Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma.

BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).

Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma.

Asthma is a chronic lung disease that has a high prevalence. The therapeutic intervention of this disease can be made more effective if genetic variability in patients' response to medications is implemented. However, a clear picture of the genetic architecture of asthma intervention response remains elusive. We conducted a genome-wide association study (GWAS) to identify drug response-associated genes for asthma, in which 909 622 SNPs were genotyped for 120 randomized participants who inhaled multiple doses of glucocorticoids. By integrating pharmacodynamic properties of drug reactions, we implemented a mechanistic model to analyze the GWAS data, enhancing the scope of inference about the genetic architecture of asthma intervention. Our pharmacodynamic model observed associations of genome-wide significance between dose-dependent response to inhaled glucocorticoids (measured as %FEV1) and five loci (P=5.315 × 10(-7) to 3.924 × 10(-9)), many of which map to metabolic genes related to lung function and asthma risk. All significant SNPs detected indicate a recessive effect, at which the homozygotes for the mutant alleles drive variability in %FEV1. Significant associations were well replicated in three additional independent GWAS studies. Pooled together over these three trials, two SNPs, chr6 rs6924808 and chr11 rs1353649, display an increased significance level (P=6.661 × 10(-16) and 5.670 × 10(-11)). Our study reveals a general picture of pharmacogenomic control for asthma intervention. The results obtained help to tailor an optimal dose for individual patients to treat asthma based on their genetic makeup.

Impact of a novel nutritional formula on asthma control and biomarkers of allergic airway inflammation in children.

BACKGROUND: A novel nutritional formula (NNF) enriched in eicosapentaenoic (EPA) and gamma-linolenic fatty acids and antioxidants reduces airway inflammation and improves clinical outcomes in critically ill patients, but NNF has not been evaluated in chronic inflammatory diseases such as persistent asthma. OBJECTIVE: To evaluate the efficacy, compliance, and safety of NNF in asthmatic children. METHODS: Children, 6-14 years of age, with mild to moderate persistent asthma, on as needed albuterol alone, were randomized to receive daily NNF (n=23) or control formula (n=20) for 12 weeks, with multiple assessments of asthma control, spirometry, measures of airway inflammation, formula tolerance, and adverse events. RESULTS: Daily consumption of either NNF or a control formula showed improvement in asthma-free days over time (P=0.04) but there was no difference between groups. However, the NNF group had lower exhaled nitric oxide levels compared with the control group at weeks 4, 8, and 12 (P<0.05). An overall group difference in log FEV1 PC20 (P=0.05) was found in favour of the NNF group as well. Significantly higher levels of EPA in plasma (P<0.01) and peripheral blood mononuclear cell (PBMC) (P<0.01) phospholipids in the NNF group compared with control group within 2 weeks indicated good adherence with daily NNF intake. There were no differences in adverse events for NNF vs. control after 12 weeks. CONCLUSIONS: Both NNF and control groups demonstrated improvement in asthma-free days. NNF-treated group had reduced biomarkers of disease activity. Rapid PBMC fatty acid composition changes reflected an anti-inflammatory profile. Dietary supplementation with NNF was safe and well tolerated (ClinicalTrials.gov number NCT01087710).

A new perspective on concepts of asthma severity and control.

Concepts of asthma severity and control are important in the evaluation of patients and their response to treatment but the terminology is not standardised and the terms are often used interchangeably. This review, arising from the work of an American Thoracic Society/European Respiratory Society Task Force, identifies the need for separate concepts of control and severity, describes their evolution in asthma guidelines and provides a framework for understanding the relationship between current concepts of asthma phenotype, severity and control. "Asthma control" refers to the extent to which the manifestations of asthma have been reduced or removed by treatment. Its assessment should incorporate the dual components of current clinical control (e.g. symptoms, reliever use and lung function) and future risk (e.g. exacerbations and lung function decline). The most clinically useful concept of asthma severity is based on the intensity of treatment required to achieve good asthma control, i.e. severity is assessed during treatment. Severe asthma is defined as the requirement for (not necessarily just prescription or use of) high-intensity treatment. Asthma severity may be influenced by the underlying disease activity and by the patient's phenotype, both of which may be further described using pathological and physiological markers. These markers can also act as surrogate measures for future risk.

Predicting worsening asthma control following the common cold.

The asthmatic response to the common cold is highly variable, and early characteristics that predict worsening of asthma control following a cold have not been identified. In this prospective multicentric cohort study of 413 adult subjects with asthma, the mini-Asthma Control Questionnaire (mini-ACQ) was used to quantify changes in asthma control and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) to measure cold severity. Univariate and multivariable models were used to examine demographic, physiological, serological and cold-related characteristics for their relationship to changes in asthma control following a cold. Clinically significant worsening of asthma control was observed following a cold (mean+/-SD increase in mini-ACQ score of 0.69+/-0.93). Univariate analysis demonstrated that season, centre location, cold duration and cold severity measurements were all associated with a change in asthma control. Multivariable analysis of the covariates available within the first 2 days of cold onset revealed that the day 2 and cumulative sum of day 1 and 2 WURSS-21 scores were significant predictors of the subsequent changes in asthma control. In asthmatic subjects, cold severity within the first 2 days can be used to predict subsequent changes in asthma control. This information may help clinicians prevent deterioration in asthma control following a cold.

Pharmacokinetics of intranasal corticosteroids.

Topical administration of corticosteroids can reduce the total dose of corticosteroid required to treat the patient and minimize side effects. This logic has led to the development of intranasal corticosteroids (INCS) for allergic and perennial rhinitis. The second generation of these compounds includes beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. There is evidence that the INCS are effective in rhinitis; however, there is concern about the potential for these compounds to cause growth suppression. In one study, beclomethasone dipropionate significantly reduced growth in children; however, treatment of children with mometasone furoate nasal spray for 1 year showed no signs of growth suppression. It is evident that the differences among INCS lie in their pharmacokinetics. Structural differences among the various INCS influence their metabolism. The goal of INCS therapy is to have a high ratio of topical to systemic activity. The drug delivery device, absorption of the drug, and drug distribution all contribute to effective topical activity of an INCS. In addition, individual drug metabolism and elimination (half-life and drug clearance) also contribute to the therapeutic index of a drug. Overall, the second-generation INCS cause minimal systemic effects at recommended doses.

Challenges in assessing outcomes for pediatric asthma.

Although progress has been made in understanding asthma, much remains unknown; as a result, diagnosis and treatment are not optimal. Information is still needed about the natural history of asthma to better understand which patients are at risk of inflammation and at what point during their disease that inflammation occurs. In the case of children, a greater understanding of the disease's natural history is needed to establish criteria for early diagnosis and to evaluate progressive aspects of the disease so that appropriate measures of progression can be defined. The safety of various medications used as long-term controllers must also be evaluated. The growing information about medication effects on asthma provides unique opportunities to design studies that will guide improvement in asthma care. A number of disease outcomes can be used as surrogate markers of clinically significant endpoints, and a number of adverse effects may serve as surrogate markers. The consequences of poor control of pediatric asthma can be observed in a variety of clinical markers, including clinical features of the disease that worsen as it progresses, pulmonary function deterioration, lung hyperexpansion, and inflammation increases. The Childhood Asthma Management Program is an ongoing clinical trial designed to improve the diagnosis and treatment of asthma in children. Its hypothesis is that anti-inflammatory treatment of childhood asthma will not only relieve morbidity but will also improve lung growth.

Safety and reproducibility of sputum induction in asthmatic subjects in a multicenter study.

The safety of sputum induction and the reproducibility of measurements in induced sputum in multicenter studies is unknown. We examined the safety of sputum induction in a two-visit, six-center study in 79 subjects with moderate to severe asthma (mean +/- SD FEV(1) 71 +/- 12% predicted, 67% taking inhaled corticosteroids). In addition, we compared the reproducibility of markers of inflammation in induced sputum with the reproducibility of the FEV(1) and the methacholine PC(20). The FEV(1) decreased > or = 20% from the postbronchodilator baseline in 14% of all subjects and in 25% of subjects whose initial prebronchodilator baseline was 40 to 60% of predicted. All subjects responded promptly to additional albuterol treatment, and no subject developed refractory bronchoconstriction requiring treatment other than reversal of bronchospasm in the study laboratory. The reproducibility of measurements of the eosinophil percentage, eosinophil cationic protein, tryptase, and methacholine PC(20) were similar (concordance correlation coefficients of 0.74, 0.81, 0.79, and 0.74, respectively), without any significant among-center effect. We conclude that sputum induction can be performed safely in subjects with moderate to severe asthma in multicenter clinical trials when carried out under carefully monitored conditions. Importantly, we demonstrate that measurement of markers of inflammation in induced sputum is as reproducible as methacholine PC(20) and should prove useful in the assessment of airway inflammation in multicenter clinical trials.

Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial.

CONTEXT: Inhaled long-acting beta(2)-agonists improve asthma control when added to inhaled corticosteroid (ICS) therapy. OBJECTIVE: To determine whether ICS therapy can be reduced or eliminated in patients with persistent asthma after adding a long-acting beta(2)-agonist to their treatment regimen. DESIGN AND SETTING: A 24-week randomized, controlled, blinded, double-dummy, parallel-group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 through January 1999. PARTICIPANTS: One hundred seventy-five patients aged 12 through 65 years with persistent asthma that was suboptimally controlled during a 6-week run-in period of treatment with inhaled triamcinolone acetonide (400 microg twice per day). INTERVENTION: Patients continued triamcinolone therapy and were randomly assigned to receive add-on therapy with either placebo (placebo-minus group, n = 21) or salmeterol xinafoate, 42 microg twice per day (n = 154) for 2 weeks. The entire placebo-minus group was assigned and half of the salmeterol group (salmeterol-minus group) was randomly assigned to reduce by 50% (for 8 weeks) then eliminate (for 8 weeks) triamcinolone treatment. The other half of the salmeterol group (salmeterol-plus group) was randomly assigned to continue both salmeterol and triamcinolone for the remaining 16 weeks (active control group). MAIN OUTCOME MEASURE: Time to asthma treatment failure in patients receiving salmeterol. RESULTS: Treatment failure occurred in 8.3% (95% confidence interval [CI], 2%-15%) of the salmeterol-minus group 8 weeks after triamcinolone treatment was reduced compared with 2.8% (95% CI, 0%-7%) of the salmeterol-plus group during the same period. Treatment failure occurred in 46.3% (95% CI, 34%-59%) of the salmeterol-minus group 8 weeks after triamcinolone therapy was eliminated compared with 13.7% (95% CI, 5%-22%) of the salmeterol-plus group. The relative risk (95% CI) of treatment failure at the end of the triamcinolone elimination phase in the salmeterol-minus group was 4.3 (2.0-9.2) compared with the salmeterol-plus group (P<.001). CONCLUSIONS: Our results indicate that in patients with persistent asthma suboptimally controlled by triamcinolone therapy alone but whose asthma symptoms improve after addition of salmeterol, a substantial reduction (50%) in triamcinolone dose can occur without a significant loss of asthma control. However, total elimination of triamcinolone therapy results in a significant deterioration in asthma control and, therefore, cannot be recommended.

Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial.

CONTEXT: Long-acting beta(2)-agonists are prescribed for patients with persistent asthma and are sometimes used without inhaled corticosteroids (ICSs). No evidence exists, however, to support their use as monotherapy in adults with persistent asthma. OBJECTIVE: To examine the effectiveness of salmeterol xinafoate, a long-acting beta(2)-agonist, as replacement therapy in patients whose asthma is well controlled by low-dose triamcinolone acetonide, an ICS. DESIGN AND SETTING: A 28-week, randomized, blinded, placebo-controlled, parallel group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 to January 1999. PARTICIPANTS: One hundred sixty-four patients aged 12 through 65 years with persistent asthma that was well controlled during a 6-week run-in period of treatment with inhaled triamcinolone (400 microg twice per day). INTERVENTIONS: Patients were randomly assigned to continue triamcinolone therapy (400 microg twice per day; n = 54) or switch to salmeterol (42 microg twice per day; n = 54) or to placebo (n = 56) for 16 weeks, after which all patients received placebo for an additional 6-week run-out period. MAIN OUTCOME MEASURES: Change in morning and evening peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV(1)), self-assessed asthma symptom scores, rescue albuterol use, asthma-specific quality-of-life scores, treatment failure, asthma exacerbation, bronchial reactivity, and markers of airway inflammation, compared among the 3 treatment groups. RESULTS: During the 16-week randomized treatment period, no significant differences between the salmeterol and triamcinolone groups were observed for conventional outcomes of clinical studies of asthma therapy-morning PEF, evening PEF, asthma symptom scores, rescue albuterol sulfate use, or quality of life. Both active treatments were superior to placebo. However, the salmeterol group had more treatment failures than the triamcinolone group (13/54 [24%] vs 3/54 [6%]; P =.004), as well as more asthma exacerbations (11/54 [20%] vs 4/54 [7%]; P =.04), greater increases in median (interquartile range) sputum eosinophils (2.4% [0.0% to 10.6%] vs -0.1% [-0.7% to 0.3%]; P<.001), eosinophil cationic protein (71 [-2 to 430] U/L vs -4 [-31 to 56] U/L; P =.005), and tryptase (3.1 [2.1 to 7.6] ng/mL vs 0.0 [0.0 to 0.7] ng/mL; P<.001). The duration of benefit when patients were switched from active treatment to placebo after 22 weeks of randomized treatment was not significantly longer in the triamcinolone group than in the salmeterol group. CONCLUSIONS: Patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control.

Effect of polymorphism of the beta(2)-adrenergic receptor on response to regular use of albuterol in asthma.

BACKGROUND: Regular use of inhaled beta-adrenergic agonists may have adverse effects in some asthma patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect its regulation; however, results of smaller studies of the effects of such polymorphisms on response to beta-agonist therapy have been inconsistent. METHODS: We examined the possible effects of polymorphisms at codons 16 (beta(2)-AR-16) and 27 (beta(2)-AR-27) on response to albuterol by genotyping 190 asthmatics who had participated in a trial of regular versus as-needed albuterol use. RESULTS: During the 16-week treatment period, patients homozygous for arginine (Arg/Arg) at beta(2)-AR-16 who used albuterol regularly had a small decline in morning peak expiratory flow (AM PEF). This effect was magnified during a 4-week run-out period, when all patients returned to as-needed albuterol only. By the end of the study, Arg/Arg subjects who had used albuterol regularly had an AM PEF 30.5 +/- 12.1 liters/min lower (p = 0.012) than Arg/Arg patients who had used albuterol as needed only. Subjects homozygous for glycine at beta(2)-AR-16 showed no such decline. Evening PEF also declined in the Arg/Arg regular but not in as-need albuterol users. No significant differences between regular and as-needed treatment were associated with polymorphisms at beta(2)-AR-27. CONCLUSIONS: Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

The utility of peak flow, symptom scores, and beta-agonist use as outcome measures in asthma clinical research.

STUDY OBJECTIVES: Several methods of utilizing peak expiratory flow (PEF) and other markers of disease activity have been suggested as useful in the management of asthma. It remains unclear, however, as to which surrogate markers of disease status are discriminative indicators of treatment failure, suitable for use in clinical trials. DESIGN: We analyzed the operating characteristics of 66 surrogate markers of treatment failure using a receiver operating characteristic (ROC) curve analysis. PARTICIPANTS: Information regarding FEV(1), symptoms, beta(2)-agonist use, and PEF was available from 313 subjects previously enrolled in two Asthma Clinical Research Network trials, in which 71 treatment failures occurred (defined by a 20% fall in FEV(1) from baseline). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: None of the measures had an acceptable ability to discriminate subjects with a > or % fall in FEV(1) from those without, regardless of the duration of the period of analysis or the criteria for test positivity employed. Areas under the ROC curves generated ranged from 0.51 to 0.79, but none were statistically superior. Sensitivity and specificity combinations were generally poor at all cutoff values; true-positive rates could not be raised without unacceptably elevating false-positive rates concurrently. CONCLUSIONS: Studies that seek to detect treatment failure defined by a significant fall in FEV(1) should not use such individual surrogate measures to estimate disease severity.

A review of budesonide inhalation suspension in the treatment of pediatric asthma.

Asthma is recognized as an inflammatory disease, and inhaled corticosteroids are the mainstay of treatment in patients with persistent disease. Until recently, no inhaled corticosteroid was approved in the United States for children aged 4 years and younger, and no practical dosage form was available for infants and young children unable to use metered-dose inhalers effectively. Budesonide inhalation suspension (BIS) is a glucocorticoid with high topical and low systemic activity. In children aged 12 months-8 years, BIS improves asthma symptoms and lung function and decreases the need for breakthrough bronchodilators. Long-term follow-up studies in children concluded that BIS is well tolerated, with little or no effect on growth and hypothalamic-pituitary-adrenal axis function. Thus it is a valuable therapeutic alternative to systemic corticosteroid therapy in infants and young children.

Clarithromycin potentiates glucocorticoid responsiveness in patients with asthma: results of a pilot study.

BACKGROUND: Selected macrolide antibiotics have steroid-sparing effects in patients with steroid-dependent asthma. In addition to inhibiting methylprednisolone clearance, macrolides may also display anti-inflammatory effects. OBJECTIVE: To determine whether clarithromycin, by virtue of its anti-inflammatory effects, enhances glucocorticoid sensitivity. DESIGN: Open-label, pilot study in a paired design (pre- and posttreatment). PARTICIPANTS: Seven patients, mean age 27 (range 15 to 42 years), with mild to moderate asthma under good control. METHODS: Clarithromycin (500 mg) was administered twice daily for 10 days with blood drawn for lymphocyte stimulation assays at baseline, and again upon completion of therapy. Lymphocytes were stimulated with phytohemagglutinin in the presence and absence of increasing concentrations of clarithromycin and dexamethasone (DEX). RESULTS: At baseline, clarithromycin alone did not cause a significant degree of suppression of T-lymphocyte activation, yet clarithromycin significantly enhanced the sensitivity of lymphocytes to suppression by DEX as measured by a shift in the DEX dose-response curve by at least 6-fold (P = 0.04). In addition, a 10-day course of clarithromycin resulted in: 1) a significant decrease in the inhibitory concentration which results in a 50% reduction in proliferation for DEX alone, thereby increasing glucocorticoid sensitivity (P = 0.04); 2) heightened inhibitory effect of clarithromycin alone (P = 0.03); and 3) a sustained suppressive effect with the combination of clarithromycin and DEX on the inhibition of lymphocyte stimulation (P = 0.01). CONCLUSIONS: Clarithromycin acts synergistically with DEX in suppressing lymphocyte activation. In addition, a 10-day course resulted in a significant treatment effect as evidenced by lower inhibitory concentration which results in a 50% reduction in proliferation value for DEX, a heightened response to clarithromycin alone, and a consistent degree of suppression of lymphocyte stimulation when clarithromycin and DEX were used together.

Efficacy and safety overview of a new inhaled corticosteroid, QVAR (hydrofluoroalkane-beclomethasone extrafine inhalation aerosol), in asthma.

Chlorofluorocarbon (CFC)-containing inhalers are gradually being phased out and replaced with hydrofluoroalkane (HFA)-based alternatives. The reformulation provided the opportunity to improve the inhalation technology and physical characteristics of corticosteroid formulations. QVAR contains HFA-beclomethasone dipropionate (HFA-BDP) with the steroid in solution rather than suspension, which, in combination with improved inhaler technology, produces an extrafine aerosol with a mass median aerodynamic diameter of 1.1 microm (smaller than the 3.5-4.0 microm found with CFC-BDP). It was predicted and demonstrated that the smaller particle size of QVAR would be deposited in the lung to a greater extent than that found with CFC-BDP, particularly in the small airway, a major site of inflammation. Increased lung deposition of QVAR permits a reduction in dosage relative to CFC-BDP. Clinical evidence confirms that adult and elderly patients required approximately half the dose of QVAR to achieve the same degree of asthma control as with CFC-BDP. In long-term assessments, patients taking CFC-BDP could be switched to QVAR at half the daily dose without exacerbation of their asthma symptoms. QVAR was associated with a low overall incidence of side effects and, at the maximum recommended dose of 640 microg/d, caused no more adrenal suppression than 672 microg/d CFC-BDP.

The changing faces of asthma.

Over the last 20 years, the understanding of the pathogenesis of asthma has changed dramatically. Asthma is now seen as a disease of chronic airway inflammation. Consequently, the paradigm of management has expanded from "as-needed bronchodilators" to include maintenance therapy with antiinflammatory medications and action plans. Health care professionals are assessing medications as potential disease-modifying drugs. To do this, they must understand the natural history of asthma and identify the markers of the disease that reflect long-term outcomes. This article reviews the way in which the concept of asthma has changed, the impact of this new knowledge on the basis of medication selection, and the options for evaluating the effect of medications on long-term outcomes. Reevaluating information will continue to expand our horizon of methods to improve asthma management.

Asthma: the new advances.

There has been significant interest in halting and even reversing the trend of increasing asthma mortality and morbidity. One strategy is to recognize persistent asthma within the first few years of onset and to intervene early with anti-inflammatory therapy. This review summarizes the new information available on asthma pathogenesis that has helped to shape a change in direction of viewing asthma as an episodic disease to one that is chronic in nature. At the root of this change is the recognition that asthma is a chronic inflammatory disease of the airways. Inhaled steroids are recognized as the most potent anti-inflammatory medication available, and they are now profiled as the cornerstone in the management of chronic persistent asthma. This dramatic change in direction has significant implications for the primary care physician, especially the pediatrician, who is most likely to see asthma in its early stages. Recent interest has been directed toward defining a "window of opportunity" for intervention that could significantly affect the course of the disease. Although this may be an exciting opportunity to control the development of asthma, one has to be cognizant of potential risk of early and long-term therapeutic intervention. This review provides a perspective on our present knowledge and the rationale for early intervention, as well as speculates about how this new information will continue to play a role in advancing asthma care and moving toward a "cure" of this disease.

The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma.

Inhaled beta-adrenergic agonists are the most commonly used medications for the treatment of asthma although there is evidence that regular use may produce adverse effects in some patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect regulation of the receptor. Smaller studies examining the effects of such polymorphisms on the response to beta-agonist therapy have produced inconsistent results. We examined whether polymorphisms at codon 16 (beta(2)-AR-16) and codon 27 (beta(2)-AR-27) of the beta(2)-AR might affect the response to regular versus as-needed use of albuterol by genotyping the 190 asthmatics who had participated in a trial examining the effects of regular versus as needed albuterol use. During the 16-wk treatment period there was a small decline in morning peak expiratory flow in patients homozygous for arginine at B(2)-AR-16 (Arg/Arg) who used albuterol regularly. This effect was magnified during a 4-wk run out period, during which all patients returned to using as-needed albuterol, so that by the end of the study Arg Arg patients who had regularly used albuterol had a morning peak expiratory flow 30. 5 +/- 12.1 L/min lower (p = 0.012) than Arg/Arg patients who had used albuterol on an as needed basis. There was no decline in peak flow with regular use of albuterol in patients who were homozygous for glycine at beta(2)-AR-16. Evening peak expiratory flow also declined in the Arg/Arg patients who used albuterol regularly but not in those who used albuterol on an as-needed basis. No significant differences in outcomes between regular and as-needed treatment were associated with polymorphisms at position 27 of the beta(2)-AR. No other differences in asthma outcomes that we investigated occurred in relation to these beta(2)-AR polymorphisms. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

Longitudinal growth in infants and young children treated with budesonide inhalation suspension for persistent asthma.

BACKGROUND: Results of recent growth studies suggest that inhaled glucocorticosteroids may affect growth in children. OBJECTIVE: Three 52-week, open-label extension studies (studies A, B, and C) were conducted to compare the effects of budesonide inhalation suspension (BIS) with conventional asthma therapy (CAT) on long-term safety, including intermediate-term growth, in 3 different pediatric asthma populations. METHODS: Pediatric asthma patients (ages 6 months to 8 years) from 3 multicenter, randomized, 12-week, double-blind, placebo-controlled studies were eligible to enroll in the 52-week, open-label extension studies. The extension studies were multicenter, randomized, open-label, active-controlled, parallel-group studies performed at 26 centers in the United States. Subjects in each extension study were randomized in a 2:1 ratio to receive either BIS or CAT. BIS was initially administered at a dose of 0.5 mg once (studies A and C) or twice daily (study B), with attempts made at each clinical visit to gradually reduce the dose to the minimum effective dose that maintains asthma control, as judged by the investigator. CAT consisted of any available therapy for asthma, including inhaled glucocorticosteroids in studies B and C only. Height SD scores, growth velocity, and skeletal age (only in studies B and C) were examined. RESULTS: In total, 670 subjects were randomized; 223 subjects received CAT and 447 received BIS. Mean ages at entry were 63.0 months and 60.9 months in CAT and BIS groups, respectively. Median total daily doses of BIS ranged from 0.5 to 1. 0 mg and the mean duration of treatment exposure was 304 +/- 119 days and 342 +/- 83 days in CAT and BIS groups, respectively. Changes in height SD scores differed significantly between the BIS and CAT groups in study A (-0.19, P =.003), and there was a small, statistically significant decrease in growth velocity (-0.8 cm/y, P =.002) in the BIS-treated group compared with the CAT group. No significant differences were observed between BIS and CAT groups in the changes in height SD scores or in growth velocities in studies B (+0.10 and +0.7 cm/y, respectively) and C (+0.12 and +0.8 cm/y, respectively). No differences in skeletal age were observed between BIS and CAT groups in studies B and C. CONCLUSION: There was a small, statistically significant decrease in growth velocity in the BIS-treated group compared with the CAT group in the study (study A) where inhaled glucocorticosteroid use was prohibited before entry and in the CAT group during the study. In the studies (B and C) where inhaled glucocorticosteroids were allowed in the CAT group, no differences were observed in height SD scores or growth velocity. The clinical relevance of these effects, including impact on final adult height, remain to be determined in prospectively planned studies that assess growth in children.

The relationships among environmental allergen sensitization, allergen exposure, pulmonary function, and bronchial hyperresponsiveness in the Childhood Asthma Management Program.

BACKGROUND: Sensitivity and exposure to indoor allergens constitutes a risk factor for the development and persistence of asthma in children. OBJECTIVE: Our purpose was to evaluate the relationship between sensitivity and exposure to inhalant allergens and lung function and bronchial responsiveness in a group of children (n = 1041) aged 8.9 +/- 2.1 years with mild to moderate asthma enrolled in the Childhood Asthma Management Program (CAMP). METHODS: With use of the extensive CAMP baseline cross-sectional data on spirometry, bronchial responsiveness, allergen sensitivities, and household allergen levels, the relationship of sensitization and exposure to allergens to lung function and methacholine sensitivity was evaluated. Children who enrolled in CAMP stopped all antiasthma medication except rescue use of albuterol and prednisone for exacerbations during the 5- to 16-week screening period. During the last 2 of these weeks they underwent spirometry and methacholine challenge. Indoor allergen exposures were determined from questionnaires completed by the parent. Household levels of indoor allergens (mite, cat, dog, cockroach, mold) were determined on house dust samples. Allergen sensitivity was determined by percutaneous skin testing with a standard battery of allergens plus locally important pollen and fungal spores. Lung function and bronchial hyperresponsiveness were compared for children sensitive and not sensitive to both indoor and outdoor allergens on skin testing and, if sensitive, for exposed and not exposed to the allergens to which they were positive on skin testing. RESULTS: There was a strong direct correlation between increased sensitivity to inhaled methacholine and skin test sensitivity to tree, weed, Alternaria, cat, dog, and indoor molds. When the relationship was examined by stepwise regression, the skin test sensitivities showing the strongest associations with the concentration of methacholine that caused a 20% fall in FEV(1) were dog (P =.003), Alternaria (P =.01), and cat (P =.05). Children sensitive to any one of the aeroallergens tested were compared for the presence or absence of exposure to that allergen at the time that the methacholine challenge was performed. Those who were sensitive and exposed to weed and cat had greater methacholine sensitivity than those similarly sensitive but not exposed (P =.003 and P =.02, respectively). CONCLUSIONS: Sensitivity to dog or cat dander or Alternaria by skin testing was associated with increased bronchial responsiveness but not decreased lung function in children with mild to moderate asthma. These findings support the important role that sensitization to certain allergens plays in modulating bronchial responsiveness.