ISSN 2287-7614 www.oldrf.org OLD 폐쇄성폐질환 Volume 04 Number 01 JANUARY 2016 폐쇄성폐질환연구원 Volume 04 Number 01 JANUARY 2016 I. 천식치료에서 LAMA 의역할 II. COPD 의임상적표현형및 Endotype (Clinical Phenotype and Endotype of COPD) III. Phenotypes of Asthma: 중증천식중심으로 IV. 흡입용스테로이드제와결핵 V. 만성폐쇄성폐질환환자에서흡입스테로이드사용과폐렴위험성 VI. 국건영자료를이용한국내천식유병률및발병률현황 VII. 지역사회코호트에서만성폐쇄성폐질환의유병률과발생률 VIII. 산화스트레스와항산화효과가만성폐쇄성폐질환의발생과악화에미치는영향 IX. COPD 악화시항생제역할및실제 X. COPD 의치료 : 새로운치료제와병합요법
목 차 I. 천식치료에서 LAMA 의역할 1 구현경 ( 인제대학교의과대학일산백병원호흡기내과 ) II. COPD 의임상적표현형및 Endotype (Clinical Phenotype and Endotype of COPD) 5 김유일 ( 전남대학교병원호흡기내과 ) III. Phenotypes of Asthma: 중증천식중심으로 10 김상하 ( 연세대학교원주의과대학내과학교실 ) IV. 흡입용스테로이드제와결핵 15 이창훈 ( 서울대학교병원내과 ) V. 만성폐쇄성폐질환환자에서흡입스테로이드사용과폐렴위험성 18 민경훈 ( 고려대학교의과대학고려대학교구로병원호흡기내과 ) VI. 국건영자료를이용한국내천식유병률및발병률현황 23 박소영 1, 권혁수 1, 김호 2, 양현종 2, 조유숙 1 ( 1 울산대학교의과대학서울아산병원알레르기내과, 2 서울대학교보건대학원, 3 순천향대학교의과대학부천병원소아과 ) VII. 지역사회코호트에서만성폐쇄성폐질환의유병률과발생률 33 김영삼 1, 임아영 1, 박보람 2, 원성호 2 ( 1 연세대학교의과대학내과학교실, 2 서울대학교보건대학원 ) VIII. 산화스트레스와항산화효과가만성폐쇄성폐질환의발생과악화에미치는영향 37 이한별 1, 김우진 2, 양세란 1 ( 강원대학교의학전문대학원강원대학교병원 1 흉부외과, 2 호흡기내과 ) IX. COPD 악화시항생제역할및실제 43 최혜숙 ( 동국대학교의과대학경주병원호흡기내과 ) X. COPD 의치료 : 새로운치료제와병합요법 49 오연목 ( 울산대학교의과대학서울아산병원호흡기내과 )
I 천식치료에서 LAMA 의역할 구현경 인제대학교의과대학일산백병원호흡기내과 Asthma is a prevalent disease, and it can cause serious attack and even death. The treatment strategy for asthma still needs effective controller, considering number of asthma patients do not achieve asthma control status. The role of long acting muscarinic antagonist (LAMA) had been evaluated in asthma treatment by several trials. These studies confirmed, tiotropium consistently enhances lung function and peak expiratory flow rate in uncontrolled asthma without serious adverse events. Efficacy of tiotropium for asthma control is optimally expected. Key Words: Asthma, Long acting muscarinic antagonist, Respiratory function Corresponding author: Hyeon-Kyoung Koo, M.D. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Daehwa-dong 2240, Ilsanseo-gu, Goyang 10380, Korea Tel: +82-31-910-7013, Fax: +82-31-910-7219, E-mail: gusrud9@paik.ac.kr 1. 서론 천식은전세계적으로약 3억명이상의환자가존재하며 1, 서구화및도시화가진행되면서저개발국에서의유병률은점차증가추세이다 2. 하지만여러연구에따르면많은수의천식환자들이충분한조절상태에이르지못하여잦은응급실방문과입원, 사망하고있다. 최근유럽에서시행된연구에서는실제 25 45% 의환자가천식조절이되지않았고 3, 환자순응도를철저히관리한임상연구에서도 20% 정도의환자가천식조절에도달하지못하였다 4. 전세계적으로약 25만명의천식환자가매년사망하는것으로알려져있는데, 이는대부분불충분한치료와급성악화에기인하며 1 효과적인천식치료제의필요성을시사한다. 이를위해기존에사용하는흡입스테로이드 (inhaled corticosteroid, ICS) 와지속성베타작용제 (long acting β 2 adrenergics, LABA) 외에또다른기관지확장제인지속성항콜린제 (long acting muscarinic antagonist, LAMA) 가새로운해결책이될수있을지에대한관심이지속되었고, 여러무작위대조군연구에서보인효과를바탕으로 2015년 GINA 천식진료지침에서는 step 4와 5의성인천식환자에대한 tiotropium 의병합요법이적응증에추가되었다. 본종설에서는무작위대조군연구결과를통해각단계의천식환자에서지속성항콜린제의효과및역할에대해정리해보고자한다. 2. 본문 1) 고용량흡입스테로이드및지속성베타작용제와의병합요법 2011년 Kerstjens 등 5 은고용량 ICS와 LABA를사용함에도천식관련증상이조절되지않고 (asthma control questionnaire (ACQ) 1.5), 폐기능저하를보이는 (FEV 1 80%, FVC 70%) 107명의중증천식환자를대상으로 tio- 1
tropium 을추가하는무작위양측눈가림교차설계연구를수행하였다. 연구대상의평균기관지확장제사용후 (post) FEV 1 은 65.3% 였고, 이들을세군으로나누어 tiotropium respimat 10 μg qd, tiotropium respimat 5 μg qd, placebo 를기저사용하던고용량 ICS 와 LABA 에 8주간추가투여하였으며휴약기를두어각군을교차시켰다. 주평가변수는 peak FEV 1 변화로 tiotropium 10 μg 군및 5 μg 군에서각각 170 ml, 139 ml 증가되었고, 최대호기유속 (peak expiratory flow, PEF) 은 15.3 L/min, 7.9 L/min 호전되었다. 심각한부작용은세군모두에서보이지않았다. 이후 Kerstijen 과 Bateman 등은동일한환자군에게 tiotropium respimat 5 μg qd와 placebo 를추가투여하는대규모임상시험을다시진행하였고, 총 912명에게 48주투여결과를비교하였다 (PrimoTinA) 6. 이연구에서 trial 1에서는 24주후 peak FEV 1 이 86 ml, morning PEF가 21.5 L/min 증가되었고, trial 2에서는 peak FEV 1 154 ml, morning PEF 23.3 L/min 의증가되었으며, 천식악화와중증급성악화모두유의하게감소되었다. 천식조절정도 (ACQ) 와천식관련삶의질 (asthma quality of life questionnaire, AQLQ) 에대해서는 trial 1은유의한차이를보이지못했으나, trial 2에서는유의하게호전되기는하였으나, minimally clinically important difference (MICD) 에미치지는못하는수준이었다. 이연구에서역시유의할만한심각한부작용은보고되지않았다. 2) 중등도용량의흡입스테로이드와의병합요법 Bateman 등 7 은 β 2 -adrenergic receptor gene의 Arg/Arg 단일염기다형성을가지고있는천식환자들중중등도이상의 ICS (±LABA) 를사용함에도폐기능저하를보이는 ( 기관지확장제사용전 (pre) FEV 1 90% with LABA, prefev 1 80% with ICS only) 385명의환자들을대상으로 tiotropium respimat 5 μg qd, salmeterol 50 μg bid, placebo 의세군으로나누어병용투여하고 16주후의결과를비교하였다. Tiotropium 군은 placebo 군에비하여평균 morning PEF의유의한증가를보였고 (20.7 L/min), salmeterol 군에비해비열등함을증명하였으나, 호흡곤란이나천식조절정도 (ACQ), 천식관련삶의질 (AQLQ) 부문에서는 salmeterol 같은유의한호전을보이지는못하였다. 이후 Kerstjens 과 Bateman 등은다시중등도의 ICS (±LABA) 를사용함에도천식관련증상이있고 (ACQ-7 1.5), 폐기능의저하가있는 (prefev 1 60 90%) 천식환자 2,103명을대상으로 tiotropium respimat 5 μg qd, tiotropium respimat 2.5 μg qd, salmeterol 50 μg bid, placebo 의네군으로나누어 24주후 peak FEV 1 과 trough FEV 1 을비교하였다 (MezzoTinA) 8. Peak FEV 1 은 tiotriopum 5 μg, tiotropium 2.5 μg, salmeterol 군에서각기 185 ml, 223 ml, 196 ml 통계적으로유의하게증가하였고, trough FEV 1 은 146 ml, 180 ml, 114 ml 증가, morning PEF는 24.3 L/min, 25.4 L/min, 24.8 L/min 증가하였다. 저자들은이연구에서 tiotropium 5 μg 군과 tiotropium 2.5 μg이별다른결과차이를보이지않은것은 tiotropium 2.5 μg 군에기관지확장제가역성이더높은환자가많이포함되어서라고설명하였다. 이연구에서 tiotropium 2.5 μg 군은중증급성악화와천식의악화까지의시간을증가시켰지만, tiotropium 5 μg은모두유의하지않았고, salmeterol 은천식의악화까지의시간만늘려주었다. MCID 이상의삶의질향상을가져온환자의비율은세군모두에서유의하게증가하였으며, 약제사용관련하여심각한부작용은관찰되지않았다. 3) 저용량흡입스테로이드와의병합요법 2010년 NEJM에 Peters 등 9 은저용량 ICS (beclomethasone 80 μg bid) 사용에도폐기능이저하되어있고 (FEV 1 40 70%), 천식증상이지속되는 ( 일주일에 6회이상의천식증상및증상완화제사용, 2회이상의야간증상 ) 성인천식환자 210명을대상으로 14주간 tiotropium handihaler 18 μg qd 또는 salmeterol 50 μg bid를추가한군과, beclomethasone 용량을 2배로증량한군 (160 μg bid) 의치료효과를비교하였다 (TALC). Morning PEF는 tiotropium 군에서 ICS 증량군에비해 25.8 L/min 증가하고, salmeterol 군에서는 19.4 L/min 증가하였으며, 두군간의통계적으로유의한차이는보이지않았다. PreFEV 1 은 tiotropium 군에서는 ICS 증량군에비해 100 ml의유의한증가를보였으나, salmeterol 군은유의한차이를보이지못하였다. 천식조절수준 (ACQ) 과천식관련삶의질 (AQLQ) 측면에서는 tiotropium 군과 salmeterol 군모두유의한호전을보였으나두군모두 MCID에미치지못하는수준이었다. 이후 Paggiaro 등 10 이저용량 ICS 사용중폐기능저하 (FEV 1 60 90%) 와천식관련증상 (ACQ 1.5) 를보이는 465명 2
의천식환자를대상으로 tiotropium respimat 5 μg, tiotropium respimat 2.5 μg, placebo 를추가하여 12주후치료효과를비교하였다 (GraziaTinA study). Peak FEV 1 은 tiotropium 5 μg과 tiotropium 2.5 μg에서각기 128 L/min, 159 L/min 증가하였고 mean PEF 또한양군에서유의하게증가되었다. 심각한부작용은관찰되지않았다. 4) Tiotropium respimat의적절한용량중등도이상의 ICS에 tiotropium respimat 병합요법의효과를보고자했던 MezzoTinA study 와저용량 ICS에 tiotropium respimat 병합요법의효과를비교한 GraziaTinA study 모두에서 tiotropium 2.5 μg을사용한군에서통계적으로유의하지는않으나수치상으로 tiotropium 5 μg에비해더높은 FEV 1 의증가를보고하였으나, Ohta 등 11 이일본에서시행한 tiotropium 의장기효과를비교한연구를보면결과는비교적명확하다. 이들은중등도의 ICS 사용에도천식관련증상이있고 (ACQ7 1.5) 폐기능저하 (FEV 1 60 90%) 된천식환자 285명을대상으로 tiotropium respimat 5 μg qd, tiotropium respimat 2.5 μg qd, placebo 세군으로나누어 52주후치료효과와안정성을비교하였다. 24주후 tiotropium 5 μg과 2.5 μg 양군간에유의한효과차이를보이지는않았으나, 52주후 tiotropium 5 μg 군에서 tiotropium 2.5 μg 군에비해유의한 trough FEV 1 의증가 (112 ml) 와 trough PEFR의증가 (34.2 L/min) 를보고하였기때문에천식환자에대하여 tiotropium respimat 을추가할때는 5 μg의용량을사용하는것을추천할수있겠다. 이연구에서 tiotropium 의 52주장기사용후에도심혈관사건을포함한특별한부작용은차이를보이지않았다. 3. 결론 Tiotropium 의병합요법은흡입스테로이드사용에도불구하고증상조절이잘되지않고폐기능저하가있는천식환자에서폐기능과최대호기유속을호전시키고, 급성악화의빈도를감소시켜효과적인천식조절에도움이될것으로기대된다. 현재 COPD 환자를대상으로사용중인약물이며임상시험결과로는비교적안전한것으로여겨지지만, 향후장기간사용시의안전성과실효성에대한추가연구가필요하다. References 1. World Health Organization. Global surveillance, prevention and control of chronic respiratory diseases. The Global Alliance against Chronic Respiratory Diseases 2007. Geneva: World Health Organization; 2007. 2. 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;59:469-78. 3. Demoly P, Gueron B, Annunziata K, Adamek L, Walters RD. Update on asthma control in five European countries: results of a 2008 survey. Eur Respir Rev 2010;19:150-7. 4. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, et al; GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;170:836-44. 5. Kerstjens HA, Disse B, Schröder-Babo W, Bantje TA, Gahlemann M, Sigmund R, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol 2011;128:308-14. 6. Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012;367:1198-207. 7. Bateman ED, Kornmann O, Schmidt P, Pivovarova A, Engel M, Fabbri LM. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol 2011;128:315-22. 8. Kerstjens HA, Casale TB, Bleecker ER, Meltzer EO, Pizzichini E, Schmidt O, et al. Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, place- 3
4 bo-controlled, parallel-group, active-comparator, randomised trials. Lancet Respir Med 2015;3:367-76. 9. Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, et al; National Heart, Lung, and Blood Institute Asthma Clinical Research Network. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010;363:1715-26. 10. Paggiaro P, Halpin DM, Buhl R, Engel M, Zubek VB, Blahova Z, et al. The Effect of Tiotropium in Symptomatic Asthma Despite Low- to Medium-Dose Inhaled Corticosteroids: A Randomized Controlled Trial. J Allergy Clin Immunol Pract 2015. doi: 10.1016/j.jaip.2015.08.017. [Epub ahead of print] 11. Ohta K, Ichinose M, Tohda Y, Engel M, Moroni-Zentgraf P, Kunimitsu S, et al. Long-Term Once-Daily Tiotropium Respimat Is Well Tolerated and Maintains Efficacy over 52 Weeks in Patients with Symptomatic Asthma in Japan: A Randomised, Placebo-Controlled Study. PLoS One 2015;10:e0124109.
II COPD의임상적표현형및 Endotype (Clinical Phenotype and Endotype of COPD) 김유일 전남대병원호흡기내과 Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder that has many clinical phenotypes and endotypes. Clinical phenotypes include the groups of patients with similar clinical characteristics, prognosis, or therapeutic needs such as frequent exacerbators or asthma-copd overlap syndrome (ACOS). Endotypes represent subtypes of patients defined by a distinct biological or pathophysiological mechanism such as the patients with persistent systemic inflammation or raised eosinophils. Recently, several new potential COPD clinical phenotypes and endotypes with biomarkers have been suggested. All these developments should pave the way towards personalized tailored treatment of COPD and a reclassification of complex COPD diseases. Pharmacotherapy can be tailored according to each phenotypes with available bronchodilators and anti-inflammatory drugs targeting specific biomarkers. However, study for many COPD phenotypes with personalized medicine is very limited and it should be more evaluated. Key Words: COPD, Clinical phenotype, Endotype Corresponding author: Yu-Il Kim, M.D., Ph.D. Division of Pulmonology, Department of Internal Medicine, Chonnam National University Hospital, 42, Jebong-ro, Dong-gu, Gwangju 61469, Korea Tel: +82-62-220-6296, Fax: +82-62-225-8578, E-mail: kyionly@chonnam.ac.kr 1. 서론 COPD 의여러표현형이지금까지알려져왔고, 이러한표현형은크게임상적표현형과 endotype 으로나눠볼수있다. 임상증상이나 outcome ( 예 : 급성악화군, 기관지염이나폐기종군, asthma-copd overlap syndrome: ACOS 등 ) 에따른임상적표현형과 1,2, 병태생리학적기전에따른호산구나 Th2세포증가형, 세균집락군, α-1 antitrypsin (α1at) deficiency 등으로분류되는 endotype 이있다 2-6. 이외에도 COPD 표현형을영상의학적으로 chest CT 소견 ( 폐기종의정량화, 소기도질환의정량화, 기도크기및기도벽변화 ) 에따라서분류하고, 영상학적표현형과호흡생리학적지표들과의연관성이높음이보고되고있다 7,8. 이러한다양한표현형에대한연구는표현형에따라다른예후를보이거나, 표현형에따른맞춤치료법개발로 COPD 치료및예후개선을위함이주목적중의하나이다. 이에본논문에서는 COPD 표현형중에서도실제임상에서치료법과연관된대표적인임상적표현형을중심으로기술하였고, 최근소개된 endotype 2 등에대해서는간단히문헌고찰과함께기술하였다. 5
2. 임상적표현형및 Endotype (Clinical Phenotype and Endotype of COPD) 잦은급성악화군 9,10 1년에 2회이상악화를보이는경우나입원할정도로심한악화가연 1회라도있었던경우를주로일컫는다. 이러한환자군들의대표적인특징으로, 급성악화가자주일어나는것을예측할수있는가장좋은지표는이전급성악화병력으로알려져있다. 기류제한이심해짐에따라급성악화빈도가증가하고입원, 사망도증가한다 10,11. 이러한환자에서지속형기관지확장제등약물치료로급성악화빈도를낮출수있으며 11,12, 해당약제로 longlong-acting β-agonists (LABA)/ 흡입용스테로이드복합제, roflumilast 와 azithromycin 등이있다. 특히 long-acting muscarinic antagonists (LAMA; e.g. tiotropium, glycopyrronium) 은 exacerbation frequency를 20% 이상감소시킬수있다는보고가있다 (GLOW2 trial) 13. LABAs 약제에대한메타분석에서도급성악화를 20% 정도낮출수있었지만, formoterol 의경우에는 ICS와함께사용하였을때만이급성악화예방효과가있었다. Salmeterol 의경우에는단독사용으로도악화빈도를줄일수있었다. LAMA/LABA 복합제사용으로도급성악화빈도를낮출수있으며, 대표적으로 SPARK study (indacaterol and glycopyrronium) 에서는 the combination only reduced exacerbations by a further 12% over monotherapy 14. Macrolides 의 anti-inflammatory effects 로이용한치료연구보고에서는, azithromycin 사용으로첫악화발생시기를 174일에서 266일로늦추는효과가있음이보고되었다 15. 그러나약제내성균발생위험성이있다는문제점이제기되고있다 16. 만성기관지염은최소 2년동안 3개월이상지속되는가래증상을보이는경우로 17, 외국문헌보고에서는 COPD 환자의 45% 에서만성기관지염형태로나타남을보고하였다 18. 이러한질환군의특징을가진환자는보다더급성악화빈도가흔하며폐기능저하속도가더빠른것으로알려지고있다 19. 만성기관지염임상상을보이는경우에대한특이적인치료약제에대한보고가되어지고있는데 20, 특히 Roflumilast 는만성기관지염을가진 COPD 환자의악화예방효과와함께일부 FEV1 개선효과도있는것으로보고되었다 21. Mucolytics 도일부급성악화를낮추는효과가강하지는않지만일부효과있음이보고되었다 22. NETT (National Emphysema Treatment Trial) study에서보고된폐상부에주로국한된폐기종 (upper zone dominant emphysema) 을가진 COPD 표현형환자들에게는폐용적축소절제술 (lung volume reduction surgery, LVRS) 이좋은치료옵션이되는것으로알려졌다 23. 이러한표현형환자치료로최근에는 endobronchial valves 를이용한폐용적축소술도시행중이며 24, 다른기저유전적위험인자도가지고있는것으로알려지고있다 25. 이외에도 COPD 환자의호흡부전증은저산소증이나고탄산혈증형태로각각달리나타날수있는데, 저산소증 COPD군에서는 long-term oxygen therapy (LTOT; oxygen for >15 h per day) 26,27 를고탄산혈증을보이는환자군에게는비침습적양압환기기 (noninvasive ventilation, NIV) 를적용할수있다 28. 호산구성 COPD 는천식과중복 ( 천식 /COPD 중복증후군 ) 될가능성이있어서논란이있지만, COPD 환자의객담이나혈액내호산구수가증가한경우 (blood eosinophil counts >2%) 에는스테로이드에대한반응이좋다는최근보고가되어지고있다 29,30. 천식 /COPD 중복증후군 (asthma-copd overlap syndrome, ACOS) 은천식과 COPD 의특성을모두갖고있는증후군을말한다 31,32. 즉천식의특징인알레르기감작, 기도과민성, 가역성기류제한과 COPD 의특징인흡연력, 지속적인기류제한을동시에함께갖는증후군이다. 두질환은기도염증이라는공통된병태생리를가지고있지만 32, 중복중후군진단기준으로나라와연구자마다조금씩다르며아직까지일반적으로통용되는진단기준및치료기준은정립되지않은실정이다 33. 폐기능검사를기준으로하면, 기관지확장제투여후 FEV1/FVC <70% 인비가역성기류제한을보이면서메타콜린혹은만니톨등의검사로증명된기도과민성을보이는경우다 34. 스페인연구자들은그외에임상양상을추가하여주진단기준 31 으로 1) 기관지확장제투여후 FEV1 15% 이면서 400 ml의증가 2) 객담내호산구증가 3) 40세이전의천식진단을, 부진단기준으로 1) 총 IgE의증가 2) 아토피과거력 3) 기관지확장제투여후 FEV1 12% 이면서 200 ml의증가가 2번이상나타남을제시하였고, 이중주진단기준이 2개이상이거나주진단기준이 1개이면서부진단기준이 2개이상충족되면 ACOS로진단할것을제시하였다. 기존의연구에서 ACOS 환자들의임상양상은각각의질환에비해나쁜편으로, 천식이나 COPD 환자에 6
비해삶의질이낮으며, 잦은악화와입원을경험하였다 35. 또한 ACOS 가아닌 COPD 환자와비교해도훨씬더자주응급실을방문하였고, 자주입원하였으며, 의료비지출도많았다 36. 일반적으로 ACOS 환자들에서흡입스테로이드의투여를고려해야하며, 천식환자의치료와비슷하게증상조절, 폐기능및객담호산구유무에따라용량을조절해야하지만, ACOS 환자들을대상으로시행된무작위대조군연구가없어서향후이에대한연구가필요하겠다. Biomass 와같은환경오염에의한 COPD 는주로개발도상국여성에게흔하며 37, 폐기종보다는주로기도변형을동반하는경우 (airway predominant phenotypes) 가흔하다. 또한기관지과민성과천식 /COPD 중복증후군형태를나타내는경우가많다 38,39. 이는이러한환자군에게는흡입용스테로이드치료제가효과가있을것임을시사하나이에대한임상연구가아직거의없는실정이다. 전신염증반응 (systemic inflammation) 을가진표현형 40 은 ECLIPSE 연구에의하면약 16% 환자가이에해당되었으며, 사망률과악화력이높은것으로보고되어지고있다. 하지만이러한군에서다른치료를적용해야될지에대해서는연구된바가없다. COPD 환자의 30 70% 에서는기도내세균집락 (bacterial colonization, 주로 >1 106 cfuㆍml 1)) 을가지고있으며, 이러한환자들은가래색깔, 악화빈도가증가하며호흡기염증반응이증가하므로하나의표현형으로인식되고있다 41,42. 이에대해서는 moxifloxacin 43 이나 macrolides 를이용한급성악화빈도감소등치료효과가일부보고되고있다. 이외에도다양한표현형으로기관지확장증 44, 과거력상폐결핵병력 45, 폐동맥고혈압 46, 폐암, 심혈관계질환등동반질환에따른표현형연구가보고되어지고있다. 그러나이러한환자에서도동일한기관지확장제등동일한 COPD 약제를사용해야되는지, 또는그효과는어떤지에대해서는추후연구가필요한실정이다. 3. 요약 COPD 는다양한임상적표현형과 endotypes 으로이루어져있다. 예후및치료약제선정등과밀접한관련이있는대표적인잦은급성악화군 (frequent exacerbators), 천식 /COPD 중복증후군 (asthma-copd overlap syndrome, ACOS), 만성기관지염등이있다. 임상적표현형의기초가되는병태생리학적표현형인 endotypes 으로는, persistent systemic inflammation 및 eosinophils 증가를동반한 COPD 가있다. 최근각각의표현형에대한치료제개발이이루어지고있다. 그러나이외의다양한여러표현형에따른치료나다기관연구가부족한실정으로향후이러한각각의표현형에대한치료연구를통해서향후에는각표현형에따른맞춤치료시대가다가오리라기대한다. References 1. Han MK, Agusti A, Calverley PM, Celli BR, Criner G, Curtis JL, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med 2010;182:598-604. 2. Woodruff PG, Agusti A, Roche N, Singh D, Martinez FJ. Current concepts in targeting chronic obstructive pulmonary disease pharmacotherapy: making progress towards personalised management. Lancet 2015;385:1789-98. 3. O'Neil SE, Lundbäck B, Lötvall J. Proteomics in asthma and COPD phenotypes and endotypes for biomarker discovery and improved understanding of disease entities. J Proteomics 2011;75:192-201. 4. Lin TY, Poon AH, Hamid Q. Asthma phenotypes and endotypes. Curr Opin Pulm Med 2013;19:18-23. 5. Blasi F, Chalmers JD, Aliberti S. COPD and bronchiectasis: phenotype, endotype or co-morbidity? COPD 2014;11:603-4. 6. Antoniu SA. Phenotype/endotype-driven therapy in COPD: potential economic implications. Expert Rev Pharmacoecon Outcomes Res 2013;13:421-3. 7. Kim YI, Schroeder J, Lynch D, Newell J, Make B, Friedlander A, et al. Gender differences of airway dimensions in anatomically matched sites on CT in smokers. COPD 2011;8:285-92. 8. Mohamed Hoesein FA, Schmidt M, Mets OM, Gietema HA, Lammers JW, Zanen P, et al. Discriminating dominant 7
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III Phenotypes of Asthma: 중증천식중심으로 김상하 연세대학교원주의과대학내과학교실 It is increasingly revealed that asthma is not a single disease, but a syndrome with vast heterogeneity in pathogenic mechanism, symptom severity, and treatment response. Approximately 10 to 20% of asthmatic patients remain refractory to current standards for its treatment. In the 1990s and 2000s, initial studies have attempted to define phenotypes of asthma. This review will discuss the present understanding of different asthma phenotypes and endotypes that lead to more targeted and personalized therapy to asthma, especially severe asthma. Key Words: Asthma, Phenotype, Heterogeneity Corresponding author: Sang-Ha Kim, M.D., Ph.D. Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20, Ilsan-ro, Wonju 26399, Korea Tel: +82-33-741-0926, Fax: +82-33-741-0928, E-mail: sanghakim@yonsei.ac.kr 1. 서론 천식은전통적으로가역적인기류제한과기도과민성, 만성적인기도염증으로인한다양한임상증상들을종합하여정의되는일종의증후군이다. 발작적인기침, 가슴답답함, 호흡곤란, 쌕쌕거림등의특징적인증상들이일중변화혹은계절적인변화를보일때천식진단을고려한다. 발병시기, 아토피유무, 흡연상태등의다양한임상적인정보와함께폐활량검사를이용한기도가역성의확인또는최대호기유속측정기를통한가역적인기류제한을확인하여천식을진단하도록진료지침들은권고하고있다. 천식의치료는비특이적으로항염증효과를나타내는흡입스테로이드를기본으로하여흡입지속성베타작용제, 항류코트리엔제등의약제로천식조절상태에따라단계를조정하여치료하도록추천되고있다. 앞서기술한바와같이진단과정에서고려되는여러가지임상적인특성들이실제로는다양한조합으로개별환자에서확인되며, 이러한이질성 (heterogeneity) 은천식환자의약제에대한반응도, 고정된기류제한, 급성악화의빈도, 동반질병의양상등치료, 예후와관련된지표들에영향을미친다 1,2. 그럼에도불구하고아직까지천식진료지침은조절상태에따른일반화된단계별치료만이권고되고있다. 이는현재진료지침의근거가되는대부분의임상시험들이이러한천식환자들의이질성이고려되지않은연구들이었음에기인한다. 하지만대부분의천식환자들은진료지침의권고안에따른표준화된치료로천식조절상태에도달가능하지만, 10 20% 환자들은치료에잘반응하지않는다 3,4. 진료지침에의거하여최대로높은단계의치료로도잘조절되지않는이른바중증천식환자들은비록적은수이지만이들을위해지출되는의료비용은전체천식환자비용의 30% 로천식환자관리의중요한부분을차지한다. 최근까지전체천식환자를대상으로질환의이질성을고려하여이를소집단화하고자하는연구분석들이있었다. 이러한연구들에서사용되는표현형 (phenotype) 이란용어는본래유전형 (genotype) 과대비하여사용되었던용어이다. 최근에는이용어가 ʻ질환의임상양상과관련하여개별환자들간의구별을가능하게하는특성ʼ을기술하고자 10
할때사용되고있다. 더나아가그특성들이생물학적, 병태생리학적기전으로설명이가능한경우에는 endotype이란용어가사용된다. 본종설에서는특별히기존치료에잘조절되지않는중증천식과관련된천식표현형 (endotype 포함 ) 에대하여기술하고자한다. 2. 중증천식의임상적인특성을확인한연구와결과들 중증천식과관련하여중요한대규모연구들이 10여년전에있었으며 5-7, 이들연구결과에서공통적으로확인되는중증천식의임상적인특성들은다음과같다. 중증천식환자들은급성악화가자주발생하며응급실방문또는입원이필요한정도의중증급성악화가발생하고, 기저폐기능이낮으며고용량의흡입스테로이드나경구스테로이드에의존적인특성이있었다. 최근에진행된연구에서는비부동염을동반하거나그로인한증상이있는경우, 흡연자이거나혹은직업적으로가스, 분진, 흄등에노출되는경우, 여성과노령인경우를중증천식의위험요소로확인한바있다 8,9. 이외에도발병연령, 기도확장제의반응정도, 고정된기류제한, 아토피유무, 비만, 호산구 / 호중구성기도염증등이중증천식의표현형을결정짓는요소들로알려져있다. 이러한천식표현형과관련된연구들은환자들을다양한표현형으로분류하여분석함으로써천식발생의위험요소를확인하는연구결과들의검증력을향상시킨다. 또한천식표현형을규명하는연구들을통하여아직까지는충분하게밝혀져있지않은천식의생물학적발병기전에대한새로운가설검증의기회가마련될수있다. 더나아가기전으로설명이가능한천식 endotype을규명하는것은이에맞는특정 endotype 의특화된표적치료제를개발하고사용가능하게하는길을열어줄것이다. 3. 중증천식의표현형 /endotypes 소개 1) Early onset allergic ( 조기발병알레르기천식형 ) 이표현형에속하는중증천식환자들은어린시절에천식이발생하고알레르기피부반응에서양성을보인다. 이중에서어린시절발병할당시부터중증천식이었던군과오랜시간에걸쳐점차중증천식으로진행한군이각각어느정도차지하고있는지는잘알려져있지않다. 하지만전체중증환자의 40% 를차지하는이표현형의중증천식환자는질병의이환기간이길고알레르기피부반응의양성개수가많은것이특징으로알려져있다 7. 유전적인근거로는아토피또는 IgE 관련 Th2 유전자와의관련성이확인된바있으며, Th2 관련유전자다형성의개수가많을수록천식의중증도가높아지는것으로보고되었다 10,11. 이표현형에대한생물표지자 (biomarker) 로서가능성이있는것들은 Th2 염증반응과관련이있는것으로알려진 periostin 과호기산화질소등이있으며 12,13, 향후임상적인적용을위해서는생물표지자로서의선택성 (selectivity) 이확인되어야하며, 스테로이드치료를유지하고있는환자에서도지속적으로확인가능한지에대한검증이필요하다. 치료와관련하여서는이표현형을대상으로하는임상시험은없었으나, 알레르기면역요법을통한효과를기대해볼수있으며 IgE에대한단일클론항체인 omalizumab 의사용도이표현형에대하여더효과적일지에대한향후연구가필요하다 14,15. 2) Late onset eosinophilic ( 후기발병호산구천식형 ) 이표현형의환자들은대부분 20대후반에서 40대에발병하며, 부비동질환의동반은흔하지만아토피피부염과같은다른알레르기질환의동반은적다. 이표현형과유사한특성을보이는 aspirin exacerbated respiratory disease (AERD) 는일반적으로성인이되어서발생하며호산구증가와부비동질환또는비용종등의동반을특징으로한다 2. AERD 가이표현형의하나의아형이라면, 아마도가장많이연구가이루어진아형이될것이다. AERD 에서는 cysteinyl leukotriene (cyslt) 경로와관련된유전자의변이들이발표된바있으며 16,17, 이러한결과들은앞으로여러중증천식코호트내에서도분석을통하여확인되어야할것이다. 11
호산구증가가지속적으로관찰될수있다는것은스테로이드치료에대한불응 (refractoriness) 을의미하는것으로이표현형의중요한특성중에하나이지만비특이적이다. 오히려 Th2 관련시토카인인 IL-13과 IL-5은스테로이드사용으로억제되기는하지만여전히하기도와비용종등의조직에서관찰되고있어서더중요한생물표지자로사용될수있을것이다 18,19. 최근 IL-4/IL-13 과 IL-5 통로를차단하는약제들의임상시험이중증천식환자를대상으로진행이되었다 20,21. 중증호산구천식환자를대상으로 IL-5 단클론항체 (mepolizumab) 를사용한연구에서 mepolizumab 은말초혈액과폐에존재하는호산구의수를감소시켰으며급성악화를줄였고, 전신적스테로이드의사용을줄이는효과를보였다. 3) Obesity related ( 비만관련천식형 ) 이표현형에속한환자들은주로성인기에발병하고여성이많으며체질량지수가높은것을특징으로한다. 환자들은대체로증상이심하고중등도의폐기능저하를동반하여의료기관의이용률이높다. 이들은다른알레르기질환을잘동반하지않으며, 지속적인호산구염증소견을보이기도한다. 비만과관련된천식표현형의기전과관련하여아디포카인의역할, 호산구의지방조직에서폐조직으로의이동, 활성화된대식세포의면역학적인변화등이그기전으로제안되고있으나 22, 이와관련된생물표지자의개발은아직미흡한상태이다. 4) Neutrophilic ( 호중구천식형 ) 중증천식표현형중에서호중구가증가된특성은흡연과관련이있고고용량의스테로이드치료가필요한표현형으로잘알려져왔다. 이들은폐기능이떨어져있으며가슴컴퓨터단층촬영에서공기걸림 (air trapping) 이관찰된다 23. 호중구이외의다른생물표지자에대한연구는부족하며, 마크롤라이드항생제의치료가조절에도움이될수있다 24. 5) Smoker s ( 흡연자천식형 ) 천식은흡연을시작하기전이나혹은후에모두발생가능하므로, 흡연자천식의표현형은천식자체가가지는이질성보다더복잡한양상을띠게된다. 흡연자천식환자들은급성악화가자주발생하며, 폐기능이떨어져있고스테로이드치료에반응이좋지않다고알려져있으나 25,26, 아직까지유전적, 병태생리학적기전이나생물표지자등에대한연구는부족하다. 4. 결론 대규모환자들을대상으로천식표현형을구분하여소개한연구결과들이소개되면서천식이가지고있는이질성을극복할수있는길이모색되고있다. 앞으로는천식환자들의특성에따라구분하는것을넘어서서표현형에해당하는기전의발견과이를임상에서활용할수있는생물표지자를개발하는노력이더욱필요하다. 이러한노력들은특별히기존치료제로조절되지않는중증천식환자들을위해서더욱필요하며, 기전을기반으로하는표적치료제의개발로맞춤형치료의길이열릴것으로기대된다. References 1. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al; National Heart, Lung, and Blood Institute's Severe Asthma Research Program. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010;181:315-23. 2. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol 2003;111:913-21. 3. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, et al; GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care 12
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IV 흡입용스테로이드제와결핵 이창훈 서울대학교병원내과 Key Words: 흡입용스테로이드제, 결핵 Corresponding author: Chang-Hoon Lee, M.D., Ph.D. Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-4743, Fax: +82-2-762-9662, E-mail: kauri670@gmail.com 1. 서론 1990년이래사망자가 47% 나감소하는등커다란진전이있긴하지만, 여전히 1년에 150만명을죽음에이르게하고있는결핵은여전히인류의큰위협임에분명하다 1. 결핵은 HIV 감염을비롯하여저체중, 규폐증, 당뇨병, 만성콩팥병등질환이있는경우재활성화되어발병하는경우가대부분이다 2. 결핵발병의위험을높이는요인중에는약제가있고대표적인것이 TNF-α 억제제 2 와전신스테로이드제 3 와같은면역억제제가있다. 그런데근래에는만성기도질환에서널리쓰이고있는흡입용스테로이드제가결핵의위험을높이는가에대한여러연구가발표되었다. 오늘은이에대해간단히정리해보고자한다. 2. 본론 1) 흡입용스테로이드제가결핵위험을높인다는연구결과들이에대해첫주목할만한연구는캐나다에서이루어졌다. 퀘벡지역보험자료를이용하여 427,648명을분석한이연구에서결핵발생의위험은흡입용스테로이드제를 1년이내사용한경우 27% (RR, 1.27; 95% CI, 1.05 1.53), 30일이내사용한경우 33% (RR, 1.33; 95% CI, 1.04 1.74) 유의하게증가하는것으로나타났다 4. 그런데캐나다지역은결핵감염의유병률이낮고이에따라발생률도낮은지역으로이연구에서도 1990 2005년사이에겨우 564명의결핵환자만확인되었다. 즉흡입용스테로이드제를투약하는환자의대부분은결핵발생의위험이낮은사람으로효과가저평가될가능성이있는것이다. 이런가운데결핵의유병률이높은한국에서 2편의연구가연달아보고된다. 첫번째연구는한국의국민건강보험자료를이용하였고 2007 년에서 2010 년사이에흡입용약제를한번이라도쓴적이있는 1,341,299명에대한후향적코호트연구를수행하였다. 총 4,146명의결핵환자가진단되었고코호트내환자-대조군연구 (nested case-control study) 를시행한결과, 흡입용스테로이드제를 30일이상투여한경우결핵발생의위험이 20% 더높은것으로나타났다 (OR, 1.20; 95% CI, 1.08 1.34). 이연구에서는용량-의존적으로흡입용스테로이드의누적용량이증가함에따라결핵위험이더높은결과도역시확인하였다 5. 이런건강보험자료는대규모자료라는장점이있다. 비록엄격한방식으로결핵발생을정의하였긴하지만, 청구자료의한계상결핵진단의불확실성과같은단점은피할수가없다. 이에비해한국에서나온또다른후향적코호트연구는병원에서추적관찰한환자를이용한결과란장점이있다. 이연구는 2000 2005년사이에만성폐쇄성폐질환으로진단된 15
778명을추적관찰하여이중 20명에서결핵이발생하였음을확인하였다. 분석결과, 가슴 X-선검사에서과거결핵의흔적이있으면서흡입용스테로이드제를투여한경우는가슴 X-선검사에서과거결핵의흔적이없으면서흡입용스테로이드제를투여하지않은대조군과비교하여 25배정도결핵발생의위험이높았다 (HR, 24.95; 95% CI, 3.1 201.4). 가슴 X-선검사에서과거결핵의흔적이없지만흡입용스테로이드제를투여한군도대조군에비해 9배결핵발생의위험이높았다 (HR, 9.08; 85% CI, 1.01 81.4) 6. 이런후향적코호트연구결과들에이어흡입용스테로이드제를이용한무작위임상시험들에대한체계적문헌고찰결과도등장한다. 25개임상시험총 22,898 명에대한메타분석결과흡입용스테로이드제치료는결핵발생의위험을 2.3배높이는것으로나타났다 (peto OR, 2.29; 95% CI, 1.04 5.03) 7. 2) 흡입용스테로이드제가왜결핵발생의위험을높이는가? 전신스테로이드제가결핵발생의위험을높인다는것은잘알려져있고흡입용스테로이드제역시같은기전일것으로이해되고있다. 스테로이드는대식세포 (macrophage) 기능을억제하고살균능력을떨어뜨리며인터루킨-1과 TNF-α 생성을줄이고 T 림프구의활성화를억제함으로써결핵에대한면역작용을감소시키는역할을한다고알려져있다 8,9. 비록흡입용약제는전신흡수가적어이에따른부작용이적다는장점이있지만약제의일부는폐실질까지도달하여전신흡수가발생한다. 또한전신스테로이드제에비해흡입용스테로이드제는보다장기적으로사용하는경우가많다. 따라서흡입용스테로이드제역시전신스테로이드제에서발생할수있는부작용의가능성이있다는우려가있었고 10 결핵이중요한그중요한예로확인이된것이다. 3) 흡입용스테로이드제에의한결핵발생의위험은과연절대적으로높은수준인가? 상술한바와같이흡입용스테로이드제투약이실제결핵발생의위험을높인다고봐야할것이다. 그렇다면정말임상적으로의미있는정도의위험증가인가? 메타분석의결과를보면결핵이유행하는지역에서는 NNH (the number of needed to harm) 가 909, 즉 909명에게흡입용스테로이드제를투여하면결핵발생이 1명증가해서하고비유행지역에서는 1,667명치료당 1명이발생하는것으로나타났다 7. 이정도의 NNH라면사실임상적인의미는크지않다고할수있다. 다만이메타분석에서비유행지역에비해유행지역의 NNH가 1/2 수준이라는말은결핵의유병률이높으면높을수록흡입용스테로이드제로인한결핵발생의위험도더욱클수있음을시사한다. 이와관련하여상술한한국에서이루어진후향적코호트연구결과가관심을끈다. 이연구에서는약 3년정도추적관찰하였을때 309명흡입용스테로이드제투여하여 17명에서결핵이발생하였고 307명의흡입용스테로이드제비투여군에서는 3명이발생하여 300 명당대략 14명의차이를보이고있다 6. 즉 NNH 가 21명정도에불과한것이다. 하지만이연구는평균 65세이상이면서대다수의흡연가를대상으로한데다결핵환자가 20명진단된데불과하다는점은고려해야겠다. 참고로전신스테로이드제를투여받은환자는흡입스테로이드제에의한추가적인결핵발생의위험증가는없었다 4,5. 3. 결론 흡입용스테로이드제는전신스테로이드제와같은기전으로면역반응을억제함으로써결핵발생의위험을증가시킨다. 결핵의유병률도높고천식과만성폐쇄성폐질환등흡입용스테로이드제를투여할질병의유병률도높은한국에서는흡입용스테로이드제에의한결핵발생위험증가를무시할상황이못된다. 약제의투약시이런정보를바탕으로모니터링을잘하며환자관리를해야할것이다. References 1. World Health Organization. Global tuberculosis report. Geneva: World Health Organization; 2015. 16
2. Horsburgh CR Jr, Rubin EJ. Clinical practice. Latent tuberculosis infection in the United States. N Engl J Med 2011;364:1441-8. 3. Jick SS, Lieberman ES, Rahman MU, Choi HK. Glucocorticoid use, other associated factors, and the risk of tuberculosis. Arthritis Rheum 2006;55:19-26. 4. Brassard P, Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and risk of tuberculosis in patients with respiratory diseases. Am J Respir Crit Care Med 2011;183:675-8. 5. Lee CH, Kim K, Hyun MK, Jang EJ, Lee NR, Yim JJ. Use of inhaled corticosteroids and the risk of tuberculosis. Thorax 2013;68:1105-13. 6. Kim JH, Park JS, Kim KH, Jeong HC, Kim EK, Lee JH. Inhaled corticosteroid is associated with an increased risk of TB in patients with COPD. Chest 2013;143:1018-24. 7. Dong YH, Chang CH, Lin Wu FL, Shen LJ, Calverley PM, Löfdahl CG, et al. Use of inhaled corticosteroids in patients with COPD and the risk of TB and influenza: a systematic review and meta-analysis of randomized controlled trials. a systematic review and meta-analysis of randomized controlled trials. Chest 2014;145:1286-97. 8. Segal BH, Sneller MC. Infectious complications of immunosuppressive therapy in patients with rheumatic diseases. Rheum Dis Clin North Am 1997;23:219-37. 9. Fauci AS, Dale DC, Balow JE. Glucocorticosteroid therapy: mechanisms of action and clinical considerations. Ann Intern Med 1976;84:304-15. 10. Patton JS, Fishburn CS, Weers JG. The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc 2004;1:338-44. 17
V 만성폐쇄성폐질환환자에서흡입스테로이드사용과폐렴위험성 민경훈 고려대학교의과대학고려대학교구로병원호흡기내과 Inhaled corticosteroids (ICS) are commonly prescribed for patients with chronic obstructive airway diseases such as bronchial asthma and severe chronic obstructive pulmonary disease. Although their use improves quality of life and reduces exacerbations in chronic obstructive pulmonary disease, it is associated with increased risk of pneumonia. The risk of pneumonia is associated with types of ICS, duration of use of ICS, and doses of ICS. However, all current studies find either no difference or a reduction in pulmonary-related mortality associated with the use of ICS. Clinicians should be evaluated as a balance between the benefits and the risks of ICS use for an individual patient with chronic obstructive pulmonary disease. Key Words: Chronic obstructive lung disease, Inhaled corticosteroids, Pneumonia, Pneumonia related mortality Corresponding author: Kyung Hoon Min, M.D., Ph.D. Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University Medical School, 148, Gurodong-ro, Guro-gu, Seoul 08308, Korea Tel: +82-2-2626-3308, Fax: +82-2-2626-1166, E-mail: minkyunghoon@korea.ac.kr 1. 서론 흡입스테로이드 (inhaled corticosteroid, ICS) 는항염증효과를가지는효과적인약제로대표적인폐쇄성폐질환인기관지천식과만성폐쇄성폐질환 (chronic obstructive pulmonary disease, COPD) 에서기도염증을조절하기위하여사용되는약물이다. 기관지천식에서흡입스테로이드의사용은천식증상의감소, 삶의질호전, 폐기능개선, 기도과민성감소, 기도염증조절, 악화의빈도와중증도감소, 천식으로인한사망을감소시킨다 1,2. COPD 에서흡입스테로이드의사용은논란의여지가있지만폐기능이정상예측치의 60% 미만에서지속기관지확장제의병합요법으로사용했을때 COPD 증상을감소시키고, 건강상태를향상시키며, 급성악화의빈도를감소시킨다 3,4. 흡입스테로이드를사용하였을때구인두캔디다증, 목소리변형등과같은국소부작용과함께고용량흡입스테로이드를장기간사용하였을때부신기능의억제, 골밀도감소등의전신적부작용이발생할수있다. 또한고용량흡입스테로이드를장기간사용하였을때폐결핵의발생의위험성이증가한다는보고도있다 1-4. 현재까지연구결과에따르면기관지천식환자에서는흡입스테로이드의사용이폐렴발생을증가시키지않는것으로보고하고있다. 하지만 COPD 환자에서는흡입스테로이드사용이폐렴의발생을증가시킨다는최근연구결과와함께이를다른관점에서반박하는연구결과들이발표되면서논란이지속되고있다. 이에현재까지의연구결과를바탕으로 COPD 환자에서흡입스테로이드사용과폐렴위험성에대해서정리해보고자한다. 18
2. 본론 1) COPD 환자에서흡입스테로이드사용과폐렴발생 2007년 6,000명이상의환자를대상으로진행된대규모무작위대조군연구인 Toward a Revolution in COPD Health (TORCH) 연구에서최초로흡입스테로이드를사용한환자에서폐렴발생이증가된다고발표한이후 (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.33 2.02) 5, Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) 연구를포함한대부분의무작위대조군연구에서유사한연구결과를발표하였다 (HR, 1.90 [95% CI, 1.04 3.49] to 3.09 [95% CI, 1.34 7.12]) 6-10. 또한 6,235 명을대상으로한코크란메타분석에서역시흡입스테로이드사용이폐렴발생증가와관련되어있음을보고하였다 (odd ratio [OR]: 1.56, 95% CI: 1.30 1.86) 11. 언급된무작위대조군연구결과는폐렴의진단에있어체계적인진단과영상의학적확인이결여되어있는무보정이상반응보고에의존하였다는제한점을갖고있었다. 하지만이를보정한여러대규모관찰연구에서도흡입스테로이드의사용이폐렴발생을증가시킨다는기존의연구와같은결과를보여주었다 (HR, 1.10 [95% CI, 1.08 1.13] to 2.65 [95% CI, 1.25 5.61]) 12-16. 현재까지의연구결과를종합하면 COPD 환자에서흡입스테로이드사용은폐렴발생을증가시키는것으로판단된다. 특히흡입스테로이드를사용하고있는 COPD 환자중 55세이상의연령, FEV 1 50% 미만, 최근 1년동안 COPD 악화경험, 호흡곤란악화, 신체비만지수가 25 kg/m 2 미만의임상적특징이있는경우가위험요소로판단된다 17,18. 2) COPD 환자에서흡입스테로이드종류따른폐렴발생 COPD 환자에서흡입스테로이드사용에의한폐렴발생을보고한대부분의앞서언급된기존연구들은흡입스테로이드단독제제혹은병합제제로서 fluticasone 를사용하였고 fluticasone 사용이폐렴을잘발생하는것으로보고하고있다. 흡입스테로이드로 budesonide 를사용한무작위대조군연구중 Vestbo 등 19 과 Rennard 등 20 의연구는위약군에비해폐렴발생의상대위험도가각각 0.67 (95% CI, 0.37 1.20) 과 0.74 (95% CI, 0.47 1.18) 로 budesonide 사용이폐렴발생의위험도를높이지않는것으로보고하였다. COPD 환자에서 fluticasone/salmeterol과 budesonide/formoterol 의폐렴과폐렴관련사망률을비교한대규모후향적관찰연구 (PATHOS 연구 ) 결과폐렴발생률과폐렴관련입원율이 fluticasone/salmeterol 군에서 budesonide/formoterol 군보다높았다 ( 각각 rate ratio, 1.73; 95% CI, 1.57 1.90; p<0.001과 rate ratio, 1.74; 95% CI, 1.56 1.94; p<0.001) 21. 또한폐렴관련사망률역시 fluticasone/salmeterol 군에서 budesonide/formoterol 군보다높았다 (HR, 1.76; 95% CI, 1.22 2.53; p=0.003). 흡입스테로이드의종류에따른이러한차이는명확히규명되지는않았지만, fluticasone 과 budesonide 의효능혹은기도에서의제거율의차이와관련되어있는것으로보인다 22,23. 즉 fluticasone 의강한지용성이기도의상피세포표면에서천천히분해하여장시간기도표면에머무르면서국소적면역체계에영향을줌으로써폐렴발생의빈도에영향을줄수있을것이다. 3) COPD 환자에서흡입스테로이드용량에따른폐렴발생흡입스테로이드용량관련하여 Ernst 등 14 은 COPD 환자에서 fluticasone 용량을기준으로하여저용량군 (fluticasone <500 μg/day), 중간용량군 (fluticasone 500 999 μg/day), 고용량군 ( 1,000 μg/day) 으로나누어, 각군에서폐렴발생의위험도를분석하였을때, 저용량군보다는중간용량군에서, 중간용량군보다는고용량군에서폐렴이더많이발생되었다고발표하였다 ( 각각 adjusted rate ratio, 1.50 [95% CI, 1.38 1.62]; 1.63 [95% CI, 1.55 1.71]; 2.25 [95% CI, 2.07 2.44]). 따라서사용하는흡입스테로이드용량에비례하여폐렴이잘발생되는것으로생각된다. 19
4) COPD 환자에서흡입스테로이드사용기간에따른폐렴발생흡입스테로이드사용기간과관련하여 COPD 환자를대상으로한관찰연구에서흡입스테로이드사용후첫 3년동안폐렴발생이별로증가하지않았으나, 4년정도지나면서흡입스테로이드를사용하지않는환자에비해서 2배정도폐렴발생이증가하였다 24. 다른관찰연구에서는흡입스테로이드사용한지 18 24 개월째에폐렴발생이 1.8배정도증가되었다 24. 반대로흡입스테로이드를중단하면점차적으로폐렴발생위험성이서서히감소하지만, 1년정도가지나도폐렴발생의위험성은 1.2배정도로남아있었다 14. 5) COPD 환자에서흡입스테로이드사용과폐렴관련사망률 TORCH 연구를포함한다섯개의무작위대조군연구들에서 COPD 환자를대상으로흡입스테로이드사용군과비사용군사이의폐렴관련사망률은차이가없음을보고하였으나, TORCH 연구를제외한연구들은신뢰구간이너무커서폐렴관련사망률을평가하기어렵다거나사망의원인을폐렴과연관시키기에는기준이모호하다는등의제한점이있었다 7,9,17,18,25. 흡입스테로이드를사용중인 COPD 환자중폐렴으로인해입원한환자에대한폐렴관련사망률을분석한 7개의관찰연구를체계적으로분석한결과, 연구대상 75% 를포함한국가관리데이터베이스를분석한 3개의관찰연구에서폐렴관련 30일째사망률이감소함을보여주었다 ( 관찰연구 1 16 : covariate-adjusted relative risk [RR], 0.50 [95% CI 0.41 0.60]; 관찰연구 2 15 : OR, 0.74 [95% CI: 0.66 0.83]; 관찰연구 3 12 : RR, 0.75 [95% CI: 0.69 0.82]) 12,15,16. 연구대상 25% 를포함한 4개의관찰연구에서는폐렴관련 30일때사망률을높이지않는것으로나타났다 26-29. 언급된다섯개의무작위대조군연구와일곱개의관찰연구결과는 Ernst 등 14 의 COPD 환자를대상으로흡입스테로이드사용에대한연구결과의소집단분석에서흡입스테로이드사용한환자가폐렴관련 30일째사망률이증가한다는보고와상반된다. 하지만 Ernst 등 14 의연구에서소집단분류에있어지나치게중증폐질환을갖고있거나 COPD 악화로인한입원빈도가높은환자가많아그로인해전신스테로이드혹은항생제등을포함한다양한호흡기계약물이투여되었던점이소집단분석에영향을주었을가능성을감안하여결과를수용해야할필요가있다. 3. 결론 COPD 환자에서흡입스테이드의치료는일부환자군에서 COPD 증상을감소시키고, 건강상태를향상시키며, 급성악화의빈도를감소시키는이점이있기는하나, 흡입스테로이드의종류에따라정도의차이가있기는하지만용량과사용기간에비례하여폐렴발생을증가시키는단점이있는것은분명해보인다. 하지만현재까지연구결과에따르면이로인한폐렴관련사망률은높이지는않는것으로나타났다. 따라서 COPD 환자에서흡입스테로이드를사용을선택하려고할때는이러한장단점을비교하여필요한경우최소한의용량으로흡입스테로이드를사용하는것이좋을것으로생각된다. 4. 감사의글 This study was supported by a grant from Korea University, Seoul, Korea (K1326181). References 1. GINA. USA: Global strategy for asthma management and prevention [Internet]. 2015 [cited 2015 Novermber 15]. Available from: http://www.ginasthma.org/local/uploads/files/gina_report_2015_aug11.pdf. 2. The Korean Academy of Tuberculosis and Respiratory Diseases. The Korean guideline for management of asthma 20
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VI 국건영자료를이용한국내천식유병률및발병률현황 박소영 1, 권혁수 1, 김호 2, 양현종 2, 조유숙 1 1 울산대학교의과대학서울아산병원알레르기내과, 2 서울대학교보건대학원, 3 순천향대학교의과대학부천병원소아과 The purpose of this study is to produce nationwide data regarding prevalence and risk factor of asthma for national asthma management administration and research. A nationwide study revealed that old age, female sex, low lung function at asthma diagnosis, history of allergic disease, use of antibiotics, geological location were a risk factor for asthma. Large nationwide studies to evaluate environmental/epidemiologic risk factor are required to see the cause of geological differences in asthma prevalence. Funding and support to study elderly asthma is required. These should be financial support for the integration of diverse asthma cohorts in Korea to produce more organized and accurate asthma cohort data. Key Words: Asthma, Prevalence, Incidence, National health & Nutrition Examination Survey, National Health Insurance Corresponding author: You Sook Cho, M.D., Ph.D. Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, 86, Asanbyeongwon-gil, Songpa-gu, Seoul 05505, Korea Tel: +82-2-3010-3280, Fax: +82-2-3010-6969, E-mail: yscho@amc.seoul.kr 1. 서론 천식은발생요인이다양하고환자에따라질환의발생시기, 진전양상및치료예후등의차이가있어질병부담이큰질환이며조기발견및조기치료가필요한만성질환이다 1,2. 천식은선진국형질환으로사회가발전할수록유병률과사회경제적부담이급증하고있으며미래에도지속될것으로예측된다 3. 또한천식은출생직후영유아기부터노인천식까지전연령에서발생하며발생시기와연령에따라다른경과를보이는질환이고, 국가, 인종, 연령에따른유발요인및악화요인, 자연경과, 치료효과등이차이가있어그에따른국가적대응이요구되는질환이다 2,4-7. 국내천식유병률은국민건강영양조사등을통하여파악되고있으나, 천식이환집단이나천식환자등위험군만을대상으로하는국가수준의분석및실태자료는아직미흡한실정이다. 따라서국민일반집단군과천식등만성호흡기질환환자군대상의실태조사및비교분석을통한국가수준의천식예방및관리에필요한근거자료마련이필수적이다. 이에따라본연구자들은국가천식관리정책및연구개발의기반자료가될수있는국민일반집단군과천식질환군의유병및위험인자실태파악비교분석을통하여국가수준의자료를생산하고자하였다. 2. 연구대상및연구방법 일반인을대상으로한천식연구를위해국민건강영양조사, 지역사회건강조사, 국민건강보험공단의 100만코호트자료를분석에활용하여다양한실태조사를하였다. 천식환자의조작적정의는 2002년 1월 1일부터 2012년 12월 23
31일까지각연도별로의료기관을방문하여주진단명또는부진단명중천식상병코드 (J45 46) 가 1회이상있으면서천식약물을 1개이상처방받은경우또는지정된천식관련검사를 1회이상시행한경우로정의하였다. 이러한국가건강자료중천식관련자료를이용한국민일반군에대한천식의위험인자조사는자료가일반적인변수로되어있어천식질환코호트내에서시행하였다. 천식악화의조작적정의는천식환자중천식관련입원또는응급실방문, 외래방문시전신스테로이드가같이처방된경우로하였다. 성인천식질환군은보건산업진흥원지원으로 2004년부터수집한성인천식자료로구성된 Cohort for Reality and Evolution of Adult Asthma in Korea (COREA) 코호트를활용하였다. COREA 코호트는약 3,000여명의임상자료및시료, 유전자자료를확보하고있는다기관코호트이다. 이후순천향부천병원의성인천식환자코호트에서동일한방법으로재분석하여결과를비교하였다 8,9. 소아천식질환군은질병관리본부지원으로구축된 600여명의학동전기천식코호트와 3,000여명의아토피, 천식원인규명을위한장기추적연구자료를활용하였고, 두집단을짝짓기방법으로비교분석하였다 10. 성인천식질환군내에서는천식질환악화의위험인자를분석하였고, 소아천식질환군내에서는천식발생의위험인자를분석하였다. 자료의분석은종단형자료분석 (longitudinal analysis) 을이용하였다. 이는연도별추세분석과같은반복측정자료에대한분석방식으로, 반복되는단위에서생성되는상관성을모델에반영하는방법이다. 코호트자료와같은반복측정자료는관찰값간의상관성이강하게존재하기때문에일반적인회귀분석으로는진행할수없다. 또한시군구와같은지역적인공간상관성분석을고려하여야하기때문에이러한공간상관을고려한연도별추세분석에가장적합한 Generalized Linear Mized Model (GLMM) 방법을활용한분석을진행하였다. 코호트내각변수간의연관성을파악하기위한방법으로는회기분석 (logistic regression) 을시행하였고, 단변량분석 (univariate analysis) 및다변량분석 (multiple regression) 을시행하여연관성이높은유의한변수를추출하고각각의오즈비 (odds ratio) 를계산하였다. 3. 연구결과 1) 국민일반집단군의위험인자비교분석 (1) 국민건강영양조사 1998년에서 2013년도까지연도별연령별천식유병률은 60세이상의고연령군에서지속적으로높게확인되었고유병률의변동이있는것으로확인되었으나, 연령대가낮은 60세미만의그룹에서는대체적으로증가하는추세를보여주었다 (Figure 1). 1998년에서 2013년도까지연령별성별천식유병률은 65세이상의고연령군여성에서특히높은것으로확인되었다. 남성은 65세이상의고연령군에서점차적으로유병률이감소하는형태를보였다 (Figure 2). 행정구역별천식유병률의차이분석결과는 1998년부터 2009년까지읍ㆍ면행정단위에서의유병률이동단위보 Figure 1. 1998 2013 년도연도별연령별천식유병률. 24
다높았다 (Figure 3). 18세까지의소아학동기의천식유병률분석은 2013년을기준으로시행하였으며, 성별연령별유병률은남아의경우 6 11 세, 여아의경우 12 14 세에서가장높은것을확인할수있었다 (Figure 4). 행정구역별유병률은읍ㆍ면행정단위에서의유병률이높았다 (Figure 5). (2) 지역사회건강조사 2008년부터 2013년까지성별과연령을표준화한천식평생의사진단경험률을천식의유병률로보고분석한결과전국적으로천식유병률은다른만성질환의유병률에비해낮았고, 6개년도지역별평균값은지역자기상관성이없었다 (Moranʼs I=0.177368, p-value<0.0001) (Figure 6). 조율은그지역자체의수치를의미하며, 표준화율은지역에성별과연령을표준화시켜지역간비교에이용한다. 시도단위별천식평생의사진단경험률을조율로보았을때, 서울과인천, 경기도, 전라북도, 제주도가증가추세에있었고 2008년부터 2012년까지 5개년간의천식유병률평균은전라남도영광군에서가장높은것으로확인되었다 (Table 1). 표준화율로보았을때에는인천광역시남동구가가장높은것으로확인되었다 (Table 2). 연도별지역별천식평생의사진단경험률의증가율을분석하였고, 253개시ㆍ군ㆍ구보건소단위경험률의증가율이낮은지역과높은지역을추출하였다. 강원도철원군과경상북도상주시가 2008년 2013년 6년동안감소추세를보였고충청북도옥천군이증가율이높게나타났다 (Figure 7). Figure 2. 1998 2013 년도연도별성별천식유병률. Figure 3. 행정구역별천식유병률. 25
Figure 4. 2013 년도소아학동기성별연령별천식유병률. Figure 5. 2013 년소아학동기행정구역별천식유병률. (3) 국민건강보험공단표본코호트천식유병률은 2002년도부터 2013년도까지꾸준하게증가하는추세로, 시간이흐름에따라천식환자가증가하고있으며, 연도와무관하게여성이남성에비해유병률이지속적으로높았다 (Figure 8). 연령대별로는 1 4세, 5 9세, 75세이상순으로유병률이높았는데이는소아에서네블라이저처방을위한상병입력과연관성이높다는것을감안하여야하는결과로보인다 (Figure 9). 지역별로는시 (city) 단위로는광주시가꾸준히높은천식유병률을나타냈고, 울산시의증가율이다른지역에비해높으며, 서울시와부산시는다른도시에비해낮은것으로분석되었다. 도 (province) 단위분석결과대체적으로모두증가추세를보이는것으로나타났다. 또한세종시를제외하고는전지역에서여성천식환자가더많았다. 천식의평균발생률은 2009년이전에는평균발생률이 20 이하였지만, 2009년이후에는 20 이상을보였으며, 여성이남성에비해항상높은발생률을보였다 (Figure 10). 각해의천식환자중악화가발생하는경우는천식환자중 25 35% 내외를보이며시간에따른증가를보이지는않았다. 천식환자의중증도는약제의종류와용량에따라구분하였고, 약 80% 의대부분의환자가중간용량의약제를처방받았다. 2) 성인천식질환군의위험요인비교분석총 1,832 명의 COREA 환자를대상으로분석한결과 1년동안 1회이상의악화를경험한환자는 213 명 (11.63%) 으로확인되었고악화에영향을미치는유의한변수를단변량분석 (univariate analysis) 시행한결과 1 여성 2 등록당시 26
Figure 6. 2008 2013 년 6 개년도전국평균천식평생의사진단경험률. 의낮은폐기능 (pre-bronchodilator FEV1, FVC, FEV1/FVC, post-bronchodilator FEV1, FEV1/FVC) 3 uric acid 4 증상으로인한지속적인긴치료기간 5 1년추적관찰기간동안의폐기능 FEV1의변화 6 1년추적관찰기간중 Asthma Control Test (ACT) 변화 7 3년추적관찰중폐기능 FEV1의변화 8 3년추적관찰기간중 Asthma Control Test (ACT) 변화항목들이유의한항목으로확인되었다. 이항목들을활용하여다변량분석을 (multiple regression) 시행하였고, 악화위험인자는 1 여성 2 등록당시의낮은폐기능 (pre-bronchodilator FEV1 (%), FEV1/FVC) 3 증상에대한긴치료기간 4 1년추적관찰기간중 FEV1의큰변화 5 1년추적관찰기간중 ACT score의큰변화 6 3년추적관찰기간중 ACT score의큰변화로확인되었다 (Table 3). 이를바탕으로연령별, 성별초기폐기능에따른악화위험도를추가분석한결과 60세이상의고령의환자에서특히폐기능이낮을수록악화의위험도가높은것으로확인되었고, 유사하게남성보다는여성에서폐기능이낮을수록악화의위험도가특히증가하는것으로확인되었다 (Figure 11). 동일한분석방법으로재현성을확립하기위해부천순천향병원코호트내에서재분석을시행하였고, 총 2,195명을분석한결과 1년동안 1회이상의악화를경험한환자는 283명 (12.89%), 악화를경험하지않은환자는 1,912 명 (87.11%) 으로분류되었다. 단변량분석을시행후유의한결과를보인변수를다변량분석을시행하였고, 최종적으로유의한항목으로는 1 등록당시의낮은폐기능 (pre-bronchodilator FEV1%) 2 등록당시의높은폐용적 (pre-bronhodilator FVC) 3 높은 Total IgE (Log(Total IgE)) 4 주증상이긴경우가확인되었다. 성별과연령의항목은여성과고연령군이 odds ratio 가높아위험인자로확인되었으나통계적으로유의하지는않았다. 27