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INFECTIOUS DISEASES: Edited by Michael S. Niederman and Alimuddin Zumla

Lethal zoonotic coronavirus infections of humans – comparative phylogenetics, epidemiology, transmission, and clinical features of coronavirus disease 2019, The Middle East respiratory syndrome and severe acute respiratory syndrome

Hui, David S.a,b; Zumla, Alimuddinc,d; Tang, Julian W.e

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Current Opinion in Pulmonary Medicine: May 2021 - Volume 27 - Issue 3 - p 146-154
doi: 10.1097/MCP.0000000000000774
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Abstract

INTRODUCTION

Coronaviruses (CoV) were first identified as human pathogens in the 1960s. Over the past two decades, three lethal zoonotic coronaviruses have jumped the species barrier and cause lethal disease in humans: severe acute respiratory syndrome coronavirus (SARS-CoV-1) emerged in China in November 2002 and caused the SARS epidemic and disappeared by 2004; The Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) causing MERS, first identified in September 2012 in Jeddah, Saudi Arabia, 2012 and continues to cause sporadic and localized outbreaks; and SARS-CoV-2, the cause of the ongoing global coronavirus disease 2019 (COVID-19) pandemic. In this article, we review the phylogenetics, epidemiology, transmission, and comparative clinical features of SARS-CoV-2, SARS-CoV-1, and MERS-CoV. 

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Box 1:
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CLASSIFICATION AND PHYLOGENETICS

CoVs (order Nidovirales, family Coronaviridae, subfamily Coronavirinae) are a group of enveloped, positive-sense, highly diverse, single-stranded, RNA viruses that may cause respiratory and diseases of other systems of varying severity in many animal species, including humans. There are four genera of CoVs including αCoV, βCoV, γCoV and δCoV [1]. Prior to the SARS epidemic, the main coronaviruses causing respiratory tract infection in humans were HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1. A novel group 2b βCoV (SARS-CoV-1) was discovered in March 2003 as the causative agent responsible for SARS outbreaks [2]. SARS-CoV-2 emerged at the end of 2019 in Wuhan, China [3▪▪] and led to a pandemic since March 2020. SARS-CoV-1 and SARS-CoV-2 and MERS-CoV are βCoV. SARS-CoV-1 and SARS-CoV-2 belong to lineage B whereas MERS-CoV belongs to lineage C (Fig. 1) [4].

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FIGURE 1:
A maximum likelihood tree of the full genomes of the 7 known human coronaviruses, including SARS-CoV-1, SARS-CoV-2 (including South African 501Y.V2, Brazilian B.1.1.28(K417N/E484K/N501Y) and UK VOC-202012/01 variants), MERS-CoV and seasonal coronaviruses 229E, OC43, NL63, HKU1. Sequences were aligned using MAFFT (https://www.ebi.ac.uk/Tools/msa/mafft/) and manually edited using BioEdit v7.2.5. Phylogenetic tree construction was performed using FastTree v2.1.11 and displayed using FigTree v1.4.4. Shimodaira-Hasegawa-like local values (as implemented in FastTree) are shown as branch supports. MERS-CoV, The Middle East respiratory syndrome; SARS-CoV, severe acute respiratory syndrome-coronaviruses.

CORONAVIRUS DISEASE 2019

Epidemiology

On December 31, 2019, unusual cases of pneumonia in Wuhan, China were reported to the World Health Organization (WHO) and the outbreak was associated with a seafood market where game meat was also sold. A novel CoV, later named as SARS-CoV-2, was identified as the cause of this outbreak on January 7, 2020. There was 79.6% similarity of SARS-CoV-2 in genetic sequence to SARS-CoV-1 and 96% similarity at the whole genome level to a bat CoV [5]. SARS-CoV-2 appears to be a mutated version of bat CoV-RaTG13, detected and isolated in bats from the species Rhinolophus affinis in Yunnan Province in China, between 2015 and 2017 [5,6]. Lu et al.[7] examined the genome from nine patients (eight of whom had visited the Huanan seafood market in Wuhan) and found that SARS-CoV-2 was more related to two SARS-like bat CoV from Zhoushan in eastern China: bat-SL-CoVZC45 (with 87.99% identity) and bat-SL-CoVZXC21 (with 87.23% identity), and more distant from SARS-CoV-1 (about 79%) and MERS-CoV (50%) The data suggest that bat SARS-like CoVs and human SARS-CoV-2 might share the same ancestor [8]. Pangolins were implicated as a potential intermediary source but there was only 91.02% similarity between pangolin-CoV and SARS-CoV-2 at the whole-genome level [9]. Minks were the first farm animals to experience COVID-19 outbreaks in Europe and appear to be a highly susceptible species to SARS-CoV-2 [10]. It is plausible that the widespread infection on the mink farms is related to human-to-animal transmission. Nonetheless, evidence of mink-to-human transmission is limited to one worker, according to the preliminary sequencing data [10]. Although dogs and cats can be infected, it does not necessarily mean that they are potential reservoirs of the original virus and most of these animals had mild to no symptoms [10,11].

Despite lockdown of Wuhan city on January 23, 2020, the outbreak quickly spread throughout China and many other countries by travelers from Wuhan. The outbreak was declared a Public Health Emergency of International Concern on January 30, 2020 and the WHO announced a name on February 11, 2020 for the new CoV disease as COVID-19. On March 11, 2020, the WHO announced the extent and evolution of the global outbreak of COVID-19 as reaching a pandemic [12].

As of February 9, 2021, more than 106 million cases of COVID-19 have been confirmed worldwide with over 2.3 million deaths [13]. Common presenting symptoms of COVID-19 include fever (44% on admission and then increased to 89% during hospitalization), cough mainly nonproductive (67.8%) whereas diarrhea is uncommon (3.8%). The median incubation period is 4 days (interquartile range, 2–7). The absence of fever in a high proportion of patients makes it difficult to detect these cases in the community in the early stage of infection [14▪▪].

According to the WHO, people aged ≥60 years, and those with underlying medical comorbidity (such as hypertension, cardiac and pulmonary problems, diabetes mellitus, obesity, or cancer) are at higher risk of developing serious illness from COVID-19 [15]. In the USA, the prevalence of reported severe outcomes increased with age; the percentages of hospitalization, intensive care admissions, and deaths were highest among persons aged ≥70 years, regardless of underlying conditions, and lowest among those aged ≤19 years [16]. Age is an independent risk factor for severe illness, whereas the risk in older adults is also partly related to the increased likelihood that older adults have other underlying medical conditions [17].

Transmission

Human to human transmission has been documented in the Wuhan seafood market outbreak [3▪▪]. There is evidence that patients in the presymptomatic stage and those with mild disease may transmit infection to others [18]. At least 50% of community transmission may be related to asymptomatic infection [19]. Laxminarayan et al. have shown that 5% of infected individuals account for spreading of 80% of cases [20]. Transplacental transmission of SARS-CoV-2 infection has been documented [21].

Viral kinetic studies have shown that the viral load peaks on days 2–3 of the patient's illness [22] and this explains the high potential of SARS-CoV-2 in causing community transmission among close contacts. Serology response starts on day 7 of illness whereas PCR positivity in deep throat saliva could last for at least 3 weeks in one-third of patients [23].

There have been increasing reports of COVID-19 outbreaks in long-term care facilities (LTCF) from countries in Europe and in the UK. High community prevalence of COVID-19 increases the risk of importation of the virus to institutions, possibly through asymptomatic visitors and staff with COVID-19. With the increased vulnerability of LTCF residents, COVID-19 outbreaks in these settings could have devastating effects. Increased morbidity and mortality have been reported in LTCF even with the implementation of specific control measures in these settings. The overall risk related to COVID-19 infection is assessed as being very high [24]. Short-range airborne transmission is possible in the presence of poor environmental ventilation [25].

The emergence of genetic mutants such as D614G, N501Y and the related South African (501Y.V2), Brazilian (B.1.1.28: K417N/E484K/N501Y) and UK (VOC-202012/01) variants has led to an increase in transmissibility in the community without increase in severity (Fig. 1) [26]. How wide these new variants have spread and how they may affect existing treatments and vaccines remain to be defined.

SEVERE ACUTE RESPIRATORY SYNDROME

Epidemiology

SARS-CoV-1 first emerged in Guangdong in the southern part of China in November 2002 before spreading to Singapore, Canada, Vietnam, and other countries by travelers through Hong Kong (HK) in February and March 2003 [27,28]. In November 2002, there was an unusual outbreak of ‘atypical pneumonia’ in Foshan, Guangdong Province in China, with a very high rate of nosocomial transmission to healthcare workers (HCWs) [29,30]. A retrospective study of 55 patients hospitalized with ‘atypical pneumonia’ in Guangzhou between January and February 2003 revealed positive SARS-CoV1 in their nasopharyngeal aspirates (NPA) whereas 48 (87%) patients had positive antibody to SARS-CoV-1 in their convalescent sera. Genetic analysis subsequently showed that the SARS-CoV-1 isolates from Guangzhou shared the same origin with those in other countries, with a phylogenetic pathway that matched the spread of SARS-CoV-1 to other parts of the world [31].

In March 2003, a novel CoV was confirmed as the causative agent for SARS, and recently referred to as SARS-CoV-1. A retrospective serologic survey suggested that cross-species transmission of SARS-CoV-1 or its variants from animal species to humans might have occurred frequently in the wet market where a high sero-prevalence of 16.7% was detected among asymptomatic animal handlers [32]. It was once thought that masked palm civets might have been responsible for transmission of SARS-CoV-1 to humans following detection of a close variant of SARS-CoV1 in 2003 from palm civets in Dongmen market, Shenzhen [33]. During the small-scale SARS-CoV1 infection outbreaks in late 2003 and early 2004 in China, three of the four patients had direct or indirect contact with palm civets [34,35]. However, viral genomic sequence analysis revealed that the SARS-CoV-like virus had not been present among masked civets in markets for that long. CoVs highly similar to SARS-CoV-1 were isolated in horseshoe bats in 2005 [36,37]. These bat SARS-like CoVs shared 88–92% sequence homology with human or civet isolates and the data suggest that bats could be a natural reservoir of a close ancestor of SARS-CoV-1 [38].

A 64-year old nephrologist who came from southern China to HK on February 21, 2003 was the index case causing subsequent outbreaks of SARS-CoV-1 infection in HK, Singapore and Toronto [27,28,39,40]. Sixteen hotel guests/visitors were infected by the renal physician whereas staying or visiting friends on the same floor of the hotel M, where the physician had briefly stayed. Through international air travel, these visitors spread the infection to 29 countries/regions with a total of 8098 cases and a mortality rate of 774 (9.6%) by the end of the epidemic in July 2003 [41].

Transmission

SARS-CoV1 appears to have spread by close person-to-person contact via droplet transmission or contact with fomite [42]. Super-spreading event was a hallmark of SARS-CoV-1 infection, as reflected by the nosocomial outbreak at a major teaching hospital in HK where 138 subjects (many being HCWs and previously healthy) were infected within a fortnight following exposure to one patient (a visitor of Hotel M), who was hospitalized with community-acquired pneumonia to a general medical ward [27,43]. This super-spreading event was likely caused by several factors including the use of a jet nebulizer for delivering bronchodilator to the index case, overcrowding, and poor ventilation in the hospital ward [27,43]. In addition, the temporal-spatial spread of SARS-CoV-1 among inpatients in the index medical ward of the hospital in HK was consistent with airborne transmission [44].

In addition, SARS-CoV-1 might have spread by opportunistic airborne transmission in a major community outbreak involving over 300 residents in a private residential complex, Amoy Gardens, in HK [45,46]. Drying up of ‘U-shaped’ bathroom floor drains and backflow of contaminated sewage (from a SARS-CoV1 patient with renal failure and diarrhea) related to negative pressure generated by the toilet exhaust fans might have created infectious aerosols that moved upward through the warm airshaft of the building. Based on analysis of the distribution of all confirmed cases, airborne spread was the most likely explanation in the Amoy Gardens outbreak and the SARS-CoV-1 could have spread over 200 m to nearby residential complexes [47]. Air samples obtained from a hospital room in Toronto occupied by a SARS patient and swab samples taken from frequently touched surfaces in rooms and in a nurses’ station in Toronto were positive by PCR testing [48]. These data suggest the possibility of airborne transmission and stress the importance of taking appropriate respiratory protection apart from implementing strict surface hygiene practices.

Asymptomatic SARS-CoV-1 infection appears uncommon as a meta-analysis has shown overall sero-prevalence rates of 0.1% for the general population and 0.23% for HCWs although the true incidence of asymptomatic infection remains unknown [49]. A case control study involving 124 medical wards in 26 hospitals in HK and Guangzhou has identified six independent factors of super-spreading nosocomial outbreaks of SARS-CoV-1 infection: performance of resuscitation, minimum distance between beds < 1m, staff working whereas experience symptoms, SARS-CoV-1 patients requiring oxygen therapy or noninvasive ventilation (NIV) whereas availability of washing or changing facilities for staff was protective (Table 1) [45]. A systematic review has shown that four aerosol-generating procedures would increase the risk of nosocomial SARS-CoV-1 transmission to HCWs including tracheal intubation, NIV, tracheotomy, and manual ventilation before intubation (Table 2) [46]. Thus it is important for HCWs to implement airborne precaution measures before carrying out aerosol-generating procedures.

Table 1 - Independent factors associated with increased risk ofa super-spreading events of SARS-CoV infection in the healthcare setting [data from [50]]:
Performance of resuscitation (OR 3.81, 95%CI 1.04–13.87, P = 0.04)
Staff working although experiencing symptoms (OR 10.55, 95% CI 2.28–48.87, P = 0.003)
SARS patients requiring oxygen therapy at least 6L/min (OR 4.30, 95% CI 1.00–18.43, P = 0.05)
SARS patients requiring noninvasive positive pressure ventilation (OR 11.82, 95% CI 1.97–70.80, P = 0.007)
Minimum distance between beds <1m (OR 6.94, 95% CI 1.68–28.75, P = 0.008)
Washing or changing facilities for staff (OR 0.12, 95% CI 0.02–0.97, P = 0.05)
SARS-CoV, severe acute respiratory syndrome-coronaviruses.
aA super-spreading event was defined as one patient that could infect at least 3 others.

Table 2 - Respiratory procedures reported to present an increased risk of transmission of SARS-CoV-1 to healthcare workers [n; pooled OR (95% CI)] [51]
Tracheal intubation [n = 4 cohort; 6.6 (2.3, 18.9), and n = 4 case-control; 6.6 (4.1, 10.6)],
Noninvasive ventilation [n = 2 cohort; OR 3.1(1.4, 6.8)],
Tracheotomy [n = 1 case-control; 4.2 (1.5, 11.5)] and
Manual ventilation before intubation [n = 1 cohort; OR 2.8 (1.3, 6.4)].
SARS-CoV, severe acute respiratory syndrome-coronaviruses.

MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS

Epidemiology

MERS-CoV was first identified in September 2012 when a novel βCoV was isolated from a male patient who had died of severe pneumonia and multiorgan failure in Saudi Arabia in June 2012 [52]. MERS-CoV infection has spread to 27 countries since its discovery in 2012. Globally, from September 2012 to September 2019 2016, WHO has been informed of 2468 laboratory-confirmed cases of infection with MERS-CoV, with at least 851 deaths [53].

Although the natural reservoir of MERS-CoV is still unclear, dromedary camels are an important natural host for the diversification and maintenance of MERS-CoV and appear to be the major source of zoonotic human infection [54]. The virus has been isolated from dromedary camels in the Arabian Peninsula and across North, East, West, and Central Africa, but is not found in dromedary camels in other countries such as Kazakhstan [55] or in Bactrian camels in Mongolia [56]. However, only a minority of reported MERS human cases have reported direct camel exposure [57].

Transmission

Although MERS-CoV was first described in September 2012 [52], a retrospective study of a cluster of hospital cases dated back to April 2012 in Jordan by RTPCR and serology confirmed MERS-CoV as the etiology of the outbreak that involved at least 10 HCWs [58]. The epidemiology of MERS-CoV is characterized by sporadic zoonotic transmission events, sometimes followed by nosocomial outbreaks within healthcare settings due to failure in infection control and prevention measures. Saudi Arabia has the largest MERS-CoV case load, followed by South Korea as the country with the highest case load outside the Arabic Peninsula [53].

The risk factors for primary MERS-CoV infection were examined in a case-control study of thirty primary MERS-CoV cases reported from March to November 2014 in Saudi Arabia, with two to four controls matched by age, sex and neighborhood for each case patient [59]. The investigators demonstrated by multivariate analyses that direct dromedary exposure in the two weeks before illness onset was strongly associated with MERS-CoV illness (adjusted OR 7.45, 95% CI 1.57–35.28), along with having diabetes mellitus (adjusted OR 6.99, 95% CI 1.89–25.86) or heart disease (adjusted OR 6.87, 95% CI 1.81–25.99) and current tobacco smoking (adjusted OR 6.84, 95% CI 1.68–27.94) [59]. The risk for secondary transmission from patients to household contacts was estimated at about 4% [60]. Risk factors for household transmission included sleeping in an index patient's room and touching respiratory secretions from an index patient whereas casual contact and simple proximity were not associated with transmission [61] (Table 3).

Table 3 - Risk factors for Primary and Household transmission
Independent factors associated with primary MERS-CoV illness (Saudi Arabia) [59]:
 a) Direct dromedary exposure in the 2 weeks before illness onset (adjusted OR 7.45, 95% CI 1.57–35.28)
 b) Diabetes mellitus (adjusted OR 6.99, 95% CI 1.89–25.86)
 c) Heart disease (adjusted OR 6.87, 95% CI 1.81–25.99) or currently smoking tobacco (adjusted OR 6.84, 95% CI 1.68–27.94)
 d) Direct physical contact with dromedaries in the previous 6 months (adjusted OR 14.59, 95% CI 2.38–89.55)
Risk factors for household transmission [61]:
 a) Sleeping in an index patient's room [RR 4.1 (1.5–11.2)]
 b) Removing patient's waste (urine, stool and sputum) [RR 3.2 (1.2–8.4)]
 c) Touching respiratory secretions from an index patient [RR 4.0 (1.6–9.8)]
MERS-CoV, The Middle East respiratory syndrome.

In a cross-sectional sero-surveillance study of 10,009 healthy individuals in Saudi Arabia, 0.15% had evidence of positive MERS-CoV serology, suggesting that the number of mild or asymptomatic infections far exceeds those that are recognized [62]. Sero-positivity was more common in males than in females, in central than in coastal provinces, and in camel shepherds (2.3%) and slaughterhouse workers (3.6%) than in others [62].

Nosocomial transmission is a hallmark of MERS-CoV infection. Super-spreading events of MERS-CoV infection were reported in Jordan [58], Al Hasa [63], Jeddah [64], Abu Dhabi [65] whereas the major outbreak in South Korea in 2015 was due to several super-spreading events in the hospital settings [66]. Failure in infection control and prevention measures in healthcare facilities (HCFs) resulted in large numbers of secondary cases of MERS-CoV infection involving HCWs, existing patients, and visitors in Saudi Arabia [63,64] and several other countries over the past few years [58,65,66]. Common predisposing factors include exposure to contaminated and overcrowded HCFs, poor compliance with appropriate personal protection equipment when assessing patients with febrile respiratory illness, application of potentially aerosol-generating procedures (resuscitation, continuous positive airway pressure, nebulized medications), and lack of proper isolation room facilities [58,63–67]. The customs of patients seeking care at different HCFs (‘doctor shopping’) and having friends and family members to stay with patients as caregivers at already overcrowded HCFs were unique factors in South Korea [68].

Cases specifically reported as ‘asymptomatic’ or ‘mild disease’ in Saudi Arabia occurred only among secondary cases [63,64] whereas most (90%) of index or sporadic cases had severe disease [63].

SUMMARY/CONCLUSION

Bats appear to be the common natural source of SARS-CoV-1 whereas more research is needed to examine their role in SARS-CoV-2 and MERS-CoV. The sale and consumption of the intermediary source of SARS-CoV-1 (civet cats) have been banned in China since 2003 and the transmission chain was cut.

In the Middle East, the intermediary reservoir (camels) is still widely available and there is sporadic spill-over infection from camels to humans through close contact whereas nosocomial transmission has become less frequent due to improvement in hospital infection control and prevention measures in recent years.

SARS-CoV-2 shows distinct transmission dynamics - being uniquely infectious in the presymptomatic and asymptomatic stages with high viral load peaking in the first week of illness and so the pattern of spread is different from SARS-CoV-1 and MERS-CoV because of these differing patterns of host-virus interactions. Peaking of viral loads of SARS-CoV-2 on days 2–4 of symptom onset leads to high transmission potential in the community [22]. Asymptomatic and presymptomatic transmission occurs commonly in COVID-19 [18,19].

Nosocomial outbreaks are hallmarks of SARS-CoV-1 [27–30] and MERS-CoV infections [58,63–66] whereas these are less common in COVID-19. Civet cats [32,33] and dromedary camels [59] are the intermediary animal sources for SARS-CoV-1 and MERS-CoV infection respectively whereas that of SARS-CoV-2 remains unclear (Table 4).

Table 4 - Comparative epidemiological, demographic and clinical features of SARS-CoV-2, MERS-CoV and SARS-CoV-1
SARS-CoV-2 [13,14▪▪] MERS-CoV [63,64] SARS-CoV-1 [27–29,31]
Natural reservoir Unclear (possibly bats) Unclear (possibly bats) Chinese horse shoe bats
Intermediate host Unclear Dromedary camels Civet cats
Date of first case report (place) December 2019 (Wuhan, China) April 2012 (Jordan)June 2012 (First KSA case) November 2002 (Foshan, China)
Incubation period Median 4 days (IQR 2–7)Range 2–14 days Mean: 5.2 days(95% CI:1.9–14.7). Range: 2–13 days Mean: 4.6 days (95% CI:3.8–5.8)Range: 2–14 days
Reproduction number 2.5 <1 2.4
Age group
 Adults Adults (98%) Adults (98%) Adults (93%)
 Children Children (2%) Children (2%) Children (5–7%)
Mortality
 Case fatality rate (CFR)-overall 2.2% 34.5% 9.6%
 CFR in patients with co-morbidities 73.3% 60% 46%
 Time from onset to death Mean 15.4 days Median 11.5 days Mean 23.7 days
Presenting symptoms
 Fever 43.8% on admission;88.7% on hospitalization 98% 99–100%
 Chills/rigors 11.4% 87% 15–73%
 Cough 67.8% 83% 62–100%
 -dry 34.1% 56% 29–75%
 -productive 33.7% 44% 4–29%
 Haemoptysis 0.9% 17% 0–1%
 Headache 13.6% 11% 20–56%
 Myalgia 14.9% 32% 45–61%
 Malaise 38.1% 38% 31–45%
 Shortness of breath 18.7% 72% 40–42%
 Nausea 5% 21% 20–35%
 Vomiting 5% 21% 20–35%
 Diarrhea 3.8% 26% 20–25%
 Sore throat 13.9% 14% 13–25%
 Rhinorrhoea 4.8% 6% 2–24%
 Anosmia 40–80% Unknown Unknown
MERS-CoV, The Middle East respiratory syndrome; SARS-CoV, severe acute respiratory syndrome-coronaviruses

The emergence of genetic variants, such as D614G, N501Y variants 1 and 2 [26], has led to an increase in transmissibility without increase in individual's severity and raised concern about the possibility of re-infection and impaired vaccine response. Although COVID-19 vaccination programs have commenced in many countries, continual surveillance for viral mutations is essential to monitor changing epidemiology due to viral variants and other factors.

Acknowledgements

Prof David S Hui is supported by the Commissioned Research on COVID-19 (COVID190110), Health & Medical Research Fund, Food & Health Bureau, HK. Professor Sir Zumla is co-principal investigator of the European and Developing Countries Clinical Trials Partnership the EU Horizon 2020 Framework Program, projects a) Pan-African Network on Emerging and Re-Emerging Infections (PANDORA-ID-NET https://www.pandora-id.net/), b) EDCTP NOEs CANTAM-2 and EACCR. Sir Prof Zumla is in receipt of a UK-National Institutes of Health Research senior investigator award and is a 2020 Mahathir Science Award Laureate.

None.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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Keywords:

coronaviruses; coronavirus disease 2019; The Middle East respiratory syndrome; The Middle East respiratory syndrome coronavirus; severe acute respiratory syndrome; severe acute respiratory syndrome-coronaviruses-1; severe acute respiratory syndrome-coronaviruses-2

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