Hengameh H. Raissy

Effect of Inhaled Glucocorticoids in Childhood on Adult Height

BACKGROUND The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children. The resulting decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height. METHODS We measured adult height in 943 of 1041 participants (90.6%) in the Childhood Asthma Management Program; adult height was determined at a mean (±SD) age of 24.9±2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 μg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. We calculated differences in adult height for each active treatment group, as compared with placebo, using multiple linear regression with adjustment for demographic characteristics, asthma features, and height at trial entry. RESULTS Mean adult height was 1.2 cm lower (95% confidence interval [CI], -1.9 to -0.5) in the budesonide group than in the placebo group (P=0.001) and was 0.2 cm lower (95% CI, -0.9 to 0.5) in the nedocromil group than in the placebo group (P=0.61). A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height (-0.1 cm for each microgram per kilogram of body weight) (P=0.007). The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment (-1.3 cm; 95% CI, -1.7 to -0.9). During the first 2 years, decreased growth velocity in the budesonide group occurred primarily in prepubertal participants. CONCLUSIONS The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height, although the decrease was not progressive or cumulative. (Funded by the National Heart, Lung, and Blood Institute and the National Center for Research Resources; CAMP ClinicalTrials.gov number, NCT00000575.).

Daily or Intermittent Budesonide in Preschool Children with Recurrent Wheezing

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.).

Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial

IMPORTANCE Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed. OBJECTIVE To evaluate if early administration of azithromycin, started prior to the onset of severe LRTI symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled, parallel-group trial conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institutes AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by December 2014. Participants were 607 children aged 12 through 71 months with histories of recurrent, severe LRTIs and minimal day-to-day impairment. INTERVENTION Participants were randomly assigned to receive azithromycin (12 mg/kg/d for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (childs signs or symptoms prior to development of LRTI), based on individualized action plans, over a 12- through 18-month period. MAIN OUTCOMES AND MEASURES The primary outcome measure was the number of RTIs not progressing to a severe LRTI, measured at the level of the RTI, that would in clinical practice trigger the prescription of oral corticosteroids. Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures. RESULTS A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04; absolute risk for first RTI: 0.05 for azithromycin, 0.08 for placebo; risk difference, 0.03 [95% CI, 0.00-0.06]). Induction of azithromycin-resistant organisms and adverse events were infrequently observed. CONCLUSIONS AND RELEVANCE Among young children with histories of recurrent severe LRTIs, the use of azithromycin early during an apparent RTI compared with placebo reduced the likelihood of severe LRTI. More information is needed on the development of antibiotic-resistant pathogens with this strategy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01272635.

Inhaled Corticosteroids in Lung Diseases

Inhaled corticosteroids (ICSs) are used extensively in the treatment of asthma and chronic obstructive pulmonary disease (COPD) due to their broad antiinflammatory effects. They improve lung function, symptoms, and quality of life and reduce exacerbations in both conditions but do not alter the progression of disease. They decrease mortality in asthma but not COPD. The available ICSs vary in their therapeutic index and potency. Although ICSs are used in all age groups, younger and smaller children may be at a greater risk for adverse systemic effects because they can receive higher mg/kg doses of ICSs compared with older children. Most of the benefit from ICSs occurs in the low to medium dose range. Minimal additional improvement is seen with higher doses, although some patients may benefit from higher doses. Although ICSs are the preferred agents for managing persistent asthma in all ages, their benefit in COPD is more controversial. When used appropriately, ICSs have few adverse events at low to medium doses, but risk increases with high-dose ICSs. Although several new drugs are being developed and evaluated, it is unlikely that any of these new medications will replace ICSs as the preferred initial long-term controller therapy for asthma, but more effective initial controller therapy could be developed for COPD.

Asthma across the ages: Knowledge gaps in childhood asthma

The Eunice Kennedy Shriver National Institute of Child Health and Human Development convened an Asthma Group in response to the Best Pharmaceuticals for Children Act. The overall goal of the Best Pharmaceuticals for Children Act Program is to improve pediatric therapeutics through preclinical and clinical drug trials that lead to drug-labeling changes. Although significant advances have been made in the understanding and management of asthma in adults with appropriately labeled medications, less information is available on the management of asthma in children. Indeed, many medications are inadequately labeled for use in children. In general, the younger the child, the less information there is available to guide clinicians. Because asthma often begins in early childhood, it is incumbent on us to continue to address the primary questions raised in this review and carefully evaluate the medications used to manage asthma in children. Meanwhile, continued efforts should be made in defining effective strategies that reduce the risk of exacerbations. If the areas of defined need are addressed in the coming years, namely prevention of exacerbations and progression of disease, as well as primary intervention, we will see continuing reduction in asthma mortality and morbidity along with improved quality of life for children with asthma.

Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.

BACKGROUND Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. METHODS In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. RESULTS Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. CONCLUSIONS Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).

Pretreatment with Albuterol versus Montelukast for Exercise‐Induced Bronchospasm in Children

Study Objectives. To compare pretreatment with albuterol versus montelukast added to the current asthma regimen for protection against exercise‐induced bronchospasm in children with mild‐to‐moderate asthma, and to determine whether cysteinyl leukotriene (Cys‐LT) concentrations measured in the exhaled breath condensate correlated with response to montelukast.

Risk of cataracts in the Childhood Asthma Management Program Cohort

To the editor: Use of systemic corticosteroids is a well established risk factor for the development of posterior subcapsular cataracts (PSCs) in both children and adults.1 Dose and duration of inhaled corticosteroids (ICSs) have been reported to be independent risk factors for the development of PSCs in older patients.2 Occurrence of PSCs is rare in children, and studies of children treated with ICSs have not found an increased risk of PSCs.3–5 We previously reported no risk of cataracts in 955 children in the Childhood Asthma Management Program (CAMP) assessed by lens photography after 4–6 years (mean 4.3 years) of budesonide 400 µg/day by Turbuhaler™, nedocromil 16 mg/day or placebo. However, one child in the budesonide group was diagnosed as having a barely measurable PSC on slit lamp exam 5 months after the photography.8 The CAMP cohort has been followed continuously since closure of the trial in 1999. In 2005, two additional participants (both from the budesonide arm) reported PSCs, with one requiring surgery. In response to these reports and in consultation with the CAMP Data and Safety Monitoring Board, all CAMP participants were urged to obtain a dilated slit lamp examination specifically for the presence of cataracts (Supplementary Appendices E1 and E2). The findings from the resulting exams plus the 3 reports of cataracts obtained previously form the basis of this report. Three outcomes were defined for each participant: examination for cataract, any cataract finding, and any posterior finding. Covariates included cumulative doses of ICSs and oral corticosteroid for asthma to the date of the cataract exam. The ICSs included the blinded budesonide and unblinded ICSs prescribed during the trial and ICS self-reported as taken for asthma during the observational post-trial follow-up. Prednisone bursts during the post trial follow-up were assumed to conform to the CAMP trial regimen (up to 60 mg for each of 2 days, followed by up to 30 mg for each of 2 days). The association of each outcome with randomized treatment group and with inhaled and oral corticosteroid use for asthma categorized as ever versus never was assessed by chi square analysis and logistic regression. Association of cataract posterior finding with the cumulative dose of ICS and cumulative dose of oral corticosteroid was assessed by logistic regression. Each cumulative dose was modeled first as a continuous variable and then as three indicator variables corresponding to tertiles of increasing dose. Lastly, each cumulative dose was modeled as a score based on the tertiles as a test for a dose-response effect. Analyses were performed using SAS 9.1 (SAS Institute Inc., Cary, NC) or STATA 9.2 (StataCorp, College Station, TX). 232 participants aged 15 to 26 years were examined, 22.3% of the original CAMP cohort (N=1041). Median duration from randomization to exam was 12 years (range 4–14 years), and median duration from lens photography to exam was 8 years (range 0.4–9 years). Median duration of ICS use among those using ICSs was 4.0 years (range 0–13) and median 4-day dose (per burst) of prednisone during CAMP, for those ever taking prednisone for asthma during CAMP, was 150 mg range (15–180). Sixteen participants were assessed as having cataract findings, of whom 12 were classified as having posterior findings (Table E1). The percentage of participants obtaining exams was similar across randomized treatment groups (22.8% budesonide, 22.1% nedocromil, 22.0% placebo, P=0.96: Table 1, Panel A). Among those examined, there was no evidence of increased cataracts in the budesonide compared to the placebo group (odds ratio (OR) = 1.6, 95% CI=(0.5, 4,9), P=0.44), nor any evidence of increased posterior findings (OR=1.3, 95% CI=(0.4, 4.7), P=0.67) (Table 1, Panel A). Table 1 Examination for cataracts and cataract findings by randomized treatment and ever versus never use of corticosteroids for asthma Participants ever using corticosteroids for asthma were more likely to obtain a cataract exam (25.8% ever using ICS versus 12.8% never using ICS, P<0.0001, Table 1, Panel B; 23.6% ever using oral corticosteroid versus 16.4% never using oral corticosteroid, P=0.03, Table 1, Panel C). However, in those examined, the risk of cataract finding did not differ by ICS use (OR=0.8, ever versus never, 95% CI=(0.2, 2.9), P=0.71) nor by oral corticosteroid use (OR=1.1, ever versus never, 95% CI=(0.2, 5.2), P=0.88) (Table 1, Panels B and C). Similar results were obtained for the risk of posterior finding. There was no association of cataract or posterior finding with cumulative ICS dose or cumulative oral corticosteroid dose (Table 2). Table 2 Cataracts and cataract findings by cumulative ICS dose and prednisone dose in 232 participants who obtained a dilated slit lamp examination* Our findings suggest that long-term administration of ICS in the recommended low to medium doses is not a significant risk factor for the development of PSCs in children, adolescents and young adults. We did not find an association of cataracts or specifically PSCs with ICS use. These findings are consistent with the initial CAMP report based on evaluation of lens photographs of 92% of the participants after 4–6 years of treatment.5 This now becomes the longest study to date for the development of cataracts in children treated with ICS, and our findings are consistent with 3 other non-randomized studies of long-term ICS therapy in children.3,4,6 Chronic systemic corticosteroids are associated with a risk of developing PSCs in children as well as adults. Reports in the literature vary widely but indicate that 15–35% of children on daily oral corticosteroids for at least 1 year develop PSCs.7,8 Risk factors for development of PSCs include: daily dose (> 10 mg/day); duration (> 2 years); and method of administration (daily versus every other day). It is possible that some children with multiple courses of oral prednisone per year developed PSCs that then regressed, as this has been previously reported.9 We report a 5.2% prevalence of posterior findings in our participants which is much higher than the 0.2% in healthy young adults quoted from population based studies.1,2 However, these studies used reports of clinically significant cataracts. In that regard, our finding of one patient requiring surgery for cataract is not significantly different from that reported in the NHANES 2007–2008 vision questionnaire database for participants 14–25 years old (1/232 versus 2/1621, p=0.33 Fisher’s exact test).10 Our high prevalence could be a consequence of our specific request that the eye care provider to look for cataracts. Additionally the finding of more cataracts on slit-lamp exam than on lens photography was recently reported.11 A weakness of our report is that only 22.3% of the CAMP population obtained a dilated slit lamp examination; our power to detect a difference in risk is very low, as indicated by the broad 95% confidence limits on our risk estimates. Nevertheless, ours is one of the largest studies in children with asthma to date, and despite those who had greater corticosteroid exposure being more likely to have obtained an exam, we did not find any association between cataract findings and exposure to corticosteroids for asthma (Tables1 and ​and2).2). Another weakness was lack of standardization in the ophthalmic exam and the prompt to eye care providers to look specifically for evidence of cataracts. However, this represents what happens in the real world outside of standardized clinical trials. Additionally, our dose data are a mix of prescribed dose (during the trial) and reported dose taken (during the follow-up phases). Finally, we did not include use of nasal and topical corticosteroids in the analysis, nor use of corticosteroids for conditions other than asthma. However, in a population based case-control study, exposure to topical corticosteroids did not affect the association between cataract and use of inhaled corticosteroids.2 Our findings of a lack of cumulative effect of ICSs and short bursts of oral corticosteroids does not rule out the possibility that high daily doses of ICSs will contribute to cataract formation, particularly in patients with other risk factors.3–5 In conclusion, the long-term use of ICSs in the recommended ranges in combination with occasional bursts of oral prednisone during childhood was not associated with an increased risk of cataracts. Thus, regular monitoring for cataracts does not appear to be warranted in children, adolescents and young adults with asthma being treated with low-medium dose ICS without other significant risk factors.

Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations

BACKGROUND Asthma exacerbations occur frequently despite the regular use of asthma‐controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. METHODS We studied 254 children, 5 to 11 years of age, who had mild‐to‐moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low‐dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low‐dose group) or use a quintupled dose (high‐dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control (“yellow zone”). Treatment was provided in a double‐blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. RESULTS The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high‐dose group and 0.37 exacerbations per year in the low‐dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow‐zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high‐dose group than in the low‐dose group. The difference in linear growth between the high‐dose group and the low‐dose group was ‐0.23 cm per year (P=0.06). CONCLUSIONS In children with mild‐to‐moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129.)

Comparison of the dose response to levalbuterol with and without pretreatment with S-albuterol after methacholine-induced bronchoconstriction.

Study Objective. To determine the effect of S‐albuterol on the dose response to levalbuterol in patients with moderate bronchoconstriction induced by a methacholine challenge.