pissn: eissn: Allergy Asthma Respir Dis 2(4): , September REVIEW 소아만성두드러기 유

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1 pissn: eissn: (4):236242, September REVIEW 소아만성두드러기 유진호 울산대학교의과대학서울아산병원소아청소년과 Chronic urticaria in children Jinho Yu Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Although it is difficult to find a cause of chronic urticaria in children, previous studies have been identified some triggers, such as autoimmunity, physical stimuli, food and its additives, and infection. History taking and physical examination remain the best tool for identifying an underlying cause of urticaria. First investigations include a complete blood count with differential, erythrocyte sedimentation rate, and Creactive protein in children with chronic urticaria. If physical stimuli are suspected as triggers of chronic urticaria, appropriate provocation tests can be performed. Although the frequency of autoimmune urticaria was relatively high compared to the other causes in children with chronic urticaria, it is not easy to apply routine use of autologous serum skin tests to clinical practice. Additional extensive laboratory investigations are not required in the majority of cases. Secondgeneration H1antihistamines are the mainstay of treatment from current guidelines in children with chronic urticaria, and dosage can be increased if the standard dose is not effective. Data on chronic urticaria in children are scarce, and causes have been considered to be similar to those in adults. Therefore, diagnostic approaches and treatment principles of chronic urticaria in children have been derived from extrapolating data in adults. In the future, comparative studies for the causes of chronic urticaria between children and adults, and therapeutic modalities for refractory cases will be needed. ( 2014;2:236242) Keywords: Urticaria, Child 서 두드러기는가려움을동반한팽진 (wheal) 및혈관부종 (angioedema) 을그특징으로한다. 만성두드러기에대한연구는성인을 대상으로하는것이많았고, 소아에대한연구는상대적으로적고, 성인의연구결과를소아의연구설계또는실제임상에적용하는 경우가많았다. 만성두드러기는일반적으로 6 주이상지속되는두드러기로정 의한다. 실제임상에서급성두드러기가드물게 6 주이상지속되는 경우도있으므로 12 주를주장하는연구자들도있다. 1) 만성두드러 기에서팽진과혈관부종의빈도는 226 명의만성두드러기소아를 대상으로한연구결과를보면팽진만을보인경우가 78.4%, 팽진 없이혈관부종을보인경우가 6.6% 이고나머지는두가지모두를 보였다. 2) Correspondence to: Jinho Yu Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympicro 43gil, Songpagu, Seoul , Korea Tel: , Fax: , jyu3922@gmail.com Received: August 29, 2014 Revised: September 2, 2014 Accepted: September 4, 2014 론 European Academy of Allergy and Clinical Immunology, Global Allergy and Asthma European Network, European Dermatology Forum, World Allergy Organization (EAACI/GA2LEN/EDF/ WAO) 가이드라인 2013 개정에의하면만성두드러기는크게만성 자발성두드러기 (chronic spontaneous urticaria) 와유도성두드러 기 (inducible urticaria) 로분류되고유도성두드러기는한랭두드러 기, 지연성압박두드러기, 일광두드러기, 열두드러기, 진동혈관부 종, 콜린성두드러기, 접촉성두드러기, 수인성두드러기로분류할 수있다 (Table 1). 3) 소아두드러기의유병률은 2.1% 6.7% 로보고되었는데, 남녀에서 동일하게발생하였고일반인구집단과비교하여아토피비율이높 았다. 4,5) 소아의만성두드러기유병률은그보다낮아 0.1% 3% 였다. 6) 이러한소아의만성두드러기의자연경과는보고마다다르지만, 5 년간추적시 50% 에서소실되었고, 연령, 성별, 혈관부종동반, 다른 알레르기질환동반, 자가면역질환가족력, 자가혈청피부시험 (autologous serum skin test) 결과등은예후에영향을주지못하였다. 7) 2014 The Korean Academy of Pediatric Allergy and Respiratory Disease The Korean Academy of Asthma, Allergy and Clinical Immunology This is an Open Access article distributed under the terms of the Creative Commons Attribution NonCommercial License (

2 유진호 소아만성두드러기 Table 1. Classification of chronic urticaria subtypes Chronic urticaria subtypes Chronic spontaneous urticaria* Inducible urticaria Dermographism Cholinergic urticaria Cold urticaria Solar urticaria Contact urticaria Aquagenic urticaria Delayed pressure urticaria Heat urticaria Vibratory angioedema *Definition: Spontaneous appearance of wheals, angioedema, or both for more than 6 weeks. Adapted from European Academy of Allergy and Clinical Immunology, Global Allergy and Asthma European Network, European Dermatology Forum, World Allergy Organization (EAACI/GA2LEN/EDF/WAO) guideline 2013 revision. 3) 이종설은소아만성두드러기의원인과진단및치료에대해최근 연구결과들을정리하여만성두드러기에대한이해를향상시키고 실제임상에서진단적접근과치료에도움이되는데그목적이있다. 두드러기의병태생리 두드러기는비만세포와호염기구의탈과립에의해발생한다. 전 형적인 1 형과민반응으로알레르기항원에대한 IgE 항체가비만세 포의 highaffinity IgE receptor (FcεRІ) 에결합되어있다가알레르 기항원의재노출시 crosslinking 되면서신호가전달되어히스타 민, 트립타제와같은이미형성된매개체를분비하고새롭게형성된 프로스타글란딘, 류코트리엔등의매개체와화학주성인자, 사이 토카인을분비하여결과적으로혈관확장, 발적, 팽진을형성하게 된다. 최근에는만성두드러기에서 antiige 와 antifcεrі IgG 항체 가 IgE 와 FcεRІ 를통해작용하여두드러기를유발하는자가면역 기전이대두되었다. 앞으로여기에서도 antiige 와 antifcεrі IgG 항체가양성인만성자발성두드러기를그기전에따라자가면역두 드러기라부르겠다. 그밖에비면역학적기전으로비만세포를자극 하는아편제 (opiate), C5a 와같은보체, 줄기세포인자, 신경펩티드 (neuropeptide) 등은 FcεRІ 를통하지않고별도로비만세포탈과 립화를유도할수있다. 1) 만성두드러기의원인 연구집단의다양성, 원인을찾기위해사용한검사수와양성판 독의기준에따라다를수있지만, 만성두드러기의원인을찾을수 있는경우는 21% 83% 로보고되고있다. 4) Volonakis 등 2) 은비교적 많은대상수인 226명만성두드러기소아에서원인을찾을수있는경우로물리적인자 6.2%, 감염 4.4%, 음식 4%, 음식첨가물 2.6%, 흡입알레르기항원 2.2%, 약물 1.8% 로보고하였다. 그러나최근성인에서처럼소아에서도자가면역두드러기가만성자발성두드러기 31% 47% 를차지하는것으로보고되고있다. 710) 이러한연구결과들을보면소아에서도각원인의비율이성인과차이가있을가능성은있지만, 원인의종류가성인과다르지는않을것으로생각한다. 3) 현재까지의소아에대한연구결과를종합해보면, 소아만성두드러기는그원인을찾을수없는특발성의비율이높으며, 원인으로간주되는것은그다빈도순서에따라자가면역, 유도성, 음식첨가물, 감염, 음식물, 자가면역질환순으로생각해볼수있겠다. 각원인에대해좀더구체적으로기술해보겠다. 1. 만성자발성두드러기 1) 자가면역소아의만성두드러기에서자가면역두드러기가차지하는비율은자가혈청피부시험또는호염기구히스타민유리시험 (basophil histamine release assay) 을진단검사로사용하였을때만성자발성두드러기의 31% 47% 로보고되었다. 710) 이러한자가항체에대한검사를시행하여자가면역두드러기를진단하게되면만성두드러기중가장높은비율을차지하는원인인특발성은 52% 에서 29% 로감소하게된다. 10) 성인에서는이런자가항체양성인두드러기환자가음성인환자보다중증도가심하다는보고가있지만, 11) 소아에서는임상적특징, 중증도, 그리고자연경과의차이가없다는보고가많다. 710,12) 이런점에서는자가면역진단을위한검사를소아만성자발성두드러기환자에서아직까지실제임상에적용하기는쉽지않을것으로생각한다. 그러나만성자발성두드러기에서자가혈청피부시험또는호염기구히스타민유리시험을시행하여양성이나온다면, 원인을찾기위한다른광범위한검사들을할필요가없어진다는점은고려할수있겠다. 2) 식품첨가물환자및보호자들은식품을두드러기의가장흔한원인으로생각하지만영아를제외하고는, 소아의급성두드러기의 5.3%, 만성두드러기의 2.1% 에해당될정도로결코흔한원인은아니다. 13,14) 최근의연구결과들을참고해본다면만성두드러기에서식품알레르기보다는식품첨가물가성알레르기를더높은비중을두어고려해봐야할것이다. 15) 만성자발성두드러기소아 16명에서 75% 가가성알레르기에의한두드러기라고보고하였고, 16) 120명의재발성두드러기소아에서식품첨가물을회피한후에 7가지첨가물을추가하였을때, 위약군과비교하여 46% 에서양성반응을보였다는보고가있다. 17) 놀랍게도매우높은수치에해당되지만, 최근한 systematic review에서는식품첨가물은소아만성두드러기의 18.9% 237

3 Yu J Chronic urticaria in children 를차지하는것으로보고하였다. 18) 성인을포함한연구들은 1% 에서 50% 이상으로다양한결과를보고하였다. 19) 이러한다양한연구결과들은연구대상과진단기준이서로다르기때문일것으로생각된다. 소아만성두드러기환자의병력에서식품첨가물이원인으로의심이되는경우에는 3 주간의식품첨가물함량이낮은식이를진행하여증상소실을관찰한후에식품첨가물이풍부한식이로유발검사를하여확진할필요가있다. 19) 소아에서는이러한과정중영양결핍의위험성이존재하므로영양상태의평가와대비를미리하는것이필요하다. 3) 감염감염은소아의급성두드러기의가장흔한원인이며, 특히상기도감염과관계가있다. 20) 만성두드러기에서는급성바이러스감염은악화의인자로생각되나그자체가원인으로간주되지는않는다. 21) 세균감염도두드러기와관련될수있는데, 베타용혈성연쇄구균은급성두드러기소아의 40% 에서보고되었다. 22) 또한마이코플라즈마와요로감염을급성및만성두드러기와관련이있는것으로보고하였으나, 23,24) 이러한세균감염이만성두드러기의원인의상당부분을차지하지는않는것같다. 4) EpsteinBarr 바이러스를소아에서급성두드러기의원인으로보고하였고, 24) 만성두드러기소아 93명에서 7명 (7.5%) 에서양성을보였다는보고도존재하지만, 이연구에서인과관계에대한언급은없다. 10) 기생충감염의경우도호산구증가와기생충감염이호발하는지역으로의여행력이없다면만성두드러기의원인을찾고자하는검사에포함되는것을권하지않는다. 25) 기생충검사양성인만성두드러기환자를실제기생충치료를하여도만성두드러기가호전되지않았다. 8) Helicobacter pylori와만성두드러기의관계에대한연구는주로성인에서이루어졌고, 만성두드러기환자에서 H. pylori 양성률과 H. pylori 치료후두드러기호전에대해조사한결과, 일관된연관성을보이지못하였다. 2630) 최근에대변항원을이용하여소아와성인을대상으로비교한연구를보면만성두드러기소아에서 H. pylori 양성률은 31.2%, 성인에서는 51.4% 이었고, H. pylori 치료후소아에서 100%, 성인에서 83.3% 에서두드러기호전을보였다. 31) 그러나이연구는 32명소아와 35명성인으로그대상수가적어서성인의일관되지않은결과와종합해보면소아에서 H. pylori가만성두드러기의원인이라고결론을유도하기는어려울것으로생각한다. 대상선정과 H. pylori 감염률의지역적인차이가결과에영향을줄수있으므로이러한결과를임상적으로적용하기위해서는대상수가크고선정기준을명확히한국내데이터가필요하겠다. 4) 약물소아만성두드러기의원인으로약물이 17% 을차지한다는보고가있지만, 20) 감염과관련하여약물을사용하는경우가흔하기때 문에약물이실제원인이아닐가능성이높다. 한연구에서페니실린사용후피부발진의대부분의원인은베타락탐알레르기라기보다는바이러스감염이중요한역할을한다고보고하였다. 32) 그러나비스테로이드성함염증제는면역학적기전에의하지않고두드러기를유발할수있으므로고려해봐야한다. 5) 자가면역질환소아의만성두드러기와자가면역질환과의관계에서는두드러기병력이없는소아에서보이는자가면역갑상선질환의유병률이 0.35% 1.6% 인반면에만성자발성두드러기소아의 4.3% 14.8% 에서갑상선자가면역을갖는다는보고가있다. 12,33) 이는성인의 14% 43% 의수치보다는낮다. 34,35) 갑상선자가항체는그자체가병적이라기보다는환자의자가면역성향을가진것을의미하여항체를가진대부분의환자는갑상선기능은정상이다. 36) 그밖에소아만성두드러기가류마티스성관절염, 루푸스, 인슐린의존성당뇨와도관련이있는것으로보고되었다. 14,37) 그러나이러한연관성은두드러기의원인이라기보다는자가면역성향을반영할가능성이높으며실제기저질환치료와만성두드러기의호전은일관된상관관계를보이지는않았다. 1) 2. 유도성두드러기유도성두드러기는물리적두드러기와콜린성두드러기를포함한다. 38) 소아만성두드러기에서차지하는비율을 53% 로높게보고한연구도있을정도로가장흔한원인중하나이다. 24) 의사진단에의한소아의유도성두드러기에서가장많은비율을차지하는것은피부묘기증과콜린성두드러기이다. 한연구에서는각각 38%, 19% 로보고하였다. 39) 또한유도성두드러기의 17% 에서는혼합형태를보이는데가장흔한조합은피부묘기증과콜린성두드러기로알려져있다. 혈관부종의동반도 67% 로보고되었다. 두드러기의평균기간은 47개월이었고 5년후 38.4% 에서소실되었다. 한냉두드러기는그빈도는드물지만 1/3에서아나필락시스반응을보이는것으로보고되었다. 40) 한냉두드러기는대부분일차성이지만, 바이러스감염또는 cryoglobulinaemia 와관련하여이차적으로발생할수도있다. 41) 이러한유도성두드러기는알레르기병력이있거나그빈도가많은경우예후가더좋지않다. 39) 3. 두드러기성혈관염두드러기성혈관염은 leukocytoclastic 혈관염의한형태이다. 두드러기에포함되지는않지만, 비슷한피부병변때문에두드러기로오진되기쉬우므로감별진단에필요하다. 두드러기성혈관염은전체연령에서만성두드러기의 5% 에해당하지만, 소아에서는드물다. 대개는발열, 관절통을동반하고가렵기보다는통증이있고, 24 시간지속되는두드러기또는출혈반점양상을보이고, 호전되어 238

4 유진호 소아만성두드러기 도색소침착을보이며, 적혈구침강속도 (erythrocyte sedimentation rate, ESR) 가증가한다. 25) 대부분의경우는특발성이지만보체저하를동반하기도하며, 전신질환과연관이있는경우가있다. 루프스, 류마티스성관절염, B형또는 C형간염, paraproteinemia, 비스테로드성항염증제, 페니실린, 설포나마이드에의해발생할수있다. 그밖에 EpsteinBarr 바이러스, Sjögren 증후군, IgA와 IgM monoclonal gammopathies, mixed cryoglobulins, 종양과관련이있을수있다. 42,43) 만성두드러기의진단병력과이학적소견이소아의만성두드러기원인을밝히는데기본적이면서가장좋은방법이다. 추가적인검사도병력과이학적소견의결과를토대로이루어져야한다. 특히알레르기검사는병력을통해시행여부를결정해야위양성을피할수있다. 최근 EAA CI/GA2LEN/EDF/WAO 가이드라인에서도병력과이학적검사이외의다른검사들은병력과두드러기양상에따라제한적으로시행하도록권고하고있다. 3) 우선적으로병력청취에서발열, 관절과골통증, 권태감과같은전신증상이있는지확인하고, 이러한전신증상이있는경우에는백혈구백분율과 ESR, C반응성단백 (creactive protein, CRP) 을확인한다. 양성인경우에는류마티스성관절염, cryopyrin associated periodic syndrome 과같은자가염증질환을의심해야하며, 필요에따라서조직생검이필요할수있다. 전신증상이없는경우에는팽진의지속시간이 24시간을넘는지확인하고그러한경우에는혈관염을의심하여조직생검을고려해야한다. 팽진의지속시간이 24시간미만이면우선적으로유도성두드러기인지를병력과이학적소견에서확인하고의심된다면유발검사를시행하여유도성두드러기를진단한다. 유도성두드러기진단법은 Table 2에기술하였 다. 3) 유도성두드러기가아니라면자발성두드러기를의심해야한다 (Fig. 1). 만성자발성두드러기의경우일차적으로백혈구백분율, ESR, CRP를시행하고, 병력에서약물두드러기가의심되는경우약물중단을시도해볼수있다. 이차적으로시행하는검사는병력을토대로시행해야하겠다. 이차적인검사로는그빈도를고려한다면자가혈청피부시험또는호염기구히스타민유리시험을우선적으로고려해볼수있겠다. 9) 그러나앞에서도기술한것처럼검사결과가예후에영향을주지못하고 710), 검사방법또한실제임상에적용하기가쉽지는않다. 그러나검사를시행하여양성이라면다른광범위한 2차적인검사를시행하지않아도되는임상적의미를생각해볼수있다. 그외검사로는소변검사와 H. pylori와같은감염에대한검사, 피부단자시험같은알레르기검사, 갑상선기능및갑상선자가항체, 전신알레르기증상이동반된경우트립타제, 항핵항체 (antinuclear antibody), 보체검사등이있다. 소아에서는보호자가음식물이원인이라고생각하여음식물을제한하는경우가많은데, 이런경우에음식물에대한피부단자시험은무분별한음식제한을풀어주는데도움을줄수있다. 식품첨가물이그원인으로의심스럽다면, 첨가물제거식이를 3주간시행해볼수있겠다. 그러나제거기간동안저절로두드러기가좋아질수있으므로식품첨가물유발로확진을할필요가있다. 앞에서열거한검사들은임상적으로연관성이있을때만시행하는것을권유하고있다. 25) 그리고검사와관련된질환의증상이없는만성두드러기소아에서이러한검사들의양성률은매우낮고, 검사에서양성을보여서그결과와관련된질환을치료한다해도두드러기의소실을보장할수는없다. 172명만성두드러기소아를대상으로한연구에서알레르기검사를제외한추가적인검사에서양성률은단지 5.2% 로매우낮았고, 이러한수치는 95% 신뢰수준에서보면위양성률정도수준이어서추가적검사들이필요하지않음을알수있다. 44) 근거중 Table 2. Recommended diagnostic test in inducible urticaria Subtype Routine diagnostic test Extended diagnostic test* Dermographism Elicit dermographism and threshold test (dermographometer) Differential blood count, ESR or CRP Cholinergic urticaria Exercise and hot bath provocation None Cold urticaria Cold provocation and threshold test (ice cube, cold water, cold wind) Differential blood count and ESR or CRP, cryoproteins, rule out other diseases, especially infections Solar urticaria UV and visible light of different wavelengths and threshold test Rule out other lightinduced dermatoses Contact urticaria Cutaneous provocation. Skin tests with immediate readings, e.g., prick test None Aquagenic urticaria Wet cloths at body temperature applied for 20 minutes None Delayed pressure urticaria Pressure test and threshold test None Heat urticaria Heat provocation and threshold test None Vibratory angioedema Test with, e.g., vortex None ESR, erythrocyte sedimentation rate; CRP, Creactive protein. *Extended diagnostic test: for identification of underlying causes and for ruling out differential diagnoses. Adapted from European Academy of Allergy and Clinical Immunology, Global Allergy and Asthma European Network, European Dermatology Forum, World Allergy Organization (EAACI/GA2LEN/EDF/WAO) guideline 2013 revision. 3) 239

5 Yu J Chronic urticaria in children Wheals/angioedema Recurrent unexplained fever? Joint/bone pain? Malaise? Autoinflammatory disease History, CRP, ESR Consider biopsy Average wheals duration> 24 hr Signs of vasculitis in biopsy Are symptoms inducibie? Provocation test Autoinflammatory disease JRA, and cryopyrinassociated periodic syndrome Urticarial vasculitis Chronic spontaneous urticaria Chronic inducible urticaria Fig. 1. Diagnostic approach in children with chronic urtiaria. ESR, erythrocyte sedimentation rate; CRP, Creactive protein; JRA, juvenile rheumatoid arthritis. Adapted from European Academy of Allergy and Clinical Immunology, Global Allergy and Asthma European Network, European Dermatology Forum, World Allergy Organization (EAACI/GA2LEN/EDF/WAO) guideline 2013 revision. 3) 심의원칙에입각하여원인을확인할수있을가능성이있을때만검사를시행하는것이타당할것으로생각한다. 특히, 두드러기가경미하고항히스타민제에반응이좋으면서병력과이학적소견이정상이라면추가적인검사의필요성은없다. 만성두드러기의치료치료에앞서우선적으로필요한것은교육이다. 어떤피부병변이두드러기이고아닌지를교육해야한다. 환자및보호자들은알레르기가원인이라고생각하고많은종류의음식물을제한한다거나광범위한검사를하게되는데, 대부분은심각한의학적문제가없으며안전하고효과적인치료가가능하다는점을확인시켜주어야한다. 잘조절되지않는두드러기환자는증상일기가도움이될수있다. 그빈도, 기간, 각두드러기가발생할때중증도, 유발인자를기록한다. 소아에서아직검증되지는않았지만, 최근 EAACI/GA 2LEN/EDF/WAO 가이드라인에서권고하는두드러기증상점수 (urticaria activity score) 는초기중증도를평가하는데도움이될 뿐만아니라치료에대한반응을평가하는데도움이될것으로기대한다. 3) 만성두드러기의치료는우선적으로유발인자를찾고그것을피하는것이다. 약물치료는증상완화를목표로하는것이며가장많이사용되고있는것은항히스타민제이다. 항히스타민제는소아에서도 2세대항히스타민제가기본이고상용량이효과가없을경우에는 4배까지증량할수있음을권고하고있으나, 3,45) 소아에서아직검증되지는않았다. 소아두드러기에서항히스타민제의적절한치료에대한근거는대부분비염이나아토피피부염치료의연구결과에서비롯되었고, 특히어린연령에서시행한무작위대조군연구는매우부족하다. H1항히스타민제와 H2항히스타민제의병용에대한연구는주로성인에서이루어졌고, 병용이단독사용보다효과적이라는결론을짓기에는아직까지근거가부족하다. 46) 최근에성인에서는류코트리엔길항제와병용하는것이 H1항히스타민제단독사용보다효과가있음을보고하였다. 47,48) 소아에서도 H1항히스타민제에조절되지않는만성두드러기에서는이러한병용요법들을고려해 240

6 유진호 소아만성두드러기 볼수있겠다. 그밖에치료로불응성환자에서 cyclorporin 사용에 대한제한적인보고가있다. 7 명의소아만성두드러기에서 cyclorporin 1 일 3 mg/kg 을사용하였을때수개월치료후모든환자에서 두드러기가소실되었고심각한부작용도없었다. 49) Omalizumab 은만성특발성두드러기환자 12 세이상에서효과와안정성이보 고되었다. 50) 결론 소아만성두드러기는원인을찾을수없는특발성의비율이높으 며, 원인으로는자가면역, 유도성, 음식첨가물, 감염, 음식물, 자가면 역질환등을고려해볼수있다. 진단을위해서는병력과이학적소 견이가장중요하며, 전신증상과백혈구백분율, ESR, CRP 를우선 적으로확인하고, 유도성두드러기를의심하는경우에는유발검사 를시행할수있다. 만성자발성두드러기에서각원인의빈도를고 려한다면자가면역관련검사를시행할수있지만실제임상에적 용하기가쉽지않다. 그외 2 차적인검사들은유용성이낮아원인 을확인할수있을가능성이있을때만검사를시행하는것이타당 하다. 만성두드러기의치료로 2 세대항히스타민제가기본이고상 용량이효과가없을경우에는증량할수있다. 소아만성두드러기 의원인이성인의연구결과와크게다르지않다고간주해왔고, 소 아를대상으로한연구결과는부족하기때문에그진단과치료에 성인의연구결과를적용해왔다. 앞으로성인과소아에서만성두 드러기의원인의차이에대한비교연구와소아에서상용량의항히 스타민제에반응하지않는두드러기에치료대한연구가필요하다. REFERENCES 1. Zitelli KB, Cordoro KM. Evidencebased evaluation and management of chronic urticaria in children. Pediatr Dermatol 2011;28: Volonakis M, KatsarouKatsari A, Stratigos J. Etiologic factors in childhood chronic urticaria. 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7 Yu J Chronic urticaria in children course and association with Helicobacter pylori infection. Int Arch Allergy Immunol 1999;119: Valsecchi R, Pigatto P. Chronic urticaria and Helicobacter pylori. Acta Derm Venereol 1998;78: Tebbe B, Geilen CC, Schulzke JD, Bojarski C, Radenhausen M, Orfanos CE. Helicobacter pylori infection and chronic urticaria. J Am Acad Dermatol 1996;34: Bretag AH, Archer RS, Atkinson HM, Woods WH. Circadian urticaria: another campylobacter association. Lancet 1984;1: Akelma AZ, Cizmeci MN, Mete E, Tufan N, Bozkurt B. A neglected cause for chronic spontaneous urticaria in children: Helicobacter pylori. Allergol Immunopathol (Madr) Mar 20 [Epub] /j.aller Caubet JC, Kaiser L, Lemaître B, Fellay B, Gervaix A, Eigenmann PA. The role of penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge. J Allergy Clin Immunol 2011;127: Levy Y, Segal N, Weintrob N, Danon YL. Chronic urticaria: association with thyroid autoimmunity. Arch Dis Child 2003;88: Heymann WR. Chronic urticaria and angioedema associated with thyroid autoimmunity: review and therapeutic implications. J Am Acad Dermatol 1999;40(2 Pt 1): Zauli D, Deleonardi G, Foderaro S, Grassi A, Bortolotti R, Ballardini G, et al. Thyroid autoimmunity in chronic urticaria. Allergy Asthma Proc 2001;22: Leznoff A, Josse RG, Denburg J, Dolovich J. Association of chronic urticaria and angioedema with thyroid autoimmunity. Arch Dermatol 1983; 119: Dalal I, Levine A, Somekh E, Mizrahi A, Hanukoglu A. Chronic urticaria in children: expanding the "autoimmune kaleidoscope". Pediatrics 2000; 106: Magerl M, Borzova E, GimenezArnau A, Grattan CE, Lawlor F, MathelierFusade P, et al. The definition and diagnostic testing of physical and cholinergic urticariaseaaci/ga2len/edf/unev consensus panel recommendations. Allergy 2009;64: Khakoo G, SofianouKatsoulis A, Perkin MR, Lack G. Clinical features and natural history of physical urticaria in children. Pediatr Allergy Immunol 2008;19: Alangari AA, Twarog FJ, Shih MC, Schneider LC. Clinical features and anaphylaxis in children with cold urticaria. Pediatrics 2004;113:e Pite H, Wedi B, Borrego LM, Kapp A, Raap U. Management of childhood urticaria: current knowledge and practical recommendations. Acta Derm Venereol 2013;93: Najib U, Sheikh J. The spectrum of chronic urticaria. Allergy Asthma Proc 2009;30: Mathes EF, Gilliam AE. A fouryearold boy with fever, rash, and arthritis. Semin Cutan Med Surg 2007;26: Thomas P, Perkin MR, Rayner N, Cox H, Fox AT, Leech S, et al. The investigation of chronic urticaria in childhood: which investigations are being performed and which are recommended? Clin Exp Allergy 2008;38: Church MK, Maurer M, Simons FE, BindslevJensen C, van Cauwenberge P, Bousquet J, et al. Risk of firstgeneration H(1)antihistamines: a GA(2) LEN position paper. Allergy 2010;65: Fedorowicz Z, van Zuuren EJ, Hu N. Histamine H2receptor antagonists for urticaria. Cochrane Database Syst Rev 2012;3:CD Nettis E, Colanardi MC, Paradiso MT, Ferrannini A. Desloratadine in combination with montelukast in the treatment of chronic urticaria: a randomized, doubleblind, placebocontrolled study. Clin Exp Allergy 2004; 34: Wan KS. Efficacy of leukotriene receptor antagonist with an antih1 receptor antagonist for treatment of chronic idiopathic urticaria. J Dermatolog Treat 2009;20: Doshi DR, Weinberger MM. Experience with cyclosporine in children with chronic idiopathic urticaria. Pediatr Dermatol 2009;26: Saini S, Rosen KE, Hsieh HJ, Wong DA, Conner E, Kaplan A, et al. A randomized, placebocontrolled, doseranging study of singledose omalizumab in patients with H1antihistaminerefractory chronic idiopathic urticaria. J Allergy Clin Immunol 2011;128:56773.e

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