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INTRODUCTION — In September 2012, a case of novel coronavirus infection was reported involving a man in Saudi Arabia who was admitted to a hospital with pneumonia and acute kidney injury in June 2012 . Only a few days later, a separate report appeared of an almost identical virus detected in a second patient with acute respiratory syndrome and acute kidney injury [2,3]. The second patient initially developed symptoms in Qatar but had traveled to Saudi Arabia before he became ill and then sought care in the United Kingdom . Many subsequent cases and clusters of infections have been reported, as discussed below. (See 'Epidemiology' below.)
This novel coronavirus, initially termed human coronavirus-EMC (for Erasmus Medical Center), has been named Middle East respiratory syndrome coronavirus (MERS-CoV) .
Updated information about MERS-CoV can be found on the World Health Organization website and the United States Centers for Disease Control and Prevention website.
The virology and epidemiology of MERS-CoV are discussed here. The clinical manifestations, diagnosis, treatment, and prevention of MERS-CoV are discussed separately. Community-acquired coronaviruses and severe acute respiratory syndrome coronavirus are also reviewed separately. (See "Middle East respiratory syndrome coronavirus: Clinical manifestations and diagnosis" and "Middle East respiratory syndrome coronavirus: Treatment and prevention" and "Coronaviruses" and "Severe acute respiratory syndrome (SARS)".)
VIROLOGY — Middle East respiratory syndrome coronavirus (MERS-CoV) is a lineage C betacoronavirus found in humans and camels that is different from the other human betacoronaviruses (severe acute respiratory syndrome coronavirus, OC43, and HKU1) but closely related to several bat coronaviruses [4,6-11]. (See 'Bats' below.)
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 [12,13]. 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. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is probably a coreceptor for MERS-CoV; CEACAN5 facilitates MERS-CoV cell entry and infection when DPP4 is present by augmenting the attachment of the virus to the host cell surface .
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 [15,17,18]. Further study is necessary to determine whether these in vitro findings will translate to broader species susceptibility during in vivo infections .
Because of a large increase in cases in Saudi Arabia in the spring of 2014, there was concern 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 .
Genetic analysis — In an analysis of the full or partial genomes of MERS-CoV obtained from 21 patients 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 percent highest posterior density July 2007 to June 2012).
Phylogenetic analysis during the spring of 2014 showed that viruses from patients 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 percent came from a single hospital, King Fahd Hospital. Isolates from patients 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. Viruses representing three major genetic clades were examined for their serologic differences by plaque-reduction neutralization and were found to be essentially indistinguishable . An analysis of sequences in MERS-CoV cases during the first half of 2015 reinforced the idea that epidemiologically separate outbreaks (in time and/or place) tend to be caused by viruses of fairly uniform, but distinctive, genetic sequences .
PATHOGENESIS — The pathogenesis of Middle East respiratory syndrome coronavirus (MERS-CoV) infection is not well understood.
Virus shedding — Virus is found most easily in lower respiratory tract samples (tracheal aspirates, sputum, or bronchoalveolar lavage fluid) of symptomatic patients, and this shedding may persist for several weeks . Virus shedding studies indicate that the RNA concentrations found in secretions from the lower respiratory tract are at least two orders of magnitude higher than those in upper tract secretions, serum, or stool [25,26]. Viral RNA loads in lower respiratory tract secretions decrease slowly over time, but shedding has commonly persisted for three or more weeks. The magnitude and duration of respiratory tract viral RNA concentrations appear to correlate with severity of disease [25,26].
Prolonged shedding has also been detected by polymerase chain reaction (PCR) in an asymptomatic healthcare worker . The individual was initially tested following occupational exposure to MERS-CoV. Serial PCR testing showed ongoing shedding for six weeks. These findings raise concerns that asymptomatic individuals could transmit infection to others.
In another report, two patients had positive MERS-CoV PCR results for at least one month . In one patient who died from refractory acute respiratory distress syndrome and renal failure, MERS-CoV RNA was detected in pharyngeal and tracheal swabs as well as blood and urine samples until the 30th day of illness. The second patient had multisystem organ failure but recovered; MERS-CoV RNA was detected from tracheal aspirates until the 33rd day of illness.
For reasons probably related to the scarcity of biosafety level 3 facilities, almost all studies of viral shedding have depended on real-time reverse-transcriptase polymerase chain reaction (rRT-PCR), rather than virus isolation, for detection of the MERS coronavirus. The relationship between RNA detected by PCR and infectious virus, however, is not clear. In a study from South Korea, respiratory samples from four immunocompetent patients with severe MERS-CoV pneumonia, as well as samples from environmental surfaces in their hospital rooms, were examined for MERS coronavirus by both PCR and culture . Virus was cultured from the respiratory tracts of three of the four enrolled patients 18 to 25 days after symptom onset. In addition, virus was successfully cultured from several environmental samples, including those from bed sheets, an intravenous fluid hanger, bedrail, an anteroom table, and a radiography device. Moreover, viral RNA was detected from environmental surfaces up to five days following the last positive PCR from patients' respiratory specimens. PCR was far more sensitive for RNA detection than culture was for virus detection in environmental samples (30 versus 6 positive tests in 148 samples, respectively; all tested by both methods).
Viremia — Unlike severe acute respiratory syndrome, in which viremia is present in about 80 percent of patients at the time of presentation , viremia was found in only 7 of 21 MERS-CoV–infected patients (33 percent) in plasma samples obtained at or soon after diagnosis and tested by PCR . Detectable viremia has also been associated with more severe disease [31,32].
Receptor distribution — The importance of lower respiratory tract samples in establishing the diagnosis of MERS was recognized early in the epidemic. This may be explained by the observation that dipeptidyl peptidase 4 (DPP4), the MERS-CoV receptor, is expressed in the upper respiratory tract epithelium of camels, but in humans it is expressed only in the lower respiratory tract but not in the upper respiratory tract . This may also be a reason that the limited human-to-human transmission has been observed to date. (See 'Human-to-human transmission' below.)
Histopathology — There have been few reports of autopsies or biopsies from MERS patients. The one reported autopsy, performed in a man who died of respiratory and renal failure 12 days after symptom onset, showed diffuse alveolar damage and abundant viral antigen in pneumocytes and epithelial cells of the lung but no detectable virus antigen in the kidneys or other organs, including the brain and liver . There has been one reported renal biopsy in a man with MERS-CoV infection and renal failure . The biopsy was obtained eight weeks after disease onset, and virus was not detected in the kidney tissue.
Animal models — Several animal models have been developed. Mice, ferrets, and guinea pigs do not appear to be susceptible to MERS-CoV infection . However, mice in which the human DPP4 receptor had been introduced using transgene vectors developed severe fatal infection, with recovery of virus in high titer from the lungs and brain . Rabbits, in contrast, are naturally susceptible to MERS-CoV infection; however, following inoculation with MERS-CoV, they shed virus from the lungs but have minimal histopathologic changes or clinical signs of infection .
Several studies have shown that nonhuman primates can be successfully used as animal models for MERS-CoV infection and disease [39-41]. 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 pulmonary 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 fluid specimens, viral loads were also highest on day 1 postinfection 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.
Marmosets infected with MERS-CoV develop more severe pneumonia than rhesus macaques . Pulmonary infectious virus titers were three logs higher in marmosets than macaques, and neutrophil infiltrations were measurably more dense.
EPIDEMIOLOGY — In September 2012, a novel coronavirus infection was reported in ProMed Mail, an internet-based reporting system that helps disseminate information about infectious disease outbreaks worldwide . The virus was isolated from the sputum of a man in Jeddah, Saudi Arabia, who was admitted to a hospital with pneumonia and acute kidney injury in June 2012. Shortly thereafter, a report appeared of an almost identical virus detected in a patient in Qatar with acute respiratory syndrome and acute kidney injury; the patient had traveled recently to Saudi Arabia [2-4].
Subsequent cases and clusters of infections have been reported, as discussed below (figure 1). Since April 2012, more than 2060 cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection have been reported (see 'Geographic distribution' below). The actual number of cases is likely to be higher . The median age is 48 years (range 9 months to 94 years), and 64 percent of cases have been male .
The number of cases in the Middle East increased dramatically in March and April 2014 then declined sharply in mid-May 2014 [44,45]. A smaller increase in cases occurred during March and April 2013. An outbreak of more than 180 cases occurred in South Korea in May and June 2015; the index case had recently traveled to several countries in the Arabian Peninsula [46,47].
Geographic distribution — Since April 2012, more than 2060 laboratory-confirmed human infections with MERS-CoV have been reported to the World Health Organization (WHO), occurring primarily in countries in the Arabian Peninsula (figure 2); the majority of cases have occurred in Saudi Arabia, including some case clusters [45,47-50]. Cases have also been reported from other regions, including North Africa, Europe, Asia, and North America (table 1). In countries outside of the Arabian Peninsula, patients developed illness after returning from the Arabian Peninsula or through close contact with infected individuals.
Cases and clusters — Some notable cases and clusters are summarized as follows:
●The index case was a man in Jeddah, Saudi Arabia, who was hospitalized with pneumonia in June 2012 . He developed acute respiratory distress syndrome (ARDS) and acute kidney injury and died; MERS-CoV was isolated from his sputum.
●In September 2012, a nearly identical coronavirus was detected in a man who also had an acute respiratory distress syndrome and acute kidney injury requiring admission to the intensive care unit [2,51,52]. He initially developed symptoms in Qatar but had recently traveled to Saudi Arabia and sought care in the United Kingdom .
●The two earliest confirmed cases were subsequently reported from Jordan [53,54]. Both patients died during a cluster of acute respiratory illness in April 2012, which included 10 healthcare workers. Serologic testing suggested that seven surviving hospital contacts had MERS-CoV infection.
●Several cases have occurred in individuals outside the Arabian Peninsula who had either traveled to the Arabian Peninsula in the recent past or who had had close contact with a patient with MERS who had recently returned from the Arabian Peninsula (figure 2) [55,56].
●In April 2013, a cluster of 23 confirmed cases and 11 probable cases of MERS-CoV was detected in Al-Hasa in the Eastern Province of Saudi Arabia . Almost all cases were directly linked to person-to-person exposure, most of them in the hemodialysis (nine cases) or intensive care (four cases) units of a single hospital. There were only two proven cases in healthcare workers, and only three family members (all of whom had visited the hospital) were proven infected despite a survey of over 200 household contacts.
●A sharp increase in the number of cases was reported in Saudi Arabia and the United Arab Emirates in March and April 2014 [44,58-61]. Of the over 500 cases reported, the majority represented hospital-based outbreaks in the Saudi Arabian cities of Jeddah (255 cases), Riyadh (45 cases), Tabuk, and Madinah and in Al Ain City, Abu Dhabi, United Arab Emirates, and included cases in healthcare workers, patients admitted for other medical problems, visitors, and ambulance staff. Up to 75 percent of cases during this period appeared to be acquired from exposure to persons known to be infected . Nevertheless, there has been no clear evidence of sustained human-to-human transmission of MERS-CoV in community settings. Many of the secondary infections that occurred in healthcare workers were either mildly symptomatic or asymptomatic, but 15 percent of healthcare workers presented with severe disease or died .
●The first case in the United States occurred in an American healthcare worker in his sixties who lived and worked in Riyadh, Saudi Arabia, but traveled to Indiana in April 2014, where he presented for care [63-65]. A second imported case in the United States was confirmed in May 2014 in Florida in an individual who was visiting from Saudi Arabia [63,66,67].
●The first cases in South Korea occurred in May 2015; the index case was a man who had recently traveled to Bahrain, the United Arab Emirates, Saudi Arabia, and Qatar . By early July 2015, a total of 185 secondary and tertiary cases had been reported among household and hospital contacts; 36 deaths were reported [47,68-71]. One case occurred in a man who traveled to China following exposure to two relatives with MERS-CoV infection; this patient is the first reported case in China .
●An outbreak of 130 cases occurred in a hospital in Riyadh, Saudi Arabia, in July and August of 2015 .
●Additional hospital-based outbreaks occurred in Saudi Arabia in 2017 [50,73].
Possible sources and modes of transmission — Dromedary camels appear to be the primary animal host for MERS-CoV (see 'Camels' below). The presence of case clusters strongly suggests that human-to-human transmission also occurs [56,57,74,75]. In a study of risk factors for "primary" infection (ie, infection that was not clearly traceable to exposure to a person with known MERS-CoV infection), 34 primary cases (out of 535 proven infections occurring in Saudi Arabia during eight months of 2014) were compared with 116 age-, sex-, and neighborhood-matched controls . Multivariable analysis indicated that direct contact with camels in the preceding 14 days, diabetes mellitus, heart disease, and smoking were all independently associated with MERS-CoV illness. Moreover, the age and sex of primary cases (largely older men) matches the population involved in camel farming .
Extensive modeling of cases in Saudi Arabia between January 2013 and July 2014 led to an estimate that 12 percent of cases were due to camel exposure and the remaining to human-to-human cluster transmission . A careful examination, including interviews, of 23 of 27 cases from 20 hospitals in Saudi Arabia during the first two months of 2016 indicated that 7 had direct and 7 had indirect camel exposure, 4 had contact with human cases, and 5 had an unknown mechanism of acquisition .
Serologic studies have shown low prevalence of MERS-CoV antibodies in humans in Saudi Arabia [80,81]. A broad antibody survey of 10,009 individuals representative of the general population of Saudi Arabia found seropositivity in 15 (0.15 percent), all but one of whom resided in 5 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 percent) were seropositive.
Among 5235 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; 3210 individuals were screened pre-Hajj, and 2025 were screened post-Hajj .
Bats — Studies performed in Europe, Africa, and Asia, including the Middle East, have shown that coronavirus RNA sequences are found frequently in bat fecal samples and that some of these sequences are closely related to MERS-CoV sequences [8-10]. In a study from Saudi Arabia, 823 fecal and rectal swab samples were collected from bats, and, using a 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 percent identity with a MERS-CoV isolate cloned from the index patient with MERS-CoV infection; the sequence was detected from a fecal pellet of a Taphozous perforatus bat captured from a site near the home of the patient.
MERS-CoV grows readily in several bat-derived cell lines . Following experimental inoculation, MERS-CoV has also been shown to cause widespread but asymptomatic infection of Jamaican fruit bats, supporting the hypothesis that bats may be ancestral reservoirs for MERS-CoV .
Although bats may 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 .
Camels — As noted above, it is likely that camels serve as hosts 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 man with fatal infection and from one of his camels; full-genome sequencing demonstrated that the viruses isolated from the man and his camel were identical . The study had the following findings:
●A previously healthy 44-year-old man was admitted to the intensive care unit of a hospital in Jeddah, Saudi Arabia, with severe dyspnea. He initially developed fever, rhinorrhea, cough, and malaise eight days prior to admission, and he became dyspneic three days prior to admission. He owned a herd of nine dromedary camels; he had visited the camels daily until three days before admission. Four of the camels had been ill with nasal discharge during the week before the onset of the man's illness. The man had applied a topical medicine to the nose of one of the ill camels seven days before he became ill. The patient died 15 days after hospital admission.
●Nasal swabs collected from the patient on hospital days 1, 4, 14, and 16 were all positive for MERS-CoV by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR). The first nasal specimen collected from one symptomatic camel was also positive by rRT-PCR; a repeat nasal specimen collected 28 days later was negative. Nasal specimens that were collected from the other camels on day 1 (seven camels) and day 28 (eight camels) were negative by rRT-PCR. Milk, urine, and rectal specimens collected from all camels were negative by rRT-PCR.
●Separate Vero cell cultures inoculated with the first specimens obtained from the patient and from the PCR-positive camel both grew MERS-CoV strains, which, on full-genome sequencing, were identical.
●A serum specimen collected from the patient on day 1 was negative for MERS-CoV antibodies (<1:10) by immunofluorescence assay, whereas the specimen collected on day 14 had an antibody titer of 1:1280. Paired serum specimens from the infected camel also showed a >4-fold increase in the antibody titer. Four other camels had increases in antibody, and the remaining four camels had high, stable antibody titers to MERS-CoV.
These results suggest that MERS-CoV can infect dromedary camels and can be transmitted from them to humans by close contact. An outbreak in the Al-Hasa region of Saudi Arabia appeared to originate in a 62-year-old man with close camel contact, followed by human-to-human spread both within his large family and several hospitals, resulting in 52 proven cases over 9 weeks with a 40 percent mortality rate .
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 [87-90].
A study of 9 seropositive and 43 seronegative camel workers in Qatar indicated that training of camels (as opposed to simple camel care), milking of camels, and absence of handwashing before and after working with camels were all associated with MERS-CoV infection .
Serologic studies have also suggested that camels are an important source of MERS-CoV:
●Of 203 serum samples from dromedary camels in various regions of Saudi Arabia collected in 2013, 150 (74 percent) had antibodies to MERS-CoV by enzyme-linked immunosorbent assay . The rate of seropositivity was higher in adult than juvenile camels (>95 percent among camels >2 years of age versus 55 percent in camels ≤2 years of age). Using stored serum samples from 1992 to 2010, antibodies to MERS-CoV were detected as early as 1992. No MERS-CoV–specific antibodies were detected in domestic sheep or goats in Saudi Arabia.
●Almost all adult camels (>90 percent) from countries in the Arabian Peninsula, Jordan, Egypt, Nigeria, and Ethiopia show antibody evidence of prior MERS-CoV infection; adult camels in other countries of the region (Kenya, Burkina Faso, Morocco, Tunisia, Spain, Canary Islands) are also MERS-CoV antibody positive but at a lower prevalence [87,89,90,92-100]. Camels in other parts of Europe and in the Americas do not have MERS-CoV antibodies, and no other domestic animals tested have shown evidence of infection [18,99].
In another study, three dromedary camels inoculated with MERS-CoV intratracheally, intranasally, and conjunctivally shed large quantities of virus from the upper respiratory tract . Infectious virus was detected in nasal secretions for 7 days postinoculation and viral RNA for up to 35 days postinoculation. In another study, viral RNA was detected in the milk of camels .
In a surveillance study of coronaviruses in dromedary camels in Saudi Arabia between May 2014 and April 2015, MERS-CoV species and two non-MERS–related coronaviruses cocirculated at high prevalence, with frequent coinfections in the upper respiratory tracts . The two non-MERS coronavirus species were genetically similar to human coronaviruses 229E and OC43. Several MERS-CoV lineages were present in the camels, including a recombinant lineage that has been dominant since December 2014 and that subsequently led to an outbreak in humans in 2015. Although coronaviruses were detected nearly year round in the camels, there was a higher prevalence of MERS-CoV and the 229E-like coronavirus, "camelid alpha-coronavirus," from December 2014 to April 2015. Juvenile camels (6 months to 1 year of age) had the highest levels of respiratory coronavirus infections, followed by calves <6 months of age. The overall positive rates of MERS-CoV from nasal swabs was 12 percent and no rectal swabs were positive for MERS-CoV.
Several strains of MERS-CoV obtained from camels have been shown to be similar or identical to a human-derived MERS-CoV strain in their capacity to infect ex-vivo cultures of human tracheal and lung cells .
Human-to-human transmission — Case clusters in the United Kingdom, Tunisia, and Italy and in healthcare facilities in Saudi Arabia, the United Arab Emirates, Iran, France, and South Korea strongly suggest that human-to-human transmission occurs [20,44,56,57,69,74,105-108]. The number of contacts infected by individuals with confirmed infections, however, appears to be usually limited [109-113].
Exceptions to this are two hospital-based outbreaks, one in South Korea in May and June 2015 and one in Riyadh in July and August 2015. In both outbreaks, there were many secondary, some tertiary, and even some quaternary cases. In South Korea, a total of 186 cases were reported as a result of a single imported case [46,47,68-71]. In Riyadh, a total of 130 individuals were infected over about 6 weeks; there were 26 community-acquired cases and over 100 hospital-acquired cases, which included healthcare workers, patients, and visitors. Most hospital-acquired infections occurred from exposure in the emergency department .
The outbreak in South Korea was the first MERS outbreak in which superspreader events were identified [47,71]. Superspreaders are individuals who are responsible for a disproportionately large number of transmission events . In this outbreak, 83 percent of transmission events were epidemiologically linked to five superspreaders, all of whom had pneumonia at presentation; these individuals were each in contact with hundreds of people . The severe acute respiratory syndrome (SARS) outbreak in Hong Kong in 2003 was also associated with superspreaders. (See 'Cases and clusters' above and "Severe acute respiratory syndrome (SARS)", section on 'Transmission'.)
Secondary cases have tended to be milder than primary cases, and many secondary cases have been reported to be asymptomatic [62,113]. Possible modes of transmission 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 [44,58,117]. A phylogenetic analysis of viruses isolated during the outbreaks in Saudi Arabia in the spring of 2014 is discussed above. (See 'Genetic analysis' above.)
In a report describing a hospital outbreak in South Korea in May and June 2015, 37 infections were associated with the index case, who was hospitalized from May 15 to May 17; 25 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 also clearly demonstrated the importance of superspreaders, 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 people between May 27 and May 29 while being treated in the emergency department of a single hospital in Seoul, South Korea. An analysis of the Korean outbreak identified several significant risk factors for transmission: a longer interval from symptom onset to imposition of isolation precautions, pre-isolation hospitalization or visit to an emergency room, and a higher concentration of virus in the respiratory secretion sample obtained for diagnosis .
Secondary transmission has also occurred in the household setting. In the largest study to date, 280 household contacts of 26 index patients with MERS-CoV infection were sampled by PCR of a pharyngeal swab and/or serology, and 12 probable cases of secondary transmission were detected (4 percent, 95% CI 2 to 7 percent) . 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 PCR only four days after illness onset in the index cases. Although some secondary cases may have been missed because only 108 of 280 contacts had samples available for serologic testing >3 weeks after onset of symptoms in the index case, this study implies that spread of MERS-CoV in households is unusual.
In contrast with this was an investigation of a cluster of infections in a single extended family containing five known MERS-CoV infected individuals . Seventy-nine relatives in four households were examined, using PCR of upper respiratory tract samples and serology. Fourteen additional infections were found, and, in all, 11 family members were hospitalized and 2 died. Transmissions took place in two of the four households: in one, the adult attack rate was 64 percent; in the other, it was 42 percent. On univariate analysis, risk factors for transmission were sleeping in the same room as an index patient, touching an index patient's respiratory secretions, and removing biologic waste from an index patient.
In an early 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 . Transmissibility studies based on hospital outbreaks in Saudi Arabia in 2014 and in South Korea in 2015 have estimated R0's between 2.0 and 6.7  and 2.0 and 7.0 , respectively. However, there is risk of inaccuracy in estimating R0 values in the pre-pandemic stage of an emerging infectious disease [124,125].
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●Basics topic (see "Patient education: Middle East respiratory syndrome coronavirus (The Basics)")
SUMMARY AND RECOMMENDATIONS
●A novel coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), causing severe respiratory illness emerged in 2012 in Saudi Arabia. Many additional cases and clusters of MERS-CoV infections have been detected subsequently in the Arabian Peninsula, particularly in Saudi Arabia (figure 1 and figure 2). Cases have also been reported from other regions, including North Africa, Europe, Asia, and North America (table 1). In countries outside of the Arabian Peninsula, patients developed illness after returning from the Arabian Peninsula or through close contact with infected individuals. (See 'Introduction' above and 'Epidemiology' above.)
●MERS-CoV is a lineage C betacoronavirus found in humans and camels that is different from the other human betacoronaviruses (severe acute respiratory syndrome coronavirus, OC43, and HKU1) but closely related to several bat coronaviruses. (See 'Virology' above.)
●In an analysis of the full or partial genomes of MERS-CoV obtained from 21 patients 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 single hospital outbreak, there was evidence of more than one virus introduction. (See 'Genetic analysis' above.)
●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 South Korea from May until early July 2015; the index case was an individual who had traveled to the Arabian Peninsula. Another large outbreak began in a hospital in Riyadh, Saudi Arabia, in the summer of 2015. (See 'Introduction' above and 'Epidemiology' above.)
●MERS-CoV is closely related to coronaviruses found in bats, suggesting that bats may be a reservoir of MERS-CoV. Camels likely serve as hosts for MERS-CoV. (See 'Possible sources and modes of transmission' above.)
●Case clusters in the United Kingdom, Tunisia, and Italy and in healthcare facilities in Saudi Arabia, France, Iran, and South Korea strongly suggest that human-to-human transmission occurs. The number of contacts infected by individuals with confirmed infections, however, appears to be limited. (See 'Human-to-human transmission' above.)
●Additional information about MERS-CoV can be found on the World Health Organization's website and the United States Centers for Disease Control and Prevention's website.
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- 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.
- 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.
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