In-depth analysis: Human respiratory disease associated with Middle East Respiratory Syndrome Coronavirus

Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

In March 2018, 17 new cases of Middle East Respiratory Syndrome (MERS) were reported. The majority of new cases were reported from Saudi Arabia (n=16). A total of 2183 cases of Middle East Respiratory Syndrome Coronavirus (MERS-CoV), including at least 760 deaths, have been reported globally since 2012.  Further information can be found in the in depth analysis section below.

Contents

• Background
• Source of exposure
• Virus characteristics
• Clinical manifestations
• Event summary: January to March 2018
• Global epidemiological analysis
• Age and sex distribution
• Temporal distribution
• Geographical distribution
• Vaccines against MERS-CoV
• Limitations
• Conclusion
• References

From Human Emerging Respiratory Pathogens Bulletin Issue 015 (April 2018).

Background

On June 13, 2012, a 60 year old Saudi man was admitted to a private hospital in Jeddah, Saudi Arabia, after reporting respiratory symptoms like cough, expectoration, shortness of breath, and fever^{Footnote 1Footnote 2}. Eleven days after admission, on June 24, 2012, he died of progressive respiratory and renal failure^{Footnote 1}. The investigation into the etiological agent responsible for his condition began at the laboratory attached to the hospital. After two months of testing clinical isolates from the patient for multiple viruses (influenza virus A, influenza virus B, parainfluenza virus, paramyxovirus, hantavirus, enterovirus and adenovirus), the isolate was tested for coronavirus using a pancoronavirus RT-PCR^{Footnote 3}. The test was positive, but negative for SARS specific primers, suggesting the discovery of a novel coronavirus^{Footnote 3}. On September 20th, 2012, after further confirmation by another laboratory (the Erasmus Medical Center), the discovery of a novel coronavirus was announced through ProMED^{Footnote 3Footnote 4}. This coronavirus, the etiological agent for Middle East Respiratory Syndrome (MERS), was eventually named Middle East Respiratory Syndrome Coronavirus (MERS-CoV), the 6th strain of human coronavirus discovered^{Footnote 5}.

Since that time, over 2000 cases have been reported globally. Family clusters and hospital outbreaks have occurred both within the Middle East and elsewhere, and the cases have spread from the region to some other countries [Figure 1]^{Footnote 6}. There has also been important progress in laboratory diagnostics, virus characterization, vaccine development, and understanding of the clinical course of illness and the mechanism of transmission [Figure 1]. This in-depth analysis provides a summary of the descriptive epidemiology of human infection with MERS-CoV since its emergence in 2012, with a focus on the demographic, geographic and temporal distribution of reported cases, as well as a review of the clinical symptoms, sources of exposure, and virus characteristics.

Source of exposure

Primary cases of MERS are associated with zoonotic transmission from camels. Though research suggests that MERS-CoV emerged from bats, multiple studies on the emergence and transmission of MERS-CoV point to the role of camels as a reservoir and primary source of zoonotic infection due to the high prevalence of MERS-CoV antibodies in camels across the Arabian Peninsula and North and Eastern Africa^{Footnote 47Footnote 62Footnote 63Footnote 64Footnote 65}. The detection of MERS-CoV by RT-PCR in respiratory secretions, urine, feces and milk of dromedary camels, and demonstration of similarities in the genomic sequence of viruses isolated from infected individuals and camels^{Footnote 47Footnote 62Footnote 63Footnote 64Footnote 65} further support the role of camels in zoonotic transmission of MERS-CoV. These findings also highlight the importance of focusing prevention and control measures on camels. Challenge studies conducted in camels suggest that infection of MERS-CoV in dromedary camels results in mild respiratory disease with mild to no signs of illness^{Footnote 19}. To date, despite the number of reported zoonotic cases, only 14 camel outbreaks of MERS have been reported to the World Organization for Animal Health (OIE) signifying that outbreaks in camel herds are likely to go undetected and allow for an ongoing risk of transmission to humans^{Footnote 66}. Based on sero-epidemiological studies carried out in other livestock, alpacas are the only other domestic livestock in which MERS-CoV-specific antibodies have been identified; however, no human cases with exposure to alpacas have been reported^{Footnote 23}.

Although the route of camel to human transmission is not fully understood, zoonotic infections of MERS likely occur through direct or indirect contact with camels or camel-related products (e.g. raw milk)^{Footnote 31}. Serological studies that compare the presence of MERS-CoV antibodies in individuals with and without contact to dromedary camels have left a conflicting picture about the role of camel exposure in the zoonotic transmission of MERS. Some studies have found no serological evidence of MERS-CoV infections in humans with various levels of exposure to dromedary camels^{Footnote 21Footnote 67Footnote 68}. These findings suggest that zoonotic transmission is rare^{Footnote 21Footnote 67Footnote 68}. However, other studies have found a significantly higher seroprevalence of MERS-CoV antibodies in camel-exposed individuals compared to the general population, suggesting a greater risk of MERS-CoV infection among individuals exposed to camels^{Footnote 22Footnote 69}. Based on the available information to date, further studies are needed to fully understand how human-animal interactions contribute to the transmission of MERS-CoV.

Human-to-human transmission of MERS-CoV has largely been associated with nosocomial outbreaks; however, household transmission has also been reported^{Footnote 10Footnote 70}. Nosocomial outbreaks of MERS have played an important role in increasing the magnitude of reported cases. To date large scale hospital outbreaks have been reported in Saudi Arabia, United Arab Emirates, and South Korea^{Footnote 42Footnote 71Footnote 72}. Lack of IPC measures (e.g. overcrowding, delays in isolation of cases, lack of knowledge of MERS case definitions amongst healthcare workers) along with intra- and inter-hospital transmission, super spreaders, and asymptomatic cases are factors that have contributed to these hospital outbreaks in the past^{Footnote 73}. A study published in 2017 evaluating the implementation of IPC measures during a large hospital outbreak found that strict adherence to IPC measures allowed for rapid identification of cases and a significant decrease in secondary cases, which may explain why recent outbreaks in Saudi Arabia were quickly contained^{Footnote 27Footnote 28Footnote 74}.

Virus characteristics

MERS- CoV is a single stranded RNA virus belonging to the Coronaviridae family^{Footnote 2Footnote 75}. Though caused by the same genera of coronavirus as SARS, MERS-CoV is distinct in that it belongs to lineage C whereas SARS belongs to lineage B. Entry of MERS-CoV into host cells is mediated by its spike (S) protein binding to the host cell receptor, dipeptidyl peptidase 4 (DPP4)^{Footnote 76}. DDP4 is a surface cell protein that is mainly expressed in the human respiratory tract, but is also extensively expressed on epithelial cells in the kidneys, small intestine, liver, prostate, and activated leukocytes^{Footnote 55}. In the case of SARS, extensive mutations in the virus resulted in its ability to adapt to the human cell receptor angiotensin-converting enzyme 2 (ACE 2) which allowed for increased human-to-human transmission^{Footnote 77}. Though sequenced viral isolates from camels and humans indicate that MERS-CoV has undergone recombination and genetic changes since its introduction to humans in 2012, none of these viral mutations have allowed more efficient adaptation to the human cell receptor DPP4^{Footnote 78}. In fact, analysis of viral isolates with a mutation in the receptor binding domain from the South Korea outbreak showed reduced affinity to human DPP4^{Footnote 79}. Given the magnitude of South Korea outbreak, these findings further convolute the role of the S protein and DPP4 in the human adaptation of this virus. Overall, the coronaviruses possess the abilities of efficient mutation and recombination, and a propensity to cross host species and adapt to a new environment. These abilities raise concerns that MERS-CoV would gain virulence and an enhanced ability to transmit from human-to-human. However, sustained human-to-human transmission has not occurred in the general population. Potential hotspots of animal-to-human and human-to-human transmission need to be monitored on an on-going basis.

Clinical manifestations

Human infection with MERS-CoV results in a wide range of clinical manifestations, from asymptomatic infection to severe clinical disease^{Footnote 2}. Common clinical symptoms include fever, cough and shortness of breath that can rapidly progress to severe acute pneumonia, acute respiratory distress syndrome, septic shock, multi-organ failure and death^{Footnote 2Footnote 56}. In some instances, cases have experienced gastrointestinal symptoms of abdominal pain, vomiting and diarrhea^{Footnote 2}. In comparison to human illness with other coronaviruses such as Severe Acute Respiratory Syndrome (SARS) (global CFR 14%-15%), MERS has a high case fatality rate of 35% among all cases reported globally and 40% in cases reported from Saudi Arabia ^{Footnote 6Footnote 32Footnote 57}. Studies assessing risk factors for disease severity and mortality have found that pre-existing health conditions, older age, sex (being male) and co-infection with other bacterial or viral agents to be significant risk factors for increased odds of mortality and disease severity^{Footnote 56Footnote 58}.

Pediatric cases

Based on case information available to date, pediatric cases of MERS are rare^{Footnote 34Footnote 60Footnote 61}. Thus far, approximately 2% of all cases have occurred in the pediatric population (individual ≤ 18 years of age) and the case fatality rate is 2.5% . In 2016 Al-Tawfiq et al., published a study that aimed to summarize both the epidemiological and clinical characteristics of pediatric cases reported from June 2012 to April 19, 2016 (n=31)^{Footnote 60}. Of the cases for which clinical information was available (n=29), 45% were asymptomatic and 7% presented with mild respiratory symptoms^{Footnote 60}. Of the cases for which information on source of exposure was available (n=15), 68% acquired their infection through household contact^{Footnote 60}. Although the number of pediatric cases is low it is important to remain vigilant in the documentation of the clinical presentation to better understand whether the clinical picture in this population differs from that of the general population.

Event summary: January to March 2018

Between January 1, 2018 and March 31, 2018, 54 cases of MERS including 5 deaths (CFR=36%) of the individuals with known outcomes were reported to the World Health Organization (WHO) and by the Kingdom of Saudi Arabia's Ministry of Health (KSA MOH)^{Footnote 24}. The case count and case fatality rates were comparable to those reported during the same time period in 2016 and 2017, but substantially lower than in 2015 and 2014^{Footnote 25}. The age and sex distribution of cases has remained relatively consistent with previous years: most cases were male (75%), and the median age was 59 years (range 5 years to 89 years). Geographically, cases were less dispersed than previous years with only three countries (Malaysia, Saudi Arabia, and Oman) reporting cases to date. The case reported from Oman was locally acquired, while the case reported from Malaysia was imported from Saudi Arabia – the country with the majority of reported cases^{Footnote 26}. Of the cases for which exposure information was available (n=5), 29% reported exposure to camels while 21% reported exposure to a positive MERS case, giving a similar proportion of secondary^{Footnote a} cases to primary^{Footnote b} cases reported to the WHO this year so far. Between January 1 and March 31, 2018, one nosocomial outbreak was reported in a private hospital in the Hafr Albatin region of Saudi Arabia, while a cluster of nosocomial infections was detected in a health facility in the Riyadh region of Saudi Arabia^{Footnote 27Footnote 28}.

Global epidemiological analysis

Since the emergence of MERS-CoV in 2012, 2183 human infections including at least 760 deaths (CFR =35%) have been reported from 27 countries^{Footnote 6Footnote 32}. The epidemiological analyses of the MERS-CoV to date reflect sporadic zoonotic infections with amplified human to human transmission in health care settings. Overall, two-thirds  of the reported cases (66%) have occurred in men with the median age of 54 years (range of 9 months to 109 years). Though cases of MERS continue to be reported each year, there has been a decline in the number of reported cases and the case fatality rate since 2014 [Table 1]^{Footnote 29}. Given the association between amplified human-to-human transmission and outbreaks in health care settings, strict adherence to infection prevention and control (IPC) measures is likely the main driver for the observed reduction in the incidence of cases according to the WHO^{Footnote 30}.

Table 1 . Epidemiologic characteristics of MERS cases reported between January – December 2013 to 2017 and January to March 2018.

Characteristics	2013	2014	2015	2016	2017	2018
Number of reported cases (CFR %)	188 (53)	758 (38)	672 (33)	251 (29)	250 (29)	54 (36)
Median age (range) in years	51 (2-94)	48 (4-99)	54 (9 months-109)	54 (18-94)	53 (10-88)	59 (5-89)
% Male	65	65	65	73	72	75
Number of countries reporting cases	10	17	12	7	5	3
% Healthcare workers	20	26	10	13	17	4
Note: Data for epidemiological characteristics of MERS cases from 2013-2016 were sourced from the WHO Regional Office for the Eastern Mediterranean (EMRO) January-February 2017 MERS Situation update and compared to data retrieved from WHO Disease Outbreak News (DON) on July 6th on MERS cases reported from Jan-Jun 2017 data. Epidemiological characteristics for cases reported from June 2017-March 2018 were based on data retrieved from WHO DON on March 15th and cases reported by the Kingdom of Saudi Arabia (KSA) Ministry of Health (MOH) up until the end of March 2018. Data reported in this table are subject to change as a result of ongoing investigations and updated analysisFootnote 24Footnote 29Footnote 32.

Age and sex distribution

Overall, the age-sex distribution of cases is skewed towards older men [Figure 2]. However, further investigation of exposure type reveals distinctive age-sex patterns between primary and secondary cases [Figure 3]^{Footnote 31}. Exposure and demographic information was available for 109 primary cases and 62 secondary cases (total=171) reported by the WHO Disease Outbreak News (DON) and the KSA MOH between January 1, 2017 and March 31, 2018^{Footnote 24Footnote 32}. Primary cases were skewed towards older men: a significantly higher proportion of primary cases were male (88%) and aged 50 years and older (67%). In contrast, secondary cases had a more balanced age-sex distribution: there was no significant difference between the proportion of males to females or between age groups^{Footnote 25}. Further, secondary cases had a significantly lower mean age, compared to primary cases (46 years vs. 56 years). The observed age-sex pattern in primary cases – people infected through direct contact with camels – is hypothesized to be due socio-cultural behaviours, such as camel rearing being an activity popular among middle-aged and retired men^{Footnote 31}.

Temporal distribution

The overall temporal distribution of the MERS epidemic can be characterized by multiple intermittent peaks that correspond to large-scale or simultaneously occurring hospital outbreaks. Between 2014 and June 2016, these peaks occurred every 12 to 26 weeks, on average [Figure 4]. However, between 2016 and 2017, there was a 52-week period between peak activity and there has been no peak in activity in 2018 thus far. The recent increased duration between peak activity, resulting in low but ongoing activity, suggests that there have been improvements in the implementation of IPC measures and a decrease in hospital-acquired cases since 2015 as noted by the WHO^{Footnote 28Footnote 30}.

Early analysis of the temporal distribution of MERS cases between 2012 and 2014 suggested a seasonal pattern with cases increasing from March to April each year. At the time, this seasonal pattern had been linked to the calving and weaning patterns of camels; however, this pattern has not been observed since 2014^{Footnote 33}. Analysis of the temporal distribution of annual MERS cases reported since 2014 demonstrates that the majority of cases (approximately 61% to 84%) occur during the first 6 months of the year, with peaks corresponding with reported hospital outbreaks that involve more than 20 cases [Figure 5]. Further analysis of the temporal distribution of primary and secondary cases may help determine whether MERS truly exhibits seasonality.

Geographical distribution

To date, 27 countries located in the Middle East, Northern Africa, Europe, North America and Asia have reported imported and locally-acquired cases of MERS [Figure 6]^{Footnote 6}. The majority of cases (n=1845, 90%), have been reported from countries within the Arabian Peninsula with 92% of those cases reported from Saudi Arabia. Research on the human-animal interactions and the circulation of MERS-CoV in dromedary camels suggest that in addition to the dromedary camel population within the Arabian Peninsula, economic, cultural, and recreational practices specific to the area—such as the movement towards more intensive camel farming clustered around cities—are the cause for the observed concentration of cases^{Footnote 31Footnote 33 Footnote 47Footnote 48Footnote 49Footnote 50}. 

Currently, the majority of the world's dromedary camel population (>60%) is located in the Greater Horn of Africa (GHA); a region that regularly exports camels to countries in the Arabian Peninsula^{Footnote 48}. Though serological studies conducted on dromedary camels from multiple countries in Africa (Egypt, Ethiopia, Nigeria, Somalia, Sudan) have demonstrated that camels in these areas have high seroprevalence of MERS-CoV, no local zoonotic infections with MERS have been reported from any country in Africa; only 6 cases have been reported from countries in Africa and all cases have been imported or linked to an imported case from the Middle East^{Footnote 47}. Additionally, a study on the circulation of coronavirus species in Saudi Arabia found that local camels had significantly higher carrier rates than imported camels^{Footnote 49}. Lineage testing identified MERS-CoV found in African camels is genetically different from MERS-CoV found in camels and humans in the Middle East^{Footnote 48Footnote 83}. This evidence suggests that zoonotic MERS cases seen in Saudi Arabia and other countries in the Arabian Peninsula are connected to factors specific to the Arabian Peninsula and Saudi Arabia.

Given that MERS-CoV has been endemic in Saudi Arabia dromedary camels for over two decades and that the virus is widespread within the Arabian Peninsula, further cases are expected to be reported and exported from these areas^{Footnote 51}. Countries like India and Bangladesh, with a large volume of citizens that travel to Saudi Arabia for religious pilgrimages, have been identified as potential high-risk areas for MERS-CoV importation^{Footnote 52Footnote 53}. To date the largest number of cases to be reported from outside the Middle East occurred in South Korea in 2015: the majority of the 186 reported cases were associated with a large multi-hospital outbreak^{Footnote 54}. Overall, cases were the most geographically dispersed in the 2014 season when 17 countries reported cases [Figure 7].

Vaccines against MERS-CoV

No vaccine or effective antiviral treatment is currently available for MERS-CoV. Research is underway and many candidate vaccines targeted for humans are under development. These candidates use a wide range of platforms including whole virus vaccine (live attenuated and inactivated), vectored-virus vaccines, DNA vaccine, and protein-based vaccines, with many of the viruses targeting the S (envelope) protein or the DPP4 receptor binding domain (RBD) of the S protein^{Footnote 80}. Thus far, only one candidate vaccine has advanced to clinical development: a DNA-only vaccine called GLS-5300 that generated protective MERS-CoV antibodies in mice, camels and monkeys, and advanced to Phase 1 human clinical trials in February 2016^{Footnote 81}. This candidate vaccine has also been tested and reduced virus shedding in dromedary camels^{Footnote 81}. The DNA-based vaccines directed at inducing anti S responses also induce protection in non-human primates^{Footnote 80}. As the spike protein (specifically S1) is highly divergent among different CoVs, the neutralizing antibodies only provide homotypic protection. In contrast, the amino acid sequence of the spike protein, specifically of S2 domain, is conserved with minimal variability among MERS-CoV strains. Additionally, the circulating MERS-CoV strains also lack significant variation in the serological reactivity. As the S2 domain protein is more conserved among coronaviruses, the adaptive immune response directed against S2 protein can potentially constitute the basis for the development of an vaccine capable of inducing heterotypic protection against circulating MERS-CoV strains. Additionally, a modified vaccinia Ankara based vaccine that reduced virus shedding and generated protective antibodies and mucosal immunity is currently scheduled for a Phase 1 safety trial ^{Footnote 82}.

Limitations

This in-depth analysis of MERS-CoV is subject to several limitations. The majority of data in this report represent laboratory-confirmed cases of MERS-CoV reported in the Kingdom of Saudi Arabia. Very limited data are available about cases' clinical manifestation, diagnosis, treatment and comorbidities. There is the possibility of unknown selection biases as the primary cases are only detected following presentation with illness. The asymptomatic primary cases or cases with limited access to health care remain undetected. It remains challenging to interpret risk factors for the acquisition of MERS-CoV particularly in the absence of evidence from extensive case-control epidemiology studies.

Conclusion

In 2015, the WHO created a Blueprint list of priority diseases that pose major public health risks and require further research and development. Both the original list and the update provided in February 2018 deemed MERS-CoV a potential public health emergency^{Footnote 59}. Since the emergence of MERS in 2012, human cases, predominantly from countries within the Arabian Peninsula, continue to be reported. Transmission patterns of the disease have remained consistent with repeated introductions in the human population occurring through zoonotic transmission followed by amplified human to human transmission in health care settings. A better understanding of the transmission of MERS-CoV in healthcare settings is required, especially of the exposures that result in human-to-human transmission, the potential role of asymptomatic infected health-care workers, and the possible role of environmental contamination, in order to mitigate the risk of nosocomial outbreaks. Though the number of cases reported annually appears to be on the decline, it is clear that continued research and surveillance is needed to further bridge the gaps in knowledge surrounding the virus origin and characteristics, transmission of this disease in the community, the exact mode of zoonotic transmission, and potential environmental sources of disease.

References

Footnotes