Allen J. Dozor

Lansoprazole for children with poorly controlled asthma: a randomized controlled trial.

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.

The role of oxidative stress in the pathogenesis and treatment of asthma

The role of oxidative stress in asthma is gaining increasing scientific attention. The hallmark of asthma is airway inflammation. Oxidative stress may initiate and augment inflammation, and may also result from inflammation. Exposure to tobacco smoke, ozone, diesel exhaust, and a variety of other pollutants generates reactive oxygen species and other oxidative stressors. Some studies suggest that asthmatics have a decreased ability to respond to oxidative stress, while others find upregulated antioxidative function. Oxidative stress may alter the Th1/Th2 immune response and result in activation of NF‐kβ, a powerful inducer of pro‐inflammatory genes. Genetic polymorphisms may play an important role in determining susceptibility to oxidative stress. Many therapeutic strategies to decrease oxidative stress in asthma have been suggested. Dietary changes, antioxidant vitamins, other antioxidant drugs, Ayurvedic supplements, and even radon exposure in a hot bathroom have been studied. Minimizing exposure of young children to environmental tobacco smoke remains paramount.

Dietary Intake of Soy Genistein is Associated with Lung Function in Patients with Asthma

To determine if micronutrient intake is associated with asthma severity, we administered the Block food frequency questionnaire to participants in a randomized clinical trial of the safety of influenza vaccine for asthmatics. The nutrition substudy included 1033 participants, aged 12–75. Intake of antioxidant vitamins, soy isoflavones, total fruits and vegetables, fats, and fiber was compared with asthma severity at baseline [forced expiratory volume in 1 second (FEV1), peak expiratory flow rate (PEF), asthma symptoms] and the rate of asthma exacerbations during the 2 weeks following influenza vaccination. The only nutrient that had a consistent association with asthma severity was genistein, a soy isoflavone. None of the nutrients evaluated were related to asthma exacerbation rate when adjusted for known confounders. The FEV1 in genistein consumers of at least 250 µg/1000 Kcal/day was 82.1% predicted, 79.9% predicted for those who consumed between 1 and 249 µg/1000 kcal, and 76.2% predicted in genistein nonconsumers (p = 0.006); the PEF was 82.7% predicted, 80.8% predicted, and 78.3% predicted, respectively (p = 0.009). There were no differences in the Asthma Symptom Utility Index (ASUI). We could not account for these results based on differences in demographics, body mass index, or consumption of other nutrients. Thus, increasing consumption of genistein is associated with better lung function in patients with asthma. Further studies are needed to determine whether dietary supplementation with genistein can reduce asthma severity.

Staphylococcus aureus nasal colonization among pediatric cystic fibrosis patients and their household contacts.

Background: Little is known about the prevalence of Staphylococcus aureus nasal colonization and the epidemiology of methicillin-susceptible and methicillin-resistant S. aureus (MRSA) among cystic fibrosis (CF) patients and their household members. Objectives: We sought to determine the epidemiology of S. aureus among children and adolescents with CF and their household members. Methods: Three CF centers enrolled case subjects with at least 1 MRSA-positive respiratory tract culture from 2001 to 2006 and control subjects with MRSA-negative cultures. S. aureus isolates from the anterior nares of CF subjects and their household members were assessed for staphylococcal chromosomal cassette (SCC) mec type. Strain similarity was determined by pulsed-field gel electrophoresis. Results: S. aureus nasal colonization occurred in 52.4% (22/42), 27.0% (17/63), and 25.0% (72/288) of case, control, and household participants, respectively. Case subjects and their contacts were more likely to harbor MRSA in their nares and be from a multipatient CF family. Of 31 MRSA strains, 10 (32.3%) were SCCmec type IVa, associated with community-acquisition. Overall, 27.6% of 98 households had ≥2 members colonized with closely related isolates. Household members were equally likely to be colonized with closely related strains of MRSA (20/31, 65%) versus MSSA (38/80, 48%). Conclusions: This study demonstrated that household members of CF children harbor both MSSA and MRSA, including CA-MRSA, and that S. aureus is transmitted within CF households. Carriage of S. aureus by household members of CF children may have implications for infection control and treatment strategies. Future studies should monitor the distribution and virulence of SCCmecA types in patients with CF.

Lung Lesions in Children With Crohn's Disease Presenting as Nonresolving Pneumonias and Response to Infliximab Therapy

Lung lesions in children with Crohns disease are often difficult to diagnose and treat. We report here 3 children (aged 13, 14, and 17 years) on immunosuppressive therapy for previously diagnosed Crohns disease who presented with nonresolving pneumonias. All 3 had unfavorable response to empiric antibiotics and had progression of lesions. Cultures of sputum and blood did not yield any organisms. Subsequent lung biopsies revealed noncaseating granulomas with giant cells in 2 subjects and bronchiolitis obliterans with organizing pneumonia in the third. All patients were treated with infliximab, a novel anti–tumor necrosis factor monoclonal antibody, and showed rapid clinical and radiologic response. We emphasize that a high index of suspicion for noninfectious etiologies needs to be maintained in patients with Crohns disease who present with lung lesions to ensure timely intervention. Infliximab therapy seems to be effective and well tolerated in such patients.

Use of Decubitus Radiographs in the Diagnosis of Foreign Body Aspiration in Young Children

Background: Lateral decubitus radiographs are often obtained in young children with suspected foreign body aspiration. Their usefulness has not been well studied. Objectives: To assess the value of decubitus radiographs in detecting foreign body aspiration in young children and compare their value to history and physical examination. Methods: Retrospective review of children younger than 4 years with suspected foreign body aspiration who had decubitus radiographs and underwent bronchoscopy over a 5-year period. Patients with proven foreign body aspiration were compared with those without foreign bodies for differences in symptoms, signs, location and character of the foreign body, and the diagnostic value of standard and decubitus chest radiographs. Results: Twenty-eight of 41 children who underwent bronchoscopy for possible foreign body aspiration had decubitus radiographs. Foreign bodies were identified in 22 patients (79%). A total of 27% of children with foreign body aspiration and 33% of children without a foreign body had suggestive decubitus radiographs (P = not significant). As a measure of detecting foreign body aspiration, positive decubitus radiographs had a sensitivity of 27%, a specificity of 67%, a positive predictive value of 75%, and a negative predictive value of 20%. The odds ratio of finding a foreign body with suggestive decubitus radiographs was 0.75 (95% confidence interval [CI], 0.1-5.2; P = 0.57). Foreign body aspiration was confirmed in 94% of children if there was both a sudden onset of symptoms and a witnessed choking episode (odds ratio, 13.3; 95% confidence interval, 1.3-138.9; P = 0.02). Conclusion: Decubitus chest radiographs, at least as routinely performed and interpreted, seem to add little to the evaluation of young children with suspected foreign body aspiration. A history of a witnessed choking episode combined with a sudden onset of respiratory symptoms remains the most important indication for bronchoscopy.

Learning from a Distance: Effectiveness of Online Spirometry Training in Improving Asthma Care

OBJECTIVE We evaluated the effectiveness of a virtually delivered quality improvement (QI) program designed to improve primary care management for children with asthma. METHODS Thirty-six physicians, nurses, and medical assistants from 14 primary care pediatric practices (7 matched practice pairs) participated in a cluster randomized trial from October 2007 to September 2008. All practices received a spirometer and standard vendor training. A 7-month QI program delivered during the study period included: 1) Spirometry Fundamentals™ CD-ROM, a multimedia tutorial; 2) case-based, interactive webinars led by clinical experts; and 3) an internet-based spirometry quality feedback reporting system. Practice pairs were compared directly to each other, and between-group differences were analyzed with the use of mixed effects regression models. Our main outcome measures were the frequency of spirometry testing, percentage of acceptable quality spirometry tests, asthma severity documentation, and appropriate controller medication prescribing. RESULTS Participating practices uploaded a total of 1028 spirometry testing sessions, of which 340 (33.1%) were of acceptable quality. During the 7-month intervention period, there was no difference between intervention and control practices in the frequency of spirometry tests performed. Intervention practices were estimated to have significantly greater odds of conducting tests with acceptable quality compared with matched control practices, adjusting for quality in the baseline period (odds ratio 2.85; 95% confidence interval 1.78-4.56, P < .001). Intervention providers also had significantly greater odds of documenting asthma severity during the intervention period (odds ratio 2.9, 95% confidence interval 1.8-4.5; P < .001). Although use of controller medications among patients with persistent asthma approached 100% for both groups, the proportion of asthma patients labeled as persistent increased from 43% to 62% among intervention practices, and decreased from 57% to 50% among controls (NS). CONCLUSIONS A multifaceted distance QI program resulted in increased spirometry quality and improved assessment of asthma severity levels. Successful participation in QI programs can occur over distance.

Exhaled breath condensate pH and ammonia in cystic fibrosis and response to treatment of acute pulmonary exacerbations.

Exhaled breath condensate (EBC) pH reflects the acid–base homeostasis of the airway lining fluid and is up to 3 log order lower in various inflammatory lung diseases including asthma, COPD, bronchiectasis, and cystic fibrosis (CF) than in normal controls. The aim of this study was to confirm this finding in CF and determine if there was a significant change in EBC pH after treatment of an acute pulmonary exacerbation. Ten subjects with CF and a pulmonary exacerbation, and 10 healthy age‐matched control subjects were studied. EBC was collected at the onset of an acute pulmonary exacerbation and after treatment with intravenous antibiotics (median duration: 14 days (interquartile range, IQR): 12–14) when the exacerbation was considered resolved. The median age for CF patients was 15.9 years (IQR: 13–18.8), compared to 18 years (IQR: 15–24.8) for the control group, P = 0.242. All CF subjects had severe lung disease, median FEV1 = 41.5% of predicted (IQR: 30.8–46.5%). Median EBC pH in CF subjects at the onset of a pulmonary exacerbation was 6.61 (IQR: 6.17–7.91) compared to median EBC pH of 8.14 (IQR: 7.45–9.08) in the control group, P < 0.02. Median EBC pH after resolution of an exacerbation was 7.02 (IQR: 5.8–8.64), not significantly different (P = 0.667) than during the acute exacerbation. EBC pH decreased in five subjects, increased in three subjects and there was no change in two subjects. There was no correlation between EBC pH and FEV1 either before or after intravenous antibiotics. EBC ammonia, an important buffer of ASL, was also measured and similarly found to be lower than in normal controls. EBC pH is lower in CF than age‐matched controls, and did not change consistently in response to treatment of an acute pulmonary exacerbation. Pediatr Pulmonol. 2009; 44:866–872.

Relationship between exhaled nitric oxide and exposure to low-level environmental tobacco smoke in children with asthma on inhaled corticosteroids.

Objectives. The relationship between exhaled nitric oxide (FeNO) and asthma severity or control is inconsistent. Active smoking lowers FeNO, but the relationship between passive smoking and FeNO is less clear. Children may be exposed to low-level environmental tobacco smoke (ETS) or thirdhand smoke, even if parents avoid smoking in the presence of their children. Our hypothesis was that FeNO is lower in children with asthma exposed to low-level ETS when compared with those who are not exposed. Methods. Children with stable asthma, 8–18 years of age, on low- or medium-dose inhaled corticosteroids (ICS) were enrolled. Spirometry, Asthma Control Questionnaire (ACQ), FeNO, exhaled breath condensate pH (EBC pH), and EBC ammonia were compared between children with and without ETS exposure as determined by urinary cotinine. Results. Thirty-three subjects were enrolled, of which 10 (30%) had urinary cotinine levels ≥1 ng/ml. There were no significant differences between the two groups in age, sex, BMI percentile, atopy status, FEV1, EBC pH, or EBC ammonia. Median ACQ was 0.29 (IQR: 0.22–0.57) for those with cotinine levels <1 ng/ml and 0.64 (IQR: 0.57–1.1) for those with cotinine levels of ≥1 ng/ml, p = .02. Median FeNO (ppb) was 23.9 (IQR: 15.2–34.5) for unexposed subjects and 9.6 (IQR: 5.1–15.8) for exposed subjects, p = .008. Conclusions: Children with asthma on low to medium doses of ICS and recent low-level ETS exposure have lower FeNO levels when compared with non-ETS-exposed subjects. Exposure to low-level ETS or thirdhand smoke may be an important variable to consider when interpreting FeNO as a biomarker for airway inflammation.

Biologic Mechanisms of Environmental Tobacco Smoke in Children with Poorly Controlled Asthma: Results from a Multicenter Clinical Trial

BACKGROUND Environmental tobacco smoke (ETS) negatively affects children with asthma. The prevalence of ETS exposure among children with poor asthma control may be changing. Importantly, the mechanisms by which ETS worsens asthma control are poorly understood. OBJECTIVE We describe how ETS affects gastroesophageal reflux (GER), respiratory infections, and leukotriene production among children with poor asthma control. METHODS We analyzed data from 306 children between 6 and 17 years of age with poorly controlled asthma enrolled in a 6-month clinical trial. We evaluated prevalence and determinants of ETS exposure by interview, questionnaire, and urinary cotinine and the association of ETS exposure on leukotriene production, respiratory infections, GER, lung function, and asthma control. We used multivariable linear, logistic, and Poisson regressions to assess outcomes. RESULTS ETS prevalence estimates ranged from 6% to 30%. Children with domestic indoor exposure had worse asthma control (c-Asthma Control Test, 17.8 vs 21.5; P = .04), worse FEV1 % predicted (84.1 vs 90.7; P = .02), and a trend for increased mean urinary leukotriene E4. ETS from any setting was associated with increased symptomatic respiratory infections (adjusted incidence rate ratio: 1.30; P = .02). However, children exposed to ETS did not have symptoms or pH probe results, suggestive of heightened GER. CONCLUSIONS Domestic smoking exposure was associated with both higher rates of symptomatic respiratory infection and poorer asthma control despite generally intensive controller therapy. ETS exposure is common among asthmatic children with poor control and may worsen asthma control by promoting respiratory infections. Further investigation is required to elucidate ETS mechanisms in poor asthma control.