Middle East respiratory syndrome coronavirus (MERS-CoV)..
Last Updated 12-Oct-2013
MERS-CoV, sometimes called nCoV (novel coronavirus), was first characterized in 2012 by Prof Ali Mohamed Zaki. That virus came from a 60-year old male with suspected viral pneumonia. Prof. Zaki ran the usual respiratory viral tests which were negative so he sent a sample to virus hunters at Erasmus Medical Centre in The Netherlands. In the interim a broad-spectrum "pan-coronavirus" RT-PCR method and returned a positive result. The first MERS disease outbreak occurred earlier, in Jordan. Most cases are in males older than 45-years and underlying medical conditions feature prominently in MERS-CoV confirmed. Disease in children seems to be milder. No deaths, and few cases have occurred among those under the age of 21-years. No definitive animal source has been identified but buts and camels are suspects for now.
Members of the subfamily Coronavirinae that infect humans currently include the respiratory coronaviruses HCoV-OC43 (a betaCoV), HCoV-229E (alphaCoV), HCoV-NL63 (alphaCoV), SARS-CoV (betaCoV), MERS-CoV and HCoV-HKU1 (both betaCoV).
A schematic representation of the MERS-CoV virion.
Quick (sometimes rough) numbers
As of 12th October; FluTrackers, CIDRAP, WHO, KSA MOH. Does not include retrospectively seropositive cases from the first known outbreak in Jordan. Two reclassified Italian cases are also removed from the tally as laboratory confirmation was not be achieved.
a Data from FluTrackers, WHO and the European CDC. b This uses numbers based on publicly available data which may lack detail. This number gives you an idea of our understanding at the moment. To be pedantic and use only the number of discharges as the denominator for the CFR is most useful at the end of an outbreak/epidemic/pandemic, but not so much when data-in-hand is poor during the beginning.
A timeline showing some key events starting from the first retrospectively confirmed human case of infection by the Middle East Respiratory Syndrome Coronavirus in June 2012.
A graph of the accumulating confirmed MERS-CoV cases (blue mountain, includes fatalities), fatalities (red line) and the rolling proportion of fatal cases (PFC; black). Please don't go nuts and draw any major conclusions based on extrapolating the PFC to the global population - this figure is solely meant to show you the numbers and trends. What it does show us is how the outbreak came to be noticed - fatalities - and how with time, the denominator (survivors) is increasing at a greater rate than deaths. This chart uses Dates of Onset (DOO) of illness, where available, but is augmented by Dates of Reporting (DOR) for the remainder. While this is inaccurate, it does serve the purpose of generally showing how quickly the cases are accumulating. These data are compiled for general interest, from multiple sources including interested parties and official organizations. This chart may not have every relevant case because of difficulties in obtaining complete data, especially dates, from these sources. They are compiled with all care however this site is one of my own construction and the data and opinions expressed are not supported by any other official organization. Use images freely but please cite VDU and Dr. Ian M Mackay.
A schematic of the complete genome of the first fully sequenced MERS-CoV variant in lineage C of the betacoronaviruses; HCoV 2c EMC/2012.1 Drawn to scale based on GenBank sequence JX869059. This genome shares 99% nucleotide identity with two other fully sequence variants, Human betacoronavirus 2c England-Qatar/2012 (KC667074) and Human betacoronavirus 2c Jordan-N3/2012 (KC7761745) complete genomes.
As of the 13th of June 2013, there are 9 complete MERS-CoV genomes. The latest 4, from the Al-Ahsa hospital cluster, can be seen to group together closely (reflecting their epidemiological linkage). Keep in in mind that despite the apparently obvious differences in the phylogenetic tree above, all of these genomes share >99% identity (29,935 identical sites; pairwise identity 99.8%, aligned using Geneious Pro, Neighbor-Joining tree made in MEGA; GenBank accession numbers are shown before each strain's name). I have added an arrow to show time advancing, and how the complete genome tree shows that accurately. More detailed analyses of MERS-CoV sequences can be found from Andrew Rambaut, Uni of Edinburgh. I also have a tree of full CoV genome at the VDU CoV page.
The genomes are:
Could another region, perhaps shorter (subgenomic) and thus more easy to amplify for smaller or less genomics-focussed laboratories, represent the same degree of accuracy as full genomes, allowing us to monitor viral change with time? The Spike gene shows limited differences (99.7% identical nucleotides sequences, as visualized in the alignment picture below) between the 9 complete genomes available at writing. However, the differences that do exist may be useful for tracking any change in the virus as it passages between people. It already appears that the older virus (that isolated from the Jordan outbreak in in April-2012) differs from the most recent genomes from the Al-Ahsa hospital outbreak, but there is very little difference in the 4 Al-Ahsa genomes
The schematic highlights the difference (black lines) between MERS-CoV isolates and the consensus sequence across the complete ~4,000nt aligned Spike gene sequences.
The complete Spike gene phylogeny (top tree) almost mimics that of the complete MERS-CoV genome tree above, but not quite. The passage of virus through time is not as accurately represented. Interestingly though, a 900nt section of the 3' end of the Spike gene, something even more suited to ease of amplification, creates a similar tree (bottom tree) generated from what could be a much more easily PCR-amplified product.
Early MERS-CoV cases...
Cluster numbering using the US CDC scheme
The first case was admitted to hospital in April 2012
The first case, admitted to hospital 10th June 2012, to yield a characterised virus was a previously healthy non-smoker who died after community-acquired pneumonia progressed to acute respiratory distress syndrome (ARDS) and acute respiratory failure (ARF). No contacts were positive.
Nasal swabs from 154 French pilgrims collected before and after Hajj-2012 tested negative for the CoV using Corman's assays5, despite 90% suffering from respiratory symptoms during their stay in Saudi Arabia.8
By far, most MERS-CoV cases have originated for the Kingdom of Saudi Arabia (KSA). The adjacent figure provides a graphical representation of the available data.These data are compiled for general interest, from multiple sources including interested parties and official organizations. This chart may not have every relevant case because of difficulties in obtaining complete data from these sources. They are compiled with all care however this site is one of my own construction and the data and opinions expressed are not supported by any organization. Use images freely but please cite VDU and Dr. Ian M Mackay.
A number of human clusters have been reported:
Cluster 1: Jordan, 2 cases/2 of whom died: Utilising a WHO collaboration (via a United States Naval Medical Research Unit No. 3 [NAMRU-3] team in Cairo, Egypt), the Jordanian Ministry of Health sent samples from an outbreak of severe pneumonia among mainly healthcare workers during April 2012, for characterization. At the time (24th April, 2012)the samples were negative for normal coronaviruses as this preceded the existence of any MERS-CoV-specific diagnostics. However, 2 deaths from this time were subsequently confirmed as RT-PCR positive to, or had an antibody-conversion against, the MERS-CoV by NAMRU-3 (November, 2012; once tests were in use).11. Patient 1-25M University student, onset 21.03.12, 7d cough, fever, shortness of breath, died 25.04.12; Patient 2-40F intensive care unit nurse, onset 02.04.12, death 19.04.12)11. A mission from the WHO Eastern Mediterranean Regional Office (EMRO) was despatched on the 29th November to assist with surveillance. A complete genome (Human betacoronavirus 2c Jordan-N3/2012) is available from this cluster. 124 samples were sent to the US CDC ion late May 2013 for retrospective analyses.
Cluster 2: Saudi Arabia, 4 cases/2 deaths: This was a family cluster of four cases and two deaths.12 Patient 1 (70M), showed signs of disease from Oct 5, 2012 was hospitalized Oct 13 and died Oct 23 from cardiogenic and septic shock. He was given steroids. He had type 2 diabetes, ischemic heart disease and hypertension. Patient 2 (39M), eldest son of Patient 1, presented Oct 28 after 4 days of fever, rigors, anorexia and a productive cough requiring continuous positive airway pressure (CPAP) until his oxygen levels normalised and he was discharged. He was re-admitted, this time to intensive care, on Oct 29. He was given oseltamivir Oct 26 but died Nov 2. He was a chronic smoker with a history of airway disease. Patient 3 (16M), eldest son of Patient 2, reported malaise (feeling rotten), fever, sore throat, cough, wheeze and anorexia from Nov 3 and was admitted with a measurable fever, continuing symptoms and diarrhoea and abdominal pain. He was discharged Nov 11. Patient 4 (31M), brother of Patient 1, reported fever, rigors, night sweats and productive cough Nov 4 and was admitted Nov 6 and discharged Nov 14. He was a smoker. All were treated with oseltamivir and antibiotics.
Cluster 3: United Kingdom, 3 cases/2 deaths: Illness in a 60-year old male (60M) returned from travelling in Pakistan and Saudi Arabia led to his hospitalization during which he tested positive for the MERS-CoV (Feb 1)9. A second, non-travelling adult male with an underlying medical condition, also from the same household died after contracting the virus and becoming ill on Feb 5 after hospital-based contact with the index case. A female became ill Feb 5 after contact with the index case in hospital and recovered, as an outpatient, by Feb 19. This family cluster was classified as person-to-person transmission.
Cluster 4: Saudi Arabia:
Cluster 5: Saudi Arabia:
Cluster 6: France, 2 cases/1 death: A 64M became symptomatic on 22nd of April, 5-days after returning to France from travelling to Dubai.10 He was hospitalized on the 24th, subsequently required extracorporeal membrane oxygenation (ECMO)and died 28th May due to multiple organ failure. The second case in this cluster was a 51M who became ill while located 1.5m from 64M, in the same hospital room for 3-days (admitted for unrelated reasons). Like other visitors and healthcare workers, he wore no mask. 51M was released from hospital Apr 30 but was admitted to another hospital May 9 with symptoms. His infection was confirmed May 11, he suffered respiratory failure May 12 and remains hospitalised.
Cluster 7: Tunisia:
Cluster 8: Italy: The supposed new local acquisitions have since been reclassified by WHO as "probable: cases. Presumably lab testing was not sufficient to confirm MERS-CoV after all.
A cumulative epidemic curve of the total confirmed MERS-CoV cases (pale blue background) and the case numbers by week (black bars). These data are compiled for general interest, from multiple sources including interested parties and official organizations. This chart may not have every relevant case because of difficulties in obtaining complete data from these sources. In particular, there are >30 dates of onset missing from public data. They are compiled with all care however this site is one of my own construction and the data and opinions expressed are not supported by any organization. Use images freely but please cite VDU and Dr. Ian M Mackay.
Global distribution of MERS-CoV cases...
Cases are all be linked to a point of origin in the Arabian Peninsula, in particular, the Kingdom of Saudi Arabia (KSA).
A global map of the countries in which a MERS-CoV-positive case has been found highlighting those countries that have hosted local human or non-human spread of infections.
A chart showing the accumulation of MERS-CoV laboratory confirmed cases by area in which they originated. This chart uses Dates of Onset (DOO) of illness, where available, but is augmented by Dates of Reporting (DOR) for the remainder. While this is inaccurate, it does serve the purpose of showing where the cases are accumulating from, and roughly how quickly that is happening, at each location.
Risk assessments from the European CDC (ECDC; 17.05.13) suggest the need to (1) be on alert for cases with severe respiratory symptoms, also including systemic disease, especially in patients with underlying conditions, that have traveled from the Arabian Peninsula, (2) include patient samples from the lower respiratory tract, not just the nasopharynx/throat.
Large droplet transmission is suspected as the most likely route.10 Human-to-human transmission is not sustained; it does not continue beyond individuals in close contact with an confirmed case. Nasopharyngeal swabs may be less sensitive than specimens of the lower respiratory tract according to WHO, June 2013.
The MERS-CoV variant that has been most well characterized, HCoV-EMC, does not use the same cell receptor (angiotensin-converting enzyme 2; ACE2)as the severe acute respiratory syndrome (SARS) CoV, and can infect human, pig and bat cells.6
Most MERS-CoV cases are in males (includes surviving and fatal cases) but the bias towards males among the fatal cases is extreme. This is likely linked to the high proportion of underlying medical conditions among males who died and were positive for the virus. It may also be due to some other factor that puts males at greater risk of exposure to the suspected animal host(s) of MERS-CoV. These data are compiled for general interest, from multiple sources including interested parties and official organizations. This chart may not have every relevant case because of difficulties in obtaining complete data from these sources. They are compiled with all care however this site is one of my own construction and the data and opinions expressed are not supported by any organization. Use images freely but please cite VDU and Dr. Ian M Mackay.
a) the proportion of MERS-CoV positives HCWs who have died (red) vs. survived (blue), (b) the proportion of fatal cases (PFC; red) of MERS-CoV worldwide vs. the proportion of surviving cases (PSC; blue) (c) breakdown HCWs as a proportion of all MERS-CoV cases (blue), HCW deaths as a proportion of all MERS cases (green) and HCW deaths as a proportion of all MERS-CoV deaths.These data are compiled for general interest, from multiple sources including interested parties and official organizations. This chart may not have every relevant case because of difficulties in obtaining complete data from these sources. They are compiled with all care however this site is one of my own construction and the data and opinions expressed are not supported by any organization. Use images freely but please cite VDU and Dr. Ian M Mackay.
The presumed incubation period is between 9 and 12-days.10
A close contact (CC) can be defined as a person who provides care for confirmed case. This includes health care workers, family members or anyone having similar close physical contact. CCs also include people staying/living in the same place as confirmed cases.
The WHO released the following Case Definition update 03.07.13 (abbreviated).
Inconclusive testing: Patients with an inconclusive initial testing should undergo additional virologic and serologic testing to determine if the patient can be classified as a confirmed MERS-CoV case. It is strongly advised that lower respiratory specimens such as sputum, endotracheal aspirate, or bronchoalveolar lavage fluid be used when possible. If patients do not have signs or symptoms of lower respiratory tract infection and lower track specimens are not available or clinically indicated, both nasopharyngeal and oropharyngeal swab specimens should be collected. If initial testing of a nasopharyngeal swab is negative in a patient who is strongly suspected to have MERS-CoV infection, patients should be retested using a lower respiratory specimen tract or a repeat nasopharyngeal specimen with additional oropharyngeal specimen if lower respiratory tract specimens are not possible, and paired acute and convalescent sera.
Asymptomatic cases: The demonstration of asymptomatic infection is useful for epidemiological investigations and should be pursued as part of case investigations, however, the burden of proof must be higher due to the risk misclassification because of false positive tests due to laboratory contamination. Generally, in most viral infections, an immunological response such as development of specific antibodies would be expected even with mild or asymptomatic infection and as such serological testing may be useful as additional confirmation of the diagnosis. Additional steps to reconfirm asymptomatic cases, or any case in which the diagnosis is suspect, could include re-extraction of RNA from the original clinical specimen and testing for different virus target genes, ideally in an independent laboratory.
1An inadequate specimen would include a nasopharyngeal swab without an accompanying lower respiratory specimen, a specimen that has had improper handling, is judged to be of poor quality by the testing laboratory, or was taken too late in the course of illness.
2A direct epidemiological link may include:
3Inconclusive tests may include:
4Currently confirmatory testing requires molecular diagnostics including either a positive PCR on at least two specific genomic targets or a single positive target with sequencing on a second. However, the interim recommendations for laboratory testing for MERS-CoV should be consulted for the most recent standard for laboratory confirmation (http://www.who.int/csr/disease/coronavirus_infections/en/). See also notes on asymptomatic cases in this document.
Bats are the suspected host for the nearest ancestor of this presumed-to-be-zoonotic MERS-CoV, based on the finding of genetically related CoVs (found in the Japanese pipistrelle, Pipistrellus BatCoV-HKU5 and the lesser bamboo bat, Tylonycteris BatCoV-HKU47). Most of the ground breaking work in finding CoVs in bats comes from The University of Hong Kong.7
One case from Abu Dhabi in the United Arab Emirates (UAE) had been exposed to a sick camel.
Diagnostics and detection...
The MERS-CoV strain HCoV-EMC can be grown in cell culture using LLC-MK2 and Vero cells.1,2 This method has been used to produce antigen for detection antibodies in humans via immunofluorescence methods.1,2 The HCoV-EMC strain also replicates in fully differentiated human airway bronchial epithelium (HAE) cultures grown at the air-liquid interface (ALI).4
The first genetic detection of a MERS-CoV was completed using a conventional (non-real-time) pan-coronavirus RT-PCR.3 More specific real-time RT-PCR (RT-rtPCR) assays were described subsequently.5
HAE Cultures indicated something that I will need to add when I remember to come back and add it 4
Therapies and interventions...
There is no specific drug or vaccine available for the MERS-CoV although drug testing of US FDA-approved potential formulations is underway at the Small-molecule Inhibitor Leads Versus Emerging and neglected RNA viruses (SILVER) project.