Authors:
Simone Foti Randazzese
Pediatrics Unit, Department of Clinical-Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, Pavia, Italy;
Maria Scaioli
Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy;
Marta Bajeli:
Pediatrics Unit, IRCCS Bologna University Hospital, Bologna, Italy;
Grazia Fenu:
Pediatric Pulmonology Unit, Meyer Children’s Hospital IRCCS, Florence, Italy
Uncontrolled pediatric asthma: a persistent challenge
Asthma is the most prevalent chronic respiratory disease in childhood and a leading cause of morbidity among children and adolescents worldwide. It affects more than 300 million people globally, with an estimated pediatric prevalence of 10.2% — rising to 23% in Oceania, 14% in Latin America, and 13% in North America, according to a meta-analysis of more than 1.5 million children across 164 international studies. Despite considerable therapeutic advances, disease control remains suboptimal: only 37.4–52% of children achieve adequate asthma control. Uncontrolled asthma is associated with higher hospitalization rates, more emergency department visits, greater systemic corticosteroid exposure, and impaired quality of life.
Therapeutic options for children aged 6–11 remain more limited than for adolescents and adults. In this context, long-acting muscarinic antagonists (LAMA) have emerged as a valuable add-on strategy for patients on inhaled corticosteroids (ICS), with or without long-acting β2-agonists (LABA).
Why tiotropium: the pharmacological rationale
Acetylcholine does more than drive bronchoconstriction through M3 muscarinic receptors — it also contributes to chronic airway inflammation, mucus hypersecretion, and structural remodeling. Tiotropium bromide — currently the only LAMA approved for pediatric asthma in children aged 6 and older — selectively antagonizes M1 and M3 receptors, providing sustained bronchodilation for more than 24 hours and a potential modulating effect on cholinergic-driven airway inflammation.
A systematic review and meta-analysis published in Paediatric Respiratory Reviews in March 2026 evaluated, for the first time in aggregate form, the efficacy and safety of tiotropium in children under 12 with uncontrolled asthma.
Study design
The review, conducted according to PRISMA methodology, included six studies (four randomized controlled trials and two observational studies), encompassing 1,210 children aged between 6 months and 11 years. Across all studies, tiotropium was administered as add-on therapy to ICS, with or without LABA, in patients with persistent symptoms despite optimized maintenance treatment. Control groups received placebo or non-LAMA treatment strategies.
Results: effects on lung function
Compared with control groups, the addition of tiotropium produced a significant increase in peak FEV1, with a mean difference (MD) of 86.16 mL (95% CI 18.62–153.71; p<0.01), supporting the bronchodilator efficacy of tiotropium in the pediatric population.
A significant improvement was also observed in FEF25–75% (MD 0.25 L; 95% CI 0.20–0.31; p<0.01), a parameter often considered a surrogate marker of small-airway function — though its clinical significance remains debated. No significant differences were observed in FVC. The authors note that most available evidence comes from children aged 6–11, while data in preschool-aged children remain scarce.
Results: asthma control and exacerbation risk
Patients receiving tiotropium showed a statistically significant improvement in ACQ-IA (Interviewer-Administered Asthma Control Questionnaire) scores compared with controls (MD −0.07; 95% CI −0.08 to −0.06; p<0.01) — a difference that did not reach the threshold generally considered clinically meaningful, but was directionally consistent with the observed lung-function improvements.
No significant differences were found in nocturnal awakenings or rescue medication use. The most clinically relevant finding concerned asthma exacerbations: tiotropium was associated with a 25% relative reduction in exacerbation risk (RR 0.75; 95% CI 0.60–0.94; p=0.013), though no significant reduction was observed for severe exacerbations specifically.
Safety and tolerability
Tiotropium showed a favorable safety profile: treatment was associated with a lower overall incidence of adverse events compared with control groups (RR 0.88; 95% CI 0.79–0.98; p=0.021). The most frequently reported events were nasopharyngitis, respiratory tract infections, cough, and allergic rhinitis. Serious adverse events were infrequent (<1%), with no evidence of a causal relationship to the drug. No deaths or treatment discontinuations attributable to tiotropium were reported across the included studies.
Clinical implications
Overall, this meta-analysis supports tiotropium as an effective and well-tolerated add-on therapy for children aged 6–11 with moderate-to-severe asthma that remains inadequately controlled despite guideline-based treatment. Additional high-quality prospective studies are still needed in children under 6, and to clarify long-term effects on respiratory outcomes and airway remodeling.
References
- Zhou W, Tang J. Prevalence and risk factors for childhood asthma: a systematic review and meta-analysis. BMC Pediatr. 2025 Jan 20;25(1):50. doi: 10.1186/s12887-025-05409-x. PMID: 39833735; PMCID: PMC11744885.
- Jayasooriya SM, Devereux G, Soriano JB, Singh N, Masekela R, Mortimer K, Burney P. Asthma: epidemiology, risk factors, and opportunities for prevention and treatment. Lancet Respir Med. 2025 Aug;13(8):725-738. doi: 10.1016/S2213-2600(24)00383-7. PMID: 40684789.
- Tosca MA, Pistorio A, Silvestri M, Marseglia GL, Ciprandi G; “ControL’Asma” Study Group. The comparison between children and adolescents with asthma provided by the real-world “ControL’Asma” study. J Asthma. 2022 Aug;59(8):1531-1536. doi: 10.1080/02770903.2021.1941089. PMID: 34112042.
- Global Strategy for Asthma Management and Prevention, 2026 GINA Strategy Report
- Cazzola M, Calzetta L, Matera MG. Long-acting muscarinic antagonists and small airways in asthma: Which link? Allergy. 2021 Jul;76(7):1990-2001. doi: 10.1111/all.14766. PMID: 33559139.
- Santamaria F, Ziello C, Lorello P, Bouchè C, Borrelli M. Update on Long-Acting Anticholinergics in Children and Adolescents With Difficult and Severe Asthma. Front Pediatr. 2022 Jul 19;10:896865. doi: 10.3389/fped.2022.896865. PMID: 35928684; PMCID: PMC9343620.
- Bolner G, Rossi YI, Dall’Acqua JC, Rossato AV, de Oliveira FD, Bolner K, Fischer GB, Lukrafka JL, Mocelin HT. Long-acting muscarinic antagonists as add-on treatment for asthma in children under age 12: a systematic review and meta-analysis. Paediatr Respir Rev. 2026 Mar;57:3-10. doi: 10.1016/j.prrv.2025.04.003. PMID: 40441924.
Focus on the text. Summary elements.
Tiotropium bromide is currently the only long-acting muscarinic antagonist (LAMA) approved for pediatric asthma, for children aged 6 and older, used as add-on therapy to inhaled corticosteroids
According to the 2026 meta-analysis of 1,210 children, tiotropium added to standard therapy reduces the risk of asthma exacerbations by 25% (RR 0.75; 95% CI 0.60–0.94), though it did not show a significant effect on severe exacerbations specifically.
The most common adverse events reported in studies were nasopharyngitis, respiratory tract infections, cough, and allergic rhinitis. Serious adverse events are rare (under 1%) and no direct causal link to the drug was identified; no deaths or treatment discontinuations attributable to tiotropium were reported.
Tiotropium is indicated from age 6 onward. Data in preschool-aged children (under 6) remain limited, and further studies are needed in this age group.
Tiotropium is always used as add-on therapy to ICS, with or without LABA — it does not replace them. It is indicated for children with persistent symptoms despite already optimized maintenance treatment.
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