The discrepant epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV)

Viruses have the capacity to evolve, to exchange genetic material between strains that infect different species, and to emerge into new threats to human health. The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) which causes severe acute respiratory illness with high mortality emerged in April 2012 in the Middle East and spread mainly through travel to several countries including the UK, Germany, France, Tunisia, Spain, Italy and the US (World Health Organization 2013). Comparisons have been made to SARS, a related coronavirus which displayed a classic epidemic pattern 10 years earlier. In just 8 months, SARS resulted in 8,273 cases and 775 deaths (World Health Organization). MERS-CoV in contrast to the clear epidemic pattern of SARS, has a different epidemiology, continuing to cause at least 681 non-fatal human infections and 204 deaths after two years, without a clear source (World Health Organization 2013; Wallinga and Teunis 2004). Unlike SARS, which spawned satellite epidemics in the countries to which it spread, the majority of cases of MERS have remained in the Middle East, mainly the Kingdom of Saudi Arabia (KSA), with no satellite epidemics or sustained human-to-human spread in other regions of the world, despite a large upsurge in cases in KSA in April and May 2014.

Control of emerging infectious diseases falls within the scope of biosecurity, which is a multidisciplinary field incorporating biomedical researchers, public health experts, emergency services, military, law enforcement, and risk analysts among others. This paper is intended for a broad, multidisciplinary readership, particularly for those in the non-health disciplines involved in biosecurity. The paper aims to apply a risk analysis approach to publicly available data on MERS, to shift the paradigms of thinking about emerging infectious diseases, to determine whether the current surveillance and response to MERS is asking the right questions, to consider whether MERS might be a category C bioterrorism agent, and to engage all relevant sectors in the response.

Infectious diseases are mainly classified as either epidemic, sporadic, or endemic (Anderson and May 2008). Epidemics are defined by a rapid rise in cases over time, not by the total number of cases. A small epidemic is usually termed an outbreak, and an epidemic which spreads globally is termed a pandemic. Diseases which have been present for long periods in a population but do not display a rapid rise in incidence over a short-time period, such as malaria, are classified as endemic, even with high case numbers. Diseases which have low case numbers and occur occasionally are classified as sporadic. MERS-CoV has displayed mixed features of both an epidemic and sporadic nature (World Health Organization 2013).

A classic epidemic curve is a normal distribution of cases over time (bell curve), showing a small number of first cases, a rapid rise in new cases over a short duration, an epidemic peak, and then a decline in cases. This corresponds to known mathematically predictable features of infectious diseases, which relate to human beings existing in mutually exclusive states of being infected, immune or susceptible to any infection (Anderson and May 2008). For any infection, the rate of transition of people within a given population from one state to another (e.g., susceptible to infected) can be modeled, using known parameters of the pathogen. At the beginning of an epidemic, there is a critical threshold of susceptible (non-immune) people in the population which gives rise to epidemic conditions, but at the peak, enough people in the population have been infected and are immune, thus stopping ongoing transmission. This then causes a decline in cases, giving rise to the tail end of an epidemic curve. Epidemics can be caused by humans becoming infected from either a single point source or by person-to-person transmission. A point source epidemic (such as food poisoning from a single contaminated food source consumed by many people) typically shows a unimodal epidemic curve which then dies down, whereas an epidemic with person-to-person transmission (such as influenza), may show a bimodal peak, representing the second generation of cases. Even in this case, with ongoing human-to-human transmission, eventually, when enough people are infected and become immune, the epidemic will die down and cease, until a critical threshold of susceptibility is again reached in the population, either through waning immunity, births, or migration (Anderson and May 2008).

SARS displayed all the features of an epidemic (and then a pandemic), with occurrence over a very short period of time, a rapid rise of cases from the time of onset of the first case, and classic epidemic curves and satellite epidemics in most countries which it affected, and then a decline in the epidemic (Wallinga and Teunis 2004). In the context of the well understood behavior of infectious diseases and the accepted science of epidemiology, the aim of this paper was to review the epidemiology of MERS-CoV, to compare it to SARS, and to explore all possible explanations for the observed epidemiologic data by fitting observed epidemiologic features to either epidemic or sporadic scenarios.

A literature search was conducted for all available data on MERS-CoV, including MEDLINE, EMBASE, PubMed, and gray literature reports such as from the World Health Organization (WHO) and ProMED-mail, a rapid outbreak communication site. Publicly available surveillance data were used to compare total cases over total time for MERS-CoV with a related coronavirus, SARS, and to compare the epidemiologic pattern of each virus.

The key features of the epidemiology of MERS-CoV were then analyzed in detail. Finally, a risk analysis approach was taken to classify each feature of the observed epidemiology of MERS-CoV as being consistent with either an epidemic or a sporadic pattern. An epidemic pattern would arise from sustained person-to-person transmission of infection and a R0 greater than 1 (Anderson and May 2008). A sporadic pattern would arise from some other (non-human) source of ongoing infection to humans, with generally a low R0 (<1) which does not facilitate sustained person-to-person transmission. For completeness, possible non-human sources of ongoing human infections are a zoonotic or deliberate release. No judgement was made about whether deliberate release may be an engineered virus or a naturally occurring virus, nor was any judgment made about reasons or motives for such a scenario. The available data and evidence were simply assessed according to known epidemiologic principles of disease transmission. The publicly available data and evidence were categorized into discrete epidemiologic features, and then, each feature was fitted to the pattern which best explained it, either epidemic or sporadic. Given that a clear zoonotic origin of MERS-CoV explaining all sporadic cases has not been established, and a mixed pattern has been observed, two sporadic patterns were considered—a zoonotic source or deliberate release. H5N1 is a classic example of a sporadic human infection from a zoonotic source. In the case of H5N1 infections in humans, the vast majority of cases have clear exposure to a plausible zoonotic source known to host the same virus (Uyeki 2008). This has not been the case with MERS-CoV, which justifies considering other sporadic sources such as deliberate release.

There are still uncertainties and contradictions about the epidemiology of MERS-CoV, which is clearly different to SARS, fitting a more sporadic pattern even accounting for the recent surge in cases. SARS, in contrast had a clear epidemic pattern, including in countries to which it spread. The analysis of the features of MERS-CoV suggests that the source of ongoing sporadic infections could equally be due to an animal source or to deliberate release. The finding of MERS-CoV in camels does not rule out deliberate release, as a virus which is trophic to a host will, when present in an ecosystem, find that host. The WHO is investigating animal sources of infection as well as the mode of transmission to humans (Aburizaiza et al. 2013). Animal samples collected from KSA are currently undergoing analysis in US laboratories to help and identify the underlying zoonotic source(s). Additionally, the similarity between MERS-CoV and the closest bat coronaviruses suggests animal surveillance in South Africa and certain parts of Europe would also be valuable (Cotten et al. 2013b). Person-to-person transmission as the main mode of spread could only be explained if there is a large proportion of undetected mild or asymptomatic cases. This possibility is not supported by surveillance studies, but better screening methods could be developed. Serology for the detection of specific MERS-CoV antibodies has been recently developed and validated with a limited number of specimens (Reusken et al. 2013b), but still need to be validated for use in the Arabian Peninsula and Jordan (Nicoll 2013).

The available data do not clearly fit a specific epidemiologic pattern, so it is important to think of all possible explanations, and not simply force the data into a known paradigm such as SARS. The possibility of deliberate release, which has not yet been discussed in the scientific literature, must be included for completeness, as this could explain the long persistence, the paradox of hospital outbreaks and yet no outbreaks following major mass gatherings, the evidence of multiple introductions, and the presence of multiple genotypes simultaneously in what appears on the surface to be a single hospital outbreak in Al Ahsa. This outbreak is the most puzzling to date because of the presence of multiple different genotypes in the outbreak within a very short time frame—this means that the patients with MERS-CoV had simultaneous or contemporaneous sporadic exposures (which have yet to be identified), either inside or outside the hospital. The published work to date has focused on selected parts of the epidemiology which can be explained, but no one to date has questioned this single unusual finding, and deliberate release, which is certainly a possible explanation, has not thus far been publicly debated.

It seems likely that MERS-CoV has persisted in human populations despite a low R0 due to a combination of sporadic transmission from a non-human source and some human-to-human transmission. The epidemiology appears to have changed somewhat from May 2013 onward, but there is no explanation for this change, which is due largely by an increase in KSA alone, nor evidence as yet that the virus is becoming more transmissible. The continued increase in cases in KSA in 2014, without satellite epidemics in other countries, and without consistent animal contact in all cases is inexplicable. Good diagnostic serological methods, serological surveys, contact tracing and other surveillance in affected areas are needed to quantify asymptomatic or mild infection and to identify exposures to other (non-human) sources of infection. The serological tools recently developed (Reusken et al. 2013b) can aid in large-scale contact studies. An epidemiological protocol to assess MERS-CoV cases in the UK was proposed, and related protocols to implement surveillance schemes among healthcare personnel, contacts of known and probable cases and the general population have been published by CONCISE (2013). These protocols will help quantify clinical characteristics (e.g., incubation and infectious period) and epidemiological characteristics (e.g., source, risk factors, R) of MERS-CoV. Open access to surveillance and screening data will assist in further understanding the disease (Palm et al. 2012).

In conclusion, a careful review of the paradoxes and inconsistencies in the epidemiology of MERS-CoV raises deliberate release as a possible explanation. The discrepant, varying epidemiology is consistent with deliberate release, as such an act cannot easily simulate expected natural patterns, and is likely to produce an inconsistent epidemiologic picture. When a new infectious disease emerges, bioterrorism, unless it is caused by an eradicated disease such as smallpox, may not be easily recognized for what it is unless we consider the possibility. A sporadic animal source of ongoing infections in humans is also possible, with most evidence supporting camels. However, the large increase in cases in 2014 without a clear accompanying history of camel contact in the majority of cases does not support this explanation. Other zoonotic infections which occur sporadically in humans such as H5N1 influenza show a far more consistent and clear history of contact with animals/birds. The virus may be emerging to be more transmissible, but there is no evidence for a clearly epidemic pattern as yet.

Control efforts to date been structured around an underlying assumption of a natural cause of this disease and has followed a standard public health response framework using knowledge of SARS as a guide (Perl et al. 2014). However, the epidemiologic features of MERS-Cov are clearly very different to SARS. There is a pressing need for inter-sectoral collaboration, for involvement of all stakeholders in biosecurity, including law enforcement and military, and for reflecting on the available data and interpreting it objectively, instead of trying to force the data into a paradigm created around the past SARS experience. While both are coronaviruses, their epidemiology is very different, and control of MERS coronavirus can only be achieved when we gain understanding of the observed paradoxes.