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Middle East Respiratory Syndrome(MERS-CoV)

Epidemiology on the ground identifies and tracks a newrespiratory virus.

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ast year, the infectious disease and public healthcommunities learned of a new severe acute re-spiratory infection in Saudi Arabia. The stun-

ningly rapid identification of the causative organism,the development of a diagnostic assay, online andahead-of-print publishing, and heightened global sur-veillance efforts have made it possible to track theslow emergence of this new, often deadly infection.

In September 2012, a post on ProMED-mail re-ported that a novel human coronavirus had beenisolated from the sputum of a 60-year-old Saudi Ara-bian man with pneumonia.1(ProMED-mail, foundat www.promedmail.org, is a free, Internet-basedglobal reporting system from the International Society

for Infectious Diseases that rapidly disseminates infor-mation on outbreaks of infectious disease and toxin

exposures.) The man died from acute respiratory dis-tress syndrome and renal failure in June 2012.2

A pan-coronavirus assay of postmortem lung tissuewas positive. (Coronaviruses, named for the crown-like projections on their surfaces, are among the vi-ruses that cause the common cold.) The virus wasforwarded to a research lab in Rotterdam, the Nether-lands, where it was further identified as a new humancoronavirus closely related to two bat coronaviruses.2This disease would later be named Middle East respi-ratory syndrome (MERS), and the organism wouldbe named MERS-CoV.

Also in September 2012, a previously healthy49-year-old man from Qatar (just east of Saudi Ara-bia) was hospitalized with severe respiratory symp-

toms and soon airlifted to a London ICU. With nodiagnosis yet established, and because there were simi-larities between the Qatar case and the one describedin ProMED-mail, the Qatari patient was tested forcoronavirus. The pan-coronavirus assay was positive.The United Kingdoms Health Protection Agency thencontacted the virologists in Rotterdam, who subse-quently confirmed a 99.5% match between the vi-ruses of the two patients.3

Remarkably, within a month, two real-time reverse-transcriptionpolymerase chain reaction assays for thenovel coronavirus were devised.4A test was essentialnot only for the confirmation of suspected cases, butto permit researchers to analyze the natural course ofthe infectionthe body fluids into which the virussheds, the duration and peak of viral shedding (indi-cating likely transmission periods), and the bodysresponse to treatment. In addition, asymptomaticcontacts could now be tested, possibly yielding epide-miologic clues about how these infections spread.

When an emerging infection is first recognized,clinicians and epidemiologists focus on several keyquestions: Are there other cases? What is the clinical spectrum of illness?

Where did the organism come from? What is itsreservoir?

EMERGING INFECTIONS

Electron microscope image of the MERS virus. Photo Associated Press.

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By Betsy Todd, MPH, RN, CIC

How is infection transmitted? Is there human-to-human spread? What infection control measures might stop

transmission?

CASE FINDING

Because a case definition is essential to case finding,the World Health Organization (WHO) quickly de-veloped one,5drawing on the international experi-ence with severe acute respiratory syndrome (SARS)in 2002 and 2003. SARS, too, was caused by a pre-viously unknown coronavirus, and SARS and thenew virus are the only coronaviruses known to causesevere disease in humans.

An estimate of the incubation periodthe timefrom infection to symptomshelps to shape a casedefinition. The usual SARS incubation period is upto 10 days6; with little else yet to go on, the same in-cubation period was proposed for MERS.

Case definitions are generally refined as more clin-ical and epidemiologic information becomes avail-able, and that has been the case with MERS-CoV

infection as well. (See Table 1 for current Centers forDisease Control and Prevention [CDC] definitions.)

Initially, a direct link to confirmed cases or to coun-tries where there have been confirmed cases was anintegral part of the MERS case definition.5However,the types of exposures that could lead to infectionwith this virus remain unclear. Under the currentWHO definition, MERS should be considered a pos-sible diagnosis in anyclusters of undiagnosed severeacute respiratory disease or in cases of severe acuterespiratory disease in health care workers exposed toseverely ill patients with respiratory disease.7

Cases of MERS-CoV infection have been reportedin France, Germany, Italy, Jordan, Qatar, Saudi Ara-bia, Tunisia, the United Arab Emirates, Oman, andthe United Kingdom.8Because there are no U.S. casesof MERS at this time, the CDC continues to considera link to one of these countries integral to the defini-tion of a suspected case.9As always when infectiousdisease is suspected, a travel history is an importantpart of a nursing or medical assessment.

In any unexpected cluster of infections (whetheran emerging infection is suspected, or infection iscaused by a well-understood organism), case find-

ing is retrospective as well as prospective. Havethere been previously undiagnosed illnesses with a

Table 1.MERS-CoV Case Definitions from the CDCa

A patient under investigation (PUI) has the following characteristics: fever (temperature 38C [ 100.4F]) and pneumonia or acute respiratory distress syndrome (based onclinical or radiologic evidence)and either

a history of travel from countries in or near the Arabian Peninsula bwithin 14 days before symptom onsetor

close contactcwith a symptomatic traveler who developed fever and acute respiratory illness (not neces-sarily pneumonia) within 14 days after traveling from countries in or near the Arabian Peninsulab

or is a member of a cluster of patients with severe acute respiratory illness (such as fever and pneumoniarequiring hospitalization) of unknown etiology thats being investigated, in consultation with state andlocal health departments, as possible MERS.

A probable caseWhen a PUI is a close contactcof a patient with laboratory-confirmed MERS-CoV infection but has inconclusive d

(or absent) laboratory results for MERS-CoV infection, the case is considered probable.

A confirmed caseA case is confirmed only when laboratory testing for MERS-CoV infection is positive.e

aCurrent MERS-CoV case definitions can be found at the Centers for Disease Control and Prevention: www.cdc.gov/coronavirus/mers/case-def.html.bCountries considered in or near the Arabian Peninsula are Bahrain, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Oman, Palestinian territories, Qatar, Saudi

Arabia, Syria, the United Arab Emirates, and Yemen.cClose contact is defined as: any person who provided care for the patient, including a health care worker or family member, or had similarly close

physical contact; or any person who stayed at the same place (lived with, visited) as the patient while the patient was ill.dExamples of laboratory results that may be considered inconclusive include a positive test on a single polymerase chain reaction target, a positive

test with an assay that has limited performance data available, or a negative test on an inadequate specimen.eConfirmatory laboratory testing requires a positive polymerase chain reaction test on at least two specific genomic targets or a single positive target with

sequencing on a second.

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EMERGING INFECTIONS

similar clinical picture? In the fall of 2012, MERScase-finding efforts led to the reinvestigation of anApril 2012 cluster of infections in a Jordan hospital,where two people including an ICU nurse died ofan undiagnosed respiratory infection. Retesting ofstored sputum and sera from these individuals con-firmed MERS-CoV infection.10

Its not yet clear when MERS-CoV shedding peaksor which body fluids are most likely to yield enoughvirus to test positive. Therefore, the optimal time fortestingthat is, the time during the course of infec-tion when specimens will most reliably test positiveis not yet known. The CDC recommends that lowerrespiratory tract specimens (sputum, bronchoalveolarlavage fluid, or endotracheal aspirate) be tested for

MERS-CoV when possible and that testing be re-peated at different times during the patients illnessto increase the likelihood that a diagnosis can bemade.11

Clinical findings.MERS usually presents as a rap-idly progressive pneumonia, but various other clinicalfeatures have also been described. Fever, cough, short-ness of breath, and progressively severe acute respira-tory disease are key symptoms in most cases.12Somecases of milder respiratory symptoms have been doc-umented, usually among close contacts of severecases. There have also been other manifestationsof MERS-CoV infection, including progressive re-

nal impairment2, 3, 12and gastrointestinal symptomssuch as diarrhea, vomiting, abdominal pain, andanorexia.12-14

Although most coronaviruses in humans causeonly mild illness, when zoonotic transmission oc-cursthat is, when a nonhuman virus jumps thespecies barrierthe virus can cause severe illnessand death.3Almost half of all people with confirmedMERS-CoV infections have died.8Death rates fromSARS, by contrast, were about 10%.6

When any emerging infection is first identified,severe cases and a high death rate arent always atrue reflection of the full spectrum of disease. Se-verely ill patients are more likely to seek medicalhelp; undiagnosed mild illness that resolves sponta-

neously is not likely to elicit further investigation.When enzyme-linked immunosorbent assaybased

serologic testing for MERS-CoV becomes available,serosurveys of asymptomatic individuals from thecommunities where cases have occurred will tell usmore about the continuum of disease caused byMERS-CoV.

Source and transmission.A source or reservoirfor the MERS virus has yet to be identified. In SaudiArabia more than 200 different animal species havebeen tested for the virus, and none has been positivefor MERS-CoV.15A recent study suggests that MERS-CoV or a similar virus has been circulating amongcamels,16although camels dont seem to play a centralrole in transmission; most people infected with MERS-CoV have had no direct contact with them.

Although MERS-CoV is closely related to certain

bat coronaviruses, that doesnt mean that contact withbats has been a source of human infection. Is anothermammal or bird an intermediate host?

The well-known coronaviruses are usually spreadby contact with contaminated surfaces and infectiousdroplets. These modes of transmission call for con-tact and droplet isolation precautions. But in the caseof SARS, there were instances in which spread mighthave been due to aerosolization of respiratory or fe-cal matter. With MERS-CoV, airborne transmissionappears to be possible.

The largest cluster of MERS-CoV infections todate, with 23 confirmed cases and 15 deaths, involved

hemodialysis units, ICUs, and general inpatient unitsat four hospitals in the eastern region of Saudi Ara-bia.12Most of those cases were hospital-acquired

infections, and all patient-to-patient spread occurredafter exposure to infected patients before MERS hadbeen diagnosed and, therefore, before those patientshad been isolated.

Limited person-to-person spread of MERS hasbeen documented, both among close household con-tacts and between patients and health care workers.12, 13No sustained chains of transmission have yet beenevident. As any emerging virus begins to adapt toits human host, however, limited person-to-personspread may merely be a prelude to more efficienttransmission. The large Saudi Arabian cluster men-

tioned above suggested the possibility of enhancedperson-to-person transmission of MERS-CoV.

The CDC recommends that lower respiratory tract specimens

be tested for MERS-CoV when possible and that testing be

repeated at different times during the patients illness.

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Ultimately, though, despite the extent of patient-to-patient transmission in that cluster, confirmed MERS-CoV infection developed in only three of 217 house-hold contacts and two of more than 200 exposedhealth care workers.

Infection control.The CDCs infection control rec-ommendations for suspected or confirmed cases ofMERS include the use of contact, droplet, and air-borne precautions, along with full personal protectiveequipmentgown, gloves, mask, and eye protection(goggles or face shield). Patients should be placed in anegative-pressure room. If the rooms air is not ex-hausted directly to the outside, a high-efficiency par-ticulate air filter unit should be placed in the room.17

As with active tuberculosis, the patient should

leave the negative-pressure room only for essentialtasks and needs to wear a surgical mask at suchtimes. (Surgical masks are designed to contain ex-haleddroplets; N-95 respirator masks filter inhaledparticles.) As with any emerging infectionthat is,any infection whose reservoirs and modes of trans-mission are not fully understoodthe number ofpersonnel entering the room of a patient with sus-pected or confirmed MERS should be limited.

This full spectrum of precautions is used because ofuncertainty about possible modes of MERS transmis-sion, the documented person-to-person transmission,and its apparently high mortality rate.15Note that, as

with any type of isolation precautions, routine proce-dures are adequate for the cleaning and disinfection ofenvironmental surfaces, equipment, laundry, and dish-ware and utensils. No special red bagging of items orseparate processing is necessary.17, 18

The WHO hasnt yet classified MERS-CoV asa public health emergency of international con-cern.19New cases of MERS-CoV infection con-tinue to be identified, and this virus has taken thespotlight away from other emerging viral infectionssuch as avian influenza A H1N1 and H7N9. Theseand other newly identified viruses percolate in manyparts of the globe. Because viral mutations are un-predictable, its impossible to predict whether anyof these viruses or yet another emerging virus willbe the cause of a new pandemic.

Betsy Todd is an infection prevention consultant. Contact au-thor: betsytoddrn@gmail.com. The author has disclosed no po-tential conflicts of interest, financial or otherwise.

REFERENCES

1. Zaki AM. Novel coronavirusSaudi Arabia: human isolate.International Society for Infectious Diseases (ProMED-mail);Sep 20, 2012. http://promedmail.org/direct.php?id=20120920.1302733.

2. Zaki AM, et al. Isolation of a novel coronavirus from a

man with pneumonia in Saudi Arabia. N Engl J Med2012;367(19):1814-20.

3. Bermingham A, et al. Severe respiratory illness caused by anovel coronavirus, in a patient transferred to the UnitedKingdom from the Middle East, September 2012. Euro Sur-veill2012;17(40):20290.

4. Corman VM, et al. Detection of a novel human coronavirusby real-time reverse-transcription polymerase chain reaction.Euro Surveill 2012;17(39)pii:20285.

5. World Health Organization. Global alert and response(GAR): Case definition for case finding severe respiratorydisease associated with novel coronavirus [superseded].2012. http://www.who.int/csr/disease/coronavirus_infections/case_definition_25_09_2012/en/index.html.

6. Centers for Disease Control and Prevention. Revised U.S.surveillance case definition for severe acute respiratory syn-drome (SARS) and update on SARS casesUnited Statesand worldwide, December 2003. MMWR Morb MortalWkly Rep2003;52(49):1202-6.

7. World Health Organization. Update: interim surveillancerecommendations for human infection with Middle East re-spiratory syndrome coronavirus [as of 27 June].Geneva,

Switzerland; 2013 Jun 27. http://www.who.int/csr/disease/coronavirus_infections/InterimRevisedSurveillanceRecommendations_nCoVinfection_27Jun13.pdf.

8. Centers for Disease Control and Prevention. Middle East re-spiratory syndrome (MERS). 2013. http://www.cdc.gov/coronavirus/mers.

9. Centers for Disease Control and Prevention. Middle East re-spiratory syndrome (MERS): case definitions. 2013. http://www.cdc.gov/coronavirus/mers/case-def.html.

10. Hijawi B, et al. Novel coronavirus infections in Jordan, April2012: epidemiological findings from a retrospective investi-gation. East Mediterr Health J2013;19(Suppl 1):S1-S18.

11. Centers for Disease Control and Prevention. Interim guide-lines for collecting, handling, and testing clinical specimensfrom patients under investigation (PUIs) for Middle East re-spiratory syndrome coronavirus (MERS-CoVversion 2.Atlanta; 2013 Jul 15. http://www.cdc.gov/coronavirus/mers/

downloads/guidelines-clinical-specimens.pdf.12. Assiri A, et al. Hospital outbreak of Middle East respiratory

syndrome coronavirus. N Engl J Med2013;369(5):407-16.

13. Guery B, et al. Clinical features and viral diagnosis of twocases of infection with Middle East Respiratory Syndromecoronavirus: a report of nosocomial transmission. Lancet2013;381(9885):2265-72.

14. Memish ZA, et al. Family cluster of Middle East respiratorysyndrome coronavirus infections. N Engl J Med2013;368(26):2487-94.

15. Grady D. Investigation follows trail of a virus in hospitals.New York Times2013 Jun 19. http://www.nytimes.com/2013/06/20/health/fast-spreading-virus-under-inquiry-in-saudi-arabia.html.

16. Reusken CB, et al. Middle East respiratory syndrome coro-navirus neutralising serum antibodies in dromedary camels:

a comparative serological study. Lancet Infect Dis2013;13(10):859-66.

17. Centers for Disease Control and Prevention. Interim infec-tion prevention and control recommendations for hospitalized

patients with Middle East respiratory syndrome coronavirus(MERS-CoV). 2013. http://www.cdc.gov/coronavirus/mers/infection-prevention-control.html.

18. Schulster LM, et al. Guidelines for environmental infectioncontrol in health-care facilities. Recommendations of CDCand the Healthcare Infection Control Practices AdvisoryCommittee (HICPAC). Chicago: American Society forHealthcare Engineering/American Hospital Association;2004. http://www.cdc.gov/hicpac/pdf/guidelines/eic_in_HCF_03.pdf.

19. World Health Organization. WHO statement on the secondmeeting of the IHR emergency committee concerning MERS-CoV. WHO media centre2013 Jul 17. http://www.who.int/

mediacentre/news/statements/2013/mers_cov_20130717/en/index.html.