pissn: eissn: Allergy Asthma Respir Dis 3(1):40-46, January ORIGINAL ARTICLE 아토피천식

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1 pissn: eissn: (1):40-46, January ORIGINAL ARTICLE 아토피천식소아에서기관지확장제반응과천식조절및호기 NO 농도사이의연관성 박주현 1, 이윤경 1, 김헌 2, 한윤수 1 충북대학교의과대학 1 소아청소년과학교실, 2 예방의학교실 Relationships of bronchodilator response with asthma control and fractional exhaled nitric oxide in children with atopic asthma Joohyun Park 1, Youn Kyung Lee 1, Heon-Kim 2, Youn-Soo Hahn 1 Departments of 1 Pediatrics and 2 Preventive Medicine, Chungbuk National University College of Medicine, Cheongju, Korea Purpose: Because bronchodilator response (BDR) is variable among asthmatic patients, there are practical limitations in using BDR to assess asthma control. We investigated the relationships of BDR with asthma control status and fractional exhaled nitric oxide (FeNO) in children with atopic asthma. Methods: One hundred ninety-one patients aged 8 to 16 years with atopic asthma were enrolled. Pulmonary function tests including BDR and FeNO were serially measured 10 times or more over 2 years when subjects were not receiving controller medications. During the last year of follow-up, the loss of asthma control was assessed in all participants. Results: We identified 114 children (60%) with at least 1 positive BDR ( 12%) over the 2-year observation period. Higher levels of BDRs and higher rates of positive BDRs were associated with lower lung function and lower methacholine PC20 (provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second). The loss of asthma control occurred in 106 of individuals (93%) who had positive BDRs, as compared to 52 of 77 (68%) with negative BDRs (P< 0.001). There was no difference in FeNO levels between individuals with positive and negative BDRs. However, among children with negative BDRs, those developing the loss of asthma control had higher maximal FeNO levels and higher rates of FeNO > 21 parts per billion than those who maintained asthma control (all P< 0.001). Conclusion: Positive BDRs are linked to a higher probability of asthma control loss in children with atopic asthma. In addition, high FeNO is associated with asthma control loss in asthmatic children with negative BDRs. ( 2015;3:40-46) Keywords: Asthma, Child, Lung function, FeNO 서론천식은가장흔한만성호흡기질환으로기도염증, 기도과민성, 기도가역성을특징으로한다. 1) 이중기도가역성은속효성기도확장제를흡입시킨후 forced expiratory volume in one second (FEV 1) 이상승되는정도를의미하는기관지확장제반응 (bronchodilator response, BDR) 을관찰함으로써확인할수있다. 2) 성인에서기관지 확장제반응을양성으로판정하는기준은기관지확장제에의한 FEV 1 의 12% (200 ml) 증가로제시되었으나, 3) 소아의경우기관지확장제반응에대한적절한양성기준치가성인에서처럼제시되지않고있다. 천식환자들사이에기도확장제반응의차이가심하지만, 4,5) 기도확장제반응은천식의중요한특징으로간주되어임상진료와역학연구에서이용되고있다. 기관지확장제반응은천식에서발생하는기도염증과연관성을 Correspondence to: Youn-Soo Hahn Department of Pediatrics, Chungbuk National University College of Medicine, 410 Sunbong-ro, Heungdeok-gu, Cheongju , Korea Tel: , Fax: , yshahn@chungbuk.ac.kr This work was supported by the research grant of Chungbuk National University in Received: August 25, 2014 Revised: October 29, 2014 Accepted: November 24, The Korean Academy of Pediatric Allergy and Respiratory Disease The Korean Academy of Asthma, Allergy and Clinical Immunology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( 40

2 박주현외 기관지확장제반응과천식조절및호기 NO 농도사이의연관성 보인다고보고되었다. 6-8) 또한기관지확장제반응은천식의진단뿐아니라, 장기적예후추정에도도움이된다고알려져있으며, 특히지속적인양성기관지확장제반응은더불량한임상경과와연관성이있다고보고되었다. 9) 그러나다른연구들의경우, 만성기도폐쇄를갖고있는환자들에서한번이라도기관지확장제반응이관찰된환자들의 FEV 1 은기관지확장제반응이관찰되지않았던환자들에비해더천천히저하되었으며, 10) 기관지확장제반응이클수록이후에관찰되는폐기능의저하가적었다고보고되었다. 11) 이와같은연구결과들은기관지확장제반응정도가클수록오히려임상경과가좋을수있다는것을시사한다. 또한기관지확장제반응정도가크다는것은기도개형이진행되지않아기도의유연성이크다는것을의미할수있기때문에기도개형이기도염증과연관이있다는사실을고려하면 12) 양성기관지확장제반응은기도염증으로인한기도개형이상대적으로심하지않다는것을시사할수있다. 13) 결과적으로이전의연구들을종합해볼때기관지확장제반응과임상경과또는기도염증의관계를규명하는더많은연구가필요할것으로생각된다. 본연구에서는아토피천식으로진단된소아들을대상으로 2년이상최소 10회에걸쳐기관지확장제반응과기도염증지표인 fractional exhaled nitric oxide (FeNO) 를측정한후 1년동안의천식조절상태를평가하여기도확장제반응에따른천식조절여부와기도염증의차이를관찰하고자하였다. 대상및방법 1. 연구대상본연구는 2010년 1월부터 2011년 12월사이에숨참 (shortness of breath), 가슴답답함 (chest tightness), 야간각성 (awakening) 등의천식을시사하는증상으로충북대학교병원소아청소년과에내원한 8 16세사이의아토피천식소아를대상으로하였다. 연구에포함될당시대상소아들의나이, 성별, 신장, 몸무게, body mass index (BMI), 흡연에대한노출력이기록되었다. 대상소아들은혈청특이 IgE 검사에서 Dermatophagoides pteronyssinus, Dermatophagoides farinae, Alternaria, 바퀴, 개와고양이의상피 6종의알레르겐 중한가지이상에서알레르겐에대한감작이증명되고 NAEPP (National Asthma Education and Prevention Program) 가이드라인 14) 에따라기관지확장제에대한 12% 이상의 FEV 1 증가가나타나거나메타콜린유발시험에서 8 mg/ml 이하의 provocative concentration of methacholine causing a 20% fall in FEV 1 (PC 20) 값이관찰되어천식으로진단되었다. 본연구에서는연구에포함되기전 1 년동안 1 2회의천식조절의소실이관찰된소아들중천식조절제 ( 스테로이드제제, 류코트리엔길항제, 테오필린 ) 를최소 1개월동안사용하지않은상태에서최소 2년동안 10회에걸쳐천식조절에대한평가가가능했던환자들만이포함되었다. 본연구에서는연구대상소아들의보호자들에게연구의목적과방법을설명하고동의서를받은후시행되었으며, 충북대학교병원임상시험윤리위원회의심의를통과하였다. 2. 연구방법본연구의진행과정은 Fig. 1과같다. 천식을시사하는증상을나타낸소아들에대해폐기능, 기관지확장제반응, FeNO를측정한후 3개월이상흡입스테로이드치료 (budesonide μg/day) 가시행되었으며, 이후천식조절이 1개월이상유지되면흡입스테로이드의사용이중단되었다. 흡입스테로이드를사용하지않은상태에서천식조절이최소 1개월동안유지되면메타콜린 PC 20 값이측정되었으며, 대상소아들의천식상태에대한평가는 1 3개월간격으로시행되었고천식치료는 Global Initiative for Asthma 가이드라인에따라시행되었다. 15) 연구기간동안소아들의필요에따라증상완화제가사용되었으며, 천식조절이소실되어흡입스테로이드가사용된소아들에대해 3개월이상흡입스테로이드치료가시행된후최소 1개월이상천식조절이유지될경우흡입스테로이드의사용이중단되었다. 본연구에서는최소 2년동안 10회에걸쳐흡입스테로이드를최소 1개월동안사용하지않은상태에서대상소아들의폐기능, 기관지확장제반응, fractional exhaled nitric oxide (FeNO) 가측정되었으며, 메타콜린 PC 20 는 1년에 1회측정되었다. 10회이상측정이끝난소아들이 1개월이상천식조절이유지되면 1년동안 2개월마다천식조절상태를평가하였다. 일주일에 2 회이상주간증상, 일주일에 2회이상증상완화제사용, 천식증상 Diagnosis of atopic asthma 0 yr 1 yr 2 yr 3 yr Monitoring of lung function, BDR, FeNO, methacholine PC20 Assessment of asthma control Fig. 1. Study schedule. BDR, bronchodilator response; FeNO, fractional exhaled nitric oxide; PC20, provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second. 41

3 Park J, et al. Relationship of bronchodilator response with asthma control and FeNO 으로인한야간각성, 일상적활동이나운동제한, 80% 미만의 1초간노력성호기량 (FEV 1) 예측치중하나이상이관찰될때천식조절의소실로판단하였다. 3. 폐기능검사폐기능검사는 Vmax SensorMedics (Yorba Linda, CA, USA) 를이용하여모든환자에서 FeNO 측정후에바로시행되었다. 폐기능검사를시행하기전에대상소아들에대해최소 8시간이상속효성기관지확장제가, 그리고최소 36시간이상지속성기관지확장제가투여되지않았다. 노력성폐활량 (functional vital capacity, FVC), 1초간노력성호기량 (FEV 1), 최대중간호기량 (forced expiratory flow 25% 75%, FEF 25% 75%), FEV 1/FVC가측정되었으며, FVC, FEV 1, FEF 25% 75% 의추정정상치에대한백분율인 %FVC, %FEV 1, %FEF 25% 75% 는 Third National Health and Nutrition Examination Survey 에서제시한 8 16세사이의정상멕시코계미국인소아들에서의수치를이용하여계산되었다. 16) 메타콜린 PC 20 와기관지확장제반응은 European Respiratory Society/American Thoracic Society (ERS/ ATS) 에서제시한방법에따라측정되었다. 17,18) 메타콜린을완충식염수에녹여 0.25, 0.5, 1, 2, 4, 8, 16 mg/ml의농도로희석하였고, DeVilbiss 646 nebulizer (DeVilbiss Health Care, Somerset, PA, USA) 를이용하여에어로졸을발생시켰다. 각환자에서완충생리식염수를 5분동안흡입시킨후 FEV 1 을측정하여비교기준치로하였고, 각농도의메타콜린을 5분간격으로순차적으로높여가면서 5분동안흡입시킨후 60 90초사이에 FEV 1 을측정하였다. FEV 1 이비교기준치보다 20% 이상감소할때까지농도를증가시켰고, 용량반응곡선에서로그-선형보간법을이용하여 PC 20 을구하였다. 기관지확장제반응을평가하기위해선기저상태에서 FEV 1 을측정한후 400 μg (4 puff) 의살부타몰 (Ventolin Evohaler, Glaxo-Smith- Kline, London, UK) 을 spacer (AeroChamber Plus, Trudell Medical International, St. London, ON, Canada) 를통해흡입하고 15분후 FEV 1 을재측정하였다. 기관지확장제흡입전후의 FEV 1 변화량을기관지확장제흡입전 FEV 1 값에대한비율로나타낸것을기관지확장제반응으로정의하였다. 기관지확장제반응과 FeNO를 10 회이상측정한후최대기관지확장제반응인 M-BDR (maximal value of BDR), 기관지확장제에의한 FEV 1 상승 12% 이상이었던비율인 R 12BDR (rate of BDR higher than 12% increase in FEV 1), 최대 FeNO값인 M-FeNO (maximal value of FeNO), FeNO가 21 parts per billion (ppb) 보다높았던비율인 R 21FeNO (rate of FeNO higher than 21 ppb) 를구하였으며, 이들을결과분석에이용하였다. 4. FeNO 측정 FeNO 는 ATS/ERS 기준 19) 에따라전자화학감지기 (electrochemical sensor) 를이용한 NIOX mino (Aerocrine AB, Solna, Sweden) 를사용하여측정하였으며, ppb로표시하였다. 측정전최소 2시간동안운동이나음식물섭취를제한하였다. 측정대상인소아는측정기구에부착된마우스피스를물고총폐활량까지흡기하여폐내로흡입된공기중의 NO가최대한제거되도록하였으며, 지속적으로마우스피스를문상태에서 50 ml/sec의기속으로 6 10초동안호기하도록하였다. 첫 2회측정한값들의차이가 10% 보다크지않을경우 2회측정한값의평균값을, 10% 보다크면 3회측정한값의평균값을분석에이용하였다. 5. 통계통계분석은 PASW Statistics ver (SPSS Inc., Chicago, IL, USA) 을이용하였다. 결과는평균 ± 표준편차 (mean±standard deviation) 로제시하였으나, FeNO와메타콜린 PC 20 값은정규분포를따르지않아로그값을취해통계에이용하였으며, 기하학적평균과 95% 신뢰구간 (95% confidence interval) 으로표시하였다. 기관지확장제반응과폐기능검사결과및메타콜린 PC 20 값사이의상관관계는 Pearson correlation을사용하여검정하였다. 기관지확장제반응양성의기준은 ΔFEV 1 12% 로정의하였으며, 10) 두군간의비교에서 FeNO 차이는 t-test를다른변수들의차이는 Mann- Whitney U-test를이용하여검증하였다. P값이 0.05 미만인경우통계학적으로유의한것으로판단하였다. 결과 1. 연구대상환자들의특성연구에참여한소아는총 232명이었으며, 이중 10회이상기관지확장제반응의측정이가능하여결과분석에포함된소아는 191명이었다 (Table 1). 191명중남아가 137명, 여아 54명이었으며, 평균연령은 10.8 세, 평균추적관찰기간은 2.8년이었다. 대상소아들에서 D. pteronyssinus, D. farinae, Alternaria, 바퀴, 개와고양이의상피항원 6종중평균 2.4종에대해혈청특이 IgE가증명되었다. 연구시작시점에서실시한대상환자들의메타콜린 PC 20 의기하평균은 1.44 mg/ml였다. 2. 기관지확장제반응과다른폐기능결과사이의연관성분석각환자에서 10번이상측정중가장높게측정된기관지확장제반응을선택하여대상소아들의기관지확장제반응과동일시점에측정된 %FVC, %FEV 1, FEV 1/FVC, %FEF 25% 75% 사이의상관관계를분석하였다 (Table 2). 그결과기관지확장제반응은 %FEV 1 (r = 0.19, P = 0.011), FEV 1/FVC (r = 0.40, P<0.001), %FEF 25% 75% (r = 0.36, P<0.001) 와유의한음의상관관계를보였다. 그러나기관지확장제반응은 %FVC와는연관성을보이지않았다 (r = 0.05, P = 0.718). 또한기관지확장제반응은메타콜린 PC 20 값과음의상 42

4 박주현외 기관지확장제반응과천식조절및호기 NO 농도사이의연관성 Table 1. Demographic data of the study population (n= 191) Variable Value Age (yr) 10.86± 2.96 Sex (female:male) 54:137 Height (m) 1.42± 0.16 Weight (kg) 39.85± Body mass index (kg/m 2 ) 19.15± 3.39 Exposure to smoke, n (%) 76 (39.8) Total serum IgE (IU/mL), geometric mean (95% CI) ( ) Methacholine PC20 (mg/ml), geometric mean (95% CI) 1.44 ( ) M-BDR (%) 15.58± 9.43 R12BDR (%) 21.72± Values are presented as mean± standard deviation unless otherwise indicated. CI, confidence interval; PC20, provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1); BDR, bronchodilator response; M-BDR, maximal value of BDR; R12BDR, rate of BDR higher than 12% increase in FEV1. Table 3. Characteristics of individuals with positive and negative BDRs Variable BDR+ (n= 114) BDR (n= 77) P-value Age (yr) 10.31± ± Sex (female:male) 34:80 25: Height (m) 1.38± ± Weight (kg) 39.32± ± Body mass index (kg/m 2 ) 18.92± ± Exposure to smoke, n (%) 49 (43.0) 27 (35.1) Total serum IgE (IU/mL) ± ± Methacholine PC20 (mg/ml), geometric mean (95% CI) 1.25 ( ) 1.95 ( ) M-BDR (%) < ICS use (day/yr) 74± 39 78± Values are presented as mean± standard deviation unless otherwise indicated. BDR, bronchodilator response; PC20, provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second; CI, confidence interval; M-BDR, maximal value of BDR; ICS, inhaled corticosteroid. Table 2. Association of BDR with other spirometric values Variable 관관계 (r = 0.39, P<0.001) 를보여기도가역성이증가한환자일수 록메타콜린 PC 20 로평가한기도과민성이증가된다는것을확인할 수있었다. r BDR P-value %FVC %FEV FEV1/FVC 0.40 < %FEF25% 75% 0.36 < lnpc < BDR, bronchodilator response; %FVC, percent predicted functional vital capacity; %FEV1, percent predicted forced expiratory volume in one second; %FEF25% 75%, percent predicted forced expiratory flow 25% 75%; lnpc20, natural log-transformed provocative concentration of methacholine causing a 20% fall in FEV1. 3. 기관지확장제반응에따른천식조절상태와 FeNO 차이비교 결과분석에포함된소아 191 명중기관지확장제반응이최소 1 회이상양성이었던소아들은 114 명이었으며, 음성인소아들은 77 명이었다 (Table 3). 기관지확장제반응이양성과음성이었던소아 들사이에는나이, 성별, 신장, 체중, BMI, 흡연에대한노출비율, 총 IgE 농도, 흡입스테로이드사용일수에서는차이가관찰되지않았 다. 그러나두군사이에메타콜린 PC 20 값과 M-BDR 의유의한차이 가관찰되었다. 기관지확장제반응이양성이었던소아들에서 M- BDR 평균은 20.7% 로음성이었던소아들에서의 8.0% 에비해유의 하게높았다 (P<0.001). 기관지확장제반응이양성이었던소아들 중 106 명 (93%) 은추적기간 1 년동안 1 회이상천식조절의소실이 관찰된반면, 음성이었던소아들에서는 52 명 (68%) 에서관찰되었 다 (P< 0.001) (Fig. 2). 또한양성기관지확장제반응을보였던소아 Table 4. Comparison of M-FeNO and R21FeNO between individuals with positive and negative BDRs 들에서천식조절소실의횟수는평균 2.2 회로음성이었던소아들 에서의 1.3 회에비해많았다 (P = 0.008). 따라서기도가역성이증가 된환자일수록천식이조절되지않은빈도가높다는것을알수있 었다. 기관지확장제반응이양성과음성이었던환자들사이에는 10 회 이상측정한 FeNO 값중최곳값 (M-FeNO) 과 10 회이상측정된 FeNO 가 21 ppb 이상이었던비율 (R 21FeNO) 의유의한차이가관찰 되지않았다 (P = and P = 0.170, respectively) (Table 4). 또한 기관지확장제반응이양성과음성이었던환자들각각에서천식조 절이소실된환자들은천식조절이유지된환자들에비해유의하 게높은 M-FeNO 와 R 21FeNO 값을나타내었다 (Table 5). 따라서기 관지확장제반응과관계없이천식조절이소실된환자들은천식조 절이유지된환자들에비해기도염증이증가되어있다는것이관 찰되었다. BDR Positive (n= 114) Negative (n= 77) 고찰 P-value M-FeNO ( ) ( ) R21FeNO ( ) ( ) Values are presented as geometric mean (95% confidence interval). M-FeNO, maximal value of fractional exhaled nitric oxide (FeNO); R21FeNO, rate of FeNO higher than 21 ppb; BDR, bronchodilator response. 본연구에서는기도가역성지표인기관지확장제반응이양성인 환자들에서음성이었던환자들에비해천식조절이소실되는비율 43

5 Park J, et al. Relationship of bronchodilator response with asthma control and FeNO P< P= No. of patients loss of control Loss of asthma control + Loss of asthma control - No. of asthma control loss per year BDR + BDR - A 0 BDR + BDR - B Fig. 2. Comparison of number of individuals developing loss of asthma control (A) and number of asthma control loss per year (B) between groups with positive and negative bronchodilator responses (BDRs). Table 5. Comparison of M-FeNO and R21FeNO between individuals with and without LOC among patients with positive and negative BDRs BDR+ (n= 114) BDR (n= 77) LOC+ (n= 106) LOC (n= 8) P-value LOC+ (n= 52) LOC (n= 25) P-value M-FeNO ( ) ( ) < ( ) ( ) < R21FeNO ( ) ( ) < ( ) ( ) < Values are presented as geometric mean (95% confidence interval). M-FeNO, maximal value of fractional exhaled nitric oxide (FeNO); R21FeNO, rate of FeNO higher than 21 ppb; BDR, bronchodilator response; LOC, loss of asthma control. 이높았다. 또한기관지확장제반응정도는기관지과민성지표인메타콜린 PC 20 와기도폐쇄정도를나타내는폐기능지표들과유의한상관관계를나타내었으나, 염증지표인 FeNO는기관지확장제반응이양성인환자들과음성인환자들사이에차이가없었다. 그러나기관지확장제반응이음성이었던환자들중에서천식조절이소실된환자들의 FeNO는천식조절이유지된환자들에의 FeNO 에비해유의하게높았다. 따라서기관지확장제반응이음성이었던환자들에서기도염증이심할수록천식조절이소실될가능성이높다는것을확인할수있었다. 저자들은 2년이상최소 10회에걸쳐대상환자들의기관지확장제반응과 FeNO를측정하였다. 그이유는천식환자에서기관지확장제반응과 FeNO이수시로변하기때문이다. 4,5,20-22) 본연구에서기관지확장제반응이양성인환자들에서 FEV 1 이 12% 이상증가한경우가평균 20.7% 였으며, 이는천식환자에서기관지확장제반응을확인하기위해서는다수의측정이필요하다는것을시사하는소견이다. 또한 FeNO도연구대상이었던전체환자에서 21 ppb보다높았던비율이평균 57.6% 였으며같은환자에서 FeNO의편차도컸다. 따라서 FeNO로기도염증양상을평가하기위해서는다수의측정이필요하다는것을알수있었다. FeNO의기준을 21 ppb로정한이유는본연구자들의이전의연구 23) 에서 FeNO값이 21 ppb보다클때천식진단에대한민감도와 특이도가가장우수하였기때문이었다. 또한기관지확장제반응과 FeNO 측정은흡입스테로이드의영향을최소화하기위하여흡입스테로이드의사용을중단한후최소 1개월이경과하였을때시행되었다. 특히 FeNO는흡입스테로이드에의해저하되기때문에 24,25) 이와같은조치가반드시필요하다고생각된다. 그리고저자들은연구대상을아토피천식환자로한정하였다. 이는아토피천식환자와비아토피천식환자사이에기관지확장제반응의차이가존재하고 26) 아토피천식환자들에비해비아토피천식환자들에서 FeNO가낮기때문에 23,27,28) 비아토피천식환자들을포함할경우왜곡된결과가도출될수있기때문이다. 기관지확장제반응정도와 %FEV 1, %FEF 25% 75%, FEV 1/FVC 사이에음의상관관계가관찰되어기관지확장제반응으로평가한기도가역성정도가심할수록기도폐쇄가심하다는것을확인할수있었다. 이는기관지확장제반응의크기는기저상태의기도수축정도에의존적이기때문에 29) 당연한결과로생각된다. 같은이유로기관지확장제반응정도와메타콜린 PC 20 값사이의음의상관관계는메타콜린 PC 20 값이낮을수록기저상태의기도수축의정도가더심할가능성을시사하는소견으로생각된다. 본연구에서는기관지확장제반응이최소 1회이상양성이었던소아들은음성이었던소아들에비해천식조절이소실되는비율이유의하게높았으며, 천식조절소실의횟수도많았다. 이는기관지 44

6 박주현외 기관지확장제반응과천식조절및호기 NO 농도사이의연관성 확장제반응이관찰되면더불량한임상경과를보인다는이전의보고 9,30) 와상응하는결과로기관지확장제반응이관찰된환자들은현재증상이없어도주의깊게관찰해야할필요성을제기한다. 그러나기관지확장제반응이양성과음성이었던소아들사이에는 M-FeNO와 R 21FeNO의차이가관찰되지않았다. 이는기관지확장제반응이양성과음성이었던환자들사이에서관찰되었던천식조절상태의차이에기도염증이기여할가능성이크지않다는것을의미한다. 기관지확장제반응과기도염증사이의연관성을보고한이전의연구들을미루어볼때 6-8) 기도염증이기관지확장제반응의상승에기여할것으로생각되나본연구의결과는기도염증을갖고있는모든환자들에서기관지확장제반응의상승이초래되지는않는다는사실을보여준다고생각된다. 또한기도염증을갖고있지만기관지확장제반응이음성인환자들에서는어느수준이상진행된기도개형으로인해기도의유연성이감소하여 FeNO 가높게유지되어도 BDR이나타나지않았을가능성이있을것으로생각된다. 이전의연구에서도스테로이드저항성천식환자에서기관지확장제반응이저하되었으며이는기도개형과연관되어있다고보고되어이를뒷받침한다. 13) 기관지확장제반응이음성이었던환자들의 68% 에서천식조절이소실되어기관지확장제반응이천식조절을결정하는유일한조건이아님을알수있다. 따라서다른조건이존재할가능성이있으며, 저자들은이들환자들중천식조절이소실된환자들과천식조절이유지된환자들사이에 M-FeNO와 R 21FeNO값을비교하였다. 그결과천식조절이소실된환자들에서천식조절이유지된환자들에비해 M-FeNO와 R 21FeNO값이유의하게높아기도가역성증가가관찰되지않았을때천식조절이소실된환자들은천식조절이유지된환자들에비해기도염증이증가되어있다는것을관찰할수있었다. 따라서본연구의결과로미루어볼때기관지확장제반응이양성인환자에비해음성인환자들에서염증성기도폐쇄가천식조절의소실에기여할것으로생각된다. 본연구의제한점은기관지확장제반응을양성으로판정하는기준으로 FEV 1 이 12% 이상상승한경우로한정했다는점이다. 다른연구에서는소아에서기관지확장제반응을양성으로판정하는기준으로더적은 FEV 1 의상승을제시하였으며, 30,31) 이기준으로기관지확장제반응을양성으로판정하면기도가역성이관찰된환자의비율이증가하여결과에영향을미쳤을가능성이있었다고생각된다. 또다른제한점은본연구가 2년이상의기간에걸쳐 FeNO와 BDR의값을측정하였기때문에측정치들의시간적변화를무시하고값들을선정하는오류를범할수있다는것이다. 저자들은이를조금이라도극복하기위해 %predicted value를사용하였으며 R 12B- DR와 R 21FeNO 를구하여최곳값을사용하는데따른오류를최소화하였다. 마지막으로천식조절소실과 FeNO 에대한바이러스호흡기감염의영향을고려하지않았다는점이다. 다만바이러스감 염과알레르겐에대한노출이천식악화에동시에영향을미친다는 이전의보고를고려할때 32,33) 본연구에포함된환자들에서관찰되 었던천식조절소실과 FeNO 상승은바이러스감염과알레르겐에 대한노출모두에영향을받았을가능성이있다고생각된다. 결론적으로기관지확장제반응이양성인환자들에서음성인환 자들에비해상대적으로천식조절이소실될가능성이높았다. 또 한기관지확장제반응이음성인소아들중에서도천식조절의소 실이관찰되었으며, 이들환자들의 FeNO 는천식조절이유지된소 아들에비해 FeNO 가유의하게높아기관지확장제반응이음성이 었던환자들에서기도염증과천식조절소실사이의연관성을확 인할수있었다. REFERENCES 1. Masoli M, Fabian D, Holt S, Beasley R; Global Initiative for Asthma (GINA) Program. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004;59: National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthmasummary report J Allergy Clin Immunol 2007;120(5 Suppl): S American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1991;144: Kerstjens HA, Brand PL, Quanjer PH, van der Bruggen-Bogaarts BA, Koeter GH, Postma DS. Variability of bronchodilator response and effects of inhaled corticosteroid treatment in obstructive airways disease. Dutch CNSLD Study Group. Thorax 1993;48: Crapo RO. Pulmonary-function testing. N Engl J Med 1994;331: Strunk RC, Szefler SJ, Phillips BR, Zeiger RS, Chinchilli VM, Larsen G, et al. Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children. J Allergy Clin Immunol 2003;112: Covar RA, Szefler SJ, Martin RJ, Sundstrom DA, Silkoff PE, Murphy J, et al. Relations between exhaled nitric oxide and measures of disease activity among children with mild-to-moderate asthma. J Pediatr 2003;142: Faul JL, Demers EA, Burke CM, Poulter LW. Alterations in airway inflammation and lung function during corticosteroid therapy for atopic asthma. Chest 2002;121: Sharma S, Litonjua AA, Tantisira KG, Fuhlbrigge AL, Szefler SJ, Strunk RC, et al. Clinical predictors and outcomes of consistent bronchodilator response in the childhood asthma management program. J Allergy Clin Immunol 2008;122:921-8.e Postma DS, de Vries K, Koeter GH, Sluiter HJ. Independent influence of reversibility of air-flow obstruction and nonspecific hyperreactivity on the long-term course of lung function in chronic air-flow obstruction. Am Rev Respir Dis 1986;134: Tantisira KG, Fuhlbrigge AL, Tonascia J, Van Natta M, Zeiger RS, Strunk RC, et al. Bronchodilation and bronchoconstriction: predictors of future lung function in childhood asthma. J Allergy Clin Immunol 2006;117: Fahy JV, Corry DB, Boushey HA. Airway inflammation and remodeling in asthma. Curr Opin Pulm Med 2000;6: Goleva E, Hauk PJ, Boguniewicz J, Martin RJ, Leung DY. Airway remod- 45

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¼Û±âÇõ 223 Table 1. Results of FEV 1.0, Methacholine Challenge Test, and Exercise Provocation Test in Eight Patients Who Performed PFT Pts Tests 1 2 3 4 5 6 7 8 FEV 1.0 (%pred) 66.6 88.8 120 101 90.5 95.4 91.6