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1 대한내과학회지 : 제 87 권제 6 호 특집 (Special Review) - 약물알레르기 아스피린및비스테로이드성항염증제과민반응 인하대학교의학전문대학원내과학교실 김철우 Hypersensitivity to Aspirin and Nonsteroidal Anti-inflammatory Drugs Cheol-Woo Kim Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medications, based on their antipyretic, analgesic, and anti-inflammatory effects. However, both aspirin and NSAIDs cause hypersensitivity reactions through immunologic as well as non-immunologic mechanisms. Except for the rare single-nsaid-induced reaction, most hypersensitivity reactions show cross-reactive features to other NSAIDs regardless of their chemical structure. An accurate correct medical history is the most important diagnostic approach, whereas the roles of blood and skin tests are limited in the majority of cases of NSAIDs hypersensitivity. Although able to confirm the presence of a hypersensitivity reaction, an oral or bronchial provocation test should be performed only under the supervision of a skilled physician at a well-equipped institution. Avoidance of the causative NSAID and all cross-reactive NSAIDs is the cornerstone of management. Patients who require treatment with aspirin or NSAIDs can undergo aspirin desensitization. Genetic predisposition to hypersensitivity to NSAIDs have been demonstrated, but a clear understanding of the pathophysiologic and phenotypic diversity of these hypersensitivity reactions requires further studies, including functional ones. (Korean J Med 2014;87: ) Keywords: Aspirin; Nonsteroidal anti-inflammatory drug; Hypersensitivity; Allergy 서론아스피린과비스테로이드성항염증제 (nonsteroidal anti-inflammatory drugs, NSAIDs) 는해열, 진통및소염효과로인하여다양한분야에서널리사용되는약제이다. 아스피린과 NSAIDs는약물유해반응을일으키는가장흔한약제로전체유해반응의약 25% 정도를차지하며 [1], 우리나라에서도약 물유해반응을일으키는가장흔한원인의하나로알려져있다 [2,3]. 아스피린과 NSAIDs에의한약물유해반응은발생기전및임상양상에따라 A형과 B형으로분류한다. A형반응은고유한약리학적기능이나약물-약물상호작용에의해서나타나는용량의존적반응으로소화불량, 위궤양또는출혈등을예로들수있다. B형약물유해반응은발생을예측하기어렵 Correspondence to Cheol-Woo Kim, M.D., Ph.D. Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, 27 Inhang-ro, Jung-gu, Incheon , Korea Tel: , Fax: , cwkim1805@inha.ac.kr Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 87, No. 6, Table 1. Clinical manifestation of hypersensitivity reaction to aspirin and NSAIDs Timing of reaction Reaction Clinical manifestation Acute Immunologic type I Anaphylaxis, urticaria, angioedema Non-immunologic Asthma exacerbation, urticaria, angioedema Delayed (more than several hours after exposure) Immunologic type II Immunologic type III Immunologic type IV Non-immunologic Hemolytic anemia, thrombocytopenia Serum sickness, vasculitis Contact dermatitis, severe exfoliative dermatoses (eg, SJS/TEN), AGEP, DRESS syndrome Pneumonitis, aseptic meningitis, nephritis NSAIDs, nonsteroidal anti-inflammatory drugs; SJS/TEN, Stevens-Johnson syndrome/toxic epidermal necrolysis; AGEP, Acute generalized exanthematous pustulosis; DRESS syndrome, Drug reaction with eosinophilia and systemic symptoms syndrome. 고투여용량에관계없이발생하며, 약리학적작용과관련이없고개인에따른면역학적또는유전적소인에의하여나타나는것으로, 약물복용후천식의악화, 두드러기, 혈관부종등을예로들수있다. 아스피린과 NSAIDs에의하여나타나는 B형유해반응을예전부터아스피린과민반응으로부르고있으나, 실제임상에서는아스피린보다 NSAIDs 사용이훨씬많기때문에 NSAIDs 복용후나타나는과민반응의빈도가훨씬높아최근에는이를 NSAIDs 과민반응으로부르기도한다 [4]. 본고에서는아스피린또는 NSAIDs에의한과민반응을 NSAIDs 과민반응으로통칭하고, NSAIDs 과민반응의분류, 기전및진단적접근에대하여간단히살펴보고자한다. 본론분류 NSAIDs 과민반응은투여후반응이나타나는시간에따라즉시반응과지연반응으로나눈다. 즉시반응은두드러기, 기관지수축또는아나필락시스와같이약물노출후 1시간이내에발생하며, 지연반응은약물투여 1시간이후에발생하고반점구진상발진과같은다양한피부발진과발열, 장기침범양상을나타낸다. 또한아스피린과 NSAIDs는투여후제1-4형면역학적기전으로과민반응을일으킬수있으며, 그외비면역학적기전에의하여다양한이상반응을일으킬수있다 (Table 1). 최근에는 NSAIDs 과민반응을다른 NSAIDs와의교차반응여부및기저질환에따라분류한다 [4]. 교차반응을보이는형태로는 NSAIDs 또는아스피린에의해악화되는호흡기질 환 (NSAIDs-exacerbated respiratory disease, NERD 또는 aspirinexacerbated respiratory disease, AERD), NSAIDs 에의해악화되는피부질환 (NSAIDs-exacerbated cutaneous disease, NECD), NSAIDs에의한두드러기 / 혈관부종 (NSAIDs-induced urticaria/ angioedema, NIUA) 등이있으며, 교차반응이없는과민반응으로단일 NSAID에의한두드러기 / 혈관부종또는아나필락시스 (single-nsaid-induced urticaria/angioedema or anaphylaxis, SNIUAA) 와단일 NSAID에의한지연형반응 (single-nsaidinduced delayed reaction, SNIDR) 등이있다 (Table 2). NERD/AERD 일반인에서 NSAIDs 과민반응은 0.3% 정도이나 [5] 성인천식환자에서는약 10-20% 까지과민반응이보고되어있다 [6]. 또한스테로이드의존성성인천식환자에서 NSAIDs 과민반응의빈도가높으며, 비용종이나부비동염이동반된천식환자의약 1/3 정도가아스피린과민반응을가지고있다. 부비동염이나비용종, 천식, 아스피린과민반응세가지가모두있는경우를 Samter 세증후 (Samter s triad) 라고한다 [7]. 따라서비용종등이있는천식환자에게아스피린이나 NSAIDs 를투여할때에는주의를요한다. 천식환자에서 NSAIDs 과민반응의기전은명확하지않으나아라키돈산대사와관련된약리학적효과와관계가있다 (Fig. 1). 즉아스피린과 NSAIDs는세포막의아라키돈산대사에중요한효소인시클로옥시게나아제 (cyclooxygenase, COX) 를억제하여해열, 진통및항염증작용을나타낸다. 그러나 COX, 특히 COX-1이차단됨으로써류코트리엔 (leukotriene, LT) 을합성하는 LTC4-synthase를억제하는 Prostaglandin E

3 - Cheol-Woo Kim. Hypersensitivity to Nonsteroidal Anti-inflammatory Drugs - Table 2. Classification of hypersensitivity reaction to aspirin and NSAIDs Reaction Underlying disease Cross-reactivity Clinical manifestation Mechanism NERD Asthma, rhinosinusitis/polyp Cross-reactive Asthma, rhinitis COX-1 inhibition NECD Chronic urticaria Cross-reactive Urticaria/angioedema COX-1 inhibition NIUA Cross-reactive Urticaria/angioedema COX-1 inhibition SNIUAA Single drug-induced Urticaria/angioedema, anaphylaxis IgE mediated SNIDR Single (or multiple) drug-induced SJS/TEN, AGEP Fixed drug eruptions T cell mediated, Other NSAIDs, nonsteroidal anti-inflammatory drugs; NERD, NSAIDs-exacerbated respiratory disease; COX, cyclooxygenase; NECD, NSAIDsexacerbated cutaneous disease; NIUA, NSAIDs-induced urticaria/angioedema; SNIUAA, single-nsaid-induced urticaria/angioedema or anaphylaxis; IgE, immunoglobulin E; SNIDR, single-nsaid-induced delayed reaction; SJS/TEN, Stevens-Johnson syndrome/toxic epidermal necrolysis; AGEP, Acute generalized exanthematous pustulosis. Figure 1. Metabolism of arachidonic acid (from Inflammatory Chemical Mediators. In: Korean Academy of Asthma, Allergy and Clinical Immunology. Asthma and allergic diseases. 2nd ed. Seoul: Ryo Moon Gak.P.Co, 2012;118). CPLA2, phospholipase A2; 5-LO, 5-lipoxygenase; COX, cyclooxygenase; FLAP, 5-lipoxygenase- activating protein; 5-HETE, 5-hydroxyeicosatetraenoic acids; 5-HPETE, 5-hydroperoxyeicosatetraenoic acids; PGG 2, prostaglandin G 2; LTB 4, leukotriene B 4; LTA 4, leukotriene A 4; LTC 4S, leukotriene C 4 synthase; PGH 2, prostaglandin H 2; LTD 4, leukotriene D 4; γ-gt, γ-glutamyl transpeptidase; DiP, dipeptidases; TXA 2, thromboxane A 2; PGD 2, prostagladin D 2; PGE 2, prostaglandine E 2; PGI 2, prostaglandin I 2; PGF 2α, prostaglandin F 2a; LTE 4, leukotriene E 4. (PGE 2) 형성이줄어들고, 아라키돈산의다른중요대사경로인 5-리폭시게나아제 (5-lipooxygenase, 5-LO) 경로가상대적으로우세해져류코트리엔생성이증가하게된다. 이렇게증가된 LTC 4, LTD 4, LTE 4 등은기관지수축을일으키고기도점액분비를촉진하며기도염증을심화시켜천식을악화시킨다 [8]. NERD 진단을위해서는복용한약물의종류, 약물복용후증상발생까지의시간및증상등에대한자세한병력청취가필요하며, 면역학적기전으로나타나지않기때문에혈액검사나피부시험은도움이되지않는다. 경구아스피린유발시험또는 lysine-aspirin을이용한흡입기관지유발시험을통하 여확진할수있으며 [9], 심한천식반응이나타날수있기때문에폐기능저하가심한중증천식환자에서는시행을금하며, 경험이풍부한의사가응급상황에대비한장비등을갖춘상태에서조심스럽게시행하여야한다. NERD 환자의대부분은여러 NSAIDs에대하여교차반응을보이며, 교차반응의정도는 COX에대한선택적억제정도에따라다르다 (Table 3). 즉 COX-1에대한억제효과가큰비선택적 COX 차단제인대부분의 NSAIDs 사이는교차반응을보이며, COX-2에대한선택적억제기능이비교적큰 meloxicam이나 nimesulide도일부환자에서교차반응을일으키므로가급적피해야하고, celecoxib 와같은선택적 COX-2 차

4 - 대한내과학회지 : 제 87 권제 6 호통권제 652 호 Table 3. COX-selectivity of NSAIDs Nonselective COX inhibitors Aspirin Aceclofenac, diclofenac, indomethacin, ketorolac, sulindac Dexibuprofen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, loxoprofen, naproxen Mefenamic acid, flufenamic acid, meclofenamic acid, tolfenmic acid Piroxicam, tenoxicam, dorxicam, lornoxicam Phenazone, phenylbutazone, propyphenazone More COX-2 inhibitors Etodolac, meloxicam, nemusulide Selective COX-2 inhibitor Celecoxib, rofecoxib, etoricoxib, parecoxib, parvocoxib COX, cyclooxygenase; NSAIDs, nonsteroidal anti-inflammatory drugs. 단제는안전하게사용할수있다. 저용량의 acetaminophen의경우 NERD 환자에서비교적안전하게투여할수있으나, acetaminophen을 1,000 mg 이상으로고용량투여하는경우 COX-1 억제효과가나타나교차반응을보일수있으므로주의를요한다 [1,10]. NECD 만성두드러기나혈관부종환자의약 1/3은아스피린이나 NSAIDs 복용 2-3시간이내에두드러기나혈관부종의악화를보이며, 일부환자에서는호흡기증상도나타난다 [11]. NSAIDs 과민반응이만성두드러기에선행하여나타나기도하며, 기저질환인만성두드러기의활성도에따라 NSAIDs 과민반응의정도도변동을보이며일부환자에서는시간이지남에따라과민반응이없어지기도한다 [12]. NECD의기전은명확하지않으나, NERD 와같이 COX-1 차단에의한 PGE 2 생성감소로인하여 LTC 4, LTD 4, LTE 4 등과같은염증매개물질증가가관여하는것으로설명하고있다. 면역학적기전이관여하지않기때문에혈청검사나알레르기피부시험은도움이되지못하며, 아스피린경구유발시험을통하여 NECD를확진할수있다. 단환자의상태에따라서아스피린경구유발시험에서음성반응을보일수있으며, 임상적으로 NSAIDs 과민반응이강력히의심될때는환자가증상이나타났을때복용한 NSAIDs를이용한경구유발시험으로추가확인을하여야한다. NERD 에서와같이대부분의 NSAIDs는교차반응을일으킬 수있으므로피해야하며, acetaminophen이나선택적 COX-2 차단제는비교적안전하게사용할수있다. 그러나 NERD와달리 celecoxib 나 rofecoxib 와같은선택적 COX-2 차단제의경우도일부환자에서증상을일으킬수있으므로주의를해야한다 [13]. NIUA NECD와달리기저질환이없는건강인에서아스피린이나 NSAIDs 복용후두드러기나혈관부종이나타날수있다. NIUA의기전은명확하지않으나 NECD와같이 COX-1 차단에의한현상으로보고있으며, 일반적으로 NSAIDs 복용후수분에서수시간사이에눈이나안면부의혈관부종이나타나는게특징이며, 전신두드러기가동반되거나두드러기만나타날수도있다. NIUA 환자의약 1/3에서나중에만성두드러기가생긴다는보고도있다 [14]. 혈액검사나피부시험은도움이안되며경구유발시험을통하여진단할수있다. 비선택적 COX 차단제는피해야하며일부환자는 meloxicam이나 nimesulide와같이 COX-2에대한상대적인차단효과가큰약제뿐만아니라 acetaminophen이나선택적 COX-2 차단제에도반응을한다. 따라서 NSAIDs 치료가필요한경우투여하고자하는약제의안전성을미리경구유발시험을통하여확인후투약하는것이좋다. SNIUAA 아스피린이나 NSAIDs의 COX 억제작용이아니라특정 NSAID에대한특이 immunoglobulin E (IgE) 반응으로알레르기반응이나타날수있으며, 이런경우에는여러 NSAIDs에교차반응을보이지않고특정약물또는구조적으로유사한 NSAIDs에만반응을보인다. 이경우에는원인되는약물만확인되면구조가다른 NSAIDs는안전하게사용할수있기때문에 NSAIDs 간의교차반응을보이는 NECD나 NIUA와구별하는게중요하다 [1,10]. SNIUAA는 COX 억제와는관계없이나타나며, 투약후수분이내에심한아나필락시스반응까지나타나는것으로보아특정약물에대한 IgE 매개반응에의한것으로생각된다. 따라서원인이되는약물을이용한알레르기피부시험에서양성으로나타날수있으며, 혈청학적검사로특이 IgE 항체를확인할수도있다. 필자는 SNIUAA가의심되는환자에서

5 - 김철우. 비스테로이드성항염증제과민반응 - 피내시험을시행하는도중심한알레르기반응을경험한바도있는데이것은 IgE 매개반응의특성을잘나타내는것이다. 병력및검사로 SNIUAA로진단된경우에는원인약제뿐만아니라교차반응의가능성이있는구조적으로유사한 NSAID는피해야하며, 아스피린이나다른 NSAID를이용한경구유발시험을시행하여교차반응이없는것을확인하는게필요하다. SNIDR NSAID 복용후수시간에서수일후에지연형반응이나타날수있다. 제2형과민반응에의하여용혈성빈혈이나혈소판감소증이나타날수있으며, 제3형과민반응으로혈청병과유사한증상이나타날수있다. 제4형과민반응또는약물특이 T세포매개반응으로반점구진상발진이흔히나타나며, 드물게중증피부유해반응인 Drug reaction with eosinophilia and systemic symptoms (DRESS) 증후군, 스티븐스-존슨증후군또는독성표피괴사용해 (toxic epidermal necrolysis, TEN) 등을일으킨다. 이외에고정약진, 폐장염, 무균성뇌막염, 신염등이 NSAID에의하여나타날수있다 [1,10]. 따라서 NSAID를포함한약물을복용중이러한증상이나타나는경우기저질환의악화뿐만아니라약제에의한새로운유해반응이아닌지꼭의심해야하며, 제4형과민반응에의한경우에는첩포검사를시행할수있으나민감도가낮고경구유발검사는심한반응을일으킬수있으므로중증반응을경험하였던환자에서는가급적시행하지않는것이좋다. NSAIDs 과민반응의진단적접근 NSAIDs 과민반응의진단에있어가장중요한사항은자세한병력청취로, 많은경우임상적인증상과약제투여와의시간적인과관계에근거한병력에바탕을두고진단을한다. 투여한약물, 증상및징후의발생시간과양상, 검사소견등모든임상양상을확인하여야하며, 과거에유사한증상을경험한적이있었는지, 그리고동일또는유사한계통의약물을사용한적이있었는지도확인하여야한다 [1,4]. 약물유해반응의진단에있어병력으로원인약물이확실치않을경우피부시험이나혈청특이 IgE 검사등을시행하나, NSAIDs 과민반응의경우단일약제에의한두드러기 / 혈관부종, SNIUAA를제외하고는이러한검사가도움이되지않는다. 따라서병력청취와기타검사로 NSAIDs 과민반응을확인할수없거나투여하고자하는 NSAIDs 의안전성을확인하기위해서는약물유발시험을고려해야한다. 유발시험은아나필락시스등과같은심한전신반응의위험성이있기때문에, 많은경험과적절한시설과장비를갖춘상태에서시행해야한다. 아스피린탈감작아스피린또는 NSAIDs에악화되는천식 (NERD) 환자에서관상동맥질환이나관절염등으로인하여아스피린이나 NSAIDs 복용이필요한경우에는, 아스피린탈감작을시행하여비교적안전하게아스피린이나 NSAIDs를투여할수있다. 그러나 NECD 또는 NIUA 환자에서의아스피린탈감작은아직이견이많으며근거가충분하지않다 [9,15]. 탈감작상태를유지하기위해서매일일정용량의아스피린을지속적으로복용해야하며, 중단할경우에는 3-4일후에과민반응이다시나타날수있다. 비용종이나비부비동염이심한 NSAIDs 과민성천식환자에서아스피린탈감작으로비부비동염과천식증상이호전되고비용종에대한수술적치료필요성이감소될수도있다 [16]. NSAIDs 과민반응의유전적요인 COX 억제가과민반응의중요한기전임이알려짐에따라아라키돈산대사를포함한다양한과정에서의유전적변이에의하여 NSAIDs 과민반응이나타남이밝혀지고있다. 즉 5-LO [17] 및 LTC4 synthase [18] 를대상으로하는유전체연구이후많은유전적변이가 NSAIDs 과민반응과관련있음이밝혀졌으며, 우리나라에서도아스피린과민성천식및아스피린유발성두드러기환자를대상으로한많은연구결과가보고되어있다 [19]. 그러나 NSAIDs 과민반응에복잡하고많은유전적요인이관여함에따라아직유전적기전이확실하게이해되지는않고있다. 향후유전체연구기법의발달과함께유전자상호작용에대한연구, 후성유전체적인접근, 그리고다양한기능적연구를통하여 NSAIDs 과민반응의유전적기전에대한보다명확한이해가필요하다

6 - The Korean Journal of Medicine: Vol. 87, No. 6, 결 다양한약제종류와광범위한분야에서의사용으로인하여아스피린과 NSAIDs에의한과민반응은앞으로도계속늘어날것이다. 아스피린과 NSAIDs는경증의피부발진에서부터생명을위협하는천식의악화또는 DRESS 증후군, 스티븐슨-존슨증후군, TEN 까지매우다양한과민반응을일으킬수있다. 병력, 약물복용력, 임상양상및증상발현시간등에대한정확하고세밀한정보를통하여원인되는약제를찾아야하며, 필요한경우유발시험을적절히시행하여원인약제와대체약제를확인하여야한다. 천식, 비부비동염, 비용종또는만성두드러기와같은기저질환이있는지를확인하는것은 NSAIDs 과민반응의다양한표현형을이해하고진단하는데크게도움이되며, 이러한접근을통하여 NSAIDs 과민반응의기전에대한이해의폭이넓어지고있다. 또한최근에많이진행되고있는유전체적연구등을통하여향후에는 NSAIDs 과민반응의예방과치료에대한많은발전을기대할수있을것이다. 중심단어 : 아스피린 ; 비스테로이드성항염증제 ; 과민반응 ; 알레르기 론 REFERENCES 1. Kowalski ML, Makowska JS, Blanca M, et al. Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) - classification, diagnosis and management: review of the EAACI/ENDA # and GA2LEN/HANNA *. Allergy 2011;66: Kim MH, Jung HY, Sohn MK, et al. Clinical features of adverse drug reactions in a tertiary care hospital in Korea. Korean J Asthma Allergy Clin Immunol 2008;28: Rew SY, Koh YI, Shin HY, et al. Reporting and clinical features of adverse drug reactions from a single university hospital. Korean J Asthma Allergy Clin Immunol 2011;31: Kowalski ML, Asero R, Bavbek S, et al. Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs. Allergy 2013;68: Settipane RA, Constantine HP, Settipane GA. Aspirin intolerance and recurrent urticaria in normal adults and children. Epidemiology and review. Allergy 1980;35: Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ 2004;328: Samter M, Beers RF Jr. Intolerance to aspirin. Clinical studies and consideration of its pathogenesis. Ann Intern Med 1968;68: Kong JS, Teuber SS, Gershwin ME. Aspirin and nonsteroidal anti-inflammatory drug hypersensitivity. Clin Rev Allergy Immunol 2007;32: Hope AP, Woessner KA, Simon RA, Stevenson DD. Rational approach to aspirin dosing during oral challenges and desensitization of patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2009;123: Mourad AA, Bahna SL. Hypersensitivities to non-steroidal anti-inflammatory drugs. Expert Rev Clin Immunol 2014; 10: Erbagci Z. Multiple NSAID intolerance in chronic idiopathic urticaria is correlated with delayed, pronounced and prolonged autoreactivity. J Dermatol 2004;31: Setkowicz M, Mastalerz L, Podolec-Rubis M, Sanak M, Szczeklik A. Clinical course and urinary eicosanoids in patients with aspirin-induced urticaria followed up for 4 years. J Allergy Clin Immunol 2009;123: Sánchez Borges M, Capriles-Hulett A, Caballero-Fonseca F, Pérez CR. Tolerability to new COX-2 inhibitors in NSAIDsensitive patients with cutaneous reactions. Ann Allergy Asthma Immunol 2001;87: Asero R. Intolerance to nonsteroidal anti-inflammatory drugs might precede by years the onset of chronic urticaria. J Allergy Clin Immunol 2003;111: Burnett T, Katial R, Alam R. Mechanisms of aspirin desensitization. Immunol Allergy Clin North Am 2013;33: Rozsasi A, Polzehl D, Deutschle T, et al. Long-term treatment with aspirin desensitization: a prospective clinical trial comparing 100 and 300 mg aspirin daily. Allergy 2008;63: In KH, Asano K, Beier D, et al. Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J Clin Invest 1997;99: Sanak M, Simon HU, Szczeklik A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet 1997;350: Kim SH, Sanak M, Park HS. Genetics of hypersensitivity to aspirin and nonsteroidal anti-inflammatory drugs. Immunol Allergy Clin North Am 2013;33:

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untitled 약물역학위해관리학회지 2018;10:49-53 REVIEW 아스피린및비스테로이드성항염증제약물과민반응의임상적접근 가천대학교길병원내과 강성윤ㆍ이상표ㆍ이상민 Approaches to the Diagnosis and Management of Hypersensitivity Reactions to Aspirin and Nonsteroidal Anti-inflammatory