 1 shot [5]. At that time, Pfizer vaccines were given to patients ages 12 and older, while Moderna and Johnson & Johnson vaccines were given to patients ages 18 and older [5]. As of December 2022, Pfizer and Moderna vaccines were being offered to children as young as 6 months of age [6].

#### **3. COVID-19 illness symptoms and severity in children**

Like adults, COVID-19 infection in children can cause severe illness, especially if they have an underlying health condition such as congenital heart disease, asthma, type 1 diabetes, obesity, cystic fibrosis, cancer, or immunosuppression [7–9]. In rare circumstances, children with severe COVID-19 infection may develop a condition known as multisystem inflammatory syndrome in children (MIS-C) [8].

MIS-C is a severe post-infectious inflammatory complication of COVID-19 in children where most patients (about 68%) required mechanical ventilation and ICU admission. The most common presentation of MIS-C was gastrointestinal symptoms such as diarrhea and abdominal pain. The majority MIS-C cases demonstrated neutrophilia and an elevated inflammatory marker called c-reactive protein (CRP) [10]. MIS-C commonly affects children ages 5–13 and has been associated with coronary artery aneurysms, left ventricular cardiac dysfunction, atrioventricular block, and multiorgan failure [11, 12]. New evidence suggests MIS-C infection in neonates, now termed multisystem inflammatory syndrome in neonates (MIS-N) [11, 13–17]. As of November 28, 2022, the CDC reports 9,139 confirmed cases of MIS-C and 74 deaths. Half of these cases were children ages 5–13 years old with a median age of 9 years old. 98% of children tested positive for COVID-19; the remaining 2% were exposed to COVID-19 [18]. **Figures 1** and **2** demonstrate the weekly cases of MIS-C throughout the pandemic and the number of cases per age range, respectively.

Recent research regarding COVID-19 infection in children versus adults is controversial. Children often experience a milder course of illness or are asymptomatic [19, 20], making it difficult to establish the number of pediatric cases. Research has shown that a component of the RAAS, ACE2, has been linked to lower COVID-19 infection

*SARS-CoV-2 Angiotensin Converting Enzyme 2 (ACE2) Receptor Expression and Its Effects… DOI: http://dx.doi.org/10.5772/intechopen.110284*

**Figure 1.** *Weekly MIS-C Cases and COVID-19 Cases Reported to CDC [18].*

**Figure 2.** *MIS-C Patients by Age Group [18].*

rates and milder symptoms of COVID-19 infection in the pediatric population compared to the adult population.

#### **4. Renin-angiotensin-aldosterone system (RAAS)**

Blood pressure is regulated by the kidneys via the RAAS. Juxtaglomerular (JG) cells in the kidney release renin, a protein that helps to increase blood pressure. A rise in blood pressure is accomplished when renin acts on angiotensinogen, which is released from the liver, to convert it into its active form, angiotensin I. Angiotensin I is then converted to angiotensin II via ACE in the lungs. Angiotensin II serves to increase blood pressure and blood volume by triggering the release of aldosterone and antidiuretic hormone (ADH). Aldosterone and ADH reabsorb sodium and water,

**Figure 3.** *Diagram of the RAAS [22].*

respectively, from the kidney. As water follows sodium into the body, blood volume increases; therefore, blood pressure increases. Angiotensin II also causes vasoconstriction that leads to an increase in blood pressure. Because of these effects, classes of medications known as ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) can be used to manage the blood pressure of hypertensive patients (**Figure 3**) [21].

#### **5. Biochemical comparison of ACE to ACE2**

ACE2 was discovered in 2001 and was named ACE2 due to its structural similarity to ACE. Consequently, it was hypothesized that ACE2 could be another potential target for the treatment of hypertension. Despite its similarity to ACE, studies determined that ACE2 did not convert angiotensin I to angiotensin II, and ACEi were unable to inhibit ACE2 [23].

Studies determined that the major structural difference between ACE and ACE2 was that ACE is a carboxy-dipeptidase that removed C-terminal dipeptide, while ACE2 acted as a carboxy-peptidase that removed only a single amino acid. ACE2 hydrolyzes angiotensin I more poorly when compared to ACE; however, it was determined that ACE2 hydrolyzes angiotensin II with a catalytic efficacy of about 400-fold compared to ACE2 hydrolysis of angiotensin I [23, 24]. Originally, the main tissue sites that expressed ACE2 receptors were the testes, heart, and kidney [23, 25].

It is now known that ACE2 receptors are present in the respiratory tract, specifically the olfactory epithelium, the nasal septal epithelium, the nasal conchae, and the paranasal sinuses [26].

#### **6. ACE2 and SARS-CoV-1**

In 2003, a novel coronavirus known as SARS-CoV-1 [27] was identified as a distinct etiological agent for SARS [28–32]. SARS is known to be a lower respiratory tract disease, and numerous coronavirus particles were found in pneumocytes [32, 33], cells that are located in the alveoli of the lungs. Furthermore, a large number of *SARS-CoV-2 Angiotensin Converting Enzyme 2 (ACE2) Receptor Expression and Its Effects… DOI: http://dx.doi.org/10.5772/intechopen.110284*

ACE2 receptors were found in type I and type II pneumocytes [32, 34], and few ACE2 receptors were discovered in the bronchial epithelium [32]. This evidence supports the hypothesis that SARS is likely linked to the ACE2 receptors as both were associated with each other in the alveoli.

The spike proteins of SARS-CoV-1 were found to target several ACE2 receptors located in various organs, including the immune system and respiratory tract, which can result in immunosuppression and respiratory distress, respectively. Therefore, it was concluded that SARS-CoV-1 was linked to the ACE2 receptor; consequently, ACE2 was hypothesized as a potential target for treatment of SARS.

#### **7. ACE2 and SARS-CoV-2**

As previously mentioned, recent research shows that ACE2 is linked to SARS-CoV-2. The binding affinity is vastly different due to amino acid differences at the biochemical level between ACE2 and ACE. There are stronger hydrophobic and salt bridge interactions between SARS-CoV-2 and ACE2 compared to those between SARS-CoV-2 and ACE. This was hypothesized as the explanation for the larger global influence COVID-19 has had compared to SARS-CoV-1 [35–37].

As stated above, the spike protein (S-protein) of SARS-CoV-2 and SARS-CoV-1 is what binds to the extracellular domains of ACE2 in the lungs. This leads to subsequent downregulation of ACE2 receptors which allows SARS-CoV-2 to be endocytosed into the cell it is infecting. ACE2 receptors have been found to protect the cells where they are expressed; therefore, their downregulation upon binding of SARS-CoV-2 is what allows endocytosis and subsequent COVID-19 infection [37–40]. **Figures 4** and **5** demonstrate the interactions between ACE2 and SARS-CoV-2 as well as the pathogenesis of COVID-19 and the human immune response.

The human immune system responds to the loss of ACE2 receptors via an imbalance of Th17 and Treg cell function leading to an overactivation of immune cells [37, 41–43]. The imbalance of the RAAS system along with ACE2 receptor loss in COVID-19 patients are additional factors that contribute to tissue and systemic inflammation [37, 44, 45].

#### **Figure 4.**

*Location of various organs that contain ACE2 receptors with their function (A) and ACE2 binding to SARS-CoV-2 (B) [37].*

**Figure 5.** *Role of ACE2 in the pathogenesis of COVID-19 and the inflammatory response [37].*

#### **8. COVID-19 infection, children versus adults**

As previously stated, the diagnosis of COVID-19 in children is more difficult than that of adults and can be controversial. This is because children who are infected with SARS-CoV-2 are often asymptomatic or mildly symptomatic; consequently, they are not typically tested for COVID-19. Anosmia and ageusia are not frequent in children, but when present, they are the strongest predictors of SARS-CoV-2 infection [46].

Data from the World Health Organization (WHO) from December 2019 to September 2021 showed that children under 5 represented 1.8% of global COVID-19 cases and 0.1% of global deaths. Children ages 5 to 14 years of age were 6.3% of global cases and 0.1% of global deaths [47, 48].

#### **9. ACE2 receptor expression, children versus adults**

It is known that the number of global COVID-19 cases in children is significantly less than that of adults. A proposed mechanism for this distribution is the hypothesis that the ACE2 receptor is expressed to a higher degree in the lungs of adults than it is in children. Data has shown that SARS-CoV-2 binds to ACE2 receptors before it is endocytosed into pneumocytes located deep in the lungs and into cells of the nasal epithelium; therefore, a lower expression of ACE2 receptors in children could explain the drastic difference in the number of cases between children and adults.

A 2020 retrospective study by Bunyavanich and colleagues involved 305 subjects between the ages of 4 to 60 years of age. They found that ACE2 receptor expression was age-dependent where the lowest number of ACE2 gene expression was found in children less than 10 years of age [49].

The number of ACE2 gene expression significantly increased as age increased [49]. Thus, the researchers proposed that this data could potentially explain why COVID-19 is less prevalent in children than in adults [49, 50].

*SARS-CoV-2 Angiotensin Converting Enzyme 2 (ACE2) Receptor Expression and Its Effects… DOI: http://dx.doi.org/10.5772/intechopen.110284*

Furthermore, it was previously mentioned that severe cases of COVID-19 in children, such as those seen in MIS-C and MIS-N, mainly exhibit gastrointestinal symptoms while severe cases in adults affect the pulmonary system more than the gastrointestinal system. A 2022 study by Schurink and colleagues found that as age increases, ACE2 receptor expression increases in the lungs and decreases in the intestines [51], which could explain why older individuals experience more severe pulmonary complications compared to children. Gastrointestinal issues in children can be caused by a variety of pathogens and can potentially be overlooked as a severe COVID-19 infection, which can also contribute to lower cases of COVID-19 cases in children.

#### **10. Conclusion**

The COVID-19 pandemic caused by SARS-CoV-2 has had a significant impact on the global population. Countless efforts have been made to decrease transmission of and eradicate the virus, including medications and vaccines. Several different studies have been performed to determine the pathogenesis of SARS-CoV-2 so we can better understand how it infects the population and to find targets for medications that can hopefully treat the infection and prevent severe illness.

Not only has COVID-19 significantly impacted the global population, but it has impacted children to a much lesser degree than adults with children representing less than 2% of global COVID-19 cases. A proposed mechanism for explaining why cases are much less prevalent in children is the lower expression of pulmonary ACE2 receptors, a component of the RAAS, in the nasal epithelium and alveolar pneumocytes of children compared to adults. Studies have shown that SARS-CoV-2 binds to ACE2 before being endocytosed into cells to cause infection. Studies also show the number of ACE2 receptors in the pulmonary system is directly related to age.

This proposed mechanism is controversial at this point in time, especially since COVID-19 cases in children may also be likely lower because they experience mildly symptomatic or asymptomatic illness. Future studies should involve compounds that specifically inhibit pulmonary ACE2 in adults to determine if the number of COVID-19 cases significantly decrease. Eventually, these developments can lead to medications to treat the virus at its early stages to decrease likelihood of transmission and, therefore, prevent severe illness.

#### **Acknowledgements**

I would like to express my sincere gratitude to Dr. Öner Özdemir for giving me the opportunity to contribute to his book: *COVID-19 Epidemiology in Children*. I would also like to thank the Sharpe Strumia Research Foundation at the Bryn Mawr Hospital at Main Line Health for funding this work. Lastly, I would like to recognize author service manager, Karla Skuliber, for her assistance in the completion of my chapter.

*Epidemiological and Clinico-Pathological Factors of COVID-19 in Children*

### **Author details**

Kevin M. Kover Main Line Health, Philadelphia, PA, USA

\*Address all correspondence to: kevinkover@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*SARS-CoV-2 Angiotensin Converting Enzyme 2 (ACE2) Receptor Expression and Its Effects… DOI: http://dx.doi.org/10.5772/intechopen.110284*

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