Middle East respiratory syndrome coronavirus: Clinical manifestations and diagnosis

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 [1]. 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 [4]. Many subsequent cases and clusters of infections have been reported [5].

This novel coronavirus, initially termed human coronavirus-EMC (for Erasmus Medical Center), has been named Middle East respiratory syndrome coronavirus (MERS-CoV) [6].

Updated 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.

The clinical manifestations and diagnosis of MERS-CoV are discussed here. The virology, epidemiology, 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: Virology, pathogenesis, and epidemiology" and "Middle East respiratory syndrome coronavirus: Treatment and prevention" and "Coronaviruses" and "Severe acute respiratory syndrome (SARS)".)

CASE DEFINITIONS — For epidemiologic purposes, the following Middle East respiratory syndrome coronavirus (MERS-CoV) infection case definitions have been proposed by the World Health Organization (WHO) [7]:

●Confirmed case – A person with laboratory confirmation of infection with MERS-CoV irrespective of clinical signs and symptoms

●Probable case – A probable case is defined by the following criteria:

•A febrile acute respiratory illness with clinical, radiographic, or histopathologic evidence of pulmonary parenchymal disease (eg, pneumonia or acute respiratory distress syndrome) and

•A direct epidemiologic link with a laboratory-confirmed MERS-CoV case and

•Testing for MERS-CoV is unavailable, negative on a single inadequate specimen, or inconclusive

OR

•A febrile acute respiratory illness with clinical, radiographic, or histopathologic evidence of pulmonary parenchymal disease (eg, pneumonia or acute respiratory distress syndrome) that cannot be explained fully by any other etiology; and

•The person resides in or traveled to the Middle East or countries where MERS-CoV is known to be circulating in dromedary camels or where human infections have recently occurred and

•Testing for MERS-CoV is inconclusive

OR

•An acute febrile respiratory illness of any severity and

•Direct epidemiologic link with a confirmed MERS-CoV case and

•Testing for MERS-CoV is inconclusive

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 [8]. 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. PCR testing is discussed in detail below. (See 'Polymerase chain reaction and sequencing' below.)

The United States Centers for Disease Control and Prevention's (CDC's) case definitions can be found on the CDC's website.

CLINICAL MANIFESTATIONS

Incubation period — In an outbreak of Middle East respiratory syndrome coronavirus (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% CI 1.9-14.7 days) [9]. In one secondary case that occurred in a patient in France who shared a room with an infected patient, the incubation period was estimated at 9 to 12 days [10]. In the 2015 outbreak in South Korea, the median incubation period was 6.3 days (95th percentile 12.1 days) [11]. The longer incubation period in South Korea was also observed in a later combined analysis, which calculated means of 5.0 days (95% CI 4.0 to 6.6) for Saudi Arabia (34 cases) versus 6.9 days (95% CI 6.3 to 7.5) for South Korea (115 cases) [12]. This finding is unexplained but could be due to factors related to the differences in data sources or, possibly, evolution in the virus itself.

The World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (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 [13]. Countries in or neighboring the Arabian Peninsula are defined below. (See 'In the United States' below.)

Clinical features

Signs and symptoms — Most reported patients with MERS-CoV infection have been adults with severe pneumonia and acute respiratory distress syndrome, and some have had acute kidney injury [4,9,10,14-20]. Many patients have required mechanical ventilation, and some have required extracorporeal membrane oxygenation.

Other clinical manifestations that have been reported are gastrointestinal symptoms (anorexia, nausea, vomiting, abdominal pain, diarrhea), pericarditis, and disseminated intravascular coagulation [10,14,15,17,21]. Among 12 critically ill patients, 11 had extrapulmonary manifestations including shock (in 11) and acute kidney injury (in 7) [18]. Two patients have been reported who presented with diarrhea, one of whom was immunocompromised [22]. In both cases, chest radiography revealed pneumonia and the correct diagnosis was made. One immunocompromised patient presented with fever, diarrhea, and abdominal pain but without early respiratory symptoms; pneumonia was identified incidentally on a chest radiograph [10,15]. Three adults with pneumonia and MERS-CoV infection also developed neurologic symptoms and showed widespread intracranial white matter lesions by magnetic resonance imaging [23].

The following clinical findings were observed among 47 patients with MERS-CoV infection in Saudi Arabia [17]:

●Fever (>38°C) – 46 patients (98 percent)

●Fever with chills or rigors – 41 patients (87 percent)

●Cough – 39 patients (83 percent)

●Shortness of breath – 34 patients (72 percent)

●Hemoptysis – 8 patients (17 percent)

●Sore throat – 10 patients (21 percent)

●Myalgias – 15 patients (32 percent)

●Diarrhea – 12 patients (26 percent)

●Vomiting – 10 patients (21 percent)

●Abdominal pain – 8 patients (17 percent)

●Abnormal chest radiograph – 47 patients (100 percent)

Of these 47 patients, 42 (89 percent) required intensive care and 34 (72 percent) required mechanical ventilation [17]. The median time from presentation for medical care to mechanical ventilation was 7 days (range 3 to 11 days) and to death was 14 days (range 5 to 36 days). A comparison of 330 critically ill MERS patients with 222 critically ill non-MERS patients in 14 Saudi Arabian hospitals over a single time period indicated several differences [20]. MERS patients were somewhat younger, more often mechanically ventilated, and had higher mortality but also showed considerable overlap in clinical features and comorbidities, emphasizing the importance of specific and rapid diagnosis for optimal management, infection control, and prognosis.

Outcomes are discussed in greater detail separately. (See "Middle East respiratory syndrome coronavirus: Treatment and prevention", section on 'Prognosis'.)

Mild and asymptomatic infections — Although many patients have had severe disease, some reports have described individuals with a mild respiratory illness not requiring hospitalization [13,24]. In one report, a patient developed a dry cough on the 10^th day of illness followed by dyspnea and hypoxia on the 11^th day of illness; prior to that, he had only nonspecific signs and symptoms (malaise, myalgias, low-grade fever) [25].

Several individuals with asymptomatic infection have been identified among contacts of patients with symptomatic infection [24,26-28]. As an example, the Saudi Arabian Ministry of Health screened more than 3000 close contacts of patients using real-time reverse-transcriptase polymerase chain reaction 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 [24]. A study that modeled clinical data from active versus passive surveillance estimated that the ratio of symptomatic to total infections was strongly age related, rising from 11 percent in those under 20 years of age to 88 percent in those 70 years old or older, with a parallel rise in the case-fatality ratio [29].

It appears that 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 [27]. Of 64 patients who were initially identified as being asymptomatic, 33 of the 64 individuals (52 percent) were available for a telephone survey. Of these 33 people, 79 percent reported at least one symptom during the month before testing and 70 percent reported more than one symptom. Unexpectedly, 36 percent 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.

However, one report describes asymptomatic infection in two men who had contact with infected dromedary camels and who were identified by active surveillance [30]. Both men were hospitalized for observation for approximately two incubation periods and remained asymptomatic.

Children — A report of pediatric cases describes 31 MERS-CoV infections in children between 9 months and 17 years of age [31]. Most were discovered in surveys performed among contacts of known cases using PCR of upper respiratory tract samples. Of 29 cases for which some clinical data were available, 13 were asymptomatic. Of 14 children with outcome information, 2 died, one a 2-year-old child with cystic fibrosis [32] and one a 9-month-old with congenital nephrotic syndrome [33]. One other, a 14-year-old girl with Down syndrome, was hospitalized and recovered [32].

Effect on pregnant women and fetuses — As of 2019, a total of 11 cases of MERS-CoV infection during pregnancy have been reported [34,35]. These included three maternal deaths and three infant deaths. One woman with MERS-CoV developed vaginal bleeding and abdominal pain on the seventh day of illness and spontaneously delivered a stillborn infant at five months gestation [36]. Two other case reports describe severe maternal disease in the third trimester, one of whom died and both of whom delivered apparently uninfected and healthy preterm infants [37,38]. Five additional cases have been reported in pregnant women; outcomes included one stillbirth at 34 weeks, one maternal death from severe pneumonia 19 days after delivery of a healthy infant, one premature delivery with death of both mother and infant, and two episodes of moderately severe pneumonia in the mother with subsequent recovery and deliveries of healthy infants [39]. In three additional cases, both mothers and infants survived [40,41].

Laboratory abnormalities — Among 47 cases of MERS-CoV infection in Saudi Arabia, laboratory abnormalities included leukopenia (14 percent), lymphopenia (34 percent), lymphocytosis (11 percent), thrombocytopenia (36 percent), elevated aspartate aminotransferase (15 percent), elevated alanine aminotransferase (11 percent), and elevated lactate dehydrogenase (49 percent) [17]. Other reports have described lymphocytopenia (with or without neutropenia), anemia, and/or thrombocytopenia [10,14,16,18]. Some patients have shown progressive renal failure, with rising blood urea nitrogen and creatinine [4,10,14,18,42]. Disseminated intravascular coagulation and hemolysis have also been reported [15,16].

Imaging findings — As noted above, among 47 cases of MERS-CoV disease in Saudi Arabia, abnormalities on chest radiography were noted in all 47 cases [17]. Imaging findings ranged from minimal to extensive abnormalities, including increased bronchovascular markings, airspace opacities, patchy infiltrates, interstitial changes, patchy to confluent airspace consolidations, nodular opacities, reticular opacities, reticulonodular shadowing, pleural effusions, and total opacification of lung segments and lobes; abnormalities were either unilateral or bilateral (image 1). In another study, ground-glass opacity in a peripheral location was the most common abnormality observed on chest radiography [43].

In patients 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 [44-46].

COMORBIDITIES — It remains unclear whether persons with specific comorbidities are disproportionately infected with Middle East respiratory syndrome coronavirus (MERS-CoV) or come to medical attention because they have more severe disease [47]. An early study of 47 patients with MERS-CoV infection in Saudi Arabia noted that 45 (96 percent) had underlying comorbidities, including diabetes mellitus, hypertension, chronic cardiac disease, chronic lung disease, and chronic kidney disease [17]. In a study of 12 critically ill patients with MERS-CoV infection, each individual had at least one comorbid condition; the median number of comorbid conditions was 3 (range 1 to 6) [18]. A meta-analysis of 12 series between 2013 and 2016 from the Middle East concluded that diabetes or hypertension was present in about one half of reported severe MERS cases, coronary or cardiovascular disease in 31 percent, and obesity in 16 percent [48]. The overall prevalence of comorbidities (ie, what proportion had at least one comorbidity) was not specified.

The high rate of comorbidities reported must be interpreted with caution, since diabetes mellitus was frequently observed in a study of more than 6000 patients presenting to an outpatient clinic in Riyadh, Saudi Arabia, and because approximately half of the 47 patients described in the first study were part of an outbreak in a hemodialysis unit [17], where rates of chronic kidney disease and hypertension would be expected to be high [49].

The most common comorbidities in the 2015 MERS outbreak in Korea (total number of cases, 186) were respiratory disorders and cancer (11 cases each), hypertension (8 cases), and cardiovascular diseases (5 cases). There were 4 cases of diabetes and none of chronic kidney disease [50]. It may be that the increased expression of DPP4 (the cellular receptor for MERS-CoV infection) found in both smokers and adults with chronic obstructive pulmonary disease plays a role in susceptibility to, as well as severity of, MERS [51-53].

The association between comorbidities and outcomes is discussed separately. (See "Middle East respiratory syndrome coronavirus: Treatment and prevention", section on 'Prognosis'.)

OUTCOMES — Mortality and other outcomes are discussed in detail elsewhere. (See "Middle East respiratory syndrome coronavirus: Treatment and prevention", section on 'Prognosis'.)

DIAGNOSIS — 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 [54].

Preferred tests and specimen types — 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 Middle East respiratory syndrome coronavirus (MERS-CoV) than testing of upper respiratory tract specimens [8,13,55,56]. (See 'Polymerase chain reaction and sequencing' below.)

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, we suggest that multiple specimens be collected from different sites and at different times to increase the likelihood of detecting MERS-CoV [8,55]. Ideally, lower respiratory tract, upper respiratory tract, and serum samples should be obtained [56]. Priority should be given to respiratory specimens (lower tract if obtainable and in all cases of severe disease; upper tract if disease is mild and lower tract specimens cannot be obtained). A serum sample should also be obtained for serologic testing [8,56].

We recommend the following diagnostic approach, which has been adapted from guidelines issued by the United States Centers for Disease Control and Prevention (CDC) and the WHO [8,55-57]:

●Lower respiratory tract specimens such as sputum, endotracheal aspirate, or bronchoalveolar lavage (BAL) fluid should be obtained for rRT-PCR testing from all cases of severe disease and from milder cases when possible.

●Upper respiratory tract specimens should be obtained for rRT-PCR testing and should be either a combined nasopharyngeal and oropharyngeal swab specimen (two synthetic fiber swabs with plastic shafts, combined in a single collection container) or a 2 to 3 mL nasopharyngeal aspirate. Obtaining upper respiratory tract specimens is especially important if the patient does not have signs or symptoms of lower respiratory tract disease or if the collection of lower respiratory tract specimens is not possible.

●If initial testing of respiratory specimens is negative in a patient 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.

●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, 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 [56].

●In certain cases, the diagnosis should be confirmed by nucleic acid sequencing [8].

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 patient from an isolation ward requires negative 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 patients in whom MERS-CoV infection is thought to be likely) [8].

Additional information about diagnostic testing can be found in a WHO document and in a CDC document [8,56].

Polymerase chain reaction and sequencing — Data from the cases sampled to date indicate that lower respiratory tract specimens (sputum, tracheal aspirates, 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, nasopharyngeal aspirates) [8,10,14-16,55,58-60]. However, upper respiratory tract specimens are still useful for diagnosing MERS-CoV. As an example, in a series of 47 patients with MERS-CoV, the majority of patients were diagnosed using nasopharyngeal swabs [17].

In a study of 37 patients with MERS-CoV infection in Saudi Arabia, lower respiratory tract specimens yielded the highest virus loads and were the most likely to be positive [60]. Of 199 lower respiratory tract samples collected during the first three weeks following diagnosis, 93 percent of tests yielded viral RNA; the average viral load was 5×10⁶ copies/mL and the maximum viral load was 6×10¹⁰ copies/mL. Of 84 upper respiratory tract specimens (throat swabs), 48 percent were positive. Of 108 serum samples tested, 33 percent yielded viral RNA, almost all during the first eight days after diagnosis. Only 15 percent of stool and 2 percent of urine samples yielded viral RNA.

In the same study, the average lower respiratory tract virus load during the first week after diagnosis was significantly higher in fatal cases than in nonfatal cases (5×10⁷ versus 3.9×10⁶ copies/mL) [60]. Another study found an association between higher virus load of MERS-CoV in the upper respiratory tract and worse clinical outcomes, including death and admission to the intensive care unit [61].

Three rRT-PCR assays for routine detection of MERS-CoV have been developed [8]. Currently described tests are an assay targeting a region upstream of the E protein gene (upE) [58] and assays targeting the open reading frame 1b (ORF 1b) [58] and the open reading frame 1a (ORF 1a) [62]. In some cases, sequencing should be performed for confirmation.

An emergency use authorization was issued by the US Food and Drug Administration in 2013 for the rRT-PCR assay developed by the CDC on clinical respiratory, blood, and stool samples [63].

Serology — Several serology assays have been developed for the detection of MERS-CoV antibodies, including immunofluorescence assays and a protein microarray assay [8,62,64-66]. The CDC has developed a two-stage approach, which uses an enzyme-linked immunosorbent assay (ELISA) for screening followed by an indirect immunofluorescence test or microneutralization test for confirmation [8]. Any positive test by a single serologic assay should be confirmed with a neutralization assay. There are limited data on the sensitivity and specificity of antibody tests for MERS-CoV.

According to the WHO, cases with a positive serologic test in the absence of PCR testing or sequencing are considered probable cases if they meet the other elements comprising the case definition of a probable case [8]. (See 'Case definitions' above.)

In a study of 37 patients with MERS-CoV infection in Saudi Arabia, all seroconversions occurred during the first two weeks following diagnosis, which corresponds to the second and third week after symptom onset [60]. All surviving patients, but only slightly more than half of the fatal cases, developed immunoglobulin (Ig)G and neutralizing antibodies. IgG and neutralizing antibody concentrations were weakly and inversely correlated with lower respiratory tract virus loads. In a study of 42 individuals in South Korea, all of whom had MERS-CoV detected by PCR from respiratory samples, none of 3 asymptomatic individuals developed neutralizing antibodies, whereas 3 of 5 with symptoms but without pneumonia, 15 of 16 with pneumonia but without respiratory failure, and all 9 with pneumonia with respiratory failure developed neutralizing antibodies [67].

Whom to test — The WHO and the CDC have developed recommendations regarding whom to test. Clinicians in countries other than the United States should use the WHO's recommendations and consult with their ministry of health for further guidance regarding the evaluation of possible new cases of MERS-CoV infection.

Outside the United States — Based upon guidelines from the WHO, we recommend that, outside the United States, the following individuals be tested for MERS-CoV [55]:

●A person with an acute respiratory infection, which may include history of fever and cough and evidence of pulmonary parenchymal disease (eg, pneumonia or acute respiratory distress syndrome [ARDS]), based upon clinical or radiographic evidence of consolidation, who requires admission to hospital, with no other etiology that fully explains the clinical presentation. Testing should be performed according to local guidance for the evaluation of community-acquired pneumonia (CAP). Examples of other etiologies of CAP include Streptococcus pneumoniae, Haemophilus influenzae type b, Legionella pneumophila, other recognized causes of bacterial pneumonia, influenza, and respiratory syncytial virus. Clinicians should be alert to the possibility of atypical presentations in patients who are immunocompromised.

AND any of the following:

•The person resides in the Middle East, particularly in regions where human MERS-CoV infections have been reported or in countries where MERS-CoV is known to be circulating in dromedary camels.

•The disease is in a cluster that occurs within a 14-day period, without regard to place of residence or history of travel. A cluster is defined as two or more persons with onset of symptoms within the same 14-day period associated with a specific setting, such as a classroom, workplace, household, extended family, hospital, other residential institution, military barracks, or recreational camp. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)

•The disease occurs in a healthcare worker who has been working in an environment where patients with severe acute respiratory infections are being cared for, particularly patients requiring intensive care, without regard to place of residence or history of travel.

•The person has history of travel within 14 days before onset of illness to the Middle East or to countries where MERS-CoV is known to be circulating in dromedary camels or to regions where human cases have recently occurred.

•The person has an unusual or unexpected clinical course, especially sudden deterioration despite appropriate treatment, without regard to place of residence or history of travel, even if another etiology has been identified that fully explains the clinical presentation.

●An individual with an acute respiratory illness of any severity who, within 14 days of onset of illness, had any of the following exposures:

•Close physical contact with a confirmed or probable case of MERS-CoV infection while that patient was ill. (See 'Case definitions' above.)

•Exposure to a healthcare facility in a country where hospital-associated MERS-CoV infections have been reported.

•Direct contact with dromedary camels or consumption or exposure to dromedary camel products (raw meat, unpasteurized milk, urine) in countries where MERS-CoV is known to be circulating in dromedary camel populations or where human infections occurred as a result of presumed zoonotic transmission.

●Countries in the Middle East are strongly encouraged to consider adding testing for MERS-CoV to testing algorithms as part of routine sentinel respiratory disease surveillance and diagnostic panels for pneumonia.

Routine testing of asymptomatic contacts of cases is not recommended [8].

In the United States — The following discussion has been adapted from recommendations issued by the CDC for the investigation of possible cases in the United States [57,68].

Healthcare providers should evaluate individuals for MERS-CoV infection if they meet the following criteria for being a patient under investigation [68]:

●Fever and pneumonia or acute respiratory distress syndrome (based on clinical or radiographic evidence) and either:

•A history of travel from countries in or near the Arabian Peninsula (countries considered in or neighboring the Arabian Peninsula include Bahrain, Iraq, Iran, Israel, Jordan, Kuwait, Lebanon, Oman, Palestinian territories, Qatar, Saudi Arabia, Syria, the United Arab Emirates, and Yemen) within 14 days before symptom onset or

•Close contact with a symptomatic traveler who developed fever and acute respiratory illness (not necessarily pneumonia) within 14 days after traveling from countries in or near the Arabian Peninsula or

•A history of being in a healthcare facility (as a patient, worker, or visitor) in South Korea within 14 days before symptom onset or

•Is a member of a cluster of patients with severe acute respiratory illness (eg, fever and pneumonia requiring hospitalization) of unknown etiology in which MERS-CoV is being evaluated in consultation with state and local health departments

OR

●Fever and symptoms of respiratory illness (eg, cough, shortness of breath) and being in a healthcare facility (as a patient, healthcare worker, or visitor) within 14 days before symptom onset in a country in or near the Arabian Peninsula in which recent healthcare-associated cases of MERS-CoV have been identified

OR

●Fever or symptoms of respiratory illness (eg, cough, shortness of breath) and close contact with a confirmed MERS-CoV case while the affected person was ill

A close contact is defined as [68]:

●Being within approximately 6 feet (2 meters) or within the room or care area for a prolonged period of time (eg, healthcare personnel, household members) while not wearing recommended personal protective equipment (ie, gowns, gloves, respirator, eye protection)

OR

●Having direct contact with infectious secretions (eg, being coughed on) while not wearing recommended personal protective equipment (ie, gowns, gloves, respirator, eye protection)

Additional information can be found on the CDC's website.

The CDC requests that state and local health departments immediately report patients under investigation for MERS-CoV infection to the CDC.

Specimen handling — Specimens should reach the laboratory as soon as possible after collection [8]. When there is likely to be a delay of more than 72 hours in the laboratory receiving respiratory tract specimens, specimens should be frozen at -80°C and shipped on dry ice. It is important to avoid repeated freezing and thawing of specimens. 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. Storage of respiratory and serum specimens in domestic frost-free freezers should be avoided, given their wide temperature fluctuations.

Where to ship specimens — For patients in the United States, clinicians 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.

For patients in countries other than the United States, clinicians should follow the recommendations of their ministry of health regarding diagnostic testing.

Reporting cases — 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 [55]. (See 'Case definitions' above.)

Additional recommendations regarding reporting of MERS-CoV infections can be found on the WHO's website and the CDC's website.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Middle East respiratory syndrome coronavirus".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Middle East respiratory syndrome coronavirus (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical features – Most reported patients with Middle East respiratory syndrome coronavirus (MERS-CoV) infection have been adults with severe pneumonia and acute respiratory distress syndrome, and some have had acute kidney injury. Many patients have required mechanical ventilation, and some have required extracorporeal membrane oxygenation. Other clinical manifestations that have been reported are gastrointestinal symptoms (anorexia, nausea, vomiting, abdominal pain, diarrhea), pericarditis, and disseminated intravascular coagulation. Frequency and severity of symptoms are directly proportional to age. (See 'Clinical features' above.)

●Incubation period – Based on limited data, the median incubation period of MERS-CoV is an estimated 5 days with a range of 2 to 15 days. (See 'Incubation period' above.)

●When to suspect MERS-CoV – Individuals with an acute respiratory infection who have an epidemiologic link to MERS-CoV (eg, relevant residence or travel history, potential exposure to known or suspected case or cluster) or who have had an unusual or unexpected clinical course (especially sudden deterioration despite appropriate treatment) should be tested for MERS-CoV. Certain other patients may also warrant evaluation for MERS-CoV infection. Specific recommendations regarding whom to test are presented above. (See 'Whom to test' above.)

●Microbiologic diagnosis – Real-time reverse-transcriptase polymerase chain reaction (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, we suggest collection of multiple specimens from different sites and at different times. (See 'Diagnosis' above and 'Preferred tests and specimen types' above.)

●Case reporting – The World Health Organization (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. (See 'Reporting cases' above.)

●WHO and CDC links – Additional information about MERS-CoV can be found on the World Health Organization (WHO) website and the Centers for Disease Control and Prevention (CDC) website.