今日の臨床サポート

中東呼吸器症候群 (Middle East respiratory syndrome, MERS)

著者: 石金正裕 国立国際医療研究センター病院 国際感染症センター

著者校正/監修レビュー済:2019/04/05

概要・推奨   

  1. これまでのアウトブレイク事例より、感染予防策が十分ではない空間(医療機関、救急車内、居住空間など)ではヒト-ヒト感染が発生することが明らかになった。感染様式は飛沫感染であることは間違いないため、MERSを疑う場合は、飛沫感染対策が推奨される(推奨度1)。 
  1. 一方、不顕性感染者の他者への感染性についてはまだ結論が得られていない。また2019年2月28日現在、明らかな空気感染の証拠はないが、MERS-CoVの一部が空気中から発見されたという報告もあるため、知見が集まるまで、および患者発生時の少なくとも初期については空気感染対策が推奨される(推奨度2)。
  1. 現時点で、有効性や安全性が確立された治療法は存在せず、発熱、吐き気、腹痛などの症状を訴える患者ではそれぞれの症状に合わせた対症治療を行う(推奨度1)。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
石金正裕 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行った。
  1. 「厚生労働省健康局結核感染症課長. 中東呼吸器症候群(MERS)の国内発生時の対応について(2017)」に基づいて日本における疑似症の定義について加筆修正を行った。
  1. WHOのリスクアセスメント(2018)に基づいて疫学情報について加筆修正を行った。
 

病態・疫学・診察

疾患情報  
ポイント:
  1. 中東呼吸器症候群(Middle East respiratory syndrome、MERS)とは、2012年にサウジアラビアで初めて確認された新種の中東呼吸器症候群コロナウイルス(Middle East Respiratory Syndrome Coronavirus、MERS-CoV)により引き起されるウイルス性呼吸器疾患である。2012年9月22日に英国よりWHOに対し、中東へ渡航歴のある重症肺炎患者から後にMERS-CoVが分離されたとの報告があって以来、中東地域に居住または渡航歴のある者、あるいはMERS患者との接触歴のある者においてMERS症例が継続的に報告されている。2015年5月に、中東地域への渡航歴のある韓国人の確定例が報告され、その後7月までに186例のMERS確定例が韓国より報告されたが、2015年12月24日に終息宣言が出された。その後も中東中心に世界で報告はされ、2018年9月には韓国で1例の報告がなされたが、2019年2月28日現在、日本での報告例はない。
 
中東呼吸器症候群コロナウイルス(Middle East Respiratory Syndrome Coronavirus、MERS-CoV)

 
  1. MERS-CoVのヒトへの感染源となるのは、MERS-CoVに感染したヒトコブラクダあるいはヒトのMERS確定症例である。動物-ヒト感染の感染経路は十分に解明されていないが、ヒトへの感染は、MERS―CoVに感染したヒトコブラクダへの直接または間接的な接触により成立する。サウジアラビアのヒトコブラクダからMERS-CoVの遺伝子が検出されており、ヒトコブラクダとの濃厚接触(ラクダ乳の喫食を含む)が感染の契機となると考えられている。さらに、中東や韓国で経験された10例以上のクラスターとなった院内感染の事例より、感染予防策が十分ではない空間(医療機関、救急車内、居住空間など)ではヒト-ヒト感染が発生することが明らかになった。不顕性感染者の他者への感染性についてはまだ結論が得られていない。感染様式は飛沫感染であり、2019年2月28日現在、明らかな空気感染の証拠はないが、MERS-CoVの一部が空気中から発見されたという報告もある[1]
  1. WHOは、国際保健規則(IHR)に基づく対応として、これまでにMERSに関する緊急委員会を2013年7月以降に計10回開催しており、直近の第10回(2015年9月2日開催)では、感染経路についてはこれまで同様、持続的なヒト-ヒト感染を示す証拠はなく、現状は「国際的に懸念される公衆の保健上の緊急事態(PHEIC)」には至っていないが、依然として国際的な拡大が懸念されるとした[2]。また同緊急委員会では、感染予防・感染制御策として、具体的に医療機関でのcapacityの確保、good practiceのための知識やトレーニングの実施、感染者の早期発見の必要性が言及され、調査・研究指針として人や動物に対するワクチンや治療法の開発という勧告が加わった。
  1. 臨床像は、無症状および軽症例から急速性呼吸切迫症候群(ARDS)を来す重症例まである。典型的には、発熱、咳嗽、息切れなどの症状から始まり急速に肺炎を発症し、しばしば呼吸器管理が必要となる。呼吸器症状以外には、約30%の患者が嘔吐、下痢などの消化器症状を呈した報告がある。典型的な検査所見では、白血球減少(リンパ球減少)を認め、場合により血小板減少症を認める。重症例ではアミノトランスフェラーゼの中等度上昇を認めることがある。MERSの潜伏期間は2~14日(中央値は5日程度)とされる。高齢者や免疫低下、腎疾患、悪性腫瘍、肺疾患、糖尿病などの慢性疾患を有する患者はMERS-CoV感染による重症化をしやすい。致命率は30~40%と報告されている。
  1. 診断は地方衛生研究所および国立感染症研究所にてPCR検査を用いて行われる。現時点で、有効性や安全性が確立された治療法は存在せず患者の状態に基づいた対症療法が中心となるが、先行研究の報告では有用性が示唆されるものもあることから、そのような国内未承認または適応外の治療法のうち、検討が必要と考えられる治療法について、対象患者の要件や具体的な投与方法などについて検討することを目的とした研究班が立ち上がった。また、感染予防策としては、確定診断例では原則は隔離を基本とし、飛沫感染の予防を徹底し、また可能な限り空気感染予防を追加する。
  1. MERSは2015年1月21日付けで、感染症法上の2類感染症に追加されており、疾患を疑った場合はただちに届出をする必要がある。2015年以降、渡航歴、接触歴、症状などからMERSの検査を実施した事例があったが、結果は全て陰性であった。全ての患者にアラビア半島またはその周辺の国への渡航歴があった。接触歴については、ラクダの騎乗、ヒトコブラクダの騎乗と生乳摂取、MERS患者との接触の疑い等であった。これらの所見から、これまでのMERS疑似症の定義では、蓋然性が低い患者もMERS疑似症として取り扱われていたことが推察された。そのため、2017年7月7日[3]にMERS疑似症の定義が以下の様に変更になった。
  1. 38℃以上の発熱及び咳を伴う急性呼吸器症状を呈し、かつ臨床的又は放射線学的に肺炎、ARDS 等の肺病変が疑われる者であって、発症前 14 日以内に流行国(※1)において、MERS であることが確定した患者との接触歴があるもの又はヒトコブラクダとの濃厚接触歴(※2)があるもの
  1. 発熱又は急性呼吸器症状(軽症の場合を含む。)を呈する者であって、発症前 14 日以内に MERS であることが確定した患者を診察、看護若しくは介護していたもの、MERSであることが確定した患者と同居(当該患者が入院する病室又は病棟に滞在した場合を含む。)していたもの又は MERS であることが確定した患者の気道分泌液、体液等の汚染物質に直接触れたもの
  1. ※1流行国:中東地域の一部なお、届出基準(別添1)第3の5の(4)感染が疑われる患者の要件における「WHOの公表内容から中東呼吸器症候群の初発例の発生が確認されている地域」についても、「中東地域の一部」とする。
  1. ※2ヒトコブラクダとの濃厚接触歴:ヒトコブラクダの鼻や口等との接触(ヒトコブラクダから顔を舐められるなど)や、ヒトコブラクダの生のミルクや非加熱の肉などの摂取
  1. また、MERSの疑いがある患者が医療機関受診して二次感染を起こす可能性を考慮すると、医療機関の受診前にまず保健所に連絡をし、対応を仰ぐことも重要である(国内対応: >詳細情報 参照)。
  1. 中東呼吸器症候群は学校保健安全法で第一種感染症に指定されており、「治癒するまで」を出席停止の期間の基準としている。
 
世界での発生状況:
  1. WHOへ報告されたMERSの検査診断による確定例は、2018年6月30日までに、27カ国より、2,228例(死亡791例:致命率35.5%)であった(WHO Disease Outbreak Newsに適宜更新情報掲載)(表<図表>)。年齢の中央値は52歳(四分位範囲:37-65歳)で、67.2%が男性であった。確定例のうち、21%が無症状もしくは軽い症状であった。46%が、死亡もしくは重篤な病態であった。報告された全体の18.6%が医療従事者であった。
  1. 症例の大部分(約83%)はサウジアラビアから報告されている(表<図表>)。ほとんどの報告患者ではラクダへの曝露歴が不明である。また、複数の院内のアウトブレイク事例において、ヒト-ヒト感染が報告されている。報告国は中東地域(バーレーン、ヨルダン、クウェート、オマーン、カタール、サウジアラビア、アラブ首長国連邦、イエメン、イラン、レバノン)、アフリカ(エジプト、チュニジア、アルジェリア)、ヨーロッパ(フランス、ドイツ、ギリシャ、イタリア、英国、オランダ、オーストリア、トルコ)、アジア(マレーシア、フィリピン、タイ、韓国、中国)、北アメリカ(米国)で、中東地域以外の国からの報告例は、すべて中東地域への渡航歴のある者、もしくはその接触者であった。
  1. 中東以外の国で、輸入例を発端とした国内感染事例が報告されているのは、イギリス、フランス、チュニジア、韓国の4カ国である。
 
国・地域別MERS症例報告数の流行曲線

国・地域別MERS-CoV感染。2012年~2018年6月30日までに、2,229例が報告された。

 
国別MERS報告数

国別のMERS-CoV感染。2012年~2018年6月30日までに報告された2,229例が報告された。
*感染源が不明な症例が報告されている国、**輸入例を発端としたヒト-ヒト感染が報告された国

 
韓国での発生状況:
  1. 医療機関におけるMERS症例の集積は中東の国(特にサウジアラビア)から継続的に報告されているが、中東以外の国では2013年に英国(計3例)、フランス(計2例)から報告されているのみでいずれも輸入例を発端としていた[4][5]。しかし、2015年5月~7月にかけて、韓国では186例のMERS症例が報告され(中国で診断された1例を含む)(表<図表>)、サウジアラビア(表<図表>)に次いで2番目の報告数となった。
  1. 最初のMERS確定例は68歳男性で、2015年4月18日~5月3日に中東(バーレーン、アラブ首長国連邦、サウジアラビア、カタール)に滞在し5月4日に韓国に帰国し、5月11日(帰国7日目)に上気道炎症状を認めた。しかし、この男性は医療機関を受診した際に、渡航歴を適切に伝えておらず、さらに発症してから確定診断がつくまでの10日間に(5月20日に確定診断)計4カ所の医療機関を受診していた。このため、多くの医療従事者や患者らに接触することになり、複数の医療機関でこの男性を発端とした二次感染もしくはそれ以上の感染伝播をもたらすことになり(発端者は直接28例に感染伝播を起こした)、6月8日には6医療機関より計64例が報告され、「持続的なヒト-ヒト感染」の懸念が広がった。
  1. このような状況下、WHOは韓国政府とJoint missionを6月9~13日に実施し、感染拡大の原因について、医療従事者と一般社会におけるMERSに関する知識の欠如、不十分な院内感染対策、混雑した救急外来や多病床の病室でのMERS患者との密接で持続的な接触、ドクターショッピング、多くの見舞客や患者や家族が病室内で感染者と滞在する習慣などを指摘した。また、韓国で分離されたMERS-CoVの遺伝子配列は、中東からの分離株と比較して著しい変異は認めないとして、ウイルス学的にも疫学的にも持続的なヒト-ヒト感染を示す証拠はないとした[6]
  1. 韓国では接触者調査や院内感染対策が強化され、報告数は6月1日をピークとして減少し、最後の新規症例は7月2日に発生した。韓国政府は7月28日に事実上のMERS終息宣言をしたが、10月12日に、MERSから回復し2度MERS-CoV陰性と判定された35歳男性が、発熱し再びMERS-CoV陽性と判定された。11月25日に、韓国政府はこの症例は基礎疾患である悪性リンパ腫治療中の経過が急激に増悪して死亡したと報告した。この症例からの二次感染の報告はなく、12月24日に韓国政府はWHOの基準(最後の陽性患者のウイルス陰性化から28日後を終息宣言とする)に基づき、終息宣言とした。合計で、12例の無症候例を含む186例(前述の再度陽性となった症例は1例として集計)が確定例と確認された。確定例は全て医療機関およびその関連車両などで発生しており、16の医療機関に広がり、隔離対象者となった接触者は計16,693名にのぼった[7]
 
韓国と中国におけるMERSアウトブレイクの流行曲線

MERS-CoVの韓国と中国での感染者数と死亡者数(2015年5月11日~7月2日)。7月2日までに186例が報告された。

 
  1. 年齢中央値は55歳(範囲:16~87歳)、男性が111例(60%)で、基礎疾患では糖尿病が最多(28%)、次いで悪性疾患(23.1%)であった。医療従事者は39例(21%、死亡例なし)であった。死亡38例(MERSと死亡との因果関係は不明な者を含む、致命率20%)のうち33例(87%)は高齢者、もしくは基礎疾患(悪性腫瘍、心疾患、呼吸器疾患、腎疾患、糖尿病、免疫不全など)を有していた。潜伏期間は6.8日(95%信頼区間:6.3-7.4日)で、患者の95%は発症までに13.5日(95%信頼区間:12.2-14.7日)を、残りの5%の患者は発症までに2.3日(95%信頼区間:2.0-2.5日)を要した。Serial interval (発生源の発症から次の感染者の発症までの間隔)は12.5日(95%信頼区間:11.8-13.2日)であった。スーパースプレッダー(韓国事例では1人で4人以上に感染伝播させた症例と定義)には5例が該当し、感染伝播の83.2%がこの5例との疫学的関連があった。それぞれ、6例、11例、23例、28例、85例に感染伝播を起こした。5例の年齢中央値は41歳(範囲:35-68歳)で、2例のみが基礎疾患(気管支喘息、多発性骨髄腫)を有した[7]
  1. 臨床症状は、発熱138例(74.2%)、筋肉痛47例(25.3%)、咳嗽33例(17.7%)、消化器症状24例(12.9%)、頭痛16例(8.6%)、喀痰14例(7.5%)、呼吸困難10例(5.4%)、咽頭痛8例(4.3%)で、消化器症状が中東からの既報告(20-30%)と比較して頻度が低かった[7]。死亡の危険因子は既存の研究と同様に、高齢と呼吸器疾患を有することで、多変量解析で65歳以上は4.9倍(95%信頼区間:1.9-12.5、p<0.01)、呼吸器疾患は4.9倍(95%信頼区間:1.6-14.7、p<0.01)を示した[7]
  1. 韓国でのアウトブレイク事例において、MERS患者が入院していた部屋の清掃後に、空気、空調設備の排気口、高頻度接触面、物品の表面において、MERS-CoV遺伝子(RT-PCR法による検出)が検出された[8]。一方、韓国の院内感染事例では、接触者調査においてウイルスに汚染された環境表面を介して感染した患者は確認されていない[9]
  1. 韓国でのアウトブレイク事例の報告によれば、重症例の気道分泌液中のウイルス RNA 量は発症 2 週目でピーク(中央値;7.21 log10 copies/ ml)となり、軽症例(5.54 log10copies/ml)に比べて有意に高値を示したとされている[10]。また、ウイルス排泄期間も発症から 21 日まで遷延した。
  1. 2015年のアウトブレイク以降、韓国では報告はなかったが、2018年9月9日に1例に輸入例が報告された[11]。この症例は、8月16日から9月6日まで仕事のためクウェートに渡航した61歳の男性であった。クウェートから韓国に戻った直後に発熱、下痢、呼吸器症状で入院し、隔離され治療を受けた。確定症例はこの1例のみで、アウトブレイクは起きなかった。
 
韓国事例からの教訓:
  1. 2015年の韓国における院内感染拡大の要因として、医療機関での感染予防策の不徹底、混雑した外来や病棟、MERSの診断の遅れ、不十分な接触者調査と隔離などが指摘された[12][13][14][9]
  1. 隣国の先進国であるMERSの感染拡大は、改めて平時からの感染対策徹底の重要性を示した。例えば、急性感染症患者への渡航歴の確認、医療機関での標準予防策の徹底、患者への咳エチケットの指導、感染管理体制の整備、住民へのリスクコミュニケーションなどである。わが国においても、MERSをはじめ、新興感染症に対する対応を今後も定期的に確認することが重要である[15]
 
MERSの臨床的特徴:
  1. 臨床像は、無症状および軽症例からARDSを来す重症例まである。典型的には、発熱、咳嗽、息切れなどの症状から始まり急速に肺炎を発症し、しばしば呼吸器管理が必要となる。呼吸器症状以外には、約30%の患者が嘔吐、下痢などの消化器症状を呈した報告がある。典型的な検査所見では、白血球減少(リンパ球減少)を認め、場合により血小板減少症を認める。重症例ではアミノトランスフェラーゼの中等度上昇を認めることがある[16]。高齢者や免疫低下、腎疾患、悪性腫瘍、肺疾患、糖尿病などの慢性疾患を有する患者はMERS-CoV感染による重症化をしやすい[16]。致命率は30~40%と報告されている。MERSの潜伏期間は2~14日(中央値は5日程度)とされる。致命率は30~40%と報告されている[17]
 
各臨床症状の頻度:
  1. 来院時の各症状の頻度の報告として、47人のコホート研究では以下のような頻度での症状の発症が報告されている[17]。ほぼ全例で発熱と胸部X線写真の異常を認め、また多くの症例で咳と息切れを認めている。
  1. 発熱(>38℃) - 46人(98%)
  1. 悪寒と戦慄を伴った発熱 - 41人(87%)
  1. 咳 - 39人(83%)(乾性47%、湿性36%)
  1. 息切れ - 34人(72%)
  1. 血痰- 8人(17%)
  1. 咽頭痛 - 10人(21%)
  1. 筋肉痛 - 15人(32%)
  1. 下痢 - 12人(26%)
  1. 嘔吐 - 10人(21%)
  1. 腹痛 - 8人(17%)
  1. 胸痛 - 7人(15%)
  1. 頭痛 - 6人(13%)
  1. 鼻炎 - 2人(4%)
  1. 胸部X線写真の異常 - 47人(100%)(重症から軽症まであり)

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文献 

著者: Esam I Azhar, Anwar M Hashem, Sherif A El-Kafrawy, Sayed Sartaj Sohrab, Asad S Aburizaiza, Suha A Farraj, Ahmed M Hassan, Muneera S Al-Saeed, Ghazi A Jamjoom, Tariq A Madani
雑誌名: MBio. 2014 Jul 22;5(4):e01450-14. doi: 10.1128/mBio.01450-14. Epub 2014 Jul 22.
Abstract/Text Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel betacoronavirus that has been circulating in the Arabian Peninsula since 2012 and causing severe respiratory infections in humans. While bats were suggested to be involved in human MERS-CoV infections, a direct link between bats and MERS-CoV is uncertain. On the other hand, serological and virological data suggest dromedary camels as the potential animal reservoirs of MERS-CoV. Recently, we isolated MERS-CoV from a camel and its infected owner and provided evidence for the direct transmission of MERS-CoV from the infected camel to the patient. Here, we extend this work and show that identical MERS-CoV RNA fragments were detected in an air sample collected from the same barn that sheltered the infected camel in our previous study. These data indicate that the virus was circulating in this farm concurrently with its detection in the camel and in the patient, which warrants further investigations for the possible airborne transmission of MERS-CoV. Importance: This work clearly highlights the importance of continuous surveillance and infection control measures to control the global public threat of MERS-CoV. While current MERS-CoV transmission appears to be limited, we advise minimal contact with camels, especially for immunocompromised individuals, and the use of appropriate health, safety, and infection prevention and control measures when dealing with infected patients. Also, detailed clinical histories of any MERS-CoV cases with epidemiological and laboratory investigations carried out for any animal exposure must be considered to identify any animal source.

Copyright © 2014 Azhar et al.
PMID 25053787  MBio. 2014 Jul 22;5(4):e01450-14. doi: 10.1128/mBio.014・・・
著者: Health Protection Agency (HPA) UK Novel Coronavirus Investigation team
雑誌名: Euro Surveill. 2013 Mar 14;18(11):20427. Epub 2013 Mar 14.
Abstract/Text In February 2013, novel coronavirus (nCoV) infection was diagnosed in an adult male in the United Kingdom with severe respiratory illness, who had travelled to Pakistan and Saudi Arabia 10 days before symptom onset. Contact tracing identified two secondary cases among family members without recent travel: one developed severe respiratory illness and died, the other an influenza-like illness. No other severe cases were identified or nCoV detected in respiratory samples among 135 contacts followed for 10 days.

PMID 23517868  Euro Surveill. 2013 Mar 14;18(11):20427. Epub 2013 Mar ・・・
著者: Benoit Guery, Julien Poissy, Loubna el Mansouf, Caroline Séjourné, Nicolas Ettahar, Xavier Lemaire, Fanny Vuotto, Anne Goffard, Sylvie Behillil, Vincent Enouf, Valérie Caro, Alexandra Mailles, Didier Che, Jean-Claude Manuguerra, Daniel Mathieu, Arnaud Fontanet, Sylvie van der Werf, MERS-CoV study group
雑誌名: Lancet. 2013 Jun 29;381(9885):2265-72. doi: 10.1016/S0140-6736(13)60982-4. Epub 2013 May 30.
Abstract/Text BACKGROUND: Human infection with a novel coronavirus named Middle East Respiratory Syndrome coronavirus (MERS-CoV) was first identified in Saudi Arabia and the Middle East in September, 2012, with 44 laboratory-confirmed cases as of May 23, 2013. We report detailed clinical and virological data for two related cases of MERS-CoV disease, after nosocomial transmission of the virus from one patient to another in a French hospital.
METHODS: Patient 1 visited Dubai in April, 2013; patient 2 lives in France and did not travel abroad. Both patients had underlying immunosuppressive disorders. We tested specimens from the upper (nasopharyngeal swabs) or the lower (bronchoalveolar lavage, sputum) respiratory tract and whole blood, plasma, and serum specimens for MERS-CoV by real-time RT-PCR targeting the upE and Orf1A genes of MERS-CoV.
FINDINGS: Initial clinical presentation included fever, chills, and myalgia in both patients, and for patient 1, diarrhoea. Respiratory symptoms rapidly became predominant with acute respiratory failure leading to mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Both patients developed acute renal failure. MERS-CoV was detected in lower respiratory tract specimens with high viral load (eg, cycle threshold [Ct] values of 22·9 for upE and 24 for Orf1a for a bronchoalveolar lavage sample from patient 1; Ct values of 22·5 for upE and 23·9 for Orf1a for an induced sputum sample from patient 2), whereas nasopharyngeal specimens were weakly positive or inconclusive. The two patients shared the same room for 3 days. The incubation period was estimated at 9-12 days for the second case. No secondary transmission was documented in hospital staff despite the absence of specific protective measures before the diagnosis of MERS-CoV was suspected. Patient 1 died on May 28, due to refractory multiple organ failure.
INTERPRETATION: Patients with respiratory symptoms returning from the Middle East or exposed to a confirmed case should be isolated and investigated for MERS-CoV with lower respiratory tract sample analysis and an assumed incubation period of 12 days. Immunosuppression should also be taken into account as a risk factor.
FUNDING: French Institute for Public Health Surveillance, ANR grant Labex Integrative Biology of Emerging Infectious Diseases, and the European Community's Seventh Framework Programme projects EMPERIE and PREDEMICS.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23727167  Lancet. 2013 Jun 29;381(9885):2265-72. doi: 10.1016/S01・・・
著者: Korea Centers for Disease Control and Prevention
雑誌名: Osong Public Health Res Perspect. 2015 Aug;6(4):269-78. doi: 10.1016/j.phrp.2015.08.006. Epub 2015 Sep 5.
Abstract/Text OBJECTIVES: The outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection in the Republic of Korea started from the index case who developed fever after returning from the Middle East. He infected 26 cases in Hospital C, and consecutive nosocomial transmission proceeded throughout the nation. We provide an epidemiologic description of the outbreak, as of July 2015.
METHODS: Epidemiological research was performed by direct interview of the confirmed patients and reviewing medical records. We also analyzed the incubation period, serial interval, the characteristics of superspreaders, and factors associated with mortality. Full genome sequence was obtained from sputum specimens of the index patient.
RESULTS: A total of 186 confirmed patients with MERS-CoV infection across 16 hospitals were identified in the Republic of Korea. Some 44.1% of the cases were patients exposed in hospitals, 32.8% were caregivers, and 13.4% were healthcare personnel. The most common presenting symptom was fever and chills. The estimated incubation period was 6.83 days and the serial interval was 12.5 days. A total of 83.2% of the transmission events were epidemiologically linked to five superspreaders, all of whom had pneumonia at presentation and contacted hundreds of people. Older age [odds ratio (OR) = 4.86, 95% confidence interval (CI) 1.90-12.45] and underlying respiratory disease (OR = 4.90, 95% CI 1.64-14.65) were significantly associated with mortality. Phylogenetic analysis showed that the MERS-CoV of the index case clustered closest with a recent virus from Riyadh, Saudi Arabia.
CONCLUSION: A single imported MERS-CoV infection case imposed a huge threat to public health and safety. This highlights the importance of robust preparedness and optimal infection prevention control. The lessons learned from the current outbreak will contribute to more up-to-date guidelines and global health security.

PMID 26473095  Osong Public Health Res Perspect. 2015 Aug;6(4):269-78.・・・
著者: Sung-Han Kim, So Young Chang, Minki Sung, Ji Hoon Park, Hong Bin Kim, Heeyoung Lee, Jae-Phil Choi, Won Suk Choi, Ji-Young Min
雑誌名: Clin Infect Dis. 2016 Aug 1;63(3):363-9. doi: 10.1093/cid/ciw239. Epub 2016 Apr 18.
Abstract/Text BACKGROUND: The largest outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) outside the Middle East occurred in South Korea in 2015 and resulted in 186 laboratory-confirmed infections, including 36 (19%) deaths. Some hospitals were considered epicenters of infection and voluntarily shut down most of their operations after nearly half of all transmissions occurred in hospital settings. However, the ways that MERS-CoV is transmitted in healthcare settings are not well defined.
METHODS: We explored the possible contribution of contaminated hospital air and surfaces to MERS transmission by collecting air and swabbing environmental surfaces in 2 hospitals treating MERS-CoV patients. The samples were tested by viral culture with reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence assay (IFA) using MERS-CoV Spike antibody, and electron microscopy (EM).
RESULTS: The presence of MERS-CoV was confirmed by RT-PCR of viral cultures of 4 of 7 air samples from 2 patients' rooms, 1 patient's restroom, and 1 common corridor. In addition, MERS-CoV was detected in 15 of 68 surface swabs by viral cultures. IFA on the cultures of the air and swab samples revealed the presence of MERS-CoV. EM images also revealed intact particles of MERS-CoV in viral cultures of the air and swab samples.
CONCLUSIONS: These data provide experimental evidence for extensive viable MERS-CoV contamination of the air and surrounding materials in MERS outbreak units. Thus, our findings call for epidemiologic investigation of the possible scenarios for contact and airborne transmission, and raise concern regarding the adequacy of current infection control procedures.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.
PMID 27090992  Clin Infect Dis. 2016 Aug 1;63(3):363-9. doi: 10.1093/c・・・
著者: Sun Young Cho, Ji-Man Kang, Young Eun Ha, Ga Eun Park, Ji Yeon Lee, Jae-Hoon Ko, Ji Yong Lee, Jong Min Kim, Cheol-In Kang, Ik Joon Jo, Jae Geum Ryu, Jong Rim Choi, Seonwoo Kim, Hee Jae Huh, Chang-Seok Ki, Eun-Suk Kang, Kyong Ran Peck, Hun-Jong Dhong, Jae-Hoon Song, Doo Ryeon Chung, Yae-Jean Kim
雑誌名: Lancet. 2016 Sep 3;388(10048):994-1001. doi: 10.1016/S0140-6736(16)30623-7. Epub 2016 Jul 9.
Abstract/Text BACKGROUND: In 2015, a large outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection occurred following a single patient exposure in an emergency room at the Samsung Medical Center, a tertiary-care hospital in Seoul, South Korea. We aimed to investigate the epidemiology of MERS-CoV outbreak in our hospital.
METHODS: We identified all patients and health-care workers who had been in the emergency room with the index case between May 27 and May 29, 2015. Patients were categorised on the basis of their exposure in the emergency room: in the same zone as the index case (group A), in different zones except for overlap at the registration area or the radiology suite (group B), and in different zones (group C). We documented cases of MERS-CoV infection, confirmed by real-time PCR testing of sputum samples. We analysed attack rates, incubation periods of the virus, and risk factors for transmission.
FINDINGS: 675 patients and 218 health-care workers were identified as contacts. MERS-CoV infection was confirmed in 82 individuals (33 patients, eight health-care workers, and 41 visitors). The attack rate was highest in group A (20% [23/117] vs 5% [3/58] in group B vs 1% [4/500] in group C; p<0·0001), and was 2% (5/218) in health-care workers. After excluding nine cases (because of inability to determine the date of symptom onset in six cases and lack of data from three visitors), the median incubation period was 7 days (range 2-17, IQR 5-10). The median incubation period was significantly shorter in group A than in group C (5 days [IQR 4-8] vs 11 days [6-12]; p<0·0001). There were no confirmed cases in patients and visitors who visited the emergency room on May 29 and who were exposed only to potentially contaminated environment without direct contact with the index case. The main risk factor for transmission of MERS-CoV was the location of exposure.
INTERPRETATION: Our results showed increased transmission potential of MERS-CoV from a single patient in an overcrowded emergency room and provide compelling evidence that health-care facilities worldwide need to be prepared for emerging infectious diseases.
FUNDING: None.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 27402381  Lancet. 2016 Sep 3;388(10048):994-1001. doi: 10.1016/S0・・・
著者: Myoung-Don Oh, Wan Beom Park, Pyoeng Gyun Choe, Su-Jin Choi, Jong-Il Kim, Jeesoo Chae, Sung Sup Park, Eui-Chong Kim, Hong Sang Oh, Eun Jung Kim, Eun Young Nam, Sun Hee Na, Dong Ki Kim, Sang-Min Lee, Kyoung-Ho Song, Ji Hwan Bang, Eu Suk Kim, Hong Bin Kim, Sang Won Park, Nam Joong Kim
雑誌名: N Engl J Med. 2016 Sep 29;375(13):1303-5. doi: 10.1056/NEJMc1511695.
Abstract/Text
PMID 27682053  N Engl J Med. 2016 Sep 29;375(13):1303-5. doi: 10.1056/・・・
著者: Moran Ki
雑誌名: Epidemiol Health. 2015;37:e2015033. doi: 10.4178/epih/e2015033. Epub 2015 Jul 21.
Abstract/Text The distinct characteristic of the Middle East Respiratory Syndrome (MERS) outbreak in South Korea is that it not only involves intra-hospital transmission, but it also involves hospital-to-hospital transmission. It has been the largest MERS outbreak outside the Middle East, with 186 confirmed cases and, among them, 36 fatal cases as of July 26, 2015. All confirmed cases are suspected to be hospital-acquired infections except one case of household transmission and two cases still undergoing examination. The Korean health care system has been the major factor shaping the unique characteristics of the outbreak. Taking this as an opportunity, the Korean government should carefully assess the fundamental problems of the vulnerability to hospital infection and make short- as well as long-term plans for countermeasures. In addition, it is hoped that this journal, Epidemiology and Health, becomes a place where various topics regarding MERS can be discussed and shared.

PMID 26212508  Epidemiol Health. 2015;37:e2015033. doi: 10.4178/epih/e・・・
著者: Kyung Min Kim, Moran Ki, Sung-Il Cho, Minki Sung, Jin Kwan Hong, Hae-Kwan Cheong, Jong-Hun Kim, Sang-Eun Lee, Changhwan Lee, Keon-Joo Lee, Yong-Shik Park, Seung Woo Kim, Bo Youl Choi
雑誌名: Epidemiol Health. 2015;37:e2015041. doi: 10.4178/epih/e2015041. Epub 2015 Sep 17.
Abstract/Text OBJECTIVES: This study investigated the epidemiologic features of the confirmed cases of Middle East Respiratory Syndrome (MERS) in Pyeongtaek St. Mary's Hospital, where the outbreak first began, in order to identify lessons relevant for the prevention and control of future outbreaks.
METHODS: The patients' clinical symptoms and test results were collected from their medical records. The caregivers of patients were identified by phone calls.
RESULTS: After patient zero (case #1) was admitted to Pyeongtaek St. Mary's Hospital (May 15-May 17), an outbreak occurred, with 36 cases between May 18 and June 4, 2015. Six patients died (fatality rate, 16.7%). Twenty-six cases occurred in the first-generation, and 10 in the second-generation. The median incubation period was five days, while the median period from symptom onset to death was 12.5 days. While the total attack rate was 3.9%, the attack rate among inpatients was 7.6%, and the inpatients on the eighth floor, where patient zero was hospitalized, had an 18.6% attack rate. In contrast, caregivers and medical staff showed attack rates of 3.3% and 1.1%, respectively.
CONCLUSIONS: The attack rates were higher than those of the previous outbreaks in other countries. The outbreak spread beyond Pyeongtaek St. Mary's Hospital when four of the patients were moved to other hospitals without appropriate quarantine. The best method of preventing future outbreaks is to overcome the vulnerabilities observed in this outbreak, such as ward crowding, patient migration without appropriate data sharing, and the lack of an initial broad quarantine.

PMID 26725225  Epidemiol Health. 2015;37:e2015041. doi: 10.4178/epih/e・・・
著者: K H Kim, T E Tandi, J W Choi, J M Moon, M S Kim
雑誌名: J Hosp Infect. 2017 Feb;95(2):207-213. doi: 10.1016/j.jhin.2016.10.008. Epub 2016 Oct 14.
Abstract/Text BACKGROUND: Since the first case of Middle East respiratory syndrome coronavirus (MERS-CoV) in South Korea was reported on 20th May 2015, there have been 186 confirmed cases, 38 deaths and 16,752 suspected cases. Previously published research on South Korea's MERS outbreak was limited to the early stages, when few data were available. Now that the outbreak has ended, albeit unofficially, a more comprehensive review is appropriate.
METHODS: Data were obtained through the MERS portal by the Ministry for Health and Welfare (MOHW) and Korea Centres for Disease Control and Prevention, press releases by MOHW, and reports by the MERS Policy Committee of the Korean Medical Association. Cases were analysed for general characteristics, exposure source, timeline and infection generation. Sex, age and underlying diseases were analysed for the 38 deaths.
FINDINGS: Beginning with the index case that infected 28 others, an in-depth analysis was conducted. The average age was 55 years, which was a little higher than the global average of 50 years. As in most other countries, more men than women were affected. The case fatality rate was 19.9%, which was lower than the global rate of 38.7% and the rate in Saudi Arabia (36.5%). In total, 184 patients were infected nosocomially and there were no community-acquired infections. The main underlying diseases were respiratory diseases, cancer and hypertension. The main contributors to the outbreak were late diagnosis, quarantine failure of 'super spreaders', familial care-giving and visiting, non-disclosure by patients, poor communication by the South Korean Government, inadequate hospital infection management, and 'doctor shopping'. The outbreak was entirely nosocomial, and was largely attributable to infection management and policy failures, rather than biomedical factors.

Copyright © 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
PMID 28153558  J Hosp Infect. 2017 Feb;95(2):207-213. doi: 10.1016/j.j・・・
著者: Yaseen M Arabi, Hanan H Balkhy, Frederick G Hayden, Abderrezak Bouchama, Thomas Luke, J Kenneth Baillie, Awad Al-Omari, Ali H Hajeer, Mikiko Senga, Mark R Denison, Jonathan S Nguyen-Van-Tam, Nahoko Shindo, Alison Bermingham, James D Chappell, Maria D Van Kerkhove, Robert A Fowler
雑誌名: N Engl J Med. 2017 Feb 9;376(6):584-594. doi: 10.1056/NEJMsr1408795.
Abstract/Text
PMID 28177862  N Engl J Med. 2017 Feb 9;376(6):584-594. doi: 10.1056/N・・・
著者: Abdullah Assiri, Allison McGeer, Trish M Perl, Connie S Price, Abdullah A Al Rabeeah, Derek A T Cummings, Zaki N Alabdullatif, Maher Assad, Abdulmohsen Almulhim, Hatem Makhdoom, Hossam Madani, Rafat Alhakeem, Jaffar A Al-Tawfiq, Matthew Cotten, Simon J Watson, Paul Kellam, Alimuddin I Zumla, Ziad A Memish, KSA MERS-CoV Investigation Team
雑誌名: N Engl J Med. 2013 Aug 1;369(5):407-16. doi: 10.1056/NEJMoa1306742. Epub 2013 Jun 19.
Abstract/Text BACKGROUND: In September 2012, the World Health Organization reported the first cases of pneumonia caused by the novel Middle East respiratory syndrome coronavirus (MERS-CoV). We describe a cluster of health care-acquired MERS-CoV infections.
METHODS: Medical records were reviewed for clinical and demographic information and determination of potential contacts and exposures. Case patients and contacts were interviewed. The incubation period and serial interval (the time between the successive onset of symptoms in a chain of transmission) were estimated. Viral RNA was sequenced.
RESULTS: Between April 1 and May 23, 2013, a total of 23 cases of MERS-CoV infection were reported in the eastern province of Saudi Arabia. Symptoms included fever in 20 patients (87%), cough in 20 (87%), shortness of breath in 11 (48%), and gastrointestinal symptoms in 8 (35%); 20 patients (87%) presented with abnormal chest radiographs. As of June 12, a total of 15 patients (65%) had died, 6 (26%) had recovered, and 2 (9%) remained hospitalized. The median incubation period was 5.2 days (95% confidence interval [CI], 1.9 to 14.7), and the serial interval was 7.6 days (95% CI, 2.5 to 23.1). A total of 21 of the 23 cases were acquired by person-to-person transmission in hemodialysis units, intensive care units, or in-patient units in three different health care facilities. Sequencing data from four isolates revealed a single monophyletic clade. Among 217 household contacts and more than 200 health care worker contacts whom we identified, MERS-CoV infection developed in 5 family members (3 with laboratory-confirmed cases) and in 2 health care workers (both with laboratory-confirmed cases).
CONCLUSIONS: Person-to-person transmission of MERS-CoV can occur in health care settings and may be associated with considerable morbidity. Surveillance and infection-control measures are critical to a global public health response.

PMID 23782161  N Engl J Med. 2013 Aug 1;369(5):407-16. doi: 10.1056/NE・・・
著者: Ziad A Memish, Jaffar A Al-Tawfiq, Hatem Q Makhdoom, Abdullah Assiri, Raafat F Alhakeem, Ali Albarrak, Sarah Alsubaie, Abdullah A Al-Rabeeah, Waleed H Hajomar, Raheela Hussain, Ali M Kheyami, Abdullah Almutairi, Esam I Azhar, Christian Drosten, Simon J Watson, Paul Kellam, Matthew Cotten, Alimuddin Zumla
雑誌名: J Infect Dis. 2014 Nov 15;210(10):1590-4. doi: 10.1093/infdis/jiu292. Epub 2014 May 15.
Abstract/Text BACKGROUND: Analysis of clinical samples from patients with new viral infections is critical to confirm the diagnosis, to specify the viral load, and to sequence data necessary for characterizing the viral kinetics, transmission, and evolution. We analyzed samples from 112 patients infected with the recently discovered Middle East respiratory syndrome coronavirus (MERS-CoV).
METHODS: Respiratory tract samples from cases of MERS-CoV infection confirmed by polymerase chain reaction (PCR) were investigated to determine the MERS-CoV load and fraction of the MERS-CoV genome. These values were analyzed to determine associations with clinical sample type.
RESULTS: Samples from 112 individuals in which MERS-CoV was detected by PCR were analyzed, of which 13 were sputum samples, 64 were nasopharyngeal swab specimens, 30 were tracheal aspirates, and 3 were bronchoalveolar lavage specimens; 2 samples were of unknown origin. Tracheal aspirates yielded significantly higher MERS-CoV loads, compared with nasopharyngeal swab specimens (P = .005) and sputum specimens (P = .0001). Tracheal aspirates had viral loads similar to those in bronchoalveolar lavage samples (P = .3079). Bronchoalveolar lavage samples and tracheal aspirates had significantly higher genome fraction than nasopharyngeal swab specimens (P = .0095 and P = .0002, respectively) and sputum samples (P = .0009 and P = .0001, respectively). The genome yield from tracheal aspirates and bronchoalveolar lavage samples were similar (P = .1174).
CONCLUSIONS: Lower respiratory tract samples yield significantly higher MERS-CoV loads and genome fractions than upper respiratory tract samples.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
PMID 24837403  J Infect Dis. 2014 Nov 15;210(10):1590-4. doi: 10.1093/・・・
著者: Jaffar A Al-Tawfiq, Kareem Hinedi, Jihad Ghandour, Hanan Khairalla, Samir Musleh, Alaa Ujayli, Ziad A Memish
雑誌名: Clin Infect Dis. 2014 Jul 15;59(2):160-5. doi: 10.1093/cid/ciu226. Epub 2014 Apr 9.
Abstract/Text BACKGROUND: There is a paucity of data regarding the differentiating characteristics of patients with laboratory-confirmed and those negative for Middle East respiratory syndrome coronavirus (MERS-CoV).
METHODS: This is a hospital-based case-control study comparing MERS-CoV-positive patients (cases) with MERS-CoV-negative controls.
RESULTS: A total of 17 case patients and 82 controls with a mean age of 60.7 years and 57 years, respectively (P = .553), were included. No statistical differences were observed in relation to sex, the presence of a fever or cough, and the presence of a single or multilobar infiltrate on chest radiography. The case patients were more likely to be overweight than the control group (mean body mass index, 32 vs 27.8; P = .035), to have diabetes mellitus (87% vs 47%; odds ratio [OR], 7.24; P = .015), and to have end-stage renal disease (33% vs 7%; OR, 7; P = .012). At the time of admission, tachypnea (27% vs 60%; OR, 0.24; P = .031) and respiratory distress (15% vs 51%; OR, 0.15; P = .012) were less frequent among case patients. MERS-CoV patients were more likely to have a normal white blood cell count than the control group (82% vs 52%; OR, 4.33; P = .029). Admission chest radiography with interstitial infiltrates was more frequent in case patients than in controls (67% vs 20%; OR, 8.13; P = .001). Case patients were more likely to be admitted to the intensive care unit (53% vs 20%; OR, 4.65; P = .025) and to have a high mortality rate (76% vs 15%; OR, 18.96; P < .001).
CONCLUSIONS: Few clinical predictors could enhance the ability to predict which patients with pneumonia would have MERS-CoV. However, further prospective analysis and matched case-control studies may shed light on other predictors of infection.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
PMID 24723278  Clin Infect Dis. 2014 Jul 15;59(2):160-5. doi: 10.1093/・・・
著者: Who Mers-Cov Research Group
雑誌名: PLoS Curr. 2013 Nov 12;5. doi: 10.1371/currents.outbreaks.0bf719e352e7478f8ad85fa30127ddb8. Epub 2013 Nov 12.
Abstract/Text BACKGROUND: Between September 2012 and 22 October 2013, 144 laboratory-confirmed and 17 probable MERS-CoV cases from nine countries were notified to WHO.
METHODS: We summarize what is known about the epidemiology, virology, phylogeny and emergence of MERS-CoV to inform public health policies.
RESULTS: The median age of patients (n=161) was 50 years (range 14 months to 94 years), 64.5% were male and 63.4% experienced severe respiratory disease. 76.0% of patients were reported to have ≥1 underlying medical condition and fatal cases, compared to recovered or asymptomatic cases were more likely to have an underlying condition (86.8% vs. 42.4%, p<0.001). Analysis of genetic sequence data suggests multiple independent introductions into human populations and modelled estimates using epidemiologic and genetic data suggest R0 is <1, though the upper range of estimates may exceed 1. Index/sporadic cases (cases with no epidemiologic-link to other cases) were more likely to be older (median 59.0 years vs. 43.0 years, p<0.001) compared to secondary cases, although these proportions have declined over time. 80.9% vs. 67.2% of index/sporadic and secondary cases, respectively, reported ≥1 underlying condition. Clinical presentation ranges from asymptomatic to severe pneumonia with acute respiratory distress syndrome and multi-organ failure. Nearly all symptomatic patients presented with respiratory symptoms and 1/3 of patients also had gastrointestinal symptoms.
CONCLUSIONS: Sustained human-to-human transmission of MERS-CoV has not been observed. Outbreaks have been extinguished without overly aggressive isolation and quarantine suggesting that transmission of virus may be stopped with implementation of appropriate infection control measures.

PMID 24270606  PLoS Curr. 2013 Nov 12;5. doi: 10.1371/currents.outbrea・・・
著者: Jacqui Wise
雑誌名: BMJ. 2012 Sep 24;345:e6455. doi: 10.1136/bmj.e6455. Epub 2012 Sep 24.
Abstract/Text
PMID 23008211  BMJ. 2012 Sep 24;345:e6455. doi: 10.1136/bmj.e6455. Epu・・・
著者: Abdullah Assiri, Jaffar A Al-Tawfiq, Abdullah A Al-Rabeeah, Fahad A Al-Rabiah, Sami Al-Hajjar, Ali Al-Barrak, Hesham Flemban, Wafa N Al-Nassir, Hanan H Balkhy, Rafat F Al-Hakeem, Hatem Q Makhdoom, Alimuddin I Zumla, Ziad A Memish
雑誌名: Lancet Infect Dis. 2013 Sep;13(9):752-61. doi: 10.1016/S1473-3099(13)70204-4. Epub 2013 Jul 26.
Abstract/Text BACKGROUND: Middle East respiratory syndrome (MERS) is a new human disease caused by a novel coronavirus (CoV). Clinical data on MERS-CoV infections are scarce. We report epidemiological, demographic, clinical, and laboratory characteristics of 47 cases of MERS-CoV infections, identify knowledge gaps, and define research priorities.
METHODS: We abstracted and analysed epidemiological, demographic, clinical, and laboratory data from confirmed cases of sporadic, household, community, and health-care-associated MERS-CoV infections reported from Saudi Arabia between Sept 1, 2012, and June 15, 2013. Cases were confirmed as having MERS-CoV by real-time RT-PCR.
FINDINGS: 47 individuals (46 adults, one child) with laboratory-confirmed MERS-CoV disease were identified; 36 (77%) were male (male:female ratio 3·3:1). 28 patients died, a 60% case-fatality rate. The case-fatality rate rose with increasing age. Only two of the 47 cases were previously healthy; most patients (45 [96%]) had underlying comorbid medical disorders, including diabetes (32 [68%]), hypertension (16 [34%]), chronic cardiac disease (13 [28%]), and chronic renal disease (23 [49%]). Common symptoms at presentation were fever (46 [98%]), fever with chills or rigors (41 [87%]), cough (39 [83%]), shortness of breath (34 [72%]), and myalgia (15 [32%]). Gastrointestinal symptoms were also frequent, including diarrhoea (12 [26%]), vomiting (ten [21%]), and abdominal pain (eight [17%]). All patients had abnormal findings on chest radiography, ranging from subtle to extensive unilateral and bilateral abnormalities. Laboratory analyses showed raised concentrations of lactate dehydrogenase (23 [49%]) and aspartate aminotransferase (seven [15%]) and thrombocytopenia (17 [36%]) and lymphopenia (16 [34%]).
INTERPRETATION: Disease caused by MERS-CoV presents with a wide range of clinical manifestations and is associated with substantial mortality in admitted patients who have medical comorbidities. Major gaps in our knowledge of the epidemiology, community prevalence, and clinical spectrum of infection and disease need urgent definition.
FUNDING: None.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23891402  Lancet Infect Dis. 2013 Sep;13(9):752-61. doi: 10.1016/・・・
著者: Maimuna S Majumder, Sheryl A Kluberg, Sumiko R Mekaru, John S Brownstein
雑誌名: Emerg Infect Dis. 2015 Nov;21(11):2088-90. doi: 10.3201/eid2111.151231.
Abstract/Text As of July 15, 2015, the South Korean Ministry of Health and Welfare had reported 186 case-patients with Middle East respiratory syndrome in South Korea. For 159 case-patients with known outcomes and complete case histories, we found that older age and preexisting concurrent health conditions were risk factors for death.

PMID 26488869  Emerg Infect Dis. 2015 Nov;21(11):2088-90. doi: 10.3201・・・
著者: Ali S Omrani, Mustafa M Saad, Kamran Baig, Abdelkarim Bahloul, Mohammed Abdul-Matin, Amal Y Alaidaroos, Ghaleb A Almakhlafi, Mohammed M Albarrak, Ziad A Memish, Ali M Albarrak
雑誌名: Lancet Infect Dis. 2014 Nov;14(11):1090-5. doi: 10.1016/S1473-3099(14)70920-X. Epub 2014 Sep 29.
Abstract/Text BACKGROUND: Middle East respiratory syndrome coronavirus (MERS-CoV) infection is associated with high mortality and has no approved antiviral therapy. We aimed to compare ribavirin and interferon alfa-2a treatment for patients with severe MERS-CoV infection with a supportive therapy only.
METHODS: In this retrospective cohort study, we included adults (aged ≥16 years) with laboratory-confirmed MERS-CoV infection and pneumonia needing ventilation support, diagnosed between Oct 23, 2012, and May 1, 2014, at the Prince Sultan Military Medical City (Riyadh, Saudi Arabia). All patients received appropriate supportive care and regular clinical and laboratory monitoring, but patients diagnosed after Sept 16, 2013, were also given oral ribavirin (dose based on calculated creatinine clearance, for 8-10 days) and subcutaneous pegylated interferon alfa-2a (180 μg per week for 2 weeks). The primary endpoint was 14-day and 28-day survival from the date of MERS-CoV infection diagnosis. We used χ(2) and Fischer's exact test to analyse categorical variables and the t test to analyse continuous variables.
FINDINGS: We analysed 20 patients who received ribavirin and interferon (treatment group; initiated a median of 3 days [range 0-8] after diagnosis) and 24 who did not (comparator group). Baseline clinical and laboratory characteristics were similar between groups, apart from baseline absolute neutrophil count, which was significantly lower in the comparator group (5·88 × 10(9)/L [SD 3·95] vs 9·88 × 10(9)/L [6·63]; p=0·023). 14 (70%) of 20 patients in the treatment group had survived after 14 days, compared with seven (29%) of 24 in the comparator group (p=0·004). After 28 days, six (30%) of 20 and four (17%) of 24, respectively, had survived (p=0·54). Adverse effects were similar between groups, apart from reduction in haemoglobin, which was significantly greater in the treatment group than in the comparator group (4·32 g/L [SD 2·47] vs 2·14 g/L [1·90]; p=0·002).
INTERPRETATION: In patients with severe MERS-CoV infection, ribavirin and interferon alfa-2a therapy is associated with significantly improved survival at 14 days, but not at 28 days. Further assessment in appropriately designed randomised trials is recommended.
FUNDING: None.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 25278221  Lancet Infect Dis. 2014 Nov;14(11):1090-5. doi: 10.1016・・・
著者: Jaffar A Al-Tawfiq, Hisham Momattin, Jean Dib, Ziad A Memish
雑誌名: Int J Infect Dis. 2014 Mar;20:42-6. doi: 10.1016/j.ijid.2013.12.003. Epub 2014 Jan 6.
Abstract/Text BACKGROUND: The Middle East respiratory syndrome coronavirus (MERS-CoV) has been reported to have a high case-fatality rate. Currently, there is no specific therapy or vaccine with proven effectiveness for MERS-CoV infections.
METHODS: A combination of ribavirin and interferon therapy was used for the treatment of five MERS-CoV-positive patients. We reviewed the therapeutic schedule and the outcome of these patients.
RESULTS: All patients were critically ill with acute respiratory distress syndrome treated with adjunctive corticosteroids and were on mechanical ventilation at the time of initiation of therapy. The median time from admission to therapy with ribavirin and interferon was 19 (range 10-22) days. None of the patients responded to the supportive or therapeutic interventions and all died of their illness.
CONCLUSIONS: While ribavirin and interferon may be effective in some patients, our practical experience suggests that critically ill patients with multiple comorbidities who are diagnosed late in the course of their illness may not benefit from combination antiviral therapy as preclinical data suggest. There is clearly an urgent need for a novel effective antiviral therapy for this emerging global threat.

Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
PMID 24406736  Int J Infect Dis. 2014 Mar;20:42-6. doi: 10.1016/j.ijid・・・
著者: Minal Kapoor, Kimberly Pringle, Alan Kumar, Stephanie Dearth, Lixia Liu, Judith Lovchik, Omar Perez, Pam Pontones, Shawn Richards, Jaime Yeadon-Fagbohun, Lucy Breakwell, Nora Chea, Nicole J Cohen, Eileen Schneider, Dean Erdman, Lia Haynes, Mark Pallansch, Ying Tao, Suxiang Tong, Susan Gerber, David Swerdlow, Daniel R Feikin
雑誌名: Clin Infect Dis. 2014 Dec 1;59(11):1511-8. doi: 10.1093/cid/ciu635. Epub 2014 Aug 6.
Abstract/Text BACKGROUND: The Middle East respiratory syndrome coronavirus (MERS-CoV) was discovered September 2012 in the Kingdom of Saudi Arabia (KSA). The first US case of MERS-CoV was confirmed on 2 May 2014.
METHODS: We summarize the clinical symptoms and signs, laboratory and radiologic findings, and MERS-CoV-specific tests.
RESULTS: The patient is a 65-year-old physician who worked in a hospital in KSA where MERS-CoV patients were treated. His illness onset included malaise, myalgias, and low-grade fever. He flew to the United States on day of illness (DOI) 7. His first respiratory symptom, a dry cough, developed on DOI 10. On DOI 11, he presented to an Indiana hospital as dyspneic, hypoxic, and with a right lower lobe infiltrate on chest radiography. On DOI 12, his serum tested positive by real-time reverse transcription polymerase chain reaction (rRT-PCR) for MERS-CoV and showed high MERS-CoV antibody titers, whereas his nasopharyngeal swab was rRT-PCR negative. Expectorated sputum was rRT-PCR positive the following day, with a high viral load (5.31 × 10(6) copies/mL). He was treated with antibiotics, intravenous immunoglobulin, and oxygen by nasal cannula. He was discharged on DOI 22. The genome sequence was similar (>99%) to other known MERS-CoV sequences, clustering with those from KSA from June to July 2013.
CONCLUSIONS: This patient had a prolonged nonspecific prodromal illness before developing respiratory symptoms. Both sera and sputum were rRT-PCR positive when nasopharyngeal specimens were negative. US clinicians must be vigilant for MERS-CoV in patients with febrile and/or respiratory illness with recent travel to the Arabian Peninsula, especially among healthcare workers.

Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
PMID 25100864  Clin Infect Dis. 2014 Dec 1;59(11):1511-8. doi: 10.1093・・・
著者: Karuppiah Muthumani, Darryl Falzarano, Emma L Reuschel, Colleen Tingey, Seleeke Flingai, Daniel O Villarreal, Megan Wise, Ami Patel, Abdullah Izmirly, Abdulelah Aljuaid, Alecia M Seliga, Geoff Soule, Matthew Morrow, Kimberly A Kraynyak, Amir S Khan, Dana P Scott, Friederike Feldmann, Rachel LaCasse, Kimberly Meade-White, Atsushi Okumura, Kenneth E Ugen, Niranjan Y Sardesai, J Joseph Kim, Gary Kobinger, Heinz Feldmann, David B Weiner
雑誌名: Sci Transl Med. 2015 Aug 19;7(301):301ra132. doi: 10.1126/scitranslmed.aac7462.
Abstract/Text First identified in 2012, Middle East respiratory syndrome (MERS) is caused by an emerging human coronavirus, which is distinct from the severe acute respiratory syndrome coronavirus (SARS-CoV), and represents a novel member of the lineage C betacoronoviruses. Since its identification, MERS coronavirus (MERS-CoV) has been linked to more than 1372 infections manifesting with severe morbidity and, often, mortality (about 495 deaths) in the Arabian Peninsula, Europe, and, most recently, the United States. Human-to-human transmission has been documented, with nosocomial transmission appearing to be an important route of infection. The recent increase in cases of MERS in the Middle East coupled with the lack of approved antiviral therapies or vaccines to treat or prevent this infection are causes for concern. We report on the development of a synthetic DNA vaccine against MERS-CoV. An optimized DNA vaccine encoding the MERS spike protein induced potent cellular immunity and antigen-specific neutralizing antibodies in mice, macaques, and camels. Vaccinated rhesus macaques seroconverted rapidly and exhibited high levels of virus-neutralizing activity. Upon MERS viral challenge, all of the monkeys in the control-vaccinated group developed characteristic disease, including pneumonia. Vaccinated macaques were protected and failed to demonstrate any clinical or radiographic signs of pneumonia. These studies demonstrate that a consensus MERS spike protein synthetic DNA vaccine can induce protective responses against viral challenge, indicating that this strategy may have value as a possible vaccine modality against this emerging pathogen.

Copyright © 2015, American Association for the Advancement of Science.
PMID 26290414  Sci Transl Med. 2015 Aug 19;7(301):301ra132. doi: 10.11・・・
著者: Matthew Cotten, Simon J Watson, Paul Kellam, Abdullah A Al-Rabeeah, Hatem Q Makhdoom, Abdullah Assiri, Jaffar A Al-Tawfiq, Rafat F Alhakeem, Hossam Madani, Fahad A AlRabiah, Sami Al Hajjar, Wafa N Al-nassir, Ali Albarrak, Hesham Flemban, Hanan H Balkhy, Sarah Alsubaie, Anne L Palser, Astrid Gall, Rachael Bashford-Rogers, Andrew Rambaut, Alimuddin I Zumla, Ziad A Memish
雑誌名: Lancet. 2013 Dec 14;382(9909):1993-2002. doi: 10.1016/S0140-6736(13)61887-5. Epub 2013 Sep 20.
Abstract/Text BACKGROUND: Since June, 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has, worldwide, caused 104 infections in people including 49 deaths, with 82 cases and 41 deaths reported from Saudi Arabia. In addition to confirming diagnosis, we generated the MERS-CoV genomic sequences obtained directly from patient samples to provide important information on MERS-CoV transmission, evolution, and origin.
METHODS: Full genome deep sequencing was done on nucleic acid extracted directly from PCR-confirmed clinical samples. Viral genomes were obtained from 21 MERS cases of which 13 had 100%, four 85-95%, and four 30-50% genome coverage. Phylogenetic analysis of the 21 sequences, combined with nine published MERS-CoV genomes, was done.
FINDINGS: Three distinct MERS-CoV genotypes were identified in Riyadh. Phylogeographic analyses suggest the MERS-CoV zoonotic reservoir is geographically disperse. Selection analysis of the MERS-CoV genomes reveals the expected accumulation of genetic diversity including changes in the S protein. The genetic diversity in the Al-Hasa cluster suggests that the hospital outbreak might have had more than one virus introduction.
INTERPRETATION: We present the largest number of MERS-CoV genomes (21) described so far. MERS-CoV full genome sequences provide greater detail in tracking transmission. Multiple introductions of MERS-CoV are identified and suggest lower R0 values. Transmission within Saudi Arabia is consistent with either movement of an animal reservoir, animal products, or movement of infected people. Further definition of the exposures responsible for the sporadic introductions of MERS-CoV into human populations is urgently needed.
FUNDING: Saudi Arabian Ministry of Health, Wellcome Trust, European Community, and National Institute of Health Research University College London Hospitals Biomedical Research Centre.

Copyright © 2013 Cotten et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by Elsevier Ltd. All rights reserved.
PMID 24055451  Lancet. 2013 Dec 14;382(9909):1993-2002. doi: 10.1016/S・・・
著者: David S Hui
雑誌名: Lancet. 2013 Dec 14;382(9909):1962-4. doi: 10.1016/S0140-6736(13)61955-8. Epub 2013 Sep 20.
Abstract/Text
PMID 24055454  Lancet. 2013 Dec 14;382(9909):1962-4. doi: 10.1016/S014・・・
著者: Ali M Zaki, Sander van Boheemen, Theo M Bestebroer, Albert D M E Osterhaus, Ron A M Fouchier
雑誌名: N Engl J Med. 2012 Nov 8;367(19):1814-20. doi: 10.1056/NEJMoa1211721. Epub 2012 Oct 17.
Abstract/Text A previously unknown coronavirus was isolated from the sputum of a 60-year-old man who presented with acute pneumonia and subsequent renal failure with a fatal outcome in Saudi Arabia. The virus (called HCoV-EMC) replicated readily in cell culture, producing cytopathic effects of rounding, detachment, and syncytium formation. The virus represents a novel betacoronavirus species. The closest known relatives are bat coronaviruses HKU4 and HKU5. Here, the clinical data, virus isolation, and molecular identification are presented. The clinical picture was remarkably similar to that of the severe acute respiratory syndrome (SARS) outbreak in 2003 and reminds us that animal coronaviruses can cause severe disease in humans.

PMID 23075143  N Engl J Med. 2012 Nov 8;367(19):1814-20. doi: 10.1056/・・・
著者: B Hijawi, M Abdallat, A Sayaydeh, S Alqasrawi, A Haddadin, N Jaarour, S Alsheikh, T Alsanouri
雑誌名: East Mediterr Health J. 2013;19 Suppl 1:S12-8.
Abstract/Text In April 2012, an outbreak of acute respiratory illness occurred in a public hospital in Zarqa city, in Jordan; 8 health care workers were among the 11 people affected, 1 of who later died. The cause of the outbreak was unknown at the time and an epidemiological investigation including laboratory testing carried out immediately afterthe outbreak was inconclusive. Following the discovery of novel coronavirus infection (nCoV) in the Arabian peninsula in September 2012, stored respiratory and serum samples of patients from this outbreak were retested and the diagnosis of nCoV was confirmed in 2 deceased patients. This paper describes the epidemiological findings of retrospective investigation carried out in November 2012 and highlights the likelihood of nosocomial transmission of nCoV infection in a health-care setting. A total of 2 laboratory-confirmed and 11 probable cases were identified from this outbreak of whom 10 were HCWs and 2 were family members of cases.

PMID 23888790  East Mediterr Health J. 2013;19 Suppl 1:S12-8.
著者: Stephanie R Bialek, Donna Allen, Francisco Alvarado-Ramy, Ray Arthur, Arunmozhi Balajee, David Bell, Susan Best, Carina Blackmore, Lucy Breakwell, Andrew Cannons, Clive Brown, Martin Cetron, Nora Chea, Christina Chommanard, Nicole Cohen, Craig Conover, Antonio Crespo, Jeanean Creviston, Aaron T Curns, Rebecca Dahl, Stephanie Dearth, Alfred DeMaria, Fred Echols, Dean D Erdman, Daniel Feikin, Mabel Frias, Susan I Gerber, Reena Gulati, Christa Hale, Lia M Haynes, Lea Heberlein-Larson, Kelly Holton, Kashef Ijaz, Minal Kapoor, Katrin Kohl, David T Kuhar, Alan M Kumar, Marianne Kundich, Susan Lippold, Lixia Liu, Judith C Lovchik, Larry Madoff, Sandra Martell, Sarah Matthews, Jessica Moore, Linda R Murray, Shauna Onofrey, Mark A Pallansch, Nicki Pesik, Huong Pham, Satish Pillai, Pam Pontones, Kimberly Pringle, Scott Pritchard, Sonja Rasmussen, Shawn Richards, Michelle Sandoval, Eileen Schneider, Anne Schuchat, Kristine Sheedy, Kevin Sherin, David L Swerdlow, Jordan W Tappero, Michael O Vernon, Sharon Watkins, John Watson, Centers for Disease Control and Prevention (CDC)
雑誌名: MMWR Morb Mortal Wkly Rep. 2014 May 16;63(19):431-6.
Abstract/Text Since mid-March 2014, the frequency with which cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection have been reported has increased, with the majority of recent cases reported from Saudi Arabia and United Arab Emirates (UAE). In addition, the frequency with which travel-associated MERS cases have been reported and the number of countries that have reported them to the World Health Organization (WHO) have also increased. The first case of MERS in the United States, identified in a traveler recently returned from Saudi Arabia, was reported to CDC by the Indiana State Department of Health on May 1, 2014, and confirmed by CDC on May 2. A second imported case of MERS in the United States, identified in a traveler from Saudi Arabia having no connection with the first case, was reported to CDC by the Florida Department of Health on May 11, 2014. The purpose of this report is to alert clinicians, health officials, and others to increase awareness of the need to consider MERS-CoV infection in persons who have recently traveled from countries in or near the Arabian Peninsula. This report summarizes recent epidemiologic information, provides preliminary descriptions of the cases reported from Indiana and Florida, and updates CDC guidance about patient evaluation, home care and isolation, specimen collection, and travel as of May 13, 2014.

PMID 24827411  MMWR Morb Mortal Wkly Rep. 2014 May 16;63(19):431-6.
著者: Daniel K W Chu, Leo L M Poon, Mokhtar M Gomaa, Mahmoud M Shehata, Ranawaka A P M Perera, Dina Abu Zeid, Amira S El Rifay, Lewis Y Siu, Yi Guan, Richard J Webby, Mohamed A Ali, Malik Peiris, Ghazi Kayali
雑誌名: Emerg Infect Dis. 2014 Jun;20(6):1049-53. doi: 10.3201/eid2006.140299.
Abstract/Text We identified the near-full-genome sequence (29,908 nt, >99%) of Middle East respiratory syndrome coronavirus (MERS-CoV) from a nasal swab specimen from a dromedary camel in Egypt. We found that viruses genetically very similar to human MERS-CoV are infecting dromedaries beyond the Arabian Peninsula, where human MERS-CoV infections have not yet been detected.

PMID 24856660  Emerg Infect Dis. 2014 Jun;20(6):1049-53. doi: 10.3201/・・・
著者: Thomas Briese, Nischay Mishra, Komal Jain, Iyad S Zalmout, Omar J Jabado, William B Karesh, Peter Daszak, Osama B Mohammed, Abdulaziz N Alagaili, W Ian Lipkin
雑誌名: MBio. 2014 Apr 29;5(3):e01146-14. doi: 10.1128/mBio.01146-14. Epub 2014 Apr 29.
Abstract/Text ABSTRACT Complete Middle East respiratory syndrome coronavirus (MERS-CoV) genome sequences were obtained from nasal swabs of dromedary camels sampled in the Kingdom of Saudi Arabia through direct analysis of nucleic acid extracts or following virus isolation in cell culture. Consensus dromedary MERS-CoV genome sequences were the same with either template source and identical to published human MERS-CoV sequences. However, in contrast to individual human cases, where only clonal genomic sequences are reported, detailed population analyses revealed the presence of more than one genomic variant in individual dromedaries. If humans are truly infected only with clonal virus populations, we must entertain a model for interspecies transmission of MERS-CoV wherein only specific genotypes are capable of passing bottleneck selection. IMPORTANCE In most cases of Middle East respiratory syndrome (MERS), the route for human infection with the causative agent, MERS coronavirus (MERS-CoV), is unknown. Antibodies to and viral nucleic acids of MERS-CoV have been found in dromedaries, suggesting the possibility that they may serve as a reservoir or vector for human infection. However, neither whole viral genomic sequence nor infectious virus has been isolated from dromedaries or other animals in Saudi Arabia. Here, we report recovery of MERS-CoV from nasal swabs of dromedaries, demonstrate that MERS-CoV whole-genome consensus sequences from dromedaries and humans are indistinguishable, and show that dromedaries can be simultaneously infected with more than one MERS-CoV. Together with data indicating widespread dromedary infection in the Kingdom of Saudi Arabia, these findings support the plausibility of a role for dromedaries in human infection.

PMID 24781747  MBio. 2014 Apr 29;5(3):e01146-14. doi: 10.1128/mBio.011・・・
著者: Maged G Hemida, Daniel K W Chu, Leo L M Poon, Ranawaka A P M Perera, Mohammad A Alhammadi, Hoi-Yee Ng, Lewis Y Siu, Yi Guan, Abdelmohsen Alnaeem, Malik Peiris
雑誌名: Emerg Infect Dis. 2014 Jul;20(7):1231-4. doi: 10.3201/eid2007.140571.
Abstract/Text A prospective study of a dromedary camel herd during the 2013-14 calving season showed Middle East respiratory syndrome coronavirus infection of calves and adults. Virus was isolated from the nose and feces but more frequently from the nose. Preexisting neutralizing antibody did not appear to protect against infection.

PMID 24964193  Emerg Infect Dis. 2014 Jul;20(7):1231-4. doi: 10.3201/e・・・
著者: V Stalin Raj, Elmoubasher A B A Farag, Chantal B E M Reusken, Mart M Lamers, Suzan D Pas, Jolanda Voermans, Saskia L Smits, Albert D M E Osterhaus, Naema Al-Mawlawi, Hamad E Al-Romaihi, Mohd M AlHajri, Ahmed M El-Sayed, Khaled A Mohran, Hazem Ghobashy, Farhoud Alhajri, Mohamed Al-Thani, Salih A Al-Marri, Mamdouh M El-Maghraby, Marion P G Koopmans, Bart L Haagmans
雑誌名: Emerg Infect Dis. 2014 Aug;20(8):1339-42. doi: 10.3201/eid2008.140663.
Abstract/Text We obtained the full genome of Middle East respiratory syndrome coronavirus (MERS-CoV) from a camel in Qatar. This virus is highly similar to the human England/Qatar 1 virus isolated in 2012. The MERS-CoV from the camel efficiently replicated in human cells, providing further evidence for the zoonotic potential of MERS-CoV from camels.

PMID 25075761  Emerg Infect Dis. 2014 Aug;20(8):1339-42. doi: 10.3201/・・・
著者: Matthew Cotten, Simon J Watson, Alimuddin I Zumla, Hatem Q Makhdoom, Anne L Palser, Swee Hoe Ong, Abdullah A Al Rabeeah, Rafat F Alhakeem, Abdullah Assiri, Jaffar A Al-Tawfiq, Ali Albarrak, Mazin Barry, Atef Shibl, Fahad A Alrabiah, Sami Hajjar, Hanan H Balkhy, Hesham Flemban, Andrew Rambaut, Paul Kellam, Ziad A Memish
雑誌名: MBio. 2014 Feb 18;5(1). doi: 10.1128/mBio.01062-13. Epub 2014 Feb 18.
Abstract/Text UNLABELLED: The Middle East respiratory syndrome coronavirus (MERS-CoV) was first documented in the Kingdom of Saudi Arabia (KSA) in 2012 and, to date, has been identified in 180 cases with 43% mortality. In this study, we have determined the MERS-CoV evolutionary rate, documented genetic variants of the virus and their distribution throughout the Arabian peninsula, and identified the genome positions under positive selection, important features for monitoring adaptation of MERS-CoV to human transmission and for identifying the source of infections. Respiratory samples from confirmed KSA MERS cases from May to September 2013 were subjected to whole-genome deep sequencing, and 32 complete or partial sequences (20 were ≥ 99% complete, 7 were 50 to 94% complete, and 5 were 27 to 50% complete) were obtained, bringing the total available MERS-CoV genomic sequences to 65. An evolutionary rate of 1.12 × 10(-3) substitutions per site per year (95% credible interval [95% CI], 8.76 × 10(-4); 1.37 × 10(-3)) was estimated, bringing the time to most recent common ancestor to March 2012 (95% CI, December 2011; June 2012). Only one MERS-CoV codon, spike 1020, located in a domain required for cell entry, is under strong positive selection. Four KSA MERS-CoV phylogenetic clades were found, with 3 clades apparently no longer contributing to current cases. The size of the population infected with MERS-CoV showed a gradual increase to June 2013, followed by a decline, possibly due to increased surveillance and infection control measures combined with a basic reproduction number (R0) for the virus that is less than 1.
IMPORTANCE: MERS-CoV adaptation toward higher rates of sustained human-to-human transmission appears not to have occurred yet. While MERS-CoV transmission currently appears weak, careful monitoring of changes in MERS-CoV genomes and of the MERS epidemic should be maintained. The observation of phylogenetically related MERS-CoV in geographically diverse locations must be taken into account in efforts to identify the animal source and transmission of the virus.

PMID 24549846  MBio. 2014 Feb 18;5(1). doi: 10.1128/mBio.01062-13. Epu・・・
著者: Chantal B E M Reusken, Lilia Messadi, Ashenafi Feyisa, Hussaini Ularamu, Gert-Jan Godeke, Agom Danmarwa, Fufa Dawo, Mohamed Jemli, Simenew Melaku, David Shamaki, Yusuf Woma, Yiltawe Wungak, Endrias Zewdu Gebremedhin, Ilse Zutt, Berend-Jan Bosch, Bart L Haagmans, Marion P G Koopmans
雑誌名: Emerg Infect Dis. 2014 Aug;20(8):1370-4. doi: 10.3201/eid2008.140590.
Abstract/Text We found serologic evidence for the circulation of Middle East respiratory syndrome coronavirus among dromedary camels in Nigeria, Tunisia, and Ethiopia. Circulation of the virus among dromedaries across broad areas of Africa may indicate that this disease is currently underdiagnosed in humans outside the Arabian Peninsula.

PMID 25062254  Emerg Infect Dis. 2014 Aug;20(8):1370-4. doi: 10.3201/e・・・
著者: Benjamin Meyer, Marcel A Müller, Victor M Corman, Chantal B E M Reusken, Daniel Ritz, Gert-Jan Godeke, Erik Lattwein, Stephan Kallies, Artem Siemens, Janko van Beek, Jan F Drexler, Doreen Muth, Berend-Jan Bosch, Ulrich Wernery, Marion P G Koopmans, Renate Wernery, Christian Drosten
雑誌名: Emerg Infect Dis. 2014 Apr;20(4):552-9. doi: 10.3201/eid2004.131746.
Abstract/Text Middle East respiratory syndrome coronavirus (MERS-CoV) has caused an ongoing outbreak of severe acute respiratory tract infection in humans in the Arabian Peninsula since 2012. Dromedary camels have been implicated as possible viral reservoirs. We used serologic assays to analyze 651 dromedary camel serum samples from the United Arab Emirates; 151 of 651 samples were obtained in 2003, well before onset of the current epidemic, and 500 serum samples were obtained in 2013. Recombinant spike protein-specific immunofluorescence and virus neutralization tests enabled clear discrimination between MERS-CoV and bovine CoV infections. Most (632/651, 97.1%) camels had antibodies against MERS-CoV. This result included all 151 serum samples obtained in 2003. Most (389/651, 59.8%) serum samples had MERS-CoV-neutralizing antibody titers >1,280. Dromedary camels from the United Arab Emirates were infected at high rates with MERS-CoV or a closely related, probably conspecific, virus long before the first human MERS cases.

PMID 24655412  Emerg Infect Dis. 2014 Apr;20(4):552-9. doi: 10.3201/ei・・・
著者: Victor M Corman, Joerg Jores, Benjamin Meyer, Mario Younan, Anne Liljander, Mohammed Y Said, Ilona Gluecks, Erik Lattwein, Berend-Jan Bosch, Jan Felix Drexler, Set Bornstein, Christian Drosten, Marcel A Müller
雑誌名: Emerg Infect Dis. 2014 Aug;20(8):1319-22. doi: 10.3201/eid2008.140596.
Abstract/Text Dromedary camels are a putative source for human infections with Middle East respiratory syndrome coronavirus. We showed that camels sampled in different regions in Kenya during 1992-2013 have antibodies against this virus. High densities of camel populations correlated with increased seropositivity and might be a factor in predicting long-term virus maintenance.

PMID 25075637  Emerg Infect Dis. 2014 Aug;20(8):1319-22. doi: 10.3201/・・・
著者: Mohamed Ali, Rabeh El-Shesheny, Ahmed Kandeil, Mahmoud Shehata, Basma Elsokary, Mokhtar Gomaa, Naglaa Hassan, Ahmed El Sayed, Ahmed El-Taweel, Heba Sobhy, Folorunso Oludayo Fasina, Gwenaelle Dauphin, Ihab El Masry, Abebe Wossene Wolde, Peter Daszak, Maureen Miller, Sophie VonDobschuetz, Subhash Morzaria, Juan Lubroth, Yilma Jobre Makonnen
雑誌名: Euro Surveill. 2017 Mar 16;22(11). doi: 10.2807/1560-7917.ES.2017.22.11.30487.
Abstract/Text A cross-sectional study was conducted in Egypt to determine the prevalence of Middle East respiratory syndrome coronavirus (MERS-CoV) in imported and resident camels and bats, as well as to assess possible transmission of the virus to domestic ruminants and equines. A total of 1,031 sera, 1,078 nasal swabs, 13 rectal swabs, and 38 milk samples were collected from 1,078 camels in different types of sites. In addition, 145 domestic animals and 109 bats were sampled. Overall, of 1,031 serologically-tested camels, 871 (84.5%) had MERS-CoV neutralising antibodies. Seroprevalence was significantly higher in imported (614/692; 88.7%) than resident camels (257/339; 5.8%) (p < 0.05). Camels from Sudan (543/594; 91.4%) had a higher seroprevalence than those from East Africa (71/98; 72.4%) (p < 0.05). Sampling site and age were also associated with MERS-CoV seroprevalence (p < 0.05). All tested samples from domestic animals and bats were negative for MERS-CoV antibodies except one sheep sample which showed a 1:640 titre. Of 1,078 camels, 41 (3.8%) were positive for MERS-CoV genetic material. Sequences obtained were not found to cluster with clade A or B MERS-CoV sequences and were genetically diverse. The presence of neutralising antibodies in one sheep apparently in contact with seropositive camels calls for further studies on domestic animals in contact with camels.

This article is copyright of The Authors, 2017.
PMID 28333616  Euro Surveill. 2017 Mar 16;22(11). doi: 10.2807/1560-79・・・
著者: Carlos Gutiérrez, María Teresa Tejedor-Junco, Margarita González, Erik Lattwein, Stefanie Renneker
雑誌名: Euro Surveill. 2015;20(37). doi: 10.2807/1560-7917.ES.2015.20.37.30019.
Abstract/Text In 2012, a new betacoronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), was identified in humans. Several studies confirmed dromedary camels to be a potential reservoir and a source for human infection. Camels located on the Canary Islands were included in those studies and ca 10% of them were positive for MERS-CoV-specific antibodies. However, these findings could not be correctly interpreted because epidemiological information was not provided. Thus, further investigations were necessary to clarify these results. A total of 170 camels were investigated in this survey, of which seven (4.1%) were seropositive by ELISA. Epidemiological information revealed that all seropositive camels had been imported from Africa 20 or more years prior. We conclude that seropositive camels had contact with MERS-CoV in Africa and that there is no shedding of the virus among camels or people around the farms on the Canary Islands. However, the presence of antibodies in the camel herds should be monitored.

PMID 26536463  Euro Surveill. 2015;20(37). doi: 10.2807/1560-7917.ES.2・・・
著者: Muhammad Saqib, Andrea Sieberg, Muhammad Hammad Hussain, Muhammad Khalid Mansoor, Ali Zohaib, Erik Lattwein, Marcel Alexander Müller, Christian Drosten, Victor Max Corman
雑誌名: Emerg Infect Dis. 2017 Mar;23(3):550-551. doi: 10.3201/eid2303.161285.
Abstract/Text Dromedary camels from Africa and Arabia are an established source for zoonotic Middle East respiratory syndrome coronavirus (MERS-CoV) infection among humans. In Pakistan, we found specific neutralizing antibodies in samples from 39.5% of 565 dromedaries, documenting significant expansion of the enzootic range of MERS-CoV to Asia.

PMID 28221127  Emerg Infect Dis. 2017 Mar;23(3):550-551. doi: 10.3201/・・・
著者: Ulrich Wernery, Victor M Corman, Emily Y M Wong, Alan K L Tsang, Doreen Muth, Susanna K P Lau, Kamal Khazanehdari, Florian Zirkel, Mansoor Ali, Peter Nagy, Jutka Juhasz, Renate Wernery, Sunitha Joseph, Ginu Syriac, Shyna K Elizabeth, Nissy Annie Georgy Patteril, Patrick C Y Woo, Christian Drosten
雑誌名: Emerg Infect Dis. 2015 Jun;21(6):1019-22. doi: 10.3201/eid2106.150038.
Abstract/Text Camels carry Middle East respiratory syndrome coronavirus, but little is known about infection age or prevalence. We studied >800 dromedaries of all ages and 15 mother-calf pairs. This syndrome constitutes an acute, epidemic, and time-limited infection in camels <4 years of age, particularly calves. Delayed social separation of calves might reduce human infection risk.

PMID 25989145  Emerg Infect Dis. 2015 Jun;21(6):1019-22. doi: 10.3201/・・・
著者: Danielle R Adney, Neeltje van Doremalen, Vienna R Brown, Trenton Bushmaker, Dana Scott, Emmie de Wit, Richard A Bowen, Vincent J Munster
雑誌名: Emerg Infect Dis. 2014 Dec;20(12):1999-2005. doi: 10.3201/eid2012.141280.
Abstract/Text In 2012, a novel coronavirus associated with severe respiratory disease in humans emerged in the Middle East. Epidemiologic investigations identified dromedary camels as the likely source of zoonotic transmission of Middle East respiratory syndrome coronavirus (MERS-CoV). Here we provide experimental support for camels as a reservoir for MERS-CoV. We inoculated 3 adult camels with a human isolate of MERS-CoV and a transient, primarily upper respiratory tract infection developed in each of the 3 animals. Clinical signs of the MERS-CoV infection were benign, but each of the camels shed large quantities of virus from the upper respiratory tract. We detected infectious virus in nasal secretions through 7 days postinoculation, and viral RNA up to 35 days postinoculation. The pattern of shedding and propensity for the upper respiratory tract infection in dromedary camels may help explain the lack of systemic illness among naturally infected camels and the means of efficient camel-to-camel and camel-to-human transmission.

PMID 25418529  Emerg Infect Dis. 2014 Dec;20(12):1999-2005. doi: 10.32・・・
著者: Kazuya Shirato, Akinori Azumano, Tatsuko Nakao, Daisuke Hagihara, Manabu Ishida, Kanji Tamai, Kouji Yamazaki, Miyuki Kawase, Yoshiharu Okamoto, Shigehisa Kawakami, Naonori Okada, Kazuko Fukushima, Kensuke Nakajima, Shutoku Matsuyama
雑誌名: Jpn J Infect Dis. 2015;68(3):256-8. doi: 10.7883/yoken.JJID.2015.094.
Abstract/Text
PMID 25993975  Jpn J Infect Dis. 2015;68(3):256-8. doi: 10.7883/yoken.・・・
著者: Chantal B E M Reusken, Bart L Haagmans, Marcel A Müller, Carlos Gutierrez, Gert-Jan Godeke, Benjamin Meyer, Doreen Muth, V Stalin Raj, Laura Smits-De Vries, Victor M Corman, Jan-Felix Drexler, Saskia L Smits, Yasmin E El Tahir, Rita De Sousa, Janko van Beek, Norbert Nowotny, Kees van Maanen, Ezequiel Hidalgo-Hermoso, Berend-Jan Bosch, Peter Rottier, Albert Osterhaus, Christian Gortázar-Schmidt, Christian Drosten, Marion P G Koopmans
雑誌名: Lancet Infect Dis. 2013 Oct;13(10):859-66. doi: 10.1016/S1473-3099(13)70164-6. Epub 2013 Aug 9.
Abstract/Text BACKGROUND: A new betacoronavirus-Middle East respiratory syndrome coronavirus (MERS-CoV)-has been identified in patients with severe acute respiratory infection. Although related viruses infect bats, molecular clock analyses have been unable to identify direct ancestors of MERS-CoV. Anecdotal exposure histories suggest that patients had been in contact with dromedary camels or goats. We investigated possible animal reservoirs of MERS-CoV by assessing specific serum antibodies in livestock.
METHODS: We took sera from animals in the Middle East (Oman) and from elsewhere (Spain, Netherlands, Chile). Cattle (n=80), sheep (n=40), goats (n=40), dromedary camels (n=155), and various other camelid species (n=34) were tested for specific serum IgG by protein microarray using the receptor-binding S1 subunits of spike proteins of MERS-CoV, severe acute respiratory syndrome coronavirus, and human coronavirus OC43. Results were confirmed by virus neutralisation tests for MERS-CoV and bovine coronavirus.
FINDINGS: 50 of 50 (100%) sera from Omani camels and 15 of 105 (14%) from Spanish camels had protein-specific antibodies against MERS-CoV spike. Sera from European sheep, goats, cattle, and other camelids had no such antibodies. MERS-CoV neutralising antibody titres varied between 1/320 and 1/2560 for the Omani camel sera and between 1/20 and 1/320 for the Spanish camel sera. There was no evidence for cross-neutralisation by bovine coronavirus antibodies.
INTERPRETATION: MERS-CoV or a related virus has infected camel populations. Both titres and seroprevalences in sera from different locations in Oman suggest widespread infection.
FUNDING: European Union, European Centre For Disease Prevention and Control, Deutsche Forschungsgemeinschaft.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23933067  Lancet Infect Dis. 2013 Oct;13(10):859-66. doi: 10.1016・・・
著者: The Lancet Infectious Diseases
雑誌名: Lancet Infect Dis. 2013 Aug;13(8):639. doi: 10.1016/S1473-3099(13)70205-6.
Abstract/Text
PMID 23886321  Lancet Infect Dis. 2013 Aug;13(8):639. doi: 10.1016/S14・・・
著者: M G Hemida, R A Perera, P Wang, M A Alhammadi, L Y Siu, M Li, L L Poon, L Saif, A Alnaeem, M Peiris
雑誌名: Euro Surveill. 2013 Dec 12;18(50):20659. Epub 2013 Dec 12.
Abstract/Text In Saudi Arabia, including regions of Riyadh and Al Ahsa, pseudoparticle neutralisation (ppNT) and microneutralisation (MNT) tests detected no antibodies to Middle East Respiratory Syndrome coronavirus (MERS-CoV) in sheep (n= 100), goats (n= 45), cattle (n= 50) and chickens (n= 240). Dromedary camels however, had a high prevalence of MERS-CoV antibodies. Bovine coronavirus (BCoV) infected sera from cattle had no cross-reactivity in MERS-CoV ppNT or MNT, while many dromedary camels’ sera reacted to both BCoV and MERS-CoV. Some nevertheless displayed specific serologic reaction profiles to MERS-CoV.

PMID 24342517  Euro Surveill. 2013 Dec 12;18(50):20659. Epub 2013 Dec ・・・
著者: Esam I Azhar, Sherif A El-Kafrawy, Suha A Farraj, Ahmed M Hassan, Muneera S Al-Saeed, Anwar M Hashem, Tariq A Madani
雑誌名: N Engl J Med. 2014 Jun 26;370(26):2499-505. doi: 10.1056/NEJMoa1401505. Epub 2014 Jun 4.
Abstract/Text We describe the isolation and sequencing of Middle East respiratory syndrome coronavirus (MERS-CoV) obtained from a dromedary camel and from a patient who died of laboratory-confirmed MERS-CoV infection after close contact with camels that had rhinorrhea. Nasal swabs collected from the patient and from one of his nine camels were positive for MERS-CoV RNA. In addition, MERS-CoV was isolated from the patient and the camel. The full genome sequences of the two isolates were identical. Serologic data indicated that MERS-CoV was circulating in the camels but not in the patient before the human infection occurred. These data suggest that this fatal case of human MERS-CoV infection was transmitted through close contact with an infected camel.

PMID 24896817  N Engl J Med. 2014 Jun 26;370(26):2499-505. doi: 10.105・・・
著者: Marcel A Müller, Benjamin Meyer, Victor M Corman, Malak Al-Masri, Abdulhafeez Turkestani, Daniel Ritz, Andrea Sieberg, Souhaib Aldabbagh, Berend-J Bosch, Erik Lattwein, Raafat F Alhakeem, Abdullah M Assiri, Ali M Albarrak, Ali M Al-Shangiti, Jaffar A Al-Tawfiq, Paul Wikramaratna, Abdullah A Alrabeeah, Christian Drosten, Ziad A Memish
雑誌名: Lancet Infect Dis. 2015 May;15(5):559-64. doi: 10.1016/S1473-3099(15)70090-3. Epub 2015 Apr 8.
Abstract/Text BACKGROUND: Scientific evidence suggests that dromedary camels are the intermediary host for the Middle East respiratory syndrome coronavirus (MERS-CoV). However, the actual number of infections in people who have had contact with camels is unknown and most index patients cannot recall any such contact. We aimed to do a nationwide serosurvey in Saudi Arabia to establish the prevalence of MERS-CoV antibodies, both in the general population and in populations of individuals who have maximum exposure to camels.
METHODS: In the cross-sectional serosurvey, we tested human serum samples obtained from healthy individuals older than 15 years who attended primary health-care centres or participated in a national burden-of-disease study in all 13 provinces of Saudi Arabia. Additionally, we tested serum samples from shepherds and abattoir workers with occupational exposure to camels. Samples were screened by recombinant ELISA and MERS-CoV seropositivity was confirmed by recombinant immunofluorescence and plaque reduction neutralisation tests. We used two-tailed Mann Whitney U exact tests, χ(2), and Fisher's exact tests to analyse the data.
FINDINGS: Between Dec 1, 2012, and Dec 1, 2013, we obtained individual serum samples from 10,009 individuals. Anti-MERS-CoV antibodies were confirmed in 15 (0·15%; 95% CI 0·09-0·24) of 10,009 people in six of the 13 provinces. The mean age of seropositive individuals was significantly younger than that of patients with reported, laboratory-confirmed, primary Middle Eastern respiratory syndrome (43·5 years [SD 17·3] vs 53·8 years [17·5]; p=0·008). Men had a higher antibody prevalence than did women (11 [0·25%] of 4341 vs two [0·05%] of 4378; p=0·028) and antibody prevalence was significantly higher in central versus coastal provinces (14 [0·26%] of 5479 vs one [0·02%] of 4529; p=0·003). Compared with the general population, seroprevalence of MERS-CoV antibodies was significantly increased by 15 times in shepherds (two [2·3%] of 87, p=0·0004) and by 23 times in slaughterhouse workers (five [3·6%] of 140; p<0·0001).
INTERPRETATION: Seroprevalence of MERS-CoV antibodies was significantly higher in camel-exposed individuals than in the general population. By simple multiplication, a projected 44,951 (95% CI 26,971-71,922) individuals older than 15 years might be seropositive for MERS-CoV in Saudi Arabia. These individuals might be the source of infection for patients with confirmed MERS who had no previous exposure to camels.
FUNDING: European Union, German Centre for Infection Research, Federal Ministry of Education and Research, German Research Council, and Ministry of Health of Saudi Arabia.

Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 25863564  Lancet Infect Dis. 2015 May;15(5):559-64. doi: 10.1016/・・・
著者: Anne Liljander, Benjamin Meyer, Joerg Jores, Marcel A Müller, Erik Lattwein, Ian Njeru, Bernard Bett, Christian Drosten, Victor Max Corman
雑誌名: Emerg Infect Dis. 2016 Jun;22(6):1086-9. doi: 10.3201/eid2206.160064. Epub 2016 Jun 15.
Abstract/Text Dromedaries in Africa and elsewhere carry the Middle East respiratory syndrome coronavirus (MERS-CoV). To search for evidence of autochthonous MERS-CoV infection in humans, we tested archived serum from livestock handlers in Kenya for MERS-CoV antibodies. Serologic evidence of infection was confirmed for 2 persons sampled in 2013 and 2014.

PMID 27071076  Emerg Infect Dis. 2016 Jun;22(6):1086-9. doi: 10.3201/e・・・
著者: Yoon-Seok Chung, Jeong Min Kim, Heui Man Kim, Kye Ryeong Park, Anna Lee, Nam-Joo Lee, Mi-Seon Kim, Jun Sub Kim, Chi-Kyeong Kim, Jae In Lee, Chun Kang
雑誌名: Emerg Infect Dis. 2019 May 17;25(5). doi: 10.3201/eid2505.181534. Epub 2019 May 17.
Abstract/Text We evaluated genetic variation in Middle East respiratory syndrome coronavirus (MERS-CoV) imported to South Korea in 2018 using specimens from a patient and isolates from infected Caco-2 cells. The MERS-CoV strain in this study was genetically similar to a strain isolated in Riyadh, Saudi Arabia, in 2017.

PMID 30753126  Emerg Infect Dis. 2019 May 17;25(5). doi: 10.3201/eid25・・・
著者: Basem M Alraddadi, John T Watson, Abdulatif Almarashi, Glen R Abedi, Amal Turkistani, Musallam Sadran, Abeer Housa, Mohammad A Almazroa, Naif Alraihan, Ayman Banjar, Eman Albalawi, Hanan Alhindi, Abdul Jamil Choudhry, Jonathan G Meiman, Magdalena Paczkowski, Aaron Curns, Anthony Mounts, Daniel R Feikin, Nina Marano, David L Swerdlow, Susan I Gerber, Rana Hajjeh, Tariq A Madani
雑誌名: Emerg Infect Dis. 2016 Jan;22(1):49-55. doi: 10.3201/eid2201.151340.
Abstract/Text Risk factors for primary Middle East respiratory syndrome coronavirus (MERS-CoV) illness in humans are incompletely understood. We identified all primary MERS-CoV cases reported in Saudi Arabia during March-November 2014 by excluding those with history of exposure to other cases of MERS-CoV or acute respiratory illness of unknown cause or exposure to healthcare settings within 14 days before illness onset. Using a case-control design, we assessed differences in underlying medical conditions and environmental exposures among primary case-patients and 2-4 controls matched by age, sex, and neighborhood. Using multivariable analysis, we found that direct exposure to dromedary camels during the 2 weeks before illness onset, as well as diabetes mellitus, heart disease, and smoking, were each independently associated with MERS-CoV illness. Further investigation is needed to better understand animal-to-human transmission of MERS-CoV.

PMID 26692185  Emerg Infect Dis. 2016 Jan;22(1):49-55. doi: 10.3201/ei・・・
著者: Reina S Sikkema, Elmoubasher A B A Farag, Sayed Himatt, Adel K Ibrahim, Hamad Al-Romaihi, Salih A Al-Marri, Mohamed Al-Thani, Ahmed M El-Sayed, Mohammed Al-Hajri, Bart L Haagmans, Marion P G Koopmans, Chantal B E M Reusken
雑誌名: J Infect Dis. 2017 Jun 1;215(11):1702-1705. doi: 10.1093/infdis/jix174.
Abstract/Text The transmission routes and risk factors for zoonotic Middle East respiratory syndrome coronavirus (MERS-CoV) infections are still unknown. We used the World Health Organization questionnaire for MERS-CoV case-control studies to assess risk factors for human MERS-CoV seropositivity at a farm complex in Qatar. Nine camel workers with MERS-CoV antibodies and 43 workers without antibodies were included. Some camel-related activities may pose a higher risk of MERS-CoV infection, as may cross-border movements of camels, poor hand hygiene, and overnight hospital stays with respiratory complaints. The risk factors identified in this study can be used to develop infection prevention and control measures for human MERS-CoV infections.

© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
PMID 28387845  J Infect Dis. 2017 Jun 1;215(11):1702-1705. doi: 10.109・・・
著者: Simon Cauchemez, Christophe Fraser, Maria D Van Kerkhove, Christl A Donnelly, Steven Riley, Andrew Rambaut, Vincent Enouf, Sylvie van der Werf, Neil M Ferguson
雑誌名: Lancet Infect Dis. 2014 Jan;14(1):50-6. doi: 10.1016/S1473-3099(13)70304-9. Epub 2013 Nov 13.
Abstract/Text BACKGROUND: The novel Middle East respiratory syndrome coronavirus (MERS-CoV) had, as of Aug 8, 2013, caused 111 virologically confirmed or probable human cases of infection worldwide. We analysed epidemiological and genetic data to assess the extent of human infection, the performance of case detection, and the transmission potential of MERS-CoV with and without control measures.
METHODS: We assembled a comprehensive database of all confirmed and probable cases from public sources and estimated the incubation period and generation time from case cluster data. Using data of numbers of visitors to the Middle East and their duration of stay, we estimated the number of symptomatic cases in the Middle East. We did independent analyses, looking at the growth in incident clusters, the growth in viral population, the reproduction number of cluster index cases, and cluster sizes to characterise the dynamical properties of the epidemic and the transmission scenario.
FINDINGS: The estimated number of symptomatic cases up to Aug 8, 2013, is 940 (95% CI 290-2200), indicating that at least 62% of human symptomatic cases have not been detected. We find that the case-fatality ratio of primary cases detected via routine surveillance (74%; 95% CI 49-91) is biased upwards because of detection bias; the case-fatality ratio of secondary cases was 20% (7-42). Detection of milder cases (or clinical management) seemed to have improved in recent months. Analysis of human clusters indicated that chains of transmission were not self-sustaining when infection control was implemented, but that R in the absence of controls was in the range 0·8-1·3. Three independent data sources provide evidence that R cannot be much above 1, with an upper bound of 1·2-1·5.
INTERPRETATION: By showing that a slowly growing epidemic is underway either in human beings or in an animal reservoir, quantification of uncertainty in transmissibility estimates, and provision of the first estimates of the scale of the epidemic and extent of case detection biases, we provide valuable information for more informed risk assessment.
FUNDING: Medical Research Council, Bill & Melinda Gates Foundation, EU FP7, and National Institute of General Medical Sciences.

Copyright © 2014 Cauchemez et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.
PMID 24239323  Lancet Infect Dis. 2014 Jan;14(1):50-6. doi: 10.1016/S1・・・
著者: Romulus Breban, Julien Riou, Arnaud Fontanet
雑誌名: Lancet. 2013 Aug 24;382(9893):694-9. doi: 10.1016/S0140-6736(13)61492-0. Epub 2013 Jul 5.
Abstract/Text BACKGROUND: The new Middle East respiratory syndrome coronavirus (MERS-CoV) infection shares many clinical, epidemiological, and virological similarities with that of severe acute respiratory syndrome (SARS)-CoV. We aimed to estimate virus transmissibility and the epidemic potential of MERS-CoV, and to compare the results with similar findings obtained for prepandemic SARS.
METHODS: We retrieved data for MERS-CoV clusters from the WHO summary and subsequent reports, and published descriptions of cases, and took into account 55 of the 64 laboratory-confirmed cases of MERS-CoV reported as of June 21, 2013, excluding cases notified in the previous 2 weeks. To assess the interhuman transmissibility of MERS-CoV, we used Bayesian analysis to estimate the basic reproduction number (R0) and compared it to that of prepandemic SARS. We considered two scenarios, depending on the interpretation of the MERS-CoV cluster-size data.
RESULTS: With our most pessimistic scenario (scenario 2), we estimated MERS-CoV R0 to be 0·69 (95% CI 0·50-0·92); by contrast, the R0 for prepandemic SARS-CoV was 0·80 (0·54-1·13). Our optimistic scenario (scenario 1) yielded a MERS-CoV R0 of 0·60 (0·42-0·80). Because of recent implementation of effective contact tracing and isolation procedures, further MERS-CoV transmission data might no longer describe an entire cluster, but only secondary infections directly caused by the index patient. Hence, we calculated that, under scenario 2, eight or more secondary infections caused by the next index patient would translate into a 5% or higher chance that the revised MERS-CoV R0 would exceed 1--ie, that MERS-CoV might have pandemic potential.
INTERPRETATION: Our analysis suggests that MERS-CoV does not yet have pandemic potential. We recommend enhanced surveillance, active contact tracing, and vigorous searches for the MERS-CoV animal hosts and transmission routes to human beings.
FUNDING: Agence Nationale de la Recherche (Labex Integrative Biology of Emerging Infectious Diseases), and the European Community's Seventh Framework Programme project PREDEMICS.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23831141  Lancet. 2013 Aug 24;382(9893):694-9. doi: 10.1016/S0140・・・
著者: Ikwo K Oboho, Sara M Tomczyk, Ahmad M Al-Asmari, Ayman A Banjar, Hani Al-Mugti, Muhannad S Aloraini, Khulud Z Alkhaldi, Emad L Almohammadi, Basem M Alraddadi, Susan I Gerber, David L Swerdlow, John T Watson, Tariq A Madani
雑誌名: N Engl J Med. 2015 Feb 26;372(9):846-54. doi: 10.1056/NEJMoa1408636.
Abstract/Text BACKGROUND: A marked increase in the number of cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection occurred in Jeddah, Saudi Arabia, in early 2014. We evaluated patients with MERS-CoV infection in Jeddah to explore reasons for this increase and to assess the epidemiologic and clinical features of this disease.
METHODS: We identified all cases of laboratory-confirmed MERS-CoV infection in Jeddah that were reported to the Saudi Arabian Ministry of Health from January 1 through May 16, 2014. We conducted telephone interviews with symptomatic patients who were not health care personnel, and we reviewed hospital records. We identified patients who were reported as being asymptomatic and interviewed them regarding a history of symptoms in the month before testing. Descriptive analyses were performed.
RESULTS: Of 255 patients with laboratory-confirmed MERS-CoV infection, 93 died (case fatality rate, 36.5%). The median age of all patients was 45 years (interquartile range, 30 to 59), and 174 patients (68.2%) were male. A total of 64 patients (25.1%) were reported to be asymptomatic. Of the 191 symptomatic patients, 40 (20.9%) were health care personnel. Among the 151 symptomatic patients who were not health care personnel, 112 (74.2%) had data that could be assessed, and 109 (97.3%) of these patients had had contact with a health care facility, a person with a confirmed case of MERS-CoV infection, or someone with severe respiratory illness in the 14 days before the onset of illness. The remaining 3 patients (2.7%) reported no such contacts. Of the 64 patients who had been reported as asymptomatic, 33 (52%) were interviewed, and 26 of these 33 (79%) reported at least one symptom that was consistent with a viral respiratory illness.
CONCLUSIONS: The majority of patients in the Jeddah MERS-CoV outbreak had contact with a health care facility, other patients, or both. This highlights the role of health care-associated transmission. (Supported by the Ministry of Health, Saudi Arabia, and by the U.S. Centers for Disease Control and Prevention.).

PMID 25714162  N Engl J Med. 2015 Feb 26;372(9):846-54. doi: 10.1056/N・・・
著者: Christian Drosten, Benjamin Meyer, Marcel A Müller, Victor M Corman, Malak Al-Masri, Raheela Hossain, Hosam Madani, Andrea Sieberg, Berend Jan Bosch, Erik Lattwein, Raafat F Alhakeem, Abdullah M Assiri, Waleed Hajomar, Ali M Albarrak, Jaffar A Al-Tawfiq, Alimuddin I Zumla, Ziad A Memish
雑誌名: N Engl J Med. 2014 Aug 28;371(9):828-35. doi: 10.1056/NEJMoa1405858.
Abstract/Text BACKGROUND: Strategies to contain the Middle East respiratory syndrome coronavirus (MERS-CoV) depend on knowledge of the rate of human-to-human transmission, including subclinical infections. A lack of serologic tools has hindered targeted studies of transmission.
METHODS: We studied 26 index patients with MERS-CoV infection and their 280 household contacts. The median time from the onset of symptoms in index patients to the latest blood sampling in contact patients was 17.5 days (range, 5 to 216; mean, 34.4). Probable cases of secondary transmission were identified on the basis of reactivity in two reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays with independent RNA extraction from throat swabs or reactivity on enzyme-linked immunosorbent assay against MERS-CoV S1 antigen, supported by reactivity on recombinant S-protein immunofluorescence and demonstration of neutralization of more than 50% of the infectious virus seed dose on plaque-reduction neutralization testing.
RESULTS: Among the 280 household contacts of the 26 index patients, there were 12 probable cases of secondary transmission (4%; 95% confidence interval, 2 to 7). Of these cases, 7 were identified by means of RT-PCR, all in samples obtained within 14 days after the onset of symptoms in index patients, and 5 were identified by means of serologic analysis, all in samples obtained 13 days or more after symptom onset in index patients. Probable cases of secondary transmission occurred in 6 of 26 clusters (23%). Serologic results in contacts who were sampled 13 days or more after exposure were similar to overall study results for combined RT-PCR and serologic testing.
CONCLUSIONS: The rate of secondary transmission among household contacts of patients with MERS-CoV infection has been approximately 5%. Our data provide insight into the rate of subclinical transmission of MERS-CoV in the home.

PMID 25162889  N Engl J Med. 2014 Aug 28;371(9):828-35. doi: 10.1056/N・・・
著者: Ziad A Memish, Alimuddin I Zumla, Rafat F Al-Hakeem, Abdullah A Al-Rabeeah, Gwen M Stephens
雑誌名: N Engl J Med. 2013 Jun 27;368(26):2487-94. doi: 10.1056/NEJMoa1303729. Epub 2013 May 29.
Abstract/Text A human coronavirus, called the Middle East respiratory syndrome coronavirus (MERS-CoV), was first identified in September 2012 in samples obtained from a Saudi Arabian businessman who died from acute respiratory failure. Since then, 49 cases of infections caused by MERS-CoV (previously called a novel coronavirus) with 26 deaths have been reported to date. In this report, we describe a family case cluster of MERS-CoV infection, including the clinical presentation, treatment outcomes, and household relationships of three young men who became ill with MERS-CoV infection after the hospitalization of an elderly male relative, who died of the disease. Twenty-four other family members living in the same household and 124 attending staff members at the hospitals did not become ill. MERS-CoV infection may cause a spectrum of clinical illness. Although an animal reservoir is suspected, none has been discovered. Meanwhile, global concern rests on the ability of MERS-CoV to cause major illness in close contacts of patients.

PMID 23718156  N Engl J Med. 2013 Jun 27;368(26):2487-94. doi: 10.1056・・・

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