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Original Contribution |

Lansoprazole for Children With Poorly Controlled Asthma:  A Randomized Controlled Trial FREE

Writing Committee for the American Lung Association Asthma Clinical Research Centers
[+] Author Affiliations

Authors/Writing Committee: The following investigators of the American Lung Association Asthma Clinical Research Centers take authorship responsibility for the study results: Janet T. Holbrook, MPH, PhD, Center for Clinical Trials, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Robert A. Wise, MD, Johns Hopkins University School of Medicine; Benjamin D. Gold, MD, Children's Center for Digestive Healthcare, Atlanta, Georgia; Kathryn Blake, PharmD, Nemours Children's Clinic, Jacksonville, Florida; Ellen D. Brown, MS, Center for Clinical Trials, Johns Hopkins School of Public Health; Mario Castro, MD, Washington University School of Medicine, St Louis, Missouri; Allen J. Dozor, MD, Maria Fareri Children's Hospital at Westchester Medical Center and New York Medical College, Valhalla; John J. Lima, PharmD, Nemours Children's Clinic; John G. Mastronarde, MD, Ohio State University Medical Center, Davis Heart and Lung Research Institute, Columbus; Marianna M. Sockrider, MD, DrPH, Baylor College of Medicine, Texas Children's Hospital, Houston; and W. Gerald Teague, MD, University of Virginia School of Medicine, Charlottesville.


JAMA. 2012;307(4):373-380. doi:10.1001/jama.2011.2035.
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Context Asymptomatic gastroesophageal reflux (GER) is prevalent in children with asthma. Untreated GER has been postulated to be a cause of inadequate asthma control in children despite inhaled corticosteroid treatment, but it is not known whether treatment with proton pump inhibitors improves asthma control.

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

Design, Setting, and Participants The Study of Acid Reflux in Children With Asthma, a randomized, masked, placebo-controlled, parallel clinical trial that compared lansoprazole with placebo in children with poor asthma control who were receiving inhaled corticosteroid treatment. Three hundred six participants enrolled from April 2007 to September 2010 at 19 US academic clinical centers were followed up for 24 weeks. A subgroup had an esophageal pH study before randomization.

Intervention Participating children were randomly assigned to receive either lansoprazole, 15 mg/d if weighing less than 30 kg or 30 mg/d if weighing 30 kg or more (n = 149), or placebo (n = 157).

Main Outcome Measures The primary outcome measure was change in Asthma Control Questionnaire (ACQ) score (range, 0-6; a 0.5-unit change is considered clinically meaningful). Secondary outcome measures included lung function measures, asthma-related quality of life, and episodes of poor asthma control.

Results The mean age was 11 years (SD, 3 years). The mean difference in change (lansoprazole minus placebo) in the ACQ score was 0.2 units (95% CI, 0.0-0.3 units). There were no statistically significant differences in the mean difference in change for the secondary outcomes of forced expiratory volume in the first second (0.0 L; 95% CI, −0.1 to 0.1 L), asthma-related quality of life (−0.1; 95% CI, −0.3 to 0.1), or rate of episodes of poor asthma control (relative risk, 1.2; 95% CI, 0.9-1.5). 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 vs placebo was observed for any asthma outcome. Children treated with lansoprazole reported more respiratory infections (relative risk, 1.3 [95% CI, 1.1-1.6]).

Conclusion In this trial of children with poorly controlled asthma without symptoms of GER who were using inhaled corticosteroids, the addition of lansoprazole, compared with placebo, improved neither symptoms nor lung function but was associated with increased adverse events.

Trial Registration clinicaltrials.gov Identifier: NCT00442013

Figures in this Article

Asthma and gastroesophageal reflux (GER) disease are both common disorders in children, and symptoms of GER are frequently reported among children with asthma.14 Gastroesophageal reflux identified by esophageal pH monitoring often presents with respiratory symptoms57 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 treatment.

Proton pump inhibitors (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 2005.10 Additionally, expert panels have indicated that the utility of testing and treating children with refractory asthma symptoms for asymptomatic GER has been inadequately studied.3,11 Hence, it is of clinical importance to determine whether antireflux therapy, the most common of which are PPIs, improves 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.1214 An open-label prospective study evaluated 44 children with moderate, persistent asthma and GER disease who showed clinical improvement in asthma symptoms after 1 year of treatment with esomeprazole and metoclopramide. Children who continued the combination treatment for 6 months had fewer asthma exacerbations than those who switched to ranitidine.15

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 would have improved asthma control with lansoprazole treatment compared with placebo. We also investigated whether asymptomatic GER as identified by pH probe testing would identify children who respond to PPI treatment.

Study Design

The Study of Acid Reflux in Children With Asthma was a randomized (allocation ratio, 1:1), double-masked, placebo-controlled, parallel clinical trial designed to evaluate the effectiveness of lansoprazole for treatment of asthma in children. The study was conducted at 19 American Lung Association Asthma Clinical Research Center sites from April 2007 to April 2011. The study was approved by the institutional review board at each center; legal guardians signed informed consent statements and participants signed assent statements according to local regulatory policy.

Children were randomly assigned to receive either lansoprazole (15 mg/d for children weighing <30 kg; 30 mg/d for children weighing ≥30 kg) or a matching placebo. A permuted-block treatment assignment schedule stratified by clinical center was used; treatment assignment schedules were generated by the data coordinating center using the Stata Ralloc procedure version 3.2.3 (Stata Corp). Study drug kits were identified by unique identification numbers and were masked to participants, clinical personnel, and data analysts throughout the study. Clinical center personnel, usually a coordinator, requested treatment assignment by keying eligibility information into a program on the study Web site that released the study drug kit identification code.

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. Participants were paid, on average, $50 for each study visit and $200 for undergoing a pH probe study.

Participant Selection

Participants were between 6 and 17 years of age and had physician-diagnosed asthma and labile airways function defined as a 12% or greater increase in postbronchodilator forced expiratory volume in the first second (FEV1), a methacholine challenge (provocative dose of methacholine to reduce percent predicted FEV1 by 20% [PC20]) of less than 16 mg/mL, or a positive exercise bronchoprovocation test result of a 20% or greater decrease in FEV1 after exercise demonstrated within the prior 12 months. Participants were treated with inhaled corticosteroids (≥176 μg/d of fluticasone equivalents) and had no change in controller therapies for at least 8 weeks prior to enrollment.

Poor asthma control was defined as any 1 of the following: use of short-acting β-agonists for asthma symptoms 2 or more times per week; nocturnal awakenings with asthma symptoms more than once per week during the month before enrollment; 2 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 Asthma Control Questionnaire (ACQ) at the screening visit.

Recruits were excluded from the study if they self-reported any of the following: symptoms of GER requiring treatment; treatment with a PPI or other reflux medications (other than occasional oral antacids); history of antireflux surgery or a previous trachea-esophageal fistula repair; an FEV1 of less than 60% predicted; history of neonatal respiratory distress or premature birth at 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 nonadherence (<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/ethnicity, cigarette or cigar smoke exposure, past asthma treatments, and asthma triggers were collected via interview. Participants were asked to identify their ethnicity (non-Hispanic vs Hispanic) and race (open-ended). These data were used for reporting to the National Heart, Lung, and Blood Institute and for calculating predictive values for lung function. Children were followed up between 2 and 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.

Outcome Measures

The primary outcome measure for the trial was change in ACQ score 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-point change in ACQ score reflects a meaningful clinically important difference in asthma control. Patients with ACQ scores of 0.75 or less are classified as having well-controlled asthma and those with scores of 1.5 or greater are classified as having inadequately controlled asthma.17,18

Secondary outcomes included the rate of acute episodes of poor asthma control14; Asthma Symptom Utility Index19 (ASUI; score range, 0-1.0; meaningful clinically important difference, 0.15 [Christian Bime, MD, written communication to American Thoracic Society, December 2011]); Asthma Control Test for adolescents (aged 12-17 years)/children (aged 6-11 years) (ACT20/cACT21; score range, 5-25/0-27, respectively; meaningful clinically important difference, 3 for ACT22 and undefined for cACT); asthma-specific quality of life for children (AQLQ; score range, 1-7; meaningful clinically important difference, 0.4)23 and for their caregivers (cAQLQ; score range 1-7; meaningful clinically important difference, 0.5)24; methacholine PC2025; spirometry26; exhaled nitric oxide; gastrointestinal symptoms (score range, 0-441; meaningful clinically important difference undefined)27; and nocturnal awakenings.

We defined 2 types of episodes of poor asthma control derived from the daily diaries: an episode of poor asthma control type 1 was a decrease of greater than 30% in morning peak flow rate from personal best (assessed during run-in) for 2 consecutive days, addition of an oral corticosteroid to treat asthma symptoms, or unscheduled contact with a health care practitioner for asthma symptoms. An episode of poor asthma control type 2 also included increased use of short-acting β-agonists from baseline (≥4 additional puffs of rescue medication or ≥2 additional nebulizer treatments in 1 day). Episodes of poor asthma control type 1 excluded use of rescue medications because we were concerned that heartburn symptoms could be mistaken for asthma symptoms and result in increased rescue medication use.

In a post hoc analysis of treatment effect in subgroups defined by either FEV1 at baseline (percent predicted prebronchodilator FEV1 ≤80% vs >80%) or use of oral steroids for asthma in the past year, there was no evidence of an improvement in ACQ score associated with lansoprazole (eTable 1). There was no statistically significant effect of study site on change in ACQ score (P = .07). Participants were questioned about potential adverse effects of treatment at each visit. Subsequent to a US Food and Drug Administration (FDA) advisory on the risk of bone fractures in adults,28 clinics were asked to review participant records for fractures.

Esophageal pH studies were performed prior to randomization at 13 clinical centers according to a standard protocol and were centrally reviewed. At least 16 hours of monitoring was required for evaluation. The thresholds used for the definition of pathological GER were esophageal pH of 4 or lower for 6% or more of the time for a 6- to 11-year-old and for 4% or more of the time for a 12- to 17-year-old.3

Sample Size

The planned sample size of 300 participants provided 90% power to detect a 0.6-unit change in the primary outcome, ACQ score, assuming an SD of 1.5 with a 2-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 with an unstructured or exchangeable covariance matrix to adjust for repeated measures29; saturated means models including indicators for each visit and each visit × treatment interaction were constructed with missing data indicators to maintain data structure. Hence, all participants with baseline or follow-up data were included in the models to estimate treatment effects. Data were assumed to be missing at random. The visits were defined as ordinal variables by visit code. Negative binomial regression models were used to evaluate differences in the rate of episodes of poor asthma control30; 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 1 interim analysis during the trial after approximately 50% of the participants completed follow-up. P values were 2-sided and P ≤.05 was considered statistically significant; P values were not adjusted for multiple looks or multiple comparisons. Post hoc sensitivity analyses were performed including measures of asthma severity and study site, a stratification variable, in the model. Data were analyzed using SAS version 9.2 (SAS Institute Inc) and Stata version 11 (Stata Corp).

Recruitment and Follow-up

A total of 2453 children were screened for eligibility. Three hundred six children were randomized; 157 were randomly assigned to receive placebo and 149 to receive lansoprazole (Figure 1). More than 88% of participants completed the study and 94% of follow-up visits were completed. Baseline characteristics of participants completing the study (n = 263) were similar to those who did not complete the final visit (n = 43), with the following exceptions: postbronchodilator FEV1 and forced vital capacity (FVC) were higher in those who completed the study (FEV1, 110% vs 95%; P = .03 and FVC, 104% vs 99%; P = .04), and montelukast use was more common (57% vs 40%; P = .02). Self-reported adherence to study treatments was high in both groups according to diary cards and interviews at study visits; study drug was reported to be taken on more than 90% of follow-up days in both groups.

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Figure 1. Participant Flow
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Characteristics of Study Participants

The demographic and asthma characteristics at baseline were similar in the 2 treatment groups (Table 1). The children had a mean age of 11 years, there were more boys than girls, and 50% of participants were black. 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% vs 8.5% in the placebo group; P = .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 vs 2.5 mg/mL in the placebo group; P = .04).

Table Graphic Jump LocationTable 1. Characteristics of Study Participants
GER Status

One hundred fifty-two participants underwent 24-hour esophageal pH monitoring studies. Of these, 115 had adequate results for interpretation, 49 (43%) of whom had abnormal esophageal acid exposure as assessed by frequent acid reflux events, prolonged acid reflux episodes (>5 minutes), or overall 24-hour esophageal acid reflux greater than established thresholds. Gastrointestinal symptom scores were not different between patients with normal vs abnormal pH probe study results (mean scores, 15 [95% CI, 10-20] vs 20 [95% CI, 12-27], respectively). There were no differences in prebronchodilator percent predicted FEV1 or FVC between participants with a positive pH probe study result and those with a negative result (FEV1, 91% [SD, 16%] vs 93% [SD, 15%]; P = .45 and FVC, 101% [SD, 14%] vs 102% [SD, 14%]; P = .80).

Effects of Treatment on Asthma Outcomes

The mean ACQ score at screening was high and consistent with poor asthma control in both groups (1.6 for both groups; P = .96). Between the screening and randomization visits, ACQ scores decreased in both groups. After randomization, the ACQ score decreased by less than the meaningful clinically important difference in both groups (lansoprazole, −0.1; 95% CI, −0.2 to 0.1 and placebo, −0.2; 95% CI, −0.4 to −0.1); the change was not statistically different (P = .12) between treatment groups (Table 2 and Figure 2). There were no significant treatment effects for any of the secondary indexes of asthma control, including the ASUI, ACT, cACT, AQLQ, and cAQLQ (Table 2). Likewise, there was no significant treatment effect on lung function, including prebronchodilator FEV1 or FVC, over the 6-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 episodes of poor asthma control type 1 or 2 rates (Table 3).

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Figure 2. Change in Asthma Control Questionnaire (ACQ) Score in Children With Poor Asthma Control Receiving Lansoprazole vs Placebo
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Lower scores indicate better asthma control. Error bars indicate 95% CIs.

Table Graphic Jump LocationTable 2. Questionnaire Scores and Lung Function Measures at 24 Weeks of Follow-up
Table Graphic Jump LocationTable 3. Episodes of Poor Asthma Control by Treatment Assignment
Subanalysis of Children With Abnormal Esophageal pH Study Results

Among the 115 children with adequate 24-hour esophageal monitoring studies, 43% (n = 49) had positive results for GER; 38% (n = 20) who received placebo had GER vs 47% (n = 29) who received lansoprazole (P = .33). In a subanalysis 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, lung function, or bronchial hyperresponsiveness (eTable 2 and eTable 3).

Adverse Events

Ten participants in the lansoprazole group and 9 in the placebo group had 1 or more serious adverse events. The most common serious adverse event in both groups was asthma exacerbation (15 of 25 reports). Treatment with lansoprazole was associated with a greater prevalence of upper respiratory tract infections, sore throats, and episodes of bronchitis (Table 4).

Activity-related bone fractures were not different in children treated with lansoprazole vs placebo (6/149 vs 1/157; P = .06). Children who had fractures were between ages 7 and 14 years and all had been receiving inhaled corticosteroids throughout the trial; 2 (1 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 (n = 1), 5 months (n = 3), and 6 months (n = 2) of follow-up.

Among children with poorly controlled asthma, lansoprazole treatment had no effect on asthma control measures. This was the case even though GER was prevalent (43% as evidenced by positive esophageal pH test results) in the study sample. In a subanalysis 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. Nor was lansoprazole effective in subgroups defined by markers of asthma severity (either FEV1 at baseline or oral steroid use in the past year). 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 children, most with demonstrable GER, PPI improved asthma symptoms31 or improved airways reactivity.32 However, a placebo-controlled trial of omeprazole in 38 children with asthma and GER showed no significant effect of omeprazole on asthma outcomes.33 These results, in conjunction with ours, indicate that PPI therapy for poorly controlled asthma is not warranted.

Although our results are robust, there are hypotheses about the role of GER in asthma that we did not address. We focused on patients without symptomatic GER because these children do not have an independent indication for PPI treatment. The possible role of nonacid reflux in worsening asthma control is unclear, and the observed failure of acid-suppressive therapy to improve asthma does not address this mechanism. It is also possible that the dose of PPI was not adequate to suppress all acid production; however, we did not think it was justified to use doses that exceeded the FDA-approved dose of lansoprazole in children. We also did not conduct on-treatment pH probe studies to confirm acid suppression. Furthermore, adherence to study drug, although high by self-report, could have influenced our results.

Our study does not refute the possibility that GER may trigger chronic cough in children.34 In a recent study in nonasthmatic children with chronic cough, episodes of GER preceded cough in 22 of 26 patients.35 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 increase in asthma symptoms.36

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 PPIs for poorly controlled asthma. In our trial, participants with positive pH probe study results did not have significantly worse measures of lung function.

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 respiratory symptoms, including sore throats and bronchitis. In a clinical trial of lansoprazole vs placebo in infants, lansoprazole was associated with more lower respiratory tract infections.37 In addition, PPI use has been associated with increased risk of community-acquired pneumonia in adults and children,3841 which is thought to be related to a reduction in the host defense against bacterial colonization imparted by low gastric acid.4244

The use of PPIs in children has increased dramatically in the past decade, from about 875 000 prescriptions in 2002 to 2.6 million in 2009, which represents about 5% of children in the United States at that time.45 The increase, especially among infants, along with safety signals in adults, has resulted in 2 FDA advisory board reviews of existing data related to the use of PPIs in children and infants within the past 2 years.46,47 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.45 Our results reinforce the need for continued study of PPI safety in children.

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 warrant further study.

Corresponding Author: Janet T. Holbrook, MPH, PhD, Johns Hopkins Center for Clinical Trials, 911 S Ann St, Baltimore, MD 21231 (jholbroo@jhsph.edu).

Author Contributions: Drs Holbrook and Wise had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The protocol committee for the trial also served as the writing committee.

Study concept and design: Holbrook, Wise, Gold, Blake, Brown, Castro, Dozor, Lima, Mastronarde, Sockrider, Teague.

Acquisition of data: Holbrook, Wise, Gold, Blake, Brown, Castro, Dozor, Lima, Mastronarde, Sockrider, Teague.

Analysis and interpretation of data: Holbrook, Wise, Gold, Blake, Dozor, Lima, Mastronarde, Sockrider, Teague.

Drafting of the manuscript: Holbrook, Wise, Teague.

Critical revision of the manuscript for important intellectual content: Holbrook, Wise, Gold, Blake, Brown, Castro, Dozor, Lima, Mastronarde, Sockrider, Teague.

Statistical analysis: Holbrook.

Obtained funding: Holbrook, Wise, Lima, Teague.

Administrative, technical, or material support: Holbrook, Wise, Gold, Brown, Dozor, Lima, Teague.

Study supervision: Holbrook, Wise, Blake, Castro, Dozor, Teague.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Investigators and Staff of the American Lung Association Asthma Clinical Research Centers:Baylor College of Medicine: Nicola Hanania, MD, FCCP (principal investigator), Marianna Sockrider, MD, DrPH (co–principal investigator), Laura Bertrand, RN, RPFT (principal clinic coordinator), Mustafa Atik, MD, Luz Giraldo, RCP, RCPT, Blanca A. Lopez, LVN (coordinators); Columbia University–New York University Consortium: Joan Reibman, MD (principal investigator), Emily DiMango, MD, Linda Rogers, MD (co–principal investigators), Elizabeth Fiorino, MD (coinvestigator at New York University), Cherie Cammarata, MSN, MA, Karen Carapetyan, MA (clinic coordinators at New York University), Jennifer Sormillon, BSN, Erin Simpson (clinic coordinators at Columbia University); Duke University Medical Center: Larry Williams, MD (principal investigator), John Sundy, MD, PhD (co–principal investigator), Peter Michelson, MD, MSC, Brian Vickery, MD, Ginny Dudek, RN (principal clinic coordinator), Rebecca Newton, RN, Amy Dugdale, RN, Catherine Foss, BS, RRT, CCRC, Denise Jaggers, RN (coordinators); Emory University School of Medicine: W. Gerald Teague, MD (principal investigator), Anne Fitzpatrick, PhD, RN, CPNP, Sumita Khatri, MD (co–principal investigators), Rachna Patel, BS (principal clinic coordinator), Jeannie Peabody, RN, Eric Hunter, BS, Denise Whitlock, RRT, CRP (coordinators); Illinois Consortium: Lewis Smith, MD (principal investigator), James Moy, MD, Adrienne Prestridge, MD (co–principal investigators), Jenny Hixon, BS, CCRC (principal clinic coordinator), Abbi Brees, BA, CCRC, Janine Judge, RRT (coordinators); Indiana University, Asthma Clinical Research Center: Michael Busk, MD, MPH (principal investigator), Paula Puntenney, RN, MA (principal clinic coordinator), Nancy Busk, BS, MS, Janet Hutchins, BSN (coordinators); University of Pennsylvania: Frank Leone, MD, MS (principal investigator), Michelle Hayes-Hampton, RN (principal clinic coordinator); National Jewish Health: Rohit Katial, MD (principal investigator), Marzena Krawiecz, MD (co–principal investigator), Holly Currier, RN (principal clinic coordinator); Nemours Children's Clinic–University of Florida Consortium: John Lima, PharmD (principal investigator), Kathryn Blake, PharmD (co–principal investigator), Jason Lang, MD (co–principal investigator), David Schaeffer, MD (investigator), Donald George, MD (investigator), Mary Warde, RN, BSN (principal coordinator), Nancy Archer, RN, BSN (coordinator), Melissa McRae, RN (coordinator), Amber Santos, RN, MBA (coordinator); Hofstra University School of Medicine (formerly North Shore–Long Island Jewish Health System): Rubin Cohen, MD (principal investigator), Maria Santiago, MD (co–principal investigator), Ramona Ramdeo, MSN, FNP-C, RN, RT (principal clinic coordinator); Northern New England Consortium (formerly Vermont Lung Center at the University of Vermont): Charles Irvin, PhD (principal investigator), Anne E. Dixon, MD, David A. Kaminsky, MD, Thomas Lahiri, MD, Paul S. Shapero, MD, (co–principal investigators), Richard Colletti, MD (gastrointestinal consultant), Stephanie M. Burns, Laurianne V. Griffes, Roberta Pratt, RN, Michelle Doucette, RN, Pam Oertel (coordinators); Ohio State University Medical Center/Columbus Children's Hospital: John Mastronarde, MD (principal investigator), Karen McCoy, MD (co–principal investigator), Jonathan Parsons, MD (coinvestigator), Janice Drake, CCRC (principal clinic coordinator), Rachael A. Compton, Laura Raterman, RN, David Cosmar, BA (coordinators); Maria Fareri Children's Hospital at Westchester Medical Center and New York Medical College: Allen J. Dozor, MD (principal investigator), Sankaran Krishnan, MD, Jay Boyer, MD, Nadav Traeger, MD (coinvestigators), Ingrid Gherson, MPH (principal clinic coordinator), Lisa Monchil, RRT, CCRC (research coordinator); University of Alabama at Birmingham: Lynn B. Gerald, PhD, MSPH (principal investigator), William C. Bailey, MD, Roni Grad, MD (co–principal investigators), Sue Erwin, CRT (principal clinic coordinator), Ann Kelley, RN, Debra Laken, MaED, RRT, AE-C (coordinators); University of Miami, Miami–University of South Florida: Adam Wanner, MD (principal investigator, Miami), Richard Lockey, MD (principal investigator, Tampa), Eliana S. Mendes, MD (principal clinic coordinator for University of Miami), Shirley McCullough, BS (principal clinic coordinator for University of South Florida), Michelle Grandstaff-Singleton, BHSc, LPN, Diana Miller, BA (coordinators); University of Minnesota: Malcolm N. Blumenthal, MD (principal investigator), Gail Brottman, MD, John Hagen, MD (co–principal investigators), Athena Decker, MA, Debra Lascewski, RN, Sheila Kelleher, MA (principal clinic coordinators), Kay A. Bachman, RN, Cindy Quintard, CCRC, Cherylee Sherry, MPH, CHES (coordinators); University of Missouri, Kansas City School of Medicine: Gary Salzman, MD (principal investigator), Chitra Dinakar, MD, Dennis Pyszczynski, MD (coinvestigators), Patti Haney, RN, BSN, CCRC (principal clinic coordinator); St Louis Asthma Clinical Research Center, Washington University: Mario Castro, MD, MPH (principal investigator), Leonard Bacharier, MD, Kaharu Sumino, MD (coinvestigators), Jaime J. Tarsi, RN, MPH (principal coordinator), Brenda Patterson, MSN, RN, FNP (coordinator); University of California San Diego: Stephen Wasserman, MD (principal investigator), Joe Ramsdell, MD (co–principal investigator), Paul Ferguson, MS, Katie Kinninger, AS, Tonya Greene, AA (clinic coordinators); Chairman's Office, University of Alabama, Birmingham (formerly at Respiratory Hospital, Winnipeg, Manitoba, Canada): William C. Bailey, MD, Nicholas Anthonisen, MD, PhD (research group chair); Co–Principal Investigators' Office, University of Virginia School of Medicine, Department of Pediatrics (formerly at Emory University): W. Gerald Teague, MD (study co–principal investigator); Data Coordinating Center, Johns Hopkins University Center for Clinical Trials: Robert Wise, MD (center director), Janet Holbrook, PhD, MPH (deputy director), Ellen Brown, MS (principal coordinator), Debra Amend-Libercci, Katherine Barry, BA, Marie Daniel, BA, Andrea Lears, BS, Gwen Leatherman, BSN, MS, RN, Charlene Levine, BS, Deborah Nowakowski, Nancy Prusakowski, MS, Sobharani Rayapudi, MD, ScM, Suzanna Roettger, MA, April Thurman, David Shade, JD, Elizabeth Sugar, PhD, Johnson Ukken, BA, Christine Wei, MS; Esophageal pH Probe Quality Control Center, Children's Center for Digestive Healthcare Pediatric Gastroenterology, Hepatology, and Nutrition (formerly at Emory University School of Medicine): Benjamin Gold, MD (center director); Data and Safety Monitoring Board: Stephen C. Lazarus, MD (chair), William J. Calhoun, MD, Michelle Cloutier, MD, Peter Kahrilas, MD, Bennie McWilliams, MD, Andre Rogatko, PhD, Christine Sorkness, PharmD; Project Office, American Lung Association: Elizabeth Lancet, MPH (project officer), Norman Edelman, MD (scientific consultant), Susan Rappaport, MPH; Project Office, National Heart, Lung, and Blood Institute: Virginia Taggart, MPH, Robert Smith, PhD (project officers), Gail Weinmann, MD (data and safety monitoring board executive secretary; deputy director, Division of Lung Diseases); American Lung Association Scientific Advisory Committee: E. Neil Schacter, MD (chair), William C. Bailey, MD, Mario Castro, MD, MPH, Brian Christman, MD, Amy Chuang, MD, Candy Holloway, Judith A. Neubauer, PhD, Jonathan M. Samet, MD, Erik Swenson, MD, Dona J. Upson, MD, Daniel J. Weiss, MD, PhD, Robert Wise, MD.

Funding/Support: This study was supported by the American Lung Association Asthma Clinical Research Centers Infrastructure Award and National Institutes of Health/National Heart, Lung, and Blood Institute grants U01 HL080450 (Dr Holbrook) and U01 HL080433 (Dr Teague). Lansoprazole and placebo were provided by Takeda Pharmaceuticals; albuterol was provided by GlaxoSmithKline.

Role of the Sponsor: Takeda and GlaxoSmithKline had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. The American Lung Association and National Heart, Lung, and Blood Institute reviewed the protocol and/or had a role in the management/review of the study.

Online-Only Material: The Author Video Interview is available here.

Tucci F, Resti M, Fontana R, Novembre E, Lami CA, Vierucci A. Gastroesophageal reflux and bronchial asthma: prevalence and effect of cisapride therapy.  J Pediatr Gastroenterol Nutr. 1993;17(3):265-270
PubMed   |  Link to Article
Cinquetti M, Micelli S, Voltolina C, Zoppi G. The pattern of gastroesophageal reflux in asthmatic children.  J Asthma. 2002;39(2):135-142
PubMed   |  Link to Article
Vandenplas Y, Rudolph CD, Di Lorenzo C,  et al; North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.  Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN).  J Pediatr Gastroenterol Nutr. 2009;49(4):498-547
PubMed   |  Link to Article
Hancox RJ, Poulton R, Taylor DR,  et al.  Associations between respiratory symptoms, lung function and gastro-oesophageal reflux symptoms in a population-based birth cohort.  Respir Res. 2006;7:142
PubMed   |  Link to Article
Andze GO, Brandt ML, St Vil D, Bensoussan AL, Blanchard H. Diagnosis and treatment of gastroesophageal reflux in 500 children with respiratory symptoms: the value of pH monitoring.  J Pediatr Surg. 1991;26(3):295-299, discussion 299-300
PubMed   |  Link to Article
El-Serag HB, Gilger M, Kuebeler M, Rabeneck L. Extraesophageal associations of gastroesophageal reflux disease in children without neurologic defects.  Gastroenterology. 2001;121(6):1294-1299
PubMed   |  Link to Article
Harding SM, Richter JE. The role of gastroesophageal reflux in chronic cough and asthma.  Chest. 1997;111(5):1389-1402
PubMed   |  Link to Article
Sheikh S, Stephen T, Howell L, Eid N. Gastroesophageal reflux in infants with wheezing.  Pediatr Pulmonol. 1999;28(3):181-186
PubMed   |  Link to Article
Sherman PM, Hassall E, Fagundes-Neto U,  et al.  A global, evidence-based consensus on the definition of gastroesophageal reflux disease in the pediatric population.  Am J Gastroenterol. 2009;104(5):1278-1295, quiz 1296
PubMed   |  Link to Article
Nelson SP, Kothari S, Wu EQ, Beaulieu N, McHale JM, Dabbous OH. Pediatric gastroesophageal reflux disease and acid-related conditions: trends in incidence of diagnosis and acid suppression therapy.  J Med Econ. 2009;12(4):348-355
PubMed   |  Link to Article
 Expert Panel Report 3: Guidelines for the Diagnosis and Management of AsthmaBethesda, MD: National Asthma Education and Prevention Program, National Heart, Lung, and Blood Institute; 2007. NIH publication 08-4051
Kiljander TO, Harding SM, Field SK,  et al.  Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial.  Am J Respir Crit Care Med. 2006;173(10):1091-1097
PubMed   |  Link to Article
Kiljander TO, Junghard O, Beckman O, Lind T. Effect of esomeprazole 40 mg once or twice daily on asthma: a randomized, placebo-controlled study.  Am J Respir Crit Care Med. 2010;181(10):1042-1048
PubMed   |  Link to Article
Mastronarde JG, Anthonisen NR, Castro M,  et al; American Lung Association Asthma Clinical Research Centers.  Efficacy of esomeprazole for treatment of poorly controlled asthma.  N Engl J Med. 2009;360(15):1487-1499
PubMed   |  Link to Article
Khoshoo V, Haydel R Jr. Effect of antireflux treatment on asthma exacerbations in nonatopic children.  J Pediatr Gastroenterol Nutr. 2007;44(3):331-335
PubMed   |  Link to Article
Juniper EF, Gruffydd-Jones K, Ward S, Svensson K. Asthma Control Questionnaire in children: validation, measurement properties, interpretation.  Eur Respir J. 2010;36(6):1410-1416
PubMed   |  Link to Article
Juniper EF, Bousquet J, Abetz L, Bateman ED.GOAL Committee.  Identifying “well-controlled” and “not well-controlled” asthma using the Asthma Control Questionnaire.  Respir Med. 2006;100(4):616-621
PubMed   |  Link to Article
Reddel HK, Taylor DR, Bateman ED,  et al.  An official American Thoracic Society/European Respiratory Society Statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.  Am J Respir Crit Care Med. 2009;180(1):59-99
PubMed   |  Link to Article
Revicki DA, Leidy NK, Brennan-Diemer F, Sorensen S, Togias A. Integrating patient preferences into health outcomes assessment: the multiattribute Asthma Symptom Utility Index.  Chest. 1998;114(4):998-1007
PubMed   |  Link to Article
Nathan RA, Sorkness CA, Kosinski M,  et al.  Development of the asthma control test: a survey for assessing asthma control.  J Allergy Clin Immunol. 2004;113(1):59-65
PubMed   |  Link to Article
Liu AH, Zeiger R, Sorkness C,  et al.  Development and cross-sectional validation of the Childhood Asthma Control Test.  J Allergy Clin Immunol. 2007;119(4):817-825
PubMed   |  Link to Article
Schatz M, Kosinski M, Yarlas AS, Hanlon J, Watson ME, Jhingran P. The minimally important difference of the Asthma Control Test.  J Allergy Clin Immunol. 2009;124(4):719-723, e1
PubMed   |  Link to Article
Juniper EF, Guyatt GH, Feeny DH, Ferrie PJ, Griffith LE, Townsend M. Measuring quality of life in children with asthma.  Qual Life Res. 1996;5(1):35-46
PubMed   |  Link to Article
Juniper EF, Guyatt GH, Feeny DH, Ferrie PJ, Griffith LE, Townsend M. Measuring quality of life in the parents of children with asthma.  Qual Life Res. 1996;5(1):27-34
PubMed   |  Link to Article
Crapo RO, Casaburi R, Coates AL,  et al.  Guidelines for methacholine and exercise challenge testing—1999.  Am J Respir Crit Care Med. 2000;161(1):309-329
PubMed   |  Link to Article
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population.  Am J Respir Crit Care Med. 1999;159(1):179-187
PubMed   |  Link to Article
Deal L, Gold BD, Gremse DA,  et al.  Age-specific questionnaires distinguish GERD symptom frequency and severity in infants and young children: development and initial validation.  J Pediatr Gastroenterol Nutr. 2005;41(2):178-185
PubMed   |  Link to Article
US Food and Drug Administration.  FDA drug safety communication: possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm. Accessed October 5, 2011
Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes.  Biometrics. 1986;42(1):121-130
PubMed   |  Link to Article
Keene ON, Jones MR, Lane PW, Anderson J. Analysis of exacerbation rates in asthma and chronic obstructive pulmonary disease: example from the TRISTAN study.  Pharm Stat. 2007;6(2):89-97
PubMed   |  Link to Article
Tolia V, Ferry G, Gunasekaran T, Huang B, Keith R, Book L. Efficacy of lansoprazole in the treatment of gastroesophageal reflux disease in children.  J Pediatr Gastroenterol Nutr. 2002;35:(suppl 4)  S308-S318
PubMed   |  Link to Article
Khoshoo V, Mohnot S, Haydel R Jr, Saturno E, Edell D, Kobernick A. Bronchial hyperreactivity in non-atopic children with asthma and reflux: effect of anti-reflux treatment.  Pediatr Pulmonol. 2009;44(11):1070-1074
PubMed   |  Link to Article
Størdal K, Johannesdottir GB, Bentsen BS,  et al.  Acid suppression does not change respiratory symptoms in children with asthma and gastro-oesophageal reflux disease.  Arch Dis Child. 2005;90(9):956-960
PubMed   |  Link to Article
Tolia V, Vandenplas Y. Systematic review: the extra-oesophageal symptoms of gastro-oesophageal reflux disease in children.  Aliment Pharmacol Ther. 2009;29(3):258-272
PubMed   |  Link to Article
Blondeau K, Mertens V, Dupont L,  et al.  The relationship between gastroesophageal reflux and cough in children with chronic unexplained cough using combined impedance-pH-manometry recordings.  Pediatr Pulmonol. 2010;46:286-294
PubMed   |  Link to Article
DiMango E, Holbrook JT, Simpson E,  et al; American Lung Association Asthma Clinical Research Centers.  Effects of asymptomatic proximal and distal gastroesophageal reflux on asthma severity.  Am J Respir Crit Care Med. 2009;180(9):809-816
PubMed   |  Link to Article
Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease.  J Pediatr. 2009;154(4):514-520, e4
PubMed   |  Link to Article
Meijvis SC, Cornips MC, Voorn GP,  et al.  Microbial evaluation of proton-pump inhibitors and the risk of pneumonia.  Eur Respir J. 2011;38(5):1165-1172
PubMed   |  Link to Article
Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis.  CMAJ. 2011;183(3):310-319
PubMed
Laheij RJ, Sturkenboom MC, Hassing RJ, Dieleman J, Stricker BH, Jansen JB. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs.  JAMA. 2004;292(16):1955-1960
PubMed   |  Link to Article
Canani RB, Cirillo P, Roggero P,  et al; Working Group on Intestinal Infections of the Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition.  Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children.  Pediatrics. 2006;117(5):e817-e820
PubMed   |  Link to Article
Ohara T, Arakawa T. Lansoprazole decreases peripheral blood monocytes and intercellular adhesion molecule-1-positive mononuclear cells.  Dig Dis Sci. 1999;44(8):1710-1715
PubMed   |  Link to Article
Yoshida N, Yoshikawa T, Tanaka Y,  et al.  A new mechanism for anti-inflammatory actions of proton pump inhibitors—inhibitory effects on neutrophil-endothelial cell interactions.  Aliment Pharmacol Ther. 2000;14:(suppl 1)  74-81
PubMed   |  Link to Article
Zedtwitz-Liebenstein K, Wenisch C, Patruta S, Parschalk B, Daxböck F, Graninger W. Omeprazole treatment diminishes intra- and extracellular neutrophil reactive oxygen production and bactericidal activity.  Crit Care Med. 2002;30(5):1118-1122
PubMed   |  Link to Article
Taylor AM. Pediatric focused safety review: proton pump inhibitors: esomeprazole, lansoprazole, omeprazole, rabeprazole. June 21, 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM216303.pdf. Accessed October 5, 2011
US Food and Drug Administration.  Transcripts of the June 21, 2010, meeting of the Pediatric Advisory Committee. June 21, 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM219336.pdf. Accessed October 5, 2011
US Food and Drug Administration.  Transcripts of the November 5, 2010, meeting of the Gastrointestinal Drugs Advisory Committee. November 5, 2010.http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM237495.pdf. Accessed October 5, 2011

Figures

Place holder to copy figure label and caption
Figure 1. Participant Flow
Graphic Jump Location
Place holder to copy figure label and caption
Figure 2. Change in Asthma Control Questionnaire (ACQ) Score in Children With Poor Asthma Control Receiving Lansoprazole vs Placebo
Graphic Jump Location

Lower scores indicate better asthma control. Error bars indicate 95% CIs.

Tables

Table Graphic Jump LocationTable 1. Characteristics of Study Participants
Table Graphic Jump LocationTable 2. Questionnaire Scores and Lung Function Measures at 24 Weeks of Follow-up
Table Graphic Jump LocationTable 3. Episodes of Poor Asthma Control by Treatment Assignment

References

Tucci F, Resti M, Fontana R, Novembre E, Lami CA, Vierucci A. Gastroesophageal reflux and bronchial asthma: prevalence and effect of cisapride therapy.  J Pediatr Gastroenterol Nutr. 1993;17(3):265-270
PubMed   |  Link to Article
Cinquetti M, Micelli S, Voltolina C, Zoppi G. The pattern of gastroesophageal reflux in asthmatic children.  J Asthma. 2002;39(2):135-142
PubMed   |  Link to Article
Vandenplas Y, Rudolph CD, Di Lorenzo C,  et al; North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.  Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN).  J Pediatr Gastroenterol Nutr. 2009;49(4):498-547
PubMed   |  Link to Article
Hancox RJ, Poulton R, Taylor DR,  et al.  Associations between respiratory symptoms, lung function and gastro-oesophageal reflux symptoms in a population-based birth cohort.  Respir Res. 2006;7:142
PubMed   |  Link to Article
Andze GO, Brandt ML, St Vil D, Bensoussan AL, Blanchard H. Diagnosis and treatment of gastroesophageal reflux in 500 children with respiratory symptoms: the value of pH monitoring.  J Pediatr Surg. 1991;26(3):295-299, discussion 299-300
PubMed   |  Link to Article
El-Serag HB, Gilger M, Kuebeler M, Rabeneck L. Extraesophageal associations of gastroesophageal reflux disease in children without neurologic defects.  Gastroenterology. 2001;121(6):1294-1299
PubMed   |  Link to Article
Harding SM, Richter JE. The role of gastroesophageal reflux in chronic cough and asthma.  Chest. 1997;111(5):1389-1402
PubMed   |  Link to Article
Sheikh S, Stephen T, Howell L, Eid N. Gastroesophageal reflux in infants with wheezing.  Pediatr Pulmonol. 1999;28(3):181-186
PubMed   |  Link to Article
Sherman PM, Hassall E, Fagundes-Neto U,  et al.  A global, evidence-based consensus on the definition of gastroesophageal reflux disease in the pediatric population.  Am J Gastroenterol. 2009;104(5):1278-1295, quiz 1296
PubMed   |  Link to Article
Nelson SP, Kothari S, Wu EQ, Beaulieu N, McHale JM, Dabbous OH. Pediatric gastroesophageal reflux disease and acid-related conditions: trends in incidence of diagnosis and acid suppression therapy.  J Med Econ. 2009;12(4):348-355
PubMed   |  Link to Article
 Expert Panel Report 3: Guidelines for the Diagnosis and Management of AsthmaBethesda, MD: National Asthma Education and Prevention Program, National Heart, Lung, and Blood Institute; 2007. NIH publication 08-4051
Kiljander TO, Harding SM, Field SK,  et al.  Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial.  Am J Respir Crit Care Med. 2006;173(10):1091-1097
PubMed   |  Link to Article
Kiljander TO, Junghard O, Beckman O, Lind T. Effect of esomeprazole 40 mg once or twice daily on asthma: a randomized, placebo-controlled study.  Am J Respir Crit Care Med. 2010;181(10):1042-1048
PubMed   |  Link to Article
Mastronarde JG, Anthonisen NR, Castro M,  et al; American Lung Association Asthma Clinical Research Centers.  Efficacy of esomeprazole for treatment of poorly controlled asthma.  N Engl J Med. 2009;360(15):1487-1499
PubMed   |  Link to Article
Khoshoo V, Haydel R Jr. Effect of antireflux treatment on asthma exacerbations in nonatopic children.  J Pediatr Gastroenterol Nutr. 2007;44(3):331-335
PubMed   |  Link to Article
Juniper EF, Gruffydd-Jones K, Ward S, Svensson K. Asthma Control Questionnaire in children: validation, measurement properties, interpretation.  Eur Respir J. 2010;36(6):1410-1416
PubMed   |  Link to Article
Juniper EF, Bousquet J, Abetz L, Bateman ED.GOAL Committee.  Identifying “well-controlled” and “not well-controlled” asthma using the Asthma Control Questionnaire.  Respir Med. 2006;100(4):616-621
PubMed   |  Link to Article
Reddel HK, Taylor DR, Bateman ED,  et al.  An official American Thoracic Society/European Respiratory Society Statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.  Am J Respir Crit Care Med. 2009;180(1):59-99
PubMed   |  Link to Article
Revicki DA, Leidy NK, Brennan-Diemer F, Sorensen S, Togias A. Integrating patient preferences into health outcomes assessment: the multiattribute Asthma Symptom Utility Index.  Chest. 1998;114(4):998-1007
PubMed   |  Link to Article
Nathan RA, Sorkness CA, Kosinski M,  et al.  Development of the asthma control test: a survey for assessing asthma control.  J Allergy Clin Immunol. 2004;113(1):59-65
PubMed   |  Link to Article
Liu AH, Zeiger R, Sorkness C,  et al.  Development and cross-sectional validation of the Childhood Asthma Control Test.  J Allergy Clin Immunol. 2007;119(4):817-825
PubMed   |  Link to Article
Schatz M, Kosinski M, Yarlas AS, Hanlon J, Watson ME, Jhingran P. The minimally important difference of the Asthma Control Test.  J Allergy Clin Immunol. 2009;124(4):719-723, e1
PubMed   |  Link to Article
Juniper EF, Guyatt GH, Feeny DH, Ferrie PJ, Griffith LE, Townsend M. Measuring quality of life in children with asthma.  Qual Life Res. 1996;5(1):35-46
PubMed   |  Link to Article
Juniper EF, Guyatt GH, Feeny DH, Ferrie PJ, Griffith LE, Townsend M. Measuring quality of life in the parents of children with asthma.  Qual Life Res. 1996;5(1):27-34
PubMed   |  Link to Article
Crapo RO, Casaburi R, Coates AL,  et al.  Guidelines for methacholine and exercise challenge testing—1999.  Am J Respir Crit Care Med. 2000;161(1):309-329
PubMed   |  Link to Article
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population.  Am J Respir Crit Care Med. 1999;159(1):179-187
PubMed   |  Link to Article
Deal L, Gold BD, Gremse DA,  et al.  Age-specific questionnaires distinguish GERD symptom frequency and severity in infants and young children: development and initial validation.  J Pediatr Gastroenterol Nutr. 2005;41(2):178-185
PubMed   |  Link to Article
US Food and Drug Administration.  FDA drug safety communication: possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm. Accessed October 5, 2011
Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes.  Biometrics. 1986;42(1):121-130
PubMed   |  Link to Article
Keene ON, Jones MR, Lane PW, Anderson J. Analysis of exacerbation rates in asthma and chronic obstructive pulmonary disease: example from the TRISTAN study.  Pharm Stat. 2007;6(2):89-97
PubMed   |  Link to Article
Tolia V, Ferry G, Gunasekaran T, Huang B, Keith R, Book L. Efficacy of lansoprazole in the treatment of gastroesophageal reflux disease in children.  J Pediatr Gastroenterol Nutr. 2002;35:(suppl 4)  S308-S318
PubMed   |  Link to Article
Khoshoo V, Mohnot S, Haydel R Jr, Saturno E, Edell D, Kobernick A. Bronchial hyperreactivity in non-atopic children with asthma and reflux: effect of anti-reflux treatment.  Pediatr Pulmonol. 2009;44(11):1070-1074
PubMed   |  Link to Article
Størdal K, Johannesdottir GB, Bentsen BS,  et al.  Acid suppression does not change respiratory symptoms in children with asthma and gastro-oesophageal reflux disease.  Arch Dis Child. 2005;90(9):956-960
PubMed   |  Link to Article
Tolia V, Vandenplas Y. Systematic review: the extra-oesophageal symptoms of gastro-oesophageal reflux disease in children.  Aliment Pharmacol Ther. 2009;29(3):258-272
PubMed   |  Link to Article
Blondeau K, Mertens V, Dupont L,  et al.  The relationship between gastroesophageal reflux and cough in children with chronic unexplained cough using combined impedance-pH-manometry recordings.  Pediatr Pulmonol. 2010;46:286-294
PubMed   |  Link to Article
DiMango E, Holbrook JT, Simpson E,  et al; American Lung Association Asthma Clinical Research Centers.  Effects of asymptomatic proximal and distal gastroesophageal reflux on asthma severity.  Am J Respir Crit Care Med. 2009;180(9):809-816
PubMed   |  Link to Article
Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease.  J Pediatr. 2009;154(4):514-520, e4
PubMed   |  Link to Article
Meijvis SC, Cornips MC, Voorn GP,  et al.  Microbial evaluation of proton-pump inhibitors and the risk of pneumonia.  Eur Respir J. 2011;38(5):1165-1172
PubMed   |  Link to Article
Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis.  CMAJ. 2011;183(3):310-319
PubMed
Laheij RJ, Sturkenboom MC, Hassing RJ, Dieleman J, Stricker BH, Jansen JB. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs.  JAMA. 2004;292(16):1955-1960
PubMed   |  Link to Article
Canani RB, Cirillo P, Roggero P,  et al; Working Group on Intestinal Infections of the Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition.  Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children.  Pediatrics. 2006;117(5):e817-e820
PubMed   |  Link to Article
Ohara T, Arakawa T. Lansoprazole decreases peripheral blood monocytes and intercellular adhesion molecule-1-positive mononuclear cells.  Dig Dis Sci. 1999;44(8):1710-1715
PubMed   |  Link to Article
Yoshida N, Yoshikawa T, Tanaka Y,  et al.  A new mechanism for anti-inflammatory actions of proton pump inhibitors—inhibitory effects on neutrophil-endothelial cell interactions.  Aliment Pharmacol Ther. 2000;14:(suppl 1)  74-81
PubMed   |  Link to Article
Zedtwitz-Liebenstein K, Wenisch C, Patruta S, Parschalk B, Daxböck F, Graninger W. Omeprazole treatment diminishes intra- and extracellular neutrophil reactive oxygen production and bactericidal activity.  Crit Care Med. 2002;30(5):1118-1122
PubMed   |  Link to Article
Taylor AM. Pediatric focused safety review: proton pump inhibitors: esomeprazole, lansoprazole, omeprazole, rabeprazole. June 21, 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM216303.pdf. Accessed October 5, 2011
US Food and Drug Administration.  Transcripts of the June 21, 2010, meeting of the Pediatric Advisory Committee. June 21, 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM219336.pdf. Accessed October 5, 2011
US Food and Drug Administration.  Transcripts of the November 5, 2010, meeting of the Gastrointestinal Drugs Advisory Committee. November 5, 2010.http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM237495.pdf. Accessed October 5, 2011
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