Past and current coronavirus outbreaks; Focusing on coronavirus disease 2019 in comparison with severe acute respiratory syndrome and middle east respiratory syndrome.

Background: Coronavirus Disease 2019 (COVID-19) is currently the most significant public health concern globally, having affected more than 24 million patients and caused an excess of 0.83 million deaths since its emergence in December 2019 in the city of Wuhan, China. There have been similar Coronavirus outbreaks in the past, namely Severe Acute Respiratory Syndrome Coronavirus-1 (SARS-CoV-1) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). In this review article, we discussed the epidemiology, virology, clinical presentation, diagnostic approaches, and effective treatment modalities for COVID-19 in light of existing literature. Methodology: The aim of conducting this systematic review was to compare the three human coronavirus outbreaks: Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and Corona Virus Disease 2019 (COVID-19). Multiple search engines were used and PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines were referenced. Results: The findings suggest that COVID-19 shares substantial characteristics with both SARS and MERS, SARS being more closely related to COVID-19 in terms of epidemiological characters, particularly their viral reservoirs. SARS-CoV-1 and SARS-CoV-2 use the same receptor to gain access to the host cells, while MERS-CoV uses a different entry point. The radiological manifestations of SARS, MERS and COVID-19 are similar as well. Conclusion: The recurrent appearance of coronaviruses in the human population makes it crucial to study them in great details. Furthermore, owing to its similarity to previous coronavirus outbreaks, the lasting effects of COVID-19 on pulmonary tissue must be investigated. Moreover, at the time of writing this paper, no vaccines are available against COVID-19, a facet that requires extensive global research.


Introduction
In December 2019, reports started emerging about clusters of patients being affected by a pneumonia-like febrile illness in Wuhan, China. Initially considered an illness of unknown origin, the disease was later attributed to a novel mutation of coronavirus following the isolation of the strain (SARS-CoV-2) from the bronchoalveolar secretions of the affected patients 1 . As of 30th August 2020, COVID-19 has affected 24,854,140 people across 216 countries with a death toll of 838,924 globally 2 .
Coronaviruses have been identified as a family of enveloped RNA viruses that are responsible for a vast array of respiratory tract infections in humans, with variable manifestations ranging from mild, self-limiting upper respiratory tract symptoms to more critical lower respiratory tract manifestations like Acute Lung Injury also known as ALI and Acute Respiratory Distress Syndrome also termed as ARDS 3,4 . Moreover, in the last two decades, additional strains belonging to the coronavirus family have been implicated in two similar and sizeable epidemics: The Severe Acute Respiratory Syndrome (SARS) in 2003 and the Middle East Respiratory Syndrome (MERS) in 2012 5 . This mini review aims to compare SARS-CoV-2 to SARS-CoV-1, and MERS-CoV in terms of epidemiological characteristics, virology, clinical course, diagnostic approaches, and treatment modalities in light of existing literature.

Origin, reservoirs and hosts
The first clinical case of COVID-19 was reported in Wuhan, a city of Hubei province, China, in December 2019 6 . About 66% of the initial cluster of 41 confirmed cases could be traced back to the seafood market in Huanan, Wuhan, China, that was considered ground zero for the COVID-19 outbreak 7 . Many of these index patients worked at the market or were regular patrons. Moreover, SARS-CoV-2 RNA was detected in the environmental samples acquired from the Huanan seafood market in December of 2019, further strengthening the hypothesis of the Huanan seafood market being the source of COVID-19 6 .
Previously, the SARS-CoV-1 outbreak of 2002 originated in southern China and, more specifically, in the city of Foshan, Guangdong province 8 . Subsequent studies found that bats were the natural reservoir for SARS-CoV-1 with Himalayan palm civets (Gem-faced civets or masked palm civets), Raccoon dogs, and Chinese-ferret-badgers acting as intermediate hosts 9 . Recently, viral genomic sequencing has determined that SARS-CoV-2 is almost 80% identical to SARS-CoV-1. Owing to this fact as well as the evolutionary analysis of the virus, bats are being postulated as the natural reservoir of SARS-CoV-2 2,6,7 , while pangolins, snakes, and turtles are thought to be potential intermediate hosts 10 .
Conversely, the earliest clinical case of MERS was reported in a different geographical setting, the Kingdom of Saudi Arabia in 2012 with infected Dromedary camels being implicated as the primary host. However, in light of the virus's genomic analysis, it is postulated that the virus may have chiropteran (bat) origins and was transmitted to camels at some point in the past 11 .

Mode of Transmission
According to the information currently available, there are two modes of transmission of SARS-CoV-2: Droplet-borne and fomite-borne. In certain circumstances, airborne transmission can occur as well 12 . Droplet-borne transmission can occur within 1 m of an infected person when they cough or sneeze. It can also occur through fomites in close proximity of the infected person 13 . However, the airborne transmission may occur under specific conditions only, particularly when aerosolgenerating procedures are performed (CPR, endotracheal intubation, tracheostomy, airway suctioning, and nebulized medication administration NIPPV ventilation, proning the patient, disconnecting a ventilator) 12 . Isolated incidents of vertical transmission of SARS-CoV-2 as well as the virus's presence in the fecal matter have also been reported 12,14 . Similarly, the route of transmission of SARS-CoV-1 was determined to be via respiratory droplet inhalation. In some cases, transmission through the fecal-oral route through contact with contaminated fomites has been noted. A vast majority of the cases were acquired through the nosocomial route 8 .
In contrast, although the transmission of MERS-CoV occurred through human-to-human contact in both community and nosocomial settings, the majority of cases occurred in healthcare settings with poor infection control practices. Sustained transmission from human-to-human has not been noted to date 11 .

Infectivity
"Basic reproductive number" (Ro) determines the incidence and prevalence of contagion and is defined as the average number of secondary cases generated by an index case in a predisposed group of individuals. Furthermore, a Ro that is not much larger than 1 indicates a high chance that the infection will likely fade away instead of snowballing into a pandemic 15,16 . The Ro estimates for SARS-CoV-1 ranged between 2 and 3 17 . Conversely, the Ro for MERS-CoV was calculated to be 0.69 18 . Based on recent studies, the estimated basic reproductive number of SARS-CoV-2 is about 2.2 16 .

Incubation Period
It was postulated that a longer incubation period might be the basis for the rapid spread of SARS-CoV-2 as longer incubation periods are associated with high rates of asymptomatic or subclinical infection in immunocompetent people 19 . However, the differences between estimated incubation periods of SARS-COV-2 (mean incubation period 5.2 days) 15 , SARS-CoV-1 (mean incubation period 4.0 days) 20 and MERS-CoV (Incubation period 4.5-5.2 days) 21 were negligible, disproving this hypothesis 19 .

Incidence and Case Fatality Rate
As of 30 th August 2020, 24,854,140 confirmed cases of COVID-19 have been reported across 216 countries globally, with 838,924 confirmed deaths 2 . The case fatality rate varies from country to country, from less than 0.1% to over 25% 22

Virology of Coronavirus
They are enveloped, positive-sense, singlestranded RNA viruses that belong to the family of Beta-corona virus, a subfamily of Coronavirinae 24 . The virions are spherical, and the most significant feature of coronaviruses is that they possess clubshaped spiky pointed projections on their external surface. Spikes are the hallmark features of the virion and impart the semblance of a solar radiating corona, hence the name, coronaviruses. The nucleocapsids of coronaviruses are located within the viral envelope and are helically symmetrical, which is an anomaly among positivesense RNA viruses, but a frequent occurrence in negative-sense RNA viruses 25 .
The structural proteins of coronaviruses include spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins. The heavily N-linked glycosylated protein employed to gain entry to the endoplasmic reticulum is called the S protein (~150 kDa). It does so by an N-terminal signal sequence. Homotrimers of the S protein are attributed for the distinctive spike structure on the surface of the virus 26,27 . A fifth structural protein, named the Hemagglutinin-Esterase (HE), found only in some of β-coronaviruses mimics hemagglutinin, binding sialic acids on glycoproteins on the surface and containing acetyl-esterase activity 28 . Describing the other three structural proteins is beyond the scope of this study.
MERS-CoV enters into the host cells by binding to human receptor dipeptidylpeptidase-4 (hDPP4) on the target cell surface via its receptor-binding domain (RBD) present on its spiky glycoprotein, in contrast to SARS which gains access to the target cells via angiotensin-converting enzyme 2 (ACE2) [29][30][31] . Host proteases are used by MERS-CoV to enter into pulmonary cells 31 . Furin protease activates the spike protein on the viral envelope. This reaction is the mediator of membrane fusion and eventually supports the viral access to the host cell 30 . Consequently, protease inhibitors block MERS-CoV entry into cells 32 .

Clinical Features
The three coronavirus infections present mainly with fever and cough, frequently leading to pneumonia with poor clinical outcomes often associated with elderly individuals, or those with associated comorbidities 33,34 .

SARS CoV 2 Presentation
Patients affected by SARS CoV 2 have presented with a vast array of clinical features from mild, moderate, and severe to rapidly progressive to fulminant disease 33 . The signs and symptoms involving the upper respiratory tract include high to low-grade fever, cough, runny nose, malaise, and fatigue. Moreover, symptomatology may progress to include severe lower respiratory tract or even extra-pulmonary manifestations like severe shortness of breath, rashes, changes in the sense of smell and taste, headache, hemoptysis, diarrhea, and vomiting. The COVID-19 symptomatology is nonspecific, and clinical profile may range from asymptomatic to severe pneumonia and eventual death 33 . Zhang et al. analyzed 140 COVID-19 patients at the Hospital of Wuhan and observed that a vast majority of the patients affected were in the middle-aged and elderly age group, with an almost 1:1 male-female ratio. Fever (91.7%), fatigue (75.0%) and cough (75.0%) were the predominant symptoms in patients with COVID-19. Over a third of the described patients complained of chest tightness, dyspnea and gastrointestinal symptoms, namely nausea, anorexia, and diarrhea 35 .

MERS Presentation
MERS-CoV infected patient's clinical symptoms were comparable with that of SARS but exhibited a unique clinical course and with a high mortality rate of 34.4%. Most patients had symptoms of influenza-like illness (ILI) such as pyrexia, rhinorrhea, non-productive cough, sore throat, headache, myalgia, nausea, vomiting, diarrhea, and abdominal pain 36,37 .

SARS CoV 1 Presentation
A study conducted by Jann-Tay Wang et al. in one of the primary care facilities for SARS outbreak in Taiwan in the year 2003 stated the primary presenting complaints of patients with SARS were fever, myalgia, cough, dyspnea, and diarrhea 38 , with the severity of the disease being dependent on the host's individual characteristics 39 . Respiratory distress was present in 90.8% of such patients during the course of their hospitalization 38 . The duration from onset of the infection to severe respiratory distress was found to be an average of 9.8±3.0 days 38 .

Diagnostic Investigations
As is the case with any novel pathogen, COVID-19 was initially a diagnostic dilemma for medical practitioners. However, considerable progress has been made with respect to diagnostic testing since the onset of the pandemic.

Screening
The criteria for suspected cases of COVID-19 include positive symptomatology, history of travel to "hot-spots" of SARS-CoV-2 or having close contact with probable or confirmed cases of COVID-19 40 . All patients that fulfill the criteria for suspected cases of COVID-19 should undergo screening for confirmation of the disease. For confirmation of COVID-19, clinical specimens are subjected to serological or molecular testing. Serological testing entails detecting SARS-CoV-2 specific proteins using ELISA or Western blot, while molecular analysis involves detecting SARS-CoV-2 viral nucleic using RT-PCR 41 . Clinical samples to be analyzed are acquired from the upper respiratory tract (Swabs from the nasopharynx or the oropharynx, or nasopharyngeal aspirate) or, if possible, from the lower respiratory tract [Expectorated sputum, bronchoalveolar lavage (BAL) or endotracheal tube aspirate]. Additionally, secretions from the lower respiratory tract merit a higher consideration in terms of diagnosis, but procedures like BAL are associated with a higher degree of risk to the medical personnel involved in the procedure 42 . Furthermore, the virus can also be detected in other bodily secretions, namely the blood and feces 43 .
Similarly, RT-PCR targeting specific areas of SARS-CoV-1 and MERS-CoV genomes remains the mainstay for laboratory confirmation of SARS and MERS 44,45 . Moreover, over the years, a myriad of assays have been developed for the detection of anti-MERS-CoV antibodies, including ELISA, IFA, and neutralization assays 46 , while serological testing for SARS-CoV-1 employs ELISA and Western blot to detect SARS-CoV-1 specific proteins 47 .

Radiological Investigations
Although the diagnosis of COVID-19 and other SARS-like CoV associated illnesses depends mostly on the patient's symptomatology, serological and molecular assays, radiological imaging of the chest plays a vital role in determining the extent of pulmonary involvement as well as the progression of the disease.

SARS Chest x-ray Manifestations
About 80% of the patients with SARS usually show abnormal manifestations on initial chest radiographs, with most cases showing unilateral and poorly-defined zones of air-space opacities predominantly involving the peripheries of the lower lung zones. The pulmonary involvement is estimated to be focal in about 50% cases and multifocal in the remaining patients. Diffuse pulmonary manifestations can be appreciated in less than 10% cases 48 . Over the next 6-12 days, the chest x-ray shows progressive multifocal areas of consolidation unilaterally or bilaterally. However, in about 25% of the cases, unilateral foci of consolidation persist 49 .

CT Chest Manifestations
The most common findings on CT chest involve the lower zones of the lungs. These radiological manifestations include bilateral peripheral lesions showing ground glass opacifications or mixed ground-glass opacifications with consolidation, predominantly in the lower lobes of the lungs. Other manifestations of clinical significance include interlobular septal thickening and interlobular interstitial thickening 50

MERS Chest X-ray Manifestations
Similarly, early chest radiographs will show a certain degree of abnormality in 83% of the cases of MERS with unifocal peripheral ground-glass opacities being the commonest radiological manifestation to be noted. Although the lesions initially have a predilection to the middle and the lower zones' peripheries, progression to the upper and perihilar zones with the advancement of the disease. Other findings of clinical interest include consolidation, mixed ground-glass opacification with consolidation, and consolidation with airbronchogram 51 .

CT Chest Manifestations
The CT chest of MERS patients will frequently show peripheral ground-glass opacification, predominantly involving the basal lung zones. Moreover, mixed ground-glass opacities and consolidation, pleural effusion, interlobular thickening may also be observed 52 . Rarely, tree-inbud opacities and cavitation be appreciated as well 53 .

COVID-19 Chest X-ray Manifestations
Typically, the chest radiographs of patients with COVID-19 show manifestations similar to other CoV pneumonia: Patchy or diffuse asymmetric areas of air-space consolidation involving the lower lung zones. However, the findings in COVID-19 are bilateral as opposed to other CoV pneumonia and usually peak in severity about 10-12 days after the onset of symptoms 54,55 .

CT Chest Manifestations
Of the initial cluster of SARS-CoV-2 positive patients reported, bilateral lung involvement was noted in 40 out of 41 cases on CT chest. The majority of the ICU patients showed consolidation while ground-glass appearance was observed in non-ICU patients 56 . A recent study (Chung M. et al.) analyzed the CT scans of 21 patients with COVID-19 and noted the findings in the table 1 57 . Moreover, CT chest appears to be a valuable tool for the initial screening of suspected COVID-19 cases, owing to its high sensitivity of (false-negative rate: 3.9%) 58 . Its usefulness was further highlighted when reports emerged of five confirmed COVID-19 patients who initially tested negative on RT PCR but had radiographic manifestations suggestive of COVID-19 and later tested positive on repeat swab test 59 .

Long-Term Follow-up Imaging
Follow-up CT chest in recovered SARS patients may show transient interlobular septal thickening and reticulation over weeks to months in addition to areas of air trapping from injury to the ciliated respiratory epithelium 60,61 . Evidence of fibrosis (intra-lobular and inter-lobular reticulation, traction, honey-combing, bronchiectasis) might be observed in about 33% of persistent pulmonary symptoms 62 . Likewise, MERS' post-recovery cases may show transient interlobular septal thickening and radiological findings consistent with fibrosis 63,64 .
Although long-term manifestations of COVID-19 have yet to be reported, follow-up imaging using CT chest is highly recommended to evaluate longterm or permanent lung changes in light of SARS and MERS' experiences.

Management of SARS CoV 2
At this point in time, there are no specific antiviral drugs formulated against COVID-19. As such, the mainstay of treatment is still supportive care and invasive and non-invasive ventilation modalities 65 . For prevention and timely management, viral testing should be initiated early for disease confirmation 65 . Based on experiences of MERS, if the patient's tests show a negative result despite strong suspicion of having SARS-CoV-2 infection, a second test is recommended from various respiratory sites including sputum, nose, and endotracheal aspirate 64 .

Isolation
As soon as the COVID-19 suspected patient is confirmed positive, he/she must be shifted to a single occupancy room, and infection prevention and control principles (IPC) must be undertaken. The patient ideally, should be shifted to an isolated room with negative pressure. Providers must practice contact, airborne and droplet precautions 64 .

Supportive Management
Empirical therapy for community-acquired pneumonia should be considered, utilizing antibiotics which are active against typical as well as atypical respiratory pathogens and clinical usage of fluids for hydration. Currently, there is no known treatment or vaccine effective for combating the disease.
However, individual experimental medications and drug combinations, including Remdesivir, Lopinavir-Ritonavir, or Lopinavir-Ritonavir, and Interferon Beta-1b, are under clinical trials around the world and may be considered for sympathetic use in critically ill patients 65,66 . Given the enormous cytokine exodus induced by SARS-CoV-1, MERS-CoV, and SARS-CoV-2 infections 67 , corticosteroids have been frequently utilized to treat patients at critical stages of the diseases, under the pretext of reducing inflammation induced lung damage. Despite the justified use, current evidence suggests that corticosteroids do not affect mortality, rather they delayed the

Management of SARS CoV 1
According to reports, SARS-CoV-2 shares around 80% of its genome with SARS-CoV-1, so the line of treatment is very similar to SARS-CoV-2 73

Conclusion
In conclusion, the frequent emergence of CoVdiseases along with their spontaneous mutations, high transmissibility and pathogenicity has made it imperative for investigating them in greater detail. This is not only to elucidate their propensity for inter-specie transmission, reservoirs, replication process, and pathogenesis as well as the long term pulmonary effects of the disease on radiological imaging. Numerous clinical trials are underway to develop newer drugs and determine the efficacy of existing modalities in treating COVID-19, including previous antiviral drugs and convalescent plasma, each of which has its pros and cons. Moreover, rapid vaccine development follows the drastic mutations in the viral genome and penetrance in hosts' cells over a large scale; this aspect of the disease needs substantial funding and research globally.

Conflicts of Interest
None.