대한내과학회지 : 제 74권제6호2008 종 설 (Review) 천식과호흡기질환에서호기산화질소측정 한양대학교의과대학내과학교실 김상헌 윤호주 Use of the exhaled nitric oxide for management of asthma and respiratory diseases Sang-Heon Kim, M.D. and Ho Joo Yoon, M.D. Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea Measurement of fractional exhaled nitric oxide (FeNO) is one of the useful markers for airway inflammation. It detects NO in exhaled breath, which is increased along airway inflammation such as asthma. While there are a few tests assessing airway inflammation in noninvasive manners, FeNO has many advantages in that it can be measured easily and repeatedly in very short time with accuracy. In addition it reflects eosinophilic airway inflammation with significant correlation with eosinophilia in bronchial biopsy and sputum. The use of FeNO is useful in screening and diagnosis of asthma, prediction of steroid response, estimation of treatment response, and assessment of asthma control. Furthermore dose of medication can be titrated based on FeNO. The measurement of FeNO can play complementary role in asthma management along with pulmonary function test and airway hyperresponsiveness. In addition to asthma, FeNO maybe used for diagnosis of chronic obstructive pulmonary disease and chronic cough. With advent of new and cheap NO analyzer in near future, the use of FeNO could be introduced in routine practice of asthma. (Korean J Med 74:579-586, 2008) Key Words : Exhaled nitric oxide; Asthma; Respiratory diseases; Biomarker 서 천식은매우흔한호흡기질환중하나이지만, 진단이그리쉽지않다. 만성적이고반복적인증상을보이지만흔히감기를비롯한다른호흡기질환으로오인하기쉬우며또한천식을의심하더라도일차진료기관에서쉽게진단할수있는방법이부족하다. 흔히기도폐쇄를반영하는폐기능검사와메타콜린등을이용한기관지유발시험을시행하여기도과민성을측정하여진단에도움을받지만, 이러한검사를갖추고있지못하거나, 시행이어려운소아나고령의환자에서는검사하기곤란하다. 천식을진단한후치료할때에도치료가잘되고있는지평가하고, 치료약물을적정 론 화할때에도천식증상외에사용할수있는지표가제한적이어서폐기능검사나기관지과민성의평가에의존하고있다. 천식이만성적인기도염증에의한질환임을고려하여볼때염증을평가할수있는표지자(inflammometer) 가개발되면천식의진단과관리에매우유용하게사용될수있다. 현재까지개발된표지자중임상에서쉽게적용할수있는방법으로호기산화질소 (fractional exhaled NO, FeNO) 의측정은쉽고, 빠르며, 비침습적이라는점에서관심을끌었으며임상에서유용성이입증되어실제천식환자의진료에도적용되기시작하였다. 이글에서는기도염증에서산화질소의발생과역할,FeNO 의측정방법,FeNO측정값에영향을줄수있는요인들을알아보고천식의진단과관리 This work was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Korea (Grant No. 0412-CR03-0704-0001). - 579 -
The Korean Journal of Medicine : Vol. 74, No. 6, 2008 Figure 1. Diagram of a configuration for the breathing circuit for measurement of FeNO 11). C, computer; ER, expiratory resistance; FM, flow meter; IG, inspired gas; MP, mouthpiece; NO-SL, nitric oxide sampling line; PG, pressure gauge; P-SL, pressure sampling line; V, three-way valve. 에서 FeNO의유용성과다른호흡기질환에서 FeNO의사용에대해살펴보기로한다. 기도에서산화질소의역할 NO는인체내에서생성되는내인성조절물질중의하나로정상적인생리과정을담당할뿐아니라, 염증과정에서생성이증가하여급성및만성염증에서도중요한염증매개체이다. NO는 NO synthase (NOS) 에의해합성되는데 neuronal NOS (nnos, NOS1), endothelial NOS (enos, NOS3) 와같은constitutional NOS (cnos) 와inducible NOS (inos, NOS2) 등의동형이있다 1). 평상시에는주로 enos, nnos 등에의해비교적일정하게소량의 NO가합성되어기도평활근이완등의생리학적인역할을한다. 반면염증과정에서는 tumor necrosis factor-α, interleukin-1β, interferon-γ 등과같은염증사이토카인에의하여기도상피세포등에서 enos의발현이증가하여많은량의 NO가생성되게된다 2). 이렇게증가한 NO는 DNA 합성을저해하여종양세포를죽이거나, 바이러스의성장을억제하고, 세균과곰팡이의증 - 식을억제하는기능이있으며, superoxide anion (O 3 ) 등과결합하여 peroxinitrite anion (ONOO - ) 를형성하여세포독성물질로작용하게되어염증을악화시킨다 3). 천식과같은기도염증에서호산구, 대식세포, 비만세포, T 세포등의기도 유입등과염증매개체및사이토카인이증가하게되는데, 이과정에서 NO의합성이많아져서 FeNO 가증가하게된다. 염증표지자로서 FeNO 위에서살펴본것처럼 FeNO는기도염증에서생성이증가하므로기도염증정도를반영하는지표로서유용성이크다. 특히호산구성염증과높은관련이있는데, 천식환자의유도객담 4) 과기도점막생검 5), 기관지폐포세척액 6) 에서측정한호산구수또는 eosinophil cationic protein과같은호산구활성화지표와유의한상관관계를보였다. 반면중증천식이나천식악화에서보이는중성구증가와의연관성은뚜렷하지않다. FeNO 의측정방법과표준화 1991년정상인에서도호기에서 NO를측정할수있고특히천식환자의호기산화질소농도가정상인에비해높다는것이보고되면서 8) 호기산화질소측정의호흡기질환의임상진료에서유용성에대하여연구가뒤따랐다. 호기 NO는오존과반응하여발생하는화학발광을통해측정하며 ppb (part per billion) 단위로측정된다. 여러 NO 측정기 (NO analyzer) 가개발되었으나대부분연구목적의사용에그친경우가많았고, 국내에서도현재대부분연구목적으 7), - 580 -
Sang-Heon Kim, et al : Use of the exhaled nitric oxide for management of asthma and respiratory diseases 로사용되고있다. 현재유일하게스웨덴의 Aerocrine사에서개발한제품 (NIOX ) 이미국 FDA에서천식환자의진료에승인을받아사용되고있다 9). 또한크기를줄인휴대형 NO 측정기(NIOX MINO ) 도개발되어임상진료현장에서쉽게사용할수있으며, 환자가자가로평가하는것도가능해졌다 10). 측정방법에따라온라인과오프라인측정방법으로분류하여볼수있는데온라인방법은실시간으로측정기에연결된관을통해호기한공기를전달하여측정하는방법이고( 그림 1), 오프라인방법은저장백에호기가스를담은후, 나중에측정기에연결하여측정하는방법을의미한다. 측정방법은폐기능검사와유사하다. 마우스피스를통해총폐용적(total lung capacity) 까지공기를들이마신후, 주저없이호기를시작하는데폐기능검사때와의차이는호기유속을일정하게유지하여야한다는점이다. 호기과정에서폐포의공기가기도를통해체외로이동하는데, 이과정에서기도에높은농도로존재하는 NO가확산에의해기도내강으로이동하여호기중 NO 의농도가증가하게된다. 따라서호기속도가빠르면확산에의한 NO증가가제한되므로속도가느릴때에비하여 FeNO 가낮게측정된다. 천식, 바이러스감염과같이기도염증이지속되는경우에는기도상피에 inos 발현이증가되어 NO 생성이증가하고호기중 FeNO가 2 3 배증가된다. 이에따라측정값을비교할때에는유속을동일하게한조건에서측정하였는지확인하는것이필요하며, 미국흉부학회와유럽호흡기학회지침에서 11, 는유속을0.05 L/sec으로측정할것을권장하고있다 12). 그런데천식등의기도염증뿐아니라바이러스감염과같은기도감염, 알레르기비염이나만성부비동염과같은상기도의염증에서는비강내 NO 의농도가매우높아진다. 따라서측정과정중에비강 NO에의한오염과영향을최소화하는것이필요하다. 이를위해서호기할때인위적으로저항을두어호기압력을어느정도높게하여구강덮개 (velum) 이닫혀서비강과구강이서로통하지않게한다. 압력이너무높을때에는검사자에게불편을초래할수있으므로,5 10 cm H 2 O 정도에서유지되도록하는데, 검사할때에모니터를통해나타나는압력을모니터링하면서호기압을조절할수있다. 또한대기중의 NO 농도가너무높으면검사에영향을줄수있으므로,NO가포함되지않은공기를들이마신후에호기하여측정하는것이권장된다. 상추와같이질산염이많이포함된음식을먹고검사를하면측정값에영향을줄수있으므로주의하여야한다. 폐기능 검사와함께시행하는경우에서는폐기능검사가측정값을낮출수있으므로, 폐기능검사보다먼저측정하도록한다. 위와같이측정방법과검사전여러요인들이검사값에영향을줄수있으므로측정방법표준화의필요성이제기되었고현재 2005년에발행된미국흉부학회와유럽호흡기학회지침 11) 을통해권장사항이발표된바있으며, 이후의대부분의연구들은이에따라측정한값을보고하고있다. FeNO 측정의장점과제한점 그러나지금까지기도염증을평가하기위해개발된방법들은유도객담검사, 기관지생검또는기관지폐포세척액검사, 소변내류코트리엔측정등의방법이있다. 이중유도객담검사는객담내염증세포의수와종류를측정하는방법이며, 주로호산구의분율을계산하여호산구성염증의유무와중증도를평가하는데이용되었다. 비침습적이긴하지만, 객담유도과정중에기관지폐색을초래할수있고, 객담채취와객담처리에시간과인력이많이소요되므로일상적인천식진료에포함시키기에는제한점이크다. 기관지생검은가장직접적인검사방법이기는하지만침습적이라는점에서마찬가지로제한적이다. 소변내류코트리엔측정방법역시표준화가되어있지않고모든검사실에서시행하기에어려움이있다.FeNO측정의가장큰장점은어느검사보다비침습적이며, 재현성있는결과를수분이내에얻을수있다는것이다. 이러한장점때문에임상에도입하기에가장적절한후보로관심을끌었고, 임상적인적용에대한가치가평가되었다. 제한점으로는아직은구입비용이비싸서일차진료를포함한진료현장에보급하기어렵다. 호기압과호기속도등을일정하게하여야하므로폐기능검사의시행이어려운소아나고령의환자에서시행하기어렵고, 검사의표준화가아직미비하여여러검사기관의검사치를비교하기에는제한적이다. 검사에영향을주는요인이많고, 폐기능이나중증도와같은다른임상지표와의연관성이다소떨어진다는것등이있다. 정상인에서 FeNO 참고값 천식등호흡기질환에서의값과비교하기위한정상인에서 FeNO 참고값에대해서소아와성인으로대상을나누어보고되고있는데 5.3부터 36.9 ppb까지다양한값이보고되었다. 일반적으로소아에서는 5-20 ppb, 성인에서는 5-25 ppb 가정상값으로제시되고있으며소아가성인보다 다소낮게나타나고있다. 정상값이이와같이일치하지않 - 581 -
대한내과학회지 : 제 74권제6호통권제574 호 2008 Table 1. FeNO in respiratory diseases 46) Table 2. Usefulness of FeNO measurement in asthma Change in FeNO Increased Decreased Variable Diseases asthma allergic rhinitis viral infection hepatopulmonary syndrome pulmonary hypertension ARDS cystic fibrosis bronchiectasis COPD systemic sclerosis sarcoidosis Screening and correct diagnosis Prediction of steroid response Estimation of treatment response Assessment of asthma control Detection of asthma flare Monitoring adherence Tailored medication of inhaled corticosteroid 을수있으며, 우리나라정상성인과소아를대상으로하는정상값에대한연구가필요함을시사한다. 천식에서 FeNO 측정 고편차가크게나타나는이유는측정방법과측정대상선정방법에따른대상군의차이때문으로보인다. 즉보고자에따라서로다른측정기계를사용하였고, 호기속도등측정에영향을미칠수있는호기속도등의측정방법이통일되지않았으며, 각연구마다대상연령이달랐으며흡연및비염, 최근호흡기감염여부등에대한대상및제외기준이통일되지않았다.FeNO값은호흡기질환이없는정상인에서도개인에따라다를수있는데, 이러한 FeNO값에영향을줄수있는인자에는성별, 연령, 키, 몸무게등이있으며, 흡연여부, 신체질량지수(body mass index), 아토피여부등의연관성도보고되고있다. 소아와성인모두에서연령이증가할수록, 여자보다남자에서키가크거나몸무게가많을수록높은 FeNO값을보였으나유의성은대상에따라차이가있다. 또한아토피가있는경우에는호흡기증상이없더라도 FeNO 가높게나타났으며, 흡연자에서는 FeNO 값이낮은경향을보이고있다. 흡연으로인하여 FeNO값이왜낮아지는지에대한기전은명확히알려져있지않으나, 담배연기자체가 inos의작용을억제하는효과때문으로생각된다 13). 특히최근에는인종에따른 FeNO 정상값의차이가보고되고있는데,11 18세소아와청소년을대상으로한홍콩의연구에의하면백인에비하여중국인에서유의하게높은중앙값을보였다 14). 캐나다에서 9 12세건강한소아를대상으로한연구에서도아시아계소아가백인소아에비하여높은값을보였다 15). 또한우리나라 23 32세의젊은성인 56명을대상으로한연구에서도 16) 평균값이 28.6 ppb 정도로비교적높게보고되었다. 이러한결과들은성인에서도인종에따른측정값의차이가있 여러호흡기질환과전신질환에서 FeNO값의증가또는감소가확인되고있으나아직까지증감이명확하지않은경우도있다( 표 1). 여러질환중에서도 FeNO 측정은천식의진단과관리에가장연구가활발하였고, 현재임상진료에도입되어사용되고있다. 천식은만성적인알레르기성기도염증으로인한질환으로천식환자스크리닝과정확한진단치료반응의예측과평가와약물용량결정등에실제적용이가능하다( 표 2). 1. 천식의진단 천식환자에서천식진단의도구로서 FeNO가높다는것이처음알려지면서 8), FeNO의유용성에대한연구가잇따 랐다. 보고자에따라조금씩차이를보이지만, 천식환자의 FeNO는정상대조군에비하여약1.6 7.5배까지높은값을보이고있다. 또한천식을진단하기위한 cut-off 값역시대상자의연령과수, 측정방법, 천식진단기준등연구대상과방법에따라다양하게제시되고있으며(8-20 ppb), 아직까지는천식진단을위한 cut-off 값이확정되지못하고있다. 천식진단의유용성을폐기능검사, 유도객담, 최대호기유속등다른진단방법과비교할때에도우수하거나비슷한정도의진단적민감도와특이도가보고되고있으며, 폐기능검사와함께진단에사용하였을때에는더높은진단적가치를지니는것으로알려지고있다 17). 이와같이우수한진단적가치에도불구하고천식의진단에널리이용되지못하고있는데, 이러한이유로기관지과민성등다른방법으로확진된천식환자중에서일부는정상적인 FeNO 값을보이고있다는점이다. 정상적인또는낮은 FeNO 값을보이는천식환자가존재한다는것은천식이단순한질환 - 582 -
김상헌외 1 인 : 천식과호흡기질환에서호기산화질소측정 이라기보다는다양성을지닌질환이라는측면에기인하고있다. 천식은아토피여부, 폐기능, 중증도, 기관지과민성, 악화빈도등여러천식의표현형이혼재되어나타나는질환이다. 현재까지의보고를살펴보면천식환자중에서아 18, 19) 토피성천식, 호산구성염증 4) 이심한천식에서각각그렇지않은경우보다높은 FeNO 값을보인다. 반면에메타콜린에대한기관지과민성의정도 20) 21), 폐기능검사, 중증도와조절정도 22) 등천식의다른표현형과는상관관계가보고된바있으나, 그렇지않다는보고도있어이들표현형과의상관관계는약한것으로보인다. 특히기도염증을반영하는 FeNO와기도수축을주로반영하는 FEV1 의상관관계가없다는점은천식의병태생리학적두측면을하나의지표로평가하는것의한계를보여준다 23). 천식의표현형외에도현재흡연하고있는경우에서는그렇지않은천식환자에비해 FeNO 값이낮게나올수있다. 결론적으로천식환자에서는정상인보다높은 FeNO를보이고진단적가치가있지만,FeNO 만으로천식을배제하기는어려우며, 기관지과민성과폐기능검사등다른진단방법에보조적인역할을해야할것으로보인다. 그리고낮은 FeNO를보이는경우는중성구성염증을보이는천식, 비아토피성천식, 흡연등의가능성을생각해볼수있다. 2. 치료반응의예측과평가 천식의주된치료제인흡입스테로이드로치료를하면대부분의환자에서기도염증과함께천식증상의호전을보이지만환자에따라치료에대한반응에차이를보일수있다. 치료에반응이좋은환자들에서치료전 FeNO가높다는결과들이있으며, 이는흡입스테로이드에반응할환자 24, 25) 를선별하는데 FeNO가유용함을보여준다. 또한흡입스테로이드를사용하여치료반응을평가할때폐기능검사에서 FEV1이호전되는것보다먼저 FeNO가감소한다고알려져서, 치료에대한반응을조기에평가할수있는민감한지표로사용할수있다 26). 흡입스테로이드뿐아니라류코트리엔수용체길항제로치료할때에도 FeNO를치료반응을평가에사용할수있다 27). 최근개정된 GINA 치료지침과 Expert Panel Report 3에서는천식환자에서조절정도를평가하여이에따라치료단계를선택하도록권장하고있다. 또한천식조절수준은증상의빈도, 활동의제한, 증상완화제의사용빈도, 악화빈도를고려하고폐기능검사를시행하여 FEV1 의예측치% 값을참고하여판단하도록하고있다. 이러한조절정도의평가는위와같은여러측면을고려 해야하므로쉽지않아, Asthma Control Test, Asthma Control Questionnaire 등과같은검증된설문문항을사용하기도한다. 천식의조절이잘되지않은환자에서 FeNO가높았고 28), 치료중인환자에서 FeNO의변화가천식조절에이르거나, 조절이악화되는것을반영한다는알려졌다 29). 또한 FeNO 측정으로천식이악화되는것을조기에확인하거나 30), 치료순응도를평가하는데에도유용성이확인되고있다. 이와같은결과들은천식의치료반응과조절정도를평가할때FeNO 의유용성을보여주고있으나, 집단이아닌개별환자에서천식조절을반영하는평가지표로서는제한적일수있다. 3. FeNO 측정을이용한약물용량결정 FeNO가기도염증정도를반영하는표지자라는측면에서, 천식을관리하고흡입스테로이드를처방할때 FeNO를측정하여이를바탕으로흡입스테로이드의용량을결정하는치료방법의유용성은큰관심사항이었다. 이전에도또하나의염증지표인유도객담호산구분율을바탕으로흡입스테로이드를조절하는천식관리방법의유용성에대한연구가있었는데, 이러한접근방법으로천식급성악화의빈도를낮출수있었다 31, 32). 이와는달리 FeNO를바탕으로한천식관리는소아와성인모두에서기존의방법과비교하여천식악화를예방하는데유의한차이를보이지못하였다 33-35).Smith 등의연구에서는이러한전략이사용하는흡입스테로이드전체용량을낮출수있는장점이보고되었지만 34), 이후의연구에서는이러한결과도확인할수없었다 33, 35). 올해출간된 Cochrane review에서는 4건의무작위대조군연구에대해메타분석을시행하였고,FeNO에근거한맞춤치료전량의효과가매우작고, 불명확하다고평가하였다 36). 이러한다소실망스런결과가나온이후에이들연구에서용량을내리거나, 유지하거나, 올리는기준이되는 cut-off 값이적절하였는지, 대상이경증-중등증환자를주로포함한것이어서결과를중증천식환자를포함한전체천식환자에적용이가능한지등의문제가제기되었다 37). 또한 FeNO 가염증을반영한다고하지만, inos 발현증가와관련된염증의한부분만을반영하는것이어서천식의전체염증과정을대변하기에는한계가있을수있다. 만성폐쇄성폐질환 (COPD) 에서 FeNO 측정 천식에서 FeNO 가증가한다는것은명백하지만, COPD에서 FeNO 의증감여부는아직도명확하지않다. 몇몇연구에서는 - 583 -
The Korean Journal of Medicine : Vol. 74, No. 6, 2008 38, COPD환자들에서정상인에비해높은 FeNO를보이며 39), 천식보다는 FeNO 값이낮지만폐기능과유의한상관관계를보인다고하였다 40). 이와는달리다른연구에서는 COPD 환자 41, 42) 의FeNO는정상인과차이를확인할수없었다. 우리나라 COPD 환자를대상으로한연구에서는 COPD 환자에서높은 FeNO 를보였으나, 천식환자보다는낮았고, 폐기능과유의한상관관계는없었다 43). 이와같이서로상이한결과들이나오고있는것은 COPD 가단일한특성을가진질환이라기보다는다양한표현형을아우르는질환이라는질병특성에기인한다. 즉 COPD 환자중에서호산구성염증이높은환자에서는높은 FeNO 를나타내었을수있다. 그리고연구마다 COPD 대상군의정의가서로다른것도이러한상반된결과의한설명일수있는데, 대상기준을엄격하게적용하더라도대상자중에천식환자가어느정도포함되어있을수있어, 천식환자의높은FeNO가얼마나반영되었는가가큰변수일수있다. 또한대상자중에현재흡연자가얼마나포함되어있었는가에따라서도흡연으로인한 FeNO 저하가반영되는정도가차이가있었을것으로보인다.COPD 환자에서스테로이드사용후폐기능의호전정도와치료전 FeNO가높은상관관계를보인다는보고도있는데, 이러한결과는천식에서높은 FeNO가스테로이드반응을예측하는데도움이되는것처럼,COPD에서도치료반응을평가하고예측하는데 FeNO 측정의유용성을제시하고있다. 결론적으로 COPD의진단과관리에서 FeNO 측정의유용성은아직확립되어있지않으며추가적인연구가필요하다. FeNO 측정을이용한만성기침의진단 현재가이드라인에따르면만성기침환자의진료에서후비루증후군( 혹은상기도기침증후군), 기침이형천식, 위식도역류질환등흔한원인질환에대해필요한검사를시행하거나, 각질환에대해단계적으로경험적인치료를하여호전되는지확인하여원인질환을확인하는방법이흔히사용된다 44). 원인질환을확인하는뚜렷한진단방법이없는상황에서 FeNO를측정하여원인질환을추정하고치료방침을결정하는데도움을받을수있다. Chatkin 등은 3주이상의만성기침환자에서기침이형천식의경우에다른원인에 45) 의한경우보다높은 FeNO를보였다.FeNO가주로하기도호산구성염증과깊은상관관계가있음을고려하면, 만성기침환자에서천식과호산구성기관지염을진단하는데유용할수있다. 또한만성기침환자의접근에서흡입스테 로이드를투여할환자를선택할때메타콜린기관지유발검사를대체하거나보완적인역할을할수있는지에대한추가적인연구가필요하다. 결 FeNO의측정은기도염증을평가하는비침습적인염증표지자로, 측정이쉽고, 빠르며, 재현성이높은장점을가지고있다. 여러호흡기질환중에서도현재천식의진단과관리에서가장유용하게사용되고있으며, 천식환자의스크리닝과정확한진단, 치료반응의예측과평가, 천식조절또는악화의예측, 흡입스테로이드와같은치료약물의적정화등에도움이된다. 널리임상에보급되기위해서는측정장비의기술개발을통해보다저렴하고측정이용이해져야한다.FeNO가기도염증의지표로서의한계를넘어서기위해서는치료반응과조절의평가에폐기능검사나기도과민성등의다른지표와함께측정하여평가할수있는방법이개발되는것이필요하다. 또한천식외에 COPD, 만성기침을비롯한다른호흡기질환에서사용되기위해서는임상적유용성에대한연구가뒤따라야할것이다. 중심단어 : 호기산화질소; 천식; 호흡기질환; 생화학적지표 론 REFERENCES 1) Forstermann U, Schmidt HH, Pollock JS, Sheng H, Mitchell JA, Warner TD, Nakane M, Murad F. Isoforms of nitric oxide synthase. Characterization and purification from different cell types. Biochem Pharmacol 42:1849-1857, 1991 2) Morris SM, Jr., Billiar TR. New insights into the regulation of inducible nitric oxide synthesis. Am J Physiol 266:E829-839, 1994 3) Radi R, Beckman JS, Bush KM, Freeman BA. Peroxynitriteinduced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys 288: 481-487, 1991 4) Jatakanon A, Lim S, Kharitonov SA, Chung KF, Barnes PJ. Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax 53:91-95, 1998 5) Payne DN, Adcock IM, Wilson NM, Oates T, Scallan M, Bush A. Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in children with difficult asthma, after treatment with oral prednisolone. Am J Respir Crit Care Med 164:1376-1381, 2001 6) Warke TJ, Fitch PS, Brown V, Taylor R, Lyons JD, Ennis M, - 584 -
Sang-Heon Kim, et al : Use of the exhaled nitric oxide for management of asthma and respiratory diseases Shields MD. Exhaled nitric oxide correlates with airway eosinophils in childhood asthma. Thorax 57:383-387, 2002 7) Gustafsson LE, Leone AM, Persson MG, Wiklund NP, Moncada S. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun 181:852-857, 1991 8) Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 6:1368-1370, 1993 9) Silkoff PE, Carlson M, Bourke T, Katial R, Ogren E, Szefler SJ. The Aerocrine exhaled nitric oxide monitoring system NIOX is cleared by the US Food and Drug Administration for monitoring therapy in asthma. J Allergy Clin Immunol 114:1241-1256, 2004 10) Alving K, Janson C, Nordvall L. Performance of a new hand-held device for exhaled nitric oxide measurement in adults and children. Respir Res 7:67, 2006 11) ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 171:912-930, 2005 12) Recommendations for standardized procedures for the on-line and off-line measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children-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 160:2104-2117, 1999 13) Hoyt JC, Robbins RA, Habib M, Springall DR, Buttery LD, Polak JM, Barnes PJ. Cigarette smoke decreases inducible nitric oxide synthase in lung epithelial cells. Exp Lung Res 29:17-28, 2003 14) Wong GW, Liu EK, Leung TF, Yung E, Ko FW, Hui DS, Fok TF, Lai CK. High levels and gender difference of exhaled nitric oxide in Chinese schoolchildren. Clin Exp Allergy 35:889-893, 2005 15) Kovesi T, Kulka R, Dales R. Exhaled nitric oxide concentration is affected by age, height, and race in healthy 9- to 12-year-old children. Chest 133:169-175, 2008 16) 김상헌, 김태형, 손장원, 윤호주, 신동호, 박성수. Reference values of the fraction of nitric oxide in exhaled breath from healthy young adults in Korea. 대한내과학회지 73 suppl(1): 86, 2007 17) Smith AD, Cowan JO, Filsell S, McLachlan C, Monti- Sheehan G, Jackson P, Taylor DR. Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. Am J Respir Crit Care Med 169:473-478, 2004 18) Gratziou C, Lignos M, Dassiou M, Roussos C. Influence of atopy on exhaled nitric oxide in patients with stable asthma and rhinitis. Eur Respir J 14:897-901, 1999 19)ChngSY,VanBeverHP,LianD,LeeSX,XuXN,Wang XS, Goh DY. Relationship between exhaled nitric oxide and atopy in Asian young adults. Respirology 10:40-45, 2005 20) Dupont LJ, Rochette F, Demedts MG, Verleden GM. Exhaled nitric oxide correlates with airway hyperresponsiveness in steroid-naive patients with mild asthma. Am J Respir Crit Care Med 157:894-898, 1998 21) Sippel JM, Holden WE, Tilles SA, O'Hollaren M, Cook J, Thukkani N, Priest J, Nelson B, Osborne ML. Exhaled nitric oxide levels correlate with measures of disease control in asthma. J Allergy Clin Immunol 106:645-650, 2000 22) Delgado-Corcoran C, Kissoon N, Murphy SP, Duckworth LJ. Exhaled nitric oxide reflects asthma severity and asthma control. Pediatr Crit Care Med 5:48-52, 2004 23) Stirling RG, Kharitonov SA, Campbell D, Robinson DS, Durham SR, Chung KF, Barnes PJ. Increase in exhaled nitric oxide levels in patients with difficult asthma and correlation with symptoms and disease severity despite treatment with oral and inhaled corticosteroids. Asthma and Allergy Group. Thorax 53:1030-1034, 1998 24) Little SA, Chalmers GW, MacLeod KJ, McSharry C, Thomson NC. Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma. Thorax 55:232-234, 2000 25) Gelb AF, Flynn Taylor C, Shinar CM, Gutierrez C, Zamel N. Role of spirometry and exhaled nitric oxide to predict exacerbations in treated asthmatics. Chest 129:1492-1499, 2006 26) Piacentini GL, Bodini A, Costella S, Vicentini L, Peroni D, Zanolla L, Boner AL. Allergen avoidance is associated with a fall in exhaled nitric oxide in asthmatic children. J Allergy Clin Immunol 104:1323-1324, 1999 27) Bisgaard H, Loland L, Oj JA. NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast. Am J Respir Crit Care Med 160:1227-1231, 1999 28) Meyts I, Proesmans M, De Boeck K. Exhaled nitric oxide corresponds with office evaluation of asthma control. Pediatr Pulmonol 36:283-289, 2003 29) Michils A, Baldassarre S, Van Muylem A. Exhaled nitric oxide and asthma control: a longitudinal study in unselected patients. Eur Respir J 31:539-546, 2008 30) Jones SL, Kittelson J, Cowan JO, Flannery EM, Hancox RJ, McLachlan CR, Taylor DR. The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 164:738-743, 2001 31) Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. - 585 -
대한내과학회지 : 제 74권제6호통권제574 호 2008 Thorax 57:875-879, 2002 32) Zacharasiewicz A, Wilson N, Lex C, Erin EM, Li AM, Hansel T, Khan M, Bush A. Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children. Am J Respir Crit Care Med 171:1077-1082, 2005 33) Shaw DE, Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ, Pavord ID. The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. Am J Respir Crit Care Med 176:231-237, 2007 34) Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 352:2163-2173, 2005 35) Pijnenburg MW, Bakker EM, Hop WC, De Jongste JC. Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial. Am J Respir Crit Care Med 172:831-836, 2005 36) Petsky HL, Cates CJ, Li AM, Kynaston JA, Turner C, Chang AB. Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev:CD006340, 2008 37) Deykin A. Targeting biologic markers in asthma--is exhaled nitric oxide the bull's-eye? N Engl J Med 352:2233-2235, 2005 38) Maziak W, Loukides S, Culpitt S, Sullivan P, Kharitonov SA, Barnes PJ. Exhaled nitric oxide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 157:998-1002, 1998 39) Corradi M, Majori M, Cacciani GC, Consigli GF, de'munari E, Pesci A. Increased exhaled nitric oxide in patients with stable chronic obstructive pulmonary disease. Thorax 54:572-575, 1999 40) Ansarin K, Chatkin JM, Ferreira IM, Gutierrez CA, Zamel N, Chapman KR. Exhaled nitric oxide in chronic obstructive pulmonary disease: relationship to pulmonary function. Eur Respir J 17:934-938, 2001 41) Rutgers SR, van der Mark TW, Coers W, Moshage H, Timens W, Kauffman HF, Koeter GH, Postma DS. Markers of nitric oxide metabolism in sputum and exhaled air are not increased in chronic obstructive pulmonary disease. Thorax 54:576-580, 1999 42) Clini E, Bianchi L, Vitacca M, Porta R, Foglio K, Ambrosino N. Exhaled nitric oxide and exercise in stable COPD patients. Chest 117:702-707, 2000 43) 김태형김상헌손장원윤호주신동호박성수만성폐,,,,,. 쇄성폐질환환자에서호기산화질소의측정. Tuberculosis and Respiratory Diseases 63 suppl(2):31, 2007 44) Morice AH, Fontana GA, Sovijarvi AR, Pistolesi M, Chung KF, Widdicombe J, O'Connell F, Geppetti P, Gronke L, De Jongste J, Belvisi M, Dicpinigaitis P, Fischer A, McGarvey L, Fokkens WJ, Kastelik J. The diagnosis and management of chronic cough. Eur Respir J 24:481-492, 2004 45) Chatkin JM, Ansarin K, Silkoff PE, McClean P, Gutierrez C, Zamel N, Chapman KR. Exhaled nitric oxide as a noninvasive assessment of chronic cough. Am J Respir Crit Care Med 159:1810-1813, 1999 46) Taylor DR, Pijnenburg MW, Smith AD, De Jongste JC. Exhaled nitric oxide measurements: clinical application and interpretation. Thorax 61:817-827, - 586 -