Middle East Respiratory Syndrome Coronavirus Treatment and Prevention

22/3/2020 Middle East respiratory syndrome coronavirus: Treatment and prevention - UpToDate
Official reprint from UpToDate®

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Middle East respiratory syndrome coronavirus: Treatment and prevention

Author: Kenneth McIntosh, MD
Section Editor: Martin S Hirsch, MD
Deputy Editor: Allyson Bloom, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2020. | This topic last updated: Dec 04, 2019.
INTRODUCTION
In September 2012, a case of novel coronavirus infection was reported involving a man in Saudi Arabia who was admitted to a hospital with
pneumonia and acute kidney injury in June 2012 [1]. Only a few days later, a separate report appeared of an almost identical virus detected in a
second patient with acute respiratory syndrome and acute kidney injury [2,3]. The second patient initially developed symptoms in Qatar but had
traveled to Saudi Arabia before he became ill and then sought care in the United Kingdom [4]. Many subsequent cases and clusters of infections
have been reported.
This novel coronavirus, initially termed human coronavirus-EMC (for Erasmus Medical Center), has been named Middle East respiratory syndrome
coronavirus (MERS-CoV) [5].
Updated information about MERS-CoV can be found on the World Health Organization's website and the United States Centers for Disease Control
and Prevention's website.
The treatment and prevention of MERS-CoV are discussed here. The virology, epidemiology, clinical manifestations, and diagnosis of MERS-CoV
are discussed separately. Community-acquired coronaviruses and severe acute respiratory syndrome coronavirus are reviewed separately. (See
"Middle East respiratory syndrome coronavirus: Virology, pathogenesis, and epidemiology" and "Middle East respiratory syndrome coronavirus:
Clinical manifestations and diagnosis" and "Coronaviruses" and "Severe acute respiratory syndrome (SARS)".)
TREATMENT
As with other coronaviruses, no antiviral agents are recommended for the treatment of MERS-CoV infection [6]. The World Health Organization
(WHO) has issued recommendations for the management of severe respiratory infections suspected to be caused by MERS-CoV [7].
In cell culture and animal experiments, combination therapy with interferon (IFN)-alpha-2b and ribavirin appears promising [8,9]. In a study in which
MERS-CoV was grown in two different cell lines, high concentrations of IFN-alpha-2b or ribavirin were required to inhibit viral replication [8].
However, when used in combination at lower concentrations, IFN-alpha-2b and ribavirin resulted in a comparable reduction in viral replication as high
concentrations of either agent alone.
In a study of rhesus macaques, two groups of three monkeys were inoculated with MERS-CoV through a combination of intratracheal, intranasal,
oral, and ocular routes; one group was treated with subcutaneous IFN-alpha-2b plus intramuscular ribavirin beginning eight hours after inoculation,
and the other group was not treated [9]. In contrast with untreated macaques, treated animals did not develop breathing abnormalities and showed
no or very mild radiographic evidence of pneumonia. Treated animals had lower concentrations of serum and lung proinflammatory markers, fewer
viral genome copies, and fewer severe histopathologic changes in the lungs. In a study of common marmosets, either IFN-beta-1b or lopinavir-
ritonavir resulted in improved outcomes when used for the treatment of severe MERS-CoV infection [10].
In a retrospective cohort study in patients with severe MERS-CoV infection, combination therapy with ribavirin and IFN-alpha-2a, started a median of
three days after diagnosis (in 20 patients), was associated with significantly improved survival at 14 days, compared with 24 patients who received
only supportive care (70 versus 29 percent survival), but not at 28 days (30 versus 17 percent survival, a nonsignificant difference) [11]. There were
greater declines in hemoglobin in the ribavirin-IFN group than in the controls (4.32 versus 2.14 g/L). In a retrospective cohort study of 349 critically ill
patients with laboratory-confirmed MERS infection from 14 hospitals in Saudi Arabia, crude 90-day mortality was higher in patients who received
ribavirin and/or IFN-alpha-2a, IFN-alpha-2b, or IFN-beta-1a than in those who did not receive antiviral therapy [12]. After adjusting for confounders,
antiviral therapy was not associated with a change in 90-day mortality (adjusted hazard ratio [aHR] 1.03, 95% CI 0.73-1.44) or with more rapid
MERS-CoV RNA clearance (aHR 0.65, 95% CI 0.30-1.44).
In an analysis of 309 adults with MERS, 151 of whom received glucocorticoids, glucocorticoid treatment was not associated with a difference in
mortality but was associated with a delay in clearance of virus [13]. Their use is not recommended for MERS-CoV infections.
Other experimental therapies being investigated include convalescent plasma, neutralizing monoclonal antibodies [14-17], a polyclonal hyperimmune
antibody produced from transchromosomic cattle [18], an inhibitor of the main viral protease, entry/fusion inhibitors targeting the MERS-CoV spike
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protein, and a prodrug of a nucleotide analog [14,19-31]. A placebo-controlled trial of oral lopinavir-ritonavir and subcutaneous interferon-beta is in
progress in Saudi Arabia [32].
Although the immunosuppressive agent mycophenolate mofetil has in vitro activity against MERS-CoV, in a study of severe infection in common
marmosets, it was not effective [10].
PREVENTION
Infection control — The World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (CDC) have issued
recommendations for the prevention and control of MERS-CoV infections in healthcare settings [33-36]. An increased level of infection control
precautions is recommended when caring for patients with probable or confirmed MERS-CoV infection compared with that used for patients with
community-acquired coronaviruses or other community-acquired respiratory viruses.
The WHO recommends that standard and droplet precautions be used when caring for patients with acute respiratory tract infections [33]. Contact
precautions and eye protection should be added when caring for probable or confirmed cases of MERS-CoV infection. Airborne precautions should
be used when performing aerosol-generating procedures.
The CDC recommends the use of standard, contact, and airborne precautions for the management of hospitalized patients with known or suspected
MERS-CoV infection [36-38].
Because respiratory secretions from MERS-CoV–infected patients have been shown to contain viral RNA for at least three weeks after symptom
onset and because viable virus has been isolated from hospital room air samples and surfaces two and three weeks after first diagnosis [39],
infection control precautions should be applied until lower respiratory tract samples (sputum or tracheal aspirates) become RNA negative or until
discharge, whichever occurs first [40].
The efficacy of these recommended measures has not been formally tested. However, a large 2015 hospital-based outbreak in Riyadh, Saudi Arabia,
ended after an aggressive prevention program was instituted by a Ministry of Health Rapid Response Team [41]. Although several hospital functions
had to be closed down in the process, it seems likely that infection control measures played a role in ending the epidemic.
Additional information can be found on the WHO's website and the CDC's website.
Interim home care and isolation — The CDC recommends that ill individuals who are being evaluated for MERS-CoV infection and do not require
hospitalization may be cared for and isolated in their home [42]. Healthcare providers should contact their state or local health department to
determine whether home isolation or additional measures are indicated because recommendations might be modified as more data become
available. Isolation is defined as the separation or restriction of activities of an ill person with a contagious disease from those who are well.
Additional information on home care and isolation guidance is available on the CDC's website.
Avoiding camels — The WHO recommends that individuals at high risk of severe disease, such as immunocompromised hosts and those with
diabetes, chronic lung disease, or preexisting renal failure, take precautions when visiting farms, barn areas, camel pens, or market environments
where camels are present [43]. These measures include avoiding contact with camels, practicing good hand hygiene, avoiding drinking raw camel
milk or camel urine, avoiding eating meat that has not been cooked thoroughly, and avoiding eating food that may be contaminated with animal
secretions or products unless they are properly washed, peeled, or cooked.
The WHO recommends that when visiting a farm or barn, members of the general public adhere to general hygiene measures, including regular
hand washing before and after touching animals, avoiding contact with sick animals, and following food hygiene practices [44]. Unless wearing a face
mask and protective clothing, individuals should avoid contact with any camel that has tested positive for MERS-CoV until subsequent tests have
confirmed that the animal is free of virus [43].
Specific recommendations for camel farm and slaughterhouse workers can be found on the WHO's website.
Travel recommendations — Detailed information for travelers to Mecca, Saudi Arabia, for Hajj and/or Umrah can be found on the WHO's website
[45]. The WHO does not recommend either special screening for MERS-CoV at points of entry or the application of any travel or trade restrictions.
However, the WHO recommends that countries outside the affected region maintain a high level of vigilance, especially countries with large numbers
of travelers or guest workers returning from the Middle East [33].
There has been both active and passive screening of symptomatic and asymptomatic travelers returning from the Hajj and, to a lesser extent,
Umrah, and, although many respiratory viruses have been detected, no cases of MERS-CoV infection have been reported among Hajj pilgrims from
countries outside Saudi Arabia [46,47]. Eight cases of MERS were reported among foreign pilgrims attending Umrah between 2012 and 2014 [48].
Several of these cases had high-risk exposures, such as exposure to known MERS cases. Despite the low risk associated with Hajj and Umrah
pilgrimages, it is nevertheless recommended that MERS surveillance in these settings continue [49].
In May 2014, the CDC's travel notice was upgraded to a Level 2 Alert, which includes enhanced precautions for travelers to countries in or near the
Arabian Peninsula who plan to work in healthcare settings [42]. Such individuals should review the CDC's recommendations for infection control for
confirmed or suspected MERS patients before they depart, practice these precautions while in the area, and monitor their health closely during and
after their travel.
The CDC recommends that all United States travelers to countries in or near the Arabian Peninsula protect themselves from respiratory diseases,
including MERS-CoV, by washing their hands often and avoiding contact with persons who are ill [42]. If travelers to the region have onset of fever
with cough or shortness of breath during their trip or within 14 days of returning to the United States, they should seek medical care. They should call
ahead to their healthcare provider and mention their recent travel so that appropriate isolation measures can be taken in the healthcare setting. More
detailed travel recommendations related to MERS are available on the CDC's website.
Vaccine development — There is no licensed MERS-CoV vaccine for use in humans, although several experimental candidate MERS-CoV
vaccines are being developed [6]. Examples include a vaccine based on the major surface spike protein using recombinant nanoparticle technology,
a recombinant modified vaccine Ankara (MVA) vaccine expressing full-length MERS-CoV spike protein, a vesicular stomatitis virus (VSV)-based
vaccine in which the full-length S protein has been substituted for the VSV G protein, DNA vaccines, and vaccines encoding the full-length MERS-
CoV S protein and the S1 extracellular domain of S protein using adenovirus vectors [50-57].
Animal models have been used to evaluate candidate vaccines that could eventually be used in humans. In one study, immunogens based on full-
length S DNA and S1 subunit protein administered in a prime-boost regimen elicited robust serum neutralizing activity against several MERS-CoV
strains in mice and rhesus macaques [58]. Immunization of rhesus macaques reduced the severity of MERS-CoV–induced pneumonia, as assessed
by computed tomography. In another study, a DNA vaccine encoding the MERS spike protein induced potent cellular immunity and neutralizing
antibodies in mice, macaques, and camels [59]. Following a challenge with MERS-CoV, vaccinated macaques were protected from MERS-CoV
infection and showed no signs of clinical or radiographic signs of pneumonia.
An alternative approach to vaccinating humans involves immunizing camels against MERS-CoV, since camels are hosts for MERS-CoV and are
likely to be an important source of MERS-CoV. In one study, an MVA vaccine expressing the MERS-CoV spike protein conferred mucosal immunity
in dromedary camels [60]. Significant reductions of excreted infectious virus and viral RNA transcripts were observed in vaccinated animals following
MERS-CoV challenge compared with controls. Protection correlated with the presence of serum neutralizing antibodies against MERS-CoV.
The development and deployment of vaccines for MERS pose unique challenges related to the virus' particular ecology, the biology of coronaviruses,
and the availability and adequacy of animal models for testing [61].
Monoclonal antibodies — Monoclonal antibodies are being investigated for both prophylaxis and treatment of MERS. None are licensed for use.
Monoclonal antibodies are discussed in greater detail above. (See 'Treatment' above.)
OUTCOMES
As of late September 2019, 851 of 2468 patients (34 percent) with laboratory-confirmed MERS-CoV infection reported to the World Health
Organization (WHO) have died [62]. Because individuals with mild symptoms are less likely to be evaluated than patients with severe disease, those
with MERS-CoV and mild disease might be underrepresented in published reports and reports from the WHO [63]. The reported case-fatality rate
might therefore be an overestimate. This hypothesis is supported by an analysis pointing out that 14 of 19 (74 percent) patients with infection
detected through routine surveillance died compared with 5 of 24 (21 percent) of secondary cases [64].
In a study of 47 patients with MERS-CoV infection in Saudi Arabia, case-fatality rates rose with increasing age, from 39 percent in those younger
than 50 years of age, to 48 percent in those younger than 60 years of age, to 75 percent in those aged 60 years or older [65]. Several separate
analyses have shown similar findings [64,66]. In another study, independent risk factors for death among 939 cases reported to the Saudi Ministry of
Health were age over 80 years, underlying cardiac disease or cancer, and acquisition as a hospitalized patient [67]. In a study of 159 patients with
MERS-CoV in South Korea, older age and preexisting comorbidities were risk factors for death [68]. Another study also suggested that patients with
comorbidities had a higher risk of fatal infection [69].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society
guideline links: Middle East respiratory syndrome coronavirus".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in
plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Middle East respiratory syndrome coronavirus (The Basics)")
SUMMARY AND RECOMMENDATIONS
● A novel coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), causing severe respiratory illness emerged in 2012 in Saudi
Arabia. Many additional cases and clusters of MERS-CoV infections have been detected subsequently in the Arabian Peninsula, particularly in
Saudi Arabia (figure 1). Cases have also been reported from other regions, including North Africa, Europe, Asia, and North America (table 1). In
countries outside of the Arabian Peninsula, patients developed illness after returning from the Arabian Peninsula or through close contact with
infected individuals. (See 'Introduction' above and "Middle East respiratory syndrome coronavirus: Virology, pathogenesis, and epidemiology",
section on 'Epidemiology'.)
● There is currently no treatment recommended for coronavirus infections except for supportive care as needed. (See 'Treatment' above.)
● An increased level of infection control precautions is recommended when caring for patients with probable or confirmed MERS-CoV infection
compared with that used for patients with community-acquired coronaviruses or other community-acquired respiratory viruses. The United
States Centers for Disease Control and Prevention (CDC) recommends the use of standard, contact, and airborne precautions for the
management of hospitalized patients with known or suspected MERS-CoV infection. (See 'Infection control' above.)
● The World Health Organization (WHO) does not recommend either special screening for MERS-CoV at points of entry or the application of any
travel or trade restrictions. (See 'Travel recommendations' above.)
● There is no licensed vaccine for MERS-CoV. (See 'Vaccine development' above.)
● Additional information about MERS-CoV can be found on the WHO's website and the CDC's website.
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Topic 106550 Version 31.0
GRAPHICS
Epidemic curve of laboratory-confirmed Middle East respiratory syndrome coronavirus human infections reported to the World He
Other countries: Algeria, Austria, Bahrain, China, Egypt, France, Germany, Greece, Iran, Italy, Jordan, Kuwait, Lebanon, Malaysia, Netherlands, Oman, Philippines, Qatar, Thailand, T
Please note that the underlying data is subject to change as the investigations around cases are ongoing. Onset date estimated if not available.
Reproduced with permission from: World Health Organization. Emergencies preparedness, response: Middle East respiratory syndrome coronavirus (MERS-CoV) maps and epicurves, 16 July 201
2019).
Graphic 95981 Version 11.0
Countries with reported cases of Middle East respiratory syndrome
Algeria Netherlands
Austria Oman
Bahrain Philippines
China Qatar
Egypt Saudi Arabia
France South Korea
Germany Thailand
Greece Tunisia
Iran Turkey
Italy United Arab Emirates
Jordan United Kingdom
Kuwait United States
Lebanon Yemen
Malaysia
Graphic 102411 Version 3.0
Contributor Disclosures
Kenneth McIntosh, MD Nothing to disclose Martin S Hirsch, MD Nothing to disclose Allyson Bloom, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process,
and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
Conflict of interest policy
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Middle East Respiratory Syndrome Coronavirus Treatment and Prevention

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22/3/2020 Middle East respiratory syndrome coronavirus: Treatment and prevention - UpToDate

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Middle East respiratory syndrome coronavirus: Treatment and prevention

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SUMMARY AND RECOMMENDATIONS

● There is no licensed vaccine for MERS-CoV. (See 'Vaccine development' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

50. Novavax. Novavax produces MERS-CoV vaccine candidate. http://www.novavax.com/download/releases/2013-06-06%20CoronaV%20FINA

Topic 106550 Version 31.0

Graphic 95981 Version 11.0

Countries with reported cases of Middle East respiratory syndrome

Egypt Saudi Arabia

France South Korea

Italy United Arab Emirates

Jordan United Kingdom

Kuwait United States

Graphic 102411 Version 3.0

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