Middle East Respiratory Syndrome and MERS-CoV: the novel coronavirus

Outline of MERS cases
The Middle East Respiratory Syndrome is a new, deadly viral illness which started emerging in the past year. The first case report of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was published in September 2012.¹ Since then there have been 50 confirmed cases of this novel coronavirus ², which causes a severe respiratory illness. All cases currently have direct links to the Middle East or those thought to be infected in this region. The case fatality rate is high, currently at 54%.³ The clinical presentation of the cases is similar to SARS. This includes respriatory tract symptoms, relative lymphopenia^1,5,6 and progression to renal failure^1,5,6,7.

Worryingly, this virus has shown limited person-to-person transmission. This has been documented to occur in at least 3 outbreaks to 6 contacts in France⁵, Saudi Arabia⁶ and the UK⁸

MERS as a recent introduction of a novel coronavirus
Coronaviruses are large enveloped viruses with an RNA genome. First discovered in 1960s,⁹ six species have now been found to infect humans.¹ Four of these are endemic in humans and cause little disease. The other two represent recent jumps into humans, and are known to cause the severe respiratory illness of SARS and MERS. The genetic sequence of MERS-CoV has been confirmed to be closely related to two coronaviruses found in bats. This suggests bats are the zoonotic origin of MERS-CoV. However, the genetic sequence is 87% - strongly suggesting that MERS-CoV is not the same virus as seen in bats.¹⁰ This therefore represents a new virus, likely also existing in bats but as yet unidentified.

Why this virus has recently emerged into humans is unknown. Recent contact with bats has not been reported in any of the cases. It is possible bat meat has entered the food chain, or bat bodily fluids have contaminated another product. Alternatively, MERS-CoV may also exist in another animal(s), acting as a source for the recent infections. Bats may have infected this intermediate host through ingestion of meat or bodily fluids, like excrement.

MERS-CoV therefore represents the second documented emergence of a new coronavirus into humans in a decade, following SARS in 2003. The factors leading to such emergences are widely discussed. In this instance one tempting hypothesis is that ever expanding livestock farming has bought animals into close proximity with bats by encroaching on their natural habitats in woodland.

Remaining questions, speculation, inferences and suggestions
The pertinent questions at this time include:

• What is the natural host of MERS-CoV?
• Is there an intermediate host?
• Are there other mild clinical or subclinical cases in the community?
• What is the mechanism of human exposure including source and route?
• Is there ongoing person-to-person transmission?

Due to the nature of the outbreak: with multiple cases spread across space and time, it is likely we can make several suggestions. Firstly, there is probably ongoing transmission between new hosts: whether this is in intermediate host such as livestock or directly between humans is not clear. This would explain the disparate spatiotemporal distribution of cases: humans are undergoing multiple exposures over time and space. I favour an intermediate host for several reasons: bat contact is not reported in the cases, bat contact is unusual, ongoing human-to-human transmission is unlikely as no positive chain of infection of more than 2 people has been identified. Identification of livestock hosts should be attempted through the screening of commonly domesticated animals in the Middle East.

It would be useful to determine the mechanism of transmission from person to person. This would help to further characterise the epidemiology of the disease, and tell us the likelihood of a large scale person-to-person outbreak. This could be done by testing secretions and excretions of those infected to look for evidence of viral shedding.

Furthermore, lessons learnt from 2009 H1N1 swine flu and H5N1 bird flu may be relevant to MERS. Firstly, in these outbreaks the clinical cases were the tip of the iceberg. Many more cases and introductions existed in the community which never presented to a doctor. As such, the cases seen in hospital represented a selection bias which over-estimated the severity of the disease. To determine this, seroprevalence studies are needed to establish whether asymptomatic or mild cases of the disease are missing attention. Interestingly, the first case report of the disease also screened the serum of 2000 individuals to determine whether they had cross-reactive antibodies with MERS-CoV infected cells, which is a strong indicator of previous infection.1 This suggested others had not been exposed to MERS-CoV in the community. This needs to be replicated in other community based samples in the Middle East.

REFERENCES
1 Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. 2012. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. NEJM 367:1814-20

2 World Health Organisation 2013 Novel coronavirus summary and literature update – as of 31 May 2013 http://www.who.int/csr/disease/coronavirus_infections/update_20130531/en/index.html

3 MERS update http://www.cdc.gov/coronavirus/mers/case-def.html

4 World Health Organisation 2013 Novel coronavirus summary and literature update – as of 17 May 2013 http://www.who.int/csr/disease/coronavirus_infections/update_20130517/en/index.html

5 Guery B, et al. Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission. Lancet. Published online 29 May 2013

6 Memish ZA, et al. Family cluster of Middle East Respiratory Syndrome coronavirus infections. New England Journal of Medicine. Published online 29 May 2013. DOI: 10.1056/NEJMoa1303729.

7 Bermingham A 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, Volume 17, Issue 40, 04 October 2012

8 Health Protection Agency, EVIDENCE OF PERSON-TO-PERSON TRANSMISSION WITHIN A FAMILY CLUSTER OF NOVEL CORONAVIRUS INFECTIONS, UNITED KINGDOM, FEBRUARY 2013 Eurosurveillance, Volume 18, Issue 11, 14 March 2013

9 Hamre D & Procknow JJ. A new virus isolated from the human respiratory tract. Proc Soc Exp Biol Med 1966;121:190-193

10 Cotton M et al Full-Genome Deep Sequencing and Phylogenetic Analysis of Novel Human Betacoronavirus Emerging Infectious Diseases 19(5) May 2013