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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Genetic Diversity of Coronaviruses
- Sprache: Englisch
Genetic Diversity of Coronaviruses (Volume 1) provides a comprehensive analysis of the genetic mutations and host interactions across three major coronaviruses—SARS-CoV, MERS-CoV, and SARS-CoV-2. This volume explores the evolutionary history, mutations, and emerging variants of these viruses, with a focus on understanding how they adapt to different hosts. The book is organized into three parts: Part I covers SARS-CoV, detailing its genetic mutations, host genetic diversity, and new variants. Part II focuses on MERS-CoV, offering insights into mutations and host adaptations. Part III addresses SARS-CoV-2, discussing its evolving variants and the role of host proteins. The book also discusses the connections between coronaviruses and neurological, epigenetic, and AI-related issues.
Key Features:
- In-depth analysis of genetic mutations in coronaviruses.
- Exploration of host genetic diversity and virus adaptation.
- Insight into emerging variants of SARS-CoV, MERS-CoV, and SARS-CoV-2.
- Examination of host proteins' role in viral infections.
- Discussion on the impact of AI and epigenetics on coronavirus research.
Readership: College students, researchers, scientists, and health professionals.
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Seitenzahl: 722
Veröffentlichungsjahr: 2024
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PREFACE
Coronaviruses, such as severe acute respiratory syndrome-coronavirus (SARS-CoV) and Middle East respiratory syndrome-coronavirus (MERS-CoV), have posed significant public health threats in the last two decades. It has been revealed that bats act as natural reservoirs for these viruses, and periodic monitoring of coronaviruses in bats, dogs, civets, and other wild animals may thus provide important clues about emergent infectious viruses that transfer to humans. The Eastern bent-wing bat Miniopterus fuliginosus (M. fuliginosus) and genus Rhinolophus are distributed extensively throughout China and other countries. Therefore, there is a need to analyze the genetic diversity of coronaviruses transmitted to humans. The only coronavirus genus found was alphacoronavirus. The established alphacoronavirus genome sequences showed high similarity to other alphacoronaviruses found in other Miniopterus species and other animals. It suggests that their transmission in different Miniopterus species may provide opportunities for recombination with different alphacoronaviruses. The genetic information for these novel alphacoronaviruses will improve our understanding of the evolution and genetic diversity of coronaviruses, with potentially important implications for the transmission of human diseases. This virus is different from the previously isolated MERS-CoV and SARS-CoV, which are the seventh ones that can infect humans.
In Volume 1 of this book proposal, we consolidated the genetic diversity/mutation that occurred in 2002-12. Since both SARS-CoV and MERS-CoV are closest, the approaches discussed here will be similar and/or varying by a slight degree. In the last 18-19 years, this is the third outbreak of the same coronavirus with a slight mutation that shocked the whole world. This book should be prioritized as up-to-date literature on genetic mutations that have occurred in the form of SARS-CoV and MERS-CoV. It will act as a suitable reference if any such outbreak appears in the near future. Volume 1 of this proposed book proposal has been classified into two parts: Part I: Genetic Mutation of SARS-CoVand Part II: Genetic Mutation of MERS-CoV.
With the emergence of new coronavirus variants, different host tropism permits a thorough analysis of their genomic diversity/mutations that acquired adaptability to their host. Thus, in Part I, we start the book with chapters dealing with mutations in SARS-CoV, the host genetic diversity of SARS-CoV, newly emerging variants of SARS-CoV, the genetic architecture of host proteins involved in SARS-CoV, and the landscape of host genetic factors correlating with SARS-CoV. In Part II, a critical analysis of the MERS-CoV involves the potential to mutate its genome by opposite genetics and to get better recombinant viruses with described mutations. Such processes will assist in studying the capabilities of particular genes and their effects on virus survival and pathogenesis. These strategies can even help in determining host factors correlating with MERS-CoV genome growth and proliferation.
This book will appear as a baseline for scientists and health professionals to better understand the genetic diversity of SARS-CoV and MERS-CoV. However, this single book would not have succeeded without the enthusiasm and determination of publishers and investigators to take time from their hectic schedules and endow on time. We thank the scrutineers who contributed, directly and indirectly, to bring it to realism.
List of Contributors
History of SARS-CoV
Muhammad Zeeshan Iqbal1,Muhammad Bilal Bin Majeed2,Muhammad Saeed3,Muhammad Safdar4,Kashif Rahim5,Firasat Hussain5,Hamid Majeed6,Umair Younas1,*Abstract
Severe acute respiratory syndrome-coronavirus (SARS-CoV) is a viral disease of the respiratory system with zoonotic importance. It was initially reported in Southern China (province: Guangdong) in mid-November (2002). This disease showed a viral spread to more than thirty countries belonging to five different continents and infected 8098 people, out of which 774 died. The emergence of SARS has been found to be due to human-animal contact. SARS-CoV is not harmful in children, and there is no vertical transmission from mothers to newborns. In pediatric age groups, no death has been reported. Most SARS autopsies cases showed extensive spleen and white pulp necrosis with severe depletion of lymphocytes. The genomic sequence of SARS-CoV is detected through RT-PCR in some specimens of the brain and cerebral spinal fluid. The pathogenesis of SARS is very complex as multiple factors are involved. With the prevalence of SARS-CoV, many diseases are associated with and cause damage to different organs and systems of the body. Some strategies that can help treat SARS-CoV are host-directed therapies, the use of antibiotics, inhibitors of viral and host proteases, and interferons. The World Health Organization (WHO) issued an alert on 12th March 2003 about new deadly infectious diseases globally. After three days, the WHO named these diseases SARS. China, Singapore, Taiwan, and Hong Kong were the most severely affected areas.
INTRODUCTION
Primary epidemiological investigations revealed that severe acute respiratory syndrome-coronavirus (SARS-CoV) has an animal origin. The emergence of SARS has been found to be due to human-animal contact [1]. Horseshoe bats belonging to the genus Rhinolophus were found to be the natural reservoirs of SARS coronaviruses. Samples were collected from a live animals’ market, and closely related viruses were found in palm civets. Chinese scientists also found the same virus in Asian palm civets and cave-dwelling horseshoe bats in China [2]. Retrospective studies on human populations prove the absence of antibodies against SARS-CoV in humans before the onset of the SARS-CoV outbreak [3]. Genetically diverse SARS-CoVs were identified in Chinese horseshoe bats as natural reservoir hosts [4]. However, no evidence had been reported regarding the transmission of SARS-CoVs from bat to human. The epidemiological investigations prove the zoonotic origin of SARS-CoV [5]. The isolation and identification of SARS-CoV from masked palm civets and its detection in the serum of people involved in the trade of civets suggest that masked palm civets could be a possible source of infection initially in Guangdong people and later in the world. Furthermore, culling drastically decreased the number of infected animals in the marketplaces of Guangdong [6].
Initially, the SARS coronavirus species were reported as SARS-CoV. There was a great epidemic in China due to SARS-CoV in 2002-2004. Later, around 2017, Chinese scientists found the SARS-CoV virus in Asian palm civets and horse how cave-dwelling bats and reported them as intermediate hosts of this virus [2]. Since 2004, no new cases have been reported anywhere in the world. SARS-CoV is not harmful in children, and there is no vertical transmission from mothers to newborns. In pediatric age groups, no death has been reported [7]. The teenage patients showed symptoms of myalgia, malaise, and rigor similar to adults, while younger children showed runny nose and cough, and none showed myalgia, rigor, or chills. In younger children, there was a mild clinical course with a probable short duration.
Similarly, the radiological findings were also not serious, and these cases were resolved quickly compared to the teenager group [8]. From the histopathological findings perspective, the SARS-CoV that affected the patient’s lungs showed diffuse alveolar damage (DAD). During the first 7-10 days, extensive lung edema occurs. Then, the hyaline membrane is formed, which leads to the collapse of alveoli and the desquamation of alveolar epithelial cells. Fibrosis occurs, and fibrous tissue is formed in alveolar spaces. If the disease persists longer, DAD appears after 10-14 days [9-11]. The periarterial sheaths in the spleen decrease more sharply. The presence of infection in T lymphocytes and macrophages in the spleen shows a high viral load in splenic cells [12-14]. The kidneys of SARS-CoV patients were autopsied, and focal necrosis was found along with small-vessel vasculitis in renal and intestinal tissue [15]. The most commonly reported cases were gastrointestinal manifestations. SARS-CoV indirectly affects certain other organs of the body [12]. It is reported that more than 20% of patients had diarrhea, and up to 67% showed signs of developing diarrhea [16-18]. During illness, it infects the tubular epithelial cells of the kidney, mucosal cells of the intestines, several types of immune cells, and brain neurons.
This disease's estimated case fatality ratio was 15% [19]. This disease has caused a huge negative impact on population health, China's economy, and national and international security. Its outbreak was critical for the country’s economy and society [20]. The impact of SARS-CoV was quite serious, both socially and psychologically. This disease has profoundly impacted human society, particularly in China. Mental stress was developed in society. By March 2003, no information was confirmed officially, but the epidemic was spreading, and people started to believe rumors and purchase anti-viral drugs in Guangdong and Beijing [20]. The projected macroeconomic influence of SARS-CoV was around 3-10 million US dollars per case globally [21]. The losses caused by the 2003 SARS-CoV were about 12.3-28.4 billion US$. The projected downfall of the GDP of China and South Asia was 1% and 0.5%, respectively [22].
Animal Perspective History of SARS-CoV
The emergence of infectious diseases is primarily an ecological process. Most infectious diseases (75%) that affect human health are zoonotic. The reservoir of these diseases is direct contact of humans with wildlife or domestic animals. The zoonotic disease can be attributed to habitat fragmentation/deforestation, agricultural extension, global trade, and urbanization. These factors enhance the interaction between humans and domestic/wildlife populations, thus increasing the chances of the occurrence of spilling-over events. The emergence of SARS-CoV in China in 2003 took place due to human-animal contact [1].
The SARS-CoV was initially reported in Southern China (Guangdong) in mid-November (2002). This disease showed a viral spread to over thirty countries belonging to five different continents and infected 8098 people, out of which 774 died [23]. Primary epidemiological investigations revealed that SARS-CoV has an animal origin. Samples were collected from a live animals’ market and found the closely related virus in palm civets. Horseshoe bats belonging to the genus Rhinolophus were found to be the natural reservoir of SARS-CoVs. Chinese scientists also found the same virus in Asian palm civets and cave-dwelling horseshoe bats in China [2]. Some early cases have reported an association with occupations directly linked to wild animals, including managing, butchery, and marketing wild animals, as well as cooking and then presenting the meat of wild animals in restaurants or hotels [5]. Twenty samples were collected from wild animal traders in Shenzhen, Guandong. Eight samples (40%) were found positive for having anti-SARS-CoV antibodies in their blood [24]. After this study, the animal trader market was kept under observation. In another study, serum samples of 508 animal traders were analyzed, in which 72% of people involved in the trade of masked palm civets were found to be SARS-CoV seropositive, while 13% had antibodies against this virus [25]. However, during the SARS-CoV outbreak in Guangdong, there were no reports of SARS-CoV and atypical pneumonia in any animal traders (subclinical infection), suggesting asymptomatic infection.
The above findings prove that SARS-CoV is a causative agent in the viral spread of SARS-CoV disease. Now the question is whether it is a new virus or an evolutionary process is responsible for mutation in pre-existing human viruses, increasing its virulence. Alternatively, there might be chances that a virus belonging to some animal affected the human population. Retrospective studies on human populations prove that there were no antibodies against SARS-CoV in humans before the onset of the SARS-CoV outbreak [3]. As previously discussed, this disease had a higher representation among people working in the animal food industry and animal handlers. So, there are chances that this disease might be transferred to humans through animals. In 2003-04, during another outbreak of SARS-CoV, four patients were identified as having SARS-CoV infection [26]. The history of these patients depicted no indirect or direct link with the old documented SARS-CoV-related cases; however, most of these have animal contact. Moreover, the genomic sequence of SARC-CoV from human patients was almost identical to the genetic sequence of civets available in the market at that time, confirming SARS-CoV transmission from animals to the human population [27].
The SARS-CoV was identified in Chinese horseshoe bats as natural reservoir hosts [4]. However, no evidence has been reported regarding the transmission of SARS-CoVs from bat to human. The epidemiological investigations prove the zoonotic origin of SARS-CoV [5]. The isolation and identification of SARS-CoV from masked palm civets and its detection in the serum of people involved in the trade of civets suggest that masked palm civets could be a possible source of infection initially in Guangdong people and later in the world. In addition, culling has drastically reduced the number of sick animals in Guangdong's markets [6].
SARS-CoV Origin in Relation with Different Countries
It is reported that SARS-CoV is a viral disease of the respiratory system and bears a zoonotic value, which is a consequence of SARS-CoV or SARS-CoV-1. Until June 2003, SARS-CoV was a rare disease with 8,422 infected cases and an 11% case fatality rate (CFR) at the outbreak's end. There was a great epidemic in China due to SARS-CoV in 2002-2004. Later, around 2017, Chinese scientists found the SARS-CoV virus in Asian palm civets and horse how cave-dwelling bats and reported them as intermediate hosts of this virus [2]. In 2020, SARS-CoV was considered to be eliminated from the human population, however, it is possible to re-arise in the future because it has also infected animals [28].
History of SARS-CoV Concerning China
In November 2002, the SARS epidemic broke out in China’s province of Guangdong. The first person who showed symptoms was a farmer from Shunde, Foshan, Guangdong, and treatment was given to him at First Peoples Hospital of Foshan. He died soon, and no definitive cause of death was diagnosed. This case was reported on 16th November, 2002 [29]. Regardless of taking some preventive measures to control the outbreak, Chinese authorities failed to inform WHO until February, -2003. The deficiency of transparency had contributed to delays in attempts to overcome the disease, resulting in criticism from the international community of China. The Chinese Ministry of Health sent the first report of a newly emerged disease to WHO on 11th February 2003 and named that disease “SARS”. This report also documented that in Guangdong Province, this disease had caused 305 cases and 5 deaths [30]. China formally apologized for its tardiness in reacting to the SARS outbreak.
At the beginning of April 2003, after Jiang Yanyong, a famous physician, was pushed to disclose the risk factors for China, there seemed to be an alteration in official policy as SARS-CoV started to be even more prominent in the official media. With this intense pressure of increasing cases, Chinese officials had to allow international officials to investigate the circumstances [31].
History of SARS-CoV in Relation to Vietnam
In another case, a Chinese American businessman aged 48 years, who tended to stay in a hotel (Hong Kong), had a high fever accompanied by dry cough, myalgia, and moderate sore throat. The patient was taken to the hospital for treatment in a French hotel (Hanoi) but could not survive as he returned to Hong Kong. Later, a WHO official in Vietnam, Dr. Carlo Urbani, reported that at the French Hospital, many patients were admitted and treated for atypical pneumonia [8]. Similarly, other SARS cases were noticed among the health workers of Hanoi (Mach 5). The medical team's advice was followed for the hospital closure by Vietnam for the visitors and admittance of new patients (11th March). Some of the staff in the hospital fell ill while looking after their colleagues and patients, and some also died. To contain the disease, timely action was taken by the health minister committee. The Hanoi French Hospital was evacuated and thoroughly disinfected by 7th May [32].
History of SARS-CoV in Relation to Toronto
An older woman aged 78 years from Toronto residing on the hotel's ninth floor was found dead due to SARS (5th March). A family member of that older woman was admitted to the hospital afterward. From 13th February to 23rd February, the patient and her spouse traveled to Hong Kong to meet their relatives. Returning to her home, the woman experienced some symptoms of fever, sore throat, moderate but non-productive cough, and myalgia. She died at home after 9 days of her illness [33].
History of SARS-CoV in Relation to Taiwan
SARS-CoV cases started to emerge in Taiwan shortly after. On 14th March, initially, two suspected cases were noted in Taiwan. In February, a man traveled to the Guangdong province and then toured Hong Kong. Similarly, a resident of Hong Kong’s Amoy Gardens traveled to Taiwan (26th March) and then, seated on the train for Taichung to celebrate the Qing Ming traditional festival, became the leading SARS-CoV fatality case. Another passenger on the train was also affected. During the last week of April, the number of cases gradually increased. The Taiwanese Government imposed compulsory fourteen-day quarantine measures on passengers coming from Hong Kong, Singapore, China, Macau, and Toronto (28th April). One hundred and sixteen cases were diagnosed in Taiwan on 5th May 2003. Out of which, 8 died. Over time, cases occurred in Taiwan, and the WHO was flooded with reports from different parts of the world. In Hanoi, 14 private French hospital staff members suffered from SARS (8th March), and a team was sent by WHO to provide health support. Before 11th March, at least 23 hospital personnel at the Prince of Wales Hospital in Hong Kong and 20 in the Hanoi Hospital suffered from an unidentified acute respiratory syndrome [8, 34].
After the SARS-CoV outbreak in China and other countries, WHO prepared an international investigation team with the help of the Global Outbreak Alert and Response Network (GOARN) to bring the epidemic under control. This team worked with the health authorities to provide epidemiological, therapeutic, and logistical assistance in affected countries [35].
SARS in Children
The SARS-CoV is closely related to SARS-CoV-2 but is not the similar virus that causes COVID-19. SARS-CoV can spread quickly and is highly contagious, causing mild to severe illness or death. It is febrile and attacks the respiratory tract. In 2003, sporadic cases were reported in children globally. Since 2004, no new cases have been reported anywhere in the world. SARS-CoV is not harmful in children, and there is no vertical transmission from mothers to newborns. In pediatric age groups, no death has been reported [7].
In children, SARS-CoV is transferred through direct contact with an infected object or patient. When SARS-CoV-affected patients sneeze or cough, tiny droplets of fluid having the virus are sprayed from the nose and mouth up to 3 feet. The virus is transferred when a child touches these infected objects and then touches his mouth, nose, or eyes. There are chances that a child who has been affected may not fall ill. SARS-CoV symptoms appear about 2-10 days after virus contact in children. Initially, the symptoms are fever, headache, body aches, chills, and sometimes diarrhea. After 2-7 days of infection, dry cough and trouble in breathing occur, leading to lung infection and pneumonia. These problems lead to difficulty in breathing, and death occurs due to hypoxia or respiratory collapse. In the first two weeks of illness, the child is more contagious and needs to stay away from other people. He should stay at home from school even 10 days after the symptoms have disappeared. This practice assures that the child is no longer a risk for others (Stanford Children’s Health, 2021/ https://med.stanford.edu/).
SARS-CoV was a global issue. From countries like Singapore, Hong Kong, Canada, and Taiwan, 135 pediatric SARS-CoV patients were reported globally. Among these 135 patients, 80 were laboratory-confirmed, 28 were suspected, and 27 were probable. Among probable and laboratory-confirmed cases, commonly found SARS symptoms included vomiting/nausea (41%), cough (60%), and fever (98%). The clinical signs were the same in patients older than 12 years as in adults. However, the mild disease was observed in patients 12 years or younger who did not receive supplemental oxygen and were not admitted to any intensive care unit [36]. Males and females were equally affected, but the infection ratio in young (12 years of age) and adolescents (12-18 years of age) was 1:2 [7]. In children, the IP period was 2-10 days for SARS-CoV, with a mean of 6.4 days. It means that the time from the onset of clinical signs and admission to the hospital was reported to be three to five days.
The clinical course of SARS is less aggressive in young children than in adults and teenagers. For children younger than 15 years, only 3% of total SARS cases were accounted for in Hong Kong. A case comprising 10 children suspected of SARS-CoV was reported. These children fulfilled the WHO’s SARS definition and had close interaction with infected adults. These children showed that for a medium duration of 6 days, the fever lasted. There were clinical presentations reported with two distinct patterns. The teenage patients showed symptoms of myalgia, malaise, and rigor similar to adults, while younger children showed runny nose and cough, and none showed myalgia, rigour, or chills. In younger children, there were mild clinical courses with probable short duration.
Similarly, the radiological findings were also not serious, and these cases were resolved quickly compared to the teenager group [8]. No case has been observed for vertical transmission (from mother to newborn) of SARS-CoV. The milder disease is noticed in young children (<12 years) compared to the elderly (13-17 years), showing more constitutional features, and there might be a severe clinical course similar to the adult patients. No deaths have been reported in the SARS-CoV-affected pediatric patients [7]. Fever is the most common symptom in children [37], along with other symptoms such as lethargy, rhinorrhoea, headache, dizziness, chills, rigors, and myalgia. The less commonly encountered symptoms include sore throat, vomiting, diarrhea, nausea, abdominal pain, and febrile convulsions. Some symptoms tend to be vague, like respiratory ones. However, cough was found in more than 50% of patients and was unproductive in nature. Some symptoms were seldom noted, and symptoms mostly noted in case that were severely affected included dyspnoea, hypoxia, crepitation and chest auscultation [38].
Pathology and Pathogenesis of SARS
Many cases of complete or partial autopsies were reported after the initial outbreak of SARS in 2003, whereas DAD was a significant pathological finding. This acute pulmonary injury is caused by immune pathogenetic factors or direct viral effects [12]. Some SARS-CoV-affected patients were extensively studied to check its effect on different body organs. Different organs get affected by the SARS-CoV, including lungs and intestines, and other organs if their pathology is still unknown. Autopsies report multiple diseased areas in the lungs with edema and congestion. Also, cut sections reveal mucous in some of the lungs; however, autopsies until now have not related damage patterns and clinical symptoms [39]. SARS-CoV emerged in Guangdong province of China in 2002 and affected people worldwide. It starts with mild cold symptoms, leading to acute respiratory distress syndrome. It mainly affects the lungs and can cause lesions and damaged immune systems by inducing T-cell apoptosis and reducing their response to the SARS-CoV virus [40].
Respiratory Tract
More than 60 autopsies cases were studied to understand the pathological findings in the lungs. The gross examination of the lungs showed edematous swelling and increased weight. In most cases, the lungs were extensively consolidated. Histopathologically, the lungs of SARS-affected patients showed DAD. During the first 7-10 days, extensive lung edema occurs. Then, the hyaline membrane is formed, which leads to the collapse of alveoli and desquamation of alveolar epithelial cells. Fibrosis occurs, and fibrous tissue is formed in alveolar spaces. If the disease persists longer, DAD appears after 10-14 days [9-11]. If the disease lasts more than 2-3 weeks, more extensive fibrosis occurs, and a dense septal is formed in alveolar fibrosis cells [18, 21, 23]. After 108 onsets of disease, pathological changes show acute pulmonary injury [41].
Immune System
Most SARS-CoV autopsies showed the spleen's and white pulp's extensive necrosis with severe depletion of lymphocytes [42-44]. The periarterial sheaths in the spleen decrease more sharply. The presence of infection in T lymphocytes and macrophages in the spleen shows a high viral load in splenic cells [12-14]. In some cases, atrophy of lymph nodes and reduction of lymphocytes was observed, while in various cases, it was found that in the appendix and the intestine, there was a severe depletion of mucosal lymphoid tissue. Electron microscope and in situ hybridization are used to confirm the existence of immune cells infected with SARS-CoV in lymph nodes. In the early phase of the disease, an electron microscope detects viral particles in T lymphocytes and circulating monocytes. In many SARS-CoV autopsy cases, the infection of monocytes and T lymphocytes was established by electron microscope and in situ hybridization [45].
Central Nervous System
It was observed that SARS-CoV could cause infection in the central nervous system. The genomic sequence of SARS-CoV is detected through RT-PCR in some specimens' brain and cerebral spinal fluid [46, 47]. The autopsy of the brain has shown that this virus causes edema and focal degeneration of neurons [43, 48].
Urogenital Tract
The kidneys of SARS patients were autopsied and focal necrosis was found along with small-vessel vasculitis in renal and intestinal tissue [15]. The additional changes found are acute tubular necrosis, monocytic infiltration, nephrosclerosis, and glomerular fibrosis [44, 49, 50]. High viral load is detected in the renal system of patients affected by SARS-CoV through quantitative real-time PCR. In the distal tubules (epithelial cells), viral genomic sequences and proteins have been identified by immunohistochemistry and in situ hybridization [12].
Gastrointestinal Tract
The most commonly reported cases were gastrointestinal manifestations. It was reported that more than 20% of patients showed diarrhea, and up to 67% showed signs of developing diarrhoea [16-18]. No specific pathological changes were evident during the microscopic examination, while non-specific changes (autolysis and mild focal inflammation) were found in the tissue samples of the small and large intestines [43, 48]. The most prominent pathological signs were reduced mucosal lymphoid tissue in the appendix, pharynx, and small intestine. No obvious pathological changes were observed in the pancreas, stomach, and salivary glands [18, 51].
Liver
The level of alanine aminotransferase in the SARS-CoV patients was primarily increased during the disease, which is associated with an adverse outcome [52]. The necrosis of liver cells (hepatocytes), fatty degeneration, and cellular infiltration were observed in some autopsy cases, while no specific pathological changes were observed in other cases [53].
Bone Marrow
Bone marrow hypoplasia or reactive hemophagocytosis was found in some cases, while active bone marrow without hemophagocytosis was observed [42]. Immunohistochemistry and in situ hybridization did not detect any viral genomic sequences or antigens.
Other Organs
It was found in some SARS-CoV patients that this virus affects other body organs like the heart (edema and atrophy of myocardial fibers), testes (destruction of germ cells and spermatogenetic cells apoptosis), thyroid glands (demolition of follicular cells), adrenal gland (necrosis of lymphocytes and monocytes), etc. [8].
Pathogenesis
The SARS’s pathogenesis is quite complex as multiple factors are involved. After infection with SARS-CoV, severe injury occurs in the lower respiratory system (lungs), and then the virus is disseminated to various organs. The target of SARS-CoV is epithelial cells of the respiratory tract. Here, it causes diffuse alveolar damage and infects several other cells or organs. During illness, it infects the tubular epithelial cells of the kidney, mucosal cells of the intestines, different immune cells, and brain neurons. SARS-CoV indirectly affects specific other organs of the body [12]. Laboratory reports of infected cases describe virus distribution in cells and organs. To better understand pathogenesis, research regarding receptor interaction and immune system response is required.
Prevalence of Comorbidity
SARS-CoV is a worldwide infection caused by a virus that affects multiple body organs and systems. It is a contagious disease. In 2003, it infected 8098 patients, out of which 774 died. The damage to multiple organs in SARS-CoV is typical, and its pathogenesis is controversial. The complications in SARS-CoV-affected patients are pneumonia, coagulopathy, lymphopenia, myositis, and abnormal liver and renal functions [34, 42]. This disease also causes cardiovascular complications, which are hypertension, bradycardia, tachycardia, cardiomegaly, cardiac arrhythmia, etc.
During a study on cardiovascular complications in SARS-CoV, the Center for Disease Control and Prevention, USA, analyzed the data of 120 patients having SARS-CoV. According to the data, all the patients showed fever symptoms (100%). The other symptoms expressed by those patients were sore throat (23%), shortness of breath (10%), cough (48%), myalgia (71%), diarrhea (16%), headache (49%), and chills/rigor (68%). Chest discomfort occurred in 7% and cardiovascular symptoms of palpitation in 4% of patients. The blood tests also showed some abnormalities, including neutropenia, lymphopenia, thrombocytopenia, increased lactate dehydrogenase level, and impairment of liver and renal functions. 26% of the patients showed increased creatine phosphokinase activity, probably related to myositis. The radiological or computed tomography confirmed the evidence of pneumonitis and pneumonia in all patients. The arterial desaturation was developed in 47 patients (39%) who needed oxygen therapy, while 15% of patients were admitted to the intensive care unit. All the patients were treated with broad-spectrum antibiotics. During hospitalization, 61 (50.4%) patients experienced hypotension. In these patients, the mean systolic blood pressure ranged from 69-99 mm Hg (mean: 84.9), while diastolic blood pressure ranged from 35-57 mm Hg (mean: 46.8). These were lower than hospital admission values (systolic and diastolic: 121 and 67 mm Hg). Cardiac arrhythmia was rare in SARS-CoV-affected patients, as one patient having no history of cardiac disease showed transient paroxysmal arterial fibrillation. It means that SARS-CoV has a low arrhythmogenic effect. Cardiomegaly was observed in 13 patients (10.7%), and its duration ranges from 1 to 50 days (mean: 13.4 days). None of the patients developed any signs or symptoms of heart failure [54]. Some coronavirus strains seriously affect the heart. In an experiment on the rabbit, coronavirus induced cardiomyopathy in the rabbit, resulting in cardiac chamber dilation and destruction of systolic functions [55, 56]. SARS-CoV causes diabetes in recovered patients. This was confirmed by angiotensin-converting enzyme2 (ACE2) in different organs (epithelial lungs and small intestine). The localization of ACE2 in the endocrine parts of the pancreas proposes that SARS-CoV enters islets using ACE2 as a receptor and harms islets, producing acute diabetes. Actually, during systematic illness, coronavirus may cause severe damage to pancreatic β cells. The only human homolog of ACE (blood pressure regulator) is ACE2, which has a 42% similar protein sequence. The ACE2 can convert angiotensin 2 to angiotensin 1-7, which is responsible for diabetes, hypertension and heart problem [57, 58]. Surprisingly, the cellular entry point of SARS coronavirus is ACE2. The binding of SARS-CoV with the target cells is mediated through the S proteins of SARS with cellular receptors of target cells, and infection is mediated. ACE2 is a functional receptor for the S protein of SARS-CoV [59, 60]. In a study [61], immune-staining of different organs was done for the ACE2 protein. Strong staining was noted in the pancreatic islets, and weak staining was reported in exocrine tissue.
This staining was strong in pancreatic islets and very weak in exocrine tissues. The profuse immune staining was reported in parietal epithelial cells (Kidney), alveolar epithelial cells (lung), and myocardial cells of the heart; however, it was not reported in the hepatocytes. Some patients suspected to have died from SARS were studied, and atypical pathological changes were found, like fatty degeneration, hydropic degeneration, and interstitial cell proliferation in the heart, liver, kidney, and pancreas [15, 48]. The higher levels of aspartate transaminase (AST), lactate dehydrogenase (LDH) serum creatinine (s-Cr), and severe hypoxia are related to a greater death rate. These findings suggest that SARS may damage several organs, including the lungs, heart, and kidneys. The greater level of these parameters suggests a higher level of damage by SARS-CoV. The other reason for the higher death rate is hyperglycemia, as the coronavirus severely damages the pancreatic islets, leading to hyperglycemia [61].
With the prevalence of SARS-CoV, many diseases are associated with and cause damage to different organs and systems of the body [60]. It relates to acute myocardial infarction and increased risk of death with cardiac diseases and diabetes myelitis. Also, it relates to hypertension and kidney diseases. Patients with kidney diseases and dialysis dependence are at more risk of developing severe symptoms that can cause death [62].
Clinical Features
The clinical examinations showed that SARS-CoV causes elevated body temperature, cough, and shortness of breath. The symptoms may exceed diarrhea, headache, myalgia, and dyspnoea [63].
Laboratory Diagnosis
The reverse transcriptase-polymerase chain reaction (RT-PCR) is used in the laboratory to detect SARS-CoV. However, the detection rate through RT-PCR is usually very low in the early stages of the very first week of illness. The positivity rates have been reported as 42%, 68%, and 97% for urine, nasopharyngeal aspirate, and stool specimens, respectively, after two weeks of illness, whereas the blood specimen may take up to four weeks for a positive detection rate above 90% through RT-PCR [16], as shown in Table 1.
During the middle phase of SARS-CoV infection, about 10-14 days, the lungs represented the fibrous organization, including pneumatic hyperplasia (type II), reparative fibroblastic proliferation, and interstitial and airspace fibrosis. However, the time duration is counted from the expression of symptoms, and the pathological process may cease or recover at any stage. So, it does not evolve throughout all three stages in all cases [12, 64, 65].
Lymphopenia is a condition where CD4 and CD8 are destroyed and is quite common in about 98% of patients with SARS-CoV infection. The number of CD4 and CD8 T lymphocytes decreases at the early stage of SARS-CoV, and this fall becomes an adverse clinical outcome at presentation [66]. Some other common diagnostic conditions of SARS-CoV infection include alanine transaminase, creatine kinase, and raised lactate dehydrogenase. Whereas, some characteristics of low-grade intravascular coagulation (raised D-dimer, thrombocytopenia, and prolonged partial thromboplastin time) are diagnostic features that are usually common [16]. It was reported that lowering of left ventricular ejection fraction with contrary prognostic features like creatine kinase and lactate dehydrogenase are correlated with each other [16]. There is uncertainty about the pathogenic mechanism related to the cardiac disturbance. However, in acute SARS, there is the possibility of a large diastolic impairment (sub-clinical) [16]. In 23%–50% of SARS patients, an increase in aminotransferase levels was also seen [67]. About 75.9% of SARS-CoV patients showed liver dysfunction before and during treatment with corticosteroids and ribavirin [66].
Radiological Diagnosis
SARS and pneumonia have almost the same radiographic appearance. A good technique for detecting parenchymal opacities is the high-resolution computed tomography of the thorax [68]. In contrast, the chest radiographs were quite normal in 20% to 25% of patients with SARS-CoV [68]. Opacities occupy the axial location along with peripheral or mixed peripheral areas among 88% of patients with SARS-CoV [68]. In addition to the pleural effusion, hilar lymphadenopathy, and the absence of cavitation, there has been predominant involvement of the lower zone of the lungs and its periphery as radiographic features of SARS-CoV.
In our study, the opacities occupy a peripheral or mixed peripheral and axial location in 88% of patients [68]. Some common findings include the interlobar septal and intralobular interstitial thickening and ground-glass opacification, which is less usual with consolidation prominently with lower and peripheral lobe involvement. The close resemblance is reported to those found in bronchiolitis obliterans organizing pneumonia for the characteristic peripheral alveolar opacities [68].
The criteria to diagnose the SARS-CoV infection were given by CDC and WHO. A suspected person may have some symptoms and histories like fever (38oC), difficulty in breathing, cough, residence in the affected area, or travel history to the pandemic area. Also, there might be close contact with a person already sick of SARS-CoV infection. In comparison, the definition of a probable case is a suspected case with the radiological results of ARDS (acute respiratory syndrome) or pneumonia. Also, a positive case of SARS-CoV, according to one or more laboratory assays or autopsy findings, is ARDS. To assist in the hospital cases, the WHO definition for the suspected cases has been established and evaluated in terms of screening patients before admission to the hospital [69].
It was reported that the main characteristics in the initial stages of suspected SARS-CoV infection patients might be rigors, fever, chills, and myalgia, other than breathing difficulty and cough. However, the fever (38oC>) in some initial SARS-CoV cases is not reported until radiological evidence for the pneumonic changes is found, often proceeding to fever. The case definitions given by the CDC are more accurate and have more positive predictive value (than those given by the WHO) as these are based on epidemiological, clinical, and laboratory criteria. The definition given by WHO for a suspected SARS-CoV patient has a more negative predictive value of up to 85% and a very less positive prediction of just 26% for detecting SARS-CoV in patients who have not been admitted to hospital [69]. The CDC has also revised its exclusion criteria and case definitions to permit the elimination of cases with a recovering phase. The serum sample is collected 28 days after the onset of symptoms and found negative for antibodies to SARS-CoV [70].
Prognosis
The disease prognosis cannot be defined as it prevails in every age group, including children, adults, and older people. The symptoms also vary in different individuals as children have mild symptoms, and adults and older people have severe symptoms, which may even affect some people's central nervous system and may cause death. Overall preventions can be adopted, such as frequent hand washing, wearing a mask, and maintaining distance from affected people, effectively reducing prognosis [71]. Antibiotics can be effective for some individuals; some need steroids for treatment.
Treatment and Therapies against SARS-CoV Infection
Some strategies that can help treat SARS-CoV are host-directed therapies, the use of antibiotics, inhibitors of viral and host proteases, and interferons [72]. Different combinations of drugs can be used as a supplement when clinically proven anti-viral therapy is not present. Ribavirin, combined with corticosteroids, was frequently used during the SARS outbreak; this has an anti-inflammatory effect [73]. IFNα, combined with immunoglobulin or thymosin, stimulates T-cell development, thus increasing immunity. The IFNα and ribavirin [74, 75] were also given in a small number of cases during the SARS-CoV outbreak. The sensitivity of coronavirus can be increased by deleting the nsp14 encoding sequence, but this method is unclear as to why ribavirin is always used along with other anti-viral treatments [76]. Some potential side effects of these treatments are also present, such as depression, anemia, and fatigue. Therefore, these side effects have reduced the use of these treatments.
It was reported that protease inhibitors had been used to treat HIV, such as lopinavir and ritonavir. Protease inhibitors combined with ribavirin to treat SARS-CoV showed improved patient results compared to patients given only ribavirin treatment [77, 78]. 3CLpro and PLpro are ideal drug targets as these drugs are involved in the cleavage of polyproteins of viruses. These both also have distinct functions from cellular proteases. PLpro has better properties as it is responsible for interferons’ antagonism and viral replication. Recently several antiviral drugs like molecules or agents have been produced against 3CLpro and PLpro. These molecules were aided by the rapid report of crystal structures of these proteases [79]. Indeed, at first, PLpro was used as an excellent drug target for SARS-CoV, but recently, it has been discovered that some molecules also possess the potential activity against PLpro from MERS-CoV that targets PLpro from SARS-CoV. For instance, both 6-thioguanine and 6-mercaptopurine can inhibit SARS-CoV and MERS-CoV in vitro. However, the effectiveness of these molecules needs to be tested via in vivo trials [80].
Antibody and Plasma Therapy
Antibody therapies and plasma from recovering patients are the most proposed strategies to treat SARS-CoV. There are several benefits of using this method. For example, the survival rate increases with the case number; this is a safe treatment option. Moreover, this treatment is also best for generating monoclonal antibodies for human use with more efficacy and safety. However, using convalescent plasma to cure acute, severe respiratory disease in humans has rarely been reported, and there is no report regarding the use of monoclonal antibodies. It was noted in a post hoc meta-analysis comprising 32 studies regarding severe influenza and SARS that there was a significant reduction in mortality when plasma of recovering patients was used. However, there was a lack of a control group in this meta-analysis, with moderate to high-risk biases resulting in the low quality of the study. Therefore, a well-designed clinical trial regarding convalescent plasma is needed in severe respiratory infections [81].
Host-directed Therapies
The use of host-directed strategies may limit the replication of viruses. For example, transmembrane protease serine 2 (TMPRSS2) and possibly other host proteases can cleave the spike protein of SARS-CoV [82]. Cathepsin B and Cathepsin L also have similar functions in the cleavage. In the experiment, serine proteases of the mouse model were inhibited using camostat. This technique reduced the SARS-CoV's entry into the host and increased the host's survival rate [83]. However, targeting the viral proteases is better than targeting the host proteases as it has some unwanted side effects.
The attenuation of detrimental host responses is also defined as the host-directed strategy. Nevertheless, unfortunately, these processes are still unknown. There is limited work on animal models with other respiratory viruses, and in vitro studies reported that for the development of acute lung injury, anaphylatoxin c5a is essential and may reduce lung pathology [84]. The kinase inhibitor SB203580 inhibits the replication following the treatment of cells prior to SARS-CoV infection and MERS-CoV infection, but this treatment is effective after infection only for SARS-CoV and does not inhibit the replication of MERS-CoV after infection [85].
Concept of Quarantine in SARS-CoV
Quarantine is a period of isolation during which a person or animal that has a disease or that might have a contagious disease prevents the spread of the disease. The incubation period of SARS is 2–9 days; that is, a person who has been exposed to the disease and who may be affected is quarantined for almost 10 days to prevent the disease from spreading by implementing isolation to separate healthy people from sick ones.
