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1 DOI: /trd ISSN: (Print)/ (Online) Tuberc Respir Dis 2011;70: CopyrightC2011. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 최근 10 년간천식환자에서흡입스테로이드제처방빈도와중증악화빈도의추세분석 울산대학교의과대학서울아산병원 1 호흡기내과학교실, 2 알레르기내과학교실, 3 영상의학교실, 4 천식센터노창석 1, 이재승 1, 송진우 1,4, 김태범 2,4, 김남국 3, 조유숙 2,4, 이상도 1,4, 문희범 2,4, 오연목 1,4 Original Article Recent 10 Years' Trend Analysis of Inhaled Corticosteroids Prescription Rate and Severe Exacerbation Rate in Asthma Patients Chang Suk Noh, M.D. 1, Jae Seung Lee, M.D. 1, Jin Woo Song, M.D. 1,4, Tae-Bum Kim, M.D. 2,4, Nam Kug Kim, Ph.D. 3, You Sook Cho, M.D. 2,4, Sang-Do Lee, M.D. 1,4, Hee-Bom Moon, M.D. 2,4, Yeon-Mok Oh, M.D. 1,4 Departments of 1 Pulmonary and Critical Care Medicine, 2 Allergy and Clinical Immunology, 3 Radiology, and 4 Asthma Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Background: Inhaled corticosteroids (ICSs) are the most essential medication for asthma control. Many reports suggest that the usage of ICSs improves not only the control of asthma symptoms but also prevents exacerbation. We investigated whether increases in ICS prescriptions are associated with decreases in asthma exacerbation in the clinical practice setting. Methods: We retrospectively analyzed the database of adult asthma patients who had visited a tertiary referral hospital, the Asan Medical Center between January 2000 and December The number of emergency department (ED) visits, admissions, intensive care unit (ICU) care, deaths, and ICS prescriptions were analyzed to evaluate the time trend of asthma exacerbation as a function of the ICS prescription rate during the ten years. Results: The numbers of ED visits, admissions, and episodes of ICU care decreased during the ten years (p<0.001, p=0.033, p=0.001, respectively) while the number of ICS prescriptions increased (p<0.001). We found a correlation between the number of ICS prescriptions and the number of ED visits, admissions, or ICU care. For these outcomes, the correlation coefficients were r= 0.952, p<0.001; r= 0.673, p=0.033; r= 0.948, p<0.001, respectively. Conclusion: The number of ICS prescriptions increased during the past ten years while the number of asthma exacerbations decreased. Our results also showed a negative correlation between the ICS prescription rate and asthma exacerbation in the clinical practice setting. In other words, an increase in ICS prescription may be a major cause of a decrease in asthma exacerbations. Key Words: Asthma; Disease Exacerbation; Inhalers; corticosteroid 서 론 Address for correspondence: Yeon-Mok Oh, M.D. Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap 2-dong, Songpa-gu, Seoul , Korea Phone: , Fax: ymoh55@amc.seoul.kr Received: Feb. 5, 2011 Accepted: Apr. 10, 2011 천식치료의목적은기도염증을억제함으로써증상을조절하고유지하는데있다 1. 이러한기도염증을가장효과적으로조절할수있는약제가흡입스테로이드제라는사실은이미잘알려져있다 2. 흡입스테로이드제가천식의증상을완화시켜주고, 삶의질을향상시켜주며, 폐기능을호전시켜준다는사실은여러연구를통해서잘밝혀진 416

2 Tuberculosis and Respiratory Diseases Vol. 70. No. 5, May 2011 바있다 3-5. 뿐만아니라천식악화의빈도와중증도를감소시켜주고 6-11, 천식사망률도감소시켜준다는연구들이있었다 12. 이에흡입스테로이드제의사용빈도가꾸준히증가하고있다는외국의보고도있었지만 13, 대다수의연구들이실제임상에서의천식치료로서흡입스테로이드제가아직까지도충분하게사용되지못하는것으로보고하고있다 그이유로천식환자들의치료에증상조절제인흡입스테로이드제보다는증상완화제인기관지확장제를많이사용하는것이원인으로보인다 15,18. 이처럼외국에서는흡입스테로이드제사용에대한다양한연구및분석들이있었지만, 국내에서흡입스테로이드제사용의빈도와이에따른천식중증악화의빈도변화를조사한연구가부족하여본연구의저자들은최근 10년간서울아산병원을내원한천식환자들을분석하여천식중증악화빈도와흡입스테로이드제의처방빈도의상관성을알아보고자하였다. 대상및방법 2000년 1월 1일부터 2009년 12월 31일까지서울아산병원을내원한 18세이상의성인천식환자를대상으로흡입스테로이드제처방빈도와중증악화빈도를서울아산병원임상연구정보실무위원회를통한전산조회시스템을이용해서후향적으로분석하였다. 천식환자의정의는한국표준질병분류코드 J45에서 J46 에해당하는상병코드로진단된환자로하였고, 해당연도에중복해서병원을방문한환자의경우방문건수를각각독립된건수로간주하여분석하였다. 흡입스테로이드제는서울아산병원에서처방하는약제중스테로이드성분을포함하고있는흡입할수있는약제들을모두포함시켜분석하였다. 실제서울아산병원에서처방되었던스테로이드성분을포함한흡입약제는 budesonide (pulmicort R ), formoterol/budesonide (symbicort R ), fluticasone (flixotide R ), salmeterol/fluticasone (seretide R ), beclomethasone/formoterol (foster R ), 그리고 Ciclesonide (alvesco R ) 등이다. 흡입스테로이드제처방빈도는연도별흡입스테로이드제처방건수를각해당연도의외래방문환자수로나누어서보정하였다. 천식환자들의중증악화빈도는응급실방문건수, 입원건수, 중환자실입실건수그리고, 사망건수를통해서분석하였다. 이들각각의건수역시연도별외래방문환자수로나누어서그값을보정하였다. 통계분석은 SPSS version 18.0 (SPSS Inc., Chicago, IL, USA) 을이용하여연도에따른변화는단순선형회귀분석을, 각각의상관성여부는 Spearman 상관관계를사용하여검정하였다. p값이 0.05 미만일때통계적으로유의한것으로판정하였다. Table 1. Annual characteristics of hospital visits in asthma patients of the Asan Medical Center Year No. of hospital visits Mean age (yr)* Sex Type of hospital visits Male Female Outpatients ED Admission ICU Death ICS , ±14.9 7,575 (51.8) 7,047 (48.2) 13,636 (93.3) 543 (3.7) 443 (3.0) , , ±15.3 7,924 (50.6) 7,729 (49.4) 14,513 (92.7) 599 (3.8) 541 (3.5) , , ±15.5 8,340 (50.3) 8,225 (49.7) 15,408 (93.0) 601 (3.6) 556 (3.4) , , ±15.5 8,586 (49.0) 8,924 (51.0) 16,463 (94.0) 509 (2.9) 538 (3.1) , , ±15.7 8,243 (48.6) 8,718 (51.4) 15,964 (94.1) 500 (3.0) 497 (2.9) , , ±15.6 8,032 (48.2) 8,626 (51.8) 15,637 (93.9) 529 (3.2) 492 (2.9) , , ±15.4 7,487 (47.7) 8,206 (52.3) 14,922 (95.1) 342 (2.2) 429 (2.7) , , ±15.7 7,214 (47.3) 8,028 (52.7) 14,488 (95.1) 327 (2.1) 427 (2.8) , , ±15.8 7,548 (46.5) 8,683 (53.5) 15,409 (94.9) 333 (2.1) 489 (3.0) , , ±15.7 7,657 (45.8) 9,066 (54.2) 15,975 (95.5) 254 (1.5) 494 (3.0) ,943 Total 161, ± ,606 (48.6) 83,252 (51.4) 152,415 (94.2) 4,537 (2.8) 4,906 (3.0) ,991 Values are presented as number (%) unless otherwise indicated. *Values are mean±sd, Represents death which was recorded only inside the Asan Medical Center, but not outside, The number of prescriptions for inhaled corticosteroid. ED: emergency department; ICU: intensive care unit; ICS: inhaled corticosteroids. 417

3 CS Noh et al: Inhaled corticosteroids and severe exacerbation in asthma 결과 2000 년 1월 1일부터 2009 년 12월 31일까지서울아산병원을내원한 18세이상의성인천식환자건수는 161,858 건이었고, 이들의평균나이는 58.2±15.5세였다 (Table 1). 이들중남자가 48.6%, 여자가 51.4% 의비율분포를보였다. 병원방문형태를분석해보면외래가 152,415건으로전체방문건수의 94.2% 를차지하였고, 응급실이 4,537 건, 입원이 4,906 건이었다. 입원건수중 575건이중환자실치료를받았었고, 250건의사망건수가확인되었 Figure 1. Annual change of ED visits (A), admission (B), ICU care (C), death (D), and ICS prescription (E) in asthma patients. *r 2 and p-value were obtained by simple linear regression, For adjustment, the numbers of ED visits, admission, ICU care, death, and ICS prescription were divided by the number of outpatient visits in each year. ED: emergency department; ICS: intensive care unit; ICS: inhaled corticosteroids. 418

4 Tuberculosis and Respiratory Diseases Vol. 70. No. 5, May 2011 다. 10년간총흡입스테로이드제처방건수는 83,991건이었다. 응급실방문건수와입원건수, 중환자실입실건수, 사망건수, 흡입스테로이드제처방건수등을외래환자건수로보정하여연도별변화를보았다 (Figure 1). 응급실방문건수의연도에따른변화는단순선형회귀분석을한결과 r 2 값이 에 p값이 미만으로통계적으로유의한감소추세임을확인할수있었다. 입원건수는 r 2 값이 0.451에 p값이 0.033이었고, 중환자실입실건수는 r 2 값이 에 p값이 로두가지건수역시통계적으로유의하게감소하는추세였다. 하지만사망건수는 r 2 값이 에 p값이 으로연도에따른통계적으로유의한변화는관찰할수없었다. 흡입스테로이드제처 방건수는 r 2 값이 0.897에 p값이 미만으로연도에따라통계적으로유의하게증가하였음을알수있었다. 천식중증악화의지표로삼은각각항목들의건수와흡입스테로이드제처방건수와의상관관계를 Spearman 상관관계를이용하여상관성을분석하였다 (Figure 2). 응급실방문건수와흡입스테로이드제처방건수와의상관관계를분석한결과 Spearman 계수가 0.952로역상관관계를보였고, p값이 미만으로통계적으로유의하게나타났다. 입원건수와흡입스테로이드제처방건수와의상관관계는 Spearman 계수가 0.673으로역상관관계를보였으며, p값은 0.033으로통계적으로유의하였다. 중환자실입실건수역시흡입스테로이드제와의상관관계에서 Spearman 계수가 0.948로역상관관계를 Figure 2. Relationship between ICS prescription and ED visits (A), admission (B), ICU care (C), or death (D) in asthma patients. *Spearman's rho and p-value were obtained by Spearman's correlation, For adjustment the numbers of ED visits, admission, ICU care, death, and ICS prescription were divided by the number of outpatient visits in each year. ED: emergency department; ICS: intensive care unit; ICS: inhaled corticosteroids. 419

5 CS Noh et al: Inhaled corticosteroids and severe exacerbation in asthma 나타냈고, p값또한 미만으로통계적으로유의하였다. 하지만사망건수와흡입스테로이드제처방건수와의상관관계에있어서는 Spearman 계수가 0.171로상관관계가거의없는것으로보였고, p값역시 으로통계적유의성도찾아볼수없었다. 고찰본연구에서중증악화를나타내는여러지표중응급실내원건수와입원건수그리고중환자실입실건수가연도변화에따라그빈도가감소하였음을확인할수있었다. 하지만이러한결과는 1996 년부터 2003 년까지응급실내원환자를분석한 Mun 등 19 의연구결과와는상반된다. 이연구에의하면 2000년대에들어서면서 1990년대에비해응급실내원천식환자의수가증가함을보여줬는데그원인으로저자들은병원의사들이천식진단명을자주붙이는경향과환자들이병원응급실을자주찾는경향을그영향으로손꼽았다. 또한동일기간동안응급실을내원한천식환자의중증도도증가하였음을보여주었다. 비단국내연구뿐만아니라국외연구에서도 1990년대에천식중증도의증가를보여준결과들이있다. Russo 등 20 에의하면 19세미만소아에서산소포화도 90% 미만의심한천식발작으로입원한환자수가 1991년 31.5% 에비해 1995년 60.4% 로증가하였음을보였다. 이러한 1990 년대천식중증도의증가추세는여러가지요인들이작용하였을것으로생각되나그중에서도천식유병률증가가대표적인원인일것으로판단된다. 실제로과거에비해 1990년대까지천식유병률이과거 30년간약 2배씩증가하였다는보고가있다 21,22. 국내연구에서도소아천식이 1981년 5.6% 에서 1990년 10.1% 로증가하였다는결과가있다 23. 천식유병률증가에는위생가설과 24 함께대기오염, 스트레스, 식생활변화등이있고 25, 이러한요인들이유병률뿐만아니라중증도증가에도크게기여하였을것으로생각된다. 1990년대에계속증가하던천식중증도가 2000년대에들어서면서현저히감소하고있다는것을저자들은실제임상경험으로느낄수있었고, 본연구에서도동일한결과들을얻을수있었다. 본연구는 2000 년부터 2009 년까지사망을제외한천식중증악화의지표들이연도가증가함에따라감소하였음을보여주었다. 그리고, 이러한사망을제외한천식중증악화의지표들이흡입스테로이드제처방건수와역상관관계를보인다는것을확인할수있었다. 저자들은 2000 년대이후자료를분석하였지만, 이미일부나라에서는 1990년대에도환자교육과흡입스테로이드제사용이천식의입원률을감소시켰다는연구결과를발표한바있었다 26. 서론에서도언급하였듯이흡입스테로이드제가천식의중증악화를감소시켰다는잘설계된연구결과들이있었지만실제진료현장에서어느정도까지그효과가있는지를알아보는연구가부족했었고, 특히국내의경우전무하다시피해서본연구자료가단일기관의후향적연구임에도불구하고그의의를찾을수있다고생각한다. 하지만후향적으로자료가수집되었고, 천식진단이서울아산병원의다양한의사들에의해각각의판단기준에따라이루어지는경우도있어서진단이일관된기준으로이루어졌다고보기에는부족한측면이있다. 그렇지만분석한천식환자건수가대규모에가까워서천식진단의문제가결과에크게영향을미치지는않았을것으로생각하였고, 천식환자의중증도변화추세에그영향을미치지않을것이라고판단하였다. 또한, 본연구결과사망을제외한천식중증악화의지표들이흡입스테로이드제처방건수와역상관관계를보인것은사실이지만이러한결과로흡입스테로이드제처방이천식중증악화를줄였다고직접적으로연관지을수있는것은아닐것이다. 천식중증악화를줄이는데있어서흡입스테로이드제를제외한다른혼란변수들을고려해야하지만이미언급하였듯이기존에잘설계된연구들에서흡입스테로이드제가천식중증악화를막았다는결과를도출한바있었고, 흡입스테로이드제만큼강력하게천식중증악화에영향을미칠만한변수는없을것이라고저자들은판단하여흡입스테로이드제처방건수만으로상관관계를보았다. 분명히흡입스테로이드제가천식중증악화를막았다는직접적증거는아니겠지만, 천식중증악화감소와연관성을실제진료상황에서확인한연구로그의의가있을것이다. Suissa 등 12 에의하면흡입스테로이드제가사망률도감소시켰다고하였으나, 본연구에서는연도에따른사망률변화는보이지않았고, 흡입스테로이드제처방건수와의상관관계도없어보였다. 이는본연구의사망자들이서울아산병원에서만사망한환자만을반영했다는제한점도있고, 매년천식사망환자숫자가많지않아서해마다달리발생되는인플루엔자등과같은유행성질환의영향등이크게반영된점도있으리라생각한다. 사망에대해서는추후좀더구체적인분석이필요할것으로생각된 420

6 Tuberculosis and Respiratory Diseases Vol. 70. No. 5, May 2011 다. 본연구가단일기관의후향적연구라는제한점을가지고있어서향후에다기관공동의전향적연구가이러한제한점을해결하는데도움이될것으로기대한다. 결론적으로국내단일삼차의료기관에서천식환자의중증도는최근 10년사이에감소하였고, 흡입스테로이드제처방은점차증가하였다. 감사의글 This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A102065). 참고문헌 1. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention, updated 2010 [Internet]. Capetown, South Africa: GINA; c2010 [cited 2011 May 13]. Available from: 2. Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture Br J Pharmacol 2006; 147: Juniper EF, Kline PA, Vanzieleghem MA, Ramsdale EH, O'Byrne PM, Hargreave FE. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990;142: Haahtela T, Järvinen M, Kava T, Kiviranta K, Koskinen S, Lehtonen K, et al. Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325: van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, Duiverman EJ, Pocock SJ, Kerrebijn KF. Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness, and symptoms in children with asthma. The Dutch Chronic Non-specific Lung Disease Study Group. Am Rev Respir Dis 1992;146: Pauwels RA, Löfdahl CG, Postma DS, Tattersfield AE, O'Byrne P, Barnes PJ, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997;337: Ernst P, Spitzer WO, Suissa S, Cockcroft D, Habbick B, Horwitz RI, et al. Risk of fatal and near-fatal asthma in relation to inhaled corticosteroid use. JAMA 1992; 268: Donahue JG, Weiss ST, Livingston JM, Goetsch MA, Greineder DK, Platt R. Inhaled steroids and the risk of hospitalization for asthma. JAMA 1997;277: Barnes PJ. Current issues for establishing inhaled corticosteroids as the antiinflammatory agents of choice in asthma. J Allergy Clin Immunol 1998;101:S Blais L, Suissa S, Boivin JF, Ernst P. First treatment with inhaled corticosteroids and the prevention of admissions to hospital for asthma. Thorax 1998;53: Blais L, Ernst P, Boivin JF, Suissa S. Inhaled corticosteroids and the prevention of readmission to hospital for asthma. Am J Respir Crit Care Med 1998;158: Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000;343: Davidsen JR, Søndergaard J, Hallas J, Siersted HC, Lykkegaard J, Andersen M. Increased use of inhaled corticosteroids among young Danish adult asthmatics: an observational study. Respir Med 2010;104: Rabe KF, Vermeire PA, Soriano JB, Maier WC. Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study. Eur Respir J 2000;16: Partridge MR, van der Molen T, Myrseth SE, Busse WW. Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study. BMC Pulm Med 2006;6: Cazzoletti L, Marcon A, Janson C, Corsico A, Jarvis D, Pin I, et al. Asthma control in Europe: a real-world evaluation based on an international population-based study. J Allergy Clin Immunol 2007;120: Backer V, Nolte H, Pedersen L, Dam N, Harving H. Unawareness and undertreatment of asthma: follow-up in a different geographic area in Denmark. Allergy 2009;64: Kaplan A, Ryan D. The role of budesonide/formoterol for maintenance and relief in the management of asthma. Pulm Pharmacol Ther 2010;23: Mun JS, Choi IS, Sim MK. Recent trend in prevalence and severity of acute asthma in an emergency room. Korean J Asthma Allergy Clin Immunol 2005;25: Russo MJ, McConnochie KM, McBride JT, Szilagyi PG, Brooks AM, Roghmann KJ. Increase in admission threshold explains stable asthma hospitalization rates. 421

7 CS Noh et al: Inhaled corticosteroids and severe exacerbation in asthma Pediatrics 1999;104: Peat JK, van den Berg RH, Mellis CM, Leeder SR, Woolcock AJ. Changes in the prevalence of asthma and allergy in Australian children Am Rev Respir Dis 1993;147:A International Consensus Report on Diagnosis and Management of Asthma (NIH publication ). Bethesda, MD: US Department of Health and Human Services, Public Health Service, National Institutes of Health; Shin TS, Lee GJ, Yoon HS. A survey of the distribution of allergic diseases in primary schoolchildren. Allergy 1990;10: Kemp A, Björkstén B. Immune deviation and the hygiene hypothesis: a review of the epidemiological evidence. Pediatr Allergy Immunol 2003;14: Suh JK, Lee SR, Lee SY, Lee SH, Cho JY, Shim JJ, et al. Clinical Characteristics of Asthmatic Patients Who Visited Emergency Room. Tuberc Respir Dis 1997; 44: Wennergren G, Kristjánsson S, Strannegård IL. Decrease in hospitalization for treatment of childhood asthma with increased use of antiinflammatory treatment, despite an increase in prevalence of asthma. J Allergy Clin Immunol 1996;97:

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386-390.hwp 386 HANYANG MEDICAL REVIEWS Vol. 29 No. 4, 2009 우리나라 미숙아의 통계와 의료비용 Statistics and Medical Cost of Preterm in Korea 윤혜선 을지대학교 노원을지병원 소아청소년과학교실 Hye Sun Yoon, M.D., Ph.D., Department of Pediatrics, Nowon