Clinical Context

Children have a high prevalence of asthma and gastroesophageal reflux (GER). Children with asthma often report symptoms of GER and also have a high prevalence of asymptomatic GER.

Some experts have suggested that untreated GER may cause persistent asthma control problems in children refractory to treatment with inhaled corticosteroids. However, whether treatment with proton pump inhibitors (PPIs) improves asthma control has not previously been determined. The objective of this study by Holbrook and colleagues was to determine whether lansoprazole is effective in reducing asthma symptoms in children without overt GER.

Study Synopsis and Perspective

Use of PPIs in children with poorly controlled asthma who were using inhaled corticosteroids and who had no symptoms of GER was not found to improve asthma control and was, in fact, associated with an increase in adverse effects, according to results of a study published in the January 25 issue of JAMA.

PPIs "are often prescribed for poorly controlled asthma regardless of reflux symptoms, and there have been large increases in the use of PPIs among children between 2000 and 2005.... Hence, it is of clinical importance to determine whether antireflux therapy, the most common of which are PPIs, improves control of asthma in children," write Janet T. Holbrook, MPH, PhD, from the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and colleagues from the Writing Committee for the American Lung Association Asthma Clinical Research Centers.

The goal of this placebo-controlled, double-masked, randomized study was to determine whether the PPI lansoprazole was effective in controlling asthma symptoms in children with asthma, but no overt GER. The researchers also investigated whether pH testing would identify children with GER who responded to PPI therapy.

Between April 2007 and September 2010, the Study of Acid Reflux in Children With Asthma enrolled 306 children at 19 US academic clinical trial centers. The children had physician-diagnosed asthma that was poorly controlled and were receiving inhaled corticosteroids (≥176 μg/day of fluticasone equivalents) for at least 8 weeks before enrollment. Participants were excluded if they had any symptoms of GER, were receiving any PPI or other reflux medications, or had any history of esophageal disease or other major illness. Participants were evaluated over the course of 24 weeks and ranged in age from 6 to 17 years (mean, 11 years of age).

The children were randomly assigned to receive either lansoprazole (15 mg/day for those weighing <30 kg; 30 mg/day for those weighing ≥30 kg; n = 149) or a matching placebo (n = 157). The researchers found that the mean difference in the Asthma Control Questionnaire (ACQ) score between the 2 groups was 0.2 units (95% confidence interval [CI], 0.0 - 0.3 units), which was not statistically significant (P = .12).

There also was no significant difference in the forced expiratory volume in the first second (FEV₁; 0.0 L; 95% CI, −0.1 to 0.1 L), and no change in the rate of episodes of poor asthma control (relative risk [RR], 1.2; 95% CI, 0.9 - 1.5) or asthma-related quality of life (−0.1; 95% CI, −0.3 to 0.1). In addition, children treated with lansoprazole developed more respiratory infections (RR, 1.3; 95% CI, 1.1 - 1.6; P = .02) than those in the placebo group.

A subgroup of children in the study (n = 115) underwent esophageal pH studies before randomization; the prevalence of GER among this group was found to be 43%. In those children with a positive pH study, there was no positive treatment effect with lansoprazole vs placebo for any asthma outcome.

The researchers evaluated a change in the ACQ score between case and control participants as their primary outcome. The questionnaire was administered at enrollment, and again at the 24-week follow-up visit. Secondary outcomes included the rate of acute episodes of poor asthma control, the Asthma Symptom Utility Index, the Asthma Control Test for adolescents (aged 12 - 17 years)/children (aged 6 - 11 years), asthma-specific quality of life score, methacholine provocative concentration, spirometry, exhaled nitric oxide, gastrointestinal symptoms, and nocturnal awakenings.

The authors also required the children to maintain a journal at home to record any asthma exacerbations, rescue treatments, morning peak expiratory flow, nocturnal awakenings, oral corticosteroid use, and unscheduled healthcare visits for asthma symptoms.

The most common adverse event reported among both groups was asthma exacerbation. A higher prevalence of upper respiratory tract infections, sore throats, and episodes of bronchitis was noted among patients in the lansoprazole group. The study authors speculate that this may be a result of loss of host defense against bacterial colonization as a result of higher gastric pH levels. Activity-related bone fractures were not statistically different between the 2 groups (6/149 in the lansoprazole group vs 1/157 in the placebo group; P = .06).

"The results of this clinical trial are uniformly negative regarding the benefit of acid suppression therapy on symptom relief, lung function, airway reactivity, or quality of life," write the authors. The results also "indicate that PPI therapy for poorly controlled asthma is not warranted."

In an accompanying editorial, Fernando Martinez, MD, from the Arizona Respiratory Center, University of Arizona, Tucson, notes that although it is not a statistically significant difference, the increase in activity-related bone fractures in the lansoprazole group also raises concerns. This potential complication has prompted an advisory from the US Food and Drug Administration about the risk for fractures in adults receiving chronic PPI therapy. "In this context, a less conservative test assessing if the odds ratio was significantly greater than 1.0 (not just different from 1 in any direction) might have been more appropriate and may have yielded a statistically significant result," writes Dr. Martinez.

Overall, however, Dr. Martinez praises the work of Dr. Holbrook and colleagues and concludes that "[g]iven their potential adverse effects, these medications should thus be used with great restraint for treatment of GER/[gastroesophageal reflux disease] during childhood. The substantial increase in use of PPIs in children during the last decade is worrisome and unwarranted."

Support for this study was provided by the American Lung Association Asthma Clinical Research Centers Infrastructure Award and National Institutes of Health/National Heart, Lung, and Blood Institute grants. Dr. Holbrook and colleagues have disclosed no relevant financial relationships. Dr. Martinez has served as a consultant to MedImmune and has presented at an Abbott-sponsored seminar.

JAMA. 2012;307:373-381, 406-407.

Clinical Implications

• Findings of a randomized, placebo-controlled trial suggest that PPI treatment of children with poorly controlled asthma but without symptomatic GER is not effective in reducing asthma symptoms or improving lung function.
• In this randomized, placebo-controlled trial, the addition of lansoprazole was associated with increased adverse events, particularly respiratory tract infections. There may be significant safety concerns for long-term PPI use in children, meriting further research.

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