Supplementary Material for: Different Phenotypes of Non-Steroidal Anti-Inflammatory Drug Hypersensitivity during Childhood

<b><i>Background:</i></b> Although non-steroidal anti-inflammatory drug hypersensitivity (NSAID-H) has been widely studied in adults, there is still a lack of data regarding the features and phenotypes of NSAID-H in children. Our aim was to define risk factors and different phenotypes according to clinical patterns. <b><i>Methods:</i></b> Patients with a history of reaction to any NSAIDs referred between January 2012 and October 2014 were included. After completing a European Network for Drug Allergy (ENDA) questionnaire, initial skin and/or oral provocation tests (OPTs) were performed for the offending drug. Additional OPTs were done with aspirin in case of NSAID-H to determine cross-reactivity. NSAID-hypersensitive patients were defined as being either a selective responder (SR) or cross-intolerant (CI) and further categorized according to either the ENDA/GA²LEN classification or an alternative scheme by Caimmi et al. [Int Arch Allergy Immunol 2012;159:306-312]. <b><i>Results:</i></b> Among 121 patients [58.7% male, average age 7.8 years (4.7-10.8)] with 161 NSAID-related reactions, 110 patients with 148 reactions were assessed. NSAID-H was diagnosed in 30 (27%) patients with 37 (25%) reactions. Multivariate regression analysis revealed that an immediate-type reaction and respiratory symptoms during the reaction increased the risk of a reproducible NSAID-related reaction (OR 3.508, 95% CI 1.42-8.7, p = 0.007; OR 3.951, 95% CI 1.33-11.77, p = 0.014, respectively). Additional OPTs revealed 13 SRs and 14 CIs. A family history of allergic disease was more frequent in CIs compared to SRs (57.1 vs. 15.4%, p = 0.031). Reactions belonging to CIs were more frequently characterized by angioedema compared to those of SRs (81.3 vs. 46.2%, p = 0.019). SRs and CIs were further classified as single NSAID-induced urticaria/angioedema and/or anaphylaxis (n = 13), NSAID-induced urticaria/angioedema (n = 7), NSAID-exacerbated cutaneous disease (n = 2) and NSAID-exacerbated respiratory disease (n = 1). Four CIs could not be categorized according to either classification system. One SR could not be categorized according to ENDA/GA²LEN. <b><i>Conclusion:</i></b> During childhood, NSAID-H exhibits different phenotypes and the majority of them can be categorized with current classification systems; however, classifications based on adult data may not exactly fit NSAID-H in paediatric patients.<b><i>背景：</i></b> 尽管成人非甾体类抗炎药超敏反应（non-steroidal anti-inflammatory drug hypersensitivity, NSAID-H）已得到广泛研究，但目前仍缺乏儿童非甾体类抗炎药超敏反应的特征与表型相关数据。本研究旨在明确其危险因素，并依据临床模式划分不同表型。<b><i>方法：</i></b> 纳入2012年1月至2014年10月期间转诊的、有任何非甾体类抗炎药用药后不良反应史的患者。完成欧洲药物过敏网络（European Network for Drug Allergy, ENDA）调查问卷后，针对致敏药物开展初始皮肤试验和/或口服激发试验（oral provocation tests, OPTs）。若确诊非甾体类抗炎药超敏反应，则加用阿司匹林行口服激发试验以明确交叉反应性。将非甾体类抗炎药超敏患者分为选择性应答者（selective responder, SR）与交叉不耐受者（cross-intolerant, CI）两类，并依据ENDA/GA²LEN分类标准或Caimmi等人提出的替代方案[《国际过敏与免疫学档案》（Int Arch Allergy Immunol）2012;159:306-312]进行进一步分类。<b><i>结果：</i></b> 共纳入121例患者（其中男性占58.7%，平均年龄7.8岁，四分位间距4.7~10.8岁），共计161例非甾体类抗炎药相关不良反应事件；最终对110例患者的148例不良反应事件进行评估。其中30例患者（占比27%）确诊非甾体类抗炎药超敏反应，涉及37例不良反应事件（占比25%）。多因素回归分析显示，不良反应发作时出现速发型反应与呼吸道症状可增加非甾体类抗炎药相关不良反应重现的风险（比值比OR=3.508，95%置信区间CI：1.42~8.7，p=0.007；OR=3.951，95%CI：1.33~11.77，p=0.014）。追加口服激发试验结果显示，13例为选择性应答者，14例为交叉不耐受者。交叉不耐受者的过敏性疾病家族史发生率高于选择性应答者（57.1% vs 15.4%，p=0.031）。与选择性应答者相比，交叉不耐受者的不良反应更常表现为血管性水肿（81.3% vs 46.2%，p=0.019）。进一步依据分类标准对两类患者进行细分：选择性应答者与交叉不耐受者可分为单一非甾体类抗炎药诱导的荨麻疹/血管性水肿和/或过敏反应（n=13）、非甾体类抗炎药诱导的荨麻疹/血管性水肿（n=7）、非甾体类抗炎药加重的皮肤疾病（n=2）以及非甾体类抗炎药加重的呼吸道疾病（n=1）。另有4例交叉不耐受者无法通过任一分类系统进行归类，1例选择性应答者无法通过ENDA/GA²LEN分类标准进行归类。<b><i>结论：</i></b> 儿童期非甾体类抗炎药超敏反应存在多种不同表型，多数可通过现有分类系统进行归类；然而基于成人数据制定的分类标准或许并不完全适用于儿科患者的非甾体类抗炎药超敏反应。