Approach

Although MERS has not yet reached pandemic potential, it is a potentially severe infection with a high case fatality rate. Therefore, quick diagnosis is essential to prevent transmission and to provide supportive care in a timely manner. Physicians should have a high index of suspicion for all patients who present with fever and/or respiratory symptoms in the correct epidemiological context (i.e., travel from the Middle East), and these patients should be promptly evaluated. There are no pathognomonic features; therefore, molecular and serological testing is required to confirm the diagnosis. Co-infection with other respiratory viruses has been reported.

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

Infection prevention and control measures

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

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

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

History

A detailed history helps to clarify the level of risk for MERS and assess the possibility of other causes. Obtaining an epidemiological history is crucial for timely diagnosis and preventing potential outbreaks.[19][21] All confirmed cases have either travelled to, resided in, or been in contact with someone who has travelled 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, the West Bank, and Gaza; Jordan; Lebanon; Syria). Failure to recognise 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] 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] Infection in children is rare, although the reason for this is unknown.[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 least one comorbid illness.[4]

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

World Health Organization (WHO): MERS-CoV - initial interview questionnaire of cases external link opens in a new window

Clinical presentation

MERS may present in a similar way to the common cold. The majority of patients present with fever and respiratory symptoms (e.g., cough, dyspnoea).

  • Fever (temperature >38°C [100.4°F]): common symptom reported in 40% to 98% of cases.[7][8][9] Fever may be absent in older patients, immunocompromised patients, pregnant women, and patients with end-stage renal disease, diabetes mellitus, or haemochromatosis;[5] therefore, absence of fever should not preclude work-up for MERS.[88]

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

  • Dyspnoea: common symptom reported in 60% to 72% of cases.[8][9][27]

  • Haemoptysis: less common symptom reported in 7% to 17% of cases.[8][9][27]

Patients may also present with gastrointestinal symptoms:

  • Diarrhoea: 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 symptoms or pneumonia later in the course of infection. Other symptoms include myalgia, arthralgia, headache, chills/rigors, sore throat, and rhinorrhoea.[4][5][6][7][8][9] Some patients, particularly young, healthy patients, 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, rapidly progressive pneumonia, acute respiratory distress syndrome, septic shock, or multi-organ failure resulting in death.

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

Case definitions

Case 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 all clinical presentations will fit the case definitions. Physicians should be vigilant for identifying suspected cases regardless of whether they fit the case definitions or not. For example, the absence of fever has been reported in cases of confirmed infection, despite most case definitions including fever as a prerequisite for diagnosis.

Current case definitions:

Initial laboratory investigations

Laboratory testing is recommended in any patient who presents with symptoms such as fever, respiratory symptoms, gastrointestinal symptoms, and/or myalgia in the correct epidemiological context.

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

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

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

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

Molecular testing

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

Lower respiratory tract specimens (e.g., sputum, tracheal aspirates, bronchoalveolar lavage fluid) are the preferred specimen for RT-PCR as sputum and tracheal aspirates contain the highest viral loads, and hence have the highest yield.[5][93] However, bronchoscopy may generate aerosols and is generally not recommended. Upper respiratory tract specimens (e.g., nasopharyngeal and oropharyngeal swabs, nasopharyngeal aspirate/wash) and serum collection for virus detection are recommended, especially if lower respiratory specimens are not available and it is 7 days or less since symptom onset. Both upper and lower respiratory tract specimens should be collected whenever possible.[89][94][95] Urine and stool specimens may also be used; however, these specimens contain lower levels of the virus compared with respiratory 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 respiratory syndrome coronavirus (MERS-CoV) infection:[94]

  • MERS-CoV RT-PCR (upE): highly sensitive screening assay targeting regions upstream of the E protein 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 with the 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 upE assay.

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

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

com.bmj.content.model.Caption@42c399e7[Figure caption and citation for the preceding image starts]: 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) [Citation ends].

The WHO defines a confirmed case as a person with laboratory confirmation of infection. Presence of nucleic acid can be confirmed by either a positive RT-PCR result on at least 2 specific genomic targets or a 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 with sequencing on a second for confirmation of the diagnosis.[91] The CDC has developed RT-PCR assays targeting the viral nucleocapside (N) protein gene which can be used to complement the upE and ORF 1a assays for screening and confirmation.

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

Serological testing

Serological testing is generally not used for diagnosis, but for epidemiological surveillance or investigational purposes (e.g., retrospective diagnosis). It may be used to confirm the diagnosis; however, a single specimen would only identify a probable case. Paired sampling taken at least 14 to 21 days apart is required to confirm the diagnosis.

Several serological tests have been developed for detecting MERS-CoV antibodies including an indirect fluorescent antibody (IFA) test, an enzyme-linked immunosorbent assay (ELISA), and a serum neutralisation test.

The WHO defines a confirmed case to be a patient with evidence of seroconversion in at least one screening assay (e.g., IFA, ELISA) and confirmation by a neutralisation assay in samples taken at least 14 days apart. They define a probable case as a symptomatic patient without a positive RT-PCR test who has a positive result for at least one screening assay (e.g., IFA, ELISA) plus a positive result for a neutralisation assay in a single specimen.[94]

The CDC has developed a two-stage approach to serological testing which uses an ELISA test for screening, followed by a microneutralisation test to confirm diagnosis.[95]

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

Imaging

A chest x-ray should be ordered 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]

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-glass opacities than consolidation.[97] Recognition of these patterns can aid early diagnosis of MERS; however, routine use of this test is not recommended.

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