Abstract
Introduction: Emerging evidence has underscored the positive impact of biologics on asthmatic patients. However, there is a pressing need to verify their therapeutic efficacy in children and adolescents with asthma. To address this, we conducted a network meta-analysis (NMA) to evaluate the efficacy and safety of biologics in the asthma management of this demographic. Methods: The databases of PubMed, Embase, Web of Science, and Cochrane Library were comprehensively searched in our study until May 29, 2024. Only randomized controlled trials were included to estimate the value of biologics on asthmatic children and adolescents. Data extraction and risk of bias assessment were independently performed by two researchers. Outcomes were analyzed by a fixed effects model, and the surface under the cumulative ranking (SUCRA) scores were calculated to determine the likelihood of each biologic being the most effective intervention. Results: 2,672 patients were included for comparing four different biologics (dupilumab, omalizumab, lebrikizumab, and mepolizumab) with a placebo. Dupilumab has been demonstrated to have the highest efficacy in reducing asthmatic exacerbations, improving lung function, and improving patients’ quality of life, with the SUCRA values of 0.956, 0.999, and 0.897, respectively. Omalizumab showed the best safety potential by reducing the risk of adverse and severe events, with the SUCRA values of 0.876 and 0.930. Conclusions: In this NMA, focusing on biologics that target type 2 inflammation in childhood and adolescent asthma, four biologics demonstrated a favorable safety profile. Notably, dupilumab emerged as the most effective, while omalizumab was identified as the safest therapy. Further studies must be conducted in order to confirm these findings.
Introduction
Asthma, a prevalent chronic disease, impacts an estimated 300 million people worldwide [1]. Furthermore, the International Study on Asthma and Allergy in Children (ISAAC) indicates that childhood asthma is increasingly common globally, with a current prevalence of 14% [2]. While a significant number of children with asthma achieve disease control using low- to medium-dose of inhaled corticosteroids. Among them, 2–10% of children experience severe asthma [3, 4], with gradual exacerbation of lung function and extremely low quality of life, imposing significant psychological and economic burdens on their families [5].
The key immune pathogenesis of asthma is associated with type 2 inflammation [6]. Highly effective therapies have been developed to target type 2 inflammation in recent decades, including various monoclonal antibodies against immunoglobulin E (IgE), interleukin (IL)-4, IL-5, and IL-13. These treatments, such as omalizumab, mepolizumab, dupilumab, and lebrikizumab, have demonstrated significant potential to reduce exacerbation rates, enhance lung function, and improve the quality of life for individuals with moderate to severe asthma [7‒11]. Furthermore, lots of recent network meta-analyses (NMAs) have indicated the positive therapeutic effects of those products on asthmatic patients [12‒15]. However, the distinction among children, adolescents, and adults was not made in those studies. Thus, further verification is an urgent need for the therapeutic impact of different biological agents on asthmatic children and adolescents. Therefore, for seeking the better management of asthmatic children, we conducted an NMA research to evaluate the effectiveness and safety of different biological agents in treating children and/or adolescents with asthma, in order to provide more detailed references for clinical use of biological agents.
Methods
In accordance with a pre-registered protocol with PROSPERO (Registration No. CRD42023388628), we conducted the NMA. Our analysis was reported based on the PRISMA extension statement [16].
Literature Search
We carried out a structured and comprehensive search in PubMed, Embase, Web of Science, and Cochrane Library using the MeSH terms: “asthma,” “omalizumab,” “monoclonal antibodies,” and “child,” along with the text words: “mepolizumab,” “dupilumab,” and “lebrikizumab,” until May 29, 2024. Search strategies for major databases were detailed in online supplementary Table 1 (for all online suppl. material, see https://doi.org/10.1159/000542797). Two reviewers screened the retrieved articles for relevance by reviewing titles and abstracts after removing duplicate literature with EndNoteX9. The full-text studies were then obtained and assessed by the identical reviewers to determine their suitability based on the inclusion criteria for our analysis. Two researchers screened the literature and independently verified the results. Any discrepancies were resolved through discussion with the third author.
Eligibility Criteria
Studies included fulfilled the following eligibility requirements: (a) participants: up to 18 years old with asthma of both genders; (b) intervention and comparison: studies comparing biologics and placebo, administered for a minimum of 8 weeks in a double-blind manner and followed up for at least 12 weeks; (c) study design: randomized controlled trials (RCTs); and (d) language: studies written and published only in English.
Data Extraction and Outcomes
Two researchers independently extracted data and details from the included articles, capturing information such as the first author, publication year, patient characteristics, research methods, and outcome data. The main outcome of interest focused on reducing clinically significant asthma exacerbations, with secondary outcomes including changes in prebronchodilator percent predicted forced expiratory volume in 1 s (FEV1) and asthma control questionnaire score using Asthma Control Questionnaire version 5 (ACQ-5). Safety outcomes of interest involved monitoring adverse events (AEs) and severe adverse events (SAEs) in the overall population. AEs that result in death, are life-threatening, require inpatient hospitalization, or extend a current hospital stay may be considered SAEs, which include drug hypersensitivity, pneumonia, joint dislocation, bipolar disorder, and so on.
Quality Assessment
To evaluate the risk of bias in each included trial, we utilized the Cochrane “Risk of Bias” tool (original version), assessing bias in each outcome separately across six domains on a scale of low, unclear, and high risk of bias. A thorough bias assessment was conducted for each study. Additionally, we employed the Grading of Recommendations Assessment, Development, and Evaluation framework (GRADE) to determine the certainty of evidence [17].
Statistical Analysis
Pair-wise meta-analysis was conducted by Review Manager (version 5.3), and NMAs were performed using the GEMTC package in R (version 4.3.1) with four parallel Markov chains of 5,000 samples after a 20,000-sample burn-in [18]. The convergence of Markov chains was assessed using the potential scale reduced factor, aiming for a value close to 1 for better convergence. If this was not achieved, the number of iterations was increased. Weighted mean differences (WMDs) were calculated for continuous outcomes, while risk ratios (RRs) were used for dichotomous variables to demonstrate the combined effect size. Statistical heterogeneity was evaluated by the I2 statistic. Since the heterogeneity index was low for all the included studies, a fixed-effect model was adopted. Based on the analysis findings, each intervention was ranked by considering the probability of it being the best, second best, or worst for an outcome, along with the surface under the cumulative ranking (SUCRA) score [19]. Since all data were from indirect treatment comparisons, statistical inconsistency could not be assessed [20].
Results
Study Selection
The process of literature retrieval is meticulously delineated in Figure 1. A comprehensive search yielded a total of 972 unique citations across multiple databases: PubMed (n = 175), Embase (n = 290), Cochrane Library (n = 225), and Web of Science (n = 282). Subsequent to the removal of 440 duplicates, an initial screening of titles and abstracts was conducted, culminating in the identification of 89 articles deemed suitable for full-text evaluation. Ultimately, six trials, encompassing a combined total of 2,672 participants, were selected for inclusion in our analysis.
PRISMA flow diagram of the literature search. RCT, randomized controlled trial.
Study Characteristic
Table 1 displays the key characteristics of the included trials. All six studies were randomized, placebo-controlled trials involving 2,672 patients. Among them, three compared omalizumab [7, 8, 21] to a placebo, while the remaining compared dupilumab [22], mepolizumab [23], and lebrikizumab [24] to a placebo. All the studies included children and adolescent patients with moderate-severe asthma, except for two trials in Teach 2015 which was conducted among inner-city asthmatic children with one or more recent exacerbations [21], and Jackson 2022, which recruited children who had exacerbation-prone asthma (defined as ≥2 exacerbations in the previous year) and blood eosinophils of at least 150 cells per µL [23]. The average age of patients ranged from 8.4 to 14.2 years old, and the male/female ratio varied from 75/71 to 158/67. Additionally, the average duration of asthma ranged from 5.23 to 11.0 years, the mean serum total IgE in the six trials ranged from 323 to 750 IU/mL, and the mean FEV1 ranged from 69.8% to 94.0%.
Summary of characteristics of included trials
. | Treatment length, weeks . | |||||||
---|---|---|---|---|---|---|---|---|
. | 52 . | 52 . | 52 . | 52 . | 28 . | 52 . | 52 . | 12 . |
Mean FEV1, % predicted (SD) | ||||||||
Placebo | 78.36 (14.51) | 77.87 (15.19) | 92 (18) | 87.2 (18.4) | 85 (12.17) | 69.8 (12.5) | 69.8 (12.5) | 89.3 (21.2) |
Intervention | 77.66 (14.38) | 76.37 (14.60) | 94 (16) | 86.0 (17.8) | 84 (13.33) | 73.3 (9.9) | 70.9 (10.7) | 88.7 (15.4) |
Mean duration of asthma (SD) | ||||||||
Placebo | 5.23 (2.63) | 5.54 (2.65) | / | / | 6.1 (1.83) | 9 (2.67) | 9 (2.67) | 7.24 (3.56) |
Intervention | 5.78 (2.67) | 5.78 (2.60) | / | / | 6.1 (1.83) | 11 (2.67) | 11 (2.67) | 7.72 (3.56) |
Mean serum total IgE, IU/mL (SD) | ||||||||
Placebo | 450 (531.85) | 606 (656.30) | 529.5 (694.81) | 456.9 (335.8) | 323 (197.17) | 464 (613.33) | 464 (613.33) | / |
Intervention | 635 (781.48) | 750 (843.70) | 466 (551.11) | 476.0 (339.3) | 348 (208.17) | 468.75 (667.41) | 456.75 (556.30) | / |
Mean age (SD), years | ||||||||
Placebo | 9.0 (1.6) | 9.0 (1.5) | 10.8 (2.96) | 8.4 (1.7) | 9.5 (6–12) | 14.1 (1.7) | 14.1 (1.7) | 10.1 (3.06) |
Intervention | 8.9 (1.6) | 8.9 (1.6) | 10.5 (2.96) | 8.7 (1.7) | 9.4 (5–12) | 14.2 (1.5) | 14.2 (1.6) | 10.3 (2.99) |
Gender (male/female) | ||||||||
Placebo | 78/36 | 58/26 | 89/55 | 138/69 | 73/36 | 68/49 | 68/49 | 59/30 |
Intervention | 152/84 | 116/59 | 75/71 | 287/134 | 158/67 | 70/43 | 57/59 | 174/85 |
Sample size, n | ||||||||
Placebo | 114 | 84 | 144 | 207 | 109 | 117 | 117 | 89 |
Intervention | 236 | 175 | 146 | 421 | 225 | 113 | 116 | 259 |
Total | 350 | 259 | 290 | 628 | 334 | 230 | 233 | 348 |
Placebo | Matching placebo, injection, same dose, and frequency | Matching placebo, injection, same dose, and frequency | Matching placebo, injection, same dose, and frequency | Matching placebo, injection, same dose, and frequency | Matching placebo, injection, same dose, and frequency | Matching placebo, injection, same dose, and frequency | ||
Intervention | Dupilumab subcutaneously injection, at a dose of 100 mg for those weighing ≤30 kg and 200 mg for those weighing >30 kg every 2 weeks | Mepolizumab subcutaneously injection, at a dose of 40 mg for those aging 6–11 years and 100 mg for those aging 12–17 years, every 4 weeks | Omalizumab subcutaneously injection, at a dose based on body weight and serum IgE, 75–375 mg, every 2 weeks or 4 weeks | Omalizumab subcutaneously injection, at a dose based on body weight and serum IgE (0.016 mg/kg/IgE [IU/mL]), every 4 weeks | Lebrikizumab subcutaneously injection, at a dose of 37.5 mg every 4 weeks | Lebrikizumab subcutaneously injection, at a dose of 125 mg every 4 weeks | Omalizumab subcutaneously injection, with dosing based on weight and serum IgE levels, every 2 or 4 weeks | |
Population | Uncontrolled moderate-to-severe asthma (patients with type 2 inflammatory phenotype) | Uncontrolled moderate-to-severe asthma (patients with ≥300 blood eosinophils per mm3) | Urban children with exacerbation-prone eosinophilic asthma | Inadequately controlled moderate-to-severe allergic (IgE-mediated) asthma | With moderate to severe allergic asthma requiring treatment with inhaled corticosteroids | With uncontrolled asthma diagnosed ≥12 months | Asthma diagnosis or symptoms for more than 1 year, 1 or more asthma exacerbations or hospitalization within the prior 19 months | |
Nct. No. | NCT02948959 | NCT03292588 | NCT00079937 | / | NCT01875003 | NCT01430403 | ||
Trials | Bacharier, (1) [22] (2021) | Bacharier, (2) [22] (2021) | Jackson, [23] (2022) | Lanier [7] (2009) | Milgrom [8] (2001) | Szefler (1) [24] (2022) | Szefler (2) [24] (2022) | Teach [21] (2015) |
. | Treatment length, weeks . | |||||||
---|---|---|---|---|---|---|---|---|
. | 52 . | 52 . | 52 . | 52 . | 28 . | 52 . | 52 . | 12 . |
Mean FEV1, % predicted (SD) | ||||||||
Placebo | 78.36 (14.51) | 77.87 (15.19) | 92 (18) | 87.2 (18.4) | 85 (12.17) | 69.8 (12.5) | 69.8 (12.5) | 89.3 (21.2) |
Intervention | 77.66 (14.38) | 76.37 (14.60) | 94 (16) | 86.0 (17.8) | 84 (13.33) | 73.3 (9.9) | 70.9 (10.7) | 88.7 (15.4) |
Mean duration of asthma (SD) | ||||||||
Placebo | 5.23 (2.63) | 5.54 (2.65) | / | / | 6.1 (1.83) | 9 (2.67) | 9 (2.67) | 7.24 (3.56) |
Intervention | 5.78 (2.67) | 5.78 (2.60) | / | / | 6.1 (1.83) | 11 (2.67) | 11 (2.67) | 7.72 (3.56) |
Mean serum total IgE, IU/mL (SD) | ||||||||
Placebo | 450 (531.85) | 606 (656.30) | 529.5 (694.81) | 456.9 (335.8) | 323 (197.17) | 464 (613.33) | 464 (613.33) | / |
Intervention | 635 (781.48) | 750 (843.70) | 466 (551.11) | 476.0 (339.3) | 348 (208.17) | 468.75 (667.41) | 456.75 (556.30) | / |
Mean age (SD), years | ||||||||
Placebo | 9.0 (1.6) | 9.0 (1.5) | 10.8 (2.96) | 8.4 (1.7) | 9.5 (6–12) | 14.1 (1.7) | 14.1 (1.7) | 10.1 (3.06) |
Intervention | 8.9 (1.6) | 8.9 (1.6) | 10.5 (2.96) | 8.7 (1.7) | 9.4 (5–12) | 14.2 (1.5) | 14.2 (1.6) | 10.3 (2.99) |
Gender (male/female) | ||||||||
Placebo | 78/36 | 58/26 | 89/55 | 138/69 | 73/36 | 68/49 | 68/49 | 59/30 |
Intervention | 152/84 | 116/59 | 75/71 | 287/134 | 158/67 | 70/43 | 57/59 | 174/85 |
Sample size, n | ||||||||
Placebo | 114 | 84 | 144 | 207 | 109 | 117 | 117 | 89 |
Intervention | 236 | 175 | 146 | 421 | 225 | 113 | 116 | 259 |
Total | 350 | 259 | 290 | 628 | 334 | 230 | 233 | 348 |
Placebo | Matching placebo, injection, same dose, and frequency | Matching placebo, injection, same dose, and frequency | Matching placebo, injection, same dose, and frequency | Matching placebo, injection, same dose, and frequency | Matching placebo, injection, same dose, and frequency | Matching placebo, injection, same dose, and frequency | ||
Intervention | Dupilumab subcutaneously injection, at a dose of 100 mg for those weighing ≤30 kg and 200 mg for those weighing >30 kg every 2 weeks | Mepolizumab subcutaneously injection, at a dose of 40 mg for those aging 6–11 years and 100 mg for those aging 12–17 years, every 4 weeks | Omalizumab subcutaneously injection, at a dose based on body weight and serum IgE, 75–375 mg, every 2 weeks or 4 weeks | Omalizumab subcutaneously injection, at a dose based on body weight and serum IgE (0.016 mg/kg/IgE [IU/mL]), every 4 weeks | Lebrikizumab subcutaneously injection, at a dose of 37.5 mg every 4 weeks | Lebrikizumab subcutaneously injection, at a dose of 125 mg every 4 weeks | Omalizumab subcutaneously injection, with dosing based on weight and serum IgE levels, every 2 or 4 weeks | |
Population | Uncontrolled moderate-to-severe asthma (patients with type 2 inflammatory phenotype) | Uncontrolled moderate-to-severe asthma (patients with ≥300 blood eosinophils per mm3) | Urban children with exacerbation-prone eosinophilic asthma | Inadequately controlled moderate-to-severe allergic (IgE-mediated) asthma | With moderate to severe allergic asthma requiring treatment with inhaled corticosteroids | With uncontrolled asthma diagnosed ≥12 months | Asthma diagnosis or symptoms for more than 1 year, 1 or more asthma exacerbations or hospitalization within the prior 19 months | |
Nct. No. | NCT02948959 | NCT03292588 | NCT00079937 | / | NCT01875003 | NCT01430403 | ||
Trials | Bacharier, (1) [22] (2021) | Bacharier, (2) [22] (2021) | Jackson, [23] (2022) | Lanier [7] (2009) | Milgrom [8] (2001) | Szefler (1) [24] (2022) | Szefler (2) [24] (2022) | Teach [21] (2015) |
All in mean (SD). IgE, immunoglobulin E; FEV1, forced expiratory volume in 1 s.
Figure 2 illustrates the direct comparisons available between the treatments. However, it should be noted that none of the studies conducted head-to-head comparisons of the treatments, as all employed placebos as comparators.
Evidence network of eligible comparisons for an NMA: asthma exacerbations (a), change of ppFEV1 (b), change of ACQ-5 (c), change of using rescue medicine (d), AEs (e), and SAEs (f). The width of the lines is proportional to the number of RCTs comparing every pair of treatments, and the size of every node is proportional to the number of participants. NMA, network meta-analysis; ppFEV1, prebronchodilator percent predicted FEV1; ACQ-5, Asthma Control Questionnaire version 5; AEs, adverse events; SAEs, severe adverse events; RCT, randomized controlled trial.
Evidence network of eligible comparisons for an NMA: asthma exacerbations (a), change of ppFEV1 (b), change of ACQ-5 (c), change of using rescue medicine (d), AEs (e), and SAEs (f). The width of the lines is proportional to the number of RCTs comparing every pair of treatments, and the size of every node is proportional to the number of participants. NMA, network meta-analysis; ppFEV1, prebronchodilator percent predicted FEV1; ACQ-5, Asthma Control Questionnaire version 5; AEs, adverse events; SAEs, severe adverse events; RCT, randomized controlled trial.
Risk of Bias Assessment
Figure 3 presents the quality assessment of the included trials. Two trials exhibited an unclear risk of bias in the generation of random sequences, while two others were ambiguous, and one displayed a high risk in allocation concealment. Regarding the blinding of participants and personnel, three randomized controlled trials (RCTs) were marked as having an unclear risk due to the absence of detailed blinding procedures in the publications, and one RCT was noted to have an indeterminate risk in the blinding of outcome assessment. Furthermore, one trial was identified with an unclear risk concerning attrition bias. In terms of other biases, three studies were classified as having an unclear risk, whereas the remainder demonstrated a low risk. The certainty of the evidence, assessed using the GRADE methodology, is detailed in online supplementary Table 2.
The assessment of the quality of clinical trials is shown. a “Risk of bias” graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies. b “Risk of bias” summary: review authors’ judgments about each risk of bias item for each included study. (+) denotes a low risk of bias; (−) denotes a high risk of bias; (?) denotes an unclear risk of bias.
The assessment of the quality of clinical trials is shown. a “Risk of bias” graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies. b “Risk of bias” summary: review authors’ judgments about each risk of bias item for each included study. (+) denotes a low risk of bias; (−) denotes a high risk of bias; (?) denotes an unclear risk of bias.
Network Meta-Analysis
All outcomes of NMA are delineated in Table 2, depicted through WMD or risk RRs alongside 95% confidence intervals (CI). Furthermore, the potential scale reduced factor for both efficacy and safety outcomes uniformly approached unity, signifying excellent convergence across all fitted models.
Results of network meta-analysis based on outcomes
Outcomes . | WMD or RR (95% CI) . | ||||
---|---|---|---|---|---|
Asthma exacerbations | Dupilumab | ||||
0.71 (0.51, 0.98)* | Lebrikizumab | ||||
− | − | Mepolizumab | |||
0.71 (0.4, 1.23) | 1.01 (0.55, 1.8) | − | Omalizumab | ||
0.39 (0.33, 0.47)* | 0.55 (0.42, 0.72)* | − | 0.55 (0.33, 0.95)* | Placebo | |
Change of ppFEV1 | Dupilumab | ||||
− | Lebrikizumab | ||||
12.64 (7.78, 17.49)* | − | Mepolizumab | |||
7.74 (2.67, 12.77)* | − | −4.92 (−10.67, 0.91) | Omalizumab | ||
8.04 (5.26, 10.82)* | − | −4.61 (−8.57, −0.61)* | 0.29 (−3.94, 4.52) | Placebo | |
Change of ACQ-5 | Dupilumab | ||||
−0.10 (−0.36, 0.14) | Lebrikizumab | ||||
− | − | Mepolizumab | |||
− | − | − | Omalizumab | ||
−0.43 (−0.55, −0.30)* | −0.32 (−0.53, −0.11)* | − | − | Placebo | |
Change of using rescue medicine | Dupilumab | ||||
− | Lebrikizumab | ||||
− | − | Mepolizumab | |||
− | 0.36 (−0.29, 0.99) | − | Omalizumab | ||
− | 0.06 (−0.41, 0.52) | − | −0.30 (−0.75, 0.15) | Placebo | |
AEs | Dupilumab | ||||
0.95 (0.77, 1.15) | Lebrikizumab | ||||
0.84 (0.59, 1.19) | 0.89 (0.61, 1.3) | Mepolizumab | |||
1.06 (0.96, 1.19) | 1.12 (0.95, 1.35) | 1.27 (0.91, 1.79) | Omalizumab | ||
1.04 (0.95, 1.16) | 1.1 (0.94, 1.32) | 1.24 (0.89, 1.75) | 0.98 (0.94, 1.03) | Placebo | |
SAEs | Dupilumab | ||||
1.19 (0.24, 5.91) | Lebrikizumab | ||||
0.51 (0.05, 3.71) | 0.43 (0.04, 3.7) | Mepolizumab | |||
2.42 (0.78, 8.29) | 2.03 (0.51, 9.18) | 4.72 (0.77, 42.05) | Omalizumab | ||
1.11 (0.44, 3.19) | 0.93 (0.28, 3.64) | 2.18 (0.41, 17.57) | 0.46 (0.24, 0.88)* | Placebo |
Outcomes . | WMD or RR (95% CI) . | ||||
---|---|---|---|---|---|
Asthma exacerbations | Dupilumab | ||||
0.71 (0.51, 0.98)* | Lebrikizumab | ||||
− | − | Mepolizumab | |||
0.71 (0.4, 1.23) | 1.01 (0.55, 1.8) | − | Omalizumab | ||
0.39 (0.33, 0.47)* | 0.55 (0.42, 0.72)* | − | 0.55 (0.33, 0.95)* | Placebo | |
Change of ppFEV1 | Dupilumab | ||||
− | Lebrikizumab | ||||
12.64 (7.78, 17.49)* | − | Mepolizumab | |||
7.74 (2.67, 12.77)* | − | −4.92 (−10.67, 0.91) | Omalizumab | ||
8.04 (5.26, 10.82)* | − | −4.61 (−8.57, −0.61)* | 0.29 (−3.94, 4.52) | Placebo | |
Change of ACQ-5 | Dupilumab | ||||
−0.10 (−0.36, 0.14) | Lebrikizumab | ||||
− | − | Mepolizumab | |||
− | − | − | Omalizumab | ||
−0.43 (−0.55, −0.30)* | −0.32 (−0.53, −0.11)* | − | − | Placebo | |
Change of using rescue medicine | Dupilumab | ||||
− | Lebrikizumab | ||||
− | − | Mepolizumab | |||
− | 0.36 (−0.29, 0.99) | − | Omalizumab | ||
− | 0.06 (−0.41, 0.52) | − | −0.30 (−0.75, 0.15) | Placebo | |
AEs | Dupilumab | ||||
0.95 (0.77, 1.15) | Lebrikizumab | ||||
0.84 (0.59, 1.19) | 0.89 (0.61, 1.3) | Mepolizumab | |||
1.06 (0.96, 1.19) | 1.12 (0.95, 1.35) | 1.27 (0.91, 1.79) | Omalizumab | ||
1.04 (0.95, 1.16) | 1.1 (0.94, 1.32) | 1.24 (0.89, 1.75) | 0.98 (0.94, 1.03) | Placebo | |
SAEs | Dupilumab | ||||
1.19 (0.24, 5.91) | Lebrikizumab | ||||
0.51 (0.05, 3.71) | 0.43 (0.04, 3.7) | Mepolizumab | |||
2.42 (0.78, 8.29) | 2.03 (0.51, 9.18) | 4.72 (0.77, 42.05) | Omalizumab | ||
1.11 (0.44, 3.19) | 0.93 (0.28, 3.64) | 2.18 (0.41, 17.57) | 0.46 (0.24, 0.88)* | Placebo |
WMD for change of ppFEV1, ACQ-5, and using rescue medicine and RR for asthma exacerbations, AEs, and SAEs.
WMD, weighted mean difference; RR, risk ratio; CI, confidence interval; ppFEV1, prebronchodilator percent predicted FEV1; ACQ-5, Asthma Control Questionnaire version 5; AEs, adverse events; SAEs, severe adverse events.
RR (95% CI) in bold; *p < 0.05; − not compared.
Network Meta-Analysis of Efficacy Outcomes
Concerning severe asthma exacerbations, three biologics significantly outperformed placebo in reducing exacerbation rates: dupilumab (RR, 0.39; 95% CI, 0.33–0.47), lebrikizumab (RR, 0.55; 95% CI, 0.42–0.72), and omalizumab (RR, 0.55; 95% CI, 0.33–0.95). Dupilumab also showed a significantly lower risk of asthma exacerbations compared to lebrikizumab (RR, 0.71; 95% CI, 0.51–0.98). Data on mepolizumab was excluded due to a severe asthma exacerbation rate of 1.3%, exceeding the total number of researchers, and no information on frequent asthma exacerbations was provided for reference [23].
In terms of improving FEV1, dupilumab demonstrated significant superiority over mepolizumab, omalizumab, and placebo (WMD, 12.64; 95% CI, 7.78–17.49; WMD, 7.74; 95% CI, 2.67–12.77; WMD, 8.04; 95% CI, 5.26–10.82, respectively). Conversely, mepolizumab performed worse than placebo in enhancing FEV1 (WMD, −4.61; 95% CI, −8.57 to −0.61). No data was available for lebrikizumab as the trial only provided prebronchodilator FEV1 data, not the percent predicted value, which was essential for our analysis.
In reducing ACQ scores, both dupilumab (WMD, −0.43; 95% CI, −0.55 to −0.30) and lebrikizumab (WMD, −0.32; 95% CI, −0.53 to −0.11) significantly surpassed placebo, with no notable differences between them. Data for mepolizumab and omalizumab were unavailable, as assessments in the mepolizumab group utilized the Composite Asthma Severity Index (CASI), and evaluations in the omalizumab group employed the Pediatric Asthma Quality of Life Questionnaire (PAQLQ), nocturnal asthma symptom score [8], or Childhood Asthma Control Test (C-ACT), rather than ACQ-5. No statistical differences were noted in the use of rescue medication across all interventions.
Network Meta-Analysis of Safety Outcomes
No significant statistical disparities were observed among all biologics regarding AEs in the general population. In terms of SAEs, omalizumab (RR, 0.46; 95% CI, 0.24–0.88) was associated with a reduced risk of SAEs, whereas other interventions demonstrated no statistical deviations from placebo.
Ranking of the Treatment Measures
The ranking of treatments based on SUCRA is shown in online supplementary Table 3 and Figure 4.
SUCRA curve for the outcomes: asthma exacerbations (a), change of ppFEV1 (b), change of ACQ-5 (c), change of using rescue medicine (d), AEs (e), and SAEs (f). SUCRA, surface under the cumulative ranking; ppFEV1, prebronchodilator percent predicted FEV1; ACQ-5, Asthma Control Questionnaire version 5; AEs, adverse events; SAEs, severe adverse events.
SUCRA curve for the outcomes: asthma exacerbations (a), change of ppFEV1 (b), change of ACQ-5 (c), change of using rescue medicine (d), AEs (e), and SAEs (f). SUCRA, surface under the cumulative ranking; ppFEV1, prebronchodilator percent predicted FEV1; ACQ-5, Asthma Control Questionnaire version 5; AEs, adverse events; SAEs, severe adverse events.
Ranking of the Efficacy of Interventions
Dupilumab demonstrated superior efficacy in reducing asthma exacerbations, enhancing lung function, and lowering ACQ-5 scores, with SUCRA values of 0.957, 0.999, and 0.898, respectively. Omalizumab was most effective in minimizing the use of rescue medication, achieving a SUCRA value of 0.879, and ranked second in both reducing asthma exacerbations and improving lung function, with SUCRA scores of 0.534 and 0.502. Lebrikizumab was second in lowering ACQ-5 scores and third in reducing asthma exacerbations, with SUCRA values of 0.601 and 0.503, respectively. Mepolizumab exhibited the least effectiveness in lung function improvement, with a SUCRA value of 0.019. Placebo was second in reducing rescue medication use, third in improving FEV1, and least effective in reducing exacerbations and ACQ-5 scores, with SUCRA values of 0.345, 0.478, 0.005, and 0.000, respectively.
Ranking of the Safety of the Interventions
Concerning safety profiles, omalizumab exhibited the most favorable outcomes, presenting the lowest incidence of AEs and SAEs, with SUCRA scores of 0.876 and 0.930, respectively. In contrast, mepolizumab was associated with the highest incidence of both AEs and SAEs, as indicated by SUCRA values of 0.149 and 0.176.
Additionally, lebrikizumab was associated with a higher incidence of AEs but a reduced risk of SAEs. Dupilumab demonstrated inferior safety outcomes in terms of both AEs and SAEs, while the placebo group showed comparatively better safety profiles.
Pair-Wise Meta-Analysis
Table 3 and online supplementary Figure 1 display the outcomes of the pairwise meta-analysis, characterized by WMDs or RRs accompanied by 95% CI. All findings demonstrated minimal heterogeneity.
Pair-wise meta-analysis comparing asthma exacerbations, change of ppFEV1, change of ACQ-5, change of rescue medicine, AEs, and SAEs
Outcomes . | Comparison . | Including RCTs, n . | Pair-wise meta-analysis WMD or RR (95% CI) . | I2, % . |
---|---|---|---|---|
Asthma exacerbations | Omalizumab vs. placebo | 1 | 0.54 (0.32, 0.91)* | − |
Dupilumab vs. placebo | 2 | 0.39 (0.32, 0.46)* | 0 | |
Lebrikizumab vs. placebo | 2 | 0.55 (0.42, 0.72)* | 0 | |
Change of ppFEV1 | Dupilumab vs. placebo | 2 | 8.02 (5.23, 10.82)* | 0 |
Mepolizumab vs. placebo | 1 | −4.60 (−8.56, −0.64)* | − | |
Omalizumab vs. placebo | 1 | 0.30 (−3.92, 4.52) | − | |
Change of ACQ-5 | Dupilumab vs. placebo | 2 | −0.43 (−0.55, −0.30)* | 0 |
Lebrikizumab vs. placebo | 2 | −0.32 (−0.54, −0.10)* | ||
Change of using rescue medicine | Omalizumab vs. placebo | 1 | −0.30 (−0.75, 0.15) | − |
Lebrikizumab vs. placebo | 2 | 0.05 (−0.41, 0.52) | 0 | |
AEs | Omalizumab vs. placebo | 3 | 0.99 (0.94, 1.04) | 0 |
Dupilumab vs. placebo | 1 | 1.04 (0.94, 1.15) | − | |
Lebrikizumab vs. placebo | 1 | 1.10 (0.93, 1.30) | − | |
Mepolizumab vs. placebo | 1 | 1.24 (0.89, 1.74) | − | |
SAEs | Omalizumab vs. placebo | 3 | 0.44 (0.22, 0.86)* | 0 |
Dupilumab vs. placebo | 1 | 1.07 (0.40, 2.89) | − | |
Mepolizumab vs. placebo | 1 | 2.00 (0.36, 11.09) | − | |
Lebrikizumab vs. placebo | 1 | 0.89 (0.26, 3.11) | − |
Outcomes . | Comparison . | Including RCTs, n . | Pair-wise meta-analysis WMD or RR (95% CI) . | I2, % . |
---|---|---|---|---|
Asthma exacerbations | Omalizumab vs. placebo | 1 | 0.54 (0.32, 0.91)* | − |
Dupilumab vs. placebo | 2 | 0.39 (0.32, 0.46)* | 0 | |
Lebrikizumab vs. placebo | 2 | 0.55 (0.42, 0.72)* | 0 | |
Change of ppFEV1 | Dupilumab vs. placebo | 2 | 8.02 (5.23, 10.82)* | 0 |
Mepolizumab vs. placebo | 1 | −4.60 (−8.56, −0.64)* | − | |
Omalizumab vs. placebo | 1 | 0.30 (−3.92, 4.52) | − | |
Change of ACQ-5 | Dupilumab vs. placebo | 2 | −0.43 (−0.55, −0.30)* | 0 |
Lebrikizumab vs. placebo | 2 | −0.32 (−0.54, −0.10)* | ||
Change of using rescue medicine | Omalizumab vs. placebo | 1 | −0.30 (−0.75, 0.15) | − |
Lebrikizumab vs. placebo | 2 | 0.05 (−0.41, 0.52) | 0 | |
AEs | Omalizumab vs. placebo | 3 | 0.99 (0.94, 1.04) | 0 |
Dupilumab vs. placebo | 1 | 1.04 (0.94, 1.15) | − | |
Lebrikizumab vs. placebo | 1 | 1.10 (0.93, 1.30) | − | |
Mepolizumab vs. placebo | 1 | 1.24 (0.89, 1.74) | − | |
SAEs | Omalizumab vs. placebo | 3 | 0.44 (0.22, 0.86)* | 0 |
Dupilumab vs. placebo | 1 | 1.07 (0.40, 2.89) | − | |
Mepolizumab vs. placebo | 1 | 2.00 (0.36, 11.09) | − | |
Lebrikizumab vs. placebo | 1 | 0.89 (0.26, 3.11) | − |
WMD, weighted mean difference; RR, risk ratio; CI, confidence interval; ppFEV1, prebronchodilator percent predicted FEV1; ACQ-5, Asthma Control Questionnaire version 5; AEs, adverse events; SAEs, severe adverse events.
RR (95% CI) in bold; *p < 0.05; − not compared.
Discussion
Given the unique growth and developmental considerations, along with the imperative of treatment safety, the medication options for pediatric patients are significantly limited. Furthermore, our understanding of innovative drug therapies for children has not kept pace with that of adult patients. Despite the extensive use of biological agents in asthma management for nearly two decades, supported by numerous studies confirming their effectiveness and safety, research on their application in children and adolescents remains limited. With the rising prevalence of asthma in this demographic, there is a critical need to evaluate the impact of biological agents on pediatric asthma to inform clinical practice. Current research on asthma in children and adolescents is notably sparse. This article seeks to address this gap by synthesizing existing studies and advocating for further research to corroborate our findings.
A Bayesian network meta-analysis was conducted to assess the effectiveness and safety of monoclonal antibodies for treating children and adolescents with asthma in this study, including dupilumab, mepolizumab, omalizumab, and lebrikizumab, which have indicated the positive therapeutic effects on adult asthmatic patients. Our analysis identified six relevant trials involving 2,672 participants.
Analysis of four biologics indicated a significant reduction in exacerbation rates compared to a placebo, except for mepolizumab, for which data was unavailable. It showed a notable decrease in asthma exacerbations with dupilumab treatment compared to lebrikizumab. Furthermore, our analysis revealed that dupilumab in the VOYAGE trial (patients aged 6–11 years receiving dupilumab 100 or 200 mg every two weeks) significantly improved lung function and enhanced health-related quality of life compared to mepolizumab, omalizumab, and placebo [22]. This finding was consistent with the results of the QUEST trial (patients aged 12 years or older receiving dupilumab 200 or 300 mg every two weeks) and the TRAVERSE trial (patients aged 12–84 years receiving dupilumab 300 mg every two weeks) in adults and adolescents [10, 25], with the lower dosage of dupilumab administered to children. Notably, a post hoc analysis of the 107 adolescent patients who participated in the QUEST trial demonstrated lung function improvements comparable to those observed in adults. However, the effect of dupilumab on exacerbation rates in adolescents treated with intention varied based on the dosage. In patients treated with dupilumab 200 mg every two weeks, severe acute exacerbations decreased by 46%, while in those treated with dupilumab 300 mg every two weeks, severe acute exacerbations increased by 13% [26]. Further research is necessary in the adolescent age group to fully understand which dose of dupilumab is most effective for these patients.
Besides improving asthma exacerbation, we discovered that lebrikizumab contributed to the decrease of ACQ-5 score compared with placebo, which was a point of contention compared with other findings. Liu et al. [27] found that lebrikizumab treatment for uncontrolled asthma could reduce the rate of asthma exacerbations and significantly enhance lung function, which aligns with our results. However, Edris et al. [13] reported that lebrikizumab did not show notable differences in improving asthmatic exacerbation rates. Similarly, Hanania et al. [11] demonstrated that lebrikizumab’s ability to consistently reduce exacerbation rates was limited. Additionally, it is important to note that our study indicated a correlation between improved asthma outcomes and health-related quality of life, although this contradicted the findings of another study. Edris et al. [13] observed that while lebrikizumab improved lung function, it did not impact the ACQ score, suggesting that enhanced lung function or reduced exacerbations did not necessarily translate to better health-related quality of life. We recognize that this discrepancy may be attributed to variations in dosages administered, routes of administration, and the characteristics of the subjects. Further study is needed to fully understand the efficacy of lebrikizumab in asthmatic management.
Our analysis revealed no statistically significant differences among all biologics in AEs, while omalizumab showed a lower risk of SAEs compared to a placebo. According to the GINA guidelines, omalizumab treatment is indicated for adults and children aged ≥6 years with severe allergic asthma, administered via subcutaneous injection every 2–4 weeks, with the dosage determined by body weight and serum IgE levels. Due to the high healthcare costs associated with omalizumab and the absence of clear methods to identify responders, questions remain about whether, how, and when children can safely discontinue treatment, and whether free IgE can be utilized to monitor treatment to determine the possible minimum effective dose. These issues require further investigation [28].
Moreover, we also discovered that mepolizumab, in comparison to a placebo, led to a significant enhancement of prebronchodilator percent predicted FEV1 and could potentially raise AEs and SAEs. The outcomes of a Spanish cohort consisting of 318 severe asthma patients validated that mepolizumab effectively improved lung function [29], and a systematic review involving individuals aged 12–75 years confirmed that mepolizumab marginally increased drug-related AEs and SAEs [30], which supported our discovery.
Upon thorough examination of the NMA data, it is evident that the use of biological preparations in asthma treatment leads to significant enhancements in efficacy for pediatric and adolescent patients. This includes a reduction in asthma exacerbations and improved lung function, without a corresponding increase in AEs. These results provide substantial guidance for future research endeavors. First and foremost, our findings affirm the short-term safety (up to 1 year) of various biologics in children and adolescents with asthma. However, given the critical nature of childhood and adolescence for growth and cognitive development, there is an urgent need for long-term studies. These studies should aim to clarify the long-term safety profile of biologics in pediatric patients, with particular emphasis on their impact on growth and cognitive development. While no definitive evidence currently links an increased risk of malignancy to any biologic, the duration of existing trials – limited to 4.5 years – may be insufficient to detect potential malignancy signals [31]. Therefore, extended trial durations are necessary to provide a more comprehensive understanding of any long-term risks. Moreover, reports of herpes zoster infections in a small number of patients treated with dupilumab and mepolizumab warrant close attention [32‒35], particularly considering the immature immune systems typical of children. Further investigation into the immunological effects of these treatments in pediatric patients is essential. Lastly, since our study does not include direct comparative trials, future research must focus on comparing different biologics. This comparison is vital for a more nuanced assessment of their relative efficacies and safety profiles. Such research will be instrumental in tailoring treatment strategies to individual asthma patients, thereby optimizing therapeutic outcomes and ensuring the best possible care for children and adolescents with asthma.
Owing to safety concerns in pediatric pharmacotherapy, research on the use of new biologics in childhood asthma is limited. However, numerous studies have shown that new biologics exhibit good safety and superior efficacy in treating adult asthma, aligning with our results and attesting to their reliability. Thus, our article can serve as a reference for the use of new biologics in pediatric asthma. It is important to acknowledge certain limitations. Firstly, the data on the impact of mepolizumab and omalizumab on reducing asthma exacerbations could not be statistically analyzed, potentially affecting the effectiveness results and leading to an underestimation of efficacy. Secondly, our research included only six trials, and the inclusion of additional studies could influence our findings. Further studies are necessary to confirm these findings. Lastly, there was insufficient data to construct a funnel diagram to assess publication bias [36].
In conclusion, our study revealed that all biologics targeting type 2 inflammation, such as dupilumab, lebrikizumab, omalizumab, and mepolizumab, had a distinct impact on childhood and adolescent asthma, with dupilumab exhibiting the highest SUCRA therapeutic value. Furthermore, none of the biologics increased the risk of AEs and SAEs, with omalizumab notably reducing SAEs, suggesting its superior safety profile and great future application prospects in children.
Statement of Ethics
A statement of ethics is not applicable because this study is based exclusively on published literature.
Conflict of Interest Statement
The authors declare that they have no conflicts of interest.
Funding Sources
This work was supported by the National Natural Science Foundation Youth Project (82401332), the Key-Area Research and Development Program of Guangdong Province (No. 2020B0101130015), the National Key R&D Program of China (Nos. 2022YFC2504101 and 2022YFC2504105), the National Natural Science Foundation Youth Project (No. 82401332), and the “Five by Five” Project of Third Affiliated Hospital of Sun Yat-sen University (Grant No. 2023ww602).
Author Contributions
Jinting Lin, Min Zhou, and Li Pan contributed to the conception of the study. Jinting Lin, Kexin Yang, and Qilin Zhou significantly contributed to visualization and data presentation. Jinting Lin and Kexin Yang contributed to assessing the risk of bias. Jinting Lin, Kexin Yang, and Qiqing Ye substantially contributed to analysis and manuscript preparation. Jinting Lin, Kexin Yang, and Zhuanggui Chen played a significant role in implementing the computer code and testing existing code components. Qilin Zhou, Pingping Zhang, Min Zhou, and Li Pan assisted in performing the analysis with constructive discussions.
Additional Information
Jinting Lin and Kexin Yang contributed equally to the article, and they are both the first authors.Edited by: H.-U. Simon, Bern.
Data Availability Statement
All the data are available in the manuscript and online supplement file. Further inquiries can be directed to the corresponding author.