【病毒外文文獻】2013 The emerging novel Middle East respiratory syndrome coronavirus_ The _knowns_ and _unknowns_

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The emerging syndrome coron unknowns Woo The and Received 16 April 2013 received in revised form 13 May 2013 accepted 14 May 2013 human HCoV EMC that is phylo trellus bat corona virus HKU5 which we discovered in 2007 from bats in Hong Kong has recently emerged in in humans Bisha the Kingdom red pneumonia and HO on September 23 2012 Since then a total of 70 cases including 39 fatalities have been reported in the Mid household contacts suggested possible ated in the past irs transmissibility and potential anti rights reserved Corresponding author Department of Microbiology Queen Mary Hospital The University of Hong Kong 102 Pokfulam Road Pokfulam Hong Kong China E mail address pcywoo hkucc hku hk P C Y Woo MODEL 0929 6646 see front matter Copyright 2013 Elsevier Taiwan LLC SARS the Middle East to cause a severe acute respiratory syndrome SARS like infection The first laboratory confirmed case which involved a 60 year old man from of Saudi Arabia KSA who died of rapidly progressive community acqui acute renal failure was announced by the World Health Organization W KEYWORDS coronavirus EMC A novel lineage C betacoronavirus originally named human coronavirus EMC 2012 and recently renamed Middle East respiratory syndrome coronavirus MERS CoV genetically closely related to Tylonycteris bat coronavirus HKU4 and Pipis Jasper Fuk Woo Chan Patrick Chiu Yat a State Key Laboratory of Emerging b Department of Microbiology c Research Centre of Infection Please cite this article in press as Chan and unknowns Journal of the Formosa novel Middle East respiratory avirus The knowns and a b c Susanna Kar Pui Lau a b c a b c Infectious Diseases The University of Hong Kong Hong Kong China University of Hong Kong Hong Kong China Immunology The University of Hong Kong Hong Kong China REVIEW ARTICLE JF W et al The emerging novel Middle East respiratory syndrome coronavirus The knowns n Medical Association 2013 http dx doi org 10 1016 j jfma 2013 05 010 increased to 34 with 20 deaths including two cases confirmed retrospectively from a Jordanian cluster of se 2 J F W Chan et al MODEL vere respiratory disease reported by the Ministry of Health of Jordan in April 2012 Table 1 6 7 10e14 Although the number of laboratory confirmed cases remains limited the severe clinical manifestations with an unusually high mor tality rate of over 50 the spread of the infection beyond the geographical confinement in the Middle East and the epidemiological evidence of human to human transmission arising from the recent clusters of cases in a family in the United Kingdom Cases 10 to 12 and in hospitals in KSA Cases 18 to 30 32 and 33 and France Cases 31 and 34 have raised significant concerns on the possible emergence of another SARS like epidemic in the near future In anticipation of the potential spread of this highly patho genic virus from the Middle East and Europe to other parts of the world especially the densely populated Southeast Asia an updated review of the latest research findings on MERS CoV and their implications on the clinical manage ment of MERS CoV infection is essential Viral genomic studies reveal the first lineage C betacoronavirus associated with human infection MERS CoV belongs to the genus Betacoronavirus in the family Coronaviridae under the order Nidovirales Corona viruses are enveloped viruses with positive sense single stranded RNA genomes Studies in their biodiversity comparative genomics and phylogeny in the past 10 years have improved our understanding of this family of viruses 15e30 According to the most recent classification by the Coronavirus Study Group of the International Commit tee for Taxonomy of Viruses there are four genera in Coronaviridae namely Alphacoronavirus Betacoronavirus Gammacoronavirus and Deltacoronavirus 28 31 The genus Alphacoronavirus contains two human coronaviruses HCoV 229E and HCoV NL63 which are associated with the common cold No human coronavirus has been discovered in Gammacoronavirus and Deltacoronavirus which mainly Introduction the new SARS Ten years after the devastating epidemic of severe acute respiratory syndrome SARS caused by SARS coronavirus SARS CoV which resulted in a total of 774 deaths among more than 8000 confirmed cases in over 30 countries the world is facing a new challenge posted by a SARS like infection caused by another novel coronavirus emerging from the Middle East which was originally named human coronavirus EMC 2012 HCoV EMC and recently renamed by the Coronavirus Study Group of the International Com mittee for Taxonomy of Viruses as Middle East respiratory syndrome coronavirus MERS CoV 1e8 The complete genome of the virus was sequenced and released in October 2012 after the isolation of the virus from two patients with severe community acquired pneumonia in Bisha the Kingdom of Saudi Arabia KSA and Doha Qatar first announced by the World Health Organization WHO on 23 September 2012 9 As of May 12 2013 the total number of laboratory confirmed cases of MERS CoV infection has Please cite this article in press as Chan JF W et al The emerging novel and unknowns Journal of the Formosan Medical Association 2013 contain avian coronaviruses with just a few mammalian coronaviruses The genus Betacoronavirus is comprised of four lineages A B C and D which contain four coronavi ruses associated with human infections HCoV OC43 and HCoV HKU1 lineage A SARS CoV lineage B and MERS CoV lineage C 15 MERS CoV is the first known lineage C betacoronavirus associated with human infection and is phylogenetically closely related to the other lineage C betacoronaviruses including Tylonycteris bat CoV HKU4 Ty BatCoV HKU4 and Pipistrellus bat CoV HKU5 Pi BatCoV HKU5 which were discovered in lesser bamboo bats Tylonycteris pachypus and Japanese Pipistrelle bats Pipistrellus abramus respectively captured in Hong Kong China 9 22 32 Analysis of the genome of MERS CoV revealed that it has a genome size of 30 106 bases with the RdRp and S genes having over 90 and around 70 amino acid identities with those of Ty BatCoV HKU4 and Pi BatCoV HKU5 9 32 Molecular clock analysis using the RdRp gene showed that MERS CoV might have diverged from the most recent common ancestor of lineage C betacor onaviruses in year w941 AD 529 BC to 1878 AD 32 It is postulated that the emergence of MERS CoV represents another series of interspecies transmission events in coro naviruses from bats to possibly other animals and then to humans a scenario similar to the SARS epidemic Epidemiology reports and cell line susceptibility studies suggest possible animal reservoirs and human to human transmissions Epidemiological linkage with animals including camels goats sheep and farm animals or their caretakers before symptom onset in some of the reported cases supported the hypothesis of MERS CoV being a zoonotic agent Table 1 Furthermore in vitro data from cell line susceptibility studies showed that the virus had a broad species tropism and was able to replicate in bat primate porcine rabbit and civet cell lines 33 34 As in the case of SARS CoV which likely emerged from its natural animal reservoir the horseshoe bats Rhinolophus sp and jumped to other mammals during their caging in the wild life markets of South China and then to humans MERS CoV might have also originated from bats to these susceptible animal species before adapting to humans 16 35 36 In addition to Pipis trellus bats which are the natural hosts of the closely related Pi BatCoV HKU5 and are also found in the Middle East Rousettus Rhinolophus Myotis and Carollia bat cell lines are also susceptible to MERS CoV infection in vitro 34 Active surveillance of different bat and animal species predominantly found in the Middle East would help to delineate the natural bat reservoir and the evolutionary pathway of MERS CoV among other susceptible animal species Indeed a recent study showed that a number of different bat species in Ghana and Europe are infected with coronaviruses which also share close homologies with MERS CoV 37 Determination of the virus animal hosts might in turn facilitate the control of the outbreak as in SARS where closure of the wet markets likely contributed to the cessation of the epidemic Human to human transmission represents a new stage in the evolution of MERS CoV infection There are so far six Middle East respiratory syndrome coronavirus The knowns http dx doi org 10 1016 j jfma 2013 05 010 Table 1 Characteristics of patients with laboratory confirmed MERS CoV infection as of 12 May 2013 a 6 7 10e14 Case WHO report date Demographics and epidemiological links Clinical manifestations Laboratory diagnosis sample 1 20 3 Pan CoV RT PCR BAL bronchoalveolar lavage CoV coronavirus DM diabetes mellitus F female h hour Hx history ICU intensive care unit IgG immuno globulin G IHD ischemic heart disease LRT lower respiratory tract M male MV mechanical ventilation PIF parainfluenza virus R right RRT renal replacement therapy RT PCR reverse transcription polymerase chain reaction Rx treatment TA tracheal aspirate UAE United Arab Emirates URT upper respiratory tract Two additional deaths were reported among these cases The others are under treatment a As of 23 June 2013 after the acceptance of the article the total number of laboratory confirmed cases have increased to 70 with 39 fatalities Update on MERS CoV 5 MODEL Please cite this article in press as Chan JF W e t al The emergin g novel Middle East respiratory syndrome coronaviru s The knowns and unknown s Journal of the Formosa n Medical Associat ion 2013 http dx doi org 10 1 016 j jfma 2013 05 010 HCoV 229E HCoV NL63 HCoV OC43 and HCoV HKU1 pre dominantly cause acute self limited upper respiratory tract infections and only occasionally cause lower respiratory tract infections in the elderly and immunocompromized populations Only two of 34 patients Cases 12 and 16 had a self limiting mild influenza like illness not requiring hos pitalization Asymptomatic or mild infections have other wise not been detected among the other contacts of confirmed cases by RT PCR of upper respiratory tract specimens and or serological tests 2400 Saudi residents in Jeddah by indirect immunofluorescent antibody testing of archived sera and 169 French Hajj pilgrims with upper respiratory symptoms and RT PCR of prospectively collected nasal swabs 6 7 13 44 The other 32 94 1 pa tients many of whom had no underlying medical condition developed rapid clinical deterioration with lower respira tory tract involvement and respiratory failure requiring ventilator support within a few days to 1 week after initial systemic symptoms of fever myalgia and malaise and upper respiratory tract symptoms such as rhinorrhea and sore throat This correlated with the finding in our recent cell line susceptibility study which showed that MERS CoV replicated much better in the lower respiratory tract cell lines including Calu 3 polarized airway epithelium A549 lung adenocarcinoma and HFL embryonic lung fibro blasts than the upper respiratory tract cell line Hep 2 laryngeal epidermoid carcinoma 33 Another in vitro 6 J F W Chan et al MODEL clusters of laboratory confirmed MERS CoV infection Table 1 The first cluster occurred in an intensive care unit in Zarga Jordan in April 2012 where 11 individuals including seven nurses one doctor and a brother of one of the nurses developed severe pneumonia of unknown eti ology A nurse with underlying medical conditions and the index case died Cases 8 and 9 On November 30 2012 WHO reported that the stored specimens from these two fatal cases were positive for MERS CoV while the details of the other nine patients test results were not described The second cluster occurred in October 2012 and involved three family members living within the same household in KSA Cases 4 6 and 7 with two fatalities Another small cluster occurred in KSA in February to March 2013 Cases 15 and 16 As the clinical and epidemiological details were not available for these three clusters it was suggested that exposure to a common source in the Middle East was another possible explanation besides human to human transmission of the virus However recent clusters of MERS CoV infection occurring among household contacts in the United Kingdom in January 2013 which involved three patients Cases 10e12 two of whom were without history of traveling to the Middle East and among hospital contacts in KSA Cases 18e30 32 and 33 and France Cases 31 and 34 provided strong evidence of continuing adaptations of MERS CoV for human to human transmission 12 The seroprevalence and transmissibility of MERS CoV remain undetermined although animal to human and human to human transmissions both appear to be limited at this stage Fig 1 Among 2400 persons seeking medical attention in a hospital in Jeddah KSA none had MERS CoV specific IgG detectable by indirect immunofluorescence assay suggesting that the current situation is likely to be differentfromthoseofotherhumancoronaviruseswhichare endemic in humans 6 38 The lack of secondary cases among nearly 200 contacts of Cases 2 and 5 who did not practice optimal infection control measures before the diagnosis of MERS CoV infection was confirmed implied that this novel virus might be less efficient than SARS CoV in human to human transmission 7 13 39 However the findings of these studies should be interpreted with cautions for two reasons First only a relatively small number of subjects 10 64 in Case 2 and 85 123 in Case 5 were tested by reliable labo ratory tests Second the timing of testing was not clearly described and might be suboptimal for the purpose of excluding the diagnosis It has been proposed that a second test should be performed in symptomatic patients with initially negative results by reverse transcription polymerase chain reaction RT PCR within the first 10 days of symptom onset based on the observation in SARS where viral load peaked at day 10 of symptom onset 5 40e42 Therefore the apparently limited spread of MERS CoV at present might be an underestimation and ongoing trans mission of the virus should be cautiously monitored In vitro viral characteristics and their correlations with the unusual clinical features of MERS CoV infection Unlike its close relatives in bats MERS CoV is highly path ogenic in humans The most common clinical presentation Please cite this article in press as Chan JF W et al The emerging novel and unknowns Journal of the Formosan Medical Association 2013 among the 34 laboratory confirmed cases of MERS CoV infection is acute severe community acquired pneumonia with acute renal failure following an estimated incubation period of 1e9 days Table 1 12 43 This is unusual among human infections caused by coronaviruses in which severe pneumonia with respiratory failure is seldom seen except in SARS The other human coronaviruses namely Figure 1 The world map showing countries with laboratory confirmed cases of MERS CoV infection according to the pa tients date of symptom onset as of 12 May 2013 in grey the Kingdom of Saudi Arabia KSA Qatar Jordan the United Arab Emirates UAE the United Kingdom UK and France After the article was accepted additional local or imported cases were reported in KSA UK Italy Germany Tunisia and Morocco As of 23 June 2013 the total number of laboratory confirmed cases was 70 with 39 fatalities Middle East respiratory syndrome coronavirus The knowns http dx doi org 10 1016 j jfma 2013 05 010 within an open reading frame ORF 1b with sensitivity of Update on MERS CoV 7 MODEL study also showed that pseudostratified human bronchial epithelium cultures are highly permissive to MERS CoV infection 45 In ex vivo organ cultures MERS CoV produc tively replicated in both human bronchial and lung tissues whereas SARS CoV only productively replicated in lung tis sue 46 Recently a macaque model showed that MERS CoV caused acute localized to widespread pneumonia result ing in mild to moderate clinical disease resembling the illness observed in humans 47 Radiologically pneumonia is evident by focal consolidations involving single or multiple lobes with progressive involvement of bilateral lung fields especially the lower zones In Case 1 thoracic computed tomography scans revealed mediastinal hilar lymphade nopathies airspace opacities with air bronchograms scat tered ground glass opacities interstitial septal thickenings and nodularities in the upper lobes without significant pleural and pericardial effusions 6 Acute renal failure was the other dominant clinical feature in MERS CoV infection and is seen in at least six of the 34 reported cases Many of the remaining 28 severe cases probably also developed renal impairment although their clinical details were not available This was unusual even when compared to SARS in which 28 8 of the patients had abnormal urinalysis and detectable viral load by quantitative RT PCR in urine but only 6 7 developed acute renal failure with histological evidence of acute tubular necrosis and most did not require renal replacement therapy 48 This clinical presentation correlates with the in vitro finding of efficient replication of MERS CoV in kidney cell lines including HEK 293 Vero LLC MK2 and 769P 33 34 49 More importantly the presence of renal involvement appeared to be a poor prognostic factor as those with renal failure either died or required renal replacement therapy while two cases without renal impairment survived Table 1 The lack of extrapulmonary lesions observed in the macaque model of MERS CoV infection suggested that acute renal failure was more likely due to hypoxic damage than a direct viral cyto pathic effect 47 Other clinical laboratory and microbiological findings reported in MERS CoV infection included pericarditis disseminated intravascular coagulation leukocytosis with neutrophilia and lymphopenia thrombocytopenia anemia hyponatremia hypoalbuminemia elevated liver enzymes lactate dehydrogenase C reactive protein and procalci tonin levels possible secondary bacterial pneumonia caused by Klebsiella pneumoniae Staphylococcus aureus and Acinetobacter sp and coinfection with other respira tory viruses including influenza A H1N1 pdm09 and type 2 parainfluenza virus 6 7 10e13 50 It is interesting to note the absence of watery diarrhea in the acute phase of MERS CoV infection despite the in vitro finding of viral replication in the colonic cell line Caco 2 colorectal adenocarcinoma in contrast to SARS in which around 20 of patients developed enterocolitis 1 40 It remains to be seen in future case co horts whether this is due to under reporting or a genuine difference in clinical presentations between the two dis eases Together with severe acute respiratory and renal failure these clinical features underscore the success of the innate immune evasion mechanisms of MERS CoV in humans leading to overwhelming infection and possible cytokine dysregulation as reflected by the lack of inter feron through inhibition of interferon regulatory factor Please cite this article in press as Chan JF W et al The emerging novel and unknowns Journal of the Formosan Medical Association 2013 up to 64 RNA copies per reaction have been proposed for screening and confirmation of MERS CoV infection respectively and are available in about half of the coun tries in the WHO European Region 55 56 Additional testing of other gene targets with partial or whole genome sequence analysis may also be used for confirmation 55 56 For example pan coronavirus RT PCR targeting the RdRp gene was used in Case 2 and a real time quantitative RT PCR assay targeting the N gene has been used in in vitro studies and may also be useful for clinical diagnosis although further evaluations are needed 33 Other potential family 3 IRF 3 45 49 The discovery of dipeptidyl peptidase 4 DPP4 a multifunctional 766 amino acid long type II transmembrane glycoprotein exopeptidase expressed on human non ciliated bronchial renal enteric hepatic and prostatic epithelial cells which is important in the regu lation o