MERS: Estimating the Threat

June 2014
Colorized transmission electron micrograph showing particles of Middle East respiratory syndrome coronavirus that emerged in 2012.

From time to time the world faces talk of epidemics or even a pandemic due to some novel respiratory virus. For example, apart from the ever-present concern over virulent shifts in the genetic make-up of the influenza virus, we have had “swine flu” and severe acute respiratory syndrome (SARS). And now it’s Middle East respiratory syndrome (MERS). Both MERS and SARS are caused by coronaviruses, the current one being named MERS-CoV (originally referred to as EMC-CoV).

Herewith, we turn to Thomson Reuters Web of Science for key papers on MERS. The following table collects those cited at least 25 times at this writing. Other reports are discussed in the text below.

Key Papers on Middle East Respiratory Syndrome (MERS), 2012-2013

(Listed by citations)

Rank Paper Citations
1 A.M. Zaki, et al., “Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia,” New Engl. J. Med., 367(19): 1814-20, 8 November 2012. [Erasmus MC, Rotterdam, Netherlands; Dr. Soliman Fakeeh Hosp., Jeddah, Saudi Arabia] 227
2  V.S. Raj, et al., “Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC,” Nature, 495(7440): 251-4, 14 March 2013. [7 institutions worldwide 81
3 S. van Boheemen, et al., “Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans,” mBIO, 3(6): e00473-12, Nov-Dec 2012.  [Erasmus MC, Rotterdam, Netherlands; Leiden U., Rotterdam; Dr. Soliman Fakeeh Hosp., Jeddah, Saudi Arabia; Lomonosov State U., Moscow, Russia] 78
4 A. Bermingham, et al., “Severe respiratory illness caused by a novel coronavirus in a patient transferred to the United Kingdom from the Middle East, September 2012,” Eurosurveillance, 17(40): 6-10, 4 October 2012. [5 European institutions] 55
5 A. Assiri, et al., “Hospital outbreak of Middle East Respiratory Syndrome coronavirus,” New Engl. J. Med., 369(5): 407-16, 1 August 2013. [7 institutions worldwide] 50
6 Z.A. Memish, et al., “Family cluster of Middle East Respiratory Syndrome coronavirus infections,” New Engl. J. Med., 368(26): 2487-94, 27 June 2013. 41
7 C.B.E.M. Reusken, et al., “Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study,” Lancet Infect. Dis., 13(10): 859-66, October 2013. [12 institutions worldwide] 37
8 B. Guery, et al., “Clinical features and viral diagnosis and two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission,” Lancet, 381(9885): 2265-72, 29 June 2013. [9 French institutions] 37
9 C. Drosten, et al., “Clinical features and virological analysis of a case of Middle East respiratory coronavirus infection,” Lancet Infect. Dis., 13(9): 745-51, September 2013. [9 institutions worldwide] 25
10 S. Gierer, et al., “The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies,” J. Virology, 87(10): 5502-11, May 2013. [5 German and US institutions] 25
SOURCE: Thomson Reuters Web of Science

The first recorded case of MERS was in Jordan early in 2012. This was a retrospective diagnosis, however, and the disease is more usually dated from September of that year. As of May 6, 2014, recorded cases numbered 495, and 93% of them were from Saudi Arabia or the United Arab Emirates, and all 16 reported from outside the Middle East had connections with that region (see ecdc.europa.eu for details). The first case in the United States was confirmed on May 2. Small wonder that media reporting has had everyone thinking of something on the scale of SARS.

PANDEMIC POTENTIAL?

The case fatality rate for MERS has been high, at 36% on earlier World Health Organization figures and 28% more recently. April, 2014 saw a worrying jump in cases in Saudi Arabia,  but does MERS really have pandemic potential? That’s the big question. Dr. Romulus Breban and his colleagues from the Institut Pasteur, Paris, used data from 55 of the first laboratory-confirmed cases to estimate the basic reproduction number (R0), the number of secondary cases per index case, under a pessimistic (worst-case) scenario and an optimistic one, the former being the estimate of greater interest (R. Breban, et al, Lancet, 382[9893]: 694-9, 2013; 23 citations). An R0 of more than 1 implies epidemic potential. Breban and colleagues’ estimate (worst case) is 0.69 with a 95% confidence interval not exceeding unity (0.50 – 0.92).

A group based on the UK’s Medical Research Council Centre for Outbreak Analysis and Modelling, London, have done something similar with data available as of Aug 8, 2013 (S. Cauchemez, et al., Lancet Infect. Dis., 14[1]: 50-6, 2014; 6 citations). R values (here Rcluster and Rindex) are a bit higher than those offered by Breban and colleagues, and Dr. Simon Cauchemez and his co-workers conclude that “a slowly growing epidemic is underway, but current data do not allow us to determine whether transmission is self-sustaining in man.” They also estimated that at least 62% of MERS infections might be undetected and that in the early reports there was a bias towards more severe cases.

The data set—and, therefore, the opportunity to update estimates of epidemic and pandemic  risk—is growing all the time. In their paper, Breban and colleagues had warned against the possibility that the virus might become more transmissible after mutating or for R0 to increase in situations of higher population density. Should the recent surge in MERS cases in Saudi Arabia affect our thinking? Too early to say, Dr. Arnaud Fontanet (Institut Pasteur) tells ScienceWatch. We need to know if there is “an increase in the number of introductions of the virus into human populations from its animal intermediate host, presumably dromedary camels [see below], or whether there is an increase in inter-human transmissions,” and the data to resolve this are not yet available.

NEW RESEARCH FRONT

Surprisingly, for an illness that has been in the public eye for only 18 months or so, MERS had by March of this year already achieved a sufficient density of publications and citations to constitute a Thomson Reuters Research Front. These fronts, or clusters, form when a “core” group of comparatively older papers are frequently cited together by newer papers, thus marking a distinct area of closely related research. The MERS-related front currently contains a core of 35 papers and an average citation count of 29.03—indeed, within that set lie the beginnings of two or three clusters, on the properties and mechanism of action of MERS-CoV itself, on the more directly clinical and epidemiologic evidence, and on the possibility of animal reservoirs or intermediate hosts, notably the dromedary camel Camelus dromedarius (see N. Nowotny, J. Kolodziejek, Eurosurveillance, 19[16]: pii:20781 for references to serologic and virologic data on coronaviruses in camels).

Travellers are not being warned to avoid the Middle East, but the tourist attraction of a camel ride may have taken a hit, as accumulating evidence points to this animal as an intermediate host for MERS-CoV. In one recent fatal imported case, a man diagnosed in Malaysia with MERS had a history of visiting a camel farm in Saudi Arabia. Serological data point to infection with MERS-CoV or a closely related virus in dromedary camels from 2013 (when human cases were being recorded) and a decade earlier and as far back as 1992. Betacoronaviruses (of which MERS-CoV is one) have also been found in fruit-eating bats, a species for which close human contact is much rarer than it is with camels.

More virologic research is required to confirm or reject a bat-to-camel-to-human sequence and also to monitor the behavior of MERS-CoV itself. Mutations of the sort that enabled SARS-CoV to become such a threat may not yet have been recorded for MERS-CoV but Canadian mathematicians Chris T. Mauch and Tamer Oraby (Lancet 382[9893]:662-4, 2013), noting Breban and colleagues’ conclusion that MERS-CoV is unlikely to cause a pandemic, share those authors’ caution—emphasizing MERS-CoV “in its current guise.”


A former deputy editor of The Lancet,David W. Sharp, M.A. (Cambridge), is a freelance writer living in Minchinhampton, Gloucestershire, UK.

The data and citation records included in this report are from Thomson Reuters Web of ScienceTM. Web of ScienceTM is a registered trademark of Thomson Reuters. All rights reserved.