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1 대한내과학회지 : 제 69 권제 5 호 2005 종 설 어려운천식 이화여자대학교의과대학내과학교실 조영주 =Abstract= Five ten per cent of asthmatics remain symptomatic despite high-dose treatment. Difficult asthma must be distinguished from severe asthma. Difficult asthma was defined as persistence of symptoms despite treatment at step wise recommended. It is then important in patients with suspected difficult asthma to ensure that the diagnosis is correct, and that if the patient has asthma that the attributed symptoms are indeed all genuinely due to the asthma and not to coexisting physical or psychogenic respiratory conditions. It is also important to be alert to recognize both poor perceivers and over-reactors. Asthma may be difficult for the patient, for the clinician or both because of disease factors, doctor or nurse therapist factors, and/or patient factors. Investigation requires access to the full range of respiratory, imaging and allergy tests. There remains a small number of patients with genuine steroid-resistant asthma, brittle asthma and asthma with airway remodeling. The anti-inflammatory effects of GCs are mediated through receptors that modulate inflammatory gene expression. GC resistance results from an interaction between susceptibility genes, the host's environment, and immunologic factors. The management of these patients requires a systematic approach to rule out underlying conditions that lead to GC resistance or treatment failure, as well as the use of alternative strategies to inhibit tissue inflammation. Key Words : Difficult asthma steroid resistant asthma, Airway remodeling 서 론 정의및분류 천식은중증도의정도가다양하며한환자에게서도 매우다양한경과를취한다. 천식은비교적꾸준하게단 계에맞는치료를지속하면잘조절되는질환이나 5~ 10% 정도의환자는일상생활에지장을줄정도로심하 거나, 전신적인스테로이드투여없이는잘조절되지않 는다 1-3). Difficult asthma 는우리말로도적절하게정의 하기는어려우나난치성천식, 혹은어려운천식으로해 석할수있겠다. 어려운천식은중증의천식과혼동해서 쓰이기도하지만, 확실하게구분지어져야한다 4-7). 본문에서는어려운천식와중증천식과의구분, 어려 운천식의대표적인형태인스테로이드저항성천식을 최신소개된보고들을중심으로소개하고자한다. British Thoracic Society/Scottish Intercollegiate Guideline s Network (BTS/SIGN) 지침서에서의중증천식은 천식발작으로입원한병력이있거나, 4단계 -5단계중증 8) (step 4, step 5) 으로정의하고있다. 4단계의천식은고 농도의스테로이드흡입제와지속형베타 2 항진제에류 코트리엔조절제나혹은테오필린, 기관지확장제를추가 해야하는정도의천식이고, 5 단계는간헐적으로자주, 혹은지속적으로전신적인스테로이드를사용해야하는 경우로정의하였다. 어려운천식은중증천식의상태에서 기대했던치료결과를얻지못하거나예상이외의반응을 보이는경우로정의하였다. 즉천식으로진단받은상태 에서환자의증상이나폐기능의호전이잘되지않는

2 - Young Joo Cho : Difficult asthma - Table 1. Refractory asthma Major Characteristics In order to achieve control to a level of mildmoderate persistent asthma: 1. Treatment with continuous or near continuous (> 50% of year) oral corticosteroids (CS) 2. Requirement for treatment with high-dose inhaled CS Minor Characteristics 1. Requirement for daily treatment with a controller medication in additionto inhaled CS, e.g., long-acting β-agonist, theophylline, or leukotriene antagonist 2. Asthma symptoms requiring short-acting β-agonist use on a daily or near daily basis 3. Persistent airway obstruction (FEV1<80% pred.; diurnal PEF variability >20%) 4. One or more urgent care visits for asthma per year 5. Three or more oral steroid bursts per year 6. Prompt deterioration with 25% 7. Near fatal asthma event in the past reduction in oral or inhaled CS dose * Requires that other conditions have been excluded, exacerbating factors treated, and patient felt to be generally adherent. Definition of refractory asthma requires one or both major criteria and two minor criteria. From Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med 162: , 2000 Table 2. Diagnoses in patients without asthma Chronic obstructive pulmonary disease 6 Emphysema ( 1-antitrypsin deficient) 1 Cystic fibrosis 1 Cardiomyopathy 1 Obliterative bronchiolitis 1 Respiratory muscle incoordination 1 Severe anxiety and vocal cord dysfunction From Harrison, B. D. W. et al: Internal Medicine Journal 35(9), , 2005 경우라하겠다. 이는미국의 GINA 가이드라인에서중증 천식 4단계천식을보다좀더세분화한정의이기도하다 또한어려운천식은 refractory asthma, steroid resis- tant asthma 등으로혼용해서사용되기도하는데미국 폐흉부협회 10) 에서는치료에잘반응하지않는여러가지 천식유형을포함하는천식의표현형을 refractory asthma ( 표 1) 로정의하였다. 미국흉부학회의 refractory asthma 도결국영국가이드라인의제 5단계와어려운천 식이일부혼합된형태라고하겠다. Robinson 등 11) 이 100명의어려운천식으로분류된환 자의원인을분석하였다 ( 그림 1). 어려운천식중에는실 제천식으로잘못진단된경우도많아보고에따라 12% 정도가잘못진단된경우라고하였다. 9). 또한중요한문제는천식환자에게같이존재하는기 질적호흡기질환즉, 만성폐쇄성폐질환 ( 이하 COPD), 기 관지확장증, 과호흡증, 성대이상이다. 천식환자의 11~ 16% 가 COPD 와기관지확장증이있다고보고되었으며, 13~16% 는과호흡증과성대이상이병합해있다고보고 되었다( 표 2). 다음고려해야하는사항은환자의증상과폐기능과 의불일치문제이다 12, 13) 어떤. 환자는실제의상태보다 훨씬경하게증상을감지하여이런환자들은대부분느 끼는증상이적기때문에약제복용을제대로안하는경 우가빈번하며, 심한발작, 경우에따라서는치명적인상 태로병원에오게되는위험이있다. 이에반하여과하 게감지하는환자는약물의과복용으로인한부작용과 정신적인스트레스로문제가된다. 이러한여러문제들 을감안할때광범위한의미의어려운천식은경한천 식에서부터중증의천식까지모든단계의환자에게도 적용될수있겠다. 만약천식진단이확실하고, 다른호 흡기질환이없는순순한의미의어려운천식은다음의 3 가지군으로분리할수있다 6, 14). 1) Brittle asthma, 스테로이드 -저항성천식과같은 질환적인요인. 2) 의료진요인예를들면경험이나지식의결여로적 절한상태분석및치료를못하는경우. 3) 환자요인, 순응도가낮거나, 행동학적, 성격적, 사

3 - 대한내과학회지 : 제 69 권제 5 호통권제 543 호 Figure 2. Peak flow chart in a patient with type 1brittle asthma before ( ) and after ( ) treatment with continuous subcutaneous terbutaline. (from Ayres et al Thorax, 1998) Figure 1. Flow chart showing numbers of patients in each category. All 75 patients thought to have asthma were assessed for ear, nose and throat (ENT) disease, atopy history of aspirin sensitivity and additional diagnoses. Prednisolone levels were measured in patients taking oral prednisolone and were judged as a useful measure of nonadherence if serum prednisolone was undetectable or serum cortisol was normal in patients prescribed 15 mg day1. PEF, peak expiratory flow; FEV1, forced expiratory volume in one second; GHQ 30, General Health Questionnaire; PHT, pulmonary hypertension; EAA, extrinsic allergic alveolitis. (From D.S. Robinson et al Eur Respir J 22: , 2003). 회적정신적인문제. 따라서어려운천식환자는표 3에서보였듯이아주 정밀한진단, 분석및평가를해야한다. 이중다른요 인을모두제외한순순한의미의어려운천식은질환적 인요인에의한것으로이에대하여조금자세히언급하 면다음과같다. 1. Brittle asthma 질환적요인 Brittle asthma 는용어는 1977 년도에고용량의스테 로이드사용에도불구하고최대호기속도 (peak expiratory flow: PEF) 의변화가매우심한천식의형태로처 음소개되었다 15). 현재두가지의형태로나누고있는데 Kd Normal 제 1형은일중 PEF의변화가 40% 이상인날이 150일중 50% 이상인형태이고, 제2형은잘조절되던천식이별 특별한이유없이 3시간이내에급격히악화되는형태이 다. 제2형보다는제1 형이흔하고보고가많은데, 주요위 험요인으로 1) 아토피 2) 면역부전 3) 음식에대한불내 성 4) 정신적요인 5) 질환의감지능력저하이다. Brittle asthma 의경우진단자체가매우힘들어전체천식환자의 0.05% 로보고되는매우드문형태이지만, 고용량의흡입 스테로이드를사용함에도불구하고 PEF의변화의범위 가매우넓은환자로중증의환자중제일어려운환자 라고한바있다. 이환자들은스테로이드보다오히려 기관지확장제 GC-sensitive GC-resistant Figure 3. The glucocorticoid receptor (GCR) binding affinities for dexamethasone in normals, GC-sensitive asthmatics, GC resistant asthmatics *:p<0.05 compared with normal **:p<0.05 compared with GC-sensitive (from Cho YJ and Lee KE asthma. Allergy Asthma Proc 24(5): , 2003) terburaline 을지속적으로피하주사함으 로써폐활량이향상되는경우가많다( 그림 2). 이종류의 * *

4 - 조영주 : 어려운천식 - Table 3. The essentials of a structured approach to the management of difficult asthma (C.O. Prys-Picard, pers. comm. 2005) A. History 1. Detailed history of asthma onset, events associated with exacerbations, current symptoms and therapy prescribed and taken 2. Occupational history, other drug history and therapy 3. Ear, nose and throat history, gastro-oesophageal reflux history 4. Family history 5. Compliance, psychosocial and behavioural history, pets 6. Food intolerance 7. Questionnaires 8. Asthma control, for example, Royal College of Physicians three questionsand Asthma Control Questionnaire 9. Psychological, for example, the Hospital Anxiety and Depression Scale and General Health Questionnaire B. Examination 10. Full physical examination 11. Respiratory investigations 12. Peak flow, symptoms, exposures and therapy diary for at least 3months 13. Spirometry, flow volume loop, static lung volumes, transfer factor 14. Reversibility peak flow and spirometry before and after nebulized salbutamol 5 mg 15. Histamine/metacholine challenge 16. Allergen skin tests, radioallergosorbent test, Aspergillus precipitins C. Access to other specialties 17. Ear, nose and throat, including videolaryngoscopy and speech and language therapist 18. Psychiatrist/psychologist 19. Physiotherapist D. Other investigations 20. Chest X-ray and high resolution computed tomogram 21. Blood count 22. Biochemistry 23. Anti-neutrophilic cytoplasmic antibody 24. Serum levels of prednisolone, cortisol, theophylline 25. Fibreoptic bronchoscopy h oesophageal ph study E. Research investigations 27. Induced sputum inflammatory cell counts and mediator analysis 28. Exhaled nitric oxide 29. Bronchial biopsy for inflammatory cell studies 30. Blood for genomics, proteomics and DNA 31. steroid receptor study 천식은진단자체가어려우며, 대부분중증의천식에기 준하여스테로이드용량만늘리게되며, 기관지확장제 를지속적으로피하주사하는것이문제가있기때문에 어려운천식으로분류된다 16). 2. 스테로이드저항성천식 스테로이드저항성의경우, 유전적인문제, 환자의환 경적또는여러가지면역학적인이유로인하여스테로 이드수용체결합능이나수용체형태의이상에따라생

5 - Korean Journal of Medicine : Vol. 69, No. 5, 기는질환이다 17). Cho 등 18) 은실제중증의스테로이드저 항성천식의경우고해상도훙부전산화촬영상에서비 교한기도의개형정도보다는스테로이드의스테로이 드수용체에대한결합능이더중요한인자라는것을보 고한바있다( 그림 3). 스테로이드저항성천식은임상연구차원에서적용되 는정의는하루 40 mg (20 mg 하루 2 회) 의프레드니졸 론을 7~14일간사용했는데도불구하고아침기관지확 장제투여전 FEV 1 이예상치의 15% 이상증가하지못 하는경우이며, 이런영역의환자들은일반적으로스테 로이드치료에반응도/ 민감도가낮아많은양의스테로 이드를투여하거나더오랜기간사용시조금호전되는 경우가있다. 하지만이런경우스테로이드약제의부작 용이심각해지므로, 임상적으로하루 40~60 mg의스테 로이드를 3주이상써야하는경우에는꼭스테로이드저 항성천식을의심하여야한다 17-19). 중요한점은앞에서 도언급했듯이다른여러요인들은제외시키기위한철 저한검사가선행되어야하며, 스테로이드저항성천식은 미국흉부학회에서정한천식의기준및기관지확장제 투여에의미있는반응이관찰되어야한다는점이다 10). 이는비가역적인기도의폐색이 COPD 나기도개형이진 행된중증천식을제외시키는중요한기준이된다. 이기 준을적용할때스테로이드저항성천식은어려운천식 의 19, 25% 를차지한다고보고된바있으며 20) 만성부비 동염이나비염, 아토피피부염환자, 자가면역질환환자, 심지어정상인에서도스테로이드저항성이있어최근에 는스테로이드저항성자체를하나의질환으로보는견해 21, 22) 가지배적이다. 스테로이드저항성천식에는두가지 형태가있다 23). 실제로스테로이드수용체의활성도가저 하된 glucocorticoid 수용체베타의발현이증가한경우 이고제2형은 glucocorticoid 수용체의수가적은경우이 다. 제1형은사이토카인에의하여생긴것으로일차형과 획득형의두아군으로나뉜다. 일차형은유전적다형성증 에의하여 IL-4와같은사이토카인이과하게생산되는 형이고획득형은알레르겐이나감염, 만성적인스테로이 드사용, 베타항진제등의사용으로인해생긴형이다. 제1형 은특징적으로스테로이드의부작용이많이나타나며, 원인에따라매우다양한정도및가역성을보인다 20, 23). 스테로이드저항성의경우에도실험적으로세포배양시의 사이토카인에따라가역적으로변화한다. 실제로스테로 이드저항성이라분류되는환자의상당수는스테로이드 의존성인경우와일시적으로기도의염증이심하여스 테로이드결합능이감소한경우나환자의순응도가저 하되어있는환자가대부분이라고알려져있다. 즉, 제1 형은특징적으로스테로이드의부작용이많이나타나며, 원인에따라매우다양한정도및가역성을보인다. 제 2 형은일차적인스테로이드저항성으로유전적으로스테 로이드수용체의수및기능이저하되어있어스테로이드 자체의부작용도잘나타나지않는다. 제1형이 95% 이고, 제2형은 5% 이내이며제2형의경우약제를복용안했다 고의심을받는경우가많아제2형스테로이드저항성이 의심이되면스테로이드복용후혈중 cortisol 농도의 측정이필요하다. 따라서스테로이드저항성환자의경우 어떤형태에속하는가를판단하여적절한치료나다른 항염증제의치료의보완이필요하겠다 24-26). 3. 기도개형이동반된천식 기도개형이동반된천식은우리나라말로표현할때 어려운천식보다는난치성천식으로잘표현된다. 기도개 형 27-29) 은기저하막 (subbasement membrane (SBM)) 이 두꺼워지고, 상피세포의변화가관찰되며이밖에기도 평활근의팽대와증가, 신경, 혈관의변화가관찰되는것을 특징으로한다. SBM 이두꺼워지는것은점막하에있는섬 유아세포 (fibroblast) 에서 TGF- β를분비하고 eotaxin, IL-4, IL-13 등에의해콜라겐이침착해서생기며, 기도 상피세포변화는 EGF 수용체, TGFβ2 등이기도의재 생에영향을주어배상세포변질형성 (metaplasia) 이나 점액이증가함으로야기된다 30-33). 활성화된대식세포에 서분비되는콜라겐 I, III, tenascin, fibronectin 등으로 구성된망상기저막의두께가증가하고이러한변화가 상피하섬유화를초래한다. 그리고기도상피에 epidermal growth factor 수용체, TGF-β2 등이관여하여 goblet cell metaplasia 나점액분비를증가시킨다 32). 이런천식의경우천식의중요한특징인기도협착의 가역성이적어지고, 경우에따라천식의정의에맞는 15% 이상의기저치대비 FEV 1 의증가와 200 ml 이상 의 FEV 1 의증가가관찰되지않아 COPD 와임상적으로 구분이잘안되며, 특히이런환자군에서흡연력이있는 경우더욱구분하기가어렵다 34, 35) 이전의특징적인천식 기도염증의주요세포인호산구이외에호중구도관찰 되어이런경우다른형태의천식인지아니면이런난치 성천식환자들의대분분이스테로이드를사용을이전

6 - Young Joo Cho : Difficult asthma - 에많이한경우때문인지혹은난치성천식의특징이다 른환자에비해호중구비율이높은특징이있는지에대 하여서는아직논란의여지가많다 36). 넷째로대기도와소기도의변화가나타나지만소기도 의병변에대한연구가부족하며최근의데이터에서는 중증천식에서소기도에호중구, 비반세포, fibroblasts 등이중요한염증세포로알려지고있다 33). 또한약물에 대한반응과유전자다형성에연구또한진행되고있다. 최근소아와성인천식환자에서 corticotropin releasing hormone receptor 1 의유전적변이에의해스테로이드 에대한약물효과가다름이보고되었다 37). 치 료 천식치료의근간은항염증치료이며아직스테로이드 만큼효과적인치료제는없는실정이다. 흡입제의개발 로최소한의전신적인부작용으로고용량스테로이드 흡입제를꾸준히사용시대부분의천식환자가잘조절 된다. 실제로처음에는스테로이드저항성으로보였던환 자도실제염증의정도가심하여나타난일시적인경우 가있어이런경우꾸준한흡입스테로이드치료로호전 되는예도많이보고되고있다. 이밖에흡입지속성기 관지확장제, 경구기관지확장제, 테로필린, 류코트리엔 조절제등의병합치료와악화시간혈적인전신스테로 이드치료로대부분의중증천식도거의완전조절상태의 천식에도달할수있다 11). 스테로이드저항성천식과기 도개형이동반된천식의경우아직확실하게개발된치 료는없는실정이다. 최근여러가지약제가연구중이 며스테로이드저항성자체의기전자체가매우다양하므 로어느한가지방법으로해결되지는않을것으로추축 되고있다. 고전적으로 methotrexate, gold, cyclosporine, macrolide 등의면역조절제들이시도되었지만효과는 일부경우를제외하고미약하였다 38, 39). 최근기도염증에대한병태생리학적인기전에대한 연구가진행되면서면역글로불린 E, 각세포에서분비되 는사이토카인, 사이토카인수용체, 접착분자, 전사요인 (transcription factor) 등을표적으로하는약물들이개 발되어임상시험되고있어기존의약물치료에추가로 향후어려운천식에서약제로사용될수있을것으로기 대된다 40-42). 또한약물에대한반응과유전자다형성에 결과들이발표되면서 43) 유전자를이용한약물의개발및 개인별적용또한기대해볼만하다하겠다. 결 론 어려운천식은중증의천식이포함되지만, 치료에기 대한결과를얻지못한다는점에서중증의천식과구분 될수있다. 이런천식은철저한검사와재판단에의하 여진단및다른질환과의감별이나동반여부를규명해 서다시진단을내리는것이중요하다. 이러한과정후 에진단된어려운천식의경우 brittle asthma, 스테로이 드저항성천식, 기도개형이진행된천식인지를판단하 여이에맞는적절한치료를하여과도한스테로이드치 료등으로인한약제의부작용을최소화해야하겠다. 이 런천식의새로운치료제의개발및유전자- 유전자, 유 전자-환경등의상호관계등치료방침에대한심도깊 은연구가계속되어야할것이다. Key Words : Difficult asthma, Severe asthma, Steroid resistant, Airway remodeling 색인단어 : 어려운천식, 중증천식, 스테로이드저항 성, 기도개형 REFERENCES 1) Busse WW, Banks-Schlegel S, Wenzel SE. Pathophysiology of severe asthma. J Allergy Clin Immunol 106: , ) Wenzel S. Mechanisms of severe asthma. Clin Exp Allergy 33: , ) Wenzel S. Severe/fatal asthma. Chest 123(3 Suppl): 405S-410S, ) Wenzel S. Severe asthma: epidemiology, pathophysiology and treatment. Mt Sinai J Med 70: , ) Heaney LG, Robinson DS. Severe asthma treatment: need for characterising patients. Lancet 365(9463): , ) Harrison B. D. W. Difficult asthma in adults: recognition and approaches to management Internal Medicine Journal 35: , ) European Network for Understanding Mechanisms of Severe Asthma (ENFUMOSA) Study Group. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Respir J 22: , ) British Thoracic Society; Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax 58 (Suppl 1): i194,

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ÀÇÇÐ°�ÁÂc00Ì»óÀÏ˘ Common Allergic Diseases in Children Sang - Il Lee, M.D. Department of pediatrics Sungkyunkwan University School of Medicine, Samsung Medical Center E - mail : silee@smc.samsung.co.kr Abstract Allergy