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Robert S Zeiger,
David Mauger,
Leonard B Bacharier,
Theresa W Guilbert,
Fernando D Martinez,
Robert F Lemanske,
Robert C Strunk,
Ronina Covar,
Stanley J Szefler,
Susan Boehmer, [......],
Noah J Friedman,
Michael H Mellon,
Michael Schatz,
Wayne J Morgan,
Vernon M Chinchilli,
Hengameh H Raissy,
Elizabeth Bade,
Jonathan Malka-Rais,
Avraham Beigelman, Lynn M Taussig
[show abstract]
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ABSTRACT: Daily inhaled glucocorticoids are recommended for young children at risk for asthma exacerbations, as indicated by a positive value on the modified asthma predictive index (API) and an exacerbation in the preceding year, but concern remains about daily adherence and effects on growth. We compared daily therapy with intermittent therapy.
We studied 278 children between the ages of 12 and 53 months who had positive values on the modified API, recurrent wheezing episodes, and at least one exacerbation in the previous year but a low degree of impairment. Children were randomly assigned to receive a budesonide inhalation suspension for 1 year as either an intermittent high-dose regimen (1 mg twice daily for 7 days, starting early during a predefined respiratory tract illness) or a daily low-dose regimen (0.5 mg nightly) with corresponding placebos. The primary outcome was the frequency of exacerbations requiring oral glucocorticoid therapy.
The daily regimen of budesonide did not differ significantly from the intermittent regimen with respect to the frequency of exacerbations, with a rate per patient-year for the daily regimen of 0.97 (95% confidence interval [CI], 0.76 to 1.22) versus a rate of 0.95 (95% CI, 0.75 to 1.20) for the intermittent regimen (relative rate in the intermittent-regimen group, 0.99; 95% CI, 0.71 to 1.35; P=0.60). There were also no significant between-group differences in several other measures of asthma severity, including the time to the first exacerbation, or adverse events. The mean exposure to budesonide was 104 mg less with the intermittent regimen than with the daily regimen.
A daily low-dose regimen of budesonide was not superior to an intermittent high-dose regimen in reducing asthma exacerbations. Daily administration led to greater exposure to the drug at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; MIST ClinicalTrials.gov number, NCT00675584.).
New England Journal of Medicine 11/2011; 365(21):1990-2001. · 53.30 Impact Factor
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ABSTRACT: Although nocturnal awakenings help categorize asthma severity and control, their clinical significance has not been thoroughly studied.
We sought to determine the clinical consequences of nocturnal asthma symptoms requiring albuterol (NASRAs) in children with mild-to-moderate persistent asthma outside of periods when oral corticosteroids were used for worsening asthma symptoms.
Two hundred eighty-five children aged 6 to 14 years with mild-to-moderate persistent asthma were randomized to receive one of 3 controller regimens and completed daily symptom diaries for 48 weeks. Diary responses were analyzed for the frequency and consequences of NASRAs.
NASRAs occurred in 72.2% of participants at least once, and in 24.3% of participants, they occurred 13 or more times. The majority (81.3%) of nocturnal symptoms occurred outside of exacerbation periods and were associated the next day with the following events: albuterol use (56.9% of days preceded by nocturnal symptoms vs 18.1% of days not preceded by nocturnal symptoms; relative risk [RR], 2.3; 95% CI, 2.2-2.4), school absence (5.0% vs 0.3%; RR, 10.6; 95% CI, 7.8-14.4), and doctor contact (3.7% vs 0.2%; RR, 8.8; 95% CI, 6.1-12.5). Similar findings were noted during exacerbation periods (RRs of 1.7 for albuterol use, 5.5 for school absence, and 4.9 for doctor contacts). Nocturnal symptoms did not predict the onset of exacerbations.
Nocturnal symptoms requiring albuterol in children with mild-to-moderate persistent asthma receiving controller therapy occurred predominantly outside of exacerbation periods. Despite being poor predictors of exacerbations, they were associated with increases in albuterol use, school absences, and doctor contacts the day after nocturnal symptom occurrences.
The Journal of allergy and clinical immunology 08/2011; 128(5):977-82.e1-2. · 9.17 Impact Factor
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Theresa W Guilbert,
David T Mauger,
David B Allen,
Robert S Zeiger,
Robert F Lemanske,
Stanley J Szefler,
Robert C Strunk,
Leonard B Bacharier,
Ronina Covar,
Christine A Sorkness, Lynn M Taussig,
Fernando D Martinez
[show abstract]
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ABSTRACT: The effect on linear growth of daily long-term inhaled corticosteroid therapy in preschool-aged children with recurrent wheezing is controversial.
We sought to determine the effect of daily inhaled corticosteroid given for 2 years on linear growth in preschool children with recurrent wheezing.
Children aged 2 and 3 years with recurrent wheezing and positive modified Asthma Predictive Index scores were randomized to a 2-year treatment period of chlorofluorocarbon-delivered fluticasone propionate (176 μg/d) or masked placebo delivered through a valved chamber with a mask and then followed for 2 years off study medication. Height growth determined by means of stadiometry was compared between treatment groups.
In the study cohort as a whole, the fluticasone group did not have significantly less linear growth than the placebo group (change in height from baseline difference, -0.2 cm; 95% CI, -1.1 to 0.6) 2 years after discontinuation of study treatment. In post hoc analyses children 2 years old who weighed less than 15 kg at enrollment and were treated with fluticasone had less linear growth compared with those treated with placebo (change in height from baseline difference, -1.6 cm; 95% CI, -2.8 to -0.4; P = .009).
Linear growth was not significantly different in high-risk preschool-aged children with recurrent wheezing treated with 176 μg/d chlorofluorocarbon-delivered fluticasone compared with placebo 2 years after fluticasone is discontinued. However, post hoc subgroup analyses revealed that children who are younger in age and of lesser weight relative to the entire study cohort had significantly less linear growth, possibly because of a higher relative fluticasone exposure.
The Journal of allergy and clinical immunology 08/2011; 128(5):956-63.e1-7. · 9.17 Impact Factor
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Li Wang,
Christopher S Hollenbeak,
David T Mauger,
Robert S Zeiger,
Ian M Paul,
Christine A Sorkness,
Robert F Lemanske,
Fernando D Martinez,
Robert C Strunk,
Stanley J Szefler, Lynn M Taussig
[show abstract]
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ABSTRACT: Cost-effectiveness analyses of asthma controller regimens for adults exist, but similar evaluations exclusively for children are few.
We sought to compare the cost-effectiveness of 2 commonly used asthma controllers, fluticasone and montelukast, with data from the Pediatric Asthma Controller Trial.
We compared the cost-effectiveness of low-dose fluticasone with that of montelukast in a randomized, controlled, multicenter clinical trial in children with mild-to-moderate persistent asthma. Analyses were also conducted on subgroups based on phenotypic factors. Effectiveness measures included (1) the number of asthma-control days, (2) the percentage of participants with an increase over baseline of FEV(1) of 12% or greater, and (3) the number of exacerbations avoided. Costs were analyzed from both a US health care payer's perspective and a societal perspective.
For all cost-effectiveness measures studied, fluticasone cost less and was more effective than montelukast. For example, fluticasone treatment cost $430 less in mean direct cost (P < .01) and resulted in 40 more asthma-control days (P < .01) during the 48-week study period. Considering sampling uncertainty, fluticasone cost less and was more effective at least 95% of the time. For the high exhaled nitric oxide (eNO) phenotypic subgroup (eNO ≥25 ppb) and more responsive PC(20) subgroup (PC(20) <2 mg/mL), fluticasone was cost-effective compared with montelukast for all cost-effectiveness measures, whereas not all the effectiveness measures were statistically different for the other 2 phenotypic subgroups.
For children with mild-to-moderate persistent asthma, low-dose fluticasone had lower cost and higher effectiveness compared with montelukast, especially in those with more airway inflammation, as indicated by increased levels of eNO and more responsivity to methacholine.
The Journal of allergy and clinical immunology 01/2011; 127(1):161-6, 166.e1. · 9.17 Impact Factor
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Robert F Lemanske,
David T Mauger,
Christine A Sorkness,
Daniel J Jackson,
Susan J Boehmer,
Fernando D Martinez,
Robert C Strunk,
Stanley J Szefler,
Robert S Zeiger,
Leonard B Bacharier,
Ronina A Covar,
Theresa W Guilbert,
Gary Larsen,
Wayne J Morgan,
Mark H Moss,
Joseph D Spahn, Lynn M Taussig
[show abstract]
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ABSTRACT: For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking.
We randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 microg of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 microg of fluticasone twice daily (ICS step-up), 100 microg of fluticasone plus 50 microg of a long-acting beta-agonist twice daily (LABA step-up), or 100 microg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%.
A differential response occurred in 161 of 165 patients who were evaluated (P<0.001). The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up (relative probability, 1.6; 95% confidence interval [CI], 1.1 to 2.3; P=0.004) and ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P=0.002). Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step-up (P=0.009). White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up (P=0.005).
Nearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child's asthma therapy. (ClinicalTrials.gov number, NCT00395304.)
New England Journal of Medicine 03/2010; 362(11):975-85. · 53.30 Impact Factor
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Ian M. Paul,
Lindsay Camera,
Robert S. Zeiger,
Theresa W. Guilbert,
Leonard B. Bacharier, Lynn M. Taussig,
Wayne J. Morgan,
Ronina A. Covar,
Marzena Krawiec,
Gordon R. Bloomberg,
David T. Mauger,
for the Childhood Asthma Research and Education (CARE) Network
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ABSTRACT: Paul IM, Camera L, Zeiger RS, Guilbert TW, Bacharier LB, Taussig LM, Morgan WJ, Covar RA, Krawiec M, Bloomberg GR, Mauger DT, for the Childhood Asthma Research and Education (CARE) Network. Relationship between infant weight gain and later asthma. Pediatr Allergy Immunol 2010: 21: 82–89. © 2009 John Wiley & Sons A/SLike obesity, the prevalence of asthma has increased over the past several decades. Accelerated patterns of infant growth have been associated with obesity and its co-morbidities. We aimed to determine if infant weight gain pattern is associated with asthma development later in childhood. Birth weight, growth, pulmonary function, and symptom data were collected in a trial of 2- to 3-yr-old children at-risk for asthma randomized to a 2-yr treatment with inhaled corticosteroids or placebo followed by a 1-yr observation period of study medication. Patterns of infant weight gain between birth and study enrollment were categorized as accelerated, average, or decelerated. Regression analyses were used to test the effects of infant weight gain pattern prior to study enrollment on outcomes during the observation year and at study conclusion while adjusting for demographics, baseline symptom severity, study treatment, and atopic indicators. Among the 197 study participants, early life weight gain pattern was not associated with daily asthma symptoms or lung function at the study’s conclusion. However, both prednisone courses (p = 0.01) and urgent physician visits (p < 0.001) were significantly associated with weight gain pattern with fewer exacerbations occurring amongst those with a decelerated weight gain pattern. We conclude that early life patterns of weight change were associated with subsequent asthma exacerbations, but were not associated with asthma symptoms or pulmonary function during the pre-school years for these children at-risk for asthma.
Pediatric Allergy and Immunology 08/2009; 21(1‐Part‐I):82 - 89. · 2.46 Impact Factor
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ABSTRACT: The fractional concentration of exhaled nitric oxide (FeNO) is a noninvasive marker for airway inflammation but requires further study in preschool-aged children to determine its clinical relevance.
To determine whether the risk of respiratory tract illnesses (RTIs), disease burden, and atopic features are related to FeNO in preschool-aged children with moderate-to-severe intermittent wheezing.
We determined FeNO using the off-line tidal breathing technique in 89 children, aged 12 to 59 months, with moderate-to-severe intermittent wheezing. The risk of RTI was determined by comparing participants with a baseline FeNO of greater than the 75th percentile (24.4 ppb) with those with a baseline FeNO at the 75th percentile or lower using Cox regression analysis.
The risk of RTI was significantly higher in children with an FeNO of greater than 24.4 ppb relative to those with lower FeNO values (adjusted relative risk, 3.80; 95% confidence interval, 1.74-8.22; P < .001). FeNO levels of greater than 24.4 ppb were associated with more positive skin test results to aeroallergens (P = .03) but not with other atopic characteristics or historic parameters of illness burden.
An elevated FeNO in preschool-aged children with moderate-to-severe intermittent wheezing was associated with an increased risk of RTI during a 1-year follow-up. In addition, a higher FeNO was associated with aeroallergen sensitization.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 08/2009; 103(2):108-13. · 2.83 Impact Factor
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Ian M Paul,
Lindsay Camera,
Robert S Zeiger,
Theresa W Guilbert,
Leonard B Bacharier, Lynn M Taussig,
Wayne J Morgan,
Ronina A Covar,
Marzena Krawiec,
Gordon R Bloomberg,
David T Mauger
[show abstract]
[hide abstract]
ABSTRACT: Like obesity, the prevalence of asthma has increased over the past several decades. Accelerated patterns of infant growth have been associated with obesity and its co-morbidities. We aimed to determine if infant weight gain pattern is associated with asthma development later in childhood. Birth weight, growth, pulmonary function, and symptom data were collected in a trial of 2- to 3-yr-old children at-risk for asthma randomized to a 2-yr treatment with inhaled corticosteroids or placebo followed by a 1-yr observation period of study medication. Patterns of infant weight gain between birth and study enrollment were categorized as accelerated, average, or decelerated. Regression analyses were used to test the effects of infant weight gain pattern prior to study enrollment on outcomes during the observation year and at study conclusion while adjusting for demographics, baseline symptom severity, study treatment, and atopic indicators. Among the 197 study participants, early life weight gain pattern was not associated with daily asthma symptoms or lung function at the study's conclusion. However, both prednisone courses (p = 0.01) and urgent physician visits (p < 0.001) were significantly associated with weight gain pattern with fewer exacerbations occurring amongst those with a decelerated weight gain pattern. We conclude that early life patterns of weight change were associated with subsequent asthma exacerbations, but were not associated with asthma symptoms or pulmonary function during the pre-school years for these children at-risk for asthma.
Pediatric Allergy and Immunology 08/2009; 21(1 Pt 1):82-9. · 2.46 Impact Factor
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ABSTRACT: To examine parent-reported signs and symptoms as antecedents of wheezing in preschool children with previous moderate to severe wheezing episodes, and to determine the predictive capacity of these symptom patterns for wheezing events.
Parents (n = 238) of children age 12 to 59 months with moderate-to-severe intermittent wheezing enrolled in a year-long clinical trial completed surveys that captured signs and symptoms at the start of a respiratory tract illness (RTI). Sensitivity, specificity, negative predictive value, and positive predictive value (PPV) for each symptom leading to wheezing during that RTI were calculated.
The most commonly reported first symptom categories during the first RTI were "nose symptoms" (41%), "significant cough" (29%), and "insignificant cough" (13%). The most reliable predictor of subsequent wheezing was significant cough, which had a specificity of 78% and a PPV of 74% for predicting wheezing.
Significant cough is the most reliable antecedent of wheezing during an RTI. It may be useful to consider individualized symptom patterns as a component of management plans intended to minimize wheezing episodes.
The Journal of pediatrics 04/2009; 154(6):877-81.e4. · 4.02 Impact Factor
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Leonard B Bacharier,
Theresa W Guilbert,
Robert S Zeiger,
Robert C Strunk,
Wayne J Morgan,
Robert F Lemanske,
Mark Moss,
Stanley J Szefler,
Marzena Krawiec,
Susan Boehmer,
David Mauger, Lynn M Taussig,
Fernando D Martinez
[show abstract]
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ABSTRACT: Maintenance inhaled corticosteroid (ICS) therapy in preschool children with recurrent wheezing at high-risk for development of asthma produces multiple clinical benefits. However, determination of baseline features associated with ICS responsiveness may identify children most likely to benefit from ICS treatment.
To determine if demographic and atopic features predict response to ICS in preschool children at high risk for asthma.
Two years of treatment with an ICS, fluticasone propionate (88 microg twice daily), was compared with matching placebo in a double-masked, randomized, multicenter study of 285 children 2 and 3 years old at high risk for asthma development. Baseline demographic and atopic features were related to clinical outcomes in a post hoc subgroup analysis.
Multivariate analysis demonstrated significantly greater improvement with fluticasone than placebo in terms of episode-free days among boys, white subjects, participants with an emergency department (ED) visit or hospitalization within the past year, and those who experienced more symptomatic days at baseline. Children with aeroallergen sensitization experienced greater benefits in terms of oral corticosteroid use, urgent care and ED visits, and use of supplemental controller medications.
More favorable responses to ICS than placebo in high-risk preschool children over a 2-year period were more likely in those with a ED visit or hospitalization for asthma within the past year, children with aeroallergen sensitization, boys, and white subjects.
The Journal of allergy and clinical immunology 03/2009; 123(5):1077-82, 1082.e1-5. · 9.17 Impact Factor
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Jason E Knuffman,
Christine A Sorkness,
Robert F Lemanske,
David T Mauger,
Susan J Boehmer,
Fernando D Martinez,
Leonard B Bacharier,
Robert C Strunk,
Stanley J Szefler,
Robert S Zeiger, Lynn M Taussig
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ABSTRACT: In children with mild-to-moderate persistent asthma, identification of phenotypic predictors to guide selection of a controller regimen is essential.
We sought to identify phenotypic characteristics having predictive value for the difference in treatment responses between twice-daily fluticasone and once-daily montelukast.
Data from the Pediatric Asthma Controller Trial were assessed with multivariate analysis. Outcomes included the change in asthma control days (ACDs), FEV(1), peak expiratory flow, and time to first asthma exacerbation measured over a 1-year treatment period.
The mean age was 9.6 +/- 2.1 years, 60% were male, 50% had a parental history of asthma, and 78% had positive aeroallergen skin prick test responses. The mean percent predicted prebronchodilator FEV(1) was 97.8% +/- 12.9%, the median PC(20) value was 0.93 mg/mL, and the median exhaled nitric oxide (eNO) level was 25.2 ppb. A history of parental asthma best predicted the expected treatment benefit with fluticasone compared with montelukast in terms of gain in ACDs (adjusted P = .02) and time to first exacerbation (adjusted P = .05). Increased baseline eNO levels predicted the differential treatment response for fluticasone regarding the gain in ACDs (adjusted P = .01). Prior inhaled corticosteroid (ICS) use (adjusted P = .01) and low PC(20) values (adjusted P = .03) each predicted the expected treatment benefit with fluticasone over montelukast regarding time to first exacerbation. No phenotypic characteristics predicted treatment benefits for montelukast over fluticasone for either outcome.
Physicians treating children with a parental history of asthma, increased eNO levels, low PC(20) values, or a history of ICS use can expect the best long-term outcomes with ICS therapy compared with treatment with leukotriene receptor antagonists.
The Journal of allergy and clinical immunology 02/2009; 123(2):411-6. · 9.17 Impact Factor
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Gary L Larsen,
Wayne Morgan,
Gregory P Heldt,
David T Mauger,
Susan J Boehmer,
Vernon M Chinchilli,
Robert F Lemanske,
Fernando Martinez,
Robert C Strunk,
Stanley J Szefler,
Robert S Zeiger, Lynn M Taussig,
Leonard B Bacharier,
Theresa W Guilbert,
Shelley Radford,
Christine A Sorkness
[show abstract]
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ABSTRACT: Determination of the benefits and limitations of specific physiologic tests has not been well studied in long-term clinical pediatric trials.
We sought to determine the utility of impulse oscillometry in a long-term comparison of 3 controller regimens in children with persistent asthma.
Children 6 to 14 years of age with mild-to-moderate persistent asthma were characterized with oscillometry and spirometry before entry into a clinical trial and then serially during 48 weeks of therapy with either an inhaled corticosteroid, a combination inhaled corticosteroid with a long-acting beta-agonist, or a leukotriene receptor antagonist.
The FEV(1)/forced vital capacity ratio, as well as the forced expiratory flow from 25% to 75% of forced vital capacity in terms of spirometric parameters and the reactance area (XA) from impulse oscillometry, appeared to complement information provided by FEV(1) when comparing the tests and factors that appeared to predict a response to treatment. XA was unique in that it, as distinct from spirometric variables, reflected ongoing improvement during the latter part of the trial. In general, improvements in XA during the latter part of the study occurred independently of indices of atopy and the level of airway responsiveness.
Assessment of respiratory mechanics over time with oscillometry might offer additional insights into the response of asthmatic patients to therapy. In particular, the pattern of improvement seen in XA over the course of therapy suggests this test might detect alterations in airway mechanics not reflected by spirometry. The possibility that changes in XA reflect ongoing improvement in small airway function deserves additional study.
The Journal of allergy and clinical immunology 01/2009; 123(4):861-7.e1. · 9.17 Impact Factor
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Leonard B Bacharier,
Brenda R Phillips,
Robert S Zeiger,
Stanley J Szefler,
Fernando D Martinez,
Robert F Lemanske,
Christine A Sorkness,
Gordon R Bloomberg,
Wayne J Morgan,
Ian M Paul,
Theresa Guilbert,
Marzena Krawiec,
Ronina Covar,
Gary Larsen,
Michael Mellon,
Mark H Moss,
Vernon M Chinchilli, Lynn M Taussig,
Robert C Strunk
[show abstract]
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ABSTRACT: Acute wheezing illnesses in preschoolers require better management strategies to reduce morbidity.
We sought to examine the effectiveness of episodic use of an inhaled corticosteroid and a leukotriene receptor antagonist in preschoolers with intermittent wheezing.
In a randomized, double-blind, placebo-controlled 12-month trial, 238 children aged 12 to 59 months with moderate-to-severe intermittent wheezing received 7 days of either budesonide inhalation suspension (1 mg twice daily), montelukast (4 mg daily), or placebo in addition to albuterol with each identified respiratory tract illness (RTI). Proportion of episode-free days (EFDs) during the 12-month trial was the primary outcome.
The 3 treatment groups did not differ in proportions of EFDs, with adjusted mean EFDs of 76% (95% CI, 70% to 81%) for budesonide, 73% (95% CI, 66% to 79%) for montelukast, and 74% (95% CI, 65% to 81%) for conventional therapy (P = .66). The 3 groups did not differ in oral corticosteroid use, health care use, quality of life, or linear growth. However, during RTIs, budesonide and montelukast therapy led to modest reductions in trouble breathing (38% [P = .003] and 37% [P = .003], respectively) and interference with activity scores (32% [P = .01] and 40% [P = .001], respectively) that were most evident in those with positive asthma predictive indices.
In preschool children with moderate-to-severe intermittent wheezing, episodic use of either budesonide or montelukast early in RTIs, when added to albuterol, did not increase the proportion of EFDs or decrease oral corticosteroid use over a 12-month period. However, indicators of severity of acute illnesses were reduced, particularly in children with positive asthma predictive indices.
The Journal of allergy and clinical immunology 11/2008; 122(6):1127-1135.e8. · 9.17 Impact Factor
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Robert C Strunk,
Leonard B Bacharier,
Brenda R Phillips,
Stanley J Szefler,
Robert S Zeiger,
Vernon M Chinchilli,
Fernando D Martinez,
Robert F Lemanske, Lynn M Taussig,
David T Mauger,
Wayne J Morgan,
Christine A Sorkness,
Ian M Paul,
Theresa Guilbert,
Marzena Krawiec,
Ronina Covar,
Gary Larsen
[show abstract]
[hide abstract]
ABSTRACT: Clinical trials in children with moderate-to-severe persistent asthma are limited.
We sought to determine whether azithromycin or montelukast are inhaled corticosteroid sparing.
The budesonide dose (with salmeterol [50 microg] twice daily) necessary to achieve control was determined in children 6 to 17 years of age with moderate-to-severe persistent asthma. After a budesonide-stable period of 6 weeks, children were randomized in a double-masked, parallel, multicenter study to receive once-nightly azithromycin, montelukast, or matching placebos plus the established controlling dose of budesonide (minimum, 400 microg twice daily) and salmeterol twice daily. Primary outcome was time from randomization to inadequate asthma control after sequential budesonide dose reduction.
Of 292 children screened, only 55 were randomized. Inadequate adherence to study medication (n = 80) and improved asthma control under close medical supervision (n = 49) were the major reasons for randomization failure. A futility analysis was requested by the Data Safety Monitoring Board. In data available for analyses, no differences were noted for either treatment compared with placebo in time to inadequate control status (median: azithromycin, 8.4 weeks [95% confidence limit, 4.3-17.3]; montelukast, 13.9 weeks [95% confidence limit, 4.7-20.6]; placebo, 19.1 weeks [95% confidence limit, 11.7-infinity]), with no difference between the groups (log-rank test, P = .49). The futility analysis indicated that even if the planned sample size was reached, the results of this negative study were unlikely to be different, and the trial was prematurely terminated.
Based on these results, neither azithromycin nor montelukast is likely to be an effective inhaled corticosteroid-sparing alternative in children with moderate-to-severe persistent asthma.
The Journal of allergy and clinical immunology 11/2008; 122(6):1138-1144.e4. · 9.17 Impact Factor
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ABSTRACT: Asthma exacerbations are a common cause of critical illness in children.
To determine factors associated with exacerbations in children with persistent asthma.
Regression modeling was used to identify historical, phenotypic, treatment, and time-dependent factors associated with the occurrence of exacerbations, defined by need for oral corticosteroids or emergency or hospital care in the 48-week Pediatric Asthma Controller Trial study. Children age 6 to 14 years with mild-to-moderate persistent asthma were randomized to receive either fluticasone propionate 100 microg twice daily (FP monotherapy), combination fluticasone 100 microg AM and salmeterol twice daily, or montelukast 5 mg once daily.
Of the 285 participants randomized, 48% had 231 exacerbations. Using a multivariate analysis, which included numerous demographic, pulmonary, and inflammatory parameters, only a history of an asthma exacerbation requiring a systemic corticosteroid in the past year (odds ratio [OR], 2.10; P < .001) was associated with a subsequent exacerbation during the trial. During the trial, treatment with montelukast versus FP monotherapy (OR, 2.00; P = .005), season (spring, fall, or winter vs summer; P < or = .001), and average seasonal 5% reduction in AM peak expiratory flow (OR, 1.21; P = .01) were each associated with exacerbations. Changes in worsening of symptoms, beta-agonist use, and low peak expiratory flow track together before an exacerbation, but have poor positive predictive value of exacerbation.
Children with mild-to-moderate persistent asthma with previous exacerbations are more likely to have a repeat exacerbation despite controller treatment. Inhaled corticosteroids are superior to montelukast at modifying the exacerbation risk. Available physiologic measures and biomarkers and diary card tracking are not reliable predictors of asthma exacerbations.
The Journal of allergy and clinical immunology 10/2008; 122(4):741-747.e4. · 9.17 Impact Factor
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Christine A Sorkness,
Robert F Lemanske,
David T Mauger,
Susan J Boehmer,
Vernon M Chinchilli,
Fernando D Martinez,
Robert C Strunk,
Stanley J Szefler,
Robert S Zeiger,
Leonard B Bacharier,
Gordon R Bloomberg,
Ronina A Covar,
Theresa W Guilbert,
Gregory Heldt,
Gary Larsen,
Michael H Mellon,
Wayne J Morgan,
Mark H Moss,
Joseph D Spahn, Lynn M Taussig
[show abstract]
[hide abstract]
ABSTRACT: More evidence is needed on which to base recommendations for treatment of mild-moderate persistent asthma in school-aged children.
The Pediatric Asthma Controller Trial (PACT) compared the effectiveness of 3 regimens in achieving asthma control.
A total of 285 children (ages 6-14 years) with mild-moderate persistent asthma on the basis of symptoms, and with FEV(1) >or= 80% predicted and methacholine FEV(1) PC(20) <or= 12.5 mg/mL, were randomized to 1 of 3 double-blind 48-week treatments: fluticasone 100 microg twice daily (fluticasone monotherapy), fluticasone 100 microg/salmeterol 50 microg in the morning and salmeterol 50 mug in the evening (PACT combination), and montelukast 5 mg in the evening. Outcomes included asthma control days (primary outcome), exacerbations, humanistic measurements, and pulmonary function measurements.
Fluticasone monotherapy and PACT combination were comparable in many patient-measured outcomes, including percent of asthma control days, but fluticasone monotherapy was superior for clinic-measured FEV(1)/forced vital capacity (P = .015), maximum bronchodilator response (P = .009), exhaled nitric oxide (P < .001), and PC(20) (P < .001). Fluticasone monotherapy was superior to montelukast for asthma control days (64.2% vs 52.5%; P = .004) and for all other control outcomes. Growth over 48 weeks was not statistically different (fluticasone, 5.3 cm; PACT combination, 5.3 cm; montelukast, 5.7 cm).
Both fluticasone monotherapy and PACT combination achieved greater improvements in asthma control days than montelukast. However, fluticasone monotherapy was superior to PACT combination in achieving other dimensions of asthma control. Growth was similar in all groups.
Therefore, of the regimens tested, the PACT study findings favor fluticasone monotherapy in treating children with mild-moderate persistent asthma with FEV(1) >or= 80% predicted, confirming current guideline recommendations.
Journal of Allergy and Clinical Immunology 01/2007; 119(1):64-72. · 11.00 Impact Factor
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Theresa W Guilbert,
Wayne J Morgan,
Robert S Zeiger,
David T Mauger,
Susan J Boehmer,
Stanley J Szefler,
Leonard B Bacharier,
Robert F Lemanske,
Robert C Strunk,
David B Allen,
Gordon R Bloomberg,
Gregory Heldt,
Marzena Krawiec,
Gary Larsen,
Andrew H Liu,
Vernon M Chinchilli,
Christine A Sorkness, Lynn M Taussig,
Fernando D Martinez
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ABSTRACT: It is unknown whether inhaled corticosteroids can modify the subsequent development of asthma in preschool children at high risk for asthma.
We randomly assigned 285 participants two or three years of age with a positive asthma predictive index to treatment with fluticasone propionate (at a dose of 88 mug twice daily) or masked placebo for two years, followed by a one-year period without study medication. The primary outcome was the proportion of episode-free days during the observation year.
During the observation year, no significant differences were seen between the two groups in the proportion of episode-free days, the number of exacerbations, or lung function. During the treatment period, as compared with placebo use, use of the inhaled corticosteroid was associated with a greater proportion of episode-free days (P=0.006) and a lower rate of exacerbations (P<0.001) and of supplementary use of controller medication (P<0.001). In the inhaled-corticosteroid group, as compared with the placebo group, the mean increase in height was 1.1 cm less at 24 months (P<0.001), but by the end of the trial, the height increase was 0.7 cm less (P=0.008). During treatment, the inhaled corticosteroid reduced symptoms and exacerbations but slowed growth, albeit temporarily and not progressively.
In preschool children at high risk for asthma, two years of inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third, treatment-free year. These findings do not provide support for a subsequent disease-modifying effect of inhaled corticosteroids after the treatment is discontinued. (ClinicalTrials.gov number, NCT00272441.).
New England Journal of Medicine 06/2006; 354(19):1985-97. · 53.30 Impact Factor
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ABSTRACT: The relation of infant feeding to childhood asthma is controversial. This study tested the hypothesis that maternal asthma
alters the relation of breastfeeding to childhood asthma. Questionnaires were completed at age 6, 9 or 11 years by parents
of 1043 children enrolled at birth. Active MD asthma was defined as a physician diagnosis of asthma plus asthma symptoms reported
on one of the questionnaires. Duration of exclusive breastfeeding, categorized as never, <4 months, or≥_4 months, was based
on prospective physician reports or questionnaires completed at 18 months. The relationship between breastfeeding and asthma
differed by maternal asthma status. For children with maternal asthma, the percent developing active MD asthma increased significantly
with longer duration of exclusive breastfeeding. Odds of developing asthma among these children were significantly elevated
(OR: 5.7,CI; 2.8–11.5), after adjusting for confounders. This association of longer exclusive breastfeeding with increased
risk of reported asthma among children with asthmatic mothers may be biologically based, or may reflect reporting biases.
04/2006: pages 131-137;
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Robert S Zeiger,
Stanley J Szefler,
Brenda R Phillips,
Michael Schatz,
Fernando D Martinez,
Vernon M Chinchilli,
Robert F Lemanske,
Robert C Strunk,
Gary Larsen,
Joseph D Spahn,
Leonard B Bacharier,
Gordon R Bloomberg,
Theresa W Guilbert,
Gregory Heldt,
Wayne J Morgan,
Mark H Moss,
Christine A Sorkness, Lynn M Taussig
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ABSTRACT: Outcome data are needed to base recommendations for controller asthma medication use in school-aged children.
We sought to determine intraindividual and interindividual response profiles and predictors of response to an inhaled corticosteroid (ICS) and a leukotriene receptor antagonist (LTRA).
An ICS, fluticasone propionate (100 mug twice daily), and an LTRA, montelukast (5-10 mg nightly, age dependent), were administered to children ages 6 to 17 years with mild-to-moderate persistent asthma using only as-needed bronchodilators in a multicenter, double-masked, 2-sequence, 16-week crossover trial. Clinical, pulmonary, and inflammatory responses to these controllers were evaluated.
Improvements in most clinical asthma control measures occurred with both controllers. However, clinical outcomes (asthma control days [ACDs], the validated Asthma Control Questionnaire, and albuterol use), pulmonary responses (FEV(1)/forced vital capacity, peak expiratory flow variability, morning peak expiratory flow, and measures of impedance), and inflammatory biomarkers (exhaled nitric oxide [eNO]) improved significantly more with fluticasone than with montelukast treatment. eNO was both a predictor of ACDs (P = .011) and a response indicator (P = .003) in discriminating the difference in ACD response between fluticasone and montelukast.
The more favorable clinical, pulmonary, and inflammatory responses to an ICS than to an LTRA provide pediatric-based group evidence to support ICSs as the preferred first-line therapy for mild-to-moderate persistent asthma in children. eNO, as a predictor of response, might help to identify individual children not receiving controller medication who achieve a greater improvement in ACDs with an ICS compared with an LTRA.
Journal of Allergy and Clinical Immunology 02/2006; 117(1):45-52. · 11.00 Impact Factor
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ABSTRACT: The effect of early life wheezing on respiratory function and continued symptoms through adolescence has not been fully described. Using data from a population-based birth cohort in Tucson, Arizona, we previously described four phenotypes based on the occurrence of wheezing lower respiratory illnesses before age 3 yr and active wheeze at age 6 yr: never wheezers (n = 425), transient early wheezers (n = 164), persistent wheezers (n = 113), and late-onset wheezers (n = 124).
We sought to determine the prognosis for these phenotypes, with reference to lung function and symptoms, through adolescence.
Current wheeze was assessed by questionnaire, lung function was measured by conventional spirometry, and atopy was determined by skin prick tests.
The prevalence of atopy and wheeze by age 16 yr was similar for never and transient wheezers and for persistent and late-onset wheezers. Both transient early, and persistent wheezers had significantly lower FEF(25-75) (-259 ml/s, p < 0.001, and -260 ml/s, p = 0.001, respectively), FEV1 (-75 ml, p = 0.02, and -87 ml, p = 0.03, respectively), and FEV1:FVC ratio (-1.9%, p = 0.002, and -2.5%, p = 0.001, respectively) through age 16 yr compared with never wheezers. Late-onset wheezers had levels of lung function similar to those of never wheezers through age 16 yr. There was no significant change in lung function among subjects with any of the four phenotypes, relative to their peers, from age 6 to 16 yr.
Patterns of wheezing prevalence and levels of lung function are established by age 6 yr and do not appear to change significantly by age 16 yr in children who start having asthma-like symptoms during the preschool years.
American Journal of Respiratory and Critical Care Medicine 11/2005; 172(10):1253-8. · 11.08 Impact Factor
