대한내과학회지 : 제 80 권제 2 호 2011 특집 (Special Review) - 천식치료의최신지견 천식치료의단계적접근법 Update 동아대학교의과대학내과학교실 남영희 이수걸 Stepwise Approach Update to the Asthma Treatment Young-Hee Nam and Soo-Keol Lee Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. Chronic inflammation is associated with airway hyper-responsiveness, which leads to various airway symptoms. Approaches to asthma treatment have been changing because our knowledge about the pathogenesis and treatment of asthma is continually evolving. Until recently, the stepwise approach to the treatment of asthma was based on a patient s asthma severity. However, new international guidelines have recommended that treatment should be adjusted in a continuous cycle driven by the patient s asthma-control status. If asthma is not controlled on the current treatment regimen, treatment should be stepped up until control is achieved. When control is maintained for at least 3 months, treatment can be stepped down. Ongoing monitoring is essential to maintain control and to establish the lowest step and dose of treatment to minimize cost and maximize safety. However, the stepwise approach and recommended treatments are meant to assist, not replace, the clinical decision making necessary to determine the most appropriate treatment to meet the individual patient s needs and circumstances. This article is a review of the stepwise approach to the treatment of asthma recommended by the Global Initiative for Asthma 2009 and Expert Panel Report 3 of National Heart, Lung, and Blood Institute 2007. (Korean J Med 2011;80:145-151) Key Words: Asthma; Therapy; Guideline 서론천식은현재전세계적으로 3억명정도가이환되어있고, 유병률은지역에따라차이가많으나대략 1에서 18% 정도로알려져있다 [1,2]. 국내에서는설문조사로시행된역학조사에서천식유병률은소아에서 1981년 5.6%, 1990년 10.1% 로증가하고있는것으로알려졌고 [3,4], 성인에서도천식의유병률이높아지고있는것으로조사되었는데, 특히 65세 이상의노년인구에서의유병률이 12.7% 로높은유병률을보였다 [5]. 그러므로천식으로인해서발생되는치료비등직접적인의료비뿐만아니라학교결석이나직장결근등으로발생되는상당한사회경제적부담을줄이기위한보다적극적인노력및대처가필요할것으로생각한다. 천식의치료적인접근은이질환의병태생리에대한새로운발견들이이루어지면서변화또는변천해왔다고할수있다 [6]. 과거단순하게일시적인기도평활근의수축이 * This work was supported by the Dong-A University research fund. - 145 -
- The Korean Journal of Medicine: Vol. 80, No. 2, 2011 - 중요한기전으로생각되어기관지확장제가주로사용되기도하였으나, 이후기도의만성염증이중요한원인기전으로밝혀져흡입용스테로이드 (inhaled glucocorticosteroid, ICS) 의지속적인투여가현재까지천식치료의근간으로여겨지고있다. 아직까지충분히밝혀지지않은, 기도개형의호전을목적으로다양한약제의개발이시도되고있으며, 또한알레르기면역반응의각단계에작용하는다양한매개인자에대한표적치료가현재활발히개발되고있다 [7]. 현재까지국내및국외에서흔히이용되는천식치료지침으로 Global Initiative for Asthma (GINA)[8] 와, 2007년에개정되었던미국 National Heart, Lung, and Blood Institute (NHLBI) 의 Expert Panel Report 3 (EPR 3)[9] 가있다. 국내에서는미국의 NHLBI 지침보다는국제적인 GINA 지침에기초하여한국성인천식의진료지침이개발되어널리이용되고있다 [10]. 본고에서는만성적인증상을호소하는성인천식환자의단계적치료접근법을, 주로 GINA 지침에근거한천식치료의단계적접근에대해서살펴보고, NHLBI 지침에서 GINA와상이한부분들에대해서간략히소개하고자한다. 천식치료의단계적접근법치료약제천식치료약제는질병조절제 (controller) 와증상완화제 (reliever) 로분류한다 [8]. 질병조절제는항염증효과및지속성기관지확장효과등을통하여증상이조절되도록매일장기간 사용하는약제이다. ICS 또는경구스테로이드, ICS와흡입지속성베타2 항진제 (long-acting β 2-agonist, LABA) 복합제, 류코트리엔조절제 (leukotriene receptor antagonist, LTRA), 서방형테오필린, 크로몰린제, 항 IgE 항체, 스테로이드를감량할수있는약제 (steroid-sparing agents) 그리고면역치료등이있다. 이중 ICS가현재까지가장효과적인질병조절제로알려져있다. 증상완화제는신속히기도수축을회복시켜증상을개선시키는약제로필요할때만사용한다. 증상완화제는경구용스테로이드, 흡입속효성베타2 항진제 (short-acting beta 2 agonist, SABA), 항콜린제, 속효성테오필린, 경구속효성베타2 항진제등이있다. 경구스테로이드는질병조절제에포함되기는하지만, 기도염증을강력히조절하여천식악화를신속히회복시킬수있기때문에증상완화제에도속한다. 조절의정의 2006년에새롭게개정된 GINA 지침부터과거에널리사용되던중증도에따른치료적접근대신에천식의조절, 즉천식의심한정도와치료에대한반응도를모두종합한환자의상태를감안하여치료할것을권고하고있다. 중증도에따른분류는천식을치료하기전의심한정도를뜻할뿐이므로연구목적으로만참조할것을제안하였다. GINA 지침은천식을조절정도에따라서분류하는데, 기준이되는항목들은주간증상, 일상활동제한, 야간증상 / 수면방해, 증상완화제사용횟수, 폐기능의다섯가지이다. 이들다섯가지항목을이용하여평가하고, 조절 (controlled), 부분조절 (partly Table 1. Levels of Asthma Control (GINA 2009) Characteristics Controlled (All of the following) Partly controlled (Any measure present in any week) - 146 - Uncontrolled Daytime symptoms Twice or less/week More than twice/week Three or more features of partly Limitations of activities None Any controlled asthma present in any week Nocturnal symptoms/awakening None Any Need for reliever/rescue treatment Twice or less/week More than twice/week Lung function (PEF or FEV 1) Normal <80% of predicted or of personal best (if known) B. Assessment of Future Risk (risk of exacerbations, instability, rapid decline in lung function, side-effects) Features that are associated with increased risk of adverse events in the future include poor clinical control, frequent exacerbations in past year, ever admission to critical care for asthma, low FEV 1, exposure to cigarette smoke, high-dose medications. Modified from Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA) Report 2009. Available from www.ginasthma.org
- Young-Hee Nam, et al. Stepwise Approach Update to the Asthma Treatment - Table 2. Assessing Asthma Control in Adults (NHLBI 2007) Components of Control Classification of Asthma Control (youths 12 years of age and adults) Well Controlled Not Well Controlled Very Poorly Controlled Impairment Symptoms 2 days/week >2 days/week Throughout the day Nighttime awakening 2 /month 1 3 /week 4 /week Interference with normal activity None Some limitation Extremely limited SABA use for symptom control (not prevention of EIB) 2 days/week >2 days/week Several times per day Risk FEV 1 or peak flow Validated questionnaires ATAQ ACQ ACT Exacerbations requiring oral systemic corticosteroids Progressive loss of lung function Treatment-related adverse effects >80% of predicted or of personal best 0 0.75 20 60~80% of predicted or of personal best 1~2 1.5 16~19 <60% of predicted or of personal best 3~4 N/A 15 0~1/year 2/year Consider severity and interval since last exacerbation Evaluation requires long-term follow-up care Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control, but should be considered in the overall assessment of risk Modified from National Heart Lung and Blood Institute. National Asthma Education and Prevention Program. Expert panel Report 3 (EPR-3): Guideline for the Diagnosis and Management of Asthma 2007. Available from http://www.nhlbi.nih.gov/guidelines/asthma. SABA, short-acting β 2 agonist; EIB, exercise-induced bronchoconstriction; ATAQ, Asthma Therapy Assessment Questionnaire; ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test. controlled), 조절안됨 (uncontrolled) 등으로분류한다 ( 표 1). 2009년개정판에서는천식조절의개념에미래의위험도를포함시키고있다. 2007년 NHLBI 지침은 GINA 와유사하지만몇가지차이점이있고, 특히천식조절의평가를좀더용이하게하기위해서다양한설문지의활용을적극적으로권장하고있다 ( 표 2). 천식의조절정도에따른단계적치료지침 GINA 지침 GINA 지침에서권고하는천식의조절상태에따른단계적인약물치료방법은그림 1에표시하였다. 그림에서와같이 5단계로구분되어있으며, 1단계에서 5단계로갈수록치료효능이더큰약제를선택한다. 환자의조절상태를지속적으로감시하고평가해야하며, 현재사용하는약제로조절이되지않으면치료단계를올려야하며, 3개월동안잘조절되었다면조절상태를유지하면서낮은단계의치료를하 기위하여치료단계를낮춰볼수있다. 천식이부분조절된경우라면치료단계를올릴지를고려해야한다. 처음천식치료를시작하는환자는 2단계의치료를시작하며증상이심하거나조절안된상태에서는 3단계치료를시작할수있다. 일반적으로환자는첫방문후 1개월후다시외래를방문하며, 천식이잘조절되면 3개월마다방문할것을권장한다. 모든치료단계에서증상완화제를처방하여필요시사용하도록해야한다. 단증상완화제를규칙적으로사용하는것은천식이조절되지않는다는뜻이므로질병조절제를증가시켜야한다. 제 1단계-필요할때증상완화제기침, 천명, 호흡곤란등의주간증상이주당 2회이거나야간증상은이보다더낮은빈도로관찰되며지속시간은수시간정도에지나지않을경우에해당한다. 1단계치료의대상이되는환자는증상이없을때환자의폐기능이정상 - 147 -
- 대한내과학회지 : 제 80 권제 2 호통권제 606 호 2011 - 이고, 천식증상으로밤에잠에서깨는일이없어야한다. 이단계에서는질병조절제를규칙적으로사용할필요가없고증상완화제를증상이있을때에만사용한다. 이단계의치료에대상이되는환자대부분에게 SABA 를추천한다. 다른약제에비해서약효시작이빠르고, 부작용이적기때문이다. 제 2단계-조절제한가지와증상완화제치료 2단계부터 5단계까지는질병조절제를규칙적으로사용하고필요할때마다증상완화제를사용한다. 저용량의 ICS 투여를일차적으로권장한다. ICS의용량은따로정리를하였다 ( 표 3). ICS의사용이어려운경우나, 지속적으로목이쉬는등의부작용이있을경우그리고알레르기성비염과동반된경우등에서는 LTRA를선택할수있다. 제 3단계-조절제한가지또는두가지와증상완화제저용량의 ICS로잘조절되지않은경우에는 LABA 를추가투여하는것을일차적으로권장한다. 이두조절제를한용기에혼합한흡입제를사용하기도하고각각별개의흡입 Figure 1. Management Approach Based on Control (GINA 2009). Modified from Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA) Report 2009. Available from www.ginasthma.org. ICS, inhaled glucocorticosteroid; LTRA, leukotriene receptor antagonist; Tx, treatment; LABA, long-acting β 2 agonist. * Preferred controller options are shown in shaded boxes. Table 3. Estimated equipotent daily doses of inhaled glucocorticosteroids for adults Drug Low (μg) Medium (μg) High Dose (μg) Beclomethasone dipropionate 200~500 >500~1,000 >1,000~2,000 Budesonide 200~400 >400~800 >800~1,600 Ciclesonide 80~160 >160~320 >320~1,280 Fluticasone propionate 100~250 250~500 >500~1,000 Modified from Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA) Report 2009. Available from www.ginasthma.org. - 148 -
- 남영희외 1 인. 천식치료의단계적접근법 Update - 제로사용할수도있다. 중간용량의 ICS를투여하거나, 저용량의 ICS에 LTRA 를추가하는것도고려할수있다. Budesonide와 formoterol 복합제재는완화및조절의두가지목적으로사용할수있다 [11,12]. 그러나 formoterol을증상완화제로단독사용하는것은추천하지않으며꼭 ICS와함께사용해야한다. 제 4단계-둘또는그이상의조절제와증상완화제중간혹은고용량의 ICS와 LABA 를함께투여하는것을일차적으로권장한다. 필요에따라서 LTRA와테오필린을추가투여할수있다. 일반적으로제 3단계치료에서조절이되지않는환자는천식전문가에게의뢰하는것이적절하다. 제 5단계-추가적인조절제와증상완화제경구용스테로이드및항 IgE 항제 (omalizumab) 이추가할수있는약제들이다. 경구용스테로이드는장기간투여에 따른부작용을고려하여최소한의용량을투여해야하며, 항 IgE 항체의경우는잘조절되지않는심한알레르기성천식환자에서증상및급성악화의빈도를낮출수있는것으로알려져있으나많은비용이드는것이제한점이다. NHLBI 지침 GINA 지침과는달리천식치료를받고있지않는환자는먼저천식의중증도 ( 표 4) 를분류해야한다. 중증도분류후각단계 (1~6단계) 에해당하는치료를시작한다 ( 그림 2). 그러므로 GINA와달리성인환자의경우중증천식의경우초기단계부터 4 내지 5단계치료를시작할수있다. 모든지속성천식의치료에서 ICS가가장우선시되는일차치료제이며, 중등증지속성천식에서는저용량 ICS와 LABA 동시투여와중간용량의 ICS 단독투여에동등한가치를부여하고있다. 그리고제 2~4단계에서피하면역치료를고려할수있음을도표에명기하고있다. 이러한방법으로조절치료를시작한 Figure 2. Stepwise Approach for Managing Asthma in Adults (NHLBI 2007). Modified from National Heart Lung and Blood Institute. National Asthma Education and Prevention Program. Expert panel Report 3 (EPR-3): Guideline for the Diagnosis and Management of Asthma 2007. Available from http://www.nhlbi. nih.gov/guidelines/asthma. SABA, short-acting β 2 agonist; ICS, inhaled glucocorticosteroid; LTRA, leukotriene receptor antagonist; LABA, long-acting β 2 agonist. - 149 -
- The Korean Journal of Medicine: Vol. 80, No. 2, 2011 - Table 4. Assessing asthma severity and initiating treatment in adults (NHLBI 2007) Components of Severity Impairment Normal FEV 1/FVC: 8~19 yr 85% 20~39 yr 80% 40~59 yr 75% 60~80 yr 70% Intermittent Classification of Asthma Severity 12 years of age Persistent Mild Moderate Severe Symptoms 2 days/week >2 days/week but not daily Daily Nighttime awakening 2 /week 3~4 /month >1 /week but not nightly SABA use for symptom control (not prevention of EIB) 2 days/week 2 days/week but not daily, and not more than 1 on any day Daily Throughout the day Often 7 /week Several times per day Interference with normal activity None Minor limitation Some limitation Extremely limited Lung function Normal FEV 1 between exacerbation FEV 1>80% FEV 1/FVC normal FEV 1>80% FEV 1/FVC normal FEV 1>60% but <80% FEV 1/FVC reduced 5% FEV 1<60% FEV 1/FVC reduced 5% Risk Exacerbations requiring oral systemic corticosteroids 0~1/year 2/year Recommended Step for Initiating Treatment Step 1 Step 2 Step 3 Step 4 or 5 In 2 6 weeks, evaluate level of asthma control achieved and adjust therapy Modified from National Heart Lung and Blood Institute. National Asthma Education and Prevention Program. Expert panel Report 3 (EPR-3): Guideline for the Diagnosis and Management of Asthma 2007. Available from http://www.nhlbi.nih.gov/guidelines/asthma. SABA, short-acting β2 agonist; EIB, exercise-induced bronchoconstriction. 후환자의천식조절상태를일정한간격으로지속적으로평가하며 ( 표 2), 천식조절상태에따라천식치료단계를조정하는것을권장하고있다. 천식이조절된경우에치료단계낮추기천식치료단계를낮추는방법에대한연구가향후더필요하기는하지만현재까지연구를토대로다음과같이추천할수있다. 1) 증간및고용량 ICS 단독투여의경우는 3개월간격으로 50% 감량한다. 2) 저용량 ICS 단독치료로조절이이루어질경우격일투여로전환한다. 3) ICS 와 LABA 병합치료로조절이이루어진경우는 LABA 는그대로지속하고, ICS의용량을 50% 감량한다. 조절이지속되면 ICS를저용량까지감량하고, LABA 를중지한다. 또다른접근법은병합요법을하루한번투여로전환하는것이다. 또다른하나의접근법은조기에 LABA 를중지하고, 동일한 용량의 ICS 단독으로유지하는방법이지만, 천식조절에문제를일으킬수있다. 4) ICS에추가하여 LABA 이외의다른조절제를병합치료하는경우는 ICS의용량을저용량 ICS까지감량후병합치료제를중단한다. 5) 최소용량의조절제치료로천식의조절이이루어지고 1년동안증상의재발이없으면조절제투여를중단할수있다. 천식조절에실패한경우치료단계높이기경미한증상의재발이나악화등이발생할경우, 천식조절이잘되지않는것으로판단하고주기적으로치료단계를조정한다. 속효성단기작용성 (rapid-onset, short-acting) 약제또는속효성지속성 (rapid-onset, long-acting) 약제하루또는이틀이상이러한약제를반복사용하는경우는천식조절을재평가하고질병조절제를증가시킨다. - 150 -
- Young-Hee Nam, et al. Stepwise Approach Update to the Asthma Treatment - ICS ICS의용량을일시적으로 2배중가시켜서사용하는것은권장되는방법이아니다. 성인의천식악화의경우 ICS의용량을 4배또는그이상의증가시켜서사용하는것은경구스테로이드를단기간사용하는만큼의효과가있는것으로알려졌다. 증상완화와천식조절을위한 ICS 와속효성지속성 (rapid-onset, long-acting) 기관지확장제 ( 예, formoterol) 의병합치료이들두약제를한흡입기에병합하여투여하는경우전신적스테로이드투여와입원치료를요하는천식악화의발생을줄이고천식조절을극대화할수있는것으로알려졌다. 천식악화가임박한경우, 이복합제의투여용량을 2배에서 4배까지늘려서투여함으로써예방이가능한지는추가연구가필요한상황이다. 급성악화의경우고용량의베타2 항진제를사용하며경구또는정맥으로전신스테로이드를투여한다. 천식악화의치료후에는일반적으로악화전의치료단계로유지치료를다시시작한다. 다만치료단계가부적절해서천식이잘조절되지않다가악화가발생한경우는치료단계를높여야한다. 결론천식치료의목표는조절상태를만들고유지시키는것이라고할수있다. 이와같은목표를이루기위해서는환자의천식조절상태를지속적으로감시하는것이필수요소이다. 조절되지않을경우, 약제를더높은단계로조정하여, 조절될때까지유지하고, 반대로적어도 3개월이상조절이잘유지될때는낮은단계로하향조정한다. 처음치료하는경우는 GINA 지침의경우 2내지 3단계에서시작하고, NHLBI 의지침을따를경우는치료전중증도에따라서처방한다. 천식조절이된경우에치료단계를낮추는방법은먼저 ICS 의용량을저용량까지감량후병합치료제를중지한다. 무엇보다도환자의상태에따른맞춤치료적인접근이필요하다. 중심단어 : 천식 ; 치료 ; 지침 REFERENCES 1. Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma: executive summary of the GINA dissemination committee report. Allergy 2004;59:469-478. 2. Beasley R. The global burden of asthma report, global initiative for asthma (GINA) 2004. Available from: http://www.ginasthma.org. 3. 이혜란, 홍동선, 손근찬. 소아알레르기에관한조사. 대한의학협회지 1983;26:254-262. 4. 신태순, 이금자, 윤혜선. 국민학교아동에서의알레르기질환에관한조사. 알레르기 1990;10:201-212. 5. Kim YK, Kim SH, Tak YJ, et al. High prevalence of current asthma and active smoking effect among the elderly. Clin Exp Allergy 2002;32:1706-1712. 6. Bousquet J. Global initiative for asthma (GINA) and its objectives. Clin Exp Allergy 2000;30(Suppl 1):S2-S5. 7. Holgate ST, Polosa R. Treatment strategies for allergy and asthma. Nat Rev Immunol 2008;8:218-230. 8. Global Strategy for Asthma Management and Prevention. Global initiative for asthma (GINA) report 2009. Available from: http://www.ginasthma.org. 9. National Heart Lung and Blood Institute. National asthma education and prevention program: expert panel Report 3 (EPR-3): guideline for the diagnosis and management of asthma 2007. Available from: http://www.nhlbi.nih.gov/guidelines/asthma. 10. 대한의학회, 보건복지가족부. 2007 년한국성인천식의치료지침. Available from: http://www.allergy.or.kr 11. O Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005;171: 129-136. 12. Rabe KF, Pizzichini E, Stallberg B, et al. Budesonide/formoterol in a single inhaler for maintenance and relief in mild-to-moderate asthma: a randomized, double-blind trial. Chest 2006;129:246-256. - 151 -