Drawing Parallels between SARS, MERS, and COVID-19: A Comparative Overview of Epidemiology, Pathogenesis, and Pathological Features

Abstract

Background:

Since November 2019, when the novel coronavirus arose in Wuhan City, over 188 million people worldwide have been infected with COVID-19. It is the third coronavirus outbreak in the twenty-first century. Until now, practically all coronavirus epidemics have occurred due to zoonotic spread from an animal or transitional host or through the consumption of their products. Coronaviruses can infect humans and cause severe illness and even death.

Material and Methods:

This review was designed to help us recognize and harmonize the similarities and differences between these three coronaviridae family members.

Result:

Measures aimed at containing the epidemic should be emphasized in this circumstance. Prioritizing and planning these activities require an understanding of the particulars of these three viruses. Given the pandemic’s enormous death toll and rapid spread, we should be cognizant of the parallels and differences between these three viruses. Additionally, this pandemic warns us to be cautious against the possibility of a future pandemic.

Conclusion:

We highlight the fundamental characteristics of coronaviruses that are critical for recognizing coronavirus epidemiology, pathogenesis, and pathological features that reveal numerous significant pathological attributes and evolutionary patterns in the viral genome that aid in better understanding and anticipating future epidemics.

INTRODUCTION

COVID-19 originated in Wuhan City in November 2019, resulting in an estimated 188 million cases globally. The illness has caused 3 million deaths across the world.[1] This is not the first time that a coronavirus has been responsible for an epidemic. Until now, practically all coronavirus epidemics have occurred due to zoonotic spread from an animal or transitional host or through the consumption of their products.

In 2002–2003, there was an epidemic of a novel illness, severe acute respiratory syndrome (SARS).[2,3] In mid-2004, the last known case of the SARS outbreak occurred. More recently, an epidemic of a similar but distinct coronavirus, the Middle East respiratory syndrome coronavirus, occurred (MERS-COV).[4] Although evidence indicates that bats may be infected with similar viruses, dromedary camels were the MERS-CoV reservoir.[5]

Unfortunately, there would be no “sure” way to stop the virus before an adequate vaccination coverage or cure is created.[6] As a result, understanding the virus’s nature, phylogeny, and transmissibility is critical in handling the pandemic. The collection and analysis of public health data about the outbreak and the epidemic were often critical in controlling and ending the pandemic.[7]

All three viruses are distinct in every manner from one another. Despite this, there are also similarities between these viruses. As for other coronaviruses, there is also more to learn about the novel virus. This review intends to compare and contrast the epidemiology, pathogenesis, and pathological features of the three coronaviruses and their associated diseases.

METHODS

We looked for relevant publications in the PubMed, Google Scholar, and Scopus databases. For the literature search, we used the terms SARS, SARS-CoV, MERS, MERS-CoV, SARS-CoV-2, COVID-19, and epidemiology, pathology, and pathogenesis.

RESULTS

Epidemiology

Human coronaviruses were first identified in 1965 by Tyrell and Bynoe and, ever since, have been an important cause of upper respiratory tract infections in both humans and animals. The first significant documented epidemic of the century caused by this family of viruses was severe acute respiratory syndrome coronavirus (SARS-CoV) between 2002 and 2003, which originated in a market in Guangdong, China, spreading to 30 countries in less than a year[8] followed by the Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in the Middle East in 2015, affecting over 2000 people, with the highest number of cases in Saudi Arabia and the Arabic Peninsula. The most recent member of this family, SARS-CoV-2, was responsible for the 2020 pandemic. Bats are the most common hosts for this virus family.[2,9] The intermediate hosts can be different. SARS-CoV has been isolated from civets, cats, raccoons, and ferret badgers,[3] MERS-CoV has been isolated from camel nose secretions,[10] and COVID-19 studies have revealed that the pangolin may be an intermediate host for the transmission of SARS-CoV-2 to humans.[11] The genetic evolution of these viruses is extremely fast. Because of their rapid genetic evolution, these viruses can cross species barriers and cause disease in humans, resulting in significant morbidity and mortality.

The basic case reproduction rate (BCR) varies within the family, with a R0 of more than 2 for SARS and COVID-19, indicating rapid disease spread, while MERS ranges from 0.8 to 1.3, indicating it is less transmissible.[12] R0 is mostly used for human-to-human transmission, and R0 differs when used for host-to-human transmission. SARS has a case fatality rate (CFR) of 9.5 percent, with 55.7 percent of those infected being women, and the average age of those infected being 40, with severity increasing with age and comorbidities.[13] MERS, on the other hand, has a higher CFR of 35%, with mechanical ventilation required in 50-89 percent of cases. Epidemiological details are further described in Table 1. The average age of MERS-infected patients was 50 years, with more than half reporting underlying cardiovascular or metabolic disease.[14]

Table 1.

Epidemiology of SARS, MERS, and COVID-19

	SARS-CoV[27-32]	MERS-CoV[27,30,32,33]	SARS-CoV-2[27,34-36]
	SARS-CoV[27-32]	MERS-CoV[27,30,32,33]	SARS-CoV-2[27,34-36]
R 0	2-5	0.8-1.3	3.3–5.7
Phylogenetic origin	Clade I, cluster IIb	Clade II	Clade I, cluster IIa
Total Confirmed Cases	8,422 cases	2,519 cases	97,264,519 cases
Case fatality Rate	9.5%	34.4%	2.16%
Possible Natural Reservoir	Bat	Bat	Bat
Possible Intermediary Host	Palm Civet	Dromedary Camel	Pangolin
First Case Identified	2002, Guangdong Province, China	2012, Saudi Arabia	2019, Wuhan City, China
Affected Countries	29	27	219
Receptor Involved	Human Angiotensin 1 converting enzyme 2 (ACE-2)	Dipeptidyl peptidase 4 (DPP4)	Human Angiotensin 1 converting enzyme 2 (ACE-2)

Concerning COVID-19, all age groups are susceptible to contracting the viruses, which cause a variety of symptoms; however, it causes a more severe process in older adults[15] and those who have underlying conditions such as hypertension, obesity, cardiovascular disease, chronic renal failure, diabetes, chronic obstructive pulmonary disease (COPD), and others.[16-18] Once within the human body, the virus prefers the respiratory system, particularly the nasal cavity, which has the highest viral load relative to the rest of the upper airways in both symptomatic and asymptomatic people.[19] The presence of the virus in the feces has been proposed as additional mode of transmission via aerosolized viral particles. This has been proved in many case studies.[20-22] However, in the case of COVID-19, no transplacental transmission was detected.[23] COVID-19 has a CFR of roughly 2% during the current pandemic, with a mean age of infection of 49 years old.[24-26]

Pathology and pathogenesis

SARS-CoV

Once inhaled, a few viral particles attach to the nasal mucosa and start replicating in epithelial cells of the nasal cavity.[37] The majority of the viral particles enter the lungs via aerosols. Upon entering the lungs, the virus infects pneumocytes. Human Angiotensin 1 converting enzyme 2 (hACE2) receptor is the cellular target of SARS-CoV, which was initially assumed to be present only on respiratory alveolar cells but was later reported to be present throughout the respiratory epithelium.[38] The presence of ACE2 receptors in various organs of the body nicely explains the tropism of the virus in support of the clinical features.[39-41] As an alternate receptor for the virus, and ICAM3-grabbing nonintegrin, a liver, lymph node, and dendritic cell-specific protein, was discovered.[42,43] However, according to a study, the affinity of this receptor is far lower than that of the ACE2 receptor.[42,44]

The pathological characteristics of SARS are primarily derived from autopsy reports. SARS-CoV sequences were recovered using fluorescent in situ hybridization (FISH) from infected patients’ alveolar pneumocytes (type II) and alveolar spaces, indicating the virus’s predilection for pneumocytes. Microscopically, epithelial cell necrosis, cilia loss, squamous metaplasia, and intrabronchial fibrin deposits were seen in the early stages of SARS.[45] Several individuals who died of SARS had multinucleated giant cells and pulmonary hyperplasia, suggesting the release of cytokines that most likely promoted epithelial hyperplasia and giant cell growth.[46] Several investigations have also found intracytoplasmic double-membrane viral inclusion bodies with diameters of 80-120 nm in these patients’ leukocytes.[47,48]

SARS-CoV has also been shown to infect Vero E6 cells and induce apoptosis in these cells. This cytopathic impact also contributes to the virus’s pathogenesis.[49] Several studies have found apoptosis of cells in multiple organs in SARS patients.[50,51] According to their findings, the virus increases the expression of transforming growth factor- in infected cells, forcing them to undergo apoptosis via the Fas-FasL pathway.[49] Edematous lungs with high gross weights and multiple regions of congestion, expansion of hilar and abdominal lymph nodes, and splenic atrophy have been the most visible visceral macroscopic changes in fatal SARS cases.[47,52] SARS-CoV has also been proven to infect the gastrointestinal system of the host. Using electron microscopy, viral particles were identified in mucosal epithelial cells (EM).[48]

Studies on SARS-CoV-infected patients revealed elevated levels of circulating tumor necrosis factor (TNF), interleukin 1 (IL1), IL6, and C-X-C motif chemokine ligand 10 (CXCL10), all of which are thought to have a role in the pathogenesis of SARS-CoV infections.[53-55] Changes in IL-4 and IL-10 levels, on the other hand, were substantially connected with the disease’s convalescent phase in Yuanchun Zhang et al.[56] study’s (p 0.01). TGF- and IL-8 levels were also observed to be decreased (p 0.01) in SARS patients. As with any other viral infection, severe SARS infection has been associated with increased interferon production.[57]

MERS-CoV

DPP-4 (CD26), a serine exopeptidase, is the main receptor for MERS-CoV. Exopeptidases are the only human coronavirus receptors discovered to date.[58,59] DPP-4 exopeptidase has a physiological role in the body by cleaving dipeptides from different molecules such as cytokines and hormones, the most frequent of which being Glucagon-like Peptide 1 (GLP1) and Gastric inhibitory polypeptide. It has the ability to cleave/bonds.[60] Immune regulation, signal transmission, and cell death are all mediated by DPP-4 receptors. This process is hampered by the virus’s interaction with this receptor. MERS-CoV virus interacts with the DPP-4 receptor via the N-terminus of its Spike (S) protein. According to one study, the S protein attaches to 2,3-sialic acid molecules on the host surface, as well as 5-N-acetylated neuraminic acid.[58] The S protein is divided into two domains: S1 and S2. The S2 protein undergoes a series of conformational changes when it binds to its receptor, culminating in the production of a pre-hairpin intermediate. By introducing the fusion peptide into the host cell membrane, the hydrophobic HR1 subunit expands from its pre-hairpin shape and enables fusion.[61]

MERS-CoV antigen expression was discovered in type I and II alveolar pneumocytes, ciliated bronchial epithelium, non-ciliated cuboidal cells of terminal bronchioles, and endothelial cells of pulmonary arteries in a research.[62] Unlike SARS-CoV, which only affects type II pneumocytes, MERS-CoV affects both kinds of pneumocytes. MERS-CoV may infect a wide spectrum of cells inside the body since its receptor is located in numerous sites.[30]

MERS-CoV has been reported to infect neutrophils and dendritic cells in addition to macrophages.[63-65] Patients with COPD and smokers were shown to be more vulnerable to MERS. This is because, unlike healthy humans, who express DPP-4 only in type II pneumocytes, these patients express DPP-4 receptors in both types of pneumocytes, increasing susceptibility because pneumocyte type I covers 96 percent of the alveolar surface area and participates in gaseous exchange.[66-69] Many animal investigations have revealed that animals with DPP-4 expression on type I pneumocytes had poorer clinical signs and prognosis.[70-73] Furthermore, MERS-CoV has been shown to upregulate mothers’ expression of decapentaplegic homolog 7 (Smad7) and fibroblast growth factor 2 (FGF2), both of which can promote apoptosis in renal and pulmonary cells, albeit the mechanisms remain unclear.

CoV-nsp1 is the virulence factor responsible for the bulk of MERS-cellular CoV’s effects. nsp1 aids in virion replication and monitors gene expression in host cells.[74] MERS-CoV replication patterns in human cell cultures have been extensively examined in vitro. In cultured respiratory tissue, the virus replicated efficiently.[75] MERS infection was characterized by severe acute hemorrhagic pneumonia, widespread alveolar destruction, mononuclear infiltrates, and blood and fibrin deposits in the airspaces.[76]

SARS-CoV-2

The novel virus, like SARS-CoV, enters the nasal cavity and replicates within the epithelial cells there.[37] At this time, virus RNA can be detected in nasal swabs using RT-PCR. At this point, a viral load can be estimated.[77] SARS-CoV-2 uses the same receptor as SARS-CoV, namely the hACE2 receptor. The receptor-binding domain (RBD) of the spike’s S1 subunit facilitates particle binding to the receptor.[78] The S1 subunit is divided further into two operational domains, one N-terminal and one C-terminal. The RBD is a 211 amino acid sequence (amino acids 319-529) in the S1 C-terminal domain of SARS-CoV-2 that plays a key role in viral entry and serves as a neutralizing antibody epitope.[79,80] Binding to hACE2 receptors causes these receptors to be downregulated.[81] As previously discussed, these receptors are found at numerous locations throughout our bodies. As with SARS-CoV, lung damage results from the inhibition of ACE2 and AT2 action.[44] Virus infection is detected by host cell pattern recognition receptors (PRRs), which signal downstream via recruited adaptor proteins, ubiquitin ligases, and kinases, resulting in the expression of several immune proteins such as IFNs, cytokines, and chemokines. The IFN pathway is frequently a primary focus of evasion due to its rapidity and efficacy in reducing viral contamination. CoVs have developed several mechanisms to target signaling components of many PRR-IFN pathways in order to live in host cells.[82] Much like SARS-CoV, this virus replicates inside ciliated bronchial epithelial cells and is responsible for causing a “cytokine storm” in the affected individual.[83-85] This is because SARS-CoV-2 probably restrains antigen-presenting cells that “present” to a host dendritic cell and macrophages, which, in turn, release pro-inflammatory cytokines. Acute respiratory distress syndrome and respiratory failure are the most common causes of death in COVID-19 cases, which are certainly caused due to the cytokine storm.[86] Many underlying diseases, including as cancer and autoimmune disorders, deteriorate as cytokine levels rise in COVID-19 patients. Furthermore, the deterioration of these conditions exacerbates the virus’s pathogenicity.[84] As a result, SARS-escape CoV-2’s of IFN signaling and reduced IFN synthesis in human peripheral blood immune cells may play a role in COVID-19’s active viral replication, dissemination, and extreme pathogenicity, although more research is needed to fully understand these alleged evasion routes.[87] Apart from interacting with the immune system, it has been linked to the development of deadly diseases such as mucormycosis, klebsiella, and others after the infection has cleared, possibly due to immune system interference.[88,89]

DISCUSSION

Human coronaviruses have been implicated in both human and animal upper respiratory tract diseases. Until now, practically all coronavirus epidemics have resulted from zoonotic transmission from an animal or intermediate host, or from ingesting their products.[9] SARS-CoV has been identified from civets, cats, raccoons, and ferret badgers,[3] MERS-CoV has been isolated from camel nose secretions,[10] and research on COVID-19 have suggested that the pangolin is probably an intermediary host for increasing SARS-CoV-2 transmission to humans.[11] The BCR varies within the family, with a R0 of more than 2 for SARS and COVID-19, indicating rapid disease dissemination, while MERS ranges from 0.8 to 1.3, indicating it is less transmissible.[12] In comparison to MERS-CoV, this suggests that the probability of transmissibility is quite high in the case of SARS and SARS-CoV-2, and hence the potential to produce future pandemics. R0 is usually utilized for human-to-human transmission, and R0 differs when used for host-to-human transmission. Unlike the COVID-19 pandemic, no successful public health interventions were implemented during the SARS or MERS pandemics.[14]

Among the three, SARS-CoV-2 has had the lowest CFR, yet spreading worldwide and causing a pandemic. Although MERS-CoV and SARS-CoV did not have the potential to spread worldwide and cause the pandemic, SARS-CoV-2 demonstrated the same. Transmission through healthcare settings is the most common way for SARS and MERS to spread between adults. According to a Hong Kong study on SARS, 49.3 percent of infected people worked in clinics, hospitals, or nursing homes, and healthcare workers accounted for 23% of infected people.[13]

Although the SARS-CoV, MERS-CoV, and SARS-CoV-2 viruses are structurally identical and rely on the S protein to link to target cellular receptors, the pathophysiology associated with each of these infections is vastly different. Unlike SARS and MERS, COVID-19 is a multisystem illness with main involvement of the lungs and secondary involvement of the heart, brain, and, less commonly, the gastrointestinal tract, kidneys, integumentary, and endocrine systems. All of these instances had pathology linked with inflammatory and immune response activation.

In terms of pathological aspects, the COVID-19 exhibits exudative diffuse alveolar damage without hyaline membrane development in the early stage, but hyaline membrane formation in addition to DAD in the later stage. Pleural effusion and adhesion, mucous plug development, infiltration of macrophages, neutrophils, and lymphocytes, and microvascular damage (microthrombi) are all possible. When it comes to MERS and SARS, the key characteristics are acute exudative DAD (fibrinous interstitial and airspace and hyperplastic pneumocytes) and proliferative DAD (alveolar epithelial cells impairment, alveoli collapse, and fibrous tissue in alveolar spaces). The distinctions in all of these scenarios are extremely general. Autopsies revealed that COVID-19 patients had a systemic viral infection, as well as substantial activation of the inflammatory and immune systems. Patients infected with SARS-CoV-2 have a hypercoagulable baseline and are more likely to develop pulmonary thrombotic microangiopathy, deep venous thromboses, and severe pulmonary thromboembolism, suggesting that COVID-19 is a vascular sickness.[90,91]

Implications of the study: SARS-CoV-2 and COVID-19 literature have recently seen a tremendous uptick. Many previously unknown characteristics of the novel virus have been revealed so far, with many more still to be discovered. Although this review did not address and compare the clinical and laboratory features differences of these three coronaviruses, studying the pathological and epidemiological differences is important not only for the SARS-CoV-2 pandemic but also for future unsaid coronavirus pandemics or any other virus pandemic, particularly those infecting the respiratory tract. Understanding the pathology and pathogenesis of virus infection and disease will undoubtedly aid clinicians in planning the management approach of suspected cases (as well as any similar cases arising from any future outbreak) and pharmacologists in developing new drug therapies against infections from these viruses.

CONCLUSION

In this review, we highlighted the fundamental characteristics of coronaviruses that are critical for understanding coronavirus epidemiology, pathogenesis, and pathological features. The recurring development of highly pathogenic human CoVs has posed a significant burden and hazard to people. This epidemic is anticipated to be underpinned and eliminated through global contact and collaboration among many nations. This study focuses on many important clinical and epidemiological characteristics, as well as variations between these viruses, in terms of epidemiology and pathology, which help in better understanding and forecasting future outbreaks. Gaining the knowledge and particulars about the contrast between these three viruses will be a crucial part of the view of epidemiologists, pathologists, and clinicians. This implies that they should be especially vigilant about the precautionary actions indicated earlier.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.