2014 Coronaviruses

2014·0.28 MB·English

REVIEW
CURRENT Coronaviruses: severe acute respiratory syndrome
O
PINION
coronavirus and Middle East respiratory syndrome
coronavirus in travelers
Jaffar A. Al-Tawfiqd,e, Alimuddin Zumlaa,c, and Ziad A. Memisha,b
Purposeofreview
Middle Eastrespiratory syndrome coronavirus (MERS-CoV)is currently the focusof globalattention. In this
review, wedescribe virological, clinical, epidemiological featuresand interim travel advice and guidelines
regarding MERS-CoV.Wecompare and contrast these withthe severeacute respiratory syndrome
coronavirus (SARS-CoV).
Recent findings
MERS-CoV isanovel bCoVthat causes aspectrum of clinicalillness from asymptomatic tothe rapidly fatal
disease mainly inthosewithcomorbid conditions. Epidemiological andgenomic studiesshow zoonotic
transmission to humansfrom camels and possibly bats. Incontrast to the SARS-CoV pandemic, verylimited
global spread offatal MERS-CoV has occurred outside the ArabianPeninsula. Although mainly currently
restricted to Middle Eastern countries, MERS-CoVwasreported from at least10other countriesinEurope,
Asia and the UnitedStates. All primarycases havebeen linked to travel tothe Middle East. Nosocomial
transmission of MERS-CoVhas occurred because ofpoor infection controlmeasures. Specific molecular
diagnostic tests areavailable. Currently, there areno specific drugsfor prevention ortreatment for MERS-
CoVand vaccine development isinthe early stages. Adviceand guidance for travelersto the Middle East
are updated regularlyby the WorldHealth Organization (WHO)and the Centers forDisease Control and
Prevention (CDC).
Summary
Like SARS-CoV, MERS-CoV threatens globalhealth security.All physicians and travelers tothe Middle East
should be aware ofthe new threat caused byMERS-CoV and followCDCand WHO guidelines. Those
who develop ill health duringtheir trip orsoonafter their return should seek medical care.
Keywords
coronaviruses, MERS-CoV, Middle East, SARS-CoV, travel
INTRODUCTION features, and interim travel advice and guidelines
for the MERS-CoV, a new threat to travelers to the
Coronaviruses (CoVs) are a group of viruses known
Middle East. It was first detected in Saudi Arabia in
to cause mild to severe diseases in humans. The
group consists of alpha, beta, gamma, and delta
subgroups. Six human CoVs (HCoVs) are known
aGlobal Centre for Mass Gatherings Medicine, Ministry of Health,
to cause disease in humans: HCoV-229E, HCoV-
bCollege of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi
OC43, HCoV-NL63, HCoV-HKU1, severe acute Aarabia, cDepartment of Infection, Division of Infection and Immunity,
respiratory syndrome coronavirus (SARS-CoV), CentreforClinicalMicrobiology,UniversityCollegeLondon,andNIHR
and most recently the Middle East respiratory syn- Biomedical Research Centre, University College London Hospitals,
London, UK, dJohns Hopkins Aramco Healthcare, Dhahran, Kingdom
dromecoronavirus(MERS-CoV)[1].BothSARS-CoV
ofSaudiArabiaandeIndianaUniversitySchoolofMedicine,Indianapolis,
andMERS-CoVbelongtothebetaCoVs.SARS-CoV
Indiana,USA
initially emerged in 2003 in China [2] and MERS-
Correspondence to Professor Ziad A. Memish, MD, FRCP(Can),
CoV was first identified in the Kingdom of Saudi
FRCP(Edin),FRCP(Lond),FACP,MinistryofHealth,P.O.Box54146,
Arabiain2012[3].WhilstMERS-CoVandSARS-CoV Riyadh11514,SaudiArabia.Tel:[phone];e-mail:zmemish@
sharesomecommonvirologicalandclinicalfeatures yahoo.com
there are several important differences [4&&]. Here, CurrOpinInfectDis2014,27:411–417
we describe virological, clinical, epidemiological DOI:10.1097/QCO.0000000000000089
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Tropical and travel-associated diseases
WHAT ARE THE VIRAL RECEPTORS?
KEY POINTS
Thetargetofthevirusseemstobedifferentbetween
(cid:1) Similarities exist betweenSARS and MERSinrelation to SARS-CoV and MERS-CoV. Although angiotensin-
the clinical and laboratory data. converting enzyme 2 is the host receptor of SARS-
CoV [20], dipeptidyl peptidase 4 (DPP4, otherwise
(cid:1) Case fatality rateof MERS was60% initiallyand now
knownasCD26)wasidentifiedasthecellularrecep-
approaches 30%as more asymptomatic casesare
tor for MERS-CoV [21,22]. DPP4 homologues are
recognized.
present in a variety of cell lines [23,24].
(cid:1) Travel-associated infections withSARSand MERS have
occurred, but itseems these arelowerwithMERS-CoV.
RISK OF IN-FLIGHT TRANSMISSION
The risk ofin-flight transmission ofMERS-CoV was
calculatedtobeonenewinfectionina5-hourflight
September2012,andiscurrentlythefocusofglobal in first class, and 15 infections from a ‘super-
attention because of its epidemic potential. We spreader’ traveling 13h in an economy class [25].
compareandcontrastthesewiththeSARS-CoVfirst So far, there has been no confirmed in-flight trans-
detected at the end of 2002 in China and which missionofMERS-CoV.TwocasesofMERS-CoVwere
spread globally via travelers. reported to be introduced to United States from
patients who traveled from Saudi Arabia with no
documented in-flight transmission [26&].
INITIAL CASES
The in-flight transmission of SARS was studied
SARS-CoV was first reported in 2003 from China, in a few reports. In one study of a flight carrying a
Guangdong Province, and later spread to 37 symptomatic SARS patient, laboratory-confirmed
countriesandresultedin8273confirmedcaseswith SARS developed in 16 of 119 (13.4%) passengers.
a case fatality rate of 9% [5]. Outbreaks of atypical Development of SARS was related to the physical
pneumonia were reportedin Vietnam,Hong Kong, proximitytotheindexpatient,SARSwasreportedin
Canada, and Singapore in February–March 2003 eightof23personsseatedinthethreerowsinfront
[2,6–9].Itwasreportedthatthesecaseswerelinked of the index patient, and in 10 of the 88 persons
toindexpatientswhostayedontheninthfloorofa seated elsewhere [27]. In a second flight with four
hotel in Hong Kong on 21–22 February 2003 [10]. symptomatic persons, only one passenger devel-
Most of the reported cases occurred in Southeast oped illness and no illness was documented in
Asia (China, Hong Kong, Taiwan, Singapore, and passengers on a third flight with presymptomatic
Vietnam).InNorthAmerica,27caseswereimported SARSpassenger[27].Twopatientswereexposedtoa
into the United States and 251 cases were recorded SARS patient in flight from Hanoi to Paris [28] and
in Canada [11]. inotherinstances[29].Otherstudiesfailedtoshow
MERS-CoV was first reported from a Saudi in-flight transmission [30–32].
ArabianpatientinSeptember,2012,whodiedfrom
severe respiratory illness in June 2012 [3,12]. The
CLINICAL PRESENTATIONS, LABORATORY
virus was originally known as HCoV-EMC [3], and
FINDINGS, AND RADIOGRAPHIC
was subsequently designated as MERS-CoV [13&].
PRESENTATION
Retrospectively,thefirstknownoutbreakwasident-
ified in a hospital in Zarqa, Jordan [14&,15]. This TheincubationperiodofSARSwascalculated tobe
outbreak was recognized after the identification of 4.6days[33],andthatofMERS-CoVtobe5–14days
theMERS-CoVinSeptember2012,astwospecimens [34&&]. The median time from symptom onset of
from deceased patients were retrospectively tested MERS-CoVpatientstohospitalizationwas3–4days
positive for MERS-CoV by real-time polymerase and the median time from admission to an ICU
chain reaction [15]. and to death was 5 and 11.5 days, respectively
Intrafamilial clusters of MERS-CoV infection [34&&,35&&]. In MERS-CoV, there is a male predom-
showed that MERS-CoV infection usually causes inancedissimilarfromSRAS[2,36,37,38&&,39&].There
mild or asymptomatic infection in these contacts isahugeoverlapintheclinicalpresentationsbetween
[16,17].Subsequentstudiesdocumentedseveredis- SARS-CoV and MERS-CoV infections [2,36,37,38&&,
easeinfamilycontacts[18&].Sincetheemergenceof 39&].Commonpresentingsymptomsinclude:fever,
MERS-CoVin2012,therehasbeenarecentincrease cough,dyspnea,chills,rigor,headache,myalgia,and
innumberofcases.InApril2014,therewereatotal malaise[2,9,33,40–44].Atypicalinitialsymptomsof
of145cases,or56%ofthetotalcasesreportedfrom diarrheaandvomitingwerereportedinpatientswith
Saudi Arabia and United Arab Emirates [19]. MERS and SARS [34&&,35&&,38&&]. The initial cases of
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Coronaviruses Al-Tawfiq etal.
MERS-CoVinfectionshowedrelativelydifferentfind- and 14.7% of Pipistrellus bats in Ghana and four
ings from SARS. In patients with SARS, preexisting European countries [53]. One fragment of MERS-
chronicillnesseswerelesscommon:diabetes,24vs. CoV was found in one Taphozous bat out of 1100
68%; renal disease, 2.6 vs. 49%, and heart disease, batsamples,withclosematchingtoahumanisolate
10 vs. 28% [35&&]. SARS cases were mainly seen in of MERS-CoV [54&]. Recent studies point toward
younghealthy individuals;this isincontrasttothe camels as a possible source of MERS-CoV infection.
fact that more than half of the cases of MERS-CoV Neutralizing antibody levels against MERS-CoV
infectionoccurredinindividualsolderthan50years were found in camels from the Spanish Canary
[34&&,35&&,38&&,45&]. The mortality rate of the initial Islands,Oman,andEgypt[55&].Avirologicalconfir-
casesofMERS-CoVwasabout70%ofsevere disease mationofanoutbreakofMERS-CoVinvolvingthree
and later the case-fatality rate was much lower camels and two humans in Qatar showed that the
[34&&,35&&,38&&,39&,46]. isolated MERS-CoV was very similar to the MERS-
InpatientswithSARS-CoVandMERS-CoVinfec- CoV from two human cases on the same farm and
tions, patients typically have lymphopenia and a MERS-CoV isolate from Hafr Al-Batin [56&]. In
may have increased activated prothrombin time Oman, five (6.5%) of 76 dromedary camels tested
[34&&,35&&,38&&]. However, lymphopenia was not positiveforMERS-CoV,andtheMERS-CoVsequen-
different in cases and control of MERS-CoV [38&&]. ces (3754 nucleotides) from Oman and Qatar were
The viral loads in the lower respiratory tract were closely related to human MERS-CoV sequences
higher than in the upper respiratory tract and the [57&].CompleteMERS-CoVgenomesequenceswere
yieldofgenomicfractionwashigheraswellinlower obtained from nasal swabs of dromedary camels in
respiratory tract samples [47&&]. Tracheal aspirates SaudiArabiaandthedromedaryMERS-CoVgenome
produced higher MERS-CoV viral load compared sequences were identical to human MERS-CoV
with nasopharyngeal swabs (P¼0.005) and to sequences[58&].Therewasmorethanonegenomic
sputum (P¼0.0001) and tracheal aspirates had a variantinindividualdromedaries[58&].Althougha
similar viral load compared with bronchoalveolar high percentage of dromedary camels had cir-
lavage (P¼0.3079) [47&&]. In both SARS-CoV and culating MERS-CoV-neutralizing antibodies, sheep,
MERS-CoV, there is a predominance of peripheral goats, and cows were negative for MERS-CoV-
and lower zone pulmonary infiltrate, then the neutralizing antibodies [59,60]. These data link
progressive development of multifocal or bilateral camels to MERS-CoV, although another source of
pulmonary infiltrates with more rapid progression anintermediatehostthatisyettobeidentifiedmust
in MERS-CoV than SARS-CoV infection [2,3,36,37, exist, as only a portion of index cases reported
38&&,39&]. contact with camels.
SEVERE ACUTE RESPIRATORY TRAVEL-RELATED MIDDLE EAST
SYNDROME CORONAVIRUS AND MIDDLE RESPIRATORY SYNDROME
EAST RESPIRATORY SYNDROME CORONAVIRUS
CORONAVIRUS ANIMAL RESERVOIRS
MERS-CoV is currently restricted to Middle Eastern
SincetheinitialdescriptionofbothSARSandMERS, countries and was reported from Saudi Arabia,
it was speculated that these viruses were linked to UnitedArabEmirates,Qatar,Oman,Jordan,Kuwait,
bats[3].Batsingeneralandspeciallythehorseshoe Yemen,andLebanon.MERS-CoVhasbeenreported
bats (Rhinolophus genus) exhibited detectable anti- from at least 10 other countries in Europe and Asia
bodies to SARS-CoV and carried CoVs that were and the first two cases have been reported recently
phylogenetically related to SARS-CoV, SARS-CoV- from the United States [61]. Countries with travel-
like coronaviruses [48,49]. SARS-CoV-like CoVs associated cases include: United Kingdom, France,
had 88–92% sequence homology with human or Tunisia, Italy, Malaysia, Philippines, Greece, Egypt,
civetisolatesandbatscouldbethenaturalreservoir United States, and the Netherlands [61]. The
[50]. Although the findings were questioned, there first imported MERS-CoV infection was found in a
was evidence pointing to a link between SARS-CoV 49-year-old Qatari who was treated in the United
and masked palm civets [50,51]. Kingdom [62]. The first imported case into United
ForMERS-CoV,batswerethoughttoberespon- States was announced on 2 May 2014 [63]. The
sible for the transmission of the virus. A closely patient traveled from Saudi Arabia to Indiana, via
related bat CoVs, BtCoV-HKU4 and BtCoV-HKU5 London and Chicago. The patient is a healthcare
were found to be phylogenetically linked to MERS- workerwholivesandworksinSaudiArabia[63].The
CoV [52]. Beta CoVs closely related to MERS-CoV second case was announced on 11 May 2014, in a
wereshown tobepresentin24.9%of Nycteris bats traveler who also came to the United States from
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Tropical and travel-associated diseases
Saudi Arabia and is also a healthcare worker who diseases (such as: heart disease, kidney disease,
traveled from Saudi Arabia to Orlando via London, respiratory disease and diabetes) and pilgrims with
Boston,andAtlanta[63].On17May2014,thefirst immune deficiency (congenital and acquired),
locally acquired MERS-CoV was announced in the malignancy,andterminalillnesses,pregnantwomen
United States where the first case likely passed the andchildrenunder12years[74].
infectiontoacolleagueinIndianaaftertwobusiness
meetingsinwhichtheywereincloseproximity[64].
TREATMENT FOR SEVERE ACUTE
However,subsequenttestingofthiscontactproved
RESPIRATORY SYNDROME AND MIDDLE
thathewasnegativeforMERS-CoVbyserology(see:
EAST RESPIRATORY SYNDROME
http://www.cdc.gov/media/releases/2014/p0528-
mers.html,accessed2July2014).IntheNetherlands, There is no approved therapy for SARS and MERS
twoimportedcaseswerereportedon13and15May infections. Recent publications summarized the
2014 by National Institute for Public Health and therapeuticoptions[75–77].Thesestudiesdiscussed
the Environment (RIVM) [65]. A man and woman the different options: interferon alpha, lopinavir/
sharedahotelroomfor2weeksandbothsufferfrom ritonavir, ribavarin, inhibitors of virus replication
underlying conditions [65]. Other imported cases such as cylcophilin inhibitors, inhibition of MERS-
were reported in: UK (4 cases/3 deaths), Germany CoVcellreceptors(DPP4,alsoknownasCD26),and
(2 cases/1 death), France (2 cases/1 death), Italy MERS-CoVneutralizationantibodies.Noneofthese
(1 case/0 deaths), Greece (1 case/0 deaths), Tunisia agents were shown to be conclusively effective. An
(3 cases/1 death), Malaysia (1 case/1 death), Philip- observational study used interferon and ribavarin
pines (1 case/0 deaths) [66]. Local secondary trans- for the therapy of five MERS-CoV patients [75,76].
missionfollowingimportationwasreportedfromthe The study did not reveal a survival advantage, as
UnitedKingdom,France,Tunisia,andUnitedStates these agents were used late in the course of the
[66] after a primary case was imported. The trans- disease. Recently, three human monoclonal anti-
mission resulted in the infection of one healthcare bodies,m336,m337,andm338,targetingtherecep-
worker in France, to one close contact of a primary tor(CD26/DPP4)-bindingdomainoftheMERS-CoV
case in Tunisia, and a second close contact who spikeglycoproteinneutralizedMERS-CoV[78].Also,
traveledtoSaudiArabiadevelopedconfirmedinfec- apanelofneutralizingantibodiesofferedthepossib-
tionandtotwofamilycontactsintheUK. ility of developing human monoclonal antibody-
The US CDC recommends the following for based immunotherapy [79]. More recent in-vitro
travelers to prevent MERS-CoV infection [67]: studies from 231 screening activities showed a list
of 66 compounds that were active against SARS-
(1) Wash hands often with soap and water. If soap CoV, 232 MERS-CoV, or both [80]. Of these, six
and water are not available, use an alcohol- drugs were active against SARS-CoV only, 33 drugs
based hand sanitizer. were active against MERS-CoV only, and 27 drugs
(2) Avoid touching your eyes, nose, and mouth. wereactiveagainstbothSARS-CoVandMERS-CoV,
(3) Avoid close contact with sick people. andthesedrugsweregroupedin13differentthera-
peuticclasses[80].In-vitrostudiesalsoshowedthat
chloroquine,chlorpromazine,loperamide,andlopi-
MIDDLE EAST RESPIRATORY SYNDROME
navir inhibited MERS-CoV replication and the rep-
CORONAVIRUS AND THE ANNUAL HAJJ
lication of SARS-CoV and human CoV 229E [81].
Annual Hajj attracts pilgrims from 184 countries InhibitionofSARS-CoVandMERS-CoVhelicasewas
[68,69]. There is always the concern of potential accomplished by SSYA10–001 [82].
occurrence of outbreaks during mass gatherings
such as the Hajj. The 2012 annual Hajj season had
VACCINES FOR SEVERE ACUTE
no reported MERS-CoV cases among four million
RESPIRATORY SYNDROME AND MIDDLE
pilgrims [70], and MERS-CoV test was negative
EAST RESPIRATORY SYNDROME
among300symptomaticpilgrimswithupperrespir-
atory symptoms [71] and among a cohort of 154 In general, there is no vaccination for CoVs. With
French pilgrims, [72]. For the annual 2013 Hajj, the emergence of SARS-CoV in 2003, vaccines for
MERS-CoV was not detected in 3210 pre-Hajj and SARS were being developed and were based on
2025post-Hajjsamplesobtainedfrompilgrimsfrom whole or inactivated SARS-CoV, spike subunits,
22 different countries [73&&]. The Saudi Ministry of recombinant viruses or DNA plasmids expressing
HealthrecommendationsregardingtheannualHajj SARS-CoV proteins, or virus-like particles. In mice,
advise the following people to postpone the Hajj: amodifiedvacciniavirusandspikesubunitvaccines
people 65 years and older, and those with chronic inducedMERS-CoV-neutralizingantibodies[83,84].
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Coronaviruses Al-Tawfiq etal.
30
25
20
15
Number
10
5
0
21/03/14 28/03/14 04/04/14 11/04/14 18/04/14 25/04/14 02/05/14 09/05/14 16/05/14 23/05/14
FIGURE 1. Number of reported Middle East respiratory syndrome coronavirus cases in Saudi Arabia from 21 March 2014 to
27May2014 [92].
ItwasspeculatedthattheuseofMERS-CoV-neutral- TherecentincreaseinthenumberofMERS-COV
izing monoclonal antibody in exposed individuals cases reported primarily from Jeddah in April 2014,
such as a patient’s family member or a healthcare were mainly related to poor infection control
worker before or after exposure to MERS-CoV may measures at hospitals. The total reported number
prevent or inhibit MERS-CoV infection [85]. Intra- of MERS-CoV cases since the initial description of
nasal vaccination of MERS-CoV receptor-binding thediseaseto28May2014bySaudiArabiawas562
protein (RBD)-Fc induced systemic humoral with increasing numbers of cases since March 2014
immune responses comparable with subcutaneous (Fig.1)[91,92].Tworecentcommentariesemphasize
vaccination. Intranasal vaccination also produced the need to adhere to recommended infection
more robust systemic cellular immune responses controlmeasures[64,92]. The WorldHealth Organ-
and higher local mucosal immune responses in ization recommendations of airborne infection pre-
mouse [86]. A truncated RBD protein showed cautionstobeusedinaerosol-generatingprocedures
promise for the development of an effective and [93] and the US and European Centers for Disease
welltoleratedvaccine[87].AnrMERS-CoVdeletion Control and Prevention (CDC) recommendations
mutant with the E gene deleted showed a replica- of airborne infection isolations for all MERS-CoV
tion-competent, propagation-defective virus that patients[94].
couldonlybegrowninthelaboratorybyproviding
E protein in Trans, whereas it would only survive a
CONCLUSION
single virus infection cycle in vivo and may be a
Like SARS-CoV, MERS-CoV threatens global health
vaccine candidate [88].
security. All physicians and travelers to the Middle
East should be aware of the new threat caused by
INFECTION CONTROL MERS-CoV and follow CDC and WHO guidelines.
Those who develop ill health during their trip or
Thereisaclearbutlimitedhuman-to-humantrans-
soonaftertheirreturnshouldseekmedicalcare,and
missionofMERS-CoV.Outsidethehospitalsetting,
allphysiciansmusttakeatravelhistory.Appropriate
the transmission of MERS-CoV seems to be infre-
isolation measures shouldbe undertaken in all sus-
quent and intermittent. In a study of 130 blood
pected and confirmed cases.
donors in Jeddah in 2012 and 226 abattoir workers
in Jeddah and Makkah in October 2012, eight
Acknowledgements
showedreactiveserabyimmunofluoresencetesting
and were not specific for MERS-CoV [89]. Non- None.
MERS-CoV-neutralizing antibodies were detected
in 268 samples obtained from persons from the Conflicts of interest
Eastern province of Saudi Arabia [90]. All authors have no conflict of interest to declare.
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Tropical and travel-associated diseases
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