online ML Comm Clinical Review Korean J Otorhinolaryngol-Head Neck Surg 2013;56: / pissn / eissn

Transcription

1 online ML Comm Clinical Review Korean J Otorhinolaryngol-Head Neck Surg 2013;56: / pissn / eissn Pathophysiology, Diagnosis, and Treatment of Allergic Rhinitis Yang-Gi Min Department of Otolaryngology-Head and Neck Surgery, National Medical Center, Seoul, Korea 알레르기비염의병태생리, 진단과치료 민양기 국립중앙의료원이비인후과 Received March 25, 2013 Accepted April 10, 2013 Address for correspondence Yang-Gi Min, MD, PhD Department of Otolaryngology- Head and Neck Surgery, National Medical Center, 245 Eulji-ro, Jung-gu, Seoul , Korea Tel Fax ygmin312@dreamwiz.com Allergic rhinitis (AR) requires treatment with a stepwise approach depending on the severity and duration of symptoms. Treatment options for AR include allergen avoidance, pharmacotherapy, immunotherapy, and surgery. Recently, anti-ige antibody and specific antibody to cytokines, such as interleukin (IL)-4 or IL-5, have emerged in connection with understandings of the mechanisms of AR. Sublingual immunotherapy has been widely used based on its efficacy, safety, and convenience, which replaces subcutaneous immunotherapy. Although allergen avoidance and immunotherapy are theoretically ideal, it is thought that antihistamines and intranasal corticosteroids will play the main role in the management of AR until an innovative treatment develops. However, patients main symptoms, the duration and severity of AR, patients compliance, the safety of medication, and cost-effectiveness should be considered when treatment options are selected. In this aspect, physicians should be aware of the etiology, pathophysiology, symptoms, signs, and diseases related to AR in order to make correct diagnoses and choose proper treatment options for each patient. Korean J Otorhinolaryngol-Head Neck Surg 2013;56: Key WordsZZDiagnosis ㆍ Hypersensitivity ㆍ Perennial allergic rhinitis ㆍ Physiopathology ㆍ Seasonal allergic rhinitis ㆍ Therapy. 서론 알레르기비염은외부항원에의한비강내 IgE 매개과민반응에의해서콧물, 재채기, 코가려움증그리고코막힘과같은증상이나타나는질환이다. 1) 알레르기비염은전세계적으로유병률이증가하는추세로, 미국에서는대략 6천만인구가이환되어있으며, 성인에서는 10~30%, 소아에서는 40% 정도로추정하고있다. 2-4) 1999년 11월부터 2000년 4월까지국내 23개 3차병원이비인후과외래를방문한 명의환자를대상으로알레르기비염의유병률을조사한결과통년성알레르기비염의유병률은 3.93% 였다. 5) International Study of Asthma and Allergies in Childhood 설문지를통한 42886명의한국인을대상으로한조사에서는, 초등학생 (6~12 세 ) 과중학생 (12~ 15세 ) 의 12개월유병률은각각 28.8% 와 29.1% 였다. 6) 알레르기비염은직장생활, 학교생활, 그리고수면등삶의질과연관된문제를야기하여천문학적인경제적손실을가져오고있다. 미국의경우 1996년한해동안지출비용이 19억달러였다. 7) 뿐만아니라, 알레르기비염과천식과의연관성에관한연구가진행되면서알레르기비염의치료에더욱관심이집중되고있다. 이에 Allergic Rhinitis and its Impact on Asthma(ARIA) 에서는 2001년알레르기비염치료에대한지침을제시하였고, 이후연구결과가축적되면서 2008년가이드라인을재개정하기에이르렀다. 8) ARIA 가이드라인의핵심은알레르기비염의분류를비염의지속성과증상경중에따라나눈것이며, 증상의경중에따라단계적인치료를해야한다는것이다. 그리고중증의지속성알레르기비염의경우천식에대한검진을추천한다 256 Copyright 2013 Korean Society of Otorhinolaryngology-Head and Neck Surgery

2 Allergic Rhinitis Min YG 는점이다. ARIA 2008 가이드라인에서알레르기비염치료에있어변화된점은국소분무스테로이드제재가 2차치료약의개념에서 1차치료약의개념으로바뀌고, 1세대보다는 2세대항히스타민제가추천되며, 항류코트리엔제재의등장과면역치료의역할에대한재평가등이라할수있다. 따라서, 여기에서는알레르기비염의기본병태생리, ARIA 분류, 진단법, 그리고치료에대해정리하고, 최신지견에관하여알아보고자한다. 알레르기비염의병태생리 알레르기항원 (Allergen) 감작점막표면에있는수지상세포 (dendritic cell) 와같은항원제시세포 (antigen presenting cells) 는알레르기항원을처리하고일부펩티드를 major histocompatibility complex (MHC) II molecule에표현한다. 9) 이 MHC II-항원복합체는 naive CD4+ T 세포의 T cell receptor 에작동하여알레르기항원특이 Th2 세포로분화시키게된다. 활성화된 Th2 세포는여러사이토카인을분비하여특이 IgE를생산하는 B 세포의동종형변환 (isotype switching) 을유도하고, 호산구, 비만세포, 호염기구의증식등을유발한다 (Fig. 1). 10) 생산된항원특이 IgE 는비만세포나호염기구의표면의고친화성 IgE receptor 에결합한다. 조기반응과후기반응비염환자에서원인항원에노출되면 30분이내에재채기, 비 루등이나타났다가회복되고약 6시간후에다시코막힘이나타나서서히회복되는현상을보인다. 항원에노출된후증상이발현되는 2개의양상중전자를조기반응, 후자를후기반응이라고한다. 조기반응은항원의재유입에대한비만세포의반응 ( 제1형과민반응 ) 이다. 자극을받은비만세포는히스타민, 프로스타글란딘, 류코트리엔등의화학적매개물질을분비하여코증상을일으킨다. 11) 반면, 후기반응의본질은전기반응에의해서유도된화학적매개물질에의한호산구의동원이다. 호산구를비롯한여러염증세포는비강점막에모여들어정상조직을파괴하고재형성시키는과정을일으키며, 12) 이는알레르기비염환자들이만성적으로호소하는코막힘의주된기전이된다. 신경성염증호산구에서유리된세포독성단백에의해호흡점막상피세포가손상되고지각신경종말이노출되면여러가지비특이적자극에반응한지각신경섬유는구심성경로뿐아니라지각신경이분포하고있는주위조직에원심성경로를통해그자극이전달되는역행성신경반사 (retrograde axon reflex) 를일으킨다. 이로인해지각신경에서 substance P, neurokinin A 같은 neuropeptide 를분비하여평활근의수축및배세포에서의점액분비, 모세혈관으로부터혈장삼출등을초래하게되는데이를신경성염증이라한다. 13) 기도과민반응기도과민반응은알레르기염증반응의특징적임상증상중하나이다. 호산구의침윤및비점막상피세포의파괴로인해 Allergen Dendritic cell IL-3 IL-4 IL-5 IL-9 T cell IgE Bascphil B cell Eosinophil Mast cell Fig. 1. Allergen-induced sensitization and inflammation. 10) IL: interleukin

3 Korean J Otorhinolaryngol-Head Neck Surg 2013;56: 정상적인자극에대해서도비점막의반응성이증가하여재채 기, 가려움증, 코막힘등의증상을나타낸다. 14) 이는 IgE 가관 여하지않는비면역적반응이며알레르기비염환자가원인항 원에노출된후담배연기나차갑고건조한공기와같은비특이 적자극에도감수성이증가하는것을말한다. 천식과알레르기비염과의연관성 - One airway, one disease 역학적으로천식환자의대부분이비염을가지고있을뿐아 니라, 천식환자의비강내소견은증상유무에관계없이호산 구성염증을가지고있다고보고되고있다. 15,16) 또한, 알레르기 비염환자에서천식의유병률은보고자마다다르지만 10% 에 서 40% 에이른다. 5,15,17-19) 여러임상연구에서천식이없는알레 르기비염환자의기관지점막내의호산구침윤을보고하고있 다 ) 특히, Madonini 등 24) 은꽃가루알레르기비염환자의 48% 에서꽃가루가날리는계절에기관지과민성이증가함을 증명하였고, Corren 등 25) 은알레르기비염환자의비강내항 원자극이기관지과민성을유발함을증명하였다. 이러한연구 결과를토대로, 많은연구자들은상기도와하기도의구조의유 사성과 26,27) 알레르기염증반응세포와염증매개물질, 사이토 카인의유사성으로인해 12,28) 천식과비염은별개의질환이아 니라 one airway, one disease 라는개념을도입하고, 천식환 자에서는비염을, 비염환자에서는천식병발유무를확인하고 동반된상기도및하기도의병변을함께치료할것을주장하 고있다. 이에 ARIA(2008) 에서도중등도 - 중증지속적알레 르기비염환자는천식에대한검사를시행할것을권고하고 있다. 알레르기비염의 ARIA 분류 과거에알레르기비염은항원에노출되는시기에따라서계 절성과통년성으로나뉘었다. 통년성알레르기비염은주로집 먼지진드기, 바퀴벌레, 동물의털이나각질, 곰팡이같은실내 항원에의해서야기되고, 계절성알레르기비염은주로꽃가루와같은실외항원에의해유발된다. 그러나, 꽃가루항원은지역에따라서는통년성항원이되며, 특정꽃가루의노출시기가지나도집안의카펫, 가구, 침구류등에흡착되어지속적으로노출될수도있다. 또한통년성알레르기비염환자에서일년내내증상이지속되지않기도하고, 계절성알레르기비염환자가여러항원에감작되어일년내내증상이나타나기도한다. 게다가통년성알레르기비염환자중에서통년성증상이있으면서꽃가루에노출되면계절적으로증상의악화를보이기도한다. 이와같은이유로 2001년 ARIA에서 계절성, 통년성 이라는용어대신 간헐적 (intermittent) 과 지속적 (persistent) 이라는용어를제안하였다. 또한알레르기비염의증상으로인해일상생활, 직장혹은학교생활및수면에미치는영향을주관적으로평가하여경증, 중등도- 중증으로나누어치료지침을제시하였다 (Fig. 2). 최근에는 ARIA 분류가한국인에게있어증상점수및삶의질과의연관성은높으나, 국내의진료실정에는불편한점이있어한국인을위한분류를따로만들자는목소리도있다. 29) 알레르기비염의진단 알레르기비염의진단은알레르기비염의전형적인증상과진단검사를통해서이루어진다. 8) 임상적으로수양성비루, 재채기, 코막힘그리고가려움증중 2가지이상의증상이 1시간이상만성적으로지속될때는알레르기비염이강력히의심되므로 ARIA 가이드라인에따라질환의경중분류가필요하고피부반응검사나특이 IgE 항체검사를시행하여알레르기비염으로진단한다. 반면에알레르기비염과관련이없는증상으로한쪽코에국한된증상, 점액농성의비루, 점액성후비루, 통증, 반복적비출혈, 후각소실등이있다. 피부반응검사피부반응검사는알레르기질환의원인항원을찾는데가장주 Intermittent Symptoms <4 days per week or <4 consecutive weeks Persistent Symptoms >4 days/week and >4 consecutive weeks 258 Mild All of the following Normal sleep No impairment of daily activities, sport, leisure No impairment of work and school Symptoms present but not troublesome Moderate-severe One or more items Sleep disturbance Impairment of daily activities, sport, leisure Impairment of school or work Troublesome symptoms Fig. 2. ARIA classification of allergic rhinitis. 1) ARIA: Allergic Rhinitis and its Impact on Asthma.

4 Allergic Rhinitis Min YG 요한진단도구이다. 임상에서는주로피부단자검사 (skin prick test) 가사용되는데, 위양성과위음성이존재할수있다. 이는 피부에서특정항원에대한알레르기반응이비강내의알레르 기반응과반드시일치하지않을수도있음을의미한다. 그리 고, 결과해석에이견이많고양성기준이사용자마다다르다. 뿐만아니라항히스타민제등의약제에영향을받으며피검자 의연령이나검사부위등에도영향을받고, 피부질환이있는 경우시행하기곤란한점등의문제가되지만, 이러한제한점 에도불구하고현재까지는알레르기질환의진단에있어주된 검사법으로자리잡고있다. 알레르기비염환자 1564 명의피부 반응검사결과를바탕으로한국내보고에서, 집먼지진드기가 가장흔한항원으로알레르기비염환자의약 70~80% 에서양 성반응을보였다 (Table 1). 30) 특이 IgE 항체검사 혈청내특이 IgE 를검사하는방법중최초의시도는 radioallergosorbent test(rast) 검사였는데, 정확한검사였지만방 사성동위원소를사용해야하고장비가고가이며한번에한가 지종류의항원에대해서만검사해야하는단점으로인해현 재널리사용되지않고있다. 그다음으로개발된방법은 multiple allergosorbent test(mast) 이다. 방사성동위원소대신 항원을항체와결합시켜화학발광물질을이용하여판독하는 것으로 RAST 에비해방사능물질을다루지않아도되고고가 의장비와기술이필요없으며동시에많은양의항원을검색 할수있어경제적이고간단하여최근널리이용되고있다. 항 히스타민제와같은약물사용에영향을받지않으며, 피부반응 검사보다고통이적고피부묘기증이있는환자에게도사용할 Table 1. Positive rates of common offending aeroallergens (n= 1564) 30) Allergens Positive rate (%) Mite Dermatophagoides farinae 77.6 Dermatophagoides pteronyssinus 73.3 Epithelia Cat hair 39.9 Dog hair 32.6 Pollens Mugwort 23.4 Tree 18.8 Ragweed 18.2 Grass 14.1 Others Cockroach 21.8 Fungus 6.0 수있는장점이있다. 피부반응검사와비교해민감도가떨어지는것이문제이나, Finnerty 등 31) 에의하면피부반응검사의양성기준을 3 mm로하였을때는 66.4% 의일치율을보이고양성기준을 5 mm로높였을때는양성율이 78.5% 를보여피부반응검사대신에시행할수있는검사로추천하였다. MAST보다정확한 in vitro test로 capsulated hydrophilic carrier polymer(cap) 시스템이있다. 원리는 MAST와비슷한데가장큰차이는고정체 (solid phase) 를사용하여항원결합력이좋다는점이다. MAST의경우얇은실위에항원이부착되어있는데반해, CAP는스폰지처럼생긴 cellulose 중합체의무수한기포방울내부에항원이부착되어있어훨씬더정량적인 IgE 측정이가능하다. 천식과관련된다양한임상지표 Guerra 등 32) 이시행한연구에서비염증상의중증도와지속성을수치화하여장기간추적관찰한결과알레르기비염의중증도가천식의발병과양의상관관계가있으며, 혈청 IgE가증가된알레르기비염환자군에서천식의발병률이 5배이상증가된다고보고하였다. Silvestri 등 33) 은비강내호산구수치가기도과민성과관련이있고, 비강유발검사후비강내호산구수치및호산구분포의변화도기도과민성과연관이있어, 알레르기비염의국소반응도기도과민성을예측할수있음을시사하였다. 83명의소아알레르기비염환자와 32명의정상소아를비교분석한국내의한연구에서, 알레르기비염소아환자에서기도과민성이증가하고 (32.5% vs. 9.4%), 관련인자로지속성알레르기비염과부모의천식병력을제시한바있다. 34) 알레르기비염환자에서기도과민성의존재는향후천식발병에관한중요한예측인자가될수있다고알려져있다. 35) 집먼지진드기와고양이알레르기같은실내항원에양성인환자의경우천식의발생및중등도와관련이있다고알려져있다. 또한, 실내와실외항원모두에감작이되어있는중등도- 중증알레르기비염환자에서더욱천식의유병률이높은것으로알려져있다. 알레르기비염의치료 회피요법집먼지진드기등의실내항원에대한회피요법을시행하기는현실적으로어려운측면이많고, 효과를보기도힘들다. 이러한이유로이에관한연구가많이이루어지지못해 2001년 AR- IA 가이드라인에서는 evidence D로낮게분류하였다. 1) 2008 년 ARIA 가이드라인에서도집먼지진드기나애완동물에대한여러가지회피요법의효과에대해서현재까지그근거가대부 259

5 Korean J Otorhinolaryngol-Head Neck Surg 2013;56: 분부족하다고보고하였다. 8) 하지만, 국내보고에의하면 60 C 의뜨거운물로세탁했을때 30 C의물보다더많은집먼지진드기를제거했음을보고하였다 (26.8% vs. 0.6%). 또한, 직업성알레르기비염에서회피요법은필수적이다. European Academy of Allergy and Clinical Immunology 에서는직업성알레르기비염에있어서가장안전하고효과적인치료는원인항원에대한회피요법이라고보고하였다. 36) 약물치료약물치료에대한원칙은증상의정도와기간에따른단계적접근이필요하다는것이다 (Fig. 3). 2001년 ARIA 가이드라인에서 2008년가이드라인의변화는모든알레르기비염의치료약으로류코트리엔수용체길항제를사용할수있는것으로개정되었다는점과 1세대항히스타민제보다는부작용이적은 2세대항히스타민제를추천하며국소스테로이드제가성인과소아의알레르기비염치료의가장효과적인치료제로정립되었다는점이다. 경구항히스타민제 1세대항히스타민제는 1940년대초반부터알레르기비염의치료에사용되었는데진정작용, 기억력장애, 정신운동기능이 상등의부작용으로인해사용에많은어려움이있다. 이에반해 2세대항히스타민제는뇌혈관장벽 (blood-brain barrier) 통과가적어중추신경계부작용이거의없다. 37) 이에 ARIA(2008) 에서는 2세대항히스타민제사용을권장하고있다. 경구항히스타민제는비루, 재채기, 코가려움증, 눈증상에효과적이나코막힘에는그효과가덜하다. 38) 경구항히스타민제는소아에서도안전하고효과적인것으로알려져있다. 39) Terfenadine 과 astemizole 이 2세대항히스타민제로개발되어알레르기비염에처음사용된약물인데, 두약물모두심전도상에서 QT 간격을연장시키고, torsade de pointes 같은치명적인심독성을유발할수있어, 이러한약제들은많은나라에서더이상유통되지않고있다. Ebastine 도간에서 CYP3A4 효소에의해대사되므로 CYP3A4 효소를억제하는다른약제와병용할때는주의할것을권고하며, 이미 QT 간격이연장되어있는환자나간부전혹은신부전이있는환자에서는 ebastine의사용을주의해야한다. 국소항히스타민제국소항히스타민제는코가려움증, 재채기, 비루등을감소시키는것으로알려져있지만, 40) 국소스테로이드제보다는코막힘에효과가덜하고, 눈증상에는효과가없는것으로보고되 Diagnosis of allergic rhinitis Intermittent Persistent symptoms symptoms Check for asthma especially in patients with severe and/or persistent rhinitis Mild Mild Moderatesevere Moderatesevere Not in preferred order oral H1 blocker or intranasal H1-blocker and/or decongestant or LTRA Not in preferred order oral H1 blocker or intranasal H1-blocker and/or decongestant or intranasal CS or LTRA (or cromone) In persistent rhinitis review the patient after 2-4 weeks If failure: step-up If improved: continue for 1 month In preferred order intranasal CS H1 blocker or LTRA Improved Review the patient after 2-4 weeks Failure Review diagnosis Step-down Review compliance and continue Query infections treatment or other causes for >1 month Add or increase intranasal CS dose Rhinorrhea add ipratropium Blockage add decongestant or oral CS (short term) Failure referral to specialist Allergen and irritant avoidance may be appropriate If conjunctivitis Add oral H 1-blocker or intraocular H 1-blocker or intraocular cromone (or saline) Consider specific immunotherapy Fig. 3. Rhinitis management. 8) LT- RA: leukotriene receptor antagonist, CS: corticosteroid. 260

6 Allergic Rhinitis Min YG 고있다. 41) 경구항히스타민제에반응하지않는계절성알레르기비염환자에서하루 2회국소용 azelastine을사용하여증상개선이보고되었으나, 부작용으로경미한진정효과와금속성맛이발생할수있다. 42) 국소스테로이드제국소스테로이드제는투여후활성이약한물질로곧대사되며전신흡수가적어부작용을최소화할수있다. 국소스테로이드제는알레르기비염의조기및후기반응을모두억제하고 IL-4, IL-5, IL-13 을포함한알레르기비염에중요한사이토카인분비를감소시켜, IgE 생성과호산구증다증을억제한다. 국소스테로이드제는비강내모든증상에효과가있고눈증상에도효과가있다. 특히다른약물에비해코막힘에효과가크다. 43) 스테로이드의작용기전으로인해분무후 7시간이후에반응이나타나며, 2주가지나야최고의효력을발휘하게된다. 44) 현재사용되고있는대표적인국소스테로이드제는 triamcinolone acetonide, fluticasone propionate, mometasone furoate, fluticasone furoate 등이있으며, 적절한선택을위해서는이들의약리학적특징을고려해야한다. 현재사용중인국소스테로이드제는대체적으로알레르기비염에안전하게사용할수있는것으로간주되고있다. 7~12 세의소아에게 mometasone 200 μg 또는 budesonide 400 μg을 2주동안국소분무한후측정한하지의성장률에는대조군과비교하여유의한차이가없었으나, 12개월동안 beclomethasone 를투여한연구에서는미약하나마성장률이감소했다는보고가있다. 45) 그러나 mometasone 이나 fluticasone 을 1년이상투여한연구에서는성장률에영향이없었다. 46,47) 국소스테로이드제를사용할경우천식증상을호전시키기도한다. Watson 등 48) 은국소 beclomethasone 투여가알레르기비염이있는천식환자에서기도과민성과천식증상을호전시킴을보고하였다. 유사연구로 Foresi 등 49) 은계절성알레르기비염환자에서 fluticasone propionate 사용이기도과민성을억제시킨다고보고하였다. 류코트리엔수용체길항제과거기관지천식의치료에류코트리엔수용체길항제의효과가입증되었고, 최근에는알레르기비염의치료효과에대해서도긍정적인결과를보고하고있다. 이에 ARIA(2008) 에서는류코트리엔수용체길항제에대한효과를재정립하였음을앞서언급하였다. One airway, one disease 라는주장과더불어관심이집중되는약제로이에관한많은연구가진행중이다. 현재상품화된류코트리엔수용체길항제는 pranlukast, montelukast 등이있다. Montelukast 는계절성알레르기비염 환자에서코증상과눈증상을호전시키는데효과가있고 loratadine과비슷한코막힘완화효과가있다고보고되었다. 8) 일부연구에서 montelukast 와 loratadine을병용한환자에서단독요법을사용한환자보다증상호전이있으며약효발현이빠르다는보고가있으나, 50) 아니라는보고도있다. 51) Kurowski 등 52) 은계절성알레르기비염환자에서 montelukast와 cetrizine 병용요법을꽃가루가날리는계절 6주전부터투여했을때알레르기비염의예방효과가있다고보고하였다. 그러나, 항히스타민제와의상승효과에대해서는이견이있는상태로더욱많은연구가필요하다. 현재까지류코트리엔수용체길항제의약물적효과는계절성알레르기비염에서항히스타민제와비슷하고국소스테로이드제에비해서는효과가적은것으로평가된다. 8) 항 IgE 항체 Omalizumab은 recombinant humanized monoclonal antibody로 free IgE와결합하여비만세포나호염기구와의상호작용을방해하여혈중 free IgE 농도를저하시킨다. 52) 또한혈액과비강에서항염증작용을일으키고, 53) 비만세포나호염기구의표면에존재하는 FcεRI의발현을억제시킨다. 54) Casale 등 55) 은중증계절성알레르기비염환자를대상으로항원노출이심해지기직전과항원이날리는계절에 3~4주간격으로 12 주동안 omalizumab 300 mg을피하주사한군에서알레르기증상의유의한호전을보고하였다. 부작용으로두통, 상기도감염, 부비동염등이있었으나발생빈도에있어위약치료군과유의한차이가없었고, 일부환자에서주사부위에두드러기가생길수있으나대개는자연치유되거나항히스타민제로치료되었다. 항 IgE 항체치료는심한천식에는도움이되지만, 아나필락시스쇼크의위험성이존재하는것으로보고되고있고, 가격이비싸알레르기비염치료로서적절한지에대한논란이있다. 56) 면역요법알레르기비염의면역요법은탈감작을유도하여면역학적기전을되돌림으로써알레르기질환을치료하는것으로발병기전에따른근본적치료방법이라할수있다. 알레르기면역요법은처음에는꽃가루항원에의해발생하는계절성알레르기비염을치료하는데사용되었으나현재는벌, 집먼지진드기, 동물비듬, 곰팡이등의항원으로인한알레르기질환으로확대되었다. 57) 항원들로부터얻은추출물을효과적인유지용량이될때까지규칙적으로안전하게점차용량을늘려서주입하며, 유지용량은임상증상및약물복용이줄어드는효과를오래유지하기위해 3년이상지속한다. 피하주사법이잘정립되어 261

7 Korean J Otorhinolaryngol-Head Neck Surg 2013;56: 있는치료법이나아나필락시스의위험과이를예방하기위한절차의복잡성때문에피하주사가아닌경비강, 구강, 설하요법등의대체투여경로가연구되어왔다. 이중설하면역요법법은비침습적이며자가복용이가능하고주사요법에비해부작용이현저히낮아서이를대체할수있는방법으로지난 20 여년간유럽에서널리처방되어왔다. 국내에서는 2007년에와서야집먼지진드기에대한설하면역요법이도입된바있다. 58) 여기에서는최근안전성과효능이입증된설하면역요법에대해서정리하기로한다. 설하면역요법의작용기전최근설하면역요법후의면역학적변화에관해많은연구가이루어졌다. 항원특이반응의조절 (IgG4/IgE 비증가 ) 과염증세포의모집 / 활성의억제, Th2에서 Th1 반응으로의전환, 그리고조절 T 세포 (regulatory T cell) 의활성화가설하면역요법의주된작용기전이다. 59) 면역관용에관여하는세포는조절 T 세포로알려져있으며면역치료의기전도이세포와연관이있다. 설하면역요법에서사용하는고용량의항원은조절 T 세포를유도하고이는 IL-10 과 TGF-β 를생산하여정상적인알레르기염증반응을억제하는역할을한다 (Fig. 4). 60) 설하면역요법의임상적효과설하면역요법의임상적효과에관하여최근 20년간주로유럽을중심으로많은연구가이루어졌다. 22개의보고와 979명의환자를대상으로한메타분석 (meta analysis) 에서설하면역요법은증상점수를낮추고알레르기비염약제투약빈도를줄이는것으로나타났다. 61) 집먼지진드기에대한알레르기증상을보이는소아환자들을대상으로한연구에서설하면역요법군은위약치료군에비해효과가없거나, 약물치료와동시에시행해도부가적인효과가없었다. 62) 그러나, 4~18 세소아환자를대상으로한다른메타분석에서는설하면역요법이알레르기비염증상과투약점수를유의하게호전시켰다. 63) 60세이상의알레르기비염환자를대상으로한연구에서도집먼지진드기에대한설하면역요법의임상적효과가밝혀졌다. 64) 또한설하면역요법은피하면역요법과마찬가지로천식의발병률을낮추는효과가있다. 65) 천식과알레르기비염소아환자를대상으로한장기간의추적관찰에서 4~5년동안설하면역요법을시행한후, 치료를중단해도천식의증상과천식에대한약물치료필요성이감소하였고, 최대호기속도 (peak expiratory flow rate) 도대조군에비해유의하게높아, 그효과가치료중단 4~5년후까지지속된다고보고하였다. 66) 설하면역요법이새로운항원에대한감작을낮추는효과가있다는보고가있는데, 216 명의환자를대상으로한대규모연구에서설하면역요법군의 5.9% 에서새로운항원에피부반응양성소견을보인반면, 비치료군에서는 38% 에서새로운항원에대한피부반응양성소견을보여설하면역요법이새로운항원에대한감작을예방하는효과가있다고하였다. 67) 설하면역요법의안전성설하면역요법은피하면역요법에비해안전하다. 가장흔한부작용은구강내소양증및부종과같은국소자극증상이며, 드물게복통, 두드러기, 천식유발등도보고되었다. 설하면역요법을통해아직사망하거나심한후유증을초래한치명적인부작용이보고된바는없다. 설하면역요법의전신반응에관하여포괄적인문헌검토를한연구에의하면, 설하면역요법에서 11예의아나필락시스반응이보고되었으며, 표준화내지상품화되지않은항원추출물, 항원혼합액, rush protocol, 과용량투여, 심각한부작용으로피하면역치료를중단한경험등이관련인자였다. 68) Di Rienzo 등 66) 은 3~5세의알레르기호흡기질환을가진환아에서설하면역요법을받고적어도 2년이상추적관찰한환자 126명에대해서부작용을살펴본결과총 9예의부작용이있었으며모두용량을증량하는단계에서관찰되었다. 2예는구강소양감, 1예는경도의복통이었으며, 6 예는위장관장애로용량을줄임으로써해결되었다. 따라서, 설하면역요법은 5세이하의소아에서도안전할것으로생각된다. ARIA(2008) 에서는각치료법에대한현재까지의연구결과를근거 (evidence) 에따라다음과같이정리하였다 (Table 2). Allergens Th2 Suppression B cell IgG Oral mucosal dendritic cell Th0 T REG Interleukin-10 TGF-β IgA Fig. 4. The possible mechanism of action of sublingual immunotherapy. 60) TGF-β: transforming growth factor-β. 262

8 Allergic Rhinitis Min YG Table 2. Level of evidence of different interventions in allergic rhinitis 8) H1-antihistamine Intervention Seasonal rhinitis Perennial rhinitis (mostly applies for studies 4 weeks)* Adults Children Adults Children Oral A A A A A Persistent rhinitis Intranasal A A A A No data Intraocular A A B B No data Glucocorticosteroid Intranasal A A A A No data Oral A B B B No data IM A B B B No data Cromones Intranasal A A A B No data Intraocular A A B B No data NAAGA (topical) B C C C No data Antileukotriene A A over 6 years No data Decongestant Intranasal C C C C No data Oral A No data Oral+H1-antihistamine A B B B No data Anticholinergic A A No data Homeopathy D D D D No data Acupuncture D D D D No data Phytotherapy B D D D No data Other CAM D D D D No data Specific immunotherapy: rhinoconjunctivitis Subcutaneous A A A A No data Sublingual A A A A No data Intranasal A No data Specific immunotherapy: asthma Subcutaneous A A A A Sublingual A A A A Anti-IgE A A over 12 years A A over 12 years No data Allergen avoidance House dust mites D D D D No data Other indoor allergens D D D D No data Total avoidance of occupational agent A (for asthma) No data Partial avoidance of latex B No data *very few studies longer than 4 weeks, applies to treatments of only carried out in studies with persistent rhinitis, applied to highdose treatment. IM: intramuscular, NAAGA: N-acetyl-aspartyl-glutamic acid, CAM: complementary and alternative medicine 결론 알레르기비염은전세계적으로발생이증가하고있는질환으로적절한진단검사를선택하여진단하고, 증상의지속성과중증도에따른진단분류를이용하여단계적으로치료를해야한다. 또한환자의주된증상, 증상의정도와기간, 환자의순응도, 약제의안정성, 비용-효과적인측면을종합적으로고려해서약물치료나면역요법을선택해야한다. 최근까지도 알레르기비염의병태생리와치료등에관하여여러방면에서연구가이루어지고있으며, 향후지금보다더만족스러운치료결과를얻을수있을것이다. 결론적으로, 알레르기비염의원인, 병태생리와이에따른진단및치료, 그리고최신지견에대한이해를바탕으로, 알레르기비염환자에대한정확한진단적접근과함께적절한치료를선택해서환자에따른맞춤치료가이루어져야할것이다

9 Korean J Otorhinolaryngol-Head Neck Surg 2013;56: REFERENCES 1) Bousquet J, Van Cauwenberge P, Khaltaev N; Aria Workshop Group; World Health Organization. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108(5 Suppl):S ) Nathan RA. The burden of allergic rhinitis. Allergy Asthma Proc 2007;28(1):3-9. 3) Berger WE. Allergic rhinitis in children: diagnosis and management strategies. Paediatr Drugs 2004;6(4): ) Settipane RA. Rhinitis: a dose of epidemiological reality. Allergy Asthma Proc 2003;24(3): ) Min YG, Choi BY, Kwon SK, Lee SS, Jung YH, Kim JW, et al. Multicenter study on the prevalence of perennial allergic rhinitis and allergy-associated disorders. J Korean Med Sci 2001;16(6): ) Lee SI, Shin MH, Lee HB, Lee JS, Son BK, Koh YY, et al. Prevalences of symptoms of asthma and other allergic diseases in Korean children: a nationwide questionnaire survey. J Korean Med Sci 2001;16(2): ) Reed SD, Lee TA, McCrory DC. The economic burden of allergic rhinitis: a critical evaluation of the literature. Pharmacoeconomics 2004;22(6): ) Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA (2)LEN and AllerGen). Allergy 2008;63 Suppl 86: ) Chaplin DD. 1. Overview of the human immune response. J Allergy Clin Immunol 2006;117(2 Suppl Mini-Primer):S ) Broide DH. The pathophysiology of allergic rhinoconjunctivitis. Allergy Asthma Proc 2007;28(4): ) Prussin C, Metcalfe DD. 5. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 2006;117(2 Suppl Mini-Primer):S ) Kay AB. Allergy and allergic diseases. Second of two parts. N Engl J Med 2001;344(2): ) Togias A. Unique mechanistic features of allergic rhinitis. J Allergy Clin Immunol 2000;105(6 Pt 2):S ) Gerth van Wijk RG, de Graaf-in t Veld C, Garrelds IM. Nasal hyper-reactivity. Rhinology 1999;37(2): ) Linneberg A, Henrik Nielsen N, Frølund L, Madsen F, Dirksen A, Jørgensen T; Copenhagen Allergy Study. The link between allergic rhinitis and allergic asthma: a prospective population-based study. The Copenhagen Allergy Study. Allergy 2002;57(11): ) Montnémery P, Svensson C, Adelroth E, Löfdahl CG, Andersson M, Greiff L, et al. Prevalence of nasal symptoms and their relation to self-reported asthma and chronic bronchitis/emphysema. Eur Respir J 2001;17(4): ) Bousquet J, Annesi-Maesano I, Carat F, Léger D, Rugina M, Pribil C, et al. Characteristics of intermittent and persistent allergic rhinitis: DREAMS study group. Clin Exp Allergy 2005;35(6): ) Leynaert B, Neukirch C, Kony S, Guénégou A, Bousquet J, Aubier M, et al. Association between asthma and rhinitis according to atopic sensitization in a population-based study. J Allergy Clin Immunol 2004;113(1): ) Downie SR, Andersson M, Rimmer J, Leuppi JD, Xuan W, Akerlund A, et al. Association between nasal and bronchial symptoms in subjects with persistent allergic rhinitis. Allergy 2004;59(3): ) Chakir J, Laviolette M, Boutet M, Laliberté R, Dubé J, Boulet LP. Lower airways remodeling in nonasthmatic subjects with allergic rhinitis. Lab Invest 1996;75(5): ) Djukanović R, Lai CK, Wilson JW, Britten KM, Wilson SJ, Roche WR, et al. Bronchial mucosal manifestations of atopy: a comparison of markers of inflammation between atopic asthmatics, atopic nonasthmatics and healthy controls. Eur Respir J 1992;5(5): ) Brown JL, Behndig AF, Sekerel BE, Pourazar J, Blomberg A, Kelly FJ, et al. Lower airways inflammation in allergic rhinitics: a comparison with asthmatics and normal controls. Clin Exp Allergy 2007;37(5): ) Marcucci F, Passalacqua G, Canonica GW, Frati F, Salvatori S, Di cara G, et al. Lower airway inflammation before and after house dust mite nasal challenge: an age and allergen exposure-related phenomenon. Respir Med 2007;101(7): ) Madonini E, Briatico-Vangosa G, Pappacoda A, Maccagni G, Cardani A, Saporiti F. Seasonal increase of bronchial reactivity in allergic rhinitis. J Allergy Clin Immunol 1987;79(2): ) Corren J, Adinoff AD, Irvin CG. Changes in bronchial responsiveness following nasal provocation with allergen. J Allergy Clin Immunol 1992;89(2): ) Togias A. Rhinitis and asthma: evidence for respiratory system integration. J Allergy Clin Immunol 2003;111(6): ; quiz ) Igarashi Y, Goldrich MS, Kaliner MA, Irani AM, Schwartz LB, White MV. Quantitation of inflammatory cells in the nasal mucosa of patients with allergic rhinitis and normal subjects. J Allergy Clin Immunol 1995;95(3): ) Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet 2006;368(9537): ) Dhong HJ. Classification of Allergic Rhinitis: What is Most Suitable in Korea? Allergy Asthma Immunol Res 2013;5(2): ) Bang JH, Kim YJ, Shin HS, Lee BJ. Cinical analysis of allergic rhinitis in Seoul. J Rhinol 1996;3: ) Finnerty JP, Summerell S, Holgate ST. Relationship between skinprick tests, the multiple allergosorbent test and symptoms of allergic disease. Clin Exp Allergy 1989;19(1): ) Guerra S, Sherrill DL, Martinez FD, Barbee RA. Rhinitis as an independent risk factor for adult-onset asthma. J Allergy Clin Immunol 2002;109(3): ) Silvestri M, Battistini E, Defilippi AC, Sabatini F, Sale R, Pecora S, et al. Early decrease in nasal eosinophil proportion after nasal allergen challenge correlates with baseline bronchial reactivity to methacholine in children sensitized to house dust mites. J Investig Allergol Clin Immunol 2005;15(4): ) Choi SH, Yoo Y, Yu J, Rhee CS, Min YG, Koh YY. Bronchial hyperresponsiveness in young children with allergic rhinitis and its risk factors. Allergy 2007;62(9): ) Ferdousi HA, Zetterström O, Dreborg S. Bronchial hyperresponsiveness predicts the development of mild clinical asthma within 2 yr in school children with hay-fever. Pediatr Allergy Immunol 2005;16(6): ) Moscato G, Vandenplas O, Van Wijk RG, Malo JL, Perfetti L, Quirce S, et al. EAACI position paper on occupational rhinitis. Respir Res 2009;10:16. 37) Bousquet J, Van Cauwenberge P, Bachert C, Canonica GW, Demoly P, Durham SR, et al. Requirements for medications commonly used in the treatment of allergic rhinitis. European Academy of Allergy and Clinical Immunology (EAACI), Allergic Rhinitis and its Impact on Asthma (ARIA). Allergy 2003;58(3): ) Simons FE. Advances in H1-antihistamines. N Engl J Med 2004;351 (21): ) de Blic J, Wahn U, Billard E, Alt R, Pujazon MC. Levocetirizine in children: evidenced efficacy and safety in a 6-week randomized seasonal allergic rhinitis trial. Pediatr Allergy Immunol 2005;16(3): ) McNeely W, Wiseman LR. Intranasal azelastine. A review of its efficacy in the management of allergic rhinitis. Drugs 1998;56(1): ) Yáñez A, Rodrigo GJ. Intranasal corticosteroids versus topical H1 receptor antagonists for the treatment of allergic rhinitis: a systematic review with meta-analysis. Ann Allergy Asthma Immunol 2002;89 (5): ) Berger WE, White MV; Rhinitis Study Group. Efficacy of azelastine nasal spray in patients with an unsatisfactory response to loratadine. 264

10 Allergic Rhinitis Min YG Ann Allergy Asthma Immunol 2003;91(2): ) Bhatia S, Baroody FM, detineo M, Naclerio RM. Increased nasal airflow with budesonide compared with desloratadine during the allergy season. Arch Otolaryngol Head Neck Surg 2005;131(3): ) Selner JC, Weber RW, Richmond GW, Stricker WE, Norton JD. Onset of action of aqueous beclomethasone dipropionate nasal spray in seasonal allergic rhinitis. Clin Ther 1995;17(6): ) Skoner DP, Rachelefsky GS, Meltzer EO, Chervinsky P, Morris RM, Seltzer JM, et al. Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate. Pediatrics 2000;105(2):E23. 46) Schenkel EJ, Skoner DP, Bronsky EA, Miller SD, Pearlman DS, Rooklin A, et al. Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray. Pediatrics 2000;105(2):E22. 47) Allen DB, Meltzer EO, Lemanske RF Jr, Philpot EE, Faris MA, Kral KM, et al. No growth suppression in children treated with the maximum recommended dose of fluticasone propionate aqueous nasal spray for one year. Allergy Asthma Proc 2002;23(6): ) Watson WT, Becker AB, Simons FE. Treatment of allergic rhinitis with intranasal corticosteroids in patients with mild asthma: effect on lower airway responsiveness. J Allergy Clin Immunol 1993;91(1 Pt 1): ) Foresi A, Pelucchi A, Gherson G, Mastropasqua B, Chiapparino A, Testi R. Once daily intranasal f luticasone propionate (200 micrograms) reduces nasal symptoms and inflammation but also attenuates the increase in bronchial responsiveness during the pollen season in allergic rhinitis. J Allergy Clin Immunol 1996;98(2): ) Meltzer EO, Malmstrom K, Lu S, Prenner BM, Wei LX, Weinstein SF, et al. Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized, placebo-controlled clinical trial. J Allergy Clin Immunol 2000;105(5): ) Nayak AS, Philip G, Lu S, Malice MP, Reiss TF; Montelukast Fall Rhinitis Investigator Group. Efficacy and tolerability of montelukast alone or in combination with loratadine in seasonal allergic rhinitis: a multicenter, randomized, double-blind, placebo-controlled trial performed in the fall. Ann Allergy Asthma Immunol 2002;88(6): ) Kurowski M, Kuna P, Górski P. Montelukast plus cetirizine in the prophylactic treatment of seasonal allergic rhinitis: influence on clinical symptoms and nasal allergic inflammation. Allergy 2004; 59(3): ) Plewako H, Arvidsson M, Petruson K, Oancea I, Holmberg K, Adelroth E, et al. The effect of omalizumab on nasal allergic inflammation. J Allergy Clin Immunol 2002;110(1): ) Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumab-induced reductions in mast cell Fce psilon RI expression and function. J Allergy Clin Immunol 2004;114(3): ) Casale TB, Busse WW, Kline JN, Ballas ZK, Moss MH, Townley RG, et al. Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis. J Allergy Clin Immunol 2006;117(1): ) Price KS, Hamilton RG. Anaphylactoid reactions in two patients after omalizumab administration after successful long-term therapy. Allergy Asthma Proc 2007;28(3): ) Cohen SG, Evans R 3rd. Allergen immunotherapy in historical perspective. Clin Allergy Immunol 2004;18: ) Chang H, Han DH, Mo JH, Kim JW, Kim DY, Lee CH, et al. Early compliance and efficacy of sublingual immunotherapy in patients with allergic rhinitis for house dust mites. Clin Exp Otorhinolaryngol 2009;2(3): ) Potter PC. Update on sublingual immunotherapy. Ann Allergy Asthma Immunol 2006;96(2 Suppl 1):S ) Frew AJ. Sublingual immunotherapy. N Engl J Med 2008;358(21): ) Wilson DR, Lima MT, Durham SR. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy 2005; 60(1): ) Pajno GB, Morabito L, Barberio G, Parmiani S. Clinical and immunologic effects of long-term sublingual immunotherapy in asthmatic children sensitized to mites: a double-blind, placebocontrolled study. Allergy 2000;55(9): ) Penagos M, Compalati E, Tarantini F, Baena-Cagnani R, Huerta J, Passalacqua G, et al. Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials. Ann Allergy Asthma Immunol 2006;97(2): ) Bozek A, Ignasiak B, Filipowska B, Jarzab J. House dust mite sublingual immunotherapy: a double-blind, placebo-controlled study in elderly patients with allergic rhinitis. Clin Exp Allergy 2013;43(2): ) Novembre E, Galli E, Landi F, Caffarelli C, Pifferi M, De Marco E, et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 2004;114(4): ) Di Rienzo V, Marcucci F, Puccinelli P, Parmiani S, Frati F, Sensi L, et al. Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a 10-year prospective study. Clin Exp Allergy 2003;33(2): ) Marogna M, Tomassetti D, Bernasconi A, Colombo F, Massolo A, Businco AD, et al. Preventive effects of sublingual immunotherapy in childhood: an open randomized controlled study. Ann Allergy Asthma Immunol 2008;101(2): ) Calderón MA, Simons FE, Malling HJ, Lockey RF, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy 2012;67(3):