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대한소아소화기영양학회지 : 제 14 권제 1 호 2011 DOI: 10.5223/kjpgn.2011.14.1.59 간ㆍ담도 중합효소연쇄반응으로확인된엡스타인 - 바바이러스재활성화가소아급성 A 형간염에미치는영향 연세대학교의과대학소아과학교실, * 세브란스소아간질환연구모임 백승현ㆍ김상용 * ㆍ고홍 * Effects of Reactivation of Latent Epstein-Barr Virus Using Polymerase Chain Reaction on Acute Hepatitis A in Children Seung Hyon Baek, M.D., Sang Yong Kim, M.D.* and Hong Koh, M.D.* Department of Pediatrics, Yonsei University College of Medicine, *Severance Pediatric Liver Disease Research Group, Severance Children s Hospital, Seoul, Korea Purpose: We previously reported that concurrent reactivation of latent Epstein-Barr virus (EBV) in children with hepatitis A virus (HAV) infection is common and EBV reactivation with HAV infection adversely affects the clinical features of hepatitis. However, the incidence of concurrent reactivation was not accurate because the detection of EBV reactivation was based on serologic methods. Therefore, we studied the effects of polymerase chain reaction (PCR)-proven EBV reactivation, thus a more precise concurrence, on acute HAV infection in children. Methods: PCR were conducted in 34 patients, who had enrolled previous study and diagnosed with acute HAV infection between January 2008 and June 2010. Their medical records were reviewed. Results: Among 34 patients with acute HAV infection, 12 patients (35.3%) had EBV reactivation which was proven using serologic and molecular biologic techniques. There were significant differences in the peak levels of AST and ALT between the reactivated and non-reactivated groups (p=0.001 and p<0.001, respectively). The duration of full recovery from hepatitis was more prolonged in the reactivated group (p<0.001). Clinical parameters, such as serum protein (p<0.001) and albumin concentrations (p<0.001), atypical lymphocyte count (p=0.001), prothrombin time-international normalized ratio (PT-INR, p<0.001), and splenomegaly (p<0.001), showed significant differences. The clinical features in the reactivated sub-group >10 years of age revealed more liver dysfunction compared to the non-reactivated sub-group. A comparison with a previous study was performed. Conclusion: PCR-proven reactivation of latent EBV in children with HAV infection is common and EBV reactivation with HAV infection adversely affects the clinical features of hepatitis, especially in older children. (Korean J Pediatr Gastroenterol Nutr 2011; 14: 59 66) Key Words: Epstein-Barr virus, Acute hepatitis A, Polymerase chain reaction 접수 :2010 년 8 월 9 일, 수정 :2010 년 8 월 28 일, 승인 :2010 년 8 월 28 일책임저자 : 고홍, 120-752, 서울시서대문구성산로 250, 연세대학교의과대학소아과학교실, 세브란스어린이병원 Tel: 02-2228-2050, Fax: 02-393-9118, E-mail: khong@yuhs.ac 59

60 ㆍ대한소아소화기영양학회지 : 제 14 권제 1 호 2011 서 론 치는가를재평가하였으며과거연구와의차이에대하여분석하였다. A형간염바이러스 (HAV) 는 RNA를가지는 27-nm 크기의 picornavirus이며대변-경구경로를통하여전파되어 A형간염을일으킬수있다. 급성 A형간염은세계적으로해마다 140만명이발병하는것으로보고되어있으며 1), 국내에서도 2005년부터 2008년까지급성바이러스간염원인의 83 95% 를차지하는것으로보고되었고 2009년한해에 13,000명이상의현증급성 A형간염환자가발생하였다 2). 급성 A형간염은일반적으로어릴수록무증상인경우가많고몇주앓고나면특이후유증이없이회복되며전격성간염의가능성이낮기에경과가좋은편으로알려져있는데최근에는비전형적인형태의임상양상을보이거나합병증의발생률이증가하는모습을보이고있다. 엡스타인-바바이러스 (Epstein-Barr virus, EBV) 는환자의침분비물과의접촉에의해확산되고드물게수혈에의해서도전파되며감염단핵구증 (infectious mononucleosis) 3) 과일부의 B세포관련종양및상피세포종양과연관있는것으로알려져있다 4). EBV의초회감염은대부분아동기에무증상으로일어나며그후잠재기를거치게되는데잠재기중 EBV의재활성화는다른바이러스의감염이나신체-정신적인스트레스와연관있다고알려져있으며 5-7) 재활성화된 EBV와상부위장관출혈, 포도막염, 전자율신경기능이상 (pandysautonomia), 장거짓막힘 (intestinal pseudoobstruction), 간염과관련성이보고되어왔다 8 12). 또한본저자들은혈청학적방법으로진단된 EBV 재활성화가소아급성 A형간염의임상경과에영향이있음을이미보고한바있다 13). 그러나혈청학적방법만으로 EBV 재활성화를진단하는경우에는급성 A형간염과같은급성염증성질환에서비특이적인교차반응으로인한위양성의결과가나타날수있어감별이필요하였다. 따라서본연구에서는과거발표했던연구의한계점을극복하고자혈청학적방법과함께말초혈액에대한중합효소연쇄반응 (polymerase chain reaction, PCR) 에서양성반응을보인경우를 EBV 재활성화로간주하여 EBV 재활성화가급성 A형간염환아들의임상경과에어떠한영향을미 대상및방법 1. 대상본연구는과거연구와동일한대상으로 2008년부터 2010년까지세브란스병원에서급성 A형간염으로진단받은 19세이하의환자중 EBV PCR을추가로시행한 34명으로제한하였다. 환자는 EBV의검사결과에따라재활성화군과비활성화군으로나누었고또한과거본저자들이보고한문헌 13) 에따라각군을 10세를기준으로다시나누었다. 2. 방법 1) 급성 A형간염과 EBV 재활성화진단기준 : 급성 A형간염은 electrofluoroimmunoassay (Vidas, Biomerieux, Lyon, France) 에의한 IgM anti-hav가양성으로확인되면진단하였고, EBV의재활성화여부는 EBV 특이항체검사 (ELISA; Biotest AG, Frankfurt, Germany) 결과에서 IgM EBV early antigen (EA) 과 IgG Epstein-Barr nuclear antigen (EBNA) 이양성이면말초혈액으로부터 DNA를추출하고 (QIAamp R Virus Spin Kit (QIAGEN, Germany) 이중중합효소연쇄반응법 (nested PCR, primer 제작및 HotStart Premix [Bioneer, Korea], Mastercycler R ep gradient S [Eppendort Germany]) 을다시시행하여양성결과가나온경우, 즉혈청학적으로재활성화를보이는경우에더하여말초혈액내에서 EBV의핵산이증명된경우를재활성화로판단하였다 14,15). 2) 임상양상과검사결과비교 : 대상환아의입원당시나이, 성별, 감염의유병기간, 즉 AST와 ALT가 40 U/L 이하로돌아오는데걸리는시간, AST와 ALT의최고치, 직접빌리루빈과총빌리루빈, 알칼리인분해효소 (Alkaline phosphatase, ALP), γ-glutamyl-transpeptidase (GGT), 간염이환기간중가장낮은혈청총단백과알부민, 프로트롬빈시간 (prothrombin time, PT) 및 prothrombin time-international normalized ratio (PT- INR), 비정형림프구의백분율등의혈청검사와복부초흠파결과를조사하여재활성화군과비활성화군에따

백승현외 : 중합효소연쇄반응으로확인된엡스타인 - 바바이러스재활성화가소아급성 A 형간염에미치는영향ㆍ 61 라비교해보고 10세이상과미만으로구분하여재활성화군과비활성화군을각각비교하였다. 이번연구결과와과거연구결과에서유의하게나온항목을비교분석하였고각자료의통계분석은 SPSS 18.0 (SPSS Inc., Chicago, Il, USA) 을이용하여 Student s t-test를시행하였다. 각통계의유의수준 p값은 0.05 미만으로정의하였다. 결과 1. EBV 재활성화군과비활성화군간의비교총 34명의 A형간염환자는평균연령이 10.5±4.0세였고이중남자는 19명으로 55.9% 였다. 이중에 14명이혈청학적방법으로재활성이의심되었으나중합효소연쇄반응을통해 12명만이재활성화로판정되어최종적으로비활성화군은 22명, 재활성화군은 12명으로서 EBV가재활성화된비율은 35.3% 였고비활성화군과재활성화군에서나이및성비에서통계학적차이를보이지않았다 (Table 1). AST는비활성화군과재활성화 군에서각각 1,151.7±752.0 IU/L, 2,771.9±1,730.0 IU/L (p=0.001) 였고, ALT는 1,048.9±626.2 IU/L와 3,496.3± 1,928.7 IU/L (p<0.001), 이환기간중의최소혈청단백농도는 7.0±0.5 g/dl와 5.8±0.9 g/dl (p<0.001), 이환기간중의최소혈청알부민농도는 4.1±0.4 g/dl와 3.2± 0.2 g/dl (p<0.001), 비정형림프구의백분율은 1.18±1.50% 와 4.9±4.4% (p=0.001), PT-INR은 1.04±0.15 와 1.24±0.11 (p<0.001), 간염회복기간은 28.0±17.7일과 39.7±13.8일 (p<0.001), 그리고비장비대를갖고있는비율은 13.6% 과 58.3% (p<0.001) 로두군간에통계적으로의미있는차이를보였다. 모든환자는전격간염 (fulminant hepatitis) 으로진행하지않고회복되었으며, EBV의감염에의한전염성단핵구증을포함한간외증상 (Extrahepatic manifestation) 은나타나지않았다. 2. 10세이상군과 10세미만군간의비교 10세미만인환아는 15명이었고이중비활성화군은 10명, 재활성화군은 5명으로 33.3% 의환아에서 EBV의 Table 1. Clinical Characteristics of the Patients and Correlation between Non-reactivated and Reactivated EBV Infection Groups Total (N=34) Non-reactivated (N=22) Reactivated (N=12) p-value Age (yrs) 10.5±4.0 10.0±4.6 11.5±2.5 NS Male (%) 19/34 (55.9) 13/22 (59.1) 6/12 (50.0) NS AST (IU/L) 1,723.6±1,405.4 1,151.7±752.0 2,771.9±1,730.0 0.001 ALT (IU/L) 1,912.7±1,702.6 1,048.9±626.2 3,496.3±1,928.7 <0.001 AST/ALT 0.98±0.28 1.08±0.28 0.79±0.17 0.002 Protein (g/dl) 6.6±0.9 7.0±0.5 5.8±0.9 <0.001 Albumin (g/dl) 3.8±0.6 4.1±0.4 3.2±0.2 <0.001 Atyp lym (%) 2.50±3.36 1.18±1.50 4.9±4.4 0.001 PT-INR 1.11±0.17 1.04±0.15 1.24±0.11 <0.001 Duration (days) 31.4±18.4 28.0±17.7 39.7±13.8 <0.001 Splenomegaly (%) 10/34 (29.4) 3/22 (13.6) 7/12 (58.3) <0.001 GGT (IU/L) 262.4±251.7 247.3±291.4 290.2±163.2 NS ALP (IU/L) 366.8±135.6 375.0±143.4 351.8±124.6 NS T.bil (mg/dl) 4.2±2.9 3.9±3.2 4.7±2.2 NS D.bil (mg/dl) 3.4±2.4 3.1±2.7 3.8±1.9 NS WBC (/μl) 7,855.0±4,692.6 8,862.7±5,487.4 6,007.5±1,680.0 NS Lym (%) 36.7±12.8 37.6±14.5 35.0±9.2 NS Platelet (10 3 /μl) 256.4±107.9 282.1±114.3 209.4±79.3 NS EBV: Epstein-Barr virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, Atyp lym: atypical lymphocyte, Duration: duration of full recovery from hepatitis, PT-INR: prothrombin time-international normalized ratio, GGT: r -glutamyl-transpeptidase, ALP: Alkaline phosphatase, T.bil: total bilirubin, D.bil: direct bilirubin, WBC: white blood cell, Lym: lymphocyte, All date show mean±sd.

62 ㆍ대한소아소화기영양학회지 : 제 14 권제 1 호 2011 Table 2. Clinical Characteristics and Correlation of Patients according to Status of EBV Infection in the Two Age Groups Age<10 years (N=15) Non-reactivated (N=10) Reactivated (N=5) p-value Age 10 years (N=19) Non-reactivated (N=12) Reactivated (N=7) p-value Age (yrs) 6.8±3.4 8.1±1.5 NS 12.4±1.8 12.5±1.7 NS Male (%) 6/10 (60.0) 2/5 (40.0) NS 6/8 (75.0) 5/11 (45.5) NS AST (IU/L) 971.0±792.6 791.3±612.9 NS 1,767.1±308.4 2,604.6±1,603.8 0.038 ALT (IU/L) 895.6±648.8 880.0±660.5 NS 1,595.4±528.8 3,121.9±1,675.1 0.004 Protein (g/dl) 7.0±0.5 6.9±0.4 NS 7.2±0.7 6.5±0.9 0.002 Albumin (g/dl) 4.1±0.5 3.6±0.4 NS 4.2±0.4 3.6±0.5 <0.001 Atyp lym (%) 0.1±0.3 0.3±0.4 NS 0.6±1.8 4.0±5.6 0.011 PT-INR 1.02±0.16 1.20±0.02 NS 1.03±0.14 1.27±0.13 0.004 Duration (days) 15.9±5.5 25.7±7.2 <0.001 19.5±5.0 38.6±14.5 <0.001 Splenomegaly 2/10 (20.0%) 0/5 (0.0%) NS 1/8 (12.5%) 7/8 (87.5%) <0.001 AST/ALT 1.06±0.45 0.88±0.04 NS 0.86±0.23 0.81±0.14 NS GGT (IU/L) 205.0±148.6 127.7±51.2 NS 196.5±76.4 244.3±191.6 NS ALP (IU/L) 389.5±142.7 421.0±160.2 NS 371.4±156.9 330.8±120.3 NS T.bil (mg/dl) 2.7±2.9 4.0±2.6 NS 5.0±3.6 4.8±2.4 NS D.bil (mg/dl) 2.1±2.4 3.2±2.4 NS 4.1±3.0 3.9±1.9 NS WBC (/μl) 8,339.0±6,456.3 7,493.3±2,397.4 NS 5,100.0±1,425.5 5,658.8±1,123.2 NS Lym (%) 37.9±17.9 42.6±8.2 NS 37.1±9.8 31.3±7.5 NS Platelet (10 3 /μl) 329.9±121.1 249.0±105.7 NS 227.4±77.6 201.8±74.0 NS EBV: Epstein-Barr virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, Atyp lym: atypical lymphocyte, Duration: duration of full recovery from hepatitis, PT-INR: prothrombin time-international normalized ratio, GGT: r -glutamyl-transpeptidase, ALP: Alkaline phosphatase, T.bil: total bilirubin, D.bil: direct bilirubin, WBC: white blood cell, Lym: lymphocyte. All date show mean±sd. 재활성화가발견되었고두군간의비교에서간염회복기간이비활성화군에서는 15.9±5.5일, 재활성화군에서는 25.7±7.2일 (p<0.001) 로차이를보였으나다른검사소견과임상양상에는차이가없었다 (Table 2). 10세이상의환아는 19명이었고이중비활성화군은 12명, 재활성화군은 7명으로 36.8% 의환아에서 EBV의재활성화가발견되었고, 비활성화군과활성화군에서 AST가각각 1,767.1±308.4 IU/L와 2,604.6±1,603.8 IU/L (p= 0.038), ALT는 1,595.4±528.8 IU/L와 3,121.9±1,675.1 IU/L (p=0.004), 이환기간중의최소혈청단백농도는 7.2±0.7 g/dl와 6.5±0.9 g/dl (p=0.002), 이환기간중의최소혈청알부민농도는 4.2±0.4 g/dl와 3.6±0.5 g/dl (p<0.001), 비정형림프구의백분율은 0.6±1.8% 와 4.0± 5.6% (p=0.011), PT-INR은 1.03±0.14와 1.27±0.13 (p= 0.004), 간염회복기간은 19.5±5.0일과 38.6±14.5 일 (p< 0.001), 그리고비장비대를보인경우가 12.5% 과 87.5% (p<0.001) 로통계적으로의미있는차이를보였다. 3. 과거연구결과와비교혈청학적방법을이용하여 EBV의재활성화를판단한지난연구에서비활성화군과재활성화군은간염회복기간, 비장비대, AST, ALT, AST/ALT, 최소혈청알부민농도, PT-INR이통계적으로유의미한차이를보였는데 PCR을이용하여재활성화를판단한이번연구에서는추가로최소혈청단백농도와비정형림프구의백분율이차이를보였다 (Table 3). 또한지난연구에서 10 세미만의환아에서 PT-INR과간염회복기간이비활성화군과재활성화군에서차이를보였으나금번연구에서는간염회복기간만이의미있는차이를보였고, 10세이상의환아에서 AST, ALT, AST/ALT, 최소혈청알부민농도, PT-INR, 간염회복기간, 비장비대에서유의미한차이를보였던지난연구에비해이번연구에서는 AST/ALT의유의미한차이는보이지않으나추가로최소혈청단백농도가통계적으로유의미한차이를보였다 (Table 4).

백승현외 : 중합효소연쇄반응으로확인된엡스타인 - 바바이러스재활성화가소아급성 A 형간염에미치는영향ㆍ 63 Table 3. Comparison between the Serologic and PCR Method Study Results Serologic test study Duration (p<0.001) Splenomegaly (p=0.004) AST (p=0.004) ALT (p=0.004) AST/ALT (p=0.00) PT-INR (p<0.001) Albumin (p=0.004) PCR study Duration (p<0.001) Splenomegaly (p<0.001) AST (p=0.001) ALT (p<0.001) AST/ALT (p=0.002) PT-INR (p<0.001) Albumin (p<0.001) Protein (p<0.001) Atypical lymphocyte (p=0.001) Duration: duration of full recovery from hepatitis, AST: aspartate aminotransferase, ALT: alanine aminotransferase, PT-INR: prothrombin time-international normalized ratio. 고 EBV의초회감염및재활성화의진단에혈청학적항체검사를이용하는경우가많은데이경우급성 A형간염과같은급성염증성질환에서비특이적인교차반응으로인한위양성의결과가나타날수있다. 또혈청학적항체검사는중합효소연쇄반응에비해초회감염및재활성화를진단하는데부정확하다는보고 16) 가있어본저자들이과거보고하였던 EBV의재활성화가 A 형간염의경과에영향을미친다는것을확실히하기위하여중합효소연쇄반응을이용하여 EBV의재활성화를확인하고연구를진행하는것이필요하였다. 정상인이 EBV에감염이되었을때 EBV는면역기전을회피하여평생동안감염상태를유지하는것으로알려져있는데이는 EBV의유전자가기억B세포 (Memory B cell) 에전사 (transcription) 되지않는상태로존재하여 T세포에의한면역반응을피하기때문으로설명하고있다 17). EBV의초회감염이일어나면 EBV의유전자는 B세포내부로침투하는데 B세포의항원제시 (antigen presentation) 가일어나며 CD 4+ 및 CD 8+ T세포에의한면역반응으로인해 EBV에감염된 B세포는사라지게된다. 그러나감염된 B세포의증식이 2차림프조직 (secondary lymphoid tissue) 내에서일어나면서감염된 B세포는말초에들어가기전에기억B세포로전환되고잠복기의제한된형태로바뀌게되어 T세포에의한면 찰 Table 4. Comparison between Serologic and PCR Method Study according to Age Groups Serologic test study PCR study Age<10 years Duration (p=0.017) Duration (p<0.001) PT-INR (p=0.013) Age 10 years Duration (p<0.001) Duration (p<0.001) Splenomegaly (p=0.001) Splenomegaly (p<0.001) AST (p=0.027) AST (p=0.038) ALT (p=0.001) ALT (p=0.004) PT-INR (p<0.001) PT-INR (p<0.001) Albumin (p=0.007) Albumin (p<0.001) AST/ALT (p=0.007) Protein (p=0.002) Atypical lymphocyte (p=0.011) Duration: duration of full recovery from hepatitis, PT-INR: prothrombin time-international normalized ratio, AST: aspartate aminotransferase, ALT: alanine aminotransferase 역반응을회피하게된다. 이러한과정을통해 EBV는면역능력이정상인숙주에서도평생동안감염상태를유지한다는것이다. 건강한사람에서 EBV의재활성화는약 3% 에서발견된다고알려져있으며, 본연구에서는급성 A형간염이있는환아에서 EBV가재활성화된비율이 35.3% 에이르는것으로나타나과거여러질병상태에서보고되었던 EBV 재활성화빈도보다 14,15,18) 더높았다. 급성 A 형간염이발병한경우 EBV의재활성화빈도가크게증가한것인데이의원인에대해아직진행되어있는연구가없지만 A형간염바이러스감염은바이러스자체의세포변성 (cytopathic) 효과뿐만아니라 T세포와관련한면역기전에의해간세포에손상을줄수있는것으로알려져있고 19,20) EBV의재활성화와 T세포관련면역기전에는유의한관련이있어 21 23) A형간염에의한 T세포관련면역기전의활성화가 EBV의재활성화와관련이있지않을까추측가능하다. 또한스트레스호르몬이증가하였을때 EBV의재활성화가증가하는것이알려져있는데 6) 급성 A형간염에의한신체적, 정신적스트레스로인해 EBV의재활성화가더일어날것으로생각할수있다. EBV의재활성화는여러질환과의연관성이알려져있는데상부위장관출혈의병소에서발견되거나 10), 포도막염이있는환자에서시행한 EBV의혈청학적검사

64 ㆍ대한소아소화기영양학회지 : 제 14 권제 1 호 2011 에서재활성화의빈도가높았으며 12), 전자율신경기능이상 (pandysautonomia) 및장거짓막힘 (intestinal pseudoobstruction) 과관련된 EBV의재활성화증례 8) 가있고, 원인을알수없는간염에서 EBV가관여하고있음이보고되고있으며 9), 모기물림에대한과민증에서 CD 4+ T 세포에의한 EBV의재활성화가관찰되었다 24). 또한과거본저자들의보고에의하면급성 A형간염이있는환아에서 EBV가재활성화되면비활성화군보다간염으로부터완전히회복되는데걸리는시간이더오래걸리는것으로나타났다 13). 이는본연구에서도확인할수있는데 10세미만의환아들에대한결과를보면다른소견의유의한차이는없으나간염회복기간만차이가있는것을확인할수있으며 EBV의재활성화가있는경우간염으로부터회복이더디다는것으로해석할수있다. 또한간염의예후를결정하는혈청단백이나알부민의농도, PT-INR도재활성화군에서통계적으로유의미하게좋지않은결과를보였기에 EBV의재활성화가간기능에이상을일으키며 A형간염의임상경과에좋지않은영향을미친다는것을보여준다고할수있다. 나이에따라결과를비교하여보면나이가어린환아보다는나이가많은환아에서 EBV의재활성화가많음을알수있는데이는나이가많을수록잠복기상태인 EBV감염의유병률이높으므로나이가많은환아에서재활성화의확률이증가한것으로생각할수있다. 소아에서급성 A형간염은임상증상이심하지않으나성인의경우에서 80% 이상이심한증상이나타나는것으로 19) 알려져있고본연구에서보듯 10세이상의급성 A형간염환아에서 EBV의재활성화의빈도가높고재활성화가일어나면비활성화군에비해임상양상이좋지않으므로급성 A형간염이있는환아에서 EBV의재활성화는나이가많을수록주의해야할것이다. 지난연구결과와비교하였을때최소혈청단백농도가추가로유의한결과를나타낸것으로보아 EBV의재활성화가간기능에이상을일으키며 A형간염의임상경과에좋지않은영향을미친다는것을더확실하게나타냈다고할수있다. 또지난연구에서 10세미만의환아군에서간염회복기간과 PT-INR이차이를보였으나본연구에서는간염회복기간만이차이를보이고 10 세이상의환아군에서최소혈청단백농도가추가로유 의한결과를보인것은나이가많을수록 EBV의재활성화가더좋지않은경과를보인다는것을확실히하는것이다. 본연구는단일기관연구로서그대상자수가적었다는점과급성 A형간염의경과가좋다고알려져있기에간조직검사를진행하지않아 EBV의재활성화가간에미치는영향을조직학적결과로확인할수없었다는한계가있으나, EBV의중합효소연쇄반응을통해과거연구보다정확한재활성화상태를확인하였으며이를바탕으로급성 A형간염환아에서 EBV의재활성화는빈도가정상인에비해높으며간염의경과에좋지않은영향을미치고나이가많은환아에서더좋지않은경과를보인다는것을확인할수있었다. 앞으로더많은환아를대상으로조직학결과를포함한연구가진행된다면이러한영향과대해더확실하게알수있을것이다. 요약목적 : 본저자들은급성 A형간염환아에서 EBV의재활성화가증가하였고 EBV의재활성화가 A형간염의경과에영향을미치는지보고한바있으나과거연구의한계를극복하고자중합효소연쇄반응을시행하여 EBV의재활성화가확인된급성 A형간염환아들의임상경과를분석하기로하였다. 방법 : 과거연구와동일한대상으로 2008년부터 2010년까지세브란스병원에서급성 A형간염으로진단받은 19세이하의환자중 EBV PCR을추가로시행한 34명으로제한하여입원당시의나이, 성별, 간염으로부터완전히회복될때까지걸린기간, 혈청검사결과, 초음파검사결과를조사하였다. 대상환아를 EBV 의비활성화군과재활성화군으로나누어결과를비교하였고 10세를기준으로환아를나누어비활성화군과재활성화군을비교하였으며이번연구결과와과거연구결과에서유의하게나온항목을비교분석하였다. 결과 : 재활성화된비율은 35.3% 였고비활성화군과재활성화군을비교하였을때 AST (p=0.001), ALT (p <0.001), AST/ALT ratio (p=0.002), 이환기간중의최소단백량 (p<0.001), 이환기간중의최소알부민 (p< 0.001), 비정형림프구의백분율 (p=0.001), PT-INR (p<

백승현외 : 중합효소연쇄반응으로확인된엡스타인 - 바바이러스재활성화가소아급성 A 형간염에미치는영향ㆍ 65 0.001), 간염회복기간 (p<0.001), 비장비대 (p<0.001) 가통계적으로유의한차이를보였고 10세미만에비해 10세이상의환아에서 EBV가재활성화되었을때임상양상이더좋지않았다. 지난연구결과와비교하였을때최소혈청단백농도 (p<0.001) 가추가로유의하였으며 10세미만의환아군에서 PT-INR의차이가사라지고 10세이상의환아군에서최소혈청단백농도가추가로유의한결과를보였다. 결론 : 중합효소연쇄반응을이용한본연구에서도급성 A형간염환아에서 EBV의재활성화가흔하며간염의경과에좋지않은영향을미치고나이가많은환아에서더좋지않은영향을미치는것으로확인할수있었다. 참고문헌 1) El-Kamary SS, Cheng TL. Hepatitis A. Pediatr Rev 2005;26:75-6. 2) Jung YK, Kim JH. Epidemiology and clinical features of acute hepatitis A: from the domestic perspective. Korean J Hepatol 2009;15:438-45. 3) Hallee TJ, Evans AS, Niederman JC, Brooks CM, Voegtly H. Infectious mononucleosis at the United States Military Academy. A prospective study of a single class over four years. Yale J Biol Med 1974;47:182-95. 4) Asano N, Yamamoto K, Tamaru J, Oyama T, Ishida F, Ohshima K, et al. Age-related Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders: comparison with EBV-positive classic Hodgkin lymphoma in elderly patients. Blood 2009;113:2629-36. 5) Gotlieb-Stematsky T, Rannon L, Vonsover A, Varsano N. Stimulation of antibodies to Epstein-Barr virus (EBV) in acute viral infections. Arch Virol 1978;57:199-204. 6) Stowe RP, Pierson DL, Barrett AD. Elevated stress hormone levels relate to Epstein-Barr virus reactivation in astronauts. Psychosom Med 2001;63:891-5. 7) Nystad TW, Myrmel H. Prevalence of primary versus reactivated Epstein-Barr virus infection in patients with VCA IgG-, VCA IgM- and EBNA-1-antibodies and suspected infectious mononucleosis. J Clin Virol 2007;38: 292-7. 8) Besnard M, Faure C, Fromont-Hankard G, Ansart-Pirenne H, Peuchmaur M, Cezard JP, et al. Intestinal pseudoobstruction and acute pandysautonomia associated with Epstein-Barr virus infection. Am J Gastroenterol 2000;95: 280-4. 9) Drebber U, Kasper HU, Krupacz J, Haferkamp K, Kern MA, Steffen HM, et al. The role of Epstein-Barr virus in acute and chronic hepatitis. J Hepatol 2006;44:879-85. 10) Lavin AC, Roman JG, Zarate SA, Porras MC, Caviedes JR. Acute upper gastrointestinal bleeding associated with Epstein-Barr virus reactivation in an immunocompetent patient. Am J Gastroenterol 2009;104:253-4. 11) Rajwal S, Davison S, Wyatt J, McClean P. Primary Epstein-Barr virus hepatitis complicated by ascites with epstein-barr virus reactivation during primary cytomegalovirus infection. J Pediatr Gastroenterol Nutr 2003; 37:87-90. 12) Touge C, Agawa H, Sairenji T, Inoue Y. High incidence of elevated antibody titers to Epstein-Barr virus in patients with uveitis. Arch Virol 2006;151:895-903. 13) Kim SY, Ryu IS, Baek SH, Chung KS, Koh H. Concurrent reactivation of latent EBV with hepatitis A can affect clinical feature of childhood hepatitis. Acta Paediatr 2010;99:1258-62. 14) Obel N, Hoier-Madsen M, Kangro H. Serological and clinical findings in patients with serological evidence of reactivated Epstein-Barr virus infection. APMIS 1996; 104:424-8. 15) Chung JL, Kim HS. Clinical usefulness of EBV-specific antibody panel test and PCR genotyping in the diagnosis of Epstein-Barr virus infection. Korean J Clin Pathol 2000;20:320-9. 16) Luderer R, Kok M, Niesters HG, Schuurman R, de Weerdt O, Thijsen SF. Real-time Epstein-Barr virus PCR for the diagnosis of primary EBV infections and EBV reactivation. Mol Diagn 2005;9:195-200. 17) Rowe M, Zuo J. Immune responses to Epstein-Barr virus: molecular interactions in the virus evasion of CD8+ T cell immunity. Microbes Infect 2010;12:173-81. 18) Ternak G. Epstein-Barr virus reactivation. Lancet Infect Dis 2003;3:271. 19) Siegl G, Weitz M. Pathogenesis of hepatitis A: persistent viral infection as basis of an acute disease? Microb Pathog 1993;14:1-8. 20) Vallbracht A, Maier K, Stierhof YD, Wiedmann KH, Flehmig B, Fleischer B. Liver-derived cytotoxic T cells in hepatitis A virus infection. J Infect Dis 1989;160: 209-17. 21) Rickinson AB, Moss DJ, Allen DJ, Wallace LE, Rowe M, Epstein MA. Reactivation of Epstein-Barr virusspecific cytotoxic T cells by in vitro stimulation with the autologous lymphoblastoid cell line. Int J Cancer 1981; 27:593-601.

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