Supplementary Infection & Chemotherapy MERS-CoV 항바이러스제치료지침 정용필 1, 송준영 2, 서유빈 3, 최재필 4, 신형식 5, 즉각대응팀 (Rapid Response Team) * 1 울산대학교의과대학서울아산병원감염내과, 2 고려대학교의과대학구로병원감염내과, 3 한림대학교의과대학강남성심병원감염내과, 4 서울의료원감염내과, 5 국립의료원감염내과 Middle East respiratory syndrome (MERS) is an acute infectious disease of the respiratory system caused by the new betacoronavirus (MERS coronavirus, MERS-CoV), which shows high mortality rates. The typical symptoms of MERS are fever, cough, and shortness of breath, and it is often accompanied by pneumonia. The MERS-CoV was introduced to Republic of Korea in May 2015 by a patient returning from Saudi Arabia. The disease spread mostly through hospital infections, and by the time the epidemic ended in August, the total number of confirmed diagnoses was 186, among which 36 patients died. Reflecting the latest evidence for antiviral drugs in the treatment of MERS-CoV infection and the experiences of treating MERS patients in Republic of Korea, these guidelines focus on antiviral drugs to achieve effective treatment of MERS-CoV infections. Key Words: MERS; Coronavirus; Antiviral; Treatment 1. 배경및목적 Middle East Respiratory Syndrome (MERS) MERS coronavirus (MERS-CoV) coronavirus. 2012,. MERS,,,.. MERS-CoV,. 1,. MERS-CoV,, [1]. MERS. 2015 8 1401 MERS-CoV, 500 (36% ) [2]. (85% ), 2015 5 MERS, (hospital outbreak) 186, (2015.8.15) 36 (19% ) [3]. MERS-CoV, MERS-CoV severe acute respiratory syndrome coronavirus (SARS-CoV) MERS-CoV. MERS-CoV MERS, MERS MERS-CoV. 2. 범위와대상 MERS-CoV MERS. MERS-CoV. MERS-CoV. Received: August 31, 2015 Corresponding Author : Hyoung-Shik Shin, MD, PhD Director, Center for Infectious Disease, National Medical Center, 245 Eulji-ro, Jung-gu, Seoul 04564, Korea Tel: +82-2-2260-7557, Fax: +82-2-2260-0803, E-mail: hyoungsshin@gmail.com * 즉각대응팀 : 윤희정, 최준용, 김태형, 최영화, 김홍빈, 윤희정, 이재갑, 엄중식, 송준영, 이상오, 오원섭, 정희진, 송영구, 최정현, 김우주
정용필외 MERS-CoV 항바이러스제치료지침, MERS. 3. 지침개발위원회구성 2015 7 MERS-CoV. 5. 4. 핵심질문도출 MERS-CoV SARS-CoV,, MERS-CoV 9. 5. 문헌검색방법 2002 MERS-CoV SARS-CoV. interferon, ribavirin, lopinavir/ritonavir 20. PubMed (www.pubmed.gov), middle east respiratory syndrome, severe acute respiratory syndrome, coronavirus, treatment, therapy, antiviral. MERS-CoV. 6. 권고의강도및근거수준결정 Infectious Diseases Society of America (IDSA) (Table 1). 5. 1-9,. 7. 외부전문가평가 MERS-CoV,. 항바이러스제치료지침 핵심질문 1. 어떤환자에게항바이러스제를투여해야하는가? MERS SARS (BIII)., (,,, ),, (II). MERS-CoV (BIII)., (III). ( ) x-ray MERS-CoV / (BIII). 2002-2003 SARS interferon α, ribavirin, lopinavir/ritonavir, [4]. MERS, [5, 6]. 44 MERS 14 (70% vs. 29%, P = 0.004), 28 (30% vs. 17%, P = 0.054) [5]. MERS 36%, 19%,. MERS-CoV ( 50-65 ), (,,, ),, real-time reverse transcription PCR cycle threshold (C t ) [6-10]. Table 1. Recommendation of evidentiary strength and quality Strength of recommendation Quality of evidence for recommendation A: Should always be offered I: One or more properly designed randomized, controlled trials B: Should generally be offered II: One or more well-designed, nonrandomized trial, cohort, or case-controlled analytical studies (preferably from more than one center), or dramatic results from uncontrolled experiments C: Optional III: Expert opinion or descriptive studies
MERS-CoV 항바이러스제치료지침 정용필외 [7, 9, 10]. 108 50,,, (unpublished data). Omrani MERS 14 [5]. MERS. [10, 11], MERS 108 2 (unpublished data).,. 핵심질문 2. 가장적절한항바이러스제투여시점은언제인가? (BIII). MERS-CoV, [5, 12]. SARS-CoV 6-14 (ribavirin), SARS 48 [4, 13, 14]. MERS-CoV. 핵심질문 3. 국내에서는어떤항바이러스제요법 (regimen) 을사용할수있는가? type 1 interferon + ribavirin + lopinavir/ ritonavir (BIII). ribavirin, type 1 interferon (AIII). ribavirin type 1 interferon + lopinavir/ritonavir (AIII). MERS-CoV ribavirin, (AIII) (Table 2). MERS-CoV.. Type 1 interferon, ribavirin, lopinavir/ ritonavir Table 2. Antiviral treatment for MERS-CoV Medication a Normal renal function (CrCl > 50 ml/min) A. Ribavirin, high dose c 1,200 mg po q8h for 4 days 600 mg po q8h for 4-6 days Ribavirin, alternative intermediate dose d 10 mg/kg po q8h for 10 days Impaired renal function b (CrCl 20-50 ml/min) 600 mg po q8h for 4 days 200 mg po q8h for 4-6 days 200 mg po q8h for 10 days B. Interferon-α2a f 180 µg per week for 2 weeks Same dose Same dose C. Lopinavir/ritonavir g Lopinavir/ritonavir 400 mg/ 100 mg po q12h for 10 days D. Convalescent plasma 300-500 ml of full plasma (3-5 ml/kg) Same dose Hemodialysis or CrCl < 20 ml/min 200 mg po q6h for 4 days 200 mg po q12h for 4-6 days 200 mg po q12h for 10 days e Same dose a Ribavirin 에의한부작용발생시용량을감량하거나사용을중지한다. b 지속적신대체요법 (continuous renal replacement therapy, CRRT) 시행시에는 plasma removal rate 에따라 ribavirin 용량이조절되어야하며, 계산이 어려운경우에는 CrCl 20-50 ml/min 시의용량투여를고려한다. c SARS-CoV 또는 MERS-CoV 치료시일반적으로사용된용량이다. d Ribavirin 에의한혈구감소증, 용혈빈혈등의부작용을우려하여감량한용량이다. Ribavirin + interferon α 사용시 in vitro 상승효과가있음을근거로하 고, 안정성을고려하여 RSV 치료시일반적으로사용되는용량을준용하였다. e 투석환자나심한신기능저하자에서는치명적용혈빈혈발생을우려하여 ribavirin 사용이일반적으로추천되지않으므로, 치료시용혈빈혈등의심각 한부작용을주의깊게관찰해야한다. f Pegylated interferon α2a (Pegasys ; Roche Pharmaceuticals) 이며피하투여 (subcutaneous injection, SC) 한다. Interferon β1a (Rebif, 44 μg SC three-times per week) 로대체할수있다. Interferon α2b (Pegintron ) 를사용한임상연구는없으나 hepatitis C 바이러스치료용량인 1.5 μg/kg SC once per week 투여를고려할수있다. g Lopinavir/ritonavir (Kaletra ) 는주로간에의해서대사되므로, 심한간기능저하시에는사용에주의해야한다.
정용필외 MERS-CoV 항바이러스제치료지침. Type 1 interferon interferon α2a, interferon α2b, interferon β 1a. (rhesus macaques) interferon α2b ribavirin [15]. interferon α2b ribavirin [16]. type 1 interferon ribavirin. Interferon α2a interferon β 1a ribavirin [6]. Interferon α2a ribavirin 20 14 (70%) 14 24 7 (29%) (P = 0.004) 28 30%, 17% (P = 0.054) [5].. type 1 interferon ribavirin. MERS-CoV lopinavir/ritonavir SARS-CoV [17, 18]. (common marmoset) lopinavir/ ritonavir MERS-CoV interferon β1b [19]. type 1 interferon ribavirin lopinavir/ritonavir 2 viremia [20]. type 1 interferon ribavirin lopinavir/ritonavir. Type 1 interferon in vitro interferon β interferon α. interferon β 1b EC 50 :C max ratio interferon α2a, interferon α2b, interferon β1a [21, 22]. type 1 interferon [6]. In vitro ribavirin interferon-α2b MERS-CoV [23]. ribavirin MERS-CoV, [21]. ribavirin. interferon α2b ribavirin ribavirin (synergistic effect) [23], interferon. (common marmoset) lopinavir/ritonavir MERS-CoV interferon-β1b [19]. ribavirin, interferon β1b lopinavir/ritonavir. MERS-CoV type 1 interferon lopinavir/ritonavir. MERS-CoV ribavirin., Omrani [5]. SARS-CoV [13]. ribavirin,. type 1 interferon + ribavirin in vitro respiratory syncytial virus (RSV) [24]. in vitro (dose-dependent) [22, 25]. Ribavirin (CrCl),. 핵심질문 4. 항바이러스제투약기간은? MERS-CoV 10-14 (B ). SARS-CoV 10-14, MERS-CoV 10-14 [5, 6, 13, 26]. 16 MERS-CoV interferon α2a ribavirin 10-14, 14, 28 [5]., 10 2-3 MERS-CoV [6]..,. MERS-CoV 10-14. 핵심질문 5. 임신부에서항바이러스제치료는?. (AIII).
MERS-CoV 항바이러스제치료지침 정용필외 MERS-CoV 2 [27]. ribavirin X lopinavir/ritonavir type 1 interferon C. [28]. HIV lopinavir/ritonavir [29], type 1 interferon multiple sclerosis interferon β1a. Interferon β1a [30, 31].. interferon β1a + lopinavir/ritonavir MERS.. 핵심질문 6. 항바이러스제종류에따른이상반응과주의사항은무엇인가? Ribavirin, CBC, reticulocyte, haptoglobin, bilirubin. (AIII). Type 1 interferon, CBC.,, (BIII). SARS-CoV 110 ribavirin 67 (61%) [32]. 3-5 10. 1,000-2,000 mg MERS-CoV. ribavirin hemoglobin, bilirubin, haptoglobin, reticulocyte., ribavirin lopinavir/ritonavir., (fatal hemolytic anemia) ribavirin. Ribavirin (<55/ min),, [33]. ribavirin 6 [34]. Type 1 interferon, [34]. 20%,. ribavirin, (recombinant erythropoietin). interferon [35, 36]. 핵심질문 7. MERS-CoV에항바이러스효과가있는다른약물이있는가? Mycophenolic acid, chloroquine, chlorpromazine, loperamide MERS-CoV, amiodarone SARS-CoV (III). Mycophenolic acid T, B in vitro West Nile,,,,. MERS-CoV mycophenolic acid interferon β1b (effective inhibitory concentration, EC 50 ) [37]. Chloroquine MERS-CoV 3.0 μm EC 50. Chlorpromazine clathrin-mediated endocytosis. Loperamide coronavirus (4-6 μm) [38, 39]. Amiodarone MERS-CoV SARS-CoV (post-endosomal level) (endocytic pathway) MERS-CoV [40]. MERS-CoV (transmembrane protein) dipeptidyl peptidase 4 (DPP4). Adenosine deaminase DPP4 MERS-CoV DPP4, in vitro MERS-CoV (antagonist) [41]. DPP4 incretin, DPP4 gliptin. DPP4 (gliptin) MERS-CoV DPP4,. 핵심질문 8. 회복기혈장투여가도움이되는가? MERS-CoV (BIII). MERS-CoV 2 (BIII).
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