German cockroach subcutaneous immunotherapy: Impact on nasal responses and allergen-specific immunity among urban children with asthma. German cockroach subcutaneous immunotherapy: Impact on nasal responses and allergen-specific immunity among urban children with asthma

Background: Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children.Objective: To determine if nasal allergen challenge (NAC) responses to cockroach allergen would improve following one year of SCIT.Methods: Urban children with asthma, cockroach-sensitized (skin prick test [SPT] and serum specific IgE) and reactive on NAC, participated in a yearlong randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean total nasal symptoms scores (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, SPT wheal size, serum allergen-specific antibody production and T-cell responses to cockroach allergen were assessed.Results: Changes in mean NAC TNSS did not differ between SCIT-assigned (n=28) versus placebo-assigned (n=29) participants (p=0.63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach sIgE decreased to a similar extent in both groups, while decreased cockroach SPT wheal size was greater among SCIT participants (p=0.04). A 200-fold increase in cockroach sIgG4 was observed among subjects receiving SCIT (p<0.001) but was unchanged in the placebo group. T-cell interleukin-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (p=0.002), while no effect was observed for interleukin-10 or interferon-gamma.Conclusion: A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum sIgG4 production and down-modulation of allergen stimulated T-cell responses. Overall design: CRITICAL (ClinicalTrials.gov NCT03541187) was a randomized, double-blind, placebo-controlled, multicenter trial of non-standardized aqueous glycerinated German cockroach (Blattella germanica) allergenic extract (Stallergenes Greer USA, Lenoir, NC) or placebo administered by subcutaneous injection completed between July 2018 and June 2022. Children ages 8-17 years, with persistent asthma for at least one year and living in low income areas of 10 large US cities were eligible if sensitized to German cockroach extract by both prick skin test and cockroach-specific IgE ≥ 0.35 kUA/L. A positive graded cockroach NAC, defined as either a Total Nasal Symptom Score (TNSS) ≥ 6 on a 12-point scale or a TNSS sneeze score of 3, was also required.Key exclusion criteria included National Asthma Education and Prevention Program classification of severe persistent asthma at randomization; AIT in the last year or anti-IgE, anti-IL-4R-alpha, anti-IL-5/IL5R therapy within six months of the NAC procedure; nasal polyposis or structural nasal abnormalities; a history of anaphylaxis grade 3 or higher; more than 2 courses of systemic corticosteroids within the 12 months or one course within the last 3 months prior to enrollment; or medication use or medical conditions potentially posing additional risk.

背景：蟑螂过敏是导致城市哮喘儿童患病的重要诱因之一。目前针对这类高危儿童开展蟑螂变应原皮下免疫治疗（subcutaneous immunotherapy, SCIT）效果的相关研究较为匮乏。
目的：明确接受1年SCIT治疗后，受试者针对蟑螂变应原的鼻腔变应原激发试验（nasal allergen challenge, NAC）应答是否会得到改善。
方法：纳入经皮肤点刺试验（skin prick test, SPT）与血清特异性IgE（serum specific IgE）检测证实为蟑螂致敏、且鼻腔变应原激发试验（NAC）呈阳性反应的城市哮喘儿童，开展为期1年的德国蟑螂提取物皮下免疫治疗随机双盲安慰剂对照临床试验。本研究的主要终点为SCIT治疗12个月后，NAC过程中的平均鼻腔总症状评分（total nasal symptoms scores, TNSS）变化幅度。同时评估了NAC期间受试者的鼻腔转录组应答变化、SPT风团大小、血清变应原特异性抗体生成水平以及针对蟑螂变应原的T细胞应答情况。
结果：SCIT组（n=28）与安慰剂组（n=29）受试者的NAC平均TNSS变化幅度无统计学差异（p=0.63）。鼻腔转录组应答与TNSS存在相关性，但未观察到显著的治疗效应。两组受试者的蟑螂特异性IgE（sIgE）均出现相似程度的下降，而SCIT组的蟑螂SPT风团大小降幅更为显著（p=0.04）。SCIT组受试者的蟑螂特异性IgG4（sIgG4）水平较基线升高200倍（p<0.001），安慰剂组则无明显变化。经蟑螂变应原刺激后，SCIT组受试者的T细胞白细胞介素-4（interleukin-4, IL-4）应答降幅显著高于安慰剂组（p=0.002），但白细胞介素-10（interleukin-10, IL-10）与干扰素-γ（interferon-γ, IFN-γ）应答未受明显影响。
结论：尽管SCIT治疗可对变应原特异性皮肤试验产生系统性影响、诱导血清sIgG4生成并下调变应原刺激后的T细胞应答，但1年的SCIT治疗并未改善NAC TNSS以及鼻腔转录组对蟑螂变应原激发试验的应答情况。
研究设计：本研究为CRITICAL试验（ClinicalTrials.gov注册号：NCT03541187），于2018年7月至2022年6月开展，是一项多中心、随机、双盲、安慰剂对照临床试验，受试者接受皮下注射非标准化含水甘油制剂的德国蟑螂（Blattella germanica）变应原提取物（美国Stallergenes Greer公司，北卡罗来纳州勒努瓦）或安慰剂。纳入标准为：年龄8~17岁、持续性哮喘病程至少1年、居住于美国10座大城市的低收入社区，且经皮肤点刺试验与蟑螂特异性IgE≥0.35 kUA/L两项检测证实为德国蟑螂致敏，同时需满足分级蟑螂NAC试验阳性标准：即12分制鼻腔总症状评分（TNSS）≥6分，或TNSS喷嚏项得分≥3分。
主要排除标准包括：随机分组时经《国家哮喘教育与预防计划》（National Asthma Education and Prevention Program）分类为重度持续性哮喘；NAC试验前1年内接受过变应原免疫治疗（allergen immunotherapy, AIT），或前6个月内使用过抗IgE、抗IL-4Rα（anti-IL-4R-alpha）、抗IL-5/IL5R（anti-IL-5/IL5R）疗法；患有鼻息肉或鼻腔结构异常；有3级及以上过敏反应史；入组前12个月内接受过≥2个疗程的全身性糖皮质激素治疗，或前3个月内接受过1个疗程；以及存在可能增加研究风险的用药或基础疾病情况。