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Middle East respiratorysyndrome (MERS)

The right clinical information, right where it's needed

Last updated: Mar 17, 2020

Table of ContentsSummary 3

Basics 4

Definition 4

Epidemiology 4

Etiology 5

Pathophysiology 6

Classification 6

Prevention 7

Primary prevention 7

Screening 8

Secondary prevention 9

Diagnosis 10

Case history 10

Step-by-step diagnostic approach 10

Risk factors 15

History & examination factors 17

Diagnostic tests 19

Differential diagnosis 22

Diagnostic criteria 25

Treatment 28

Step-by-step treatment approach 28

Treatment details overview 31

Treatment options 33

Emerging 42

Follow up 44

Recommendations 44

Complications 45

Prognosis 45

Guidelines 47

Diagnostic guidelines 47

Treatment guidelines 48

Online resources 49

References 51

Images 64

Disclaimer 67

Summary

◊ MERS should be considered when a severe respiratory illness occurs in the 2 weeks followingresidence in or travel to the Middle East or areas of outbreak, and/or close contact with infectedindividuals.

◊ The majority of cases are the result of human-to-human transmission, with peaks of confirmed casesoccurring during nosocomial outbreaks. Clinical presentation ranges from asymptomatic to severe,rapidly progressive, potentially fatal pneumonia.

◊ Clues on routine laboratory testing include leukopenia, lymphopenia, thrombocytopenia, andevidence of acute kidney injury. Confirmation of infection requires specialized laboratory testingincluding real-time reverse transcription polymerase chain reaction (RT-PCR) on respiratory samplesand serum.

◊ Treatment is supportive; however, several promising virus-specific therapies are under investigation.Vaccines are undergoing trials.

◊ Epidemic potential is considered low at present unless the virus mutates.

Middle East respiratory syndrome (MERS) BasicsBA

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DefinitionMiddle East respiratory syndrome (MERS) is an acute viral respiratory tract infection caused by the novelbetacoronavirus Middle East respiratory syndrome coronavirus (MERS-CoV). It was first identified in SaudiArabia in 2012. Cases have been limited to the Arabian Peninsula and its surrounding countries, and totravelers from the Middle East or their contacts. The clinical spectrum of infection varies from no symptomsor mild respiratory symptoms to severe, rapidly progressive pneumonia, acute respiratory distress syndrome,septic shock, or multiorgan failure resulting in death.

[Centers for Disease Control and Prevention (CDC): Middle East respiratory syndrome (MERS)]

[World Health Organization (WHO): Middle East respiratory syndrome coronavirus (MERS-CoV)]

EpidemiologyThe first case of MERS was reported in a 60-year-old man in Jeddah, Saudi Arabia in 2012.[14] The patientdied from severe pneumonia and multiorgan failure. Since then, many cases and clusters have beenreported with the majority of infections acquired in the Arabian Peninsula and its surrounding countries, mostcommonly Saudi Arabia, the United Arab Emirates (UAE), Oman, Qatar, and Jordan.

Cases associated with travel from these countries have been limited to small clusters of a few individuals,[15][16] [17] [18] except for one large outbreak of 186 reported cases in the Republic of Korea (South Korea)in 2015,[19] [20] [21] and one superspreader event in Riyadh (Saudi Arabia) in 2017 where 44 cases werelinked to one patient who presented with acute renal failure.[11]Two cases were reported in the US in 2014,both in travelers from Saudi Arabia.[22] There have been no cases reported in the US since. Five laboratory-confirmed cases have been reported in the UK since 2012, with the latest reported in August 2018.[23] Othercountries with travel-associated cases include France, Italy, Greece, Turkey, Lebanon, Germany, Austria,Netherlands, China, Malaysia, Thailand, Philippines, and Egypt. A case was reported in the Republic ofKorea in September 2018 in a Korean national who visited Kuwait and returned to Korea via Dubai. Twenty-one contacts are currently under active surveillance.[24]

As of the end of August 2018, 2248 laboratory-confirmed cases, including 798 deaths (35.5% case fatalityrate), were reported globally since 2012 across 27 countries. The majority of these cases were reported fromSaudi Arabia (1871 cases). The 50-59 years age group is at highest risk for acquiring primary infection.[25]

[World Health Organization (WHO): disease outbreak news]

Ninety-eight percent of cases have been reported in adults (defined as age >14 years).[8] Although infectionhas been reported in different age groups within the adult population, the median age of patients rangesfrom 50 to 67 years of age.[4] [9] [26] Age ≥50 years is associated with a higher risk of mortality.[5] [27] Inone cohort study, mortality increased with increasing age to reach 75% in patients >60 years of age.[8] Themajority of cases occur in males.[25] Infection in children is rare, although the reason for this is unknown.[12][13]

The majority of cases are a result of human-to-human transmission rather than camel-to-humantransmission, with peaks of confirmed cases occurring during nosocomial outbreaks.[6] [7] [28] Transmissionhas been well documented in family clusters.[18] [29] [30] However, it has been reported more commonly innosocomial outbreaks (e.g., hemodialysis units, intensive care units, medical wards).[6] [7] [30] [31] [32] [33][34]

4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Mar 17, 2020.BMJ Best Practice topics are regularly updated and the most recent versionof the topics can be found on bestpractice.bmj.com . Use of this content is

subject to our disclaimer. © BMJ Publishing Group Ltd 2020. All rights reserved.

http://www.cdc.gov/coronavirus/mers/index.html

http://www.who.int/emergencies/mers-cov/en/.

http://www.who.int/csr/don/archive/disease/coronavirus_infections/en/

https://bestpractice.bmj.com

Middle East respiratory syndrome (MERS) Basics

EtiologyVirology

• Infection is caused by the novel betacoronavirus Middle East respiratory syndrome coronavirus(MERS-CoV), an enveloped, positive-sense, single-stranded RNA virus with a genomic size ofapproximately 30,000 nucleotides.[35]

• The virus is a member of the Coronoviridae family (order: Nidovirales; subfamily: Coronavirinae; genusBetacoronavirus ) and is part of the lineage C group.[14] [36] It is phylogenetically distinct from allpreviously known betacoronavirus species, which include human coronaviruses HKU1 and OC43,severe acute respiratory syndrome (SARS) coronavirus, and bat coronaviruses HKU4, HKU5, andHKU9.[37]

• MERS-CoV genomes are classified into 2 clades: clade A (the earliest clusters of infection, i.e.,EMC/2012 and Jordan N3/2012) and clade B (new clusters which are genetically distinct from cladeA).[38]

Animal hosts

• It is thought that dromedary camels are the primary animal host for MERS-CoV.[39]• Antibodies to the virus have been found in the serum of these camels in the Arabian Peninsula and its

surrounding countries in multiple studies, some dating back to the 1990s.[40] [41] [42] [43] [44] [45][46] [47] [48] [49] [50] [51] [52] [53]

• MERS-CoV RNA, as well as viable virus, has also been isolated from nasal and fecal samples fromthese camels.[47] [54] [55] [56] The camels may show no sign of infection, but still excrete the virus intheir nasal fluids, feces, milk, or urine.

• Experimental MERS-CoV infection in camels resulted in mild upper respiratory infection and mildfever.[57]

• Bats are also thought to be an earlier reservoir of MERS-CoV; however, this is yet to be proven.[58]

Animal-to-human transmission

• The exact mode of transmission is unknown, but it is thought to occur from direct or indirect contactwith dromedary camels (e.g., camel milking, contact with camel nasal secretions, urine, or feces) orcamel products (e.g., unpasteurized camel milk, raw or undercooked camel meat).

• Near-identical strains of the virus were isolated from epidemiologically linked dromedary camelsand human cases in Saudi Arabia, Qatar, and the United Arab Emirates.[32] [59] [60] The strongestevidence for camel-to-human transmission comes from a study in Saudi Arabia where the virus wasisolated from a patient and one of his camels and the genome was found to be almost identical.[61][62] However, there are inconsistencies when it comes to camel-to-human transmission, and moredata are required to gain a better understanding of how transmission occurs.[63]

• A case-control study identified contact with camels to be a risk factor for MERS-CoV infection.[64]

Human-to-human transmission

• The majority of cases are a result of human-to-human transmission (rather than camel-to-humantransmission) with peaks of confirmed cases occurring during nosocomial outbreaks.[6] [7] [28]Despite this, human-to-human transmission is generally considered to be inefficient.

• Transmission is via respiratory droplets (e.g., coughing, sneezing) from an infected patient, or closecontact with an infected patient. However, airborne or fomite transmission cannot be ruled out.[65] The

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incubation period is 2 to 14 days and transmission is thought to occur during either the symptomatic orincubation stages.[8] [66]

• Transmission has been well documented in family clusters.[18] [29] [30] However, it has been reportedmore commonly in nosocomial outbreaks (e.g., hemodialysis units, intensive care units, medicalwards).[6] [7] [30] [31] [32] [33] This is likely to be due to factors which include late recognition ofthe infection, overcrowding of patients in hospitals, and inadequate infection control precautions.[6][27] [29] [31] [67] Outbreaks are facilitated by extensive environmental contamination of the patients’surroundings and the ability of the virus to survive for long periods on plastic and steel surfaces.[68][69]

• With an effective reproductive number of less than one, the epidemic potential of the infection isconsidered low at present unless the virus mutates.[70] [71] [72] Outbreaks are more restrictedcompared with SARS. Super-spreader events have not been reported; however, future adaptations ofthe virus may potentially increase human-to-human transmission or virus virulence.[Fig-1]

PathophysiologyThe pathogenesis is not completely understood. The virus is transmitted primarily via respiratory dropletsfrom an infected person which enter the human body via the respiratory tract mucosa.[73] The virus bindsto the functional receptor dipeptidyl peptidase-4 (DPP4; also called CD26) on the surface of host cells (e.g.,type I and II alveolar cells, ciliated and nonciliated bronchial epithelium, endothelium, alveolar macrophages,leukocytes). Binding is mediated by a receptor binding domain on the S1 subunit of the virus’ surface spike(S) proteins.[74] [75] Membrane fusion and cell entry is facilitated by the S2 unit through the actions of2 heptad repeat domains (HR1 and HR2) and a fusion protein.[76] [77] The virus can also bind to DPP4receptors in several species (e.g., camels, rabbits, sheep, goats, nonhuman primates).

DPP4 is expressed on the epithelial and endothelial cells of most human organs (e.g., kidney, liver,intestines). This may explain the multisystem clinical spectrum of the infection which includes severe (andsometimes fatal) pneumonia, acute respiratory distress syndrome, and multiorgan failure.[78][Fig-2]

ClassificationVirus taxonomyMERS-CoV is a member of the Coronoviridae family (order: Nidovirales; subfamily: Coronavirinae; genus Betacoronavirus ) and is part of the lineage C group.[1] [2] It is phylogenetically distinct from all previouslyknown betacoronavirus species, which include human coronaviruses HKU1 and OC43, severe acuterespiratory syndrome (SARS) coronavirus, and bat coronaviruses HKU4, HKU5, and HKU9.[3]




Middle East respiratory syndrome (MERS) Prevention

Primary preventionThere is currently no vaccine available for the prevention of MERS in humans or camels, although thereare three vaccines in development (one to prevent transmission from camels to people, and two for usein humans during outbreaks and longer-term protection of people at high risk).[83] [84] Therefore, primaryprevention is focused on preventing transmission from infected people and dromedary camels.

General prevention measures include:

• Wash hands with soap and water (or alcohol-based hand sanitizer)• Use appropriate respiratory hygiene measures (e.g., cover mouth and nose when coughing or

sneezing)• Avoid touching nose, eyes, or mouth if hands have not been washed• Clean and disinfect surfaces and objects• Avoid close personal contact with people who are unwell.

Prevention of human-to-human transmission:[85] [86]

• Human-to-human transmission occurs most commonly in healthcare settings, and community spreadis rare

• Infection prevention and control measures should be instituted in all suspected or confirmed casesof MERS. Standard precautions and droplet precautions are recommended, as well as airborneprecautions when performing aerosol-generating procedures

• Patients with probable or confirmed infection should be placed in an adequately ventilated single room,clearly segregated from other patient care areas if possible. The number of healthcare workers andvisitors should be kept to a minimum

• In addition to standard precautions, all healthcare workers and visitors when in close contact (i.e.,approximately 3 feet) with a probable or confirmed case, should always use:

• A medical mask• Eye protection• A clean, nonsterile, long-sleeved gown• Gloves

• Hand hygiene should always be performed before and after contact with the patient and theirsurroundings, and immediately after the removal of personal protective equipment

• Movement of the patient outside of the barrier nursing room or area should be avoided unlessmedically necessary.

These precautions should be implemented for the duration of the symptomatic illness and continued for24 hours after the resolution of symptoms. Detailed infection prevention and control recommendations areavailable from the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO):

[Centers for Disease Control and Prevention (CDC): interim infection prevention and controlrecommendations for hospitalized patients with MERS-CoV]

[World Health Organization (WHO): infection prevention and control during health care for probable orconfirmed cases of MERS-CoV infection]

Prevention of camel-to-human transmission:[60] [87]

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http://apps.who.int/iris/bitstream/10665/174652/1/WHO_MERS_IPC_15.1_eng.pdf?ua=1



Middle East respiratory syndrome (MERS) PreventionPR

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• In countries where Middle East respiratory syndrome coronavirus (MERS-CoV) infection is prevalentin dromedary camels (i.e., the Arabian Peninsula and its surrounding countries), the followinginterventions should be considered to prevent camel-to-human transmission:

• Individuals who are at risk of developing severe infection (i.e., age ≥50 years, diabetes mellitus,heart disease, chronic renal failure, immunocompromised) should avoid direct contact withcamels (including nasal and eye discharge, urine, and feces) and camel products (e.g., milk,meat)

• Frequent hand washing and use of personal protective equipment while handling dromedarycamels, including farmers, veterinarians, market workers, and slaughterhouse workers

• Educational campaigns that target camel owners and the general public to inform them of therisks of consuming unpasteurized camel products (e.g., milk) and undercooked meat

• Camels with detectable MERS-CoV RNA should be quarantined and tested at regular intervals• Strict regulation of camel movement, including a requirement for MERS-CoV infection clearance

prior to importation and transport of camels between farms or to slaughterhouses.

ScreeningContact screening

Contact screening identified secondary infection in only 4% of 280 close family contacts and 2% of 5065healthcare facility contacts.[115] [116]

People who may have been exposed to the virus are advised to monitor their health for 14 days from thelast day of possible contact and seek medical attention if they develop symptoms, especially fever, cough, ordyspnea. Isolation or quarantine is not currently warranted.

With an effective reproductive number of less than one, the epidemic potential of the infection is consideredlow at present unless the virus mutates. Although there has been considerable concern over the potentialglobal spread of infection during the annual Hajj pilgrimage to Mecca, where millions of pilgrims from manycountries travel to Saudi Arabia, surveillance studies have not identified infection in pilgrims while in SaudiArabia or after returning home.[117] [118] [119] [120] [121] [122]

Asymptomatic patients who test positivePatients may be asymptomatic but test positive for infection on real-time reverse transcription polymerasechain reaction (RT-PCR) as part of active case monitoring or contact investigations. These patients may goon to develop symptoms during the course of the infection. The potential for transmission from these patientsis unknown, and until more is known, patients should be isolated (hospital or home), followed up daily to seewhether symptoms have developed, and tested at least weekly. The choice of isolation location depends onnumerous factors including hospital bed capacity, the hospital's ability to monitor patients at home, conditionsof the household and its occupants, and patient risk factors for developing severe infection. Isolation shouldcontinue until 2 consecutive upper respiratory tract specimens taken at least 24 hours apart test negativeon RT-PCR. Further specific guidance for managing the patient in each location is available from the WorldHealth Organization (WHO).[123]

SurveillanceThe aims of surveillance are to detect early, sustained human-to-human transmission and determine thegeographic risk area for infection. The WHO has produced detailed guidance on surveillance for humaninfection with Middle East respiratory syndrome coronavirus (MERS-CoV) infection:




Middle East respiratory syndrome (MERS) Prevention[World Health Organization (WHO): surveillance for human infection with Middle East respiratory syndromecoronavirus (MERS-CoV)]

Secondary preventionMERS is a notifiable disease and all suspected and confirmed cases should be reported to the appropriateauthority.

Transmission of the virus can be readily interrupted with the effective implementation of infection controlprecautions. The essential elements for effective secondary prevention include:[89] [85]

• Effective environmental cleaning and adequate spatial separation of patients with suspected orconfirmed infection from other patients

• Appropriate clinical triage protocols to identify patients presenting with acute respiratory illness whohave history of travel within the past 14 days to the Middle East

• Visitors and healthcare personnel caring for patients with suspected infection should performappropriate hand hygiene and use personal protective equipment to ensure contact and dropletprecautions (e.g., gloves, gowns, face masks)

• Airborne precautions should also be applied during any aerosol-generating procedures such asendotracheal intubation. Such procedures should only be performed in negative-pressure rooms withadequate ventilation

• Infection control precautions should be continued up to 24 hours after resolution of all clinicalsymptoms and at least one negative real-time reverse transcription polymerase chain reaction (RT-PCR)

• All healthcare contacts and close contacts of patients should be identified and screened for symptomsof infection. Only those who are symptomatic should be tested. Asymptomatic contacts should befollowed up daily for 14 days and tested if they develop any symptoms suggestive of infection.

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Middle East respiratory syndrome (MERS) DiagnosisD

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Case historyCase history #1A 50-year-old man presents with a 4-day history of fever, progressive dyspnea, and dry cough, and a 2-day history of nausea and diarrhea. His history is significant for smoking and type 2 diabetes mellitus.He reports arriving in the US from the Arabian Peninsula, where he lives, 10 days ago for the purposeof a vacation. He reports recent contact with his brother, a camel herder, who is currently in the hospitalbeing investigated for an acute viral respiratory infection. Examination reveals a temperature of 100.8°F,a respiratory rate of 22 breaths per minute, and oxygen saturation of 88%. Chest examination is normal.Laboratory workup reveals leukopenia, lymphopenia, thrombocytopenia, elevated ALT, and elevatedcreatinine.

Other presentationsThe majority of patients present with fever and respiratory symptoms (e.g., cough, dyspnea); however,some patients may present with gastrointestinal symptoms only (e.g., nausea, vomiting, diarrhea,abdominal pain). Other symptoms include myalgia, arthralgia, headache, chills/rigors, sore throat, andrhinorrhea.[4] [5] [6] [7] [8] [9] Fever may be absent in older patients, immunocompromised patients,pregnant women, and patients with end-stage renal disease, diabetes mellitus, or hemochromatosis.[5]Some patients, particularly young, healthy patients, may be asymptomatic or present with mild respiratorysymptoms and a normal chest x-ray.[10] However, others, particularly older patients or those withcomorbidities, may present with severe, rapidly progressive pneumonia, acute respiratory distresssyndrome, septic shock, or multiorgan failure resulting in death. A patient who presented with acute renalfailure caused a superspreader event in Riyadh (Saudi Arabia) in 2017, highlighting the difficulties indiagnosing pneumonia in patients with renal and cardiac failure.[11] Infection in children is rare.[12] [13]

Step-by-step diagnostic approachAlthough MERS has not yet reached pandemic potential, it is a potentially severe infection with a high casefatality rate. Therefore, quick diagnosis is essential to prevent transmission and to provide supportive carein a timely manner. Physicians should have a high index of suspicion for all patients who present with feverand/or respiratory symptoms in the correct epidemiologic context (i.e., travel from the Middle East), andthese patients should be promptly evaluated. There are no pathognomonic features; therefore, molecularand serologic testing is required to confirm the diagnosis. Coinfection with other respiratory viruses has beenreported.

MERS is a notifiable disease and all suspected and confirmed cases should be reported to the appropriateauthority.

Infection prevention and control measuresIsolation procedures should be initiated in all suspected or confirmed cases of MERS. An increased levelof infection control precautions is recommended. Specifically, the World Health Organization (WHO)recommends standard, droplet, and contact precautions, as well as airborne precautions when performingaerosol-generating procedures.[85]




Middle East respiratory syndrome (MERS) Diagnosis

Detailed infection prevention and control recommendations are available from the Centers for DiseaseControl and Prevention (CDC) and WHO:

• [Centers for Disease Control and Prevention (CDC): interim infection prevention and controlrecommendations for hospitalized patients with MERS-CoV]

• [World Health Organization (WHO): infection prevention and control during health care for probableor confirmed cases of MERS-CoV infection]

Diagnostic laboratory work on clinical specimens from patients who are suspected or confirmed to beinfected should be conducted under Biosafety Level (BSL-2) practices and procedures.

HistoryA detailed history helps to clarify the level of risk for MERS and assess the possibility of other causes.Obtaining an epidemiologic history is crucial for timely diagnosis and preventing potential outbreaks.[19][21] All confirmed cases have either traveled to, resided in, or been in contact with someone who hastraveled to the Middle East in the 14 days prior to the onset of symptoms.[17] [19] [79] [80] This includesthe Arabian Peninsula (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, United Arab Emirates, Yemen) andits surrounding countries (Iraq; Iran; Israel, the West Bank, and Gaza; Jordan; Lebanon; Syria). Failureto recognize this risk resulted in a large outbreak in the Republic of Korea (South Korea) in 2015.[19] [20][21] Contact with infected dromedary camels is also a risk factor.[64]

Ninety-eight percent of cases have been reported in adults (defined as age >14 years).[8] Althoughinfection has been reported in different age groups within the adult population, the median age of patientsranges from 50 to 67 years of age.[4] [9] [26] Infection in children is rare, although the reason for this isunknown.[12] [13]

Comorbid conditions, specifically diabetes mellitus, chronic renal impairment, heart disease, and obesity,are all risk factors for infection, as is smoking.[64] Approximately 75% of patients with MERS have at leastone comorbid illness.[4]

The WHO has developed a questionnaire designed to gather initial information about the potentialexposures of a suspected or confirmed case in the 14 days before symptom onset:

[World Health Organization (WHO): MERS-CoV - initial interview questionnaire of cases]

Clinical presentationMERS may present in a similar way to the common cold. The majority of patients present with fever andrespiratory symptoms (e.g., cough, dyspnea).

• Fever (temperature >100.4°F): common symptom reported in 40% to 98% of cases.[7] [8] [9] Fevermay be absent in older patients, immunocompromised patients, pregnant women, and patients withend-stage renal disease, diabetes mellitus, or hemochromatosis;[5] therefore, absence of fevershould not preclude workup for MERS.[88]

• Cough: common symptom reported in 54% to 86% of cases. It is usually dry; however, has beenreported to be productive in 23% to 36% of patients.[8] [9] [27]

• Dyspnea: common symptom reported in 60% to 72% of cases.[8] [9] [27]• Hemoptysis: less common symptom reported in 7% to 17% of cases.[8] [9] [27]

Patients may also present with gastrointestinal symptoms:

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• Diarrhea: reported in 7% to 26% of cases[5] [8] [9]• Abdominal pain: reported in 17% to 24% of cases[8] [27]• Nausea/vomiting: reported in 7% to 21% of cases.[5] [8] [9]

Patients may present with gastrointestinal symptoms only, going on to develop respiratory symptomsor pneumonia later in the course of infection. Other symptoms include myalgia, arthralgia, headache,chills/rigors, sore throat, and rhinorrhea.[4] [5] [6] [7] [8] [9] Some patients, particularly young, healthypatients, may be asymptomatic or present with mild respiratory symptoms and a normal chest x-ray.[10]However, others, particularly older patients or those with comorbidities, may present with severe, rapidlyprogressive pneumonia, acute respiratory distress syndrome, septic shock, or multiorgan failure resultingin death.

Pneumonia is a common finding, but not always present. Rapid progression to pneumonia can occur inless than a week. Crackles/rales and bronchial breath sounds may be noted on auscultation. Chest pain,dyspnea, tachypnea, tachycardia, and cyanosis may be present.

Case definitionsCase definitions have been published by the CDC, WHO, and the Ministry of Health (Saudi Arabia).[89][90] [91] Since MERS is considered an emerging disease, definitions are constantly evolving and not allclinical presentations will fit the case definitions. Physicians should be vigilant for identifying suspectedcases regardless of whether they fit the case definitions or not. For example, the absence of feverhas been reported in cases of confirmed infection, despite most case definitions including fever as aprerequisite for diagnosis.

Current case definitions:

• [Centers for Disease Control and Prevention (CDC): interim patient under investigation (PUI)guidance and case definitions]

• [World Health Organization (WHO): case definition for reporting to WHO]• [Ministry of Health (Saudi Arabia): case definition]

Initial laboratory investigationsLaboratory testing is recommended in any patient who presents with symptoms such as fever, respiratorysymptoms, gastrointestinal symptoms, and/or myalgia in the correct epidemiologic context.

CBC commonly reveals leukopenia, lymphopenia, and thrombocytopenia.[8] [26] [81] Patients may haveleukocytosis, particularly in the setting of a secondary bacterial infection. Specific diagnostic testing forMERS should be pursued even in the absence of a typical CBC result.

A comprehensive metabolic panel should also be ordered, and may show elevated creatinine, LFTs, andlactate dehydrogenase.[8] [26] [81]

Blood cultures should be collected to test for potential bacterial pathogens that can also cause pneumoniaor sepsis.[92] They should be collected before empiric antimicrobial therapy is started, if possible.

The CDC and WHO have produced detailed guidance on laboratory testing:

• [Centers for Disease Control and Prevention (CDC): interim guidelines for collecting, handling, andtesting clinical specimens from patients under investigation for MERS-CoV]



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


http://www.who.int/csr/disease/coronavirus_infections/case_definition/en/

https://www.moh.gov.sa/CCC/StaffRegulations/Corona/Documents/MERS-CoV%20Guidelines%20for%20Healthcare%20Professionals%20-%20April%202018%20-%20v5.pdf

http://www.cdc.gov/coronavirus/mers/guidelines-clinical-specimens.html




• [World Health Organization (WHO): laboratory testing for Middle East respiratory syndromecoronavirus (MERS-CoV)]

Molecular testingAll patients with suspected MERS should undergo molecular testing. Confirmation of infection is basedon the detection of unique sequences of viral RNA by real-time reverse transcription polymerase chainreaction (RT-PCR), with confirmation by nucleic acid sequencing if necessary.

Lower respiratory tract specimens (e.g., sputum, tracheal aspirates, bronchoalveolar lavage fluid) are thepreferred specimen for RT-PCR as sputum and tracheal aspirates contain the highest viral loads, andhence have the highest yield.[5] [93] However, bronchoscopy may generate aerosols and is generallynot recommended. Upper respiratory tract specimens (e.g., nasopharyngeal and oropharyngeal swabs,nasopharyngeal aspirate/wash) and serum collection for virus detection are recommended, especially iflower respiratory specimens are not available and it is 7 days or less since symptom onset. Both upperand lower respiratory tract specimens should be collected whenever possible.[89] [94] [95] Urine and stoolspecimens may also be used; however, these specimens contain lower levels of the virus compared withrespiratory tract specimens. Healthcare workers should wear appropriate personal protective equipment(e.g., mask, eye protection, gloves, gown) when collecting specimens.[94]

There are 3 RT-PCR assays currently recommended for the diagnosis of Middle East respiratorysyndrome coronavirus (MERS-CoV) infection:[94]

• MERS-CoV RT-PCR (upE): highly sensitive screening assay targeting regions upstream of the Eprotein gene (upE)

• MERS-CoV RT-PCR (ORF 1b): confirmatory assay targeting the open reading frame 1b (ORF 1b).It is less sensitive than the upE assay, but is more specific as it does not exhibit cross-reactivity withthe 4 main coronaviruses known to infect humans (i.e., OC43, NL63, 229E, SARS)

• MERS-CoV RT-PCR (ORF 1a): confirmatory assay targeting the open reading frame 1a (ORF 1a).It is highly specific and more sensitive than the ORF 1b assay, but has similar sensitivity to the upEassay.

Assays targeting sequencing amplicons on the viral genome are also available and can aid confirmationof the diagnosis. An assay targeting the RdRp gene (RdRpSeq) broadly detects betacoronavirus cladeC sequences; however, it is not specific and will detect other coronavirus strains including humancoronaviruses HKU1 and OC43.[96] Another assay targets N gene sequencing (NSeq). This region waschosen as it comprised a 2 amino acid deletion in the corresponding sequence published from a patienttreated in the UK. It is highly sensitive and specific for detection of human coronavirus Erasmus MedicalCenter/2012 (hCoV-EMC), the strain isolated from the first person infected with MERS.[96] Both of theseassays are sensitive enough to detect the virus at very low concentrations, but if used should be coupledwith a subsequent confirmatory assay.

The WHO recommends a screening assay to be performed first and, if positive, a confirmatory assayshould be performed. If the confirmatory assay is positive, infection is confirmed. If the confirmatory assayis negative, consider repeating the tests (if epidemiologic evidence is suggestive of infection) or performsequencing assays. If sequencing indicates the presence of MERS-CoV, infection is confirmed.[94]

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Algorithm for testing cases under investigation by reverse transcription polymerase chain reaction (RT-PCR)Produced by the BMJ Evidence Centre (adapted from WHO laboratory testing for Middle East

respiratory syndrome coronavirus -interim guidance (revised) WHO/MERS/LAB/15.1/Rev1/2018)

The WHO defines a confirmed case as a person with laboratory confirmation of infection. Presence ofnucleic acid can be confirmed by either a positive RT-PCR result on at least 2 specific genomic targets ora single positive target with sequencing of a second target.[90]

The CDC requires a positive PCR on at least 2 specific genomic targets or a single positive target withsequencing on a second for confirmation of the diagnosis.[91] The CDC has developed RT-PCR assaystargeting the viral nucleocapside (N) protein gene which can be used to complement the upE and ORF 1aassays for screening and confirmation. These assays are available in the US under an Emergency UseAuthorisation.

False-negative results can occur due to poor specimen quality, incorrect handling of the specimen, orthe time of collection; therefore, in patients who test negative where there is a high index of suspicion forinfection, additional specimens should be collected (preferably lower respiratory tract specimens) andtested.

Serologic testingSerologic testing is generally not used for diagnosis, but for epidemiologic surveillance or investigationalpurposes (e.g., retrospective diagnosis). It may be used to confirm the diagnosis; however, a singlespecimen would only identify a probable case. Paired sampling taken at least 14 to 21 days apart isrequired to confirm the diagnosis.





Several serologic tests have been developed for detecting MERS-CoV antibodies including an indirectfluorescent antibody (IFA) test, an enzyme-linked immunosorbent assay (ELISA), and a serumneutralization test.

The WHO defines a confirmed case to be a patient with evidence of seroconversion in at least onescreening assay (e.g., IFA, ELISA) and confirmation by a neutralization assay in samples taken at least14 apart. They define a probable case as a symptomatic patient without a positive RT-PCR test who has apositive result for at least one screening assay (e.g., IFA, ELISA) plus a positive result for a neutralizationassay in a single specimen.[94]

The CDC has developed a two-stage approach to serologic testing which uses an ELISA test forscreening, followed by a microneutralization test to confirm diagnosis.[95]

False-positive results can occur due to cross-reactivity with other betacoronaviruses.

ImagingA chest x-ray should be ordered in all patients with suspected pneumonia. Diffuse bilateral infiltrateshave been reported in 22% to 67% of cases. Lobar infiltrates or the absence of infiltrates have also beenreported, particularly in healthy, young patients.[5] [8]

A CT scan of the chest may be helpful in patients with suspected pneumonia who have a normal chest x-ray. CT may reveal bilateral subpleural and basal airspace opacities, with more extensive ground-glassopacities than consolidation.[97] Recognition of these patterns can aid early diagnosis of MERS; however,routine use of this test is not recommended.

Useful links• [Centers for Disease Control and Prevention (CDC): Middle East respiratory syndrome (MERS)]• [World Health Organization (WHO): Middle East respiratory syndrome coronavirus (MERS-CoV)]• [Ministry of Health (Saudi Arabia): coronavirus (MERS-CoV)]

Risk factorsStrongresidence in, or travel to, the Middle East (or country where there is an activeoutbreak) in previous 14 days• All confirmed cases have either resided in, or traveled to, the Middle East in the 14 days prior to the

onset of symptoms.[17] [19] [79] [80] This includes the Arabian Peninsula (Bahrain, Kuwait, Oman,Qatar, Saudi Arabia, United Arab Emirates, Yemen) and its surrounding countries (Iraq; Iran; Israel, theWest Bank, and Gaza; Jordan; Lebanon; Syria).

close contact with infected individuals• Majority of cases are a result of human-to-human transmission (rather than camel-to-human

transmission) with peaks of confirmed cases occurring during nosocomial outbreaks.[6] [7] [28]• Transmission has been well documented in family clusters.[18] [29] [30] However, it has been reported

more commonly in nosocomial outbreaks (e.g., hemodialysis units, intensive care units, medicalwards).[6] [7] [30] [31] [32] [33]

DIAG

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http://www.moh.gov.sa/en/CCC/Pages/default.aspx



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NO

SIS

• Transmission is via respiratory droplets (e.g., coughing, sneezing) from an infected patient, or closecontact with an infected patient. However, airborne or fomite transmission cannot be ruled out.[65] Theincubation period is 2 to 14 days and transmission is thought to occur during either the symptomatic orincubation stages.[8] [66]

• All patients diagnosed outside of the Middle East have been in contact with someone who has traveledfrom the Middle East in the preceding 14 days.[17] [19] [79] [80]

exposure to infected dromedary camels• Dromedary camels are thought to be the primary animal host.[39]• Exact mode of transmission is unknown, but it is thought to occur from direct or indirect contact with

dromedary camels (e.g., camel milking, contact with camel nasal secretions, urine, or feces) or camelproducts (e.g., unpasteurized camel milk, raw or undercooked camel meat).

• Strongest evidence for camel-to-human transmission comes from a study in Saudi Arabia wherethe virus was isolated from a patient and one of his camels and the genome was found to be almostidentical.[61] [62]

• A case-control study identified contact with camels to be a risk factor.[64]

age ≥50 years• Although infection has been reported in different age groups within the adult population, the median

age of patients ranges from 50 to 67 years of age.[4] [9] [26]• Age ≥50 years is associated with more severe presentation, worse outcomes, and a higher risk of

mortality.[5] [27] In one cohort study, mortality increased with increasing age to reach 75% in patients>60 years of age.[8]

diabetes mellitus• Reported in 65% to 87% of confirmed cases and has been associated with severe infection.[5] [8] [9]

[26]• Most common comorbid condition in one cohort of 12 critically ill patients admitted to the intensive care

unit.[81]• Identified as a risk factor in a case-control study.[64]

chronic renal impairment• Reported in 33% of confirmed cases (compared with 7% of patients who were initially suspected of

being infected but who later tested negative).[9]• Patients with end-stage renal disease were reported to develop severe infection and had worse clinical

outcomes.[81] In one case series, a mortality rate of 100% was reported in patients with chronic renalimpairment, including 8 patients who were undergoing hemodialysis.[5]

• May be related to the immune dysregulation that occurs in patients with end-stage renal disease onhemodialysis.[82]

heart disease• Identified as a risk factor in a case-control study.[64]

obesity• Patients with confirmed infection had a median BMI of 32 compared with 27.8 in controls in one case-

control study.[9]• Reported to be associated with severe infection and worse clinical outcomes in several case series.[8]

[81]





tobacco smoking• Identified as a risk factor in a case-control study.[64]

History & examination factorsKey diagnostic factorsresidence in, or travel to, the Middle East (or country where there is an activeoutbreak) in previous 14 days (common)• All confirmed cases have either resided in, or traveled to, the Middle East in the 14 days prior to the

onset of symptoms.[98] [99] [100] [101] This includes the Arabian Peninsula (Bahrain, Kuwait, Oman,Qatar, Saudi Arabia, United Arab Emirates, Yemen) and its surrounding countries (Iraq; Iran; Israel, theWest Bank, and Gaza; Jordan; Lebanon; Syria).

age >14 years (common)• Ninety-eight percent of cases have been reported in adults (defined as age >14 years).[102]• Infection in children is rare, although the reason for this is unknown.[103] [104]

fever (common)• Reported in 40% to 98% of cases.[105] [102] [106]• Fever may be absent in older patients, immunocompromised patients, pregnant women, and patients

with end-stage renal disease, diabetes mellitus, or hemochromatosis;[107] therefore, absence of fevershould not preclude workup for MERS.[108]

cough (common)• Reported in 54% to 86% of cases. It is usually dry; however, has been reported to be productive in

23% to 36% of patients.[102] [106] [109]

dyspnea (common)• Reported in 60% to 72% of cases.[102] [106] [109]

Other diagnostic factorshemoptysis (common)• Reported in 7% to 17% of cases.[102] [106] [109]

diarrhea (common)• Reported in 7% to 26% of cases.[107] [102] [106]

abdominal pain (common)• Reported in 17% to 24% of cases.[102] [109]

nausea/vomiting (common)• Reported in 7% to 21% of cases.[107] [102] [106]

chills/rigors (common)• Usually associated with fever.

DIAG

NO

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NO

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myalgia (common)• Nonspecific symptom reported in some cases.[110] [107] [111] [105] [102] [106]

arthralgia (common)• Nonspecific symptom reported in some cases.[110] [107] [111] [105] [102] [106]

malaise (common)• Nonspecific symptom reported in some cases.[110] [107] [111] [105] [102] [106]

headache (common)• Nonspecific symptom reported in some cases.[110] [107] [111] [105] [102] [106]

sore throat (common)• Nonspecific symptom reported in some cases.[110] [107] [111] [105] [102] [106]

rhinorrhea (common)• Nonspecific symptom reported in some cases.[110] [107] [111] [105] [102] [106]

tachypnea (common)• Present in some cases, including patients with acute respiratory distress.

tachycardia (common)• Present in some cases, including patients with acute respiratory distress.

cyanosis (common)• Present in some cases, including patients with acute respiratory distress.

chest pain (common)• May indicate pneumonia.

crackles/rales on auscultation (common)• May indicate pneumonia.• Bronchial breath sounds may also be heard.





Diagnostic tests1st test to order

Test ResultCBC

• Recommended in all patients with suspected MERS. Commonlyreveals leukopenia, lymphopenia, and thrombocytopenia.[8] [26][81] Patients may have leukocytosis, particularly in the setting of asecondary bacterial infection.

• Other diagnostic testing for MERS should be pursued even in theabsence of a typical CBC result.

leukopenia; lymphopenia;thrombocytopenia

comprehensive metabolic panel• Recommended in all patients with suspected MERS. May reveal

elevated creatinine, AST, ALT, and lactate dehydrogenase.[8] [26] [81]

elevated creatinine;elevated LFTs; elevatedlactate dehydrogenase

pulse oximetry• Indicated in patients with respiratory distress and cyanosis.

low oxygen saturation(SpO2 <90%)

blood cultures• Blood cultures should be collected to test for potential bacterial

pathogens that can also cause pneumonia or sepsis.[92]Should becollected before empiric antimicrobial therapy is started, if possible.

negative

real-time reverse transcription polymerase chain reaction (RT-PCR)

• Confirms Middle East respiratory syndrome coronavirus (MERS-CoV)infection.

• Lower respiratory tract specimens (e.g., sputum, tracheal aspirates,bronchoalveolar lavage fluid) are the preferred specimen for RT-PCRas sputum and tracheal aspirates contain the highest viral loads,and hence have the highest yield.[5] [93] However, bronchoscopymay generate aerosols and is generally not recommended. Upperrespiratory tract specimens (e.g., nasopharyngeal and oropharyngealswabs, nasopharyngeal aspirate/wash) and serum collection forvirus detection are recommended, especially if lower respiratoryspecimens are not available and it is 7 days or less since symptomonset.[89] [94] [95] Urine and stool specimens may also be used;however, these specimens contain lower levels of the virus comparedwith respiratory tract specimens.

• Healthcare workers should wear appropriate personal protectiveequipment (e.g., mask, eye protection, gloves, gown) when collectingspecimens.[94]

• MERS-CoV RT-PCR (upE): highly sensitive screening assay targetingregions upstream of the E protein gene (upE).[112]

• MERS-CoV RT-PCR (ORF 1b): confirmatory assay targeting openreading frame 1b (ORF 1b). Less sensitive than the upE assay, butmore specific.[112]

• MERS-CoV RT-PCR (ORF 1a): confirmatory assay targeting ORF1a. Highly specific and more sensitive than ORF 1b assay, but similarsensitivity to upE assay.[96]

• The World Health Organization (WHO) recommends a screeningassay first and, if positive, a confirmatory assay performed.If confirmatory assay is positive, infection is confirmed. If theconfirmatory assay is negative, consider repeating the tests if

positive for MERS-CoVRNA

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Test Resultepidemiologic evidence is suggestive, or perform sequencingassays.[94]

• Diagnosis requires a positive PCR on at least 2 specific genomictargets or a single positive target with sequencing on a secondtarget.[90] [91]

RT-PCR sequencing assay• An assay targeting the RdRp gene (RdRpSeq) broadly detects

betacoronavirus clade C sequences; however, it is not specific andwill detect other coronavirus strains including human coronavirusesHKU1 and OC43.[96]

• N gene sequencing (NSeq) can also be used. This region waschosen as it comprised a 2 amino acid deletion in the correspondingsequence published from a patient treated in the UK. Highly sensitiveand specific for detection of human coronavirus Erasmus MedicalCenter/2012 (hCoV-EMC), the strain isolated from the first personinfected with MERS.[96]

• Both assays are sensitive enough to detect virus at very lowconcentrations, but if used should be coupled with a subsequentconfirmatory assay.

detects MERS-CoVnucleotide sequences

chest x-ray• Recommended in all patients with suspected pneumonia. Diffuse

bilateral infiltrates have been reported in 22% to 67% of cases.Lobar infiltrates or the absence of infiltrates have also been reported,particularly in healthy, young patients.[5] [8]

diffuse bilateralinfiltrates; possibly lobarinfiltrates or absence ofinfiltrates





Other tests to consider

Test Resultserology

• Generally used for epidemiologic surveillance or investigationalpurposes (e.g., retrospective diagnosis). May also be used to confirmdiagnosis; however, a single specimen would only identify a probablecase. Paired sampling taken at least 14 to 21 days apart is requiredto confirm diagnosis.

• Includes indirect fluorescent antibody (IFA), enzyme-linkedimmunosorbent assay (ELISA), and serum neutralization.

• The WHO defines a confirmed case as a patient with evidence ofseroconversion in at least one screening assay (e.g., IFA, ELISA) andconfirmation by a neutralization assay in samples taken at least 14days apart. They define a probable case as a symptomatic patientwithout a positive RT-PCR test who has a positive result for at leastone screening assay (e.g., IFA, ELISA) plus a positive result for aneutralization assay in a single specimen.[94]

• The CDC has developed a two-stage approach to serologictesting which uses an ELISA test for screening, followed by amicroneutralization test to confirm diagnosis.[91]

• False-positive results can occur due to cross-reactivity with otherbetacoronaviruses.

positive for MERS-CoVantibodies

CT chest• May be helpful in patients with suspected pneumonia who have

a normal chest x-ray. May reveal bilateral subpleural and basalairspace opacities, with more extensive ground-glass opacitiesthan consolidation.[97]Recognition of these patterns can aidearly diagnosis of MERS; however, routine use of this test is notrecommended.

bilateral subpleural andbasal airspace opacities,with more extensiveground-glass opacitiesthan consolidation

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SIS

Differential diagnosis

Condition Differentiating signs /symptoms

Differentiating tests

Coronavirus disease 2019(COVID-19)

• Residence in/travel to acountry/area or territorywith local transmission,or close contact with aconfirmed or probable caseof COVID-19, in the 14 daysprior to symptom onset.

• Signs and symptoms aresimilar so it may be difficultto differentiate between theconditions clinically.

• The situation is evolvingrapidly; see our COVID-19topic for further information.

• Real-time reversetranscription polymerasechain reaction (RT-PCR):positive for SARS-CoV-2RNA.

• It is not possible todifferentiate COVID-19 fromother causes of pneumoniaon chest imaging.

Severe acute respiratorysyndrome (SARS)

• Lack of travel history to orfrom the Middle East (orcountry where there is anongoing outbreak) in thepreceding 14 days.

• No close contact witha symptomatic travelerfrom the Middle East or asuspected or confirmed caseof MERS in the preceding 14days.

• Patients have lowerincidence of comorbiditiescompared with MERS.

• Clinical features are similar;however, patients areless likely to present withhemoptysis (1% of patientswith SARS) or dyspnea (42%of patients with SARS).[8]

• Usually less aggressive thanMERS as reflected by thelower mortality rate.[113]

• RT-PCR: positive for SARS-CoV RNA.[96] [114]

Common cold • Lack of travel history to orfrom the Middle East (orcountry where there is anongoing outbreak) in thepreceding 14 days.


• Seasonal outbreak duringwinter.

• RT-PCR: negative for MERScoronavirus (MERS-CoV)RNA.







• Differentiating MERSfrom community-acquiredrespiratory tract infections isnot possible from signs andsymptoms.

Influenza infection • Lack of travel history to orfrom the Middle East (orcountry where there is anongoing outbreak) in thepreceding 14 days.




• RT-PCR: positive forinfluenza A or B viral RNA.

Avian influenza A (H5N1)virus infection



• Close contact with infectedbirds (e.g., farmer or visitorto a live market in endemicareas) or living in an areawhere avian influenza isendemic.


• RT-PCR: positive for H5N1viral RNA.

Avian influenza A (H7N9)virus infection


• No close contact witha symptomatic travelerfrom the Middle East or a

• RT-PCR: positive for H7-specific viral RNA.

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suspected or confirmed caseof MERS in the preceding 14days.

• Close contact with infectedbirds (e.g., farmer or visitorto a live market in endemicareas) or living in an areawhere avian influenza isendemic. Up until now,the epidemic has beengeographically focused inChina.


Respiratory syncytialvirus (RSV) infection



• Common cause of lowerrespiratory tract infection inchildren <1 year of age.



• RT-PCR: positive for RSVRNA.

Community-acquiredpneumonia



• Differentiating MERSfrom community-acquiredrespiratory tract infections is

• Blood or sputum culture,or multiplex RT-PCRtesting: positive forcausative organism (e.g., Streptococcus pneumoniae, Haemophilus influenzae , Mycoplasma pneumoniae , Chlamydophila pneumoniae ,Moraxella catarrhalis ).







not possible from signs andsymptoms.

Viral respiratoryinfections




• Unlikely to cause seriousillness in young, healthypatients.

• Nasopharyngeal virusculture or RT-PCR: positivefor causative organism(e.g., parainfluenza viruses,adenoviruses, rhinoviruses,enteroviruses, humanmetapneumovirus) or viralRNA.

Diagnostic criteriaCase definitionsCase definitions have been published by the Centers for Disease Control and Prevention (CDC), WorldHealth Organization (WHO), and Ministry of Health (Saudi Arabia).[89] [90] [91] Since MERS is consideredan emerging disease, definitions are constantly evolving and not all clinical presentations will fit the casedefinitions. Physicians should be vigilant for identifying suspected cases, regardless of whether they fit thecase definitions or not. For example, the absence of fever has been reported in cases of confirmed infection,despite some definitions including fever as a prerequisite for diagnosis.

CDC: interim patient under investigation (PUI) guidance and casedefinitions[91]Patient under investigation (PUI):

• A person with both clinical features and an epidemiologic risk• Severe illness:

• fever (may be absent in specific patient groups) and pneumonia or acute respiratory distresssyndrome (based on clinical or radiologic evidence) PLUS a history of travel from countriesin or near the Arabian Peninsula within 14 days before symptom onset, or close contact witha symptomatic traveler who developed fever and acute respiratory illness (not necessarilypneumonia) within 14 days after traveling from countries in or near the Arabian Peninsula, ora member of a cluster of patients with severe acute respiratory illness of unknown etiology inwhich MERS is being evaluated.

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• Milder illness:

• fever (may be absent in specific patient groups) and symptoms of respiratory illness (e.g.,cough, dyspnea) PLUS a history of being in a healthcare facility (as a patient, worker, or visitor)within 14 days before symptom onset in a country or territory near the Arabian Peninsula inwhich recent healthcare-associated cases of MERS have been identified

• fever (may be absent in specific patient groups) or symptoms of respiratory illness (e.g., cough,dyspnea) PLUS close contact (i.e., within approximately 6 feet or the room/care area of a casefor a prolonged period of time [such as caring for, living with, visiting, or sharing a healthcarewaiting area or room with a confirmed MERS case] without recommended personal protectiveequipment, or direct contact with infectious secretions of a confirmed MERS case while notwearing recommended personal protective equipment).

Probable case:

• PUI with absent or inconclusive laboratory results for infection who is a close contact of a laboratory-confirmed case.

Confirmed case:

• Person with laboratory confirmation of infection (i.e., a positive real-time reverse transcriptionpolymerase chain reaction [RT-PCR] on at least 2 specific genomic targets, or a single positive targetwith sequencing on a second).

Note: fever may be absent in the very young, elderly, immunocompromised, or patients receiving certainmedications.

[Centers for Disease Control and Prevention (CDC): interim patient under investigation (PUI) guidance andcase definitions]

WHO: case definition for reporting to WHO[90]Probable case:

• A febrile acute respiratory illness with clinical, radiologic, or histopathologic evidence of pulmonaryparenchymal disease (e.g., pneumonia or acute respiratory distress syndrome) PLUS a directepidemiologic link with a confirmed case PLUS testing is unavailable, negative on a single inadequatespecimen, or inconclusive

• A febrile acute respiratory illness with clinical, radiologic, or histopathologic evidence of pulmonaryparenchymal disease (e.g., pneumonia or acute respiratory distress syndrome) PLUS the personresides in, or traveled to, the Middle East or in countries where the virus is known to be circulating indromedary camels or where infections have recently occurred PLUS testing is inconclusive

• An acute febrile respiratory illness of any severity PLUS a direct epidemiologic link with a confirmedcase PLUS testing is inconclusive.

Confirmed case:

• Person with laboratory confirmation (i.e., detection of viral nucleic acid or serology) of infectionirrespective of clinical signs and symptoms. Presence of nucleic acid can be confirmed by eithera positive RT-PCR result on at least 2 specific genomic targets or a single positive target withsequencing of a second target. Cases confirmed by serology require demonstration of seroconversion







in 2 samples, ideally taken 14 days apart, by ELISA or immunofluorescence antibody assay and aneutralization assay.

[World Health Organization (WHO): case definition for reporting to WHO]

Ministry of Health (Saudi Arabia): case definition[89]Suspected case:

• I. Severe pneumonia (severity score ≥3 points on CURB 65) or acute respiratory distress syndrome(based on clinical or radiological evidence)

[VIDEO: CURB-65 pneumonia severity score ]• II. Unexplained deterioration of a chronic condition in patients with congestive heart failure or chronic

kidney disease who are on hemodialysis

• III. Acute febrile illness with or without respiratory symptoms PLUS an epidemiological link

• IV. Gastrointestinal symptoms and leukopenia or thrombocytopenia PLUS an epidemiological link.

Confirmed case:

• A suspected case with laboratory confirmation of infection.

An epidemiological link is defined as one of the following within 14 days before symptom onset:

• Exposure (contact within 1.5 meters) to a confirmed case of MERS-CoV infection

• Visit to a healthcare facility where an infected patient has recently (within 2 weeks) been identified ortreated

• Contact with dromedary camels or consumption of camel products.[Ministry of Health (Saudi Arabia): case definition] D

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http://bestpractice.bmj.com/procedural-videos/en-us/56fc5576-a2fc-4c90-b878-53901bea44df



Middle East respiratory syndrome (MERS) TreatmentTR

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Step-by-step treatment approachNo specific treatment exists for MERS; however, many drugs show promise and may prove to be valuabletherapies in the future. Therefore, treatment is supportive and should focus on relieving symptoms andpreventing or treating complications. Specific management depends on the clinical presentation, and patientfactors such as age and the presence or absence of comorbidities.

Infection prevention and control measuresIsolation procedures should be initiated in all suspected or confirmed cases of MERS. An increased levelof infection control precautions is recommended. Specifically, the World Health Organization (WHO)recommends standard, droplet, and contact precautions, as well as airborne precautions when performingaerosol-generating procedures.[85]

Patients with probable or confirmed infection should be placed in an adequately ventilated single room,clearly segregated from other patient care areas if possible. The number of healthcare workers andvisitors should be kept to a minimum. In addition to standard precautions, all healthcare workers andvisitors, when in close contact (i.e., approximately 3 feet) with a probable or confirmed case, shouldalways use:

• A medical mask• Eye protection• A clean, nonsterile, long-sleeved gown• Gloves.

Hand hygiene should always be performed before and after contact with the patient and theirsurroundings, and immediately after the removal of personal protective equipment. Movement of thepatient outside of the barrier nursing room or area should be avoided unless medically necessary.

These precautions should be used for the duration of the symptomatic illness and continued for at least24 hours after the resolution of symptoms.[85]Patients should be monitored for the clearance of infectionusing the recommended real-time reverse transcription polymerase chain reaction (RT-PCR) assaysuntil there are 2 negative results on specimens taken at least 24 hours apart.[89] [92]Infection controlmeasures can be discontinued in nonventilated patients (e.g., those in home isolation) when the patient isasymptomatic and a single RT-PCR is negative.[89]

Detailed infection prevention and control recommendations are available from the Centers for DiseaseControl and Prevention (CDC) and WHO:

• [Centers for Disease Control and Prevention (CDC): interim infection prevention and controlrecommendations for hospitalized patients with MERS-CoV]

• [World Health Organization (WHO): infection prevention and control during health care for probableor confirmed cases of MERS-CoV infection]

Specimen collectionThe following specimens should be collected in all patients for diagnostic testing:[92]

• Blood cultures: for potential bacterial pathogens that can also cause pneumonia or sepsis








Middle East respiratory syndrome (MERS) Treatment

• Lower respiratory tract specimens (e.g., sputum, tracheal aspirates, bronchoalveolar lavage): forbacterial and viral testing

• Upper respiratory tract specimens (e.g., nasopharyngeal and throat swabs): for molecular viraltesting

• Serum: for molecular and serologic testing.

Specimens should be collected according to the appropriate infection control measures. Blood culturesshould be collected before antimicrobial therapy is started, if possible. Lower respiratory tract specimensare preferable to upper respiratory tract specimens, but both should be collected if possible. Upperrespiratory tract specimens (e.g., nasopharyngeal swab) are sufficient in patients isolated at home.

Frequency of specimen collection depends on local circumstances. The WHO recommends thatrespiratory tract specimens for RT-PCR should be collected at least every 2 to 4 days in the initial 2weeks, and continue until there are 2 negative test results to confirm clearance of the virus.[92] TheMinistry of Health (Saudi Arabia) recommends repeat testing one week after diagnosis, and then every 3days.[89]

Management of patients with pneumonia or comorbiditiesPatients with pneumonia or respiratory distress should be promptly admitted to an appropriate healthcarefacility and infection prevention and control measures instituted.

Any patient with the following signs should be admitted to the hospital:

• Respiratory rate >30 breaths/minute• Hypoxemia (SpO2 <90% on room air)• Severe respiratory distress• Clinical and/or radiologic evidence of pneumonia.

These patients may rapidly progress to severe pneumonia or respiratory failure; therefore, it is importantto pay attention to these clinical signs.[81]

Presence of comorbidities (e.g., diabetes mellitus, heart disease, chronic renal failure, obesity), smoking,and age ≥50 years increases the risk of developing severe infection, and these patients should also beadmitted.

Supportive therapies should be started promptly:[92] [89]

• Oxygen: patients with signs of severe respiratory distress, shock, or hypoxemia should be startedon oxygen therapy immediately. Initiate at 5 L/minute and titrate so that SpO2 ≥90%

• Fluids: cautious fluid management is recommended in patients if necessary, provided that there isno evidence of shock (more aggressive resuscitation may be required in patients with shock)

• Antimicrobials: empiric antimicrobial therapy (including antibiotics and antivirals) should be startedin inpatients with suspected MERS pneumonia (within one hour if sepsis is suspected) to coverall likely community-acquired or hospital-acquired (if patient has been admitted for >48 hours)pathogens. Antimicrobial selection should be based on local epidemiology, susceptibility data, andguidelines until diagnosis is confirmed, and empiric therapy adjusted based on results

• Antipyretics/analgesics: recommended for the control of fever and pain.

Patients with impending or established respiratory failure should be admitted to the ICU. Intubation andmechanical ventilation are recommended if the patient is deteriorating and cannot maintain a SpO2≥90% with oxygen therapy. Noninvasive mechanical ventilation, mechanical ventilation, or extracorporeal

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membrane oxygenation (ECMO) have been used in patients with MERS.[81] [125] However, noninvasiveventilation should be avoided due to the high risk of generating aerosols, and because it lacks evidence ofefficacy compared to endotracheal intubation and mechanical ventilation.[89] A small observational studyfound that ECMO was associated with lower mortality in MERS patients with refractory hypoxemia.[126]

Corticosteroids are generally not recommended; however, stress doses may be given if needed (e.g.,patient with adrenal suppression). High doses should not be used for prolonged periods of time due to ahigh risk of adverse effects, the risk of developing opportunistic infections, and a lack of proven efficacy intreating MERS.[92] [127]

Patients should be monitored closely for signs of deterioration and the development of complicationsincluding respiratory failure, acute respiratory distress syndrome, acute renal failure, septic shock, andmultiorgan failure. Supportive therapy (e.g., hemodialysis, vasopressor therapy, fluid resuscitation,antimicrobials) should be initiated immediately if required.[5] [8] [26] [81] [125]

Data on pregnant women are limited. Pregnant women can be treated with the supportive therapiesdetailed above (except ibuprofen, which is not recommended in pregnant women especially in the thirdtrimester), taking into account the physiologic changes that occur with pregnancy.

Management of patients without pneumonia or comorbiditiesPatients who are young and healthy with no comorbidities are at a lower risk of developing complications,and may be considered for home isolation, if appropriate.[89] [86] [128]These patients generallyhave mild, nonspecific symptoms such as fever, headache, malaise, cough, sore throat, or possiblygastrointestinal symptoms. Chest x-ray is normal.[10]

The CDC recommend this is appropriate only once a healthcare professional, in consultation with theirlocal or state health department, deems that the residential setting is suitable and that the patient iscapable of adhering to recommended infection control precautions.[129]The WHO recommend thatconfirmed symptomatic cases should be isolated and monitored in a hospital setting whenever possible;however, home isolation may be considered in certain patients with mild symptoms and no underlyingconditions (e.g., heart disease, renal failure) or immunocompromising conditions if inpatient care isnot available or is unsafe. The decision requires careful clinical judgement and should be informed byassessing the safety of the patient's home environment.[128]

Infection control measures are still recommended for these patients and include using a single room,single bathroom (if possible), minimizing contact with other household members, and wearing a surgicalmask if contact is necessary.[89] [86]

Supportive therapies are recommended including antipyretic and analgesics (e.g., acetaminophen,ibuprofen) for the relief of pain and fever. Patients should keep hydrated, but should not take in too muchfluid as this can worsen oxygenation.[92]

Detailed guidelines for home isolation are available from the CDC and WHO:

• [Centers for Disease Control and Prevention (CDC): implementing home care and isolation orquarantine of people not requiring hospitalization for MERS-CoV]

• [World Health Organization (WHO): home care for patients with Middle East respiratory syndromecoronavirus (MERS-CoV) infection presenting with mild symptoms and management of contacts]



http://www.cdc.gov/coronavirus/mers/hcp/home-care.html


http://apps.who.int/iris/bitstream/handle/10665/272948/WHO-MERS-IPC-18.1-eng.pdf?ua=1




Experimental therapiesThere is no conclusive evidence at this time to recommend any virus-specific treatments for patients withsuspected or confirmed infection. However, a number of treatments (e.g., interferon beta, interferon alfa,lopinavir, ribavirin, mycophenolate, and cyclosporine) have been studied for the treatment of MERS basedon encouraging in vitro and animal studies.[130] [131] So far, none of these treatments have proven to beeffective. This is partly due to a lack of randomized controlled trials and the limited number of patients thatare included in retrospective studies.

Some countries, such as Republic of Korea (South Korea), have issued guidance that permits physiciansto cautiously use some of the studied therapies.[132]

These therapies are generally only used in unstable patients with extensive pneumonia. If investigationalagents are used, the WHO recommends that these drugs only be used under standard researchtreatment protocols and occur in the context of research trials.[92] Further studies are needed to evaluatethe safety and efficacy of these agents in people with MERS.

See Emerging Therapies for more detailed information about specific experimental drugs.

Useful links• [Centers for Disease Control and Prevention (CDC): Middle East respiratory syndrome (MERS)]• [World Health Organization (WHO): Middle East respiratory syndrome coronavirus (MERS-CoV)]• [Ministry of Health (Saudi Arabia): coronavirus (MERS-CoV)]

Treatment details overviewPlease note that formulations/routes and doses may differ between drug names and brands, drugformularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

Initial ( summary )suspected MERS

1st isolation procedures

plus supportive care + monitoring

plus empiric antibiotic therapy

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with pneumonia orcomorbidities

1st admit to hospital + isolation procedures


adjunct mechanical ventilation

adjunct consider experimental therapies

without pneumonia orcomorbidities

1st consider home isolation






Treatment optionsPlease note that formulations/routes and doses may differ between drug names and brands, drugformularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

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Initialsuspected MERS

1st isolation procedures

» Isolation procedures should be initiated in allsuspected cases of MERS.

» Patients with comorbidities (e.g., diabetesmellitus, heart disease, chronic renalimpairment), age ≥50 years, or with the followingsigns should be admitted to the hospital:respiratory rate >30 breaths/minute; hypoxemia(SpO2 <90% on room air); severe respiratorydistress; or clinical and/or radiologic evidence ofpneumonia.

» Patients should be placed in an adequatelyventilated single room, clearly segregated fromother patient care areas if possible. The numberof healthcare workers and visitors should be keptto a minimum.

» The World Health Organization (WHO)recommends standard, droplet, and contactprecautions, as well as airborne precautionswhen performing aerosol-generatingprocedures.[85]

» All healthcare workers and visitors, when inclose contact (i.e., approximately 3 feet) witha probable or confirmed case, should alwaysuse: a medical mask; eye protection; a clean,nonsterile, long-sleeved gown; and gloves.

» Hand hygiene should always be performedbefore and after contact with the patient andtheir surroundings, and immediately after theremoval of personal protective equipment.

» Movement of the patient outside of the barriernursing room or area should be avoided unlessmedically necessary.

» Patients who do not require hospitalizationfor medical reasons can be isolated athome. Infection control measures are stillrecommended and include using a single room,single bathroom (if possible), minimizing contactwith other household members, and wearing asurgical mask if contact is necessary.[86] [89][128]

» [Centers for Disease Control and Prevention(CDC): interim infection prevention and controlrecommendations for hospitalized patients withMERS-CoV]









Initial» [World Health Organization (WHO): infectionprevention and control during health care forprobable or confirmed cases of MERS-CoVinfection]

» [Centers for Disease Control and Prevention(CDC): implementing home care and isolation orquarantine of people not requiring hospitalizationfor MERS-CoV]

» [World Health Organization (WHO):home care for patients with Middle Eastrespiratory syndrome coronavirus (MERS-CoV)infection presenting with mild symptoms andmanagement of contacts]


Treatment recommended for ALL patients inselected patient group

Primary options

» acetaminophen: 325-1000 mg orally every4-6 hours when required, maximum 4000 mg/day

OR

» ibuprofen: 200-400 mg orally every 4-6hours when required, maximum 2400 mg/day

» Supportive therapies (e.g., oxygen, fluids,antipyretics/analgesics) should be startedpromptly depending on the clinical presentation.

» Patients with signs of severe respiratorydistress, shock, or hypoxemia should be startedon oxygen therapy immediately. Initiate at 5L/minute and titrate so that SpO2 ≥90%.[92]Patients with impending or establishedrespiratory failure should be admitted to theICU. Intubation and mechanical ventilation arerecommended if the patient is deteriorating andcannot maintain a SpO2 ≥90% with oxygentherapy.[81] [125]

» Cautious fluid management is recommendedin patients if necessary, provided that thereis no evidence of shock (more aggressiveresuscitation may be required in patients withshock).[92]

» Data on pregnant women are limited. Pregnantwomen can be treated with the supportivetherapies detailed above (except ibuprofen,which is not recommended in pregnant womenespecially in the third trimester), taking into

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Initialaccount the physiologic changes that occur withpregnancy.

» Specimens (e.g., blood cultures, serum,lower/upper respiratory tract specimens) shouldbe collected according to the appropriateinfection control measures. Blood culturesshould be collected before antimicrobial therapyis started, if possible. Lower respiratory tractspecimens are preferable to upper respiratorytract specimens, but both should be collected ifpossible.[92]Upper respiratory tract specimens(e.g., nasopharyngeal swab) are sufficient inpatients isolated at home.

» Patients should be monitored closely forsigns of deterioration and the developmentof complications including respiratory failure,acute respiratory distress syndrome, acuterenal failure, septic shock, and multiorganfailure. Supportive therapy (e.g., hemodialysis,vasopressor therapy, fluid resuscitation,antimicrobials) should be initiated immediately ifrequired.[5] [8] [26] [81] [125]

plus empiric antibiotic therapy


» Empiric antimicrobial therapy (includingantibiotics and antivirals) should be started ininpatients with suspected MERS pneumonia(within one hour if sepsis is suspected) tocover all likely community-acquired or hospital-acquired (if patient has been admitted for >48hours) pathogens.[92]

» Antimicrobial selection should be based onlocal epidemiology, susceptibility data, andguidelines until diagnosis is confirmed, andempiric therapy adjusted based on results.

» Treatment can be discontinued once adiagnosis of MERS is confirmed.





Acuteconfirmed MERS: post initialstabilization and isolation measures

with pneumonia orcomorbidities

1st admit to hospital + isolation procedures

» Patients with comorbidities (e.g., diabetesmellitus, heart disease, chronic renalimpairment), age ≥50 years, smoking history, orwith the following signs should be admitted tothe hospital: respiratory rate >30 breaths/minute;hypoxemia (SpO2 <90% on room air); severerespiratory distress; or clinical and/or radiologicevidence of pneumonia.

» Isolation procedures should be initiated in allconfirmed cases of MERS. Patients should beplaced in an adequately ventilated single room,clearly segregated from other patient care areas.The number of healthcare workers and visitorsshould be kept to a minimum.

» The WHO recommends standard, droplet,and contact precautions, as well as airborneprecautions when performing aerosol-generating procedures.[85] All healthcareworkers and visitors, when in close contact(i.e., approximately 3 feet) with a probable orconfirmed case, should always use: a medicalmask; eye protection; a clean, nonsterile, long-sleeved gown; and gloves.

» Hand hygiene should always be performedbefore and after contact with the patient andtheir surroundings, and immediately after theremoval of personal protective equipment.

» Movement of the patient outside of the barriernursing room or area should be avoided unlessmedically necessary.

» These precautions should be used forthe duration of the symptomatic illness andcontinued for at least 24 hours after theresolution of symptoms. Patients should bemonitored for the clearance of infection usingthe recommended real-time reverse transcriptionpolymerase chain reaction (RT-PCR) assaysuntil there are 2 negative results on specimenstaken at least 24 hours apart.[92] [89]

» [Centers for Disease Control and Prevention(CDC): interim infection prevention and controlrecommendations for hospitalized patients withMERS-CoV]

» [World Health Organization (WHO): infectionprevention and control during health care for

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Acuteprobable or confirmed cases of MERS-CoVinfection]



Primary options


OR

» ibuprofen: 200-400 mg orally every 4-6hours when required, maximum 2400 mg/day

» Supportive therapies (e.g., oxygen, fluids,antipyretics/analgesics) should be startedpromptly depending on the clinical presentation.

» Patients with signs of severe respiratorydistress, shock, or hypoxemia should be startedon oxygen therapy immediately. Initiate at 5 L/minute and titrate so that SpO2 ≥90%.[92]

» Cautious fluid management is recommendedin patients if necessary, provided that thereis no evidence of shock (more aggressiveresuscitation may be required in patients withshock).[92]

» Data on pregnant women are limited. Pregnantwomen can be treated with the supportivetherapies detailed above (except ibuprofen,which is not recommended in pregnant womenespecially in the third trimester), taking intoaccount the physiologic changes that occur withpregnancy.

» Specimens (e.g., blood cultures, serum,lower/upper respiratory tract specimens) shouldbe collected according to the appropriateinfection control measures. Blood culturesshould be collected before antimicrobial therapyis started, if possible. Lower respiratory tractspecimens are preferable to upper respiratorytract specimens, but both should be collected ifpossible.[92] Frequency of specimen collectiondepends on local circumstances. The WHOrecommends that respiratory tract specimensfor RT-PCR should be collected at least every2 to 4 days in the initial 2 weeks, and continueuntil there are 2 negative test results to confirmclearance of the virus.[92] The Ministry of Health(Saudi Arabia) recommends repeat testing oneweek after diagnosis, and then every 3 days.[89]







Acute» Patients should be monitored closely forsigns of deterioration and the developmentof complications including respiratory failure,acute respiratory distress syndrome, acuterenal failure, septic shock, and multiorganfailure. Supportive therapy (e.g., hemodialysis,vasopressor therapy, fluid resuscitation,antimicrobials) should be initiated immediately ifrequired.[5] [8] [26] [81] [125]

adjunct mechanical ventilation

Treatment recommended for SOME patients inselected patient group

» Patients with impending or establishedrespiratory failure should be admitted to the ICU.

» Intubation and mechanical ventilation arerecommended if the patient is deteriorating andcannot maintain a SpO2 ≥90% with oxygentherapy.

» Noninvasive mechanical ventilation,mechanical ventilation, or extracorporealmembrane oxygenation (ECMO) have beenused in patients with MERS.[81] [125] However,noninvasive ventilation should be avoided dueto the high risk of generating aerosols, andbecause it lacks evidence of efficacy comparedto endotracheal intubation and mechanicalventilation.[89] A small observational studyfound that ECMO was associated with lowermortality in MERS patients with refractoryhypoxemia.[126]

adjunct consider experimental therapies

Treatment recommended for SOME patients inselected patient group

» These therapies are generally only used inunstable patients with extensive pneumonia.

» There is no conclusive evidence at this timeto recommend any virus-specific treatments;however, a number of treatments (e.g.,interferon beta, interferon alfa, lopinavir, ribavirin,mycophenolate, and cyclosporine) have beenstudied for the treatment of MERS based onencouraging in vitro and animal studies.[130][131]

» The WHO recommends that these drugs onlybe used under standard research treatmentprotocols and occur in the context of researchtrials.[92]

without pneumonia orcomorbidities

1st consider home isolation

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Acute» Young, healthy patients with no comorbiditiesare at a lower risk of developing complications,and can be considered for home isolation ifthey do not require hospitalization for medicalreasons.[86] [89] [128]These patients generallyhave mild, nonspecific symptoms such as fever,headache, malaise, cough, sore throat, orpossibly gastrointestinal symptoms.[10]

» The CDC recommend this is appropriate onlyonce a healthcare professional, in consultationwith their local or state health department,deems that the residential setting is suitableand that the patient is capable of adhering torecommended infection control precautions.[129]

» The WHO recommend that confirmedsymptomatic cases should be isolated andmonitored in a hospital setting wheneverpossible; however, home isolation may beconsidered in certain patients with mildsymptoms and no underlying conditions(e.g., heart disease, renal failure) orimmunocompromising conditions, if inpatientcare is not available or is unsafe. The decisionrequires careful clinical judgement and should beinformed by assessing the safety of the patient'shome environment.[128]

» Infection control measures are stillrecommended and include using a single room,single bathroom (if possible), minimizing contactwith other household members, and wearing asurgical mask if contact is necessary.[86] [89]

» [Centers for Disease Control and Prevention(CDC): implementing home care and isolation orquarantine of people not requiring hospitalizationfor MERS-CoV]

» [World Health Organization (WHO):home care for patients with Middle Eastrespiratory syndrome coronavirus (MERS-CoV)infection presenting with mild symptoms andmanagement of contacts]



Primary options


OR














Acute» ibuprofen: 200-400 mg orally every 4-6hours when required, maximum 2400 mg/day

» Supportive therapies are recommendedincluding antipyretics/analgesics (e.g.,acetaminophen, ibuprofen) for the relief of painand fever. Patients should keep hydrated, butshould not take in too much fluid as this canworsen oxygenation.[92]

» Data on pregnant women are limited. Pregnantwomen can be treated with the supportivetherapies detailed above (except ibuprofen,which is not recommended in pregnant womenespecially in the third trimester), taking intoaccount the physiologic changes that occur withpregnancy.

» Patients should be monitored for the clearanceof infection using the recommended RT-PCRassays every 2 to 4 days until there are 2negative results.[92] [89] Infection controlmeasures can be discontinued in these patientswhen the patient is asymptomatic and a singleRT-PCR is negative.[89] Upper respiratory tractspecimens (e.g., nasopharyngeal swab) aresufficient in these patients.

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EmergingExperimental therapiesThere is no conclusive evidence at this time to recommend any virus-specific treatments for patients withsuspected or confirmed infection. If investigational agents are used, the World Health Organization (WHO)recommends that these drugs only be used under standard research treatment protocols and occur in thecontext of research trials.[92] Further studies are needed to evaluate the safety and efficacy of these agentsin people with MERS.

Interferon alfaMiddle East respiratory syndrome coronavirus (MERS-CoV) has been found to be 50 to 100 timesmore sensitive to pegylated interferon alfa compared with severe acute respiratory syndrome (SARS)coronavirus.[131] The combination of interferon alfa-1b plus ribavirin has shown activity against MERS-CoV in vitro.[133] Infected rhesus macaques treated with this combination had lower viral loads, and adecreased incidence of respiratory distress and bilateral infiltrates on chest x-ray compared with infectedcontrols.[134] However, the combination did not prove to be effective in a cohort of 5 confirmed humancases.[135] Pegylated interferon alfa-2a plus ribavirin was studied in a retrospective study in humans andcompared with standard supportive treatment. This combination demonstrated significantly improved survivalat 14 days; however, it did not reach statistical significance by 28 days.[26] Studies of this same combinationin patients with various underlying conditions, including renal transplant, produced variable results.[88] [136][137]

Interferon betaInterferon beta has been shown to have superior activity in vitro against MERS-CoV compared with interferonalfa-2b and alfa-2a.[130] The combination of interferon beta plus ribavirin was compared with pegylatedinterferon alfa-2a plus ribavirin in a retrospective study of 24 patients. The study found no significantdifference in 28-day survival between the 2 patient groups.[5]

LopinavirA protease inhibitor that has previously shown efficacy in treating SARS when used in combination withribavirin.[138] It has been tested against MERS-CoV in in vitro studies; however, it has demonstratedsuboptimal efficacy so far.[131] Superior clinical outcome and survival advantage have been reportedcompared with mycophenolate when tested in animal studies.[139] A case report has documented resolutionof viremia when used in combination with interferon and ribavirin.[140] A placebo-controlled trial of lopinavir/ritonavir with interferon-beta is in progress in Saudi Arabia.[141]

CyclosporineAn immunosuppressant with known antiviral activity. Has demonstrated activity against MERS-CoV invitro; however, the peak plasma levels needed for activity against the virus are not achievable with currentapproved doses.[142] Case reports of 2 patients, who were already receiving cyclosporine for other medicalreasons and subsequently died of MERS, have been published.[17] [137] Based on the limited evidenceavailable, use of cyclosporine is questionable.

MycophenolateAn immunosuppressant with known antiviral activity. A number of in vitro studies have demonstrated activityagainst MERS-CoV.[130] [131] [143] [144] It has not been used in animal studies. There is a case reportof a renal transplant patient, who was already on mycophenolate plus prednisone, surviving MERS. Thereis also a case report of a patient receiving mycophenolate plus cyclosporine and prednisone who did notsurvive.[137] [145]

Monoclonal antibodies




Middle East respiratory syndrome (MERS) TreatmentMonoclonal antibodies which target different epitopes in the receptor binding domain on the S1 subunit of theMERS-CoV spike (S) protein have been developed (e.g., Mersmab).[146] [147] [148] These antibodies havea higher affinity (i.e., 10 to 450 times higher) for the receptor binding domain compared with the functionalreceptor dipeptidyl peptidase-4 (DPP4; also called CD26) on the surface of host cells.[147] [149] [150] [151]

Synthetic peptidesA synthetic peptide (HR2P) has been developed to block the HR1 domain on the S2 subunit of the MERS-CoV virus, and has demonstrated a potent antiviral effect in vitro.[37] [76] [152] An intranasal formulation ofthis drug (HR2P-M2) has been developed. One study showed that it was effective in mice and was enhancedby using in combination with interferon beta.[153] Enfuvirtide, a HIV fusion inhibitor, is a HR2 peptide and istherefore another potential option for treatment.[154]

Convalescent plasmaSafety and efficacy of convalescent plasma for the treatment of MERS-CoV infection is being investigated;however, there are no data as yet and availability is extremely limited. The WHO has published a positionpaper on this matter and does not recommend its use outside of a clinical trial. [World Health Organization(WHO): position paper on collection and use of convalescent plasma or serum as an element in MERS-CoVresponse]

Other drugsA cell-based enzyme-linked immunosorbent assay (ELISA) assay was used to screen a number ofcompounds for activity against MERS-CoV and found that 60 agents demonstrated activity, includingchlorpromazine, tamoxifen, and chloroquine.[37]

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RecommendationsMonitoringPatients with confirmed infection should have their vital signs (i.e., respiratory rate, heart rate, bloodpressure, oxygen saturation) monitored regularly. Renal function, liver function, and coagulation profileshould also be monitored.

Frequency of specimen collection depends on local circumstances. The World Health Organization(WHO) recommends that respiratory tract specimens for real-time reverse transcription polymerase chainreaction (RT-PCR) should be collected at least every 2 to 4 days in the initial 2 weeks, and continueuntil there are 2 negative test results to confirm clearance of the virus.[92] The Ministry of Health (SaudiArabia) recommends repeat testing one week after diagnosis, and then every 3 days.[89]

Patient instructionsPatients in home isolation should be advised to:[89] [86] [128]

• Stay home• Separate themselves from other people in the home• Call ahead before visiting their doctor• Wear a facemask when in the same room as other people• Practice respiratory hygiene (i.e., cover mouth and nose when coughing and sneezing)• Wash hands often using soap and water (or alcohol-based hand sanitizer)• Avoid sharing household items• Monitor their symptoms and seek prompt medical attention if illness is getting worse (e.g., difficulty

breathing).

Detailed guidance for home isolation patients is available from the Centers for Disease Control andPrevention (CDC) and the World Health Organization (WHO):

• [Centers for Disease Control and Prevention (CDC): preventing MERS-CoV from spreading toothers in homes and communities]

• [World Health Organization (WHO): home care for patients with Middle East respiratory syndromecoronavirus (MERS-CoV) infection presenting with mild symptoms and management of contacts]

Education:

• A fact sheet is available from the Centers for Disease Control and Prevention (CDC): [Centers forDisease Control and Prevention (CDC): information about MERS - fact sheet]

• A fact sheet is also available from the World Health Organization (WHO): [World HealthOrganization (WHO): Middle East respiratory syndrome coronavirus (MERS-CoV) fact sheet]

Travel:

• The CDC currently recommends practicing enhanced precautions (level 2 alert) when travelingto the Arabian Peninsula: [Centers for Disease Control and Prevention (CDC): travelers' health -MERS in the Arabian Peninsula]

• The WHO has produced detailed travel guidance for people participating in pilgrimages and massgatherings: [World Health Organization (WHO): technical guidance on travel and mass gatherings]

• The CDC offers the following recommendations for travelers: wash hands often with soap andwater (or alcohol-based sanitizer); avoid contact with people who are sick; wash hands beforeand after touching animals; avoid sick animals; avoid contact with camels or camel products if ata higher risk of infection (e.g., patients who are immunocompromised, or have diabetes mellitus,



https://www.cdc.gov/coronavirus/mers/hcp/home-care-patient.html




http://www.cdc.gov/coronavirus/mers/downloads/factsheet-mers_en.pdf


http://www.who.int/mediacentre/factsheets/mers-cov/en/


http://wwwnc.cdc.gov/travel/notices/alert/coronavirus-saudi-arabia-qatar


http://www.who.int/csr/disease/coronavirus_infections/technical-guidance-travel/en/


Middle East respiratory syndrome (MERS) Follow up

kidney failure, or chronic lung disease); avoid consumption of raw or undercooked meat; practicerespiratory hygiene if sick (e.g., cover mouth when coughing or sneezing).

Complications

Complications Timeframe Likelihoodacute respiratory failure short term medium

Reported in 25% to 95% of confirmed cases that required hospitalization.[8] [26] [33]

Median time to invasive mechanical ventilation was 7 days in a cohort of 47 patients.[8]

Extracorporeal membrane oxygenation has been used in some cases; however, efficacy has not beenconfirmed.[26] [81]

Risk factors include age ≥50 years, diabetes mellitus, end-stage renal disease, and obesity.[5] [8] [9] [26]

acute respiratory distress syndrome short term medium

New or worsening respiratory symptoms within one week of presentation. Chest x-ray shows bilateralopacities.[92]

High-flow oxygen (up to 50 mL/minute) is recommended in some patients, although mechanical ventilationand intubation is usually required.[92]

acute renal failure short term medium

Initially reported in a few case reports.[14] [30] [82] Has since been reported in 58% of critically ill patientsin one study, and 26% of patients in one cohort.[81] [162]

Possibly due to the presence of dipeptidyl peptidase-4 (DPP4) receptors in renal epithelial cells.[163]

Detection of the virus in urine samples has been previously documented.[161]

multiorgan failure short term low

Occurs in a minority of patients late in the course of illness.

Underlying mechanism of action is unknown.

Usually presents with thrombocytopenia, prolonged coagulation profile, and circulatory collapse.[26] [33][81]

Patients may require vasopressor and inotrope support.

Prognosis

The case fatality rate is approximately 35%.[160] This fatality rate is lower than previously reportedrates in the literature as cohort studies generally include only patients who are sick enough to requirehospitalization.[5] [8] [9] [26]

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Age ≥50 years has been associated with more severe presentation, worse outcomes, and a higher risk ofmortality.[5] [27] In one cohort study, mortality increased with increasing age to reach 75% in patients >60years of age.[8]

Presence of comorbidities (e.g., diabetes mellitus, chronic renal impairment, heart disease, obesity)increases the risk of acute respiratory failure and worse outcomes.[5] [8] [9] [26] [81]

Natural course of infectionAs the clinical presentation is highly variable and ranges from no symptoms to rapidly progressivepneumonia, the natural course is also variable.

The median time from symptom onset to death ranges from 16.5 to 20.5 days in cohort studies.[8] [27]Median time to viral clearance, documented by negative real-time reverse transcription polymerase chainreaction (RT-PCR) on respiratory specimens, is 11 days (range 6 to 35 days).[5] [161] In patients whosurvived, median time from symptom onset to discharge from hospital was 27 days (range 20 to 31.5days).[27]

Recurrence of infection in patients who have recovered has not been reported. There are currently no dataon whether previous infection offers protection against future infection.




Middle East respiratory syndrome (MERS) Guidelines

Diagnostic guidelines

International

CDC laboratory testing for Middle East respiratory syndrome coronavirus(MERS-CoV) [95]Published by: Centers for Disease Control and Prevention (CDC) Last published: 2018

CDC health information for international travel (Yellow Book): Middle Eastrespiratory syndrome (MERS) [124]Published by: Centers for Disease Control and Prevention Last published: 2017

Laboratory testing for Middle East respiratory syndrome coronavirus: interimguidance [94]Published by: World Health Organization (WHO) Last published: 2018 G

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http://www.cdc.gov/coronavirus/mers/lab/lab-testing.html


https://wwwnc.cdc.gov/travel/yellowbook/2018/table-of-contents





Middle East respiratory syndrome (MERS) GuidelinesG

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Treatment guidelines

International

Middle East respiratory syndrome (MERS): interim guidance for healthcareprofessionals [155]Published by: Centers for Disease Control and Prevention Last published: 2018

Interim US guidance for monitoring and movement of persons with potentialMiddle East respiratory syndrome coronavirus (MERS-CoV) exposure [156]Published by: Centers for Disease Control and Prevention Last published: 2017

Interim infection prevention and control recommendations for hospitalizedpatients with Middle East respiratory syndrome coronavirus (MERS-CoV) [157]Published by: Centers for Disease Control and Prevention Last published: 2017

CDC health information for international travel (Yellow Book): Middle Eastrespiratory syndrome (MERS) [124]Published by: Centers for Disease Control and Prevention Last published: 2017

Middle East respiratory syndrome coronavirus: guidelines for healthcareprofessionals [89]Published by: Ministry of Health (Saudi Arabia) Last published: 2018

Home care for patients with Middle East respiratory syndrome coronavirus(MERS-CoV) infection presenting with mild symptoms and management ofcontacts - interim guidance [128]Published by: World Health Organization Last published: 2018

Surveillance for human infection with Middle East respiratory syndromecoronavirus (MERS-CoV) - interim guidance [158]Published by: World Health Organization Last published: 2018

Considerations for mass gathering events and Middle East respiratorysyndrome coronavirus (MERS-CoV) - interim guidance [159]Published by: World Health Organization Last published: 2018

Management of asymptomatic persons who are RTPCR positive for MiddleEast respiratory syndrome coronavirus (MERS-CoV) - interim guidance [123]Published by: World Health Organization Last published: 2018

Clinical management of severe acute respiratory infection when Middle Eastrespiratory syndrome coronavirus (MERS-CoV) infection is suspected [92]Published by: World Health Organization (WHO) Last published: 2015



https://www.cdc.gov/coronavirus/mers/interim-guidance.html


https://www.cdc.gov/coronavirus/mers/hcp/monitoring-movement-guidance.html


https://www.cdc.gov/coronavirus/mers/infection-prevention-control.html




https://www.moh.gov.sa/CCC/healthp/regulations/Documents/MERS-CoV%20Guidelines%20for%20Healthcare%20Professionals%20-%20May%202018%20-%20v5.1%20%281%29.pdf





http://www.who.int/csr/disease/coronavirus_infections/surveillance-human-infection-mers/en/


http://www.who.int/csr/disease/coronavirus_infections/mers_mass_gatherings/en/


http://www.who.int/csr/disease/coronavirus_infections/management_of_asymptomatic_patients/en/


http://www.who.int/csr/disease/coronavirus_infections/case-management-ipc/en/

http://www.who.int/csr/disease/coronavirus_infections/case-management-ipc/en/


Middle East respiratory syndrome (MERS) Online resources

Online resources

1. Centers for Disease Control and Prevention (CDC): Middle East respiratory syndrome (MERS)(external link)

2. World Health Organization (WHO): Middle East respiratory syndrome coronavirus (MERS-CoV)(external link)

3. World Health Organization (WHO): disease outbreak news (external link)

4. Centers for Disease Control and Prevention (CDC): interim infection prevention and controlrecommendations for hospitalized patients with MERS-CoV (external link)

5. World Health Organization (WHO): infection prevention and control during health care for probable orconfirmed cases of MERS-CoV infection (external link)

6. World Health Organization (WHO): MERS-CoV - initial interview questionnaire of cases (external link)

7. Centers for Disease Control and Prevention (CDC): interim patient under investigation (PUI) guidanceand case definitions (external link)

8. World Health Organization (WHO): case definition for reporting to WHO (external link)

9. Ministry of Health (Saudi Arabia): case definition (external link)

10. Centers for Disease Control and Prevention (CDC): interim guidelines for collecting, handling, andtesting clinical specimens from patients under investigation for MERS-CoV (external link)

11. World Health Organization (WHO): laboratory testing for Middle East respiratory syndrome coronavirus(MERS-CoV) (external link)

12. Ministry of Health (Saudi Arabia): coronavirus (MERS-CoV) (external link)

13. World Health Organization (WHO): surveillance for human infection with Middle East respiratorysyndrome coronavirus (MERS-CoV) (external link)

14. Centers for Disease Control and Prevention (CDC): implementing home care and isolation orquarantine of people not requiring hospitalization for MERS-CoV (external link)

15. World Health Organization (WHO): home care for patients with Middle East respiratory syndromecoronavirus (MERS-CoV) infection presenting with mild symptoms and management of contacts(external link)

16. World Health Organization (WHO): position paper on collection and use of convalescent plasma orserum as an element in MERS-CoV response (external link)

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http://www.who.int/csr/disease/coronavirus_infections/MERS_case_investigation_questionnaire.pdf




















Middle East respiratory syndrome (MERS) Online resourcesO

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17. Centers for Disease Control and Prevention (CDC): preventing MERS-CoV from spreading to others inhomes and communities (external link)

18. Centers for Disease Control and Prevention (CDC): information about MERS - fact sheet (external link)

19. World Health Organization (WHO): Middle East respiratory syndrome coronavirus (MERS-CoV) factsheet (external link)

20. Centers for Disease Control and Prevention (CDC): travelers' health - MERS in the Arabian Peninsula(external link)

21. World Health Organization (WHO): technical guidance on travel and mass gatherings (external link)










http://www.who.int/csr/disease/coronavirus_infections/technical-guidance-travel/en/


Middle East respiratory syndrome (MERS) References

Key articles

• Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, et al. Epidemiological, demographic, and clinical characteristicsof 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptivestudy. Lancet Infect Dis. 2013;13:752-761. Abstract

• Shehata MM, Gomaa MR, Ali MA, et al. Middle East respiratory syndrome coronavirus: acomprehensive review. Front Med. 2016;10:120-136. Abstract

• Alraddadi BM, Watson JT, Almarashi A, et al. Risk factors for primary Middle East respiratorysyndrome coronavirus illness in humans, Saudi Arabia, 2014. Emerg Infect Dis. 2016;22:49-55. Fulltext Abstract

• Zumla A, Hui DS, Perlman S. Middle East respiratory syndrome. Lancet. 2015;386:995-1007. Full textAbstract

• World Health Organization. Clinical management of severe acute respiratory infection when MiddleEast respiratory syndrome coronavirus (MERS-CoV) infection is suspected. Interim guidance. July2015 [internet publication]. Full text

• Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, et al. Epidemiological, demographic, and clinical characteristicsof 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptivestudy. Lancet Infect Dis. 2013;13:752-761. Abstract

• Chong YP, Song JY, Seo YB, et al. Antiviral treatment guidelines for Middle East respiratory syndrome.Infect Chemother. 2015;47:212-222. Full text Abstract

References

1. Zaki AM, van Boheemen S, Bestebroer TM, et al. Isolation of a novel coronavirus from a man withpneumonia in Saudi Arabia. N Engl J Med. 2012;367:1814-1820. Full text Abstract

2. Raj VS, Osterhaus AD, Fouchier RA, et al. MERS: emergence of a novel human coronavirus. CurrOpin Virol. 2014;5:58-62. Full text Abstract

3. Chan JF, Lau SK, To KK, et al. Middle East respiratory syndrome coronavirus: another zoonoticbetacoronavirus causing SARS-like disease. Clin Microbiol Rev. 2015;28:465-522. Abstract

4. WHO MERS-CoV Research Group. State of knowledge and data gaps of Middle East respiratorysyndrome coronavirus (MERS-CoV) in humans. PLoS Curr. 2013;5. Full text Abstract

5. Shalhoub S, Farahat F, Al-Jiffri A, et al. IFN-alpha-2a or IFN-beta-1a in combination with ribavirin totreat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J AntimicrobChemother. 2015;70:2129-2132. Abstract

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http://www.ncbi.nlm.nih.gov/pubmed/23891402?tool=bestpractice.bmj.com


https://wwwnc.cdc.gov/eid/article/22/1/15-1340_article



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721578/


http://apps.who.int/iris/bitstream/10665/178529/1/WHO_MERS_Clinical_15.1_eng.pdf


https://synapse.koreamed.org/DOIx.php?id=10.3947/ic.2015.47.3.212


http://www.nejm.org/doi/full/10.1056/NEJMoa1211721#t=article





http://currents.plos.org/outbreaks/article/state-of-knowledge-and-data-gaps-of-middle-east-respiratory-syndrome-coronavirus-mers-cov-in-humans-2/




Middle East respiratory syndrome (MERS) ReferencesR

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6. Oboho IK, Tomczyk SM, Al-Asmari AM, et al. 2014 MERS-CoV outbreak in Jeddah - a link to healthcare facilities. N Engl J Med. 2015;372:846-854. Full text Abstract

7. Assiri A, McGeer A, Perl TM, et al. Hospital outbreak of Middle East respiratory syndrome coronavirus.N Engl J Med. 2013;369:407-416. Full text Abstract

8. Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, et al. Epidemiological, demographic, and clinical characteristicsof 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptivestudy. Lancet Infect Dis. 2013;13:752-761. Abstract

9. Al-Tawfiq JA, Hinedi K, Ghandour J, et al. Middle East respiratory syndrome coronavirus: a case-control study of hospitalized patients. Clin Infect Dis. 2014;59:160-165. Full text Abstract

10. Memish ZA, Zumla AI, Assiri A. Middle East respiratory syndrome coronavirus infections in health careworkers. N Engl J Med. 2013;369:884-886. Full text Abstract

11. Amer H, Alqahtani AS, Alzoman H, et al. Unusual presentation of Middle East respiratory syndromecoronavirus leading to a large outbreak in Riyadh during 2017. Am J Infect Control. 2018 Apr 13. pii:S0196-6553(18)30146-9. Abstract

12. Memish ZA, Al-Tawfiq JA, Assiri A, et al. Middle East respiratory syndrome coronavirus disease inchildren. Pediatr Infect Dis J. 2014;33:904-906. Abstract

13. Khuri-Bulos N, Payne DC, Lu X, et al. Middle East respiratory syndrome coronavirus not detected inchildren hospitalized with acute respiratory illness in Amman, Jordan, March 2010 to September 2012.Clin Microbiol Infect. 2014;20:678-682. Full text Abstract

14. Zaki AM, van Boheemen S, Bestebroer TM, et al. Isolation of a novel coronavirus from a man withpneumonia in Saudi Arabia. N Engl J Med. 2012;367:1814-1820. Full text Abstract

15. Puzelli S, Azzi A, Santini MG, et al. Investigation of an imported case of Middle East respiratorysyndrome coronavirus (MERS-CoV) infection in Florence, Italy, May to June 2013. Euro Surveill.2013;18:20564. Full text Abstract

16. Kraaij-Dirkzwager M, Timen A, Dirksen K, et al. Middle East respiratory syndrome coronavirus (MERS-CoV) infections in two returning travellers in the Netherlands, May 2014. Euro Surveill. 2014;19:20817.Full text Abstract

17. Guery B, Poissy J, el Mansouf L, et al. Clinical features and viral diagnosis of two cases of infectionwith Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission. Lancet.2013;381:2265-2272. Abstract

18. Abroug F, Slim A, Ouanes-Besbes L, et al. Family cluster of Middle East respiratory syndromecoronavirus infections, Tunisia, 2013. Emerg Infect Dis. 2014;20:1527-1530. Abstract

19. Lee SI. Costly lessons from the 2015 Middle East respiratory syndrome coronavirus outbreak in Korea.J Prev Med Public Health. 2015;48:274-276. Full text Abstract








https://academic.oup.com/cid/article/59/2/160/2895452/Middle-East-Respiratory-Syndrome-Coronavirus-A


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http://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)61157-5/fulltext




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https://www.jpmph.org/journal/view.php?doi=10.3961/jpmph.15.064




20. Hui DS, Perlman S, Zumla A. Spread of MERS to South Korea and China. Lancet Respir Med.2015;3:509-510. Abstract

21. Ha KM. A lesson learned from the MERS outbreak in South Korea in 2015. J Hosp Infect.2016;92:232-234. Abstract

22. Centers for Disease Control and Prevention. MERS in the US. September 2017 [internet publication]. Full text

23. Public Health England. MERS-CoV case in England. August 2018 [internet publication]. Full text

24. World Health Organization. Disease outbreak news. Middle East respiratory syndrome coronavirus(MERS-CoV) infection – Republic of Korea. September 2018 [internet publication]. Full text

25. World Health Organization. MERS situation update. August 2018 [internet publication]. Full text

26. Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratorysyndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis. 2014;14:1090-1095.Abstract

27. Saad M, Omrani AS, Baig K, et al. Clinical aspects and outcomes of 70 patients with Middle Eastrespiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia. Int J Infect Dis.2014;29:301-306. Full text Abstract

28. Alenazi TH, Al Arbash H, El-Saed A, et al. Identified transmission dynamics of Middle East respiratorysyndrome coronavirus infection during an outbreak: implications of an overcrowded emergencydepartment. Clin Infect Dis. 2017;65:675-679. Abstract

29. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of theimmunocompromised host. Clin Infect Dis. 2014;58:309-318. Full text Abstract

30. Memish ZA, Zumla AI, Al-Hakeem RF, et al. Family cluster of Middle East respiratory syndromecoronavirus infections. N Engl J Med. 2013;368:2487-2494. Full text Abstract

31. Omrani AS, Matin MA, Haddad Q, et al. A family cluster of Middle East Respiratory SyndromeCoronavirus infections related to a likely unrecognized asymptomatic or mild case. Int J Infect Dis.2013;17:e668-e672. Full text Abstract

32. Memish ZA, Cotten M, Watson SJ, et al. Community case clusters of Middle East respiratorysyndrome coronavirus in Hafr Al-Batin, Kingdom of Saudi Arabia: a descriptive genomic study. Int JInfect Dis. 2014;23:63-68. Full text Abstract

33. Al-Abdallat MM, Payne DC, Alqasrawi S, et al. Hospital-associated outbreak of Middle Eastrespiratory syndrome coronavirus: a serologic, epidemiologic, and clinical description. Clin Infect Dis.2014;59:1225-1233. Full text Abstract

34. Shehata MM, Gomaa MR, Ali MA, et al. Middle East respiratory syndrome coronavirus: acomprehensive review. Front Med. 2016;10:120-136. Abstract

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https://academic.oup.com/cid/article/58/3/309/340555/Executive-Summary-2013-IDSA-Clinical-Practice








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36. Raj VS, Osterhaus AD, Fouchier RA, et al. MERS: emergence of a novel human coronavirus. CurrOpin Virol. 2014;5:58-62. Full text Abstract

37. Chan JF, Lau SK, To KK, et al. Middle East respiratory syndrome coronavirus: another zoonoticbetacoronavirus causing SARS-like disease. Clin Microbiol Rev. 2015;28:465-522. Abstract

38. Cotten M, Watson SJ, Zumla AI, et al. Spread, circulation, and evolution of the Middle East respiratorysyndrome coronavirus. MBio. 2014;5:e01062-13. Full text Abstract

39. Omrani AS, Shalhoub S. Middle East respiratory syndrome coronavirus (MERS-CoV): what lessonscan we learn? J Hosp Infect. 2015;91:188-196. Abstract

40. Reusken CB, Haagmans BL, Muller MA, et al. Middle East respiratory syndrome coronavirusneutralising serum antibodies in dromedary camels: a comparative serological study. Lancet Infect Dis.2013;13:859-866. Abstract

41. 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. EuroSurveill. 2013;18:20662. Full text Abstract

42. Perera RA, Wang P, Gomaa MR, et al. Seroepidemiology for MERS coronavirus usingmicroneutralisation and pseudoparticle virus neutralisation assays reveal a high prevalence of antibodyin dromedary camels in Egypt, June 2013. Euro Surveill. 2013;18:20574. Full text Abstract

43. Muller MA, Corman VM, Jores J, et al. MERS coronavirus neutralizing antibodies in camels, EasternAfrica, 1983-1997. Emerg Infect Dis. 2014;20:2093-2095. Full text Abstract

44. Meyer B, Muller MA, Corman VM, et al. Antibodies against MERS coronavirus in dromedary camels,United Arab Emirates, 2003 and 2013. Emerg Infect Dis. 2014;20:552-559. Full text Abstract

45. Hemida MG, Perera RA, Wang P, et al. Middle East Respiratory Syndrome (MERS) coronavirusseroprevalence in domestic livestock in Saudi Arabia, 2010 to 2013. Euro Surveill. 2013;18:20659. Full text Abstract

46. Corman VM, Jores J, Meyer B, et al. Antibodies against MERS coronavirus in dromedary camels,Kenya, 1992-2013. Emerg Infect Dis. 2014;20:1319-1322. Full text Abstract

47. Alagaili AN, Briese T, Mishra N, et al. Middle East respiratory syndrome coronavirus infection indromedary camels in Saudi Arabia. MBio. 2014;5:e00884-14. Full text Abstract

48. Alexandersen S, Kobinger GP, Soule G, et al. Middle East respiratory syndrome coronavirusantibody reactors among camels in Dubai, United Arab Emirates, in 2005. Transbound Emerg Dis.2014;61:105-108. Full text Abstract



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49. Ferguson NM, Van Kerkhove MD. Identification of MERS-CoV in dromedary camels. Lancet Infect Dis.2014;14:93-94. Abstract

50. Hemida MG, Chu DK, Poon LL, et al. MERS coronavirus in dromedary camel herd, Saudi Arabia.Emerging Infect Dis. 2014;20:1231-1234. Full text Abstract

51. Hemida MG, Elmoslemany A, Al-Hizab F, et al. Dromedary camels and the transmission of MiddleEast respiratory syndrome coronavirus (MERS-CoV). Transbound Emerg Dis. 2017;64:344-353.Abstract

52. Hemida MG, Perera RA, Al Jassim RA, et al. Seroepidemiology of Middle East respiratory syndrome(MERS) coronavirus in Saudi Arabia (1993) and Australia (2014) and characterisation of assayspecificity. Euro Surveill. 2014;19:20828. Full text Abstract

53. Nowotny N, Kolodziejek J. Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedarycamels, Oman, 2013. Euro Surveill. 2014;19:20781. Full text Abstract

54. Yusof MF, Eltahir YM, Serhan WS, et al. Prevalence of Middle East respiratory syndrome coronavirus(MERS-CoV) in dromedary camels in Abu Dhabi Emirate, United Arab Emirates. Virus Genes.2015;50:509-513. Abstract

55. Farag EA, Reusken CB, Haagmans BL, et al. High proportion of MERS-CoV shedding dromedariesat slaughterhouse with a potential epidemiological link to human cases, Qatar 2014. Infect EcolEpidemiol. 2015;5:28305. Full text Abstract

56. Briese T, Mishra N, Jain K, et al. Middle East respiratory syndrome coronavirus quasispecies thatinclude homologues of human isolates revealed through whole-genome analysis and virus culturedfrom dromedary camels in Saudi Arabia. MBio. 2014;5:e01146-14. Full text Abstract

57. Adney DR, van Doremalen N, Brown VR, et al. Replication and shedding of MERS-CoV in upperrespiratory tract of inoculated dromedary camels. Emerg Infect Dis. 2014;20:1999-2005. Full text Abstract

58. Anthony SJ, Gilardi K, Menachery VD, et al. Further evidence for bats as the evolutionary source ofMiddle East respiratory syndrome coronavirus. MBio. 2017;8:e00373-17. Full text Abstract

59. Haagmans BL, Al Dhahiry SH, Reusken CB, et al. Middle East respiratory syndrome coronavirus indromedary camels: an outbreak investigation. Lancet Infect Dis. 2014;14:140-145. Abstract

60. Al Hammadi AM, Chu DKW, Eltahir YM, et al. Asymptomatic MERS-CoV infection in humans possiblylinked to infected dromedaries imported from Oman to United Arab Emirates, May 2015. Emerg InfectDis. 2015;21:2197-2200. Full text Abstract

61. Memish ZA, Cotten M, Meyer B, et al. Human infection with MERS coronavirus after exposure toinfected camels, Saudi Arabia, 2013. Emerg Infect Dis. 2014;20:1012-1015. Full text Abstract

62. Azhar EI, El-Kafrawy SA, Farraj SA, et al. Evidence for camel-to-human transmission of MERScoronavirus. N Engl J Med. 2014;370:2499-2505. Full text Abstract

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63. Hemida MG, Al-Naeem A, Perera RA, et al. Lack of Middle East respiratory syndrome coronavirustransmission from infected camels. Emerg Infect Dis. 2015;21:699-701. Full text Abstract

64. Alraddadi BM, Watson JT, Almarashi A, et al. Risk factors for primary Middle East respiratorysyndrome coronavirus illness in humans, Saudi Arabia, 2014. Emerg Infect Dis. 2016;22:49-55. Fulltext Abstract

65. Kim SH, Chang SY, Sung M, et al. Extensive viable Middle East respiratory syndrome (MERS)coronavirus contamination in air and surrounding environment in MERS isolation wards. Clin InfectDis. 2016;63:363-369. Full text Abstract

66. Centers for Disease Control and Prevention. MERS clinical features. September 2017 [internetpublication]. Full text

67. Park HY, Lee EJ, Ryu YW, et al. Epidemiological investigation of MERS-CoV spread in a singlehospital in South Korea, May to June 2015. Euro Surveill. 2015;20:21169. Full text Abstract

68. van Doremalen N, Bushmaker T, Munster VJ. Stability of Middle East respiratory syndromecoronavirus (MERS-CoV) under different environmental conditions. Euro Surveill. 2013;18:20590. Fulltext Abstract

69. Bin SY, Heo JY, Song MS, et al. Environmental contamination and viral shedding in MERS patientsduring MERS-CoV outbreak in South Korea. Clin Infect Dis. 2016;62:755-760. Abstract

70. Cauchemez S, Van Kerkhove MD, Riley S, et al. Transmission scenarios for Middle East respiratorysyndrome coronavirus (MERS-CoV) and how to tell them apart. Euro Surveill. 2013;18:20503. Fulltext Abstract

71. 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;14:50-56. Full text Abstract

72. Breban R, Riou J, Fontanet A. Interhuman transmissibility of Middle East respiratory syndromecoronavirus: estimation of pandemic risk. Lancet. 2013;382:694-699. Abstract

73. Zumla A, Hui DS. Infection control and MERS-CoV in health-care workers. Lancet.2014;383:1869-1871. Abstract

74. Raj VS, Mou H, Smits SL, et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging humancoronavirus-EMC. Nature. 2013;495:251-254. Abstract

75. Belouzard S, Millet JK, Licitra BN, et al. Mechanisms of coronavirus cell entry mediated by the viralspike protein. Viruses. 2012;4:1011-1033. Full text Abstract

76. Xia S, Liu Q, Wang Q, et al. Middle East respiratory syndrome coronavirus (MERS-CoV) entryinhibitors targeting spike protein. Virus Res. 2014;194:200-210. Abstract

77. Bosch BJ, Raj VS, Haagmans BL. Spiking the MERS-coronavirus receptor. Cell Res.2013;23:1069-1070. Full text Abstract








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78. Zumla A, Hui DS, Perlman S. Middle East respiratory syndrome. Lancet. 2015;386:995-1007. Full textAbstract

79. Reuss A, Litterst A, Drosten C, et al. Contact investigation for imported case of Middle East respiratorysyndrome, Germany. Emerg Infect Dis. 2014;20:620-625. Full text Abstract

80. Bialek SR, Allen D, Alvarado-Ramy F, et al. First confirmed cases of Middle East respiratory syndromecoronavirus (MERS-CoV) infection in the United States, updated information on the epidemiology ofMERS-CoV infection, and guidance for the public, clinicians, and public health authorities - May 2014.MMWR Morb Mortal Wkly Rep. 2014;63:431-436. Full text Abstract

81. Arabi YM, Arifi AA, Balkhy HH, et al. Clinical course and outcomes of critically ill patients with MiddleEast respiratory syndrome coronavirus infection. Ann Intern Med. 2014;160:389-397. Full text Abstract

82. Deenitchina SS, Ando T, Okuda S, et al. Cellular immunity in hemodialysis patients: a quantitativeanalysis of immune cell subsets by flow cytometry. Am J Nephrol. 1995;15:57-65. Abstract

83. Beigel JH, Voell J, Kumar P, et al. Safety and tolerability of a novel, polyclonal human anti-MERScoronavirus antibody produced from transchromosomic cattle: a phase 1 randomised, double-blind,single-dose-escalation study. Lancet Infect Dis. 2018 Apr;18(4):410-418. Abstract

84. World Health Organization. WHO target product profiles for MERS-CoV vaccines. May 2017 [internetpublication]. Full text

85. World Health Organization. Infection prevention and control during health care for probable orconfirmed cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Interimguidance. June 2015 [internet publication]. Full text

86. Centers for Disease Control and Prevention. Preventing MERS-CoV from spreading to others inhomes and communities. September 2017 [internet publication]. Full text

87. Hotez PJ, Bottazzi ME, Tseng C-T, et al. Calling for rapid development of a safe and effective MERSvaccine. Microbes Infect. 2014;16:529-531. Abstract

88. Shalhoub S, Al-Zahrani A, Simhairi R, et al. Successful recovery of MERS CoV pneumonia in a patientwith acquired immunodeficiency syndrome: a case report. J Clin Virol. 2015;62:69-71. Abstract

89. Ministry of Health (Saudi Arabia). Middle East respiratory syndrome coronavirus; guidelines forhealthcare professionals, version 5.1. May 2018 [internet publication]. Full text

90. World Health Organization (WHO). Middle East respiratory syndrome coronavirus: case definition forreporting to WHO. July 2017 [internet publication]. Full text

91. Centers for Disease Control and Prevention. Interim patient under investigation (PUI) guidance andcase definitions. September 2017 [internet publication]. Full text

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92. World Health Organization. Clinical management of severe acute respiratory infection when MiddleEast respiratory syndrome coronavirus (MERS-CoV) infection is suspected. Interim guidance. July2015 [internet publication]. Full text

93. Memish ZA, Al-Tawfiq JA, Makhdoom HQ, et al. Respiratory tract samples, viral load, and genomefraction yield in patients with Middle East respiratory syndrome. J Infect Dis. 2014;210:1590-1594. Fulltext Abstract

94. World Health Organization. Laboratory testing for Middle East respiratory syndrome coronavirus.Interim guidance (revised). January 2018 [internet publication]. Full text

95. Centers for Disease Control and Prevention. CDC laboratory testing for Middle East respiratorysyndrome coronavirus (MERS-CoV). June 2018 [internet publication]. Full text

96. Corman VM, Muller MA, Costabel U, et al. Assays for laboratory confirmation of novel humancoronavirus (hCoV-EMC) infections. Euro Surveill. 2012;17:20334. Full text Abstract

97. Ajlan AM, Ahyad RA, Jamjoom LG, et al. Middle East respiratory syndrome coronavirus (MERS-CoV)infection: chest CT findings. AJR Am J Roentgenol. 2014;203:782-787. Full text Abstract

98. Guery B, Poissy J, el Mansouf L, et al. Clinical features and viral diagnosis of two cases of infectionwith Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission. Lancet.2013;381:2265-2272. Abstract

99. Lee SI. Costly lessons from the 2015 Middle East respiratory syndrome coronavirus outbreak in Korea.J Prev Med Public Health. 2015;48:274-276. Full text Abstract

100. Reuss A, Litterst A, Drosten C, et al. Contact investigation for imported case of Middle East respiratorysyndrome, Germany. Emerg Infect Dis. 2014;20:620-625. Full text Abstract

101. Bialek SR, Allen D, Alvarado-Ramy F, et al. First confirmed cases of Middle East respiratory syndromecoronavirus (MERS-CoV) infection in the United States, updated information on the epidemiology ofMERS-CoV infection, and guidance for the public, clinicians, and public health authorities - May 2014.MMWR Morb Mortal Wkly Rep. 2014;63:431-436. Full text Abstract

102. Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, et al. Epidemiological, demographic, and clinical characteristicsof 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptivestudy. Lancet Infect Dis. 2013;13:752-761. Abstract

103. Memish ZA, Al-Tawfiq JA, Assiri A, et al. Middle East respiratory syndrome coronavirus disease inchildren. Pediatr Infect Dis J. 2014;33:904-906. Abstract

104. Khuri-Bulos N, Payne DC, Lu X, et al. Middle East respiratory syndrome coronavirus not detected inchildren hospitalized with acute respiratory illness in Amman, Jordan, March 2010 to September 2012.Clin Microbiol Infect. 2014;20:678-682. Full text Abstract

105. Assiri A, McGeer A, Perl TM, et al. Hospital outbreak of Middle East respiratory syndrome coronavirus.N Engl J Med. 2013;369:407-416. Full text Abstract



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106. Al-Tawfiq JA, Hinedi K, Ghandour J, et al. Middle East respiratory syndrome coronavirus: a case-control study of hospitalized patients. Clin Infect Dis. 2014;59:160-165. Full text Abstract

107. Shalhoub S, Farahat F, Al-Jiffri A, et al. IFN-alpha-2a or IFN-beta-1a in combination with ribavirin totreat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J AntimicrobChemother. 2015;70:2129-2132. Abstract

108. Shalhoub S, Al-Zahrani A, Simhairi R, et al. Successful recovery of MERS CoV pneumonia in a patientwith acquired immunodeficiency syndrome: a case report. J Clin Virol. 2015;62:69-71. Abstract

109. Saad M, Omrani AS, Baig K, et al. Clinical aspects and outcomes of 70 patients with Middle Eastrespiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia. Int J Infect Dis.2014;29:301-306. Full text Abstract

110. WHO MERS-CoV Research Group. State of knowledge and data gaps of Middle Eastrespiratory syndrome coronavirus (MERS-CoV) in humans. PLoS Curr. 2013;5:piiecurrents.outbreaks.0bf719e352e7478f8ad85fa30127ddb8. Full text Abstract

111. Oboho IK, Tomczyk SM, Al-Asmari AM, et al. 2014 MERS-CoV outbreak in Jeddah - a link to healthcare facilities. N Engl J Med. 2015;372:846-854. Full text Abstract

112. 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;17:20285. Full text Abstract

113. Hui DS, Memish ZA, Zumla A. Severe acute respiratory syndrome vs. the Middle East respiratorysyndrome. Curr Opin Pulm Med. 2014;20:233-241. Abstract

114. Christian MD, Poutanen SM, Loutfy MR, et al. Severe acute respiratory syndrome. Clin Infect Dis.2004;38:1420-1427. Full text Abstract

115. Memish ZA, Al-Tawfiq JA, Makhdoom HQ, et al. Screening for Middle East respiratory syndromecoronavirus infection in hospital patients and their healthcare worker and family contacts: a prospectivedescriptive study. Clin Microbiol Infect. 2014;20:469-474. Full text Abstract

116. Drosten C, Meyer B, Muller MA, et al. Transmission of MERS-coronavirus in household contacts. NEngl J Med. 2014;371:828-835. Full text Abstract

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Middle East respiratory syndrome (MERS) ImagesIM

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Images

Figure 1: Electron micrograph of a thin section of Middle East respiratory syndrome coronavirus (MERS-CoV)showing the spherical particles within the cytoplasm of an infected cell

Centers for Disease Control and Prevention (CDC)




Middle East respiratory syndrome (MERS) Images

Figure 2: Negative stain electron microscopy showing Middle East respiratory syndrome coronavirus (MERS-CoV) particles with characteristic club-like projections from the viral membrane

Centers for Disease Control and Prevention (CDC)

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Figure 3: Algorithm for testing cases under investigation by reverse transcription polymerase chain reaction(RT-PCR)

Produced by the BMJ Evidence Centre (adapted from WHO laboratory testing for Middle East respiratorysyndrome coronavirus -interim guidance (revised) WHO/MERS/LAB/15.1/Rev1/2018)




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Contributors:

// Authors:

Sarah Shalhoub, MDInfectious Diseases ConsultantKing Fahad Armed Forces Hospital, Jeddah, Saudi ArabiaDISCLOSURES: SS is the author of several references cited in this monograph.

Ali S. Omrani, MBBCh, MSc, FRCP, FRCPathAdult Infectious Diseases ConsultantKing Faisal Specialist Hospital and Research Center, Riyadh, Saudi ArabiaDISCLOSURES: ASO is the author of several references cited in this monograph.

// Peer Reviewers:

Ioannis P. Kioumis, MD, PhDAssociate Professor of Pulmonary Medicine and Infectious DiseasesAristotle University of Thessaloniki, Respiratory Medicine Clinic, General Hospital G. Papanikolaou,Thessaloniki, GreeceDISCLOSURES: IPK declares that he has no competing interests.

William A. Petri, Jr, MD, PhD, FACPChiefDivision of Infectious Diseases and International Health, University of Virginia, Charlottesville, VADISCLOSURES: WAP declares that he has no competing interests.