Slob Elise M A, Vijverberg Susanne J H, Ruffles Tom, Noij Lieke C E, Biermann Jacqueline, Brouwer Alwin F J, van den Brink Kristel, de Bruin-Kok Annette, Van Ewijk Bart E, Haarman Eric, Hammer Sanne C, Hashimoto Simone, Hogarth Fiona, Jones Christina J, Kamps Arvid W A, Kersten Elin T G, de Kleer Ismé, Lipworth Brian J, Littleford Roberta, Mérelle Marieke, Moeller Alexander, Palmer Colin N A, Pilvinyte Kristina, Rutjes Niels W, van Schaik Ron H N, Smith Helen E, Tavendale Roger, Terheggen-Lagro Suzanne W J, Turner Steve, Twisk Jos W R, Vaessen-Verberne Anja, Verwaal Mariël, de Vries Tjalling, Wesseling Judit, Pijnenburg Mariëlle W, Koppelman Gerard H, Mukhopadhyay Somnath, Maitland-van der Zee Anke H
Department of Pulmonary Medicine, AmsterdamUMC, University of Amsterdam, Amsterdam, The Netherlands.
Department of Clinical Pharmacy, Haaglanden Medical Center, The Hague, The Netherlands.
Allergy. 2025 Apr;80(4):1006-1014. doi: 10.1111/all.16438. Epub 2024 Dec 26.
Long-acting beta2-agonists (LABA) in combination with inhaled corticosteroids (ICS) are commonly used to treat asthma, however, some children lack response to the addition of LABA. This might be partially due to the presence of the Arg16Gly polymorphism, encoded by rs1042713 G>A in the ADRB2 gene. Carrying the A allele (Arg16) at this variant has been associated with an increased risk of exacerbations despite LABA treatment. We investigated whether genotype-guided treatment improved asthma-related outcomes.
We conducted an individual participant data meta-analysis of two randomised controlled trials: PUFFIN (Dutch and Swiss 6-18 year-olds) and PACT (English and Scottish 12-18 year-olds). Children with uncontrolled asthma despite ICS who required a step-up in treatment were included. Participants were randomised to genotype-guided treatment or the control group with a follow-up of at least 6 months. Genotype-guided treatment consisted of adding LABA for children with ADRB2 Gly16/Gly16, whilst children with ADRB2 Arg16/Arg16 or Arg16/Gly16 were treated with double dose ICS (PUFFIN) or add-on montelukast (PACT). The primary outcome was a change in asthma control; secondary outcomes included exacerbation rate and time to exacerbation. Repeated measures mixed models and Cox regression were used.
Fifty-nine out of 102 (PUFFIN) and 59 out of 91 (PACT) children had at least one Arg (A allele). Amongst all 193 children, no difference was observed in asthma control between the study groups. However, genotype-guided treatment resulted in lower asthma exacerbation rates (-0.08 (95%CI -0.16 to -0.00, p = 0.04)) compared to the control group.
Genotype-guided step-up treatment for children with uncontrolled asthma on ICS may lower asthma exacerbation rates and may be useful for personalising asthma care.
长效β2受体激动剂（LABA）联合吸入性糖皮质激素（ICS）常用于治疗哮喘，然而，一些儿童对加用LABA缺乏反应。这可能部分归因于ADRB2基因中由rs1042713 G>A编码的Arg16Gly多态性。尽管接受LABA治疗，但携带该变异的A等位基因（Arg16）与病情加重风险增加有关。我们研究了基因型指导的治疗是否能改善哮喘相关结局。
我们对两项随机对照试验进行了个体参与者数据荟萃分析：PUFFIN（荷兰和瑞士6至18岁儿童）和PACT（英格兰和苏格兰12至18岁儿童）。纳入尽管使用ICS但哮喘仍未得到控制且需要加强治疗的儿童。参与者被随机分配到基因型指导治疗组或对照组，随访至少6个月。基因型指导治疗包括为携带ADRB2 Gly16/Gly16的儿童加用LABA，而携带ADRB2 Arg16/Arg16或Arg16/Gly16的儿童接受双倍剂量ICS治疗（PUFFIN）或加用孟鲁司特治疗（PACT）。主要结局是哮喘控制的变化；次要结局包括病情加重率和病情加重时间。采用重复测量混合模型和Cox回归分析。
102名（PUFFIN）儿童中有59名和91名（PACT）儿童中有59名至少携带一个Arg（A等位基因）。在所有193名儿童中，研究组之间在哮喘控制方面未观察到差异。然而，与对照组相比，基因型指导治疗导致哮喘病情加重率较低（-0.08（95%CI -0.16至-0.00，p = 0.04））。
对于使用ICS但哮喘未得到控制的儿童，基因型指导的加强治疗可能会降低哮喘病情加重率，可能有助于哮喘治疗的个体化。
