Figure 1 compares SARS and MERS-CoV, showing the number of total cases and a timeline of persistence in human populations since onset of the first case. This highlights the difference between SARS and MERS-CoV, showing the short time frame within which SARS persisted and was then eliminated in humans, and the large number of cases. MERS-CoV, in contrast, has a relatively low number of cases and has persisted for almost three times the duration, and at the time of writing this, continues to occur in humans.
Comparison of features of SARS and MERS-CoV
MERS-CoV first emerged in a hospital in Jordan in April 2012 (World Health Organization 2013), with later cases and clusters in KSA, Qatar, and the United Arab Emirates. Travel from these regions resulted in four additional clusters in Europe and North Africa, and more recently in the USA (World Health Organization 2013), with limited local transmission occurring in each site. Furthermore, several of the busiest airports in the world are located in countries where MERS-CoV has been transmitted, yet no epidemic has occurred in other countries as it did with SARS, which caused classic epidemics in almost all countries to which it spread, thereby displaying a consistency in epidemiologic pattern (Anderson and May 2008; Airports Council International 2012).
The majority of MERS-CoV cases have been associated with hospital outbreaks in Jordan, KSA, UAE and France. These clusters have been somewhat variable in clinical features, with the first outbreak in Jordon notably featuring renal failure, which does not feature as much in other clusters. SARS was also predominantly a nosocomial infection (Wallinga and Teunis 2004), but MERS-CoV is unlike SARS. The median age of MERS-CoV is 51 years, and risk factors include male sex, immunosuppression, hospitalization and chronic disease (Centers for Disease Control and Prevention 2012). In contrast, SARS was characterized by younger age, more female cases and less co-morbidity. The male predominance of MERS-CoV may reflect a lower risk of exposure for Middle Eastern women due to wearing of Hijab, which covers the nose and mouth.
MERS-CoV did not display an epidemic peak in the first 12 months after emergence as did SARS (Wallinga and Teunis 2004). Rather, there was a sporadic pattern with persistence over a longer duration than expected for a disease with low estimated infectiousness (see Fig. 1). While there has been a large surge in cases in KSA in 2014, the pattern is still suggestive of a sporadic rather than epidemic source of ongoing infection in humans. The incubation period is estimated to be around 5.5 days (Cauchemez et al. 2014). The reproductive number, R0 is estimated to lie between 0.6 and 1.3, which can be interpreted as MERS-CoV having low epidemic potential (Cauchemez et al. 2013; 2014; Breban et al. 2013).
Features of MERS-CoV
In April 2013, an outbreak of 26 cases of MERS-CoV occurred in a hospital in Al Ahsa, KSA. This outbreak shows a typical short-duration epidemic curve suggestive of an infection with a R0 > 1, and consistent with a person-to-person nosocomial outbreak caused by a single strain (Assiri et al. 2013). Curiously, phylogenetic analysis of the patient samples showed at least three different genotypes were present in this outbreak, and at least five of thirteen infections could not be explained by person-to-person transmission within the hospital (Cotten et al. 2013a). This suggests the hospital outbreak was caused by multiple independent introductions, along with some person-to-person transmission (Cotten et al. 2013a). The heterogenous transmission pattern in this outbreak is reminiscent of SARS, but multiple introductions into single outbreaks were not observed in nosocomial outbreaks of SARS. Further, the source of multiple introductions is unknown for MERS-CoV. It is possible that super-spreading events may have a role in the epidemiology of MERS-CoV, but this does not explain the different genotypes present in the one outbreak. Figure 2 also shows that after more than a year of sporadic, infrequent cases that there has been a more sustained increase in cases since May 2013, mainly due to increased cases in KSA, with case numbers in other countries remaining low. Saudi Arabia is bordered by other countries and is a travel hub, yet this large increase in cases, at odds with the pattern seen from March 2012 until April 2013, has not been seen in other countries. If the large recent increase in cases in KSA is due largely to person-to-person transmission, other similar increases (satellite epidemics) would be expected in other countries (as was seen with SARS, with epidemics in each affected country), yet this consistency of global epidemiology has not been observed to date.
Travel and globalization make mass gatherings such as the Hajj pilgrimage a high risk for the spread of infectious diseases around the world. Another contradictory feature of MERS-CoV is that despite evidence of person-to-person transmission in some outbreaks such as Al Ahsa, no outbreaks arose from the Umrah or Hajj pilgrimages in KSA over two consecutive years, 2012 and 2013. More than four million pilgrims attend the Hajj alone, which is recognised as a risk for epidemics of infectious diseases (Memish and Rabeeah 2012). Active surveillance of symptomatic pilgrims in 2012 failed to detect MERS-CoV infections, and no cases were reported in returning pilgrims that year (Gautret et al. 2013). Furthermore, surveillance of Hajj pilgrims returning to high-income countries did not detect any cases in 2012 (World Health Organization 2013), nor were any antibodies detected in a serologic survey of blood donors and abattoir workers in KSA at the time (Aburizaiza et al. 2013). Rates of MERS-CoV in family and health care workers contacts are also low (Memish et al. 2014). Additionally, no cases have been reported by pilgrims who travelled to KSA to perform Umrah during July and August in either 2012 or 2013. Two unconfirmed cases in returning pilgrims to Spain and a case returning to India were reported following the 2013 Hajj; however, it is not yet know whether these cases acquired MERS-CoV during the Hajj or elsewhere in the Middle East during their travels (World Health Organization 2013). The absence of an epidemic despite highly conducive close contact conditions of four mass gatherings in KSA in 2012 and 2013, however, supports the sporadic pattern and estimated R0 < 1. Modelling shows that the probability of no secondary cases arising from the Hajj, if even one person with MERS was present at the time, is very low (Gardner et al. 2014).
MERS-CoV has persisted in the human population for at least three times as long as SARS, but with a lower R0, which in itself is contradictory. If the R0 is low, supported by current estimates and the lack of an epidemic arising from mass gatherings, then where are the infections coming from? The sources of ongoing transmission to humans can only be either person-to-person transmission, or sporadic transmission from a non-human source, or a combination of both. A non-human source could be zoonotic or deliberate release. While there is evidence of some person-to-person transmission (Assiri et al. 2013), this has not been shown to be the main mode of transmission. A zoonotic origin was identified for SARS, but spread was mainly person-to-person (Joseph et al. 2013). In contrast, person-to-person spread cannot readily explain the persistence of MERS-CoV, but if animal exposure is the source, most cases have no consistent or clear history of animal contact. MERS-CoV has been identified in various bat species (Ithete et al. 2013; Cotten et al. 2013b; Annan et al. 2013). It has been identified in camels suggesting MERS-CoV or a related virus previously infected various camel populations, as early as 2003 (Reusken et al. 2013a; Perera et al. 2013; Group TWM-CR 2013; Meyer et al. 2014). While the MERS-CoV has been reportedly identified in camels of MERS-CoV patients, the actual mode and sequence of transmission remains unclear. Phylogenic analysis dates a common ancestor for all available MERS-CoV sequenced genomes to mid-2011 (Cotten et al. 2013b; Drosten et al. 2013), before the first confirmed case in Jordon. However, a cluster of viral sequences from the eastern Arabian Peninsula share a common ancestor estimated to be later in 2012, after the Jordan outbreak. It appears that MERS-CoV has infected humans through multiple introductions over a relatively short period of time, which resulted in limited clusters of cases. This corresponds to the observed epidemiology, although it is unknown how many introductions to humans may have occurred (Cauchemez et al. 2013).
One theory of MERS-CoV transmission is that a large number of asymptomatic or mild cases have gone undetected, thereby skewing the apparent epidemiology. A modelling study explains the epidemiology with substantial undetected mild cases, estimating that 62 % of a total of 940 cases were undetected (Cauchemez et al. 2013).
Yet active screening and case finding efforts including contact tracing have not identified a substantial proportion of asymptomatic cases (Joseph et al. 2013). Only 5 out of 417 household and healthcare worker contacts became infected with MERS-CoV in the KSA cluster (Assiri et al 2013), and similarly, a serological study conducted on individuals from Jeddah and Makkah showed no evidence of widespread exposure to MERS-CoV (Aburizaiza et al. 2013). The model (Cauchemez et al. 2013) can only be fitted to the observed epidemiology of MERS-CoV if a large proportion of undetected cases are assumed to be true. Yet there is little evidence to support this. Further, if a large numbers of cases have been undetected, many of these would have arisen following mass gatherings such as the Hajj pilgrimage, where many pilgrims from high-income countries travel to and from KSA. While cases in returning international pilgrims may go undetected in low-income countries with poor health systems, the likelihood of case detection is high in countries with advanced health systems and surveillance capacity. The lack of large numbers of cases in pilgrims returning to high-income countries following the Hajj in 2012 and 2013 does not support the hypothesis of a large proportion of undetected cases.
A summary of the various epidemiologic features of MERS Coronavirus and whether they support an epidemic or one of two sporadic patterns are shown in Table 1. This shows that the evidence supports a sporadic pattern, with slightly more weight to deliberate release compared to an animal source.