천식및알레르기제27권제4호 Vol. 27, No. 4, Dec., 2007 원저 집먼지진드기면역요법후천식이소실된성인천식환자들의임상적특성 아주대학교의과대학알레르기 - 류마티스내과학교실 허규영ㆍ이현영ㆍ최길순ㆍ박한정ㆍ최성진ㆍ남동호ㆍ박해심 Clinical Features of Patients in Remission after House Dust Mite Allergen Immunotherapy in Adult Asthma Gyu-Young Hur, Hyung-Youn Lee, Gil-Soon Choi, Han-Jung Park, Sung-Jin Choi, Dong-Ho Nahm and Hae-Sim Park Department of Allergy & Rheumatology, Ajou University School of Medicine, Suwon, Korea Background: Although allergen specific immunotherapy has been used as the only curative treatment for allergic diseases, there have been few studies that observed the efficacy of immunotherapy in asthmatics. Objective: We attempted to determine clinical parameters for predicting the remission of asthma after immunotherapy with house dust mite extracts. Method: Fifty-six adult asthmatic patients undergoing immunotherapy with house dust mite extracts for more than 3 years were enrolled. They were classified into the remitted and unremitted group according to the results of following methacholine challenge test. Skin reactivity, immunologic findings, spirometry, and airway hyperreactivity were compared between the 2 groups. Key words: Remission, Bronchial hyperreactivity, Immunotherapy, Asthma Result: Twenty-six subjects (46.4%) were in the remitted group and 30 subjects (53.6%) were in the unremitted group. Both onset age of asthma symptoms and starting age of immunotherapy were significantly lower in the remitted group (P, for each). Baseline FEV 1 levels and degree of airway hyperreactivity were significantly better in the remitted group (P<0.01 and 0.05, respectively). Conclusion: Younger age, earlier immunotherapy as well as better lung function and airway hyperreactivity at baseline can be used to predict the remission of asthma in adults. Therefore, earlier allergen immunotherapy in younger age group might help achieve remission in adult allergic asthma. (Korean J Asthma Allergy Clin Immunol 2007;27:257-262) 서 알레르겐특이면역요법은기관지천식, 알레르기비염, 벌독알레르기등알레르기질환의유일한근치요법으로널리사용되고있다. 1) 지금까지알레르기천식및비염의치료에월등한효과가있다고보고되었고, 2-4) 최근아토피피부염에서도긍정적인결과가있어치료에활용되고있다. 5,6) 소아천식환자에서는집먼지진드기단독면역요법이다른흡입성항원에대한새로운감작을예방하는효과가있다고보고되었다. 7,8) 알레르겐특이면역요법의효과는증상지수, 피부반응도, 혈청내특이 IgE 항체치, 기도과민성, 약물요구량등을 본연구는보건의료기술진흥사업의지원에의하여이루어진것임 (A050571). 책임저자 : 박해심, 경기도수원시영통구원천동산 5 번지아주의대알레르기 - 류마티스내과, 우 : 442-749 Tel: 031) 219-5196, Fax: 031) 219-5154 E-mail: hspark@ajou.ac.kr 접수 : 2007 년 10 월 4 일, 통과 : 2007 년 11 월 26 일 론 지표로하여증명되는데, 비염및천식환자에서장기간의면역요법후이들지표가호전되었다는다양한보고가있다. 9,10) 국내에서도소아및성인천식환자를대상으로집먼지진드기단독면역요법후치료결과에대한다양한연구가있었으며, 임상증상의호전, 11) 피부반응도의감소, 12) 혈청내집먼지진드기특이 IgE 항체치의감소, 13,14) 호염기분비능의감소, 15) 기도과민성의호전 16) 등의효과가보고되었다. 그러나아직면역요법후기도과민성이소실된환자군에서임상적인특성을분석한연구는없었다. 이에본연구에서는성인천식환자에서장기간집먼지진드기단독면역요법을시행한후기도과민성이소실된환자의특성을분석하여, 면역요법에따른예후를예측할수있는임상인자를밝히고자하였다. 대상및방법 1. 연구대상집먼지진드기특이항원 (Novo-Helisen R Depot; Allergophar- 257
258 천식및알레르기제 27 권제 4 호 ma, Reinbek, Germany) 으로 3년이상알레르겐특이면역요법을받고있는알레르기천식환자들을대상으로하였다. 천식은미국흉부학회의기준에따라, 최근 12개월이내에호흡곤란과천명이있으면서, 1초강제호기량 (FEV 1) 변화가 12% 이상이거나메타콜린기관지유발검사상 FEV 1 이 20% 이상감소하는흡입메타콜린의농도 (PC 20) 가 16 mg/ml 이하인경우로정의하였다. 17) 그중면역요법전시행한기저메타콜린기관지유발검사상 PC 20 치가 8 mg/ml 이하인현증천식환자 56명을대상으로하였다. 면역요법기간동안기관지천식의증상조절을위한천식약제를유지하였으며, 원인항원인집먼지진드기에대한항원회피를교육하였다. 알레르기비염, 결막염및아토피성피부염등다른알레르기성질환의동반여부, 흡연력및기관지천식의가족력에대해조사하였다. 또한각환자의기관지천식증상이발현한나이, 면역요법시작전까지천식증상이있었던기간및면역요법을시작한나이등을조사하였다. 2. 연구방법 1) 알레르기피부단자시험및총 IgE, 특이 IgE 측정 : 모든대상환자에서집먼지진드기 (Dermatophagoides pteronyssinus, Dermatophagoides farinae) 를포함한흔한흡입성항원 50종 (Bencard, Bretford, UK) 으로피부단자시험을시행하였으며, 원인항원과히스타민의팽진비 (A/H ratio) 가 1 이상인경우를양성으로판정하였다. 아토피점수 (atopy score) 는피부단자시험결과양성인항원에대하여원인항원과히스타민의팽진비를더한총합으로구하였다. 혈청총 IgE 수치및혈청특이 IgE를 immunocap system (Phadia AB, Uppsala, Sweden) 으로측정하였다. 각값은면역요법기간동안매년추적하여시행하였다. 2) 메타콜린기관지유발검사 : Dosimeter 를사용하여각각 Table 1. Clinical characteristics of study subjects (N=56). Gender Male Female History of other allergic disease Allergic rhinitis Allergic rhinitis and conjunctivitis Allergic rhinitis, conjunctivitis and atopic dermatitis None Family history of asthma Smoking history Onset age of asthma symptoms (yr) Duration of asthma symptoms (yr) Age of starting immunotherapy (yr) N (%) 26 (46.4) 30 (53.6) 50 (98.0) 48 (85.7) 7 (12.5) 1 (1.8) 17 (33.3) 5 (9.8) 25.08±11.26 4.11±4.20 28.21±11.37 의농도를 5번흡입하는방식을사용하였으며, 18) 흡입메타콜린의농도는 0.31 mg/ml부터 25 mg/ml까지로하였다. PC 20 이 8 mg/ml 이하이고천식증상이있는경우, 현증천식으로정의하였다. 면역요법기간중메타콜린기관지유발검사를매년추적시행하여천식증상이소실되었으면서 25 mg/ml 농도의메타콜린을흡입하여도 FEV 1 이 20% 이상감소하지않는경우기도과민성이소실된것으로정의하였다. 추적관찰기간동안천식증상의소실과함께기도과민성이소실된경우소실군, 기도과민성이지속적인경우지속군으로각각분류하였다. 3. 통계분석 통계분석은 SPSS 12.0 (SPSS Inc., Chicago, Illinois, US) 를사용하였으며, 각값은평균 ± 표준편차로표기하였다. 각군간의임상양상및검사결과의비교는 t-test 및 χ 2 -test 를사용하였다. P값이 0.05 이하인경우통계적으로유의한것으로간주하였다. 결 1. 대상환자의특성 전체 56명의대상환자중남성이 26명 (46.4%), 여성이 30 명 (53.6%) 이었으며, 면역치료를시작한연령은평균 28.21± 11.37세였다. 대상환자중 50명 (98.0%) 에서알레르기비염을동반하고있었으며, 48명 (85.7%) 은알레르기비염및결막염을동반하고있었다. 알레르기비염, 결막염및아토피성피부염을동반한환자는 7명 (12.5%) 이었고, 다른알레르기질환의과거력이없는경우도 1명 (1.8%) 있었다. 가족 (first-degree Table 2. Laboratory findings of study subjects (N=56) Log serum total IgE (IU/mL) Sum of A/H ratios (atopy score) A/H ratio to house dust mite Serum specific IgE to house dust mite (ku/ml) Multiple sensitization Sensitized to pollen Sensitized to fungus Sensitized to animal fur Baseline % predicted FEV 1 Baseline PC 20 (mg/ml) N (%) 2.40±0.51 40.29±22.92 4.61±2.70 35.59±36.14 37 (67.3) 11 (20.0) 19 (34.5) 22 (40.0) 91.48±15.39 2.00±1.67 A/H ratio = the ratio of mean wheal diameter of allergen to histamine; Atopy score = sum of the ratio of mean wheal diameter of each allergen to histamine; FEV 1 = forced expiratory volume in one second; PC 20 = the provocative concentration of methacholine inducing a 20% decline in FEV 1 from baseline values. 과
허규영등 : House Dust Mite Allergen Immunotherapy in Adult Asthma 259 Table 3. Comparisons of clinical features between remitted and unremitted groups. Remitted (n=26) Unremitted (n=30) P Gender (male/total) Onset age of asthma symptoms Duration of asthma symptoms Age of starting immunotherapy Duration of immunotherapy (mo) Log serum total IgE (IU/mL) Sum of A/H ratios (atopy score) A/H ratio to house dust mite Serum specific IgE to house dust mite (ku/ml) Baseline % predicted FEV 1 Baseline PC 20 (mg/ml) 17/26 21.83±10.48 3.42±3.52 24.62±10.51 43.95±25.02 2.35±0.49 45.58±25.54 5.29±2.87 39.80±35.86 98.24±12.31 2.53±1.50 9/30 28.08±11.31 4.70±4.69 31.33±11.33 77.51±35.11 2.45±0.53 35.55±19.54 4.00±2.42 31.63±36.61 85.62±15.55 1.55±1.70 0.261 <0.001 0.489 0.106 0.075 0.419 <0.01 A/H ratio = the ratio of mean wheal diameter of allergen to histamine; Atopy score = sum of the ratio of mean wheal diameter of each allergen to histamine; FEV 1 = forced expiratory volume in one second; PC 20 = the provocative concentration of methacholine inducing a 20% decline in FEV 1 from baseline values. relatives) 중기관지천식이있는경우는 17명 (33.3%) 이었으며, 흡연력이있는경우가 5명 (9.8%) 이었다 (Table 1). 2. 면역요법전검사실소견집먼지진드기특이항원단독으로면역요법을시행하기전검사실소견에서, 대상환자의평균아토피점수는 40.29± 22.92였으며, 집먼지진드기에대한 A/H 비는평균 4.61±2.70 이었다. 혈청내집먼지진드기특이 IgE 항체의수치는평균 35.59±36.14 (ku/ml) 이었다. 기저 FEV 1 및메타콜린 PC 20 값은평균 91.48±15.39 (%), 2.00±1.67 (mg/ml) 이었다 (Table 2). 3. 면역요법후천식소실에따른임상적특성비교집먼지진드기특이항원단독으로면역요법을시행한뒤추적시행한메타콜린기관지유발검사결과기도과민성과천식증상이소실된군은 26명 (46.4%), 지속군이 30명 (53.6%) 이었다. 각군간의임상적차이를비교해보면, 소실군에서남성이 17명 (65.4%), 지속군에서는남성이 9명 (30.0%) 으로, 소실군에서남성의비율이유의하게높았다 (P). 소실군에서천식증상이발생한연령이유의하게낮았으며 (21.8 vs. 28.0세, P), 면역요법을시작한연령도낮았다 (24.6 vs. 31.3세, P). 면역요법전시행한혈청내총 IgE 항체및집먼지진드기특이 IgE 항체수치는두군간에유의한차이가없었으며, 집먼지진드기에대한 A/H비는소실군에서오히려더높은경향을보였다 (P=0.075). 폐기능에대해서는, 소실군에서지속군보다기저 FEV 1 및 PC 20 치가유의하게높았다 (98.24 vs. 85.6%, P<0.01; 2.53 vs. 1.55 mg/ml, P). 면역요법을시행한기간은소실군에서평균 24개월, 지속군에서 31개월로소실군에서종료시기가빨랐다 (P<0.001, Table 3). 완치군에서, 1년이내에기도과민성이소실되는경 Fig. 1. Accumulated remitted rate in remitted group during receiving allergen specific immunotherapy. 우가 34.6% 였으며, 61.2% 에서 2년이내에기도과민성이소실되었다. 또한 5년이내에 96.2% 에서기도과민성이소실되었으나소수의환자에서는 (3.8%) 6년이후에기도과민성이소실되었다 (Fig. 1). 고 집먼지진드기 (Dermatophagoides pteronyssinus, Dermatophagoides farinae) 는국내에서가장흔한실내흡입알레르겐으로서알레르기질환의발생에중요한역할을한다. 미국성인의집먼지진드기의감작률은 36.3% 이며, 19) 국내에서는소아에서 33.3%, 20) 성인에서 18.5 55.2% 까지 21,22) 다양하게보고되고있다. 또한아토피피부염및알레르기비염, 천식과같은알레르기질환이있는경우에는감작율이 90.2% 까지증가되는것으로알려져있으며, 23) 소아및성인천식발생에중요한 찰
260 천식및알레르기제 27 권제 4 호 위험인자로알려져있다. 20) 알레르기비염및천식에서면역요법의긍정적인효과는오래전부터증명되어왔으나, 임상적호전을유도하는기전에대해서는아직완전히규명되어있지않다. 최근에는면역요법의중심기전이조절 T 세포의활성화로인한면역관용이라는보고들이있다. 24-26) 따라서, 면역요법을통하여 T 세포및 B 세포의조정을유도하여호산구, 호염구, 비반세포등알레르기염증작동세포를제어시킬수있으며, 면역요법을통해활성화된알레르겐특이조절 T세포 (regulatory T cell) 는말초 T세포의면역관용을유도한다. 장기간면역요법후알레르겐특이 IgG4, IgG1 및 IgA가유의하게증가하고, 특이 IgE가감소한다. 면역요법후에는비반세포및호산구등의조직내침윤이감소하면서 Th2 사이토카인및염증매개체의분비가감소하고, T 세포의 IFN-γ의분비가증가되어알레르기염증반응이감소한다. 27,28) 면역요법은고식적으로는피하경로를통하는것이표준이나최근비강내혹은설하경로가대체경로로사용될수있으며, 동등한효능을가지는것으로보고되고있다. 29,30) 설하면역요법의경우알레르겐이구강점막내수지상세포에서포획되고수지상세포가성숙하여면역관용을유도한다. 31,32) 피하면역요법의경우 4 6주간의유도기간이후최대용량으로증량하여유지하는유지기간이필요하며, 아나필락시스, 두드러기등심한전신적부작용이발생할위험이있으나, 설하면역요법의경우구강소양증, 부종, 자극등국소적인부작용만이수분내발생하는것으로보고되며, 대부분성인및소아에서안전하게사용할수있다. 33) 천식환자를대상으로면역요법의효과를판정할때객관적지표인폐기능과기도과민성을이차성과로서사용할수있다. Pifferi 등 34) 은소아천식환자에서환자-대조군연구를시행하여집먼지진드기단독면역요법을받는경우대조군보다기도과민성이유의하게호전된다고보고하였다. 또한 Bousquet 등 35) 은소아및젊은성인천식환자에서조기에면역요법을시행하였을때더좋은효과를기대할수있다고하였다. 본연구결과에서도기도과민성이소실된환자들에서증상발생연령이더낮고조기에면역요법을시작하였으며, 기저폐기능및기도과민성이더좋은것으로나타나, 이러한특성을가진환자들은면역요법후더좋은효과를기대할수있겠다. 면역요법은알레르기질환을호전시키나모든환자에서알레르기증상을완전히경감시키지는않기때문에, 대부분의무작위임상연구에서는면역요법의효과를평가하기위해서증상및약제사용량을일차성과로판정한다. 또한객관적지표인폐기능, 기도과민성, 삶의질등을이차성과로판단하며, 임상효과를반영하고그기전을설명하기위한 대리지표로서피부반응도, 기도유발검사, 혈청내총 IgE, 특이 IgG, IgA, 림프구분획및사이토카인분비능, 염증지표등을사용할수있다. 36) 본연구에서는기도과민성뿐만아니라평균 67개월간추적관찰한피부반응도, 총 IgE, 특이 IgE 등의변화를추가적으로측정하였다. 피부반응도는기도과민성소실여부와관계없이면역요법을받은모든환자에서유의하게감소하였으나 (P<0.001, data not shown), 소실군과지속군간의유의한차이는없었다. 혈청내총 IgE 및특이 IgE는면역요법전후두군모두감소하는경향을보였으나통계적인유의성은관찰되지않았다. 일반적으로면역요법은천식환자의 65 90% 에서효과가있다고알려져있으며, Marogna 등 37) 은면역요법과약물치료를병행한경우약물치료만시행했을때보다기도과민성이소실될가능성이높다고보고하였다 (59.5 vs. 10.3%, P<0.001). 본연구결과에서도기도과민성및천식소실률이 46.5% 로유사한결과를보여준다. 본연구는면역요법후기도과민성이소실되는환자의임상인자를예측하기위하여면역요법을받는성인천식환자를대상으로하였으며, 모든환자는적절한천식치료제를사용하도록하였다. 물론기도과민성의소실이면역요법자체의효과뿐만아니라흡입스테로이드및베타2-항진제등적절한천식약제를사용하여완치에도달한결과일수있다. 그러나 Maestrelli 등 38) 은천식약물치료와병합하여면역요법을부가적으로시행하였을때기도과민성의측면에서는차이를보이지않았으나, 대조군에비하여약물사용량을경감시키고, 최대호기유속을증가시키는등, 부가적인면역요법이천식호전에도움이된다고보고하였다. 일반적으로천식환자에서천식의소실률이매우낮은것을감안하면성인천식환자에서약물치료뿐아니라면역요법을추가하여천식의소실을기대할수있다. 면역요법의적절한종료시점에대해서는아직까지확립된결과가없으나증상이소실된경우 3 5년정도지속하도록권장하고있다. 39) 종결시점을결정하는확립된지표가아직없으나, 국내에서 Kim과 Kim이 16) 기관지유발검사상 PC 20 10 mg/ml 이상을적절한종결지표로제시한바있다. 본연구결과기도과민성이소실된환자에서면역요법기간이더욱짧았다 (3.6년 vs. 6.5년, P<0.001). 이렇게각군별로치료기간의차이를보이는것은, 기도과민성이소실되는환자에서기저폐기능과기도과민성이더좋으며, 빠른시간내에기도과민성이소실되기때문에면역치료를더빨리종결하는경우가많을것으로사료된다. 또한기도과민성이소실되는환자들의경우첫 1년에 39.5%, 2년에약 60% 에서완치상태에도달하여, 면역요법후특이 IgE 및 IgG, IgA등의면역학적변화와 24,40) 표적기관의반응시기가일치하는것을알수있다.
허규영등 : House Dust Mite Allergen Immunotherapy in Adult Asthma 261 또한본연구에서 5년이내에대부분의환자가기도과민성이소실되었으나 (96.2%), 일부환자에서는 6년째에기도과민성이소실되어 (3.8%), 일반적으로권장되는면역요법의종료시점을일괄적으로적용하기보다개별화하여적용할필요가있다. 결 장기간의집먼지진드기단독면역요법을받는성인천식환자들중천식증상이일찍발생하거나조기에면역요법을시행하는경우, 그리고기저폐기능및기도과민성이우수한경우면역요법후기도과민성과천식이소실될가능성이높다. 따라서적절한천식약물치료와더불어폐기능의저하가오기전조기에부가적인면역요법을시행하는것이천식소실의유도를기대할수있는임상인자가될수있다. 론 참고문헌 1) Norman PS. Immunotherapy--state of the art. N Engl Reg Allergy Proc 1985;6:249-54 2) Kohno Y, Minoguchi K, Oda N, Yokoe T, Yamashita N, Sakane T, et al. Effect of rush immunotherapy on airway inflammation and airway hyperresponsiveness after bronchoprovocation with allergen in asthma. J Allergy Clin Immunol 1998;102:927-34 3) Gruber W, Eber E, Mileder P, Modl M, Weinhandl E, Zach MS. Effect of specific immunotherapy with house dust mite extract on the bronchial responsiveness of paediatric asthma patients. Clin Exp Allergy 1999;29:176-81 4) Passalacqua G, Durham SR. Allergic rhinitis and its impact on asthma update: allergen immunotherapy. J Allergy Clin Immunol 2007;119:881-91 5) Bussmann C, Maintz L, Hart J, Allam JP, Vrtala S, Chen KW, et al. Clinical improvement and immunological changes in atopic dermatitis patients undergoing subcutaneous immunotherapy with a house dust mite allergoid: a pilot study. Clin Exp Allergy 2007;37:1277-85 6) Cadario G, A GG, Pezza M, Appino A, Pecora MM, Mastrandrea F. Sublingual immunotherapy efficacy in patients with atopic dermatitis and house dust mites sensitivity: a prospective pilot study. Curr Med Res Opin 2007;23:2503-6 7) Inal A, Altintas DU, Yilmaz M, Karakoc GB, Kendirli SG, Sertdemir Y. Prevention of new sensitizations by specific immunotherapy in children with rhinitis and/or asthma monosensitized to house dust mite. J Investig Allergol Clin Immunol 2007;17: 85-91 8) Reha CM, Ebru A. Specific immunotherapy is effective in the prevention of new sensitivities. Allergol Immunopathol (Madr) 2007;35:44-51 9) Wang H, Lin X, Hao C, Zhang C, Sun B, Zheng J, et al. A double-blind, placebo-controlled study of house dust mite immunotherapy in Chinese asthmatic patients. Allergy 2006;61: 191-7 10) Blumberga G, Groes L, Haugaard L, Dahl R. Steroid-sparing effect of subcutaneous SQ-standardised specific immunotherapy in moderate and severe house dust mite allergic asthmatics. Allergy 2006;61:843-8 11) Chae SA, Lee KH, Yoon HS. Follow-up study for symptomatic and laboratory change in bronchial asthma on immunotherapy. Korean J Asthma Allergy Clin Immunol 1993;18:40-5 12) Kim MK, Choi BW, Moon HB, Min KU, Kim YY. Changes of skin reactivity in asthmatics with immunotherapy. Korean J Asthma Allergy Clin Immunol 1986;6:15-21 13) Kim SY, Lee JS. Changes of specific IgE, bronchial hyperreactivity and sinusitis after immunotherapy in asthmatic children. Korean J Asthma Allergy Clin Immunol 1999;19:152-62 14)Shin HC, Choi EJ, Yoon WK, Oh JS. Parameters in immunotherapy of childhood asthma. Korean J Asthma Allergy Clin Immunol 1991;11:427-36 15) Shim JY, Kim BS, Cho SH, Min KU, Hong SJ. Allergen-specific conventional immunotherapy decreases immunoglobulin E-mediated basophil histamine releasability. Clin Exp Allergy 2003;33:52-7 16)Kim MK, Kim YY. Bronchial provocation test is the most optimal termination-index of immunotherapy in extrinsic bronchial asthmatics. Korean J Asthma Allergy Clin Immunol 1993;13:215-28 17) Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986. Am Rev Respir Dis 1987;136:225-44 18) Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, et al. Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 2000;161:309-29 19) Custovic A, Simpson BM, Simpson A, Hallam CL, Marolia H, Walsh D, et al. Current mite, cat, and dog allergen exposure, pet ownership, and sensitization to inhalant allergens in adults. J Allergy Clin Immunol 2003;111:402-7 20) Lee MH, Hong SC, Kim SH, Bahn JW, Chan YS, Kim TB, et al. Prevalence of asthma and atopy in children living in rural areas of Cheju island for an interval of three years. Korean J Asthma Allergy Clin Immunol 2002;22:85-91 21) Kim HS, Park CW, Lee JS, Cho YJ. The sensitization rate to house dust mites and the prevalence of asthma in healthy young women. Korean J Asthma Allergy Clin Immunol 2004;24:103-9 22) Kim SH, Hong SC, Bae JM, Lee MH, Kim YK, Cho SH, et al. Distinct effect of sensitization of house dust mite and citrus red mite (Panonychus citri) in the development of allergic diseases in 16-18 year old adolescents living in rural areas of Jeju island. Korean J Asthma Allergy Clin Immunol 2002;22:92-9
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