Elianne J.L.E. Vrijlandt

Assessment of Controversial Pediatric Asthma Management Options Using GRADE

OBJECTIVES: To develop explicit and transparent recommendations on controversial asthma management issues in children and to illustrate the usefulness of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach in rating the quality of evidence and strength of recommendations. METHODS: Health care questions were formulated for 3 controversies in clinical practice: what is the most effective treatment in asthma not under control with standard-dose inhaled corticosteroids (ICS; step 3), the use of leukotriene receptor antagonist for viral wheeze, and the role of extra fine particle aerosols. GRADE was used to rate the quality of evidence and strength of recommendations after performing systematic literature searches. We provide evidence profiles and considerations about benefit and harm, preferences and values, and resource use, all of which played a role in formulating final recommendations. RESULTS: By applying GRADE and focusing on outcomes that are important to patients and explicit other considerations, our recommendations differ from those in other international guidelines. We prefer to double the dose of ICS instead of adding a long-acting β-agonist in step 3; ICS instead of leukotriene receptor antagonist are the first choice in preschool wheeze, and extra fine particle ICS formulations are not first-line treatment in children with asthma. Recommendations are weak and based on low-quality evidence for critical outcomes. CONCLUSIONS: We provide systematically and transparently developed recommendations about controversial asthma management options. Using GRADE for guideline development may change recommendations, enhance guideline implementation, and define remaining research gaps.

Astma bij kinderen

Dit nummer van het Tijdschrift voor Kindergeneeskunde is geheel gewijd aan astma. Astma is bij kinderen de meest voorkomende chronische aandoening en de prevalentie is na een spectaculaire stijging in de jaren tachtig en negentig de afgelopen jaren op een hoog niveau gestabiliseerd. In 2008 is het boekje Astma bij kinderen verschenen met daarin de samenvatting van de herziene richtlijnen van de Sectie Kinderlongziekten.1 Leden van verschillende werkgroepen hebben literatuur op een groot aantal vraagstellingen beoordeeld en verwerkt.

Safety and efficacy of tiotropium in children aged 1–5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial

BACKGROUND Few studies have assessed the safety and efficacy of potential asthma medications in children younger than 5 years. We descriptively assessed the safety and efficacy of tiotropium, a long-acting anticholinergic drug, in children aged 1-5 years with persistent asthmatic symptoms. METHODS This exploratory 12-week, randomised, double-blind, placebo-controlled, parallel-group, phase 2/3, regulatory multicentre trial was done at 32 hospitals, clinics, and clinical research units in 11 countries in Asia, Europe, and North America. Children aged 1-5 years with at least a 6-month history of persistent asthmatic symptoms and a need for inhaled corticosteroids were eligible. Patients were randomly allocated using an interactive voice or web-based response system to receive once-daily tiotropium 2·5 μg, tiotropium 5 μg, or placebo as an add-on to inhaled corticosteroids with or without additional controller medication. Patients and investigators were masked to study group assignment. Tiotropium was given via the Respimat inhaler once daily as two puffs of 1·25 μg in the 2·5 μg group, two puffs of 2·5 μg in the 5 μg group, or two puffs of placebo. The primary outcomes were safety, which was assessed by comparing adverse events between the tiotropium and placebo groups, and efficacy, which was measured as the change in weekly mean combined daytime asthma symptom score from baseline to week 12. Statistical analyses of treatment effects were exploratory; although endpoints were defined, they were used for descriptive analyses only. The safety and primary analyses were done in all patients who received at least one dose of their assigned treatment. This study is registered with ClinicalTrials.gov (NCT01634113), and is completed. FINDINGS Between July 26, 2012, and Dec 4, 2014, 102 children were randomly assigned to the three treatment groups (36 to receive tiotropium 2·5 μg, 32 to receive tiotropium 5 μg, and 34 to receive placebo). 101 children completed the study and were included in the analyses. The changes in adjusted weekly mean combined daytime asthma symptom scores between baseline and week 12 were not significantly different between any of the groups. The adjusted mean difference between the tiotropium 2·5 μg group and placebo group was -0·080 (95% CI -0·312 to 0·152) and the difference between tiotropium 5 μg and placebo group was -0·048 (-0·292 to 0·195). Adverse events were less frequent with tiotropium treatment than with placebo (20 [56%] of 36 children with tiotropium 2·5 μg, 18 [58%] of 31 with tiotropium 5 μg, and 25 [74%] of 34 with placebo), although no formal statistical comparison between groups was performed. A greater proportion of children reported asthma exacerbations as adverse events in the placebo group (ten [29%] of 34) than in the tiotropium groups (five [14%] of 36 in the 2·5 μg group and two [6%] of 31 in the 5 μg group). Serious adverse events were reported in three patients (all of whom received placebo); no adverse events led to discontinuation of treatment or death. INTERPRETATION To our knowledge, our small study is the first to assess the safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms. Tolerability of tiotropium was similar to that of placebo, which is consistent with previous findings in older populations. Although mean daytime asthma symptom scores were not significantly different between groups, tiotropium showed the potential to reduce asthma exacerbation risk compared with placebo. The findings of the study are limited by the small sample size and descriptive statistical analyses. Additional well powered trials are needed to further assess the safety and efficacy of tiotropium in young children. FUNDING Boehringer Ingelheim.

Safety of tiotropium in pre-school children with symptomatic persistent asthma

Introduction and objectives Asthma is the most common chronic disease of childhood (GINA 2015). For pre-school children whose asthma symptoms are not well controlled on inhaled corticosteroids, limited options are available for further treatment. Here, we evaluated the safety of once-daily (QD) tiotropium Respimat® (tioR) in patients aged 1–5 years with symptomatic persistent asthma. Methods A Phase II/III, randomised, double-blind, placebo-controlled, parallel-group trial (NCT01634113) of tioR 5 μg, tioR 2.5 μg or placebo Respimat® (pboR), administered QD in the afternoon for 12 weeks, each as add-on to usual maintenance therapy. Safety data, including post hoc analysis of a composite exacerbation end point derived from adverse events (AEs), are reported. Results No AEs leading to treatment discontinuation or death were reported. The proportion of patients with any AEs was higher with pboR (73.5%) than with tioR 5 μg (58.1%) and 2.5 μg (55.6%). Two patients each in the tioR 5 μg (6.5%) and pboR (5.9%) groups were reported with drug-related AEs. Three patients, all in the pboR group, were reported with serious AEs. Asthma exacerbation/worsening was reported by fewer patients in the tioR 5 μg and tioR 2.5 μg groups compared with the pboR group (Table). Conclusion Once-daily tiotropium Respimat® add-on to maintenance therapy is well tolerated and may reduce exacerbations in pre-school children with symptomatic persistent asthma. Abstract P154 Table 1 Composite asthma endpoint: Asthma exacerbation (broad) with pneumonia plus asthma worsening Composite end pointMedDRA preferred terms Patients, n (%) Tiotropium Respimat® 5 µg QD (n = 31) Tiotropium Respimat® 2.5 µg QD (n = 36) Placebo Respimat® QD (n = 34) Asthma exacerbation (broad)/worsening + pneumonia 9 (29.0) 12 (33.3) 19 (55.9) Asthma 2 (6.5) 5 (13.9) 10 (29.4) Bronchitis 2 (6.5) 1 (2.8) 4 (11.8) Bronchopneumonia 0 0 1 (2.9) Cough 2 (6.5) 4 (11.1) 3 (8.8) Dyspnoea 1 (3.2) 0 0 Pneumonia 0 1 (2.8) 2 (5.9) Viral respiratory tract infection 3 (9.7) 3 (8.3) 4 (11.8) Wheezing 0 2 (5.6) 0 Treated set. Percentages calculated using total number of patients per treatment as denominator. AE preferred terms defined by Medical Dictionary for Regulatory Activities version 17.1. Please refer to page A272 for declarations of interest in relation to abstract P154.

The womb and lung function later in life.

The information about the in utero influences on the development of the lungs and lung function is limited. No measurements are available at present to objectify this, and all studies in humans describing early determinants of airway function mention placental function, birth weight in relation to gestational age, sex and ethnicity, environmental factors, such as smoking, nutrition of the mother, and respiratory infections of the neonate. In fact, the womb is a black box where many factors influence the development of the foetus and, in particular, the lungs. Another complicating factor is that before birth the lungs are not involved in gas exchange and are not fully expanded. Negative effects on lung development can result from either: mother-related factors, including hypoxia, intoxications and other causes of intra-uterine stress, like pre-eclampsia, which leads to growth retardation and often to premature birth; or child-related factors, such as foetal diseases like congenital renal abnormalities and diaphragmatic hernias. In this issue, Greenough et al. 1 present interesting data on the effects of intra-uterine growth retardation (IUGR), in children born prematurely, on the severity of lung function impairment. The most important findings of their study include a significant relationship between airway resistance, on the one hand, and IUGR, maternal smoking and bronchopulmonary dysplasia, on the other hand. Almost no data on the impact of IUGR on lung function during infancy are available, until now, despite the known association between IUGR, subsequent …

Respiratory function after esophageal replacement in children

BACKGROUND Children born with esophageal atresia require an anastomosis between the proximal and distal esophagus. When this distance is too wide (long gap esophageal atresia, LGEA) esophageal replacement strategies have to be deployed. The aim of this study was to assess long-term respiratory morbidity and lung function after esophageal replacement with either stomach (gastric pull-up, GPU) or jejunum (jejunal interposition, JI) for LGEA. METHODS Retrospective cohort study. Patients operated with GPU and JI for LGEA (1985-2007) underwent a semi-structured interview and lung function testing (LFT). RESULTS Seven GPU-patients and eight JI-patients were included. Median age was 12years. One patient per group could not perform LFT. Respiratory symptoms were reported by 13/15 patients (7/7 GPU-patients vs 6/8 JI-patients). All LFT items were lower than reference values; 6/13 patients showed restriction and 6/13 obstruction. All six GPU-patients had abnormal TLC and/or FEV1/FVC vs 3/7 after JI. Restriction was noted in 4/6 GPU-patients vs 2/7 JI-patients. CONCLUSION After esophageal replacement for LGEA many children have impaired lung function and respiratory symptoms are common. Lung volumes seem decreased after GPU compared to JI. This may be caused by the intrathoracic stomach which may limit normal lung growth. Respiratory follow-up in adult life is important after esophageal replacement. LEVEL OF EVIDENCE III.