奥马珠单抗联合变应原免疫治疗在儿童过敏性哮喘治疗中的应用

Application of Omalizumab combined with allergen immunotherapy in the treatment of allergic asthma in children

目的分析奥马珠单抗(OMA)联合变应原免疫治疗(AIT)在过敏性哮喘患儿中的有效性及安全性。方法回顾性分析2018年8月至2022年10月于天津医科大学第二医院接受OMA联合双螨皮下注射免疫治疗(SCIT)的43例过敏性哮喘患儿的临床资料;男30例,女13例;年龄5~15岁。纳入20例同时期仅接受双螨SCIT的过敏性哮喘患儿作为对照组(接受常规SCIT为对照组1,接受集群SCIT为对照组2),男16例,女4例;年龄4~13岁。43例中20例先行OMA治疗(OMA-AIT组),23例先行AIT(AIT-OMA组,其中因AIT初始治疗阶段剂量上升困难加用OMA的6例为AO1组,因AIT治疗期间哮喘或共患病控制欠佳、频繁出现不良反应加用OMA的17例为AO2组)。OMA联合AIT的有效性和安全性的分析指标包括近1年和联合治疗期间哮喘急性发作次数、儿童哮喘控制测试/哮喘控制测试(C-ACT/ACT)、鼻炎视觉模拟评分(VAS)、吸入性糖皮质激素(ICS)用量、总用药评分(TMS)、共患病情况、肺功能[第1秒用力呼气容积占预计值百分比(FEV 1%pred)、呼气峰值流量占预计值百分比(PEF%pred)、最大呼气中段流量占预计值百分比(MMEF%pred)]、呼出气一氧化氮(FeNO)、完成SCIT初始治疗时间及出现不良反应情况[局部不良反应(LRs)、全身不良反应(SRs)]。服从正态分布的计量资料组间比较采用两独立样本t检验;非正态分布的组间比较采用Wilcoxon检验。计数资料的组间比较采用χ^(2)检验。结果1.基线比较:OMA-AIT组男17/20例、中重度持续性哮喘18/20例,高于AIT-OMA组的13/23例、18/23例(均P<0.05)。2.有效性:(1)OMA-AIT组:20例患儿治疗后均达AIT维持治疗阶段。至维持剂量时,C-ACT/ACT评分、VAS评分、TMS评分分别为(26.10±1.25)分、(1.50±1.24)分、(3.60±1.47)分,较基线[(24.55±2.28)分、(2.55±1.70)分、(5.45±1.19)分]均有明显改善(均P<0.05),肺功能(FEV 1%pred、PEF%pred、MMEF%pred)、FeNO与基线比较差异均无统计学意义(均P>0.05);治疗后ICS用量从基线240.00(160.00,380.00)μg/d降为140.00(80.00,300.00)μg/d(P<0.05);共患病均有所好转。治疗期间5例(25.00%)出现1次哮喘急性发作。常规和集群SCIT达维持剂量的疗程分别为(22.70±7.10)周和(13.00±4.97)周,均大于相应对照组的(15.20±1.32)周和(7.30±1.06)周,差异均有统计学意义(均P<0.05)。(2)AIT-OMA组:AO1组:至维持剂量时,患儿C-ACT/ACT评分较基线有所改善,但差异无统计学意义(P>0.05),VAS评分、TMS评分从基线3.00(1.75,3.00)分、(4.67±1.97)分降为1.00(0,1.00)分、(2.83±1.60)分(P均<0.05);与基线相比,肺功能(FEV 1%pred、PEF%pred、MMEF%pred)、FeNO无明显改善;ICS用量从基线(180.00±78.99)μg/d降为(88.88±26.23)μg/d(P<0.05)。AO2组:完成OMA治疗时,患儿C-ACT/ACT评分、VAS评分、TMS评分分别为(26.53±0.94)分、1.00(0,2.00)分、(3.41±0.94)分,较基线(25.06±2.05)分、2.00(2.00,3.50)分、(5.53±1.23)均分明显改善(均P<0.05);PEF%pred从基线(94.47±26.39)%升至(106.47±22.37)%(P<0.05),余肺功能指标及FeNO无显著改善(P均>0.05);ICS用量从基线240.00(160.00,400.00)μg/d降为80.00(20.00,160.00)μg/d(P<0.05)。联合治疗期间1例(5.88%)出现1次哮喘急性发作,合并食物过敏或特应性皮炎或结膜炎的8例患儿共患病均有所改善。3.安全性:患儿注射OMA均未出现不良反应。(1)OMA-AIT组:接受常规SCIT的患儿初始治疗阶段共注射165针次,出现13次LRs(7.88%),2次SRs(1.21%),均为1级SRs;接受集群SCIT的患儿初始治疗阶段共注射143针次,出现19次LRs(13.29%),未出现SRs。(2)AIT-OMA组:AO1组:6例在AIT初始治疗阶段出现不良反应的患儿在加用OMA后均成功达到维持治疗阶段。AO2组:因维持阶段出现不良反应而加用OMA的患儿,在联合治疗期间均未报告不良反应。结论OMA联合AIT不仅可以扩大AIT的适用范围、改善患儿过敏及哮喘症状、减少药物的使用,还可以提高AIT的安全性,减少AIT治疗期间不良反应,甚至缩短初始治疗的时间、提高患儿依从性。

ObjectiveTo analyze the efficacy and safety of Omalizumab(OMA)combined with allergen immunotherapy(AIT)on children with allergic asthma.MethodsClinical data of 43 children with allergic asthma from the Second Hospital of Tianjin Medical University between August 2018 and October 2022,who were managed by OMA combined with double mite subcutaneous immunotherapy(SCIT)were retrospectively analyzed,including 30 males and 13 females with the age of 5-15 years.Twenty children with allergic asthma who were managed by the monotherapy for SCIT during the same period,including 16 males and 4 females with the age of 4-13 years were included in the control group(group1:conventional immunotherapy;group2:cluster immunotherapy).Among the 43 cases managed by OMA combined with SCIT,20 were treated with OMA,followed by AIT(OMA-AIT group),and 23 were treated with AIT,followed by OMA(AIT-OMA group).Notably,6 cases in AIT-OMA group who were additionally given OMA due to the difficulty in increasing doses were subgrouped in AO1 group,and 17 who were additionally given OMA due to poor control of asthma or comorbidities during the course of AIT and frequent adverse events were subgrouped in AO2 group.The number of asthma exacerbations within 1 year and during the combination therapy,the Childhood Asthma Control Test/Asthma Control Test(C-ACT/ACT)findings,the Visual Analogue Scale(VAS)for grading rhinitis,inhaled corticosteroid(ICS)dosage converted to budesonide equivalent,the Total Medication Score(TMS),comorbidities,lung function[percent-predicted forced expiratory volume in 1 second(FEV 1%pred),percent-predicted peak expiratory flow(PEF%pred),percent-predicted maximal mild-expiratory flow(MMEF%pred)],exhaled nitric oxide(FeNO),completion of the initial SCIT and adverse effects[local adverse reactions(LRs)and systemic adverse reactions(SRs)]were analyzed for assessing the efficacy and safety of OMA combined with AIT on children with allergic asthma.The t-test of two independent samples was used for comparison of measurement data that followed normal distribution.Wilcoxon′s test was used for non-normally distributed between-group comparisons.The χ^(2) test was used for the between-group comparison of counting data.Results(1)Baseline comparison showed that the male ratio(17/20 cases vs.13/23 cases)and the proportion of moderate-to-severe persistent asthma(18/20 cases vs.18/23 cases)in the OMA-AIT group were significantly higher than those of the AIT-OMA group(all P<0.05).(2)Efficacy:①In OMA-AIT group,all children reached the AIT maintenance treatment stage successfully after combination therapy.At the maintenance treatment stage,the C-ACT/ACT,VAS and TMS scores(26.0±1.25 vs.24.55±2.28,1.50±1.24 vs.2.55±1.70,3.60±1.47 vs.5.45±1.19)were significantly improved from baseline(all P<0.05).There were no significant differences in lung function indexes FEV 1%pred,PEF%pred,and MMEF%pred(P>0.05),and FeNO level did not change significantly than baseline.After the combination treatment,ICS dosage significantly decreased from 240.00(160.00,380.00)μg/d at baseline to 140.00(80.00,300.00)μg/d(P<0.05).Comorbidities,including allergic rhinitis,food allergy,atopic dermatitis and angioedema were improved.Five cases(25.00%)had once asthma exacerbation during the treatment.The duration of maintenance dose of conventional(22.70±7.10 vs.15.20±1.32)and cluster immunotherapy(13.00±4.97 vs.7.30±1.06)were longer than those of the corresponding control group(all P<0.05).②AIT-OMA group:In AO1 group,the C-ACT/ACT score were improved from baseline(P<0.05),and VAS score,TMS score decreased from 3.00(1.75,3.00),(4.67±1.97)points at baseline to 1.00(0,1.00),(2.83±1.60)points by the maintenance dose in AO1 group(all P<0.05).There were no significant differences in the FEV 1%pred,PEF%pred,MMEF%pred and FeNO compared with baseline in AO1 group.ICS dosage in AO1 group significantly decreased from(180.00±78.99)μg/d at baseline to(88.88±26.23)μg/d(P<0.05).In AO2 group,the C-ACT/ACT,VAS and TMS scores at the completion of OMA treatment[26.53±0.94 vs.25.06±2.05,1.00(0,2.00)vs.2.00(2.00,3.50),3.41±0.94 vs.5.53±1.23]were significantly improved from baseline(all P<0.05).PEF%pred[(106.47±22.37)%vs.(94.47±26.39)%]significantly increased than baseline(P<0.05),and the remaining lung function indexes and FeNO were not significantly improved.ICS dosage significantly decreased from 240.00(160.00,400.00)μg/d at baseline to 80.00(20.00,160.00)μg/d(P<0.05).During the combination treatment,1 case(5.88%)had once asthma exacerbation,and all 8 cases with food allergy or atopic dermatitis or conjunctivitis had improved comorbidities.(3)Safety:adverse events during OMA injection were not reported.①In OMA-AIT group,a total of 165 OMA injections were performed in the initial treatment stage of the conventional immunotherapy group,with 13(7.88%)reported LRs and 2(1.21%)grade-1 SRs.A total of 143 OMA injections were performed in the initial treatment stage of the cluster immunotherapy group,with 19(13.29%)reported LRs and none of SRs.②In AIT-OMA group,there were 6 cases of adverse events in the initial treatment stage of AIT who were successfully reached the maintenance treatment stage after the addition of OMA in AO1 group.In AO2 group,children who were additionally given OMA due to adverse events in the maintenance treatment phase did not report adverse events during the combination therapy.ConclusionsOMA combined with AIT not only expands the scope of AIT,improves allergic and asthma symptoms in children,reduces the use of drugs,but also enhance the safety of AIT and compliance,reduces adverse events during AIT treatment,and even shortens the time of initial treatment.