Randomized Clinical Trial of Lansoprazole for Poorly Controlled Asthma in Children

Abstract

Context

Asymptomatic gastroesophageal reflux (GER) is prevalent in children with asthma. It is not known whether treatment of GER with a proton-pump inhibitor (PPI) improves asthma control.

Objective

To determine whether lansoprazole is effective in reducing asthma symptoms in children without overt GER.

Design, Setting, and Patients

A multicenter, randomized, masked, placebo controlled, parallel clinical trial comparing lansoprazole to placebo in children with poor asthma control on inhaled corticosteroid treatment conducted at 18 academic clinical centers. Participants were followed for 24 weeks. A subgroup had an esophageal pH study before randomization.

Intervention

Children received either lansoprazole (15 mg daily < 30 kg; 30 mg ≥ 30 kg) or placebo, 1:1 allocation ratio.

Main outcome

The primary outcome was the change in Asthma Control score (ACQ, range from 0 to 6). Secondary outcomes included lung function measures, asthma-related quality of life and acute episodes of poor asthma control.

Results

306 children were enrolled from April 2011 to August 2010, the median age was 11. The mean change (95% confidence interval (CI)) in the ACQ score was −0.1 (−0.2, 0.1) and −0.2 (−0.4, −0.1) units for the lansoprazole and placebo groups, respectively (P=0.12). There were no detectable treatment differences in secondary outcomes (mean (95% CI) for FEV₁(0.00 (−0.08, 0.08)), asthma quality of life (−0.1 (−0.4, 0.1) or episodes of poor asthma control, hazard ratio of 1.18 (95% CI 0.91, 1.53). Among the 115 children with esophageal pH studies, the prevalence of GER was 43%. In the subgroup with a positive pH study, no treatment effect for lansoprazole versus placebo was observed for any asthma outcome. Children treated with lansoprazole reported more upper respiratory infections (63% vs 49%, P=0.02), sore throats (52% vs 39%, P=0.02), and bronchitis (7% vs 2%, P=0.05).

Conclusion

Among children with poorly controlled asthma without symptoms of GER who were using inhaled corticosteroids, the addition of lansoprazole, as compared to placebo, did not improve symptoms nor lung function but was associated with increased adverse events.

Introduction

Asthma and gastroesophageal reflux (GER) are both common disorders in children and symptoms of GER are frequently reported among children with asthma.^1,2,3,4 GER identified by esophageal pH monitoring often presents with respiratory symptoms^5,6,7 and frequently occurs in children without characteristic gastrointestinal symptoms.^1,8,9 Untreated GER has been postulated to be a cause of inadequate asthma control in children despite inhaled corticosteroid (ICS) treatment. Additionally, expert panels have indicated that the utility of testing and treating children with refractory asthma symptoms for asymptomatic GER has been inadequately studied.^3,10 Hence, it is of clinical importance to determine whether anti-reflux therapy, the most common being proton pump inhibitors (PPI), improves the control of asthma in children.

In adults, it appears that PPIs may be helpful for asthma in some patients who manifest reflux symptoms, but are not helpful for those with asymptomatic GER. ^11,12,13 An open-label prospective study evaluated 44 children with moderate, persistent asthma and GERD who showed clinical improvement in asthma symptoms after 1 year of treatment with a esomeprazole and metoclopramide. Children who continued the combination treatment for six months had fewer asthma exacerbations than those who switched to ranitidine.¹⁴

we conducted a trial to study the efficacy of PPIs in children with poor asthma control without symptomatic GER. The primary hypothesis was that children with symptomatic asthma taking inhaled corticosteroids have improved asthma control. with lansoprazole treatment compared to placebo. We also investigated whether asymptomatic GER as identified by pH probe testing would identify children who respond to PPI treatment.

Methods

Study Design

The Study of Acid Reflux in Children with Asthma (SARCA) was a randomized (allocation ratio 1:1) double masked, placebo-controlled, parallel clinical trial designed to evaluate the effectiveness of lansoprazole (Prevacid ®, TAKEDA Pharmaceuticals North America) for treatment of asthma in children (clinicaltrial.gov NCT00442013). The study was conducted at 19 American Lung Association's Asthma Clinical Research Center (ALA-ACRC) sites from to April 2007 to April 2011. The study was approved by the institutional review board at each center, and the legal guardians signed informed consent statement and the participants signed assent statement according to local regulatory policy.

Children were randomly assigned to receive either lansoprazole (15 mg daily for children < 30 kg; 30 mg daily for children ≥ 30 kg) or a matching placebo. A permuted block treatment assignment schedule stratified by clinical center was used. Treatment assignments were masked throughout the study. After the screening and randomization visits, participants returned to the clinical centers for assessments every 4 weeks for 24 weeks. Throughout the study children kept daily diaries to record morning peak expiratory flow, asthma symptoms, nocturnal awakenings, use of short-acting β-agonists (excluding routine use before exercise), oral corticosteroid use, and unscheduled health care visits for asthma symptoms. Ambulatory esophageal pH monitoring prior to randomization was conducted in a subgroup of children who agreed to the procedure at 13 clinical centers with the capability of doing pH probe studies for the study. Participants were paid, on average, ($ ) for each study visit.

Participant Selection

Participants were between 6 and 17 years of age, had physician-diagnosed asthma, and labile airways function defined as a 12% or greater increase in FEV₁ post-bronchodilator, a methacholine challenge PC₂₀ of < 16 mg/mL, or a positive exercise-bronchoprovocation test of a 20% or greater fall in FEV₁ post-exercise demonstrated within the prior 12 months. Participants were treated with inhaled corticosteroids (≥ 176 mcg per day fluticasone equivalents) and had no change in controller therapies for at least 8 weeks prior to enrollment. Poor asthma control was defined as any one of the following: use of short-acting β-agonists for asthma symptoms two or more times per week; nocturnal awakenings with asthma symptoms more than once per week over the month before enrollment; two or more emergency department visits, unscheduled physician visits, prednisone courses, or hospitalizations for asthma in the prior year; or a score of 1.25 or higher on the ACQ at the screening visit. Recruits were excluded from the study if they exhibited any of the following: symptoms of GER requiring treatment, treatment with a PPI or other reflux medications (other than occasional oral antacids); history of anti-reflux surgery or a previous trachea-esophageal fistula repair; an FEV₁ less than 60% predicted; history of neonatal respiratory distress or prematurity less than 33 weeks gestational age; or other major chronic illnesses. Children with a known sensitivity or intolerance to lansoprazole or aspartame were not enrolled. Other exclusion criteria were non-adherence, (below 80% completion of daily diaries during run-in), inability to take study medications, perform baseline measurements or be contacted by telephone, or pregnancy. Participant characteristics related to race, cigarette or cigar smoke exposure, past asthma treatments and asthma triggers were collected via interview. Children were followed between 2 to 8 weeks before randomization and were eligible for randomization if they completed 80% of daily diary cards, maintained a stable dose of inhaled corticosteroids, had a percent predicted FEV₁ of 60% or greater and were not pregnant were eligible for randomization. After eligibility was confirmed, children were assigned to the next random treatment assignment via computer.

Outcome Measures

The primary outcome for the trial was the change in Asthma Control Questionnaire (ACQ) at the 24 week visit. ¹⁶ The ACQ integrates indicators of asthma control including use of bronchodilators, nocturnal symptoms, cough, activity level, and pulmonary function and has a range of 0 to 6 (higher values indicate worse asthma control). A 0.5 change in ACQ reflects a clinically meaningful difference in asthma control.

Secondary outcomes included the rate of acute episodes of poor asthma control (EPACs),¹⁴ Asthma Symptom Utility Index (ASUI) score (range 0 to 1.0, ?.? ,¹⁵ Asthma Control Test (ACT¹⁶/cACT¹⁷; range 5-25/0-27, respectively, meaningful difference is 3), asthma-specific quality of life for children (AQLQ; range 1-7, meaningful difference is 0.5) and their caregivers (CAQLQ; range 1-7, meaningful difference is 0.5),¹⁸ methacholine PC₂₀,¹⁹ spirometry,²⁰ exhaled nitric oxide (eNO), gastrointestinal symptoms (GSAS; range 0-441, meaningful difference not defined) and nocturnal awakenings. We defined two types of EPACs derived from the daily diaries: an EPAC1 was a decrease ≥ 30% in morning peak flow rate from personal best (assessed during run-in) for two consecutive days, or addition of an oral corticosteroid to treat asthma symptoms, or unscheduled contact with a health care provider for asthma symptoms. An EPAC2 also included increased use of short-acting β agonists from baseline (4 or more additional puffs of rescue medication or 2 or more additional nebulizer treatments in one day). Participants were questioned about potential adverse effects of treatment at each visit. Subsequent to an FDA advisory on the risk of bone fractures in adults,²¹ clinics were asked to review participant records for fractures.

Esophageal pH studies were done prior to randomization at 13 clinical centers according to a standard protocol and centrally reviewed. At least 16 hours of monitoring was required for evaluation. The thresholds used for the definition of pathological GER were: esophageal pH ≤ 4 for 6% or greater of the time for a 6-11 year old, and for 4% or greater of the time for a 12-17 year old.

Sample Size

The planned sample size of 300 participants provided 90% power to detect a 0.6 unit change in the primary outcome, ACQ, assuming a standard deviation of 1.5 with a two-sided type I error rate of 5%. The sample size was inflated by 5% to account for missing data. We estimated 80 to 90% power to detect a difference of 0.85 to 1.0 in ACQ score in the subgroup of participants who underwent pH probes.

Data Analysis

All analyses were conducted according to treatment assignment and all available data were incorporated. Longitudinal models estimated the change from baseline to 6 months in a measurement using generalized estimating equations (GEE) with an unstructured or exchangeable covariance matrix to adjust for repeated measures²² All participants with baseline or any follow-up data were included in the models. Negative binomial regression models were used to evaluate differences in the rate of EPACs;²³ participants without diary card data were excluded from these analyses. We planned to evaluate the treatment effect in subgroups defined by pH probe test results; a differential effect of treatment was evaluated by a test of interaction. There was one interim analysis during the trial after approximately 50% of the participants completed follow-up. P-values were two-sided and a P-value ≤0.05 was considered statistically significant; P-value were not adjusted for multiple looks or multiple comparisons. Data were analyzed using SAS (version 9.2) and Stats (version 10).

Results

Recruitment

2,453 children were screened for eligibility; 306 children were randomized, 157 were assigned to receive placebo and 149 were assigned to receive lansoprazole (Figure 1). More than 88% of participants completed the study and 94% of follow-up visits were completed. Self-reported compliance to study treatments was high in both groups, study drug was taken on 90 to 91% of follow-up days.

Figure 1.

CONSORT Diagram

Features of the Study Participants

The demographic and asthma characteristics at baseline were similar in the two treatment groups (Table 1). The children had a median age of 11 years, included more males than females, and 50% of participants were African American. Most participants required an intervention (urgent care, oral prednisone course or frequent use of rescue medication) for asthma symptoms in the year prior to enrollment. Mean baseline FEV₁ was 99% of predicted in both treatment groups. Children treated with lansoprazole had greater change in FEV₁ in response to a bronchodilator, 10.9% versus 8.5% in the placebo-treated group (P=0.02). Among the subgroup with methacholine provocation results at randomization, bronchial responsiveness was elevated in both groups, but relatively less in the lansoprazole group (PC₂₀ 3.4 mg/mL versus 2.5 mg/mL, P=0.04).

Table 1.

Characteristics of Study Participants

	Treatment Assignment
	Placebo	Lansoprazole
N	157	149
Age at randomization – year (mean ± standard deviation)	11 ± 3	11 ± 3
Male (%)	65	58
Race or ethnic group (%)
White	33	34
Black	50	50
Hispanic	11	11
Other	6	5
pH probe test results
N completing pH probe test	53	62
Positive test result (%)	38	47
Exposed to secondhand smoke (%)	18	17
Asthma Characteristics
Age of asthma onset – year (mean ± standard deviation)	3 ± 3	4 ± 3
Unscheduled health care for asthma in past year (%)	69	77
Oral corticosteroids for asthma in past year (%)	62	72
Use of rescue inhaler 2 or more times per week (%)	75	73
Daily use of ICS/LABA (%)	60	59
Daily use of anti-leukotriene (%)	54	55
Inhaled corticosteroid treatment at enrollment
Fluticasone/salmeterol (%)	52	53
Fluticasone (%)	22	17
Budesonide (%)	10	14
Budesonide/formoterol (%)	6	5
Beclomethasone (%)	7	5
Mometasone or triamcinolone (%)	3	6
Asthma questionnaire scores (mean ± standard deviation)
ACQ (↓score range: 0-6) at screening	1.6 ± 0.8	1.6 ± 0.8
ACQ (↓score range: 0-6) at randomization	1.2 ± 0.8	1.2 ± 0.8
ASUI score (↑score range: 0-1)	0.82 ± 0.14	0.82 ± 0.15
ACT (age 12-17, n=139)) (↑score range: 5-25)	19 ± 4	19 ± 4
C-ACT (age 6-11, n=164)) (↑score range: 0-27)	20 ± 4	20 ± 4
Mini-AQLQ score (↑) (score range: 1-7)	5.5 ± 1.1	5.4 ± 1.2
Caregiver's AQOL (↑) (score range: 1-7)	5.4 ± 1.2	5.6 ± 1.2
GERD Symptom Assessment (↓)(median, interquartile range)
Median for score (score range: 0-441)	9 (2, 220)	7 (2 ,28)
Median for number of symptom (range: 0-9)	2 (1, 4)	3 (1, 4)
Pulmonary Function (mean ± standard deviation)
Pre-bronchodilator FEV1 (% predicted)*	92.4 ± 14.6	91.3 ± 17.1
Post-bronchodilator FEV1 (% predicted)*	99.7 ± 14.1	99.6 ± 15.4
Pre-bronchodilator FVC (% predicted)*	101.1 ± 14.6	100.4 ± 13.8
Post-bronchodilator FVC (% predicted)*	102.9 ± 15.1	103.0 ± 13.2
Peak flow (% predicted)*	97.3 ± 22.1	92.7 ± 20.0
%Change in FEV1 after bronchodilator	8.5 ± 10.9	10.9 ± 11.3
%Change in FVC after bronchodilator	1.5 ± 6.0	3.0 ± 5.2
Exhaled NO (median, IQR)	35 (14, 59)	26 (10, 48)
Exhaled breath condensate pH	6.1 ± 1.0	6.2 ± 1.0
N with PC20†	108	107
PC20 (mg/mL)	2.5 ± 3.7	3.4 ± 4.0
Other Conditions (%)
GERD	1	2
Eczema	39	48
Sinusitis	28	30
Rhinitis	51	68
Food Allergies	27	26
Allergies worsen asthma	79	81

Abbreviations: ICS=inhaled corticosteroid, LABA=long-acting beta-agonist, PC20=provocative dose of methacholine to reduce percent predicted FEV₁ by 20%; ACQ=Asthma Control Questionnaire; ACT=Asthma Control Test; C-ACT=Child's Asthma Control Test; AQLQ=Asthma Quality of Life Questionnaire; GERD=Gastro-esophageal reflux disease; FEV₁=force expiratory volume in 1 second; FVC=forced vital capacity

^*predicted values of Hankinson et al.

↓ lower value indicates less severe asthma/GERD; ↑ higher value indicates less severe asthma

^†Number with data on pH probe results or PC₂₀ at baseline

GER Status

152 participants underwent 24 hour esophageal pH monitoring studies. Of these 115 were adequate for interpretation. Forty-nine participants (43%) had abnormal esophageal acid exposure as assessed by frequent acid reflux events, prolonged acid reflux episodes (longer than 5 minutes), or overall 24 hour esophageal acid relux (reflux index). GSAS scores (mean (95% CI) were not different between patients with normal versus abnormal pH probe studies (15 (10,20) vs 20 (12, 27)), respectively.

Effects of Treatment on Asthma Outcomes

At the screening visit the mean ACQ was high and consistent with poor asthma control in both treatment groups (1.6 for both groups, P=0.96). Between the screening and randomization visits, the ACQ fell in both groups, indicating improvement (Table 1) but there was no difference between treatment groups; the mean difference (95% CI) for lansoprazole-placebo was 0.2 (−0.0,0.3), Table 2, Figure 2). There was no significant treatment effect for any of the secondary indices of asthma control: ASUI, ACT for adolescents 12-17, cACT for children ages 6-11, AQLQ, and the cAQLQ for caregivers (Table 2). Likewise there was no significant treatment effect on lung function, including pre-bronchodilator FEV₁ or FVC over the six- month follow-up (Table 2). The magnitude of bronchial hyperresponsiveness increased slightly (decrease in methacholine PC₂₀) in the lansoprazole treatment group from baseline to month 6 of the study but there was no treatment effect. There was no significant treatment effect on EPAC 1 or EPAC 2 rates (Table 3). EPAC type 1 excluded use of rescue medications because we were concerned that heartburn symptoms could be mistaken for asthma symptoms and results in increased rescue medication use.

Table 2.

Questionnaire scores and lung function measures at 24 weeks of follow-up

		Value at 24 weeks		Change from baseline		Treatment Effect†	P-value
		Placebo	Lansoprazole	Placebo	Lansoprazole	Diff Change Lansoprazole-Placebo	Treatment Effect*	Interaction with GER‡
	N	--------------------------Mean (95% Confidence Interval)------------------------
Asthma Control Questionnaires
Asthma Control Questionnaire	263	1.0 (0.9, 1.1)	1.1 (0.9, 1.2)	−0.2 (−0.4, 0.1)	−0.1 (−0.2, 0.1)	0.2 (−0.0, 0.3)	0.12	0.15
Asthma Symptom Utility Index	266	0.88 (0.86, 0.90)	0.86 (0.83,0.88)	0.06 (0.03, 0.09)	0.03 (0.01, 0.06)	−0.03 (−0.07, 0.01)	0.14	0.38
Asthma Control Test 12-17 years	126	20.2 (19.4, 21.2)	20.2 (19.3, 21.1)	1.6 (0.5, 2.7)	1.0 (0.2, 1.7)	−0.6 (−2.0, 0.7)	0.37	0.86
Asthma Control Test 6-11 years	126	21.9 (21.1, 22.8)	20.9 (19.9, 21.9)	2.0 (1.0, 2.9)	1.2 (0.3, 2.1)	−0.7 (−2.0, 0.6)	0.29	0.29
Quality of Life Questionnaires
Pediatric QoL	262	6.0 (5.9, 6.0)	5.8 (5.7, 6.0)	0.5 (0.3, 0.7)	0.4 (0.3, 0.6)	−0.1 (−0.3, 0.2)	0.65	0.48
Caregiver QoL	261	6.0 (5.8, 6.2)	6.0 (5.8, 6.2)	0.5 (0.3, 0.7)	0.4 (0.2, 0.6)	−0.1 (−0.4, 0.1)	0.28	0.46
Pulmonary function
Pre-bronchodilator FEV1 (L)	259	2.3 (2.1, 2.4)	2.2 (2.1, 2.4)	0.03 (−0.03, 0.08)	0.03 (−0.03, 0.09)	0.00 (−0.08, 0.08)	0.99	0.27
FEV1 bronchodilator Response (%)	120	10.8 (7.8, 14.0)	10.7 (7.0, 14.5)	2.2 (−1.2, 5.7)	−0.1 (−4.0, 3.9)	−2.3 (−7.6, 2.9)	0.38	0.002
Pre-bronchodilator FVC (L)	259	2.9 (2.7, 3.1)	2.9 (2.7, 3.0)	0.07 (0.02, 0.11)	0.05 (0.01, 0.10)	−0.01 (−0.08, 0.05)	0.69	0.22
PC20 (mg/mL)	119	2.5 (1.7, 3.4)	2.6 (2.09, 3.4)	0.0 (−0.9, 1.0)	0.1 (−0.8, 1.1)	−0.8 (−2.1, 0.4)	0.20	0.80

^*P-values for treatment effect based on GEE models including all data points

^†For ACQ and PC₂₀ a negative number favors lansoprazole, for all other measures a positive treatment effect favors lansoprazole

^‡P-values for a differential treatment effect in patients with positive pH probe status in subgroup of patients (n=115) with those data

Figure 2.

Change in asthma control score in children with poor asthma control treated with lansoprazole and placebo.

Table 3.

Respiratory infections

	Treatment Group
	Placebo	Lansoprazole	P-value*
N	150	147
	N (%)
Upper respiratory	74 (49)	93 (63)	0.02
Sore throat	59 (39)	77 (52)	0.02
Strep throat	11 (7)	6 (4)	0.23
Bronchitis	3 (2)	10 (7)	0.04
Pneumonia	5 (3)	4 (3)	0.76
Otis media	10 (7)	12 (8)	0.62
Acute sinusitis	17 (11)	16 (11)	0.90

^*Based on Chi-square test or Fisher's Exact test

Sub-analysis of Children with Abnormal Esophageal pH Studies

Among the 115 children with adequate 24 hour esophageal monitoring studies, 42% (n= 49) were positive for GER; 38% who received placebo had GER versus 47% who received lansoprazole (P=0.33). In a sub-analysis of children with GER, there was no significant effect of lansoprazole treatment on any of the study outcomes, including the ACQ, ASUI, ACT, or cACT, asthma related quality of life, EPAC rates, lung function, or bronchial hyperresponsiveness (Supplemental tables 1 and 2).

Adverse Events

Ten participants in the lansoprazole group and 9 in the placebo group had one or more serious adverse events. The most common serious adverse event in both groups was asthma exacerbations (15 of 25 reports). Among all reported adverse events, treatment with lansoprazole was associated with a greater prevalence of upper respiratory infections, sore throats, and episodes of bronchitis (Table 4). Activity-related bone fractures in children treated with lansoprazole versus placebo (6 vs 1, P=0.06) was not different. The children experiencing fractures were between the ages of 7 and 14 and all had been receiving inhaled corticosteroids throughout the trial; 2 (one in each group) had also received a course of oral prednisone during the trial. One fracture, in the lansoprazole group, occurred on the day the patient was randomized. The others occurred after 2 months (1), 5 months (3) and 6 months (2) of follow-up.

Discussion

In children with poorly controlled asthma lansoprazole treatment had no effect on asthma control measures. This was the case even though GER was prevalent (42% as evidenced by positive esophageal pH tests) in the study sample. In a sub-analysis of the effects of lansoprazole restricted to participants with documented GER, we found no effect of lansoprazole on any of the aforementioned indicators of asthma control. Although GER is prevalent in children with poorly controlled asthma, the results of this clinical trial are uniformly negative regarding the benefit of acid suppression therapy on symptom relief, lung function, airways reactivity or quality of life.

Previous clinical trials in children with symptomatic GER and respiratory symptoms have not shown a clear benefit of PPI treatment on respiratory outcomes. In one uncontrolled study of children, 85% with demonstrable GER, lansoprazole improved asthma symptoms in a majority²⁴ or improved airways reactivity.²⁵ However, a placebo-controlled trial of omeprazole in 38 children with asthma and GER showed no significant effect of omeprazole on asthma outcomes.²⁶ These results, in conjunction with ours, indicate that PPI therapy for poorly controlled asthma is not warranted.

While our results are robust there are hypotheses about the role of GER and asthma we did not address. We focused on patients without symptomatic GER because these children do not have an independent indication for PPI treatment. There are preliminary data that suggest non-acid reflux may result in respiratory symptoms.²⁷ The possible role of non-acid reflux in worsening asthma control is unclear, and larger, well controlled studies are needed to validate this hypothesis. It is also possible that acid reflux was a cause of asthma symptoms but the FDA-approved dose of lansoprazole that we used may not have achieved adequate acid suppression in all children.

Our study does not refute the possibility that GER may trigger chronic cough in children.²⁸ In a recent study in non-asthmatic children with chronic cough, episodes of GER preceded cough in 22 of 26 patients.²⁹ In adults, proximal reflux has been reported to be associated with worse asthma control and health-related quality of life despite lack of physiologic impairment or decrease in asthma symptoms.³⁰

We confirmed previous data suggesting a high prevalence of GER in asthmatic children, and our results do not support routine esophageal pH testing to identify children who respond to PPIs, nor do they support trials of PPI for poorly controlled asthma.

Our study raises important questions about adverse effects of lansoprazole treatment of children with asthma. The lansoprazole group had significantly more self-reported episodes of upper respiratory symptoms, including sore throats, and bronchitis. In a clinical trial of lansoprazole vs placebo in infants, lansoprazole was associated with more lower respiratory infections.³¹ In additions, PPIs use has been associated with increased risk of community-acquired pneumonia in adults and children,^32,33,34,35 which is thought to be related to a reduction in the host defense against bacterial colonization imparted by low gastric acid.^36,37,38

The use of proton pump inhibitors in children has increased dramatically in the past decade, going from about 875,000 prescriptions in 2002 to 2.6 million in 2009.³⁹ The increase, especially among infants, along with safety signals in adults, has resulted in two FDA advisory board reviews of existing data related to the use of proton-pump inhibitors in children and infants within the past two years.^40,41 At the time of those reviews, there were two reports of fractures related to proton pump inhibitors in the FDA Adverse Event Reporting System. However, both committees recognized that there were limited data mostly from short-term studies and the Pediatric committee voted to receive updated reports on the safety of PPI use in children.⁴⁰ Our results reinforce the need for continued study of PPI safety in children, especially those with other risk factors, like inhaled corticosteroid use, which may already place them at higher risk for adverse events.

In conclusion the results of our study indicate that PPI treatment of children with poorly controlled asthma without symptomatic GER was not an effective therapy for asthma and there may be significant safety concerns for long term PPI use in children that warrants further study.