인플루엔자 바이러스 감염 소아 환아에서 Oseltamivir 약제 효용성과 단기간ㆍ장기간 부작용 및 안전성에 관한 임상연구

서은선,박근화,김성원,정우식,조경순,박연경,이창규,강춘,이주연,최우영,김성미 대한소아청소년과학회 2010 Clinical and Experimental Pediatrics (CEP) Vol.53 No.1

Purpose:Although oseltamivir is widely used for treatment of influenza, few clinical studies of its efficacy and resistance have been performed in Korea. We evaluated the safety, side effects, and efficacy of oseltamivir treatment in Korean pediatric patients. Methods:We analyzed 321 children diagnosed with influenza at Busan St. Mary's Medical Center, Korea, between January 2008 and June 2008 (first study period) and November 2008 and January 2009 (second study period). Patients were divided into two groups: those receiving oseltamivir treatment for 5 days and those receiving only symptomatic treatment. We investigated clinical symptoms, side effects, and resistance to oseltamivir. We also identified influenza strains and evaluated resistance to oseltamivir using an influenza virus culture. Results:One hundred eighty-six patients were assigned to the treatment group, and 135 were assigned to the control group. The treatment group showed shorter admission duration (4.4 days) compared with controls (5.0 days) (P=0.000) and had fewer lower respiratory tract complications compared with controls (P<0.05). No significant statistical difference in the virus antigenic type was observed between the groups. In the first study period, virus culture showed influenza B (41.7% vs. 49.6%), A/H3N2 (7.9% vs. 8.4%), and A/H1N1 (9.4% vs. 6.5%). In the second study period, only A/H1N1 (55.3% vs. 50.0%) was isolated, except for one case of A (H3N2) in the treatment group. No differences in short- and long-term side effects, including neuropsychologic side effects, were noted between groups. There was no resistance to oseltamivir before or after treatment in the first study period. Conclusion:Based on our results, we suggest that osetalmivir therapy in pediatric patients is effective. 목적:Oseltamivir는 neuramidase inhibitor으로 인플루엔자의 치료제로 국내에서 사용하고 있지만, 약제사용으로 인한 부작용이나 효용성 및 내성에 대한 국내 연구는 미흡하여 이에 대해서 연구하고자 하였다. 방법:2008년 1월부터 2008년 6월까지와 2008년 11월부터 2009년 1월까지의 두차례의 인플루엔자 유행기간 동안, 부산 성모 병원에서 독감 유사 증상 있어, 신속 항원 진단법으로 독감 진단받고 입원한 321명의 환아를 대상으로 하여, 환아들을 oseltamivir 치료군과 비치료군으로 무작위하여 전향적인 연구를 시행하였다. 치료군에서는 oseltamivir를 5일간 투여하였고, 비치료군에서는 증상 조절제만 사용하였다. 양군 모두에서 임상증상과 부작용을 관찰하였고 입원 기간 등을 조사하였고, 퇴원 4-8개월 후 전화 상담을 통하여 신경정신학적인 이상 유무를 확인하였다. 바이러스 배양 검사 및 oseltamivir에 대한 내성검사를 실시하였다. 결과:두 기간 동안 본원 소아청소년과에 입원하였던 총 321명의 환아들을 분석하였고, oseltamivir 치료군은 186명, 비치료군은 135명이었다. Oseltamivir 치료군에서 비치료군에 비해 입원 당시 발병후 48시간이 경과한 환아들이 많았음에도 하기도 합병증이 현저히 적었고, 두 기간 동안 의미 있는 입원 기간 단축을 보였다(4.4일 vs. 5.0일) (P=0.000). 두 기간 동안 치료 군에서 경미한 소화기계 부작용을 보였으나 심각한 정신신경학적인 부작용을 보인 예는 없었다. 전반기 동안에는 양군 모두에서 influenza B (치료군 vs. 비치료군; 41.7% vs. 49.6%)가 가장 많이 동정 되었고, A/H3N2, A/H1N1 순으로 동정되었으며, 후반기 동안에는 치료군에서 A/H3N2가 배양된 한명의 환아를 제외하고는 양군 모두에서 A/H1N1이 동정되었다. 전반기동안 배양된 바이러스에 대한 oseltamivir 내성 검사상 치료 시작 전이나 치료 후 48-72시간 모두에서 oseltamivir에 대한 약제 내성은 발견되지 않았다. 결론:oseltamivir 치료군에서는 정신신경학적인 부작용을 포함한 다른 심각한 부작용 없이 입원 기간을 단축시키면서 하기도 합병증의 감소를 보이는 임상적인 효용성을 보여 소아 인플루엔자 치료에 있어 oseltamivir 치료의 효용성과 안전성을 보여주었다.

소아에서 B형 인플루엔자 바이러스의 감염에서 oseltamivir 치료의 유용성: 2개 병원에서 조사된 환자들을 대상으로

윤송이,천지혜,이경석,나영호,최선희 대한소아감염학회 2014 Pediatric Infection and Vaccine Vol.21 No.3

Purpose: There has been little research regarding the effectiveness of oseltamivir for influenza B infections. We sought to identify the different clinical manifestations between patients treated with and without oseltamivir. Methods: We retrospectively studied the medical records of 72 inpatients or outpatients from two medical centers diagnosed with influenza B infections by either a rapid antigen test or multiplex reverse transcriptase PCR between January 2012 and July 2012. We compared gender, age, past medical history, admission period, total fever duration, fever duration after hospitalization, post-oseltamivir medication peak temperature, laboratory test, chest X-ray, antibiotic medication, and the presence of concomitant viral or bacterial infections. Results: The number of subjects in our study was 72 who were diagnosed with influenza B pneumonia, acute bronchitis, acute bronchiolitis, croup, and mean age was 3.6±2.8 year old. The demographic characteristics and clinical manifestations of oseltamivir and the non-oseltamivir groups, including hospitalization period (4.18±2.10 vs 4.79±1.49 days, P=.17) and total fever duration (5.32±2.07 vs 6.41±3.25 days, P=.09), demonstrated no significant differences. Notably, the oseltamivir group did have significantly reduced usage of antibiotic treatment than the non-oseltamivir group (P=.04). When we limited our patient group to patients under the age of three, similar results were seen. The group prescribed oseltamivir within 48 hours of fever onset had less antibiotic usage, in addition to a shorter fever duration. Conclusion: Oseltamivir appeared to have no benefit in improving the clinical course. However, if it is prescribed within the first 48 hours of symptoms, it may be more effective. 목적: 본 연구는 인플루엔자 B 바이러스에 대한 oseltamivir의 효능을 알아보고자 치료군과 비치료군간의 임상적 특징의 차이를 비교하였다. 방법: 2012년 1월부터 2012년 7월까지 입원하거나 외래 진료실을 방문하여 인플루엔자 B 바이러스에 감염된 소아 환자를 대상으로 후향적으로 의무기록을 분석하였다. 결과: 인플루엔자 B 바이러스에 의한 폐렴, 급성 기관지염, 급성세기관지염, 크룹으로 진단된 72명의 평균 나이는 3.6±2.8세 였다. oseltamivir 치료군은 38명(53 %), 비치료군은 34명(47%)이었고 치료 시기를 고려하지 않았을 때 두 군의 입원 기간(4.18±2.10일 vs 4.79± 1.49일, P=.17), 총 발열 기간(5.32±2.07일 vs 6.41± 3.25일, P=.09)을 포함한 임상적 양상에 유의한 차이가 없었다. 비치료군, 48시간 이내 치료군, 48시간 이후 치료군간의 비교에서 임상적 양상에 유의한 차이가 없었다. 3세 이하의 환자들을 대상으로 두 군간의 비교에서도 유의한 차이가 없었다. 결론: Oseltamivir 복용 전 치료군과 비치료군간의 임상적 특성에서 유의한 차이를 나타내는 항목이 없어 oseltamivir의 적응증을 도출하기 어려웠으며 치료 후 임상 경과의 유의한 차이도 없었다. 그러나 투약 시점에 따른 비교에서는 발열 시작 48시간 이내에 osetamivir를 투여한 군에서 발열 기간이 감소하는 경향을 보여주었으므로 향후 투약 시기를 고려하여 연령별 분석, 인플루엔자 B 바이러스 종에 대한 분석을 포함하는 대단위 연구가 필요하다.

Oseltamivir에 의해 유발된 급성 출혈성 대장염 1예

정덕원,손혁수,박재형,정민규,전성우,조창민,김성국 대한내과학회 2011 대한내과학회지 Vol.80 No.-

Oseltamivir is a potent selective neuraminidase enzyme inhibitor and effective against nearly all strains of influenza A and B. The importance of treating influenza has been recognized, and oseltamivir has been prescribed frequently at the onset of the H1N1 influenza A pandemic this year. However, oseltamivir can cause hemorrhagic colitis as a rare adverse effect. Until now, only two cases of hemorrhagic colitis following the use of oseltamivir have been reported in Japan, and none have been reported in Korea. We report a case of acute hemorrhagic colitis in a 15-year-old boy after the oral administration of oseltamivir for swine originating influenza A. (Korean J Med 2011;80:S87-S90) 신종 인플루엔자의 대유행과 함께 치료의 중요성이 인식되었고 치료제로 널리 처방된 oseltamivir이 드물지만 급성 출혈성 장염을 유발할 수 있다. 현재까지 국내 증례보고는 없는 상태로 저자들은 치료 및 화학적 예방요법으로 권장되는 oseltamivir (TamifluⓇ)를 복용한 환자에서 출혈성 장염의 증례를 경험하였기에 문헌고찰과 함께 보고하는 바이다.

단일 병원에서 2013-2015년에 유행한 인플루엔자 A형과 B형의 임상 양상 및 치료반응의 차이

이상민 ( Sang Min Lee ),박상규 ( Sang Kyu Park ),김지현 ( Ji Hyun Kim ),이정하 ( Jung Ha Lee ),나소영 ( So Young Na ),김도현 ( Do Hyun Kim ),강은경 ( Eun Kyeong Kang ),조성민 ( Sung Min Cho ),김희섭 ( Hee Sub Kim ) 대한소아감염학회 2017 Pediatric Infection and Vaccine Vol.24 No.1

목적: 인플루엔자 A형과 B형의 임상 양상이나 항바이러스제에 대한 치료반응에 차이가 있을 것이라는 가정에 따라 본 연구를 시행하였다. 방법: 2013년 10월부터 2015년 5월까지 인플루엔자 감염으로 동국대학교 일산병원에 입원한 환자를 대상으로 인플루엔자 임상 양상, oseltamivir의 복용 시간 및 인플루엔자 유형에 따른 치료반응의 차이를 조사하였다. 결과: 총 환자는 138명(남 69명, 여 69명)이고 평균 나이는 3.5±4.0세였다. 동반 질환으로 A형에서 는 크룹(19.2% vs. 1.7%, P =0.001)이, B형에서는 근육염(0% vs. 6.7%, P =0.021)과 장염(29.5% vs. 46.7%, P =0.038)이 더 자주 발병하였다. Oseltamivir의 투약 시점과 투약 후 발열 시간을 비교하면 열 발생 2일 이내 투약한 환자군이 다른 군에 비해 전체 발열 기간이 유의하게 짧았다. Oseltamivir 복 용 후 발열이 지속된 시간은 A형이 16.0±19.1시간, B형이 28.9±27.9시간으로 A형의 발열이 더 빨 리 호전되었다(P =0.006). 결론: 인플루엔자는 A형과 B형에 있어서 동반되는 질환과 항바이러스제의 치료반응은 차이가 있을 수 있으며, oseltamivir 투약은 열 발생 2일 이내에 복용하는 것이 중요하다. Purpose: We suspect there is a difference in the clinical manifestations and treatment response to antiviral drugs for influenza A and B. This study was conducted to investigate this difference. Methods: We collected information on pediatric patients, infected with the influenza virus, admitted to Dongguk University Ilsan Hospital from October 2013 to May 2015. We investigated the clinical manifestations of influenza and differences in treatment response to oseltamivir treatment for the two types of influenza. Results: A total of 138 patients were included. The mean age was 3.5±4.0 years. When comparing the diseases associated with influenza A and B, croup (19.2% vs. 1.7%, P =0.001) was more common with influenza A infection. Myositis (0% vs. 6.7%, P =0.021) and gastroenteritis (29.5% vs. 46.7%, P =0.038) were more common with influenza B infection. When comparing the total fever duration from the start of oseltamivir administration, patients treated with oseltamivir within 2 days of fever had the shortest duration. Among the patients treated with oseltamivir, the duration of fever, after the start of oseltamivir treatment, for was shorter for influenza A infection than for influenza B infection (16.0±19.1 hours vs. 28.9±27.9 hours, P =0.006). Conclusions: There appear to be differences in the accompanying diseases and antiviral medication responses between the two types of influenza. It is important to administer oseltamivir within 2 days of fever.

Occurrence and characterization of oseltamivir-resistant influenza virus in children between 2007-2008 and 2008-2009 seasons

Kim, Seoung Geun,Hwang, Yoon Ha,Shin, Yung Hae,Kim, Sung Won,Jung, Woo Sik,Kim, Sung Mi,Oh, Jae Min,Lee, Na Young,Kim, Mun Ju,Cho, Kyung Soon,Park, Yeon Gyeong,Min, Sang Kee,Lee, Chang Kyu,Kim, Jun Su The Korean Pediatric Society 2013 Clinical and Experimental Pediatrics (CEP) Vol.56 No.4

Purpose: There was a global increase in the prevalence of oseltamivir-resistant influenza viruses during the 2007-2008 influenza season. This study was conducted to investigate the occurrence and characteristics of oseltamivir-resistant influenza viruses during the 2007-2008 and 2008-2009 influenza seasons among patients who were treated with oseltamivir (group A) and those that did not receive oseltamivir (group B). Methods: A prospective study was conducted on 321 pediatric patients who were hospitalized because of influenza during the 2007-2008 and 2008-2009 influenza seasons. Drug resistance tests were conducted on influenza viruses isolated from 91 patients. Results: There was no significant difference between the clinical characteristics of groups A and B during both seasons. Influenza A/H1N1, isolated from both groups A and B during the 2007-2008 and 2008-2009 periods, was not resistant to zanamivir. However, phenotypic analysis of the virus revealed a high oseltamivir $IC_{50}$ range and that H275Y substitution of the neuraminidase (NA) gene and partial variation of the hemagglutinin (HA) gene did not affect its antigenicity to the HA vaccine even though group A had a shorter hospitalization duration and fewer lower respiratory tract complications than group B. In addition, there was no significant difference in the clinical manifestations between oseltamivir-susceptible and oseltamivir-resistant strains of influenza A/H1N1. Conclusion: Establishment of guidelines to efficiently treat influenza with oseltamivir, a commonly used drug for treating influenza in Korean pediatric patients, and a treatment strategy with a new therapeutic agent is required.

2009년 국내 신종플루 유행시기의 Oseltamivir 부작용 평가

도윤아,이숙향 한국임상약학회 2011 한국임상약학회지 Vol.21 No.4

The World Health Organization (WHO) declared the outbreak of H1N1 pandemic in 2009. South Korea also had outbreaks of H1N1 virus and used oseltamivir in large volume with increased reports of adverse drug reaction(ADR). The present study was aimed to investigate the ADR frequency, the factors related to ADR, and characteristics of oseltamivir's ADR. Participants for the study were patients randomly drawn from those who were prescribed oseltamivir for treatment from CHA Bundang Medical Center during October 1 and October 30. The information examined as factors related to ADR were collected by a subsequent cross-sectional telephone survey. The factors are the following; a) age; b) gender; c) patient medical history; d) diagnosis of H1N1 virus; e) adherence; f) whether taking other medication with oseltamivir or not; and g) the number of combined medications. We also asked ADR after taking oseltamivir. Total subjects were 86 patients. The average age is 22.6±18.48 years old. The gender was 45.3% women and 54.7% men. Half (50%) of all respondents showed one or more ADR, 67.4% were positively diagnosed for H1N1 virus, and 54.7% were completed the full course of oseltamivir (i.e. twice daily x 5days). The most frequently reported ADR symptoms were: dizziness (15.1%), nausea (11.6%), lethargy (10.4%), diarrhea (10.4%), abdominal pain (8.1%), headache and vomiting (6.9%). ADR classifications by categories are gastro intestinal (44.2%), neuropsychiatric events (22.1%), systemic symptom (20.9%), skin events (5.8%), eye events (4.7%), and other cases (2.3%). The onset of ADR 'after taking 1~3 doses' was 69.7%. No increase in neuropsychiatric events was detected in children and adolescents. No factors examined for the study do have significant influence on the presence of ADR. This study showed that ADR of oseltamivir have occurred in half of the patients. The use of oseltamivir is essential for treatment and prophylaxis of influenza A(H1N1). But mass treatment should be properly monitored for ADR.

증례 : 소화기 ; Oseltamivir에 의해 유발된 급성 출혈성 대장염 1예

정덕원 ( Duk Won Chung ),손혁수 ( Hyuk Su Son ),박재형 ( Jae Hyung Park ),정민규 ( Min Kyu Jung ),전성우 ( Seong Woo Jeon ),조창민 ( Chang Min Cho ),김성국 ( Sung Kook Kim ) 대한내과학회 2011 대한내과학회지 Vol.80 No.2S

신종 인플루엔자의 대유행과 함께 치료의 중요성이 인식 되었고 치료제로 널리 처방된 oseltamivir이 드물지만 급성출혈성 장염을 유발할 수 있다. 현재까지 국내 증례보고는 없는 상태로 저자들은 치료 및 화학적 예방요법으로 권장되는 oseltamivir (Tamiflu(R))를 복용한 환자에서 출혈성 장염의 증례를 경험하였기에 문헌고찰과 함께 보고하는 바이다. Oseltamivir is a potent selective neuraminidase enzyme inhibitor and effective against nearly all strains of influenza A and B. The importance of treating influenza has been recognized, and oseltamivir has been prescribed frequently at the onset of the H1N1 influenza A pandemic this year. However, oseltamivir can cause hemorrhagic colitis as a rare adverse effect. Until now, only two cases of hemorrhagic colitis following the use of oseltamivir have been reported in Japan, and none have been reported in Korea. We report a case of acute hemorrhagic colitis in a 15-year-old boy after the oral administration of oseltamivir for swine originating influenza A. (Korean J Med 2011;80:S87-S90)

Oseltamivir 복용 이후 소아에서 발생한 이상행동 및 그 인과성 평가

손병우,최중혁,이승민,박선순,최은경,유봉규,지은희 한국임상약학회 2019 한국임상약학회지 Vol.29 No.1

Oseltamivir is an antiviral medication prescribed to prevent and treat influenza A and B. A case from a community pharmacy in Korea was reported for an adverse event associated with oseltamivir administration. A 20-month-old boy had psychiatric symptoms after receiving 2 doses of oseltamivir. Therefore, an evaluation of whether the psychiatric symptoms were caused by oseltamivir was required. To determine whether the adverse event resulted from the administrated medication or other factors, three tools were used: the Naranjo scale, the Korean causality assessment algorithm (Ver.2), and the World Health Organization-Uppsala Monitoring Center (WHO-UMC) criteria. The psychiatric symptoms occurred after oseltamivir administration, and were attenuated after oseltamivir termination. A possible cause of the psychiatric symptoms is high fever, but information on the body temperature of the patient was not sufficient. Therefore, it was unclear whether there were other nonpharmacological causes of adverse drug reaction. For these reasons, in terms of causality, the results evaluated by the three tools represented, "possible", "probable", and "probable/ likely", respectively.

Delayed Onset of Manic Symptoms in a Patient with Influenza A (H1N1) after administration of Oseltamivir (Tamiflu): A Case Report

Min Jhon,Ju-Wan Kim,Hee-Ju Kang,Seon-Young Kim,Ju-Yeon Lee,Sung-Wan Kim,Il-Seon Shin,김재민 대한정신약물학회 2021 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.19 No.1

Psychiatric side effects of oseltamivir can result in accident-proneness and suicide. Reportedly, such adverse psychiatric events are more common in children than in adults, but other risk factors are not known. We present a 13-year-old girl with influenza infection who developed manic symptoms after taking oseltamivir and receiving the human papillomavirus vaccination. While other research has found that psychiatric side effects associated with oseltamivir generally occur within 48 hours after beginning administration, in this case the manic symptoms developed on the fourth day after cessation of 5-day course of oseltamivir administration. Based on our review of this case, we recommend that clinicians should carry out vigilant monitoring of each patient’s mental state when the patient is young, has a family history of psychiatric disorder, has drug sensitivity and has received medical treatments such as vaccination before or after taking oseltamivir. In addition, as side effects of oseltamivir may occur more than 48 hours after administration, it will be necessary to observe patients for several days after the prescription of oseltamivir.

Occurrence and characterization of oseltamivirresistant influenza virus in children between 2007-2008 and 2008-2009 seasons

김성균,황윤하,신용해,김성원,정우식,김성미,오재민,이나영,김문주,조경순,박연경,민상기,이창규,김준섭,강천,이주연,허만규,김창훈 대한소아청소년과학회 2013 Clinical and Experimental Pediatrics (CEP) Vol.56 No.4

Purpose: There was a global increase in the prevalence of oseltamivir-resistant influenza viruses during the 2007–2008 influenza season. This study was conducted to investigate the occurrence and characteristics of oseltamivir-resistant influenza viruses during the 2007–2008 and 2008–2009 influenza seasons among patients who were treated with oseltamivir (group A) and those that did not receive oseltamivir (group B). Methods: A prospective study was conducted on 321 pediatric patients who were hospitalized because of influenza during the 2007–2008 and 2008–2009 influenza seasons. Drug resistance tests were conducted on influenza viruses isolated from 91 patients. Results: There was no significant difference between the clinical characteristics of groups A and B during both seasons. Influenza A/H1N1, isolated from both groups A and B during the 2007–2008and 2008–2009 periods, was not resistant to zanamivir. However, phenotypic analysis of the virus revealed a high oseltamivir IC50 range and that H275Y substitution of the neuraminidase (NA ) gene and partial variation of the hemagglutinin (HA ) gene did not affect its antigenicity to the HA vaccine even though group A had a shorter hospitalization duration and fewer lower respiratory tract complications than group B. In addition, there was no significant difference in the clinical manifestations between oseltamivir-susceptible and oseltamivir-resistant strains of influenza A/H1N1. Conclusion: Establishment of guidelines to efficiently treat influenza with oseltamivir, a commonly used drug for treating influenza in Korean pediatric patients, and a treatment strategy with a new therapeutic agent is required.