In September 2012, a case of novel coronavirus infection was reported involving a Saudi Arabian gentleman who had been admitted to a hospital in June 2012 with pneumonia and acute kidney injury. A few days later, a separate report appeared of an almost identical virus detected in a second individual with acute respiratory syndrome and acute kidney injury. The second individual initially developed symptoms in Qatar but had traveled to Saudi Arabia before he became ill. He then sought care in the United Kingdom. Many subsequent cases and clusters of infections have been reported.
This novel coronavirus, initially termed human coronavirus-EMC (for Erasmus Medical Center), has been named Middle East respiratory syndrome coronavirus (MERS-CoV).
Middle East respiratory syndrome coronavirus (MERS-CoV) or EMC/2012 (HCoV-EMC/2012) is a positive-sense, single-stranded RNA novel species of the genus Betacoronavirus, lineage C. It is different from the other human betacoronaviruses (severe acute respiratory syndrome coronavirus (SARS), OC43 and HKU1) but closely related to several bat coronaviruses. Initially called novel coronavirus 2012 or simply novel coronavirus, it was first reported in 2012 after genome sequencing of a virus isolated from sputum samples from an individual who fell ill in a 2012 outbreak of a new flu.
MERS-CoV genomes are phylogenetically classified into two clades, clade A and B. The earliest cases of MERS were of clade A clusters (EMC/2012 and Jordan-N3/2012). New cases are genetically distinct (clade B).
The Taxonomy of MERS-CoV is as follows:
MERS-CoV is distinct from the SARS coronavirus and distinct from the common-cold coronavirus and known endemic human betacoronaviruses HCoV-OC43 and HCoV-HKU1. Until 23 May 2013, MERS-CoV had frequently been referred to as a SARS-like virus or simply the novel coronavirus and earlier it was referred to colloquially on message boards as the "Saudi SARS". MERS-CoV is closely related to several bat coronaviruses.
An electron micrograph of a thin section of MERS-CoV, showing the spherical particles within the cytoplasm of an infected cell.
Middle East respiratory syndrome 3-D image
Viral tropism is defined by the specificity of a virus for a particular host tissue determined in part by the interaction of viral surface structures with receptors present on the surface of the host cell.
In humans, MERS-CoV has a strong tropism for nonciliated bronchial epithelial cells. It has been shown to effectively evade the innate human immune responses and antagonize interferon (IFN) production in these cells. This tropism is unique in that most respiratory viruses target ciliated cells.
Dr. Gary Whittaker, professor of Virology, and Jean Millet at Cornell’s Biological Safety Level 3 facility located in the Animal Health Diagnostics Center discovered that a common protease enzyme known as furin activates the MERS-CoV to fuse with cell membranes and enter host cells. Whittaker and Millet suggest that blocking furin at a specific point in the host cell entry process could lead to a treatment by preventing the virus from getting into cells, where it uses the cell’s reproduction mechanism to make new viruses.
Coronaviruses have a spike protein that is activated by a protease and mediates membrane fusion and entry into a host cell. The location on the spike protein where a protease activates this process is called a cleavage site. The researchers found there were two cleavage sites for MERS-CoV, each activated by furin at different times:
MERS-CoV particles as seen by negative stain electron microscopy. Virions contain characteristic club-like projections emanating from the viral membrane.
Whittaker and Millet concluded that this might be a situation where that extra cleavage site is allowing more spread in animals or humans. With MERS, “the primary infection is in the lungs, and even there it infects additional cell types, including immune cells, which could allow dissemination throughout the body”.
Dipeptidyl peptidase 4 (DPP4, also known as, CD26), which is present on the surfaces of human nonciliated bronchial epithelial cells, is a functional receptor for MERS-CoV. Expression of human and bat DPP4 in nonsusceptible cells enables infection by MERS-CoV. The DPP4 protein displays high amino acid sequence conservation across different species including the sequence that was obtained from bat cells.
Further research identified DPP4 as a functional cellular receptor for MERS-CoV. Unlike other known coronavirus receptors, the enzymatic activity of DPP4 is not required for infection. As would be expected, the amino acid sequence of DPP4 is highly conserved across species and is expressed in the human bronchial epithelium and kidneys. Bat DPP4 genes appear to have been subject to a high degree of adaptive evolution as a response to coronavirus infections, so the lineage leading to MERS-CoV may have circulated in bat populations for a long period of time before being transmitted to humans.
To jump to humans, animal viruses such as these novel coronaviruses, and avian and swine flu viruses, must evolve to be able to latch onto proteins on the surfaces of human cells. In a paper published in Nature, Stalin Raj at the Erasmus Medical Centre in Rotterdam, the Netherlands, and a largely European team reported that spikes on the surface of HCoV-EMC bind to DPP4, a well-known receptor protein on human cells. When the binding site for the virus on DPP4 was blocked using antibodies, the virus could not infect cells. Conversely, when DPP4 was expressed on the surface of normally non-susceptible cells, HCoV-EMC could now infect them.
In a cell line susceptibility study, MERS-CoV infected several human cell lines, including lower (but not upper) respiratory, kidney, intestinal and liver cells, as well as, histiocytes. The range of tissue tropism in vitro was broader than that for any other known human coronavirus. In another study, human bronchial epithelial cells were susceptible to infection. MERS-CoV can also infect nonhuman primate, porcine, bat, civet, rabbit and horse cell lines. Further study is necessary to determine whether these in vitro findings will translate to broader species susceptibility during in vitro infections.
Because of a large increase in cases in Saudi Arabia in the spring of 2014, concern arose that MERS-CoV might have mutated to become more transmissible or virulent. However, cell culture experiments of viruses isolated during these outbreaks showed no evidence of changes in viral replication rate, immune escape, interferon sensitivity or serum neutralization kinetics compared with a contemporaneous but phylogenetically different virus recovered in Riyadh or the original MERS-CoV isolate from 2012.
In an analysis of the full or partial genomes of MERS-CoV obtained from 21 individuals with MERS-CoV infection in Saudi Arabia between June 2012 and June 2013, there was sufficient heterogeneity to support multiple separate animal-to-human transfers. Moreover, even within a hospital outbreak in Al-Hasa, Saudi Arabia, there was evidence of more than one virus introduction. By estimating the evolutionary rate of the virus, the authors concluded that MERS-CoV emerged around July 2011 (95% highest density July 2007 to June 2012).
Phylogenetic analysis during the spring of 2014 showed that viruses from individuals in Jeddah, Saudi Arabia, were genetically similar, suggesting that the outbreak in Jeddah was caused by human-to-human transmission. Of 168 specimens that were positive for MERS-CoV during the outbreak in Jeddah, 49% came from a single hospital, King Fahd Hospital. Isolates from individuals in Riyadh, Saudi Arabia, during the spring of 2014 belonged to six different clades, suggesting that these infections resulted from increased zoonotic activity or transmission from humans in other regions. One cluster of infections observed in a single hospital in Riyadh was associated with a single clade, suggesting nosocomial transmission.
At least one individual who had fallen sick with MERS was known to have come into contact with camels or recently drank camel milk.
In 2013 MERS-CoV was identified in three members of a dromedary camel herd held in a Qatar barn, which was linked to two confirmed human cases who have since recovered. The presence of MERS-CoV in the camels was confirmed by the National Institute of Public Health and Environment (RIVM) of the Ministry of Health and the Erasmus Medical Center World Health Organization Collaborating Center, the Netherlands. None of the camels showed any sign of disease when the samples were collected.
The Qatar Supreme Council of Health advised in November 2013 that individuals with underlying health conditions, such as heart disease, diabetes, kidney disease, respiratory disease, the immunosuppressed and the elderly, avoid any close animal contacts when visiting farms and markets, and to practice good hygiene, such as washing hands.
In December 2013, a further study on dromedary camels from Saudi Arabia revealed the presence of MERS-CoV in 90% of the evaluated dromedary camels (total 310), suggesting that dromedary camels not only could be the main reservoir of MERS-CoV but also the animal source of MERS.
According to the 27 March 2014 MERS-CoV summary update, recent studies support that camels serve as the primary source of the MERS-CoV infecting humans, while bats may be the ultimate reservoir of the virus. Evidence includes the frequency with which the virus has been found in camels to which human cases have been exposed, seriological data which shows widespread transmission in camels and the similarity of the camel CoV to the human CoV.
On 13 February 2013, the World Health Organization (WHO) stated "the risk of sustained person-to-person transmission appears to be very low." The cells MERS-CoV effects in the lungs only account for 20% of respiratory epithelial cells, so a large number of virions are likely needed to be inhaled to cause infection.
As of 29 May 2013[update], the WHO warned that the MERS-CoV virus is a "threat to the entire world." However, Dr. Anthony S. Fauci of the National Institutes of Health (NIH) in Bethesda, Maryland, stated that as of now MERS-CoV "does not spread in a sustained person-to-person way at all." Dr. Fauci stated that there is potential danger in that it is possible for the virus to mutate into a strain that does transmit from person-to-person.
The infection of healthcare personnel (HCP*) has led to concerns of human-to-human transmission.
* HCP refers to all individuals, paid and unpaid, working in healthcare settings whose activities potentially place them at risk for exposures to an individual with MERS-CoV. Examples of such activities include those that require direct contact with patients and exposure to the patient-care environment, including being in the patient room or in a triage or examination room or other potentially contaminated areas and handling blood, body fluids (except sweat), secretions, or excretions or soiled medical supplies, equipment or environmental surfaces.
The Centers for Disease Control and Prevention (CDC) lists MERS as transmissible from human-to-human. "MERS-CoV has been shown to spread between people who are in close contact.” Transmission from infected individuals to healthcare personnel (HCP) has also been observed. Clusters of cases in several countries are being investigated." There was also a New York Times article which provided some correlative context for this.
The first confirmed case of MERS was reported in Saudi Arabia in September 2012. Egyptian virologist Dr. Ali Mohamed Zaki isolated and identified a previously unknown coronavirus which was isolated from the sputum of a gentleman in Jeddah, Saudi Arabia, who was admitted to the hospital with pneumonia and acute kidney injury in June 2012. Dr. Zaki then posted his findings on 24 September 2012 on ProMED-mail, an internet-based reporting system that helps disseminate information about infectious disease outbreaks worldwide. The isolated cells showed cytopathic effects (CPE), in the form of rounding and syncytia formation.
A second case was found in September 2012. A 49-year-old gentleman living in Qatar presented with acute respiratory syndrome and acute kidney injury who had recently traveled to Saudi Arabia. A sequence of the virus was nearly identical to that of the first case. In November 2012, similar cases appeared in Qatar and Saudi Arabia. Additional cases were noted, with deaths associated, and rapid research and monitoring of this novel coronavirus began.
A study by Ziad Memish of Riyadh University and colleagues suggests that the virus arose sometime between July 2007 and June 2012, with perhaps as many as 7 separate zoonotic transmissions. Among animal reservoirs, CoV has a large genetic diversity yet the samples from individuals suggest a similar genome, and therefore common source, though the data are limited. It has been determined through molecular clock analysis, that viruses from the EMC/2012 and England/Qatar/2012 date to early 2011 suggesting that these cases are descended from a single zoonotic event. It would appear MERS-CoV had been circulating in the human population for greater than one year without detection and suggests independent transmission from an unknown source.
Subsequent cases and clusters* of infections have been reported (Figure 1). Since April 2012, more than 1,400 cases of MERS-CoV infection have been reported. The actual number of cases is likely to be higher. The median age is 48 years (range 9 months to 94 years) and 64% of the cases have been male.
* A cluster is defined as two or more individuals with onset of symptoms within the same 14 days period and who are associated with a specific setting such as a classroom, workplace, household, extended family, hospital, other residential institution, military barracks or recreational camp.
Epidemic Curve of MERS-CoV Cases in Humans Reported to the WHO as of 5 February 2015 (n = 971)
Reprinted from WHO, Middle East respiratory syndrome coronavirus (MERS-CoV): Summary of current situation, literature update and risk assessment - as of 5 February 2015.
The number of cases in the Middle East increased dramatically in March and April 2014 then declined sharply in mid-May 2014. A smaller increase in cases occurred during March and April 2013. An outbreak of more than 180 cases occurred in the Republic of Korea in May and June 2015. In this index case*, the gentleman had recently traveled to several countries in the Arabian Peninsula.
Since April 2012, more than 1,400 laboratory-confirmed human infections with MERS-CoV have been reported to the WHO. These occurred primarily in countries in the Arabian Peninsula* (Figure 2). The majority of cases have occurred in Saudi Arabia including some case clusters.
Countries Reporting MERS-CoV Infection as of 5 February 2015
MERS-CoV: Middle East respiratory syndrome coronavirus.World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV): Summary of current situation, iterature update and risk assessment–as of 5 February 2015. http://www.who.int/csr/disease/coronavirus_infections/mers-5-february-2015.pdf?ua=1 (Accessed on March 04, 2015). Copyright © 2015 World Health Organization.
Cases have also been reported from other regions of the world including North Africa, Europe, Asia and North America (Table 1). In countries outside of the Arabian Peninsula, individuals developed illness after returning from the Arabian Peninsula or through close contact with infected individuals.
Countries in or near the Arabian Peninsula with Laboratory-Confirmed Cases
Countries with Travel-Associated Laboratory-Confirmed Cases
Notable cases and clusters which have been reported to the WHO are summarized as follows:
October and November 2012
March and April 2014
The current outbreak situation as of 24 August 2015 is:
Total confirmed cases
MERS-CoV is a zoonotic virus that is transmitted from animals to humans. The origins of the virus are not fully understood but, according to the analysis of different virus genomes, it is believed that it has been present in bats for some time and had spread to camels by the mid-1990s. The virus appears to have spread from camels to humans in the early 2010s. The original bat host species and the time of initial infection in this species has yet to be definitively determined.
Early research suggested the virus is related to one found in the Egyptian tomb bat. In September 2012 Ron Fouchier speculated that the virus might have originated in bats. Work by epidemiologist Ian Lipkin of Columbia University in New York showed that the virus isolated from a bat looked to be a match to the virus found in humans. 2c betacoronaviruses were detected in Nycteris bats in Ghana and Pipistrellus bats in Europe that are phylogenetically related to the MERS-CoV virus.
Other research has shown that MERS-CoV is closely related to the Tylonycteris bat coronavirus HKU4 and Pipistrellus bat coronavirus HKU5. Serological evidence shows that these viruses have infected camels for at least 20 years. The most recent common ancestor of several human strains has been dated to March 2012 (95% confidence interval December 2011 to June 2012).
Studies performed in Europe, Africa and Asia, including the Middle East, have shown that the coronavirus RNA sequences are found frequently in bat fecal samples and that some of these sequences are closely related to MERS-CoV sequences. In a study from Saudi Arabia, 823 fecal and rectal swab samples were collected from bats and, using real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) assay, many coronavirus sequences were found. Most were unrelated to MERS-CoV, but, notably, one 190 nucleotide sequence in the RNA-dependent RNA polymerase (RdRp) gene was amplified that had 100% identity with a MERS-CoV isolate cloned from an index individual with MERS-CoV infection. This sequence was detected from a fecal pellet of a Taphozous perforatus bat captured from a site near the home of the index individual. MERS-CoV grows readily in several bat-derived cell lines.
Although bats might be a reservoir of MERS-CoV, it is unlikely that they are the immediate source for most human cases because human contact with bats is uncommon.
The route of transmission from animals to humans is not fully understood, but camels are likely to be a major reservoir host for MERS-CoV and an animal source of infection in humans. Strains of MERS-CoV that are identical to human strains have been isolated from camels in several countries, including Egypt, Oman, Qatar and Saudi Arabia.
It seems likely that dromedary camels are the primary animal host for MERS-CoV. The strongest evidence of camel-to-human transmission of MERS-CoV comes from a study in Saudi Arabia in which MERS-CoV was isolated from a gentleman who died of laboratory-confirmed MERS-CoV infection after close contact with camels that had rhinorrhea. Full-genome sequencing demonstrated that the viruses isolated from the gentleman and his camel were identical. The study had the following findings:
Other phylogenetic analyses comparing portions of the MERS-CoV genome obtained from camels to MERS-CoV obtained from humans with epidemiologic links to the camels have demonstrated that the viruses were similar.
Serologic studies have also suggested that camels are an important source of MERS-CoV:
The virus does not appear to pass easily from human-to-human unless there is close contact such as providing unprotected care to an infected individual. There have been clusters of cases in healthcare facilities, where human-to-human transmission appears to be more probable, especially when infection control and prevention practices are inadequate. Thus far, no sustained community transmission has been documented.
The virus appears to be circulating throughout the Arabian Peninsula, primarily in Saudi Arabia, where the majority of cases (greater than 85%) have been reported since 2012. Several cases have been reported outside the Middle East. Most of these infections are believed to have been acquired in the Middle East and then exported outside the region. The ongoing outbreak in the Republic of Korea is the largest outbreak outside of the Middle East, and while concerning, there is no evidence of sustained human-to-human transmission in the Republic of Korea. For all other exported cases, no secondary or limited secondary transmission has been reported in countries with exported cases.
Serologic studies have shown a low prevalence of MERS-CoV antibodies in humans in Saudi Arabia. A broad antibody survey of 10,009 individuals representative of the general population of Saudi Arabia found seropositivity in 15 (0.15%), all but one of whom resided in five interior provinces (of 13 total provinces). In a separate survey included in the same report, 87 camel shepherds and 140 slaughterhouse workers were tested of whom 7 (3.1%) were seropositive.
Among 5,235 adult pilgrims from 22 countries who visited Mecca, Saudi Arabia, for Hajj in 2013, none had a positive MERS-CoV polymerase chain reaction (PCR) from the nasopharynx. 3,210 individuals were screened pre-Hajj and 2,025 were screened post-Hajj.
Case clusters in the United Kingdom, Tunisia, Italy and in healthcare facilities in Saudi Arabia, France, Iran and the Republic of Korea strongly suggest that human-to-human transmission occurs (Figure 3). The number of contacts infected by individuals with confirmed infections, however, appears to be limited. An exception to this was the outbreak in the Republic of Korea in May and June 2015 where many secondary and some tertiary cases occurred.
Epidemic Curve of 536 Laboratory-Confirmed MERS-CoV Patients by Case Type (Primary versus Secondary; as of May 8, 2014)
MERS-CoV: Middle East Respiratory Syndrome Coronavirus; WHO: World Health Organization. Reproduced with permission from: World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV) summary and literature update – as of 9 May 2014.
Secondary cases have tended to be milder than primary cases and many secondary cases have been reported to be asymptomatic. Possible modes of spread include droplet and contact transmission.
More than half of all laboratory-confirmed secondary cases have been associated with healthcare settings. The majority of cases in the spring of 2014 in Saudi Arabia were acquired through human-to-human transmission in healthcare settings likely due, at least in part, to systemic weaknesses in infection control.
In a report describing a hospital outbreak in the Republic of Korea in May and June 2015, 37 infections were associated with the index case, who was hospitalized from May 15 to May 17. Twenty-five cases were secondary and 11 were tertiary. The overall median incubation period was six days, but it was four days for secondary cases and six days for tertiary cases. The Korean outbreak clearly demonstrated the importance of "super spreaders," several of whom were identified in an epidemiologic analysis and were responsible for a high proportion of cases. As an example, a single individual infected at least 70 other individuals between May 27 and May 29 while being treated in the emergency room of a single hospital in Seoul, the Republic of Korea.
Secondary transmission has also occurred in the household setting. Among 280 household contacts of 26 index individuals with MERS-CoV infection, 12 probable cases of secondary transmission were detected by rRT-PCR of a pharyngeal swab and/or serology. However, it is possible that some of the index cases and probable secondary cases may have acquired MERS-CoV from a common source, particularly since three of seven contacts tested positive for MERS-CoV by rRT-PCR only four days after illness onset in the index cases. Some secondary cases may also have been missed since only 108 of 280 contacts had samples available for serologic testing longer than 3 weeks after the onset of symptoms in the index case.
MERS-CoV is most easily found in lower respiratory tract samples (tracheal aspirates, sputum, or bronchoalveolar lavage fluid) of symptomatic individuals, and this shedding may persist for as long as two weeks. Prolonged shedding was also detected by rRT-PCR in an asymptomatic healthcare worker. The healthcare worker was initially tested following occupational exposure to MERS-CoV. Serial rRT-PCR testing revealed ongoing shedding for six weeks. These findings raised concerns that asymptomatic individuals could unknowingly transmit the infection to others.
In a study that evaluated the transmissibility and epidemic potential of MERS-CoV based upon 55 laboratory-confirmed cases detected by late June 2013, the reproduction number (R0; defined as the average number of infections caused by one infected individual in a fully susceptible population) was estimated to be between 0.60 and 0.69. The finding of an R0 less than 1 suggests that MERS-CoV does not yet have pandemic potential. Others have pointed out that the R0 might be higher in the absence of infection control measures.
The following MERS-CoV infection case definitions have been proposed by the WHO:
Confirmed Case – An individual with laboratory confirmation of MERS-CoV infection irrespective of clinical signs and symptoms. Confirmatory laboratory testing requires a positive PCR on at least two specific genomic targets or a single positive target with sequencing on a second.
Probable Case - A patient under investigation (PUI) with absent or inconclusive laboratory results for MERS-CoV infection who is a close contact* of a laboratory-confirmed MERS-CoV case. Examples of laboratory results that may be considered inconclusive include a positive test on a single PCR target, a positive test with an assay that has limited performance data available or a negative test on an inadequate specimen.
A probable case is defined by the following criteria:
The WHO criteria for laboratory confirmation require detection of viral nucleic acid or acute and convalescent serology. The presence of nucleic acid can be confirmed by positive results from at least two sequence-specific real-time reverse-transcriptase polymerase chain reactions (rRT-PCRs) or a single sequence-specific rRT-PCR test and direct sequencing from a separate genomic target. A case confirmed by serology requires demonstration of seroconversion in two samples ideally collected at least 14 days apart using at least one screening assay (enzyme-linked immunoassay, immunofluorescence assay) and a neutralization assay.
In an outbreak of MERS-CoV infection in Saudi Arabia that resulted in laboratory-confirmed MERS-CoV in 23 individuals, the median incubation period was 5.2 days (95% confidence 1.9 - 14.7 days). In one secondary case that occurred in an individual in France who shared a room with an infected individual, the incubation period was estimated at 9 - 12 days. In an outbreak in the Republic of Korea, the median incubation period was 6.3 days (95th percentile 12.1 days).
Based on current data, the incubation period* for MERS is usually about 5 or 6 days, but can range from 2 - 14 days. In MERS-CoV confirmed cases, the median time from illness onset to hospitalization is approximately 4 days. In critically ill individuals, the median time from onset to intensive care unit (ICU) admission is approximately 5 days and median time from onset to death is approximately 12 days.
The median incubation period for secondary cases associated with limited human-to-human transmission is approximately 5 days (range 2 - 14 days).
The WHO and the CDC recommend that an evaluation for MERS-CoV be considered in individuals with a syndrome of MERS who returned from travel to the Arabian peninsula or neighboring countries within the past 14 days.
Based on what researchers know so far, individuals with pre-existing medical conditions (also called comorbidities) may be more likely to become infected with MERS-CoV or have a severe case. The virus also appears to cause more severe disease in older individuals.
Most MERS-CoV cases have been reported in adults (98%) (median age approximately 50 years, male predominance), although children and adults of all ages have been infected (range 0 to 99 years, n=1,335)). Most hospitalized MERS-CoV infected individuals have had chronic comorbidities. Among confirmed MERS-CoV cases reported to date, the case fatality proportion is approximately 35%.
It is unclear whether individuals with specific conditions are disproportionately infected with MERS-CoV or MERS-CoV is more severe in these individuals. In a study of 47 individuals with MERS-CoV infection in Saudi Arabia, 45 (96%) had the following underlying comorbidities:
The high rate of comorbidities which were reported should be interpreted with caution, since diabetes mellitus was frequently observed in a study of more than 6,000 individuals presenting to an outpatient clinic in Riyadh, Saudi Arabia and because approximately half of the 47 individuals described were part of an outbreak in a hemodialysis unit where the rates of chronic kidney disease and hypertension would be expected to be high.
In a study of 12 critically ill individuals with MERS-CoV infection, each individual had at least one comorbid condition. The median number of comorbid conditions was 3 (range 1 to 6). In a case-control study that included 17 case individuals with MERS-CoV infection and 82 controls, case individuals were more likely than controls to be overweight, have diabetes mellitus and to have end-stage renal disease.
Other comorbidities include:
Healthcare providers should evaluate individuals for MERS-CoV infection based on recommendations issued by the CDC for investigation of possible cases in the United States. These recommendations include those individuals who meet the following criteria for being a PUI:
Fever and pneumonia or ARDS (based on clinical or radiologic evidence) and either:
A wide clinical spectrum of MERS-CoV infection ranges from no symptoms (asymtomatic) to mild upper respiratory symptoms rapidly progressing to pneumonitis, respiratory failure, septic shock and multi-organ failure resulting in death. Limited clinical data for MERS-CoV infected individuals are available. Most published clinical information to date is from critically ill individuals.
Several individuals with asymptomatic infection have been identified among contacts of individuals with symptomatic infection. As an example, the Saudi Arabian Ministry of Health screened more than 3,000 close contacts of individuals using rRT-PCR testing of nasopharyngeal swabs and identified seven healthcare workers with MERS-CoV infection, two of whom were asymptomatic and five of whom had mild upper respiratory tract symptoms.
Many individuals who have been reported to be asymptomatic have in fact had signs and symptoms of illness. In a study of a healthcare facility-associated outbreak in Jeddah, Saudi Arabia, in the spring of 2014, there were 255 laboratory-confirmed cases of MERS-CoV infection. Of 64 individuals who were initially identified as being asymptomatic, 33 of the 64 individuals (52%) were available for a telephone survey. Of these 33 individuals, 79% reported at least one symptom during the month before testing and 70% reported more than one symptom. Unexpectedly, 36% of the individuals reported the presence of signs and symptoms as the reason for undergoing MERS-CoV testing, even though they had been identified as being asymptomatic.
There have been reports describing individuals with a mild respiratory illness not requiring hospitalization. In one report, an individual developed a dry cough on the 10th day of illness followed by dyspnea and hypoxia on the 11th day of illness. Prior to that, he had only nonspecific signs and symptoms which included malaise, myalgias and low-grade fevers.
A typical presentation of MERS-CoV infection includes:
Atypical presentations including mild respiratory illness without fever and diarrhea preceding the development of pneumonia have been reported.
Upon hospital admission, common signs and symptoms of individuals who were laboratory-confirmed to have MERS-CoV infection may include:
Individuals who progressed from requiring admission to being transferred to an ICU often had a history of a febrile upper respiratory tract illness with rapid progression to pneumonia within a week of illness onset. Severe illness can cause respiratory failure that requires mechanical ventilation and support in an ICU. Approximately 36% of reported individuals with MERS-CoV have died.
Individuals who progressed from requiring admission to being transferred to an ICU often had a history of a febrile upper respiratory tract illness with rapid progression to pneumonia within a week of illness onset. Severe illness can cause respiratory failure that requires mechanical ventilation and support in an ICU. Approximately 36% of reported individuals with MERS-CoV have died.
For many individuals with MERS-CoV infection more severe complications usually rapidly follow including:
The following clinical findings were observed among 47 individuals with MERS-CoV infection in Saudi Arabia:
Of these 47 individuals, 42 (89%) required ICU and 34 (72%) required mechanical ventilation. The median time from presentation for medical care to mechanical ventilation was 7 days (range 3 - 11 days) and to death was 14 days (range 5 - 36 days).
There is only one published description of MERS-CoV infection in children. Of 11 infections, 9 were asymptomatic, all discovered during contact investigations of older individuals. Both symptomatic cases were in children with underlying conditions (cystic fibrosis and Downs’s syndrome).
One stillbirth at five months' gestation was reported in a woman with MERS-CoV infection. The woman developed vaginal bleeding and abdominal pain on the 7th day of illness with MERS-CoV. She spontaneously delivered a stillborn infant. In another MERS-CoV infection in pregnancy occurring near term, a woman in the United Arab Emirates gave birth to an apparently healthy baby but the mother died after delivery.
Several studies have shown that nonhuman primates develop MERS-CoV infection after inoculation with MERS-CoV and can therefore be used as animal models for studying MERS-CoV infection. In contrast, mice, ferrets and guinea pigs do not appear to be susceptible to MERS-CoV infection.
In one study, six rhesus macaques were inoculated with MERS-CoV through a combination of intratracheal, intranasal, oral and ocular routes. Within 24 hours, all animals developed anorexia, fever, tachypnea, cough, piloerection and hunched posture. Chest radiographs showed localized infiltrates and increased interstitial markings. After the animals were euthanized, postmortem examinations showed multifocal to coalescent lesions throughout the lungs. Histopathology demonstrated infiltrates of neutrophils and macrophages, compatible with acute interstitial pneumonia.
In another study by the same group, following inoculation with MERS-CoV, rhesus macaques developed a transient lower respiratory tract infection. Clinical signs, virus shedding, virus replication in respiratory tissues, gene expression, inflammatory changes on histology and cytokine and chemokine profiles peaked one day after infection and decreased rapidly over time. In nasal swabs and bronchoalveolar lavage (BAL) fluid specimens, viral loads were also highest on day 1 post infection and decreased rapidly. Two of three animals were still shedding virus from the respiratory tract on day 6 (the same day they were euthanized). MERS-CoV caused a multifocal, mild to marked interstitial pneumonia, with virus replication occurring primarily in type I and II alveolar pneumocytes.
Data from the cases sampled indicate that lower respiratory tract specimens e.g., sputum, tracheal aspirates, bronchoalveolar lavage (BAL) fluid are more sensitive for detection of MERS-CoV by rRT-PCR testing than those from the upper respiratory tract (combined nasopharyngeal and throat swab and nasopharyngeal aspirates). However, upper respiratory tract specimens are still useful for diagnosing MERS-CoV. For example, in a series of 47 individuals with MERS-CoV, the majority were diagnosed using nasopharyngeal swabs.
In a detailed analysis of an individual with multiple myeloma and MERS-CoV infection who succumbed after developing ARDS and septic shock, high concentrations of MERS-CoV were detected by rRT-PCR from respiratory specimens (BAL fluid or tracheobronchial secretions), peaking at 1.2 x106 copies/mL. MERS-CoV was also detected from oronasal secretions, stool and urine but at low concentrations. Only one of two oronasal specimens was positive by rRT-PCR (5,370 copies/mL). No virus was detected from the blood of this individual but it had been detected from the blood of another reported individual. The CDC performed rRT-PCR testing on serum samples.
Three rRT-PCR assays for routine detection of MERS-CoV have been developed:
Assay targeting a region upstream of the E protein gene (upE)
Assay targeting the open reading frame 1b (ORF 1b)
Assay targeting the open reading frame 1a (ORF 1a). In some cases, sequencing should be performed for confirmation.
An emergency use authorization was issued by the United States Food and Drug Administration in 2013 for the rRT-PCR assay developed by the CDC on clinical respiratory, blood and stool samples.
Lower respiratory tract specimens should be the first priority for collection and real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) testing, since rRT-PCR testing of lower respiratory specimens appears to be more sensitive for detection of MERS-CoV than testing of upper respiratory tract specimens.
Given the potential severity of MERS-CoV infections, the risk for human-to-human transmission and the limited data about the sensitivity of each diagnostic test, the CDC recommends that:
The following diagnostic approach has been adapted from guidelines issued by the CDC and the WHO:
Lower respiratory tract specimens such as sputum, tracheal aspirate, endotracheal aspirate or BAL fluid should be obtained for rRT-PCR testing in all cases of severe disease and from milder cases when possible. Lower respiratory tract specimens should be the first priority for collection and rRT-PCR testing, since rRT-PCR testing of lower respiratory tract specimens appears to be more sensitive for detection of MERS-CoV than testing of upper respiratory tract specimens. The MERS-CoV virus can be detected with higher viral load and longer duration in the lower respiratory tract compared to the upper respiratory tract and has been detected in feces, serum and urine. However, very limited data are available on the duration of respiratory and extrapulmonary MERS-CoV shedding.
If initial testing of respiratory specimens is negative in an individual who is strongly suspected of having MERS-CoV infection, additional respiratory specimens should be obtained from multiple respiratory sites. Possible reasons for false-negative results include that the specimen was of poor quality, that it was collected late or very early in the illness, that it was not handled and shipped appropriately or that there were technical problems with the test.
In certain cases, the diagnosis should be confirmed by nucleic acid sequencing.
Repeat testing is helpful for confirming clearance of the virus. Respiratory specimens should be tested every two to four days until there are two consecutive negative results. If the discharge of the individual from an isolation ward requires negative rRT-PCR results, specimens can be obtained daily.
Laboratories with limited experience testing for MERS-CoV are encouraged to have their results confirmed by laboratories with greater experience (particularly negative specimens from individuals in whom MERS-CoV infection is thought to be likely).
Tests for Other Respiratory Pathogens
Clinical presentation, epidemiologic and surveillance information and season should be considered when selecting which pathogens to test for. A few MERS-CoV cases have had other respiratory pathogens detected, so identification of a respiratory pathogen prior to MERS-CoV testing should not preclude testing for MERS-CoV, especially if MERS is strongly suspected. If the laboratory does not have molecular or antigen testing capability for respiratory pathogens, the state laboratory should be contacted for assistance.
A serum sample (at least 0.2 ml of serum) should be obtained in the first 10 to 12 days after onset of illness for rRT-PCR testing and a second serum sample (also at least 0.2 ml of serum) should be collected at least 14 days after onset of illness for antibody detection. Serum samples are sent for rRT-PCR testing and for antibody testing.
Serum Specimens for rRT-PCR Testing
Serum for Antibody Testing
According to the WHO, cases with a positive serologic test in the absence of rRT-PCR testing or sequencing are considered probable cases if they meet the other elements which comprise the case definition of a probable case.
Specimens should reach the laboratory as soon as possible after collection. If there may be a delay of more than 72 hours in the laboratory receiving respiratory tract specimens, specimens should be frozen at - 70°C and shipped on dry ice. Repeated freezing and thawing of specimens should be avoided. Serum should be separated from whole blood and can be stored and shipped at 4°C or frozen and shipped on dry ice or liquid nitrogen. Avoid storage of respiratory and serum specimens in domestic frost-free freezers given the freezers wide temperature fluctuations. Each specimen container should be labeled with the individuals ID number, specimen type and the date the sample was collected.
For individuals in the United States, healthcare professionals seeking information about shipping or testing should contact the CDC Emergency Operations Center at 770-488-7100. Additional information can be found on the CDC's website.
Among 47 cases of MERS-CoV infection in Saudi Arabia, laboratory abnormalities included:
Other reports have described:
Among the 47 cases of MERS-CoV infection in Saudi Arabia, abnormalities on chest radiography were noted in all 47 cases. Abnormalities in imaging findings ranged from minimal to extensive, either unilateral or bilateral, including:
Computed Tomography Scanning
In individuals with MERS-CoV who underwent computed tomography scanning, the most common findings were bilateral predominantly peripheral and basilar airspace changes with more extensive ground-glass opacities than consolidation.
No specific antiviral agents or vaccines for MERS-CoV infection are currently available. The WHO has issued recommendations for the management of severe respiratory infections suspected to be caused by MERS-CoV.
Treatment is supportive and based on the individuals’ clinical condition. Clinical management includes supportive management of complications and implementation of recommended infection prevention and control practices (IPCs). Individuals with MERS-CoV infection can seek healthcare to help relieve symptoms. For severe cases, current treatment includes care to support vital organ function.
Severe MERS-CoV infection can cause respiratory failure requiring mechanical ventilation and support in an ICU. In one series of 12 ICU patients, the median duration of mechanical ventilation was 16 days and median ICU length of stay was 30 days with 58% mortality at 90 days. Among these 12 critically ill individuals, 11 had extrapulmonary manifestations including shock (11 cases) and acute kidney injury (7 cases).
Clinical management of severe acute respiratory infection (SARI) in individuals with MERS-CoV is based on the WHO interim guidance protocols (2 July 2015):
Early Recognition of Individuals with SARI
Implementation of IPC’s (Table 2)
|When caring for ALL patients|
Standard Precautions should be applied routinely in all healthcare settings for all patients. These include:
|When caring for patients with cough or other respiratory symptoms (ARI)|
Droplet Precautions prevent large droplet transmission of respiratory viruses.
|When caring for patients with suspected MERS-CoV|
Contact Precautions prevent direct or indirect transmission from contact with contaminated surfaces or equipment (i.e. contact with contaminated oxygen tubing/interfaces).
|When performing an aerosol-generating procedure in patient with ARI|
Collection of Specimens for Laboratory Diagnosis and Antimicrobial Therapy
Early Supportive Therapy and Monitoring
Management of Severe Respiratory Distress, Hypoxemia and ARDS
Management of Septic Shock
Reduce days of invasive mechanical ventilation (IMV)
Weaning protocols that include daily assessment for readiness to breathe spontaneously.Sedation protocols to titrate administration of sedation to a target level, with or without daily interruption of continuous sedative infusions
|Reduce incidence of ventilator-associated pneumonia|
Oral intubation is preferable to nasal intubation in adolescents and adults.
Perform regular antiseptic oral care.
Keep patient in semi-recumbent position.
Use a closed suctioning system; periodically drain and discard condensate in tubing.
Use a new ventilator circuit for each patient. Once the patient is ventilated, change circuit if it is soiled or damaged but not routinely.
Change heat moisture exchanger when it malfunctions, when soiled or every 5 - 7 days.
Reduce days of IMV.
|Reduce incidence of venous thromboembolism|
Use pharmacological prophylaxis (for example, heparin 5000 units subcutaneously twice daily or a low molecular-weight heparin) in adolescents and adults without contraindications. For those with contraindications, use mechanical prophylactic device such as intermittent pneumatic compression devices.
|Reduce incidence of catheter-related bloodstream infection|
Use a simple checklist during insertion as reminder of each step needed for sterile insertion and daily reminder to remove catheter if no longer needed.
|Reduce incidence of pressure ulcers||Turn patient every two hours.|
|Reduce incidence of stress ulcers and gastric bleeding||Give early enteral nutrition (within 24 - 48 hours of admission), administer histamine-2 receptor blockers or proton-pump inhibitors.|
|Reduce incidence of ICU-related weakness|
Experimental Virus-Specific Therapeutics
Special Considerations for Pregnant Women
In cell culture and animal experiments, combination therapy with interferon (IFN)-alpha-2b and ribavirin appears promising. In a study in which MERS-CoV was grown in two different cell lines, high concentrations of IFN-alpha-2b or ribavirin were required to inhibit viral replication. However, when used in combination at lower concentrations, IFN-alpha-2b and ribavirin resulted in a comparable reduction in viral replication as high concentrations of either agent alone.
In a study of rhesus macaques, two groups of three monkeys were inoculated with MERS-CoV through a combination of intratracheal, intranasal, oral and ocular routes. One group was treated with subcutaneous IFN-alpha-2b plus intramuscular ribavirin beginning eight hours after inoculation and the other group was not treated. In contrast with untreated macaques, treated animals did not develop breathing abnormalities and showed no or very mild radiographic evidence of pneumonia. Treated animals had lower concentrations of serum and lung proinflammatory markers, fewer viral genome copies and fewer severe histopathologic changes in the lungs.
In a retrospective cohort study in individuals with severe MERS-CoV infection, combination therapy with ribavirin and IFN-alpha-2a, started a median of three days after diagnosis (20 patients), was associated with significantly improved survival at 14 days compared with 24 patients who received only supportive care (70% versus 29% survival), but not at 28 days (30% versus 17% survival, a nonsignificant difference). There were greater declines in hemoglobin in the ribavirin-interferon group than in the controls (4.32 versus 2.14 g/L). In other retrospective studies, combination therapy with ribavirin plus IFN-alpha-2a, IFN-alpha-2b or IFN-beta-1a has not been associated with a mortality benefit. It is difficult to interpret the results of these retrospective studies and further evaluation in randomized trials is needed before treatment recommendations can be made.
Glucocorticoids have been administered sporadically to MERS-CoV infected patients with no clear criteria for use and no clear conclusions regarding their effect. Glucocorticoids were extensively prescribed for patients with severe acute respiratory syndrome (SARS) but review of this experience suggests overall harm rather than benefit. Their use is not recommended for MERS-CoV infections.
Other experimental therapies being investigated include convalescent plasma, monoclonal antibodies, an inhibitor of the main viral protease, and entry/fusion inhibitors targeting the MERS-CoV spike protein.
A MERS-CoV neutralizing monoclonal antibody has been isolated from the memory B cells of an infected individual. The antibody, LCA60, binds to a novel site on the spike protein and neutralizes infection with MERS-CoV by interfering with the binding to the cellular receptor CD26. LCA60 protected mice transduced with adenovirus expressing human CD26 and infected with MERS-CoV in both prophylactic and postexposure settings. Monoclonal antibodies are being investigated for both prophylaxis and treatment of MERS-CoV. None are licensed for use.
Although the immunosuppressive agent mycophenolate mofetil has in vitro activity against MERS-CoV, in a study of severe infection in common marmosets, it was not effective.
The CDC routinely advises that all individuals help to protect themselves from respiratory illnesses by taking everyday preventive actions. These include:
Individuals who may be at increased risk for MERS-CoV include:
Transmission of the virus has occurred in healthcare settings in several countries, including from patients to healthcare providers and between patients in a healthcare setting before MERS-CoV was diagnosed. It is not always possible to identify individuals with MERS-CoV early or without testing because symptoms and other clinical features may be non-specific.
IPC’s are critical to prevent the possible spread of MERS-CoV in healthcare facilities. Facilities that provide care for individuals suspected or confirmed to be infected with MERS-CoV should take appropriate measures to decrease the risk of transmission of the virus from an infected individual to other patients, healthcare workers or visitors. Healthcare workers should be educated and trained in IPC’s should refresh these skills regularly.
The WHO and the CDC have issued recommendations for IPC’s of MERS-CoV infections in healthcare settings. An increased level of infection control precautions is recommended when caring for individuals with probable or confirmed MERS-CoV infection compared with that used for individuals with community-acquired coronaviruses or other community-acquired respiratory viruses.
The WHO recommends that standard and droplet precautions be used when caring for individuals with ARI’s. Contact precautions and eye protection should be added when caring for probable or confirmed cases of MERS-CoV infection. Airborne precautions should be used when performing aerosol-generating procedures.
The CDC recommends the use of standard, contact and airborne precautions for the management of hospitalized individuals with known or suspected MERS-CoV infection. These interim recommendations were informed by evidence-based IPCs the CDC published previously, including Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings, which includes recommendations for the related SARS-CoV, review of current evidence on MERS-CoV infection and the following considerations:
Preventing transmission of respiratory pathogens including MERS-CoV in hospital settings requires the application of infection control procedures and protocols including environmental and engineering controls, administrative controls, safer work practices and PPE.
Measures that enhance early detection and prompt triage and isolation of PUIs being evaluated for MERS-CoV are critical to ensuring effective implementation of infection control measures. Successful implementation of many, if not all, of these strategies is dependent on the presence of clear administrative policies and organizational leadership that promote and facilitate adherence to these recommendations among the various healthcare professionals within the healthcare setting, including patients, visitors and HCP.
Though these recommendations focus on the hospital setting (a setting where MERS-CoV transmission has been reported from some international locations), the recommendations for PPE, source control (i.e., placing a facemask on potentially infected individuals when outside of an airborne infection isolation room) and environmental infection control measures are applicable to any healthcare setting.
IPC recommendations for hospitalized patients with MERS-CoV include:
Use Caution When Performing Aerosol-Generating Procedures
Duration of Infection Control Precautions
Manage Visitor Access and Movement Within the Facility
Implement Engineering Controls
Monitor and Manage Ill and Exposed HCP
Train and Educate Healthcare Personnel
Implement Environmental Infection Control
Establish Reporting within Hospitals and to Public Health Authorities
The CDC recommends that ill individuals who are being evaluated for MERS-CoV infection and do not require hospitalization may be cared for and isolated in their home. HCP should contact their state or local health department to determine whether home isolation or additional measures are indicated because recommendations might be modified as more data becomes available. Isolation is defined as the separation or restriction of activities of an ill individual with a contagious disease from those who are well. Additional information on home care and isolation guidance is available on the CDC's website.
This interim guidance is for staff at local and state health departments, IPC professionals, healthcare providers and healthcare workers who are coordinating the home care and isolation or quarantine of individuals who are confirmed to have or being evaluated for MERS-CoV infection. The interim guidance is based on what is currently known about viral respiratory infections and MERS-CoV.
Individuals who are confirmed to have or being evaluated for MERS-CoV infection and do not require hospitalization for medical reasons may be cared for and isolated in a residential setting after a healthcare professional determines that the setting is suitable. Providers should contact their state or local health department to discuss home isolation, home quarantine or other measures for close contacts, especially for individuals who test positive for MERS-CoV and to discuss criteria for discontinuing any such measures.
Assess the Suitability of the Residential Setting for Home Care
Provide Guidance for Precautions to Implement during Home Care
The following interim guidance from the CDC may help prevent MERS-CoV from spreading among individuals in homes and in communities. The interim guidance is based on what is currently known about other viral respiratory infections and MERS-CoV. The CDC will update this interim guidance as additional information becomes available.
This interim guidance is for:
Prevention Steps for Individuals Confirmed to Have or are Being Evaluated for MERS-CoV Infection
If an individual is confirmed to have or is being evaluated for MERS-CoV infection, they should follow the prevention steps below until a healthcare provider or local or state health department says they can return to normal activities. The individual should be instructed to:
Prevention steps for caregivers and household members of an individual confirmed to have or are being evaluated for MERS-CoV infection should include:
Laundry should be washed thoroughly.
Prevention Steps for Close Contacts
If an individual has had close contact with someone who is confirmed to have or is being evaluated for MERS-CoV infection they should:
A person is not considered to be at risk for MERS-CoV infection if they have not had close contact with someone who is confirmed to have or is being evaluated for MERS-CoV infection. The CDC advises all individuals to follow prevention steps to help reduce their risk of getting infected with respiratory viruses, like MERS-CoV.
As a general precaution, the WHO recommends that members of the general public adhere to general hygiene measures when visiting farms, markets, barns or other places where camels and other animals are present. These general hygiene measures include:
The consumption of raw or undercooked animal products, including milk and meat, carries a high risk of infection from a variety of organisms that might cause disease in humans. Animal products that are processed appropriately through cooking or pasteurization are safe for consumption but should also be handled with care to avoid cross contamination with uncooked foods. Camel meat and camel milk are nutritious products that can continue to be consumed after pasteurization, cooking or other heat treatments.
Until more is understood about MERS-CoV, the WHO recommends that individuals at high risk such as immunocompromised individuals and those with diabetes, chronic lung disease or preexisting renal failure take precautions when visiting farms, barn areas, camel pens or market environments where camels are present. These measures should include:
Specific recommendations for camel farm and slaughterhouse workers can be found on the WHO's website.
Detailed information for travelers to Mecca, Saudi Arabia, for Hajj and/or Umrah can be found on the WHO's website. The WHO does not recommend either special screening for MERS-CoV at points of entry or the application of any travel or trade restrictions. However, the WHO recommends that countries outside the affected regions maintain a high level of vigilance, especially countries with large numbers of travelers or guest workers returning from the Middle East.
The Ministry of Health of Saudi Arabia recommended that, in 2014, the following individuals postpone their plans to travel to Mecca, Saudi Arabia, for Hajj and/or Umrah due to the outbreak of MERS-CoV infection:
No cases of MERS-CoV infection were detected during Hajj in 2012 or 2013.
In May 2014, the CDC's travel notice was upgraded to a Level 2 Alert, which includes enhanced precautions for travelers to countries in or near the Arabian Peninsula who plan to work in healthcare settings. Such individuals should review the CDC's recommendations for infection control for confirmed or suspected MERS individuals before they depart, practice these precautions while in the area and monitor their health closely during and after their travel.
The CDC recommends that all United States travelers to countries in or near the Arabian Peninsula protect themselves from respiratory diseases, including MERS-CoV, by washing their hands often and avoiding contact with individuals who are ill. If travelers to the region have onset of fever with cough or shortness of breath during their trip or within 14 days of returning to the United States, they should seek medical care. They should call ahead to their healthcare professional and mention their recent travel so that appropriate IPC’s can be taken in the healthcare setting. More detailed travel recommendations related to MERS are available on the CDC's website.
The CDC requests that healthcare providers immediately report to their state or local health department any individual being evaluated for MERS-CoV infection if they meet the criteria for a PUI. State and local health departments are then requested to immediately report PUIs for MERS-CoV infection to the CDC. The World Health Organization (WHO) has developed a questionnaire to be used for the initial investigation of cases. It can be found on the WHO's website.
There are now two options to submit a completed MERS PUI short form to the CDC:
The WHO recommends that probable and confirmed cases be reported within 24 hours of classification through the Regional Contact Point for International Health Regulations at the appropriate WHO Regional Office.
There is no licensed vaccine for MERS-CoV, although one manufacturer has developed an experimental candidate MERS-CoV vaccine based on the major surface spike protein using recombinant nanoparticle technology. Other candidate vaccines that are being studied include a full-length infectious cDNA clone of the MERS-CoV genome in a bacterial artificial chromosome, a recombinant modified vaccine Ankara (MVA) vaccine expressing full-length MERS-CoV spike protein and vaccines encoding the full-length MERS-CoV S protein and the S1 extracellular domain of S protein using adenovirus vectors.
In one study, immunogens based on full-length S DNA and S1 subunit protein administered in a prime-boost regimen elicited robust serum neutralizing activity against several MERS-CoV strains in mice and rhesus macaques. Immunization of rhesus macaques reduced the severity of MERS-CoV-induced pneumonia, as assessed by computed tomography.
The CDC responds quickly whenever there is a potential public health problem. The CDC continues to closely monitor the MERS-CoV situation globally. The CDC works collaboratively with the WHO and other partners to better understand the virus, its mode(s) of transmission, the source and risks to the public’s health. The potential for MERS-CoV to spread further and cause more cases in the United States and globally is recognized. In preparation for this, the CDC has:
The WHO is working with clinicians and scientists in affected countries and internationally to gather and share scientific evidence to better understand the virus and the disease it causes and to determine outbreak response priorities, treatment strategies and clinical management approaches. The WHO is also working with countries to develop public health prevention strategies to combat the virus.
Together with affected countries and international technical partners and networks, the WHO is coordinating the global health response to MERS-CoV, including:
The Director-General has convened an Emergency Committee under the International Health Regulations (2005) to advise her as to whether this event constitutes a Public Health Emergency of International Concern (PHEIC) and on the public health measures that should be taken. The Committee has met a number of times since the disease was first identified. The WHO encourages all Member States to enhance their surveillance for severe acute respiratory infections (SARI) and to carefully review any unusual patterns of SARI or pneumonia cases.
Countries, whether or not MERS-CoV cases have been reported in them, should maintain a high level of vigilance, especially those with large numbers of travelers or migrant workers returning from the Middle East. Surveillance should continue to be enhanced in these countries according to WHO guidelines, along with infection prevention and control procedures in healthcare facilities. The WHO continues to request that Member States report to WHO all confirmed and probable cases of infection with MERS-CoV together with information about their exposure, testing and clinical course to guide the most effective international preparedness and response.
As of July 10, 2015, 489 of 1,368 individuals (36%) with laboratory-confirmed MERS-CoV infection reported to the WHO have died. Because individuals with mild symptoms are less likely to be evaluated than individuals with severe disease, those with MERS-CoV and mild disease might be underrepresented in published reports and reports from the WHO. The reported case-fatality rate might therefore be an underestimate. This hypothesis is supported by an analysis pointing out that 14 of 19 (74%) individuals with infection detected through routine surveillance died compared with 5 of 24 (21%) of secondary cases.
In a study of 47 individuals with MERS-CoV infection in Saudi Arabia, case-fatality rates rose with increasing age, from 39% in those younger than 50 years of age, to 48% in those younger than 60 years of age, to 75% in those aged 60 years or older. A separate analysis has shown similar findings.
Middle East respiratory syndrome (MERS) is a viral respiratory disease caused by a novel coronavirus (MERS-CoV) that was first identified in Saudi Arabia in 2012.
Coronaviruses are a large family of viruses that can cause diseases ranging from the common cold to Severe Acute Respiratory Syndrome (SARS).
Many additional cases and clusters of MERS-CoV infections have been detected subsequently in the Arabian Peninsula, particularly in Saudi Arabia. Cases have also been reported from other regions, including North Africa, Europe, Asia and North America. In countries outside of the Arabian Peninsula, individuals developed illness after returning from the Arabian Peninsula or through close contact with infected individuals. The number of cases in the Arabian Peninsula increased dramatically in March and April 2014 then declined sharply in ensuing months. However, cases continue to be detected. A large outbreak occurred in the Republic of Korea in May and June 2015. The index case was an individual who had traveled to the Arabian Peninsula.
MERS-CoV is closely related to coronaviruses found in bats, suggesting that bats might be a reservoir of MERS-CoV. Although the majority of human cases of MERS-CoV have been attributed to human-to-human transmission, camels are likely to be a major reservoir host for MERS-CoV and an animal source of MERS-CoV infection in humans. However, the exact role of camels in transmission of the virus and the exact route(s) of transmission are unknown.
The presence of case clusters strongly suggests that human-to-human transmission occurs. The virus does not seem to pass easily from human-to-human unless there is close contact, such as occurs when providing unprotected care to an infected individual.
Typical MERS-CoV symptoms include fever, cough and shortness of breath. Pneumonia is common, but not always present. Gastrointestinal symptoms, including diarrhea, have also been reported.
Individuals with an acute respiratory infection who have an epidemiologic link to MERS-CoV or who have had an unusual or unexpected clinical course (especially sudden deterioration despite appropriate treatment) should be tested for MERS-CoV. Certain other individuals may also require evaluation for MERS-CoV infection.
rRT-PCR testing applied to respiratory secretions is the diagnostic assay of choice. Ideally, lower respiratory tract, upper respiratory tract and serum samples should be obtained. Lower respiratory tract specimens should be a priority for collection and testing. To increase the likelihood of detecting MERS-CoV, collection of multiple specimens from different sites should be collected at different times.
There is currently no treatment recommended for coronavirus infections except for supportive care as needed.
An increased level of IPCs is recommended when caring for individuals with probable or confirmed MERS-CoV infection compared with that used for individuals with community-acquired coronaviruses or other community-acquired respiratory viruses. The CDC recommends the use of standard, droplet, contact and airborne precautions for the management of hospitalized individuals with known or suspected MERS-CoV infection.
About 3 - 4 out of every 10 individuals reported with MERS-CoV infection have died. Most of the individuals who have died had an underlying medical condition. Approximately 36% of reported individuals with MERS-CoV have died.Some infected individuals had mild symptoms (such as cold-like symptoms) or no symptoms at all. They recovered.
There is no licensed vaccine for MERS-CoV.
Abedine, Saad (13 March 2013). "Death toll from new SARS-like virus climbs to 9". CNN. Retrieved 2013-03-13.
Abroug F, Slim A, Ouanes-Besbes L, et al. Family cluster of Middle East respiratory syndrome coronavirus infections, Tunisia, 2013. Emerg Infect Dis 2014; 20:1527.
Aburizaiza AS, Mattes FM, Azhar EI, et al. Investigation of anti-middle East respiratory syndrome antibodies in blood donors and slaughterhouse workers in Jeddah and Makkah, Saudi Arabia, fall 2012. J Infect Dis 2014; 209:243.
Adney DR, van Doremalen N, Brown VR, et al. Replication and shedding of MERS-CoV in upper respiratory tract of inoculated dromedary camels. Emerg Infect Dis 2014; 20:1999.
Ajlan AM, Ahyad RA, Jamjoom LG, et al. Middle East respiratory syndrome coronavirus (MERS-CoV) infection: chest CT findings. AJR Am J Roentgenol 2014; 203:782.
Al-Abdallat MM, Payne DC, Alqasrawi S, et al. Hospital-associated outbreak of Middle East respiratory syndrome coronavirus: a serologic, epidemiologic, and clinical description. Clin Infect Dis 2014; 59:1225.
Alagaili AN, Briese T, Mishra N, et al. Middle East respiratory syndrome coronavirus infection in dromedary camels in Saudi Arabia. MBio 2014; 5:e00884.
Ali Mohamed Zaki; Sander van Boheemen; Theo M. Bestebroer; Albert D.M.E. Osterhaus; Ron A.M. Fouchier (8 November 2012). "Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia" (PDF). New England Journal of Medicine 367 (19): 1814–20. doi:10.1056/NEJMoa1211721. PMID 23075143.
Al-Gethamy M, Corman VM, Hussain R, et al. A case of long-term excretion and subclinical infection with Middle East respiratory syndrome coronavirus in a healthcare worker. Clin Infect Dis 2015; 60:973.
Almazán F, DeDiego ML, Sola I, et al. Engineering a replication-competent, propagation-defective Middle East respiratory syndrome coronavirus as a vaccine candidate. MBio 2013; 4:e00650.
Albarrak AM, Stephens GM, Hewson R, Memish ZA. “Recovery from severe novel coronavirus infection”. Saudi Med J. 2012 Dec;33(12):1265-9.
Al-Tawfiq JA, Hinedi K, Ghandour J, Khairalla H, Musleh S, Ujayli A, et al. Middle East Respiratory Syndrome-Coronavirus (MERS-CoV): a case-control study of hospitalized patients. Clin Infect Dis. 2014 Apr 9.
Al-Tawfiq JA, Momattin H, Dib J, Memish ZA. Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. Int J Infect Dis 2014; 20:42.
Annan A, Baldwin HJ, Corman VM, et al. Human betacoronavirus 2c EMC/2012-related viruses in bats, Ghana and Europe. Emerg Infect Dis 2013; 19:456.
Arabi YM, Arifi AA, Balkhy HH, Najm H, Aldawood AS, Ghabashi A, et al. “Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection”. Ann Intern Med. 2014 Mar 18;160(6):389-97.
Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, Al-Rabiah FA, Al-Hajjar S, Al-Barrak A, et al. “Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study”. Lancet Infect Dis. 2013 Sep;13(9):752-61.
Assiri A, McGeer A, Perl TM, Price CS, Al Rabeeah AA, Cummings DA, et al. “Hospital outbreak of Middle East respiratory syndrome coronavirus”. N Engl J Med. 2013 Aug 1;369(5):407-16.
Azhar EI, El-Kafrawy SA, Farraj SA, et al. Evidence for camel-to-human transmission of MERS coronavirus. N Engl J Med 2014; 370:2499.
Bauch CT, Oraby T. Assessing the pandemic potential of MERS-CoV. Lancet 2013; 382:662.
Bermingham A, Chand MA, Brown CS, Aarons E, Tong C, Langrish C, et al. “Severe respiratory illness caused by a novel coronavirus, in a patient transferred to the United Kingdom from the Middle East, September 2012”. Euro Surveill. 2012 Oct 4;17(40):20290.
Bialek SR, Allen D, Alvarado-Ramy F, et al. First confirmed cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection in the United States, updated information on the epidemiology of MERS-CoV infection, and guidance for the public, clinicians, and public health authorities - May 2014. MMWR Morb Mortal Wkly Rep 2014; 63:431.
Breban R, Riou J, Fontanet A. Interhuman transmissibility of Middle East respiratory syndrome coronavirus: estimation of pandemic risk. Lancet 2013; 382:694.
Buchholz U, Müller MA, Nitsche A, et al. Contact investigation of a case of human novel coronavirus infection treated in a German hospital, October-November 2012. Euro Surveill 2013; 18.
"Camels May Transmit New Middle Eastern Virus". 8 August 2013. Retrieved 8 August 2013.
Cauchemez S, Fraser C, Van Kerkhove MD, et al. Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility. Lancet Infect Dis 2014; 14:50.
Centers for Disease Control and Prevention (CDC). Severe respiratory illness associated with a novel coronavirus--Saudi Arabia and Qatar, 2012. MMWR Morb Mortal Wkly Rep 2012; 61:820.
Centers for Disease Control and Prevention. Health Alert Network. Notice to health care providers: updated Guidelines for Evaluation of Severe Respiratory Illness Associated with Middle East respiratory syndrome coronavirus (MERS-CoV). http://emergency.cdc.gov/HAN/han00348.asp (Accessed on June 13, 2013).
Centers for Disease Control and Prevention (CDC). Update: Severe respiratory illness associated with Middle East Respiratory Syndrome Coronavirus (MERS-CoV)--worldwide, 2012-2013. MMWR Morb Mortal Wkly Rep 2013; 62:480.
Centers for Disease Control and Prevention. CDC announces first case of Middle East respiratory syndrome coronavirus infection (MERS) in the United States. (Accessed on May 02, 2014).
Centers for Disease Control and Prevention. Middle East respiratory syndrome (MERS). http://www.cdc.gov/CORONAVIRUS/MERS/INDEX.HTML (Accessed on May 13, 2014).
Centers for Disease Control and Prevention (CDC). Updated information on the epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV) infection and guidance for the public, clinicians, and public health authorities, 2012-2013. MMWR Morb Mortal Wkly Rep 2013; 62:793.
Centers for Disease Control and Prevention. Interim infection prevention and control recommendations for hospitalized patients with Middle East respiratory syndrome coronavirus (MERS-CoV). (Accessed on June 12, 2015).
Centers for Disease Control and Prevention. Interim guidelines for collecting, handling, and testing clinical specimens from patients under investigation (PUIs) for Middle East respiratory syndrome coronavirus (MERS-CoV) – Version 2.1. http://www.cdc.gov/coronavirus/mers/guidelines-clinical-specimens.html (Accessed on June 17, 2015).
Centers for Disease Control and Prevention. Interim guidance for healthcare professionals. (Accessed on June 17, 2015).
"Centers for Disease Control and Prevention FAQ on MERS".
Chan JF, Lau SK, To KK, et al. Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev 2015; 28:465.
Chan JF, Chan KH, Choi GK, et al. Differential cell line susceptibility to the emerging novel human betacoronavirus 2c EMC/2012: implications for disease pathogenesis and clinical manifestation. J Infect Dis 2013; 207:1743.
Chan KH, Chan JF, Tse H, et al. Cross-reactive antibodies in convalescent SARS patients' sera against the emerging novel human coronavirus EMC (2012) by both immunofluorescent and neutralizing antibody tests. J Infect 2013; 67:130.
Chu DK, Poon LL, Gomaa MM, et al. MERS coronaviruses in dromedary camels, Egypt. Emerg Infect Dis 2014; 20:1049.
Corman VM, Ithete NL, Richards LR, Schoeman MC, Preiser W, Drosten C, Drexler JF (2014) “Rooting the phylogenetic tree of middle East respiratory syndrome coronavirus by characterization of a conspecific virus from an African bat”. J Virol 88(19):11297-11303. doi: 10.1128/JVI.01498-14
Corman VM, Eckerle I, Bleicker T, et al. Detection of a novel human coronavirus by real-time reverse-transcription polymerase chain reaction. Euro Surveill 2012; 17.
Corman VM, Jores J, Meyer B, et al. Antibodies against MERS coronavirus in dromedary camels, Kenya, 1992-2013. Emerg Infect Dis 2014; 20:1319.
Corman VM, Müller MA, Costabel U, et al. Assays for laboratory confirmation of novel human coronavirus (hCoV-EMC) infections. Euro Surveill 2012; 17.
"Corona Map" (Press release). 2 May 2014.
Cotten M, Watson SJ, Zumla AI, Makhdoom HQ, Palser AL, Ong SH, Al Rabeeah AA, Alhakeem RF, Assiri A, Al-Tawfiq JA, Albarrak A, Barry M, Shibl A, Alrabiah FA, Hajjar S, Balkhy HH, Flemban H, Rambaut A, Kellam P, Memish ZA (2014) “Spread, circulation, and evolution of the Middle East respiratory syndrome coronavirus”. MBio 5(1). pii: e01062-13. doi: 10.1128/mBio.01062-13.
Cotten M, Lam TT, Watson SJ, et al. Full-genome deep sequencing and phylogenetic analysis of novel human betacoronavirus. Emerg Infect Dis 2013; 19:736.
Cotten M, Watson SJ, Kellam P, et al. Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study. Lancet 2013; 382:1993.
Cowling BJ, Park M, Fang VJ, et al. Preliminary epidemiological assessment of MERS-CoV outbreak in South Korea, May to June 2015. Euro Surveill 2015; 20.
Das KM, Lee EY, Enani MA, et al. CT correlation with outcomes in 15 patients with acute Middle East respiratory syndrome coronavirus. AJR Am J Roentgenol 2015; 204:736.
de Groot RJ, Baker SC, Baric RS, et al. Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group. J Virol 2013; 87:7790.
de Wit E, Rasmussen AL, Falzarano D, et al. Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc Natl Acad Sci U S A 2013; 110:16598.
Doucleff, Michaeleen (28 September 2012). "Holy Bat Virus! Genome Hints At Origin Of SARS-Like Virus". NPR. Retrieved 29 September 2012.
Drosten C. Is MERS another SARS? Lancet Infect Dis 2013; 13:727.
Drosten C, Seilmaier M, Corman VM, Hartmann W, Scheible G, Sack S, et al. “Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection”. Lancet Infect Dis. 2013 Sep;13(9):745-51.
Drosten C, Muth D, Corman VM, et al. An observational, laboratory-based study of outbreaks of middle East respiratory syndrome coronavirus in Jeddah and Riyadh, kingdom of Saudi Arabia, 2014. Clin Infect Dis 2015; 60:369.
Drosten C, Meyer B, Müller MA, et al. Transmission of MERS-coronavirus in household contacts. N Engl J Med 2014; 371:828.
Du L, Zhao G, Yang Y, et al. A conformation-dependent neutralizing monoclonal antibody specifically targeting receptor-binding domain in Middle East respiratory syndrome coronavirus spike protein. J Virol 2014; 88:7045.
Dziadosz, Alexander (13 May 2013). "The doctor who discovered a new SARS-like virus says it will probably trigger an epidemic at some point, but not necessarily in its current form." Reuters. Retrieved 25 May 2013.
"ECDC Rapid Risk Assessment - Severe respiratory disease associated with a novel coronavirus" (PDF). 19 Feb 2013. Retrieved 22 Apr 2014.
Falco, Miriam (24 September 2012). "New SARS-like virus poses medical mystery". CNN. Retrieved 27 September 2012.
Falzarano D, de Wit E, Martellaro C, et al. Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. Sci Rep 2013; 3:1686.
Falzarano D, de Wit E, Rasmussen AL, et al. Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med 2013; 19:1313.
"Fauci: “New Virus Not Yet a 'threat to the world' (video)". Washington Times. 2012-08-31. Retrieved 2013-05-31.
Faure E, Poissy J, Goffard A, Fournier C, Kipnis E, Titecat M, et al. “Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside?” PLoS One. 2014 Feb 14;9(2):e88716. doi: 10.1371/journal.pone.0088716. eCollection 2014.
"Florida MERS patient recovers". CNN.
Florida Health. Health officials confirm first MERS-CoV case in Florida (Accessed on May 13, 2014).
"Full-Genome Deep Sequencing and Phylogenetic Analysis of Novel Human Betacoronavirus - Vol. 19 No. 5 - May 2013 - CDC". Emerging Infectious Diseases. 2013-05-19. Retrieved 2013-06-01.
Gierer S, Hofmann-Winkler H, Albuali WH, et al. Lack of MERS coronavirus neutralizing antibodies in humans, eastern province, Saudi Arabia. Emerg Infect Dis 2013; 19:2034.
Gomersall CD, Joynt GM. Middle East respiratory syndrome: new disease, old lessons. Lancet 2013; 381:2229.
Guery B, Poissy J, el Mansouf L, Séjourné C, Ettahar N, Lemaire X, et al. “Clinical features and viral diagnosis of two cases of infection with Middle East respiratory syndrome coronavirus: a report of nosocomial transmission”. Lancet. 2013 Jun 29;381(9885):2265-72. doi: 10.1016/S0140-6736(13)60982-4. Erratum in: Lancet. 2013 Jun 29;381(9885):2254.
Guery B, van der Werf S. Coronavirus: need for a therapeutic approach. Lancet Infect Dis 2013; 13:726.
Gulland A. Two cases of novel coronavirus are confirmed in France. BMJ 2013; 346:f3114.
Haagmans BL, Al Dhahiry SH, Reusken CB, et al. Middle East respiratory syndrome coronavirus in dromedary camels: an outbreak investigation. Lancet Infect Dis 2014; 14:140.
Harriman K, Brosseau L, Trivedi K. Hospital-associated Middle East respiratory syndrome coronavirus infections. N Engl J Med 2013; 369:1761.
Health Protection Agency (HPA) UK Novel Coronavirus Investigation team. “Evidence of person-to-person transmission within a family cluster of novel coronavirus infections, United Kingdom, February 2013”. Euro Surveill. 2013 Mar 14;18(11):20427.
Hemida MG, Perera RA, Wang P, et al. Middle East Respiratory Syndrome (MERS) coronavirus seroprevalence in domestic livestock in Saudi Arabia, 2010 to 2013. Euro Surveill 2013; 18:20659.
Hemida, Maged G; Chu, Daniel KW; Poon, Ranawaka; Perera, Mohammad A A; Ng, Hoiyee-Y (Jul 2014). "MERS coronavirus in dromedary camel herd, Saudi Arabia.". Retrieved 22 Apr 2014.
Hijawi B, Abdallat M, Sayaydeh A et al. Novel coronavirus infections in Jordan, April 2012: epidemiological findings from a retrospective investigation. Eastern Mediterranean Health Journal, 2013, 19(Supplement 1):S12-18.
Hui DS, Memish ZA, Zumla A. “Severe acute respiratory syndrome vs. the Middle East respiratory syndrome”. Curr Opin Pulm Med. 2014 May;20(3):233-41.
Hui DS, Perlman S, Zumla A. Spread of MERS to South Korea and China. Lancet Respir Med 2015; 3:509.
Ithete NL, Stoffberg S, Corman VM, et al. Close relative of human Middle East respiratory syndrome coronavirus in bat, South Africa. Emerg Infect Dis 2013; 19:1697.
Jiang L, Wang N, Zuo T, et al. Potent neutralization of MERS-CoV by human neutralizing monoclonal antibodies to the viral spike glycoprotein. Sci Transl Med 2014; 6:234ra59.
Jobs (2013-08-23). "Deadly coronavirus found in bats: Nature News & Comment". Nature.com. Retrieved 2014-01-19.
Jonrl Aleccia (28 May 2014). "CDC Backtracks: Illinois Man Didn't Have MERS After All". Retrieved 2 June 2014.
Kapoor M, Pringle K, Kumar A, et al. Clinical and laboratory findings of the first imported case of Middle East respiratory syndrome coronavirus to the United States. Clin Infect Dis 2014; 59:1511.
Kim E, Okada K, Kenniston T, et al. Immunogenicity of an adenoviral-based Middle East Respiratory Syndrome coronavirus vaccine in BALB/c mice. Vaccine 2014; 32:5975.
Kindler, E.; Jónsdóttir, H. R.; Muth, D.; Hamming, O. J.; Hartmann, R.; Rodriguez, R.; Geffers, R.; Fouchier, R. A.; Drosten, C. (2013). "Efficient Replication of the Novel Human Betacoronavirus EMC on Primary Human Epithelium Highlights Its Zoonotic Potential". MBio 4 (1): e00611–12.
Kingdom of Saudi Arabia - Ministry of Health. Health regulations for travelers to Saudi Arabia for Umrah & pilgrimage (Hajj)- 1435 (2014) http://www.moh.gov.sa/en/Hajj/Pages/HealthRegulations.aspx (Accessed on September 17, 2014).
Kingdom of Saudi Arabia - Ministry of Health. MOH announces the health requirements to be met by this year's Hajj pilgrims. (Accessed on September 17, 2014).
Knickmeyer, Ellen; Al Omran, Ahmed (20 Apr 2014). "Concerns Spread as New Saudi MERS Cases Spike". Retrieved 22 Apr 2014.
Lau SK, Lee P, Tsang AK, Yip CC, Tse H, Lee RA, “Molecular epidemiology of human coronavirus OC43 reveals evolution of different genotypes over time and recent emergence of a novel genotype due to natural recombination”. J Virol. 2011;85:11325–37.
Lu G, Hu Y, Wang Q, et al. Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature 2013; 500:227.
Lu L, Liu Q, Zhu Y, et al. Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor. Nat Commun 2014; 5:3067.
Mailles A, Blanckaert K, Chaud P et al. “First cases of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infections in France, investigations and implications for the prevention of human-to-human transmission, France”, May 2013. Euro Surveill, 2013, 18(24).
McIntosh K. A new virulent human coronavirus: how much does tissue culture tropism tell us? J Infect Dis 2013; 207:1630.
Memish ZA, Mishra N, Olival KJ, Fagbo SF, Kapoor V, Epstein JH, Alhakeem R, Durosinloun A, Al Asmari M, Islam A, Kapoor A, Briese T, Daszak P, Al Rabeeah AA, Lipkin WI (2013) “Middle East respiratory syndrome coronavirus in bats, Saudi Arabia”. Emerg Infect Dis 19(11):1819-23.
Memish ZA, Al-Tawfiq JA, Assiri A, Alrabiah FA, Hajjar SA, Albarrak A, et al. Middle East respiratory syndrome coronavirus disease in children. Pediatr Infect Dis J. 2014 Apr 23.
Memish ZA, Al-Tawfiq JA, Makhdoom HQ, Assiri A, Alhakeem RF, Albarrak A, et al. Respiratory Tract Samples, Viral Load and Genome Fraction Yield in patients with Middle East Respiratory Syndrome. J Infect Dis. 2014 May 15. pii: jiu292.
Memish ZA, Zumla AI, Al-Hakeem RF, Al-Rabeeah AA, Stephens GM. Family cluster of Middle East respiratory syndrome coronavirus infections. N Engl J Med. 2013 Jun 27;368(26):2487-94. doi: 10.1056/NEJMoa1303729. Erratum in: N Engl J Med. 2013 Aug 8;369(6):587.
Memish ZA, Assiri A, Almasri M, et al. Prevalence of MERS-CoV nasal carriage and compliance with the Saudi health recommendations among pilgrims attending the 2013 Hajj. J Infect Dis 2014; 210:1067.
Memish ZA, Cotten M, Meyer B, et al. Human infection with MERS coronavirus after exposure to infected camels, Saudi Arabia, 2013. Emerg Infect Dis 2014; 20:1012.
Memish ZA, Zumla A, Alhakeem RF, et al. Hajj: infectious disease surveillance and control. Lancet 2014; 383:2073.
Memish ZA, Zumla AI, Assiri A. Middle East respiratory syndrome coronavirus infections in health care workers. N Engl J Med 2013; 369:884.
"MERS Coronaviruses in Dromedary Camels, Egypt". June 2014. Retrieved 22 Apr 2014.
Meyer B, García-Bocanegra I, Wernery U, et al. Serologic assessment of possibility for MERS-CoV infection in equids. Emerg Infect Dis 2015; 21:181.
Meyer B, Müller MA, Corman VM, et al. Antibodies against MERS coronavirus in dromedary camels, United Arab Emirates, 2003 and 2013. Emerg Infect Dis 2014; 20:552.
"Middle East respiratory syndrome coronavirus (MERS-CoV) – Republic of Korea". www.who.int. 24 May 2015.
"Middle East respiratory syndrome coronavirus (MERS-CoV) – China". 31 May 2015.
"Middle East Respiratory Syndrome (MERS) to the Far East: Hospital Associated Outbreak in South Korea - Re: Why the panic? South Korea’s MERS response questioned". TheBMJ 2 July 2015.
Mohammed Rasooldeen, Fakeih:” 80% drop in MERS infections”, Arab News, Vol XXXIX, Number 183, Page 1, 6 June 2014.
Müller MA, Raj VS, Muth D, et al. Human coronavirus EMC does not require the SARS-coronavirus receptor and maintains broad replicative capability in mammalian cell lines. MBio 2012; 3.
Müller MA, Corman VM, Jores J, et al. MERS coronavirus neutralizing antibodies in camels, Eastern Africa, 1983-1997. Emerg Infect Dis 2014; 20:2093.
Müller MA, Meyer B, Corman VM, et al. Presence of Middle East respiratory syndrome coronavirus antibodies in Saudi Arabia: a nationwide, cross-sectional, serological study. Lancet Infect Dis 2015; 15:559.
Munster VJ, de Wit E, Feldmann H. Pneumonia from human coronavirus in a macaque model. N Engl J Med 2013; 368:1560.
Novavax. Novavax produces MERS-CoV vaccine candidate. (Accessed on June 13, 2013).
Oboho IK, Tomczyk SM, Al-Asmari AM, et al. 2014 MERS-CoV outbreak in Jeddah--a link to health care facilities. N Engl J Med 2015; 372:846.
Omrani AS, Matin MA, Haddad Q et al. “A family cluster of Middle East Respiratory Syndrome Coronavirus infections related to a likely unrecognized asymptomatic or mild case”. International Journal of Infectious Diseases, (2013).
Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis 2014; 14:1090.
Park HY, Lee EJ, Ryu YW, et al. Epidemiological investigation of MERS-CoV spread in a single hospital in South Korea, May to June 2015. Euro Surveill 2015; 20.
Pascal KE, Coleman CM, Mujica AO, et al. Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection. Proc Natl Acad Sci U S A 2015; 112:8738.
Payne DC, Iblan I, Alqasrawi S, et al. Stillbirth during infection with Middle East respiratory syndrome coronavirus. J Infect Dis 2014; 209:1870.
"Philippines Confirms First Case of MERS". TIME. 6 July 2015.
Perera RA, Wang P, Gomaa MR, et al. Seroepidemiology for MERS coronavirus using microneutralisation and pseudoparticle virus neutralisation assays reveal a high prevalence of antibody in dromedary camels in Egypt, June 2013. Euro Surveill 2013; 18:pii=20574.
ProMed Mail: Novel coronavirus - Saudi Arabia: human isolate; Archive Number: 20120920.1302733 (Accessed on April 22, 2013).
Raj, V. S.; Mou, H.; Smits, S. L.; Dekkers, D. H.; Müller, M. A.; Dijkman, R.; Muth, D.; Demmers, J. A.; Zaki, A. (March 2013). "Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC". Nature 2013;495:251–4.
Raj VS, Farag EA, Reusken CB, et al. Isolation of MERS coronavirus from a dromedary camel, Qatar, 2014. Emerg Infect Dis 2014; 20:1339.
Rasmussen SA, Gerber SI, Swerdlow DL. Middle East respiratory syndrome coronavirus: update for clinicians. Clin Infect Dis 2015; 60:1686.
"Receptor for new coronavirus found". nature.com. 2013-03-13. Retrieved 2013-03-18.
Ren Z, Yan L, Zhang N, et al. The newly emerged SARS-like coronavirus HCoV-EMC also has an "Achilles' heel": current effective inhibitor targeting a 3C-like protease. Protein Cell 2013; 4:248.
Reusken CB, Messadi L, Feyisa A, et al. Geographic distribution of MERS coronavirus among dromedary camels, Africa. Emerg Infect Dis 2014; 20:1370.
Reusken CB, Haagmans BL, Müller MA, et al. Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. Lancet Infect Dis 2013; 13:859.
Reusken CB, Ababneh M, Raj VS, et al. Middle East Respiratory Syndrome coronavirus (MERS-CoV) serology in major livestock species in an affected region in Jordan, June to September 2013. Euro Surveill 2013; 18:20662.
Reusken C, Mou H, Godeke GJ, et al. Specific serology for emerging human coronaviruses by protein microarray. Euro Surveill 2013; 18:20441.
Reuss A, Litterst A, Drosten C, et al. Contact investigation for imported case of Middle East respiratory syndrome, Germany. Emerg Infect Dis 2014; 20:620.
Rha B, Rudd J, Feikin D, et al. Update on the epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, and guidance for the public, clinicians, and public health authorities - January 2015. MMWR Morb Mortal Wkly Rep 2015; 64:61.
Roos, Robert (16 Jun 2014). "Bangladesh has first MERS case". cidrap.umn.edu.
Shalhoub S, Farahat F, Al-Jiffri A, et al. IFN-α2a or IFN-β1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother 2015; 70:2129.
Song F, Fux R, Provacia LB, et al. Middle East respiratory syndrome coronavirus spike protein delivered by modified vaccinia virus Ankara efficiently induces virus-neutralizing antibodies. J Virol 2013; 87:11950.
Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med 2006; 3:e343.
Tang XC, Agnihothram SS, Jiao Y, et al. Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution. Proc Natl Acad Sci U S A 2014; 111:E2018.
"Thailand confirms first Mers case: Health ministry". 18 June 2015.
The Health Protection Agency (HPA) UK Novel Coronavirus Investigation Team. “Evidence of person-to-person transmission within a family cluster of novel coronavirus infections”, United Kingdom, February 2013. Euro Surveill, 2013, 18(11):20427.
"Three camels hit by MERS coronavirus in Qatar". Qatar Supreme Council of Health. Retrieved 28 November 2013.
United Kingdom Health Protection Agency. Partial genetic sequence information for scientists about the novel coronavirus 2012. (Accessed on September 27, 2012).
US Food and Drug Administration. Letter of authorization: CDC novel coronavirus 2012 real-time RT-PCR assay. (Accessed on June 13, 2013).
Wang Q, Qi J, Yuan Y, Xuan Y, Han P, Wan Y, Ji W, Li Y, Wu Y, Wang J, Iwamoto A, Woo PC, Yuen KY, Yan J, Lu G, Gao GF (2014) “Bat origins of MERS-CoV supported by bat coronavirus HKU4 usage of human receptor CD26”. Cell Host Microbe 16(3):328-337. doi: 10.1016/j.chom.2014.08.009.
Wise J. Patient with new strain of coronavirus is treated in intensive care at London hospital. BMJ 2012; 345:e6455.
World Health Organization: “Novel coronavirus infection” – update (13 February 2013) (accessed 13 February 2013)
"World Health Organization calls Middle Eastern virus, MERS, 'threat to the entire world' as death toll rises to 27". Daily Mail. 29 May 2013. Retrieved 29 May 2013.
World Health Organization. MERS-CoV summary and literature update - as of 09 July 2013. WHO, 2013.
World Health Organization. Novel coronavirus infection in the United Kingdom. (Accessed on September 25, 2012).
World Health Organization. Global Alert and Response. Background and summary of novel coronavirus infection – as of 30 November 2012. (Accessed on December 06, 2012).
World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV): Summary of current situation, literature update and risk assessment–as of 5 February 2015. (Accessed on March 04, 2015).
World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV) – Republic of Korea. (Accessed on May 26, 2015).
World Health Organization. MERS-CoV in the Republic of Korea at a glance. (Accessed on July 14, 2015).
World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV) – Thailand. (Accessed on June 22, 2015).
World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV) – Thailand (update). (Accessed on July 14, 2015).
World Health Organization. Global alert and response. Novel coronavirus infection – update. (Accessed on February 17, 2013).
World Health Organization. Global alert and response. Novel coronavirus summary and literature update – as of 17 May 2013. (Accessed on May 17, 2013).
World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV) summary and literature update – as of 9 May 2014. (Accessed on May 12, 2014).
World Health Organization. WHO risk assessment. Middle East respiratory syndrome coronavirus (MERS-CoV). (Accessed on April 24, 2014).
World Health Organization. Summary and risk assessment of current situation in Republic of Korea and China. (Accessed on June 04, 2015).
World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV) – Republic of Korea. (Accessed on June 10, 2015).
World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV) – China. http://www.who.int/csr/don/30-may-2015-mers-china/en/ (Accessed on June 01, 2015).
World Health Organization. Middle East respiratory syndrome coronavirus (MERS) in the Republic of Korea - situation assessment. (Accessed on June 16, 2015).
World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV) – 13 June 2014. Update on MERS-CoV transmission from animals to humans, and interim recommendations for at-risk groups. (Accessed on June 17, 2014).
World Health Organization. World - travel advice on MERS-CoV for pilgrimages. (Accessed on June 17, 2014).
World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV) summary and literature update – as of 20 January 2014. (Accessed on January 29, 2014).
World Health Organization. WHO statement on the eighth meeting of the IHR Emergency Committee regarding MERS-CoV. (Accessed on March 10, 2015).
World Health Organization. Revised case definition for reporting to WHO – Middle East respiratory syndrome coronavirus - Interim case definition as of 14 July 2014. (Accessed on March 06, 2015).
World Health Organization. Laboratory testing for Middle East respiratory syndrome coronavirus - Interim recommendations (revised), September 2014. (Accessed on March 06, 2015).
World Health Organization. Global alert and response. Background and summary of novel coronavirus infection – as of 21 December 2012. (Accessed on February 12, 2013).
World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV). Initial interview questionnaire of cases. (Accessed on August 13, 2013).
World Health Organization. Interim surveillance recommendations for human infection with Middle East respiratory syndrome coronavirus. (Accessed on March 23, 2015).
World Health Organization. Interim guidance document. Clinical management of severe acute respiratory infections when novel coronavirus is suspected: What to do and what not to do. (Accessed on April 09, 2013).
World Health Organization. WHO-ISARIC joint MERS-CoV Outbreak Readiness Workshop: Clinical management and potential use of convalescent plasma. (Accessed on December 30, 2013).
World Health Organization. Infection prevention and control of epidemic-and pandemic prone acute respiratory infections in health care - WHO guidelines. (Accessed on May 13, 2014).
Yao Y, Bao L, Deng W, et al. An animal model of MERS produced by infection of rhesus macaques with MERS coronavirus. J Infect Dis 2014; 209:236.
Ying T, Du L, Ju TW, et al. Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies. J Virol 2014; 88:7796.
Zaki AM, van Boheemen S, Bestebroer TM, et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012; 367:1814.
Zhao J, Perera RA, Kayali G, et al. Passive immunotherapy with dromedary immune serum in an experimental animal model for Middle East respiratory syndrome coronavirus infection. J Virol 2015; 89:6117.
Zumla A, Hui DS, Perlman S. Middle East respiratory syndrome. Lancet 2015.