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1.  Classification of childhood asthma phenotypes and long-term clinical responses to inhaled anti-inflammatory medications 
Background
Although recent studies have identified the presence of phenotypic clusters in asthmatic patients, the clinical significance and temporal stability of these clusters have not been explored.
Objective
Our aim was to examine the clinical relevance and temporal stability of phenotypic clusters in children with asthma.
Methods
We applied spectral clustering to clinical data from 1041 children with asthma participating in the Childhood Asthma Management Program. Posttreatment randomization follow-up data collected over 48 months were used to determine the effect of these clusters on pulmonary function and treatment response to inhaled anti-inflammatory medication.
Results
We found 5 reproducible patient clusters that could be differentiated on the basis of 3 groups of features: atopic burden, degree of airway obstruction, and history of exacerbation. Cluster grouping predicted long-term asthma control, as measured by the need for oral prednisone (P < .0001) or additional controller medications (P = .001), as well as longitudinal differences in pulmonary function (P < .0001). We also found that the 2 clusters with the highest rates of exacerbation had different responses to inhaled corticosteroids when compared with the other clusters. One cluster demonstrated a positive response to both budesonide (P = .02) and nedocromil (P = .01) compared with placebo, whereas the other cluster demonstrated minimal responses to both budesonide (P = .12) and nedocromil (P = .56) compared with placebo.
Conclusion
Phenotypic clustering can be used to identify longitudinally consistent and clinically relevant patient subgroups, with implications for targeted therapeutic strategies and clinical trials design.
PMCID: PMC4047642  PMID: 24892144
Childhood asthma; asthma phenotypes; inhaled corticosteroids; cluster analysis; asthma classification; longitudinal study
2.  The Development, Implementation, and Assessment of an Innovative Faculty Mentoring Leadership Program 
Effective mentoring is an important component of academic success. Few programs exist to both improve the effectiveness of established mentors and cultivate a multi-specialty mentoring community. In 2008, in response to a faculty survey on mentoring, leaders at Brigham and Women’s Hospital developed the Faculty Mentoring Leadership Program (FMLP) as a peer-learning experience for mid-career and senior faculty physician and scientist mentors to enhance their skills and leadership in mentoring and create a supportive community of mentors. A planning group representing key administrative, educational, clinical, and research mentorship constituencies designed the nine-month course.
Participants met monthly for an hour and a half during lunchtime. Two co-facilitators engaged the diverse group of 16 participants in interactive discussions about cases based on the participants’ experiences. While the co-facilitators discussed with the participants the dyadic mentor-mentee relationship, they specifically emphasized the value of engaging multiple mentors and establishing mentoring networks. In response to post-session and post-course (both immediately and after six months) self-assessments, participants reported substantive gains in their mentoring confidence and effectiveness, experienced a renewed sense of enthusiasm for mentoring, and took initial steps to build a diverse network of mentoring relationships.
In this article, the authors describe the rationale, design, implementation, assessment, and ongoing impact of this innovative faculty mentoring leadership program. They also share lessons learned for other institutions that are contemplating developing a similar faculty mentoring program.
doi:10.1097/ACM.0b013e3182712cff
PMCID: PMC3924178  PMID: 23095917
3.  The Childhood Asthma Management Program (CAMP): Contributions to the Understanding of Therapy and the Natural History of Childhood Asthma 
Current respiratory care reports  2012;1(4):243-250.
The Childhood Asthma Management Program (CAMP) has been in continuous existence for almost two decades, which makes it the largest randomized, placebo-controlled clinical trial with extended follow-up for children with mild to moderate asthma. As such, its cumulative data from baseline, active treatment, and post-treatment have proved to be an invaluable resource for not only assessing the efficacy and safety of long-term inhaled corticosteroid therapy in childhood, but for discovery of many other aspects of childhood asthma, including genetics and biomarkers.
doi:10.1007/s13665-012-0026-9
PMCID: PMC3546823  PMID: 23336093
Asthma; childhood; spirometry; airway hyperresponsiveness; inhaled corticosteroids; bronchodilators; bronchodilator response; allergy; pharmacogenomics; bone mineral density; vitamin D; linear growth; cataracts; hypothalamic–pituitary–adrenal axis; remission; progression; exacerbation; oral corticosteroids; nedocromil; forced expiratory volume in one second (FEV1); forced vital capacity (FVC); symptoms; health care utilization; phenotype; genetic polymorphism; eosinophils
4.  Modeling Asthma Exacerbations Through Lung Function in Children 
Background
Formal economic evaluation using a model-based approach is playing an increasingly important role in healthcare decision making.
Objective
To develop a model using an objective measure of lung function, prebronchodilator forced expiratory volume in 1 second as a percent of predicted (FEV1% predicted), as the primary independent factor to predict the frequency of adverse events related to exacerbation of asthma on a population level.
Methods
We developed a Markov simulation model of childhood asthma using data from the Childhood Asthma Management Program (CAMP). The primary outcomes were the result of asthma exacerbations defined as: hospitalizations, emergency department (ED) visits, and the need for oral corticosteroid therapy. Predicted monthly frequencies for each acute event were based on negative binomial regression equations estimated from the placebo arm of CAMP with covariates of age, prebronchodilator FEV1% predicted, time in study, prior hospitalizations, and prior nocturnal awakenings.
Results
Simulated versus observed mean number of acute events were similar within the placebo and treatment groups. While the trial demonstrated treatment effects of 48% reduction in hospitalizations, 46% reduction in ED visits, and 44% reduction in the need for oral corticosteroid therapy at 48 months; the model simulated similar reductions of 49% in hospitalizations, 41% in ED visits, and 46% in the need for oral corticosteroid therapy.
Conclusion
Our findings suggest that longitudinal intervention effects may be modeled through FEV1% predicted to estimate hospitalizations, ED visits, and need for oral corticosteroid therapy in childhood asthma for planning and evaluation purposes.
doi:10.1016/j.jaci.2012.08.009
PMCID: PMC3683131  PMID: 23021884
asthma; pediatric patients; lung function; FEV percent predicted; hospitalizations; emergency department visits; model
5.  Effect of Vitamin D and Inhaled Corticosteroid Treatment on Lung Function in Children 
Rationale: Low vitamin D levels are associated with asthma and decreased airway responsiveness. Treatment with inhaled corticosteroids improves airway responsiveness and asthma control.
Objectives: To assess the effect of vitamin D levels on prebronchodilator FEV1, bronchodilator response, and responsiveness to methacholine (PC20, provocative concentration of methacholine producing a 20% decline in FEV1) in patients with asthma treated with inhaled corticosteroids.
Methods: We measured 25-hydroxyvitamin D levels in the serum of children with persistent asthma at the time of enrollment in the Childhood Asthma Management Program. We divided subjects into the vitamin D sufficiency (>30 ng/ml), insufficiency (20–30 ng/ml), and deficiency (<20 ng/ml) groups. Covariates included age, treatment, sex, body mass index, race, history of emergency department visits, hospitalizations, and season that vitamin D specimen was drawn. Our main outcome measures were change in prebronchodilator FEV1, bronchodilator response, and PC20 from enrollment to 8–12 months.
Measurements and Main Results: Of the 1,024 subjects, 663 (65%) were vitamin D sufficient, 260 (25%) were insufficient, and 101 (10%) were deficient. Vitamin D–deficient subjects were more likely to be older, African American, and have a higher body mass index compared with the vitamin D–sufficient and insufficient subjects. In the inhaled corticosteroid treatment group, prebronchodilator FEV1 increased from randomization to 12 months by 140 ml in the vitamin D–deficient group and prebronchodilator FEV1 increased by 330 ml in the vitamin D insufficiency group and by 290 ml in the vitamin D sufficiency group (P = 0.0072), in adjusted models.
Conclusions: In children with asthma treated with inhaled corticosteroids, vitamin D deficiency is associated with poorer lung function than in children with vitamin D insufficiency or sufficiency.
doi:10.1164/rccm.201202-0351OC
PMCID: PMC3480528  PMID: 22798322
asthma; vitamin D; lung function; forced expiratory volume; children
6.  The Impact of Self-Identified Race on Epidemiologic Studies of Gene Expression 
Genetic epidemiology  2011;35(2):93-101.
Although population differences in gene expression have been established, the impact on differential gene expression studies in large populations is not well understood. We describe the effect of self-reported race on a gene expression study of lung function in asthma. We generated gene expression profiles for 254 young adults (205 non-Hispanic whites and 49 African Americans) with asthma on whom concurrent total RNA derived from peripheral blood CD4+ lymphocytes and lung function measurements were obtained. We identified four principal components that explained 62% of the variance in gene expression. The dominant principal component, which explained 29% of the total variance in gene expression, was strongly associated with self-identified race (P<10−16). The impact of these racial differences was observed when we performed differential gene expression analysis of lung function. Using multivariate linear models, we tested whether gene expression was associated with a quantitative measure of lung function: pre-bronchodilator forced expiratory volume in one second (FEV1). Though unadjusted linear models of FEV1 identified several genes strongly correlated with lung function, these correlations were due to racial differences in the distribution of both FEV1 and gene expression, and were no longer statistically significant following adjustment for self-identified race. These results suggest that self-identified race is a critical confounding covariate in epidemiologic studies of gene expression and that, similar to genetic studies, careful consideration of self-identified race in gene expression profiling studies is needed to avoid spurious association.
doi:10.1002/gepi.20560
PMCID: PMC3718033  PMID: 21254216
ancestry; gene expression; population stratification; self-identified race
7.  Asthma Outcomes: Exacerbations 
Background
The goals of asthma treatment include preventing recurrent exacerbations. Yet there is no consensus about the terminology for describing or defining “exacerbation,” or about how to characterize an episode’s severity.
Objective
National Institutes of Health (NIH) institutes and other federal agencies convened an expert group to propose how asthma exacerbation should be assessed as a standardized asthma outcome in future asthma clinical research studies.
Methods
We utilized comprehensive literature reviews and expert opinion to compile a list of asthma exacerbation outcomes, and classified them as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011.
Results
No dominant definition of “exacerbation” was found. The most widely used definitions included 3 components, all related to treatment, rather than symptoms: (1) systemic use of corticosteroids, (2) asthma-specific emergency department visits or hospitalization, and (3) use of short-acting β-agonists (SABAs) as quick-relief (sometimes referred to as “rescue” or “reliever”) medications.
Conclusions
The working group participants propose that the definition of “asthma exacerbation” be “a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome.” As core outcomes, they propose inclusion and separate reporting of several essential variables of an exacerbation. Further, they propose the development of a standardized, component-based definition of “exacerbation” with clear thresholds of severity for each component.
doi:10.1016/j.jaci.2011.12.983
PMCID: PMC3595577  PMID: 22386508
Asthma exacerbations; severity of acute asthma; asthma outcomes; urgent asthma care
8.  Effect of Inhaled Glucocorticoids in Childhood on Adult Height 
The New England journal of medicine  2012;367(10):904-912.
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.
doi:10.1056/NEJMoa1203229
PMCID: PMC3517799  PMID: 22938716
9.  Modeling the Potential Impact of a Prescription Drug Copayment Increase on the Adult Asthmatic Medicaid Population 
Objectives
The Commonwealth of Massachusetts increased the copayment for prescription drugs by $1.50 for Medicaid (MassHealth) beneficiaries in 2003. We sought to determine the likely health outcomes and cost shifts attributable to this copayment increase using the example of inhaled corticosteroids (ICS) use among adult asthmatic Medicaid beneficiaries.
Method
We compared the predicted costs and health outcomes projected over a 1-year time horizon with and without the increase in copayment from the perspective of MassHealth, providers, pharmacies, and MassHealth beneficiaries by employing decision analysis simulation model.
Results
In a target population of 17,500 adult asthmatics, increased copayments from 50¢ to $2.00 would result in an additional 646 acute events per year, caused by increased drug nonadherence. Annual combined net savings for the state and federal governments would be $2.10 million. Projected MassHealth savings are attributable to both decreased drug utilization and lower pharmacy reimbursement rates; these more than offset the additional costs of more frequent acute exacerbations. Pharmacies would lose $1.98 million in net revenues, MassHealth beneficiaries would pay an additional $0.28 million, and providers would receive additional $0.16 million.
Conclusion
Over its first year of implementation, increase in the prescription drug copayment is expected to produce more frequent acute exacerbations among asthmatic MassHealth beneficiaries who use ICS and to shift the financial burden from government to other stakeholders.
doi:10.1111/j.1524-4733.2007.00219.x
PMCID: PMC3476042  PMID: 18237365
asthma; copayment; medicaid; prescription drug
10.  Cost-effectiveness of omalizumab in adults with severe asthma: Results from the Asthma Policy Model 
Background
Omalizumab (trade name Xolair) is approved by the US Food and Drug Administration for treatment of moderate-to-severe allergic asthma. Given the high acquisition cost of omalizumab, its role and cost-effectiveness in disease management require definition.
Objective
We sought to identify the clinical and economic circumstances under which omalizumab might or might not be a cost-effective option by using a mathematic model.
Methods
We merged published data on clinical and economic outcomes (including acute event incidence, frequency/severity of hospitalizations, and health-related quality of life) to project 10-year costs, quality-adjusted life years (QALYs), and cost-effectiveness of treatment with omalizumab in addition to inhaled corticosteroids. Sensitivity analyses were conducted by using input data ranges from a variety of sources (published clinical trials and observational databases).
Results
For patients with baseline acute event rates, omalizumab conferred an additional 1.7 quality-adjusted months at an incremental cost of $131,000 over a 10-year planning horizon, implying a cost-effectiveness ratio of $821,000 per QALY gained. For patients with 5 times the baseline acute event rate, the cost-effectiveness ratio was $491,000 per QALY gained. The projected cost-effectiveness ratio could fall within a range of other programs that are widely considered to be cost-effective if the cost of omalizumab decreases to less than $200.
Conclusion
Omalizumab is not cost-effective for most patients with severe asthma. The projected cost-effectiveness ratios could fall within a favorable range if the cost of omalizumab decreases significantly.
Clinical implications
Based on the high cost of omalizumab, it is especially important that clinicians explore alternative medications for asthma before initiating omalizumab.
doi:10.1016/j.jaci.2007.07.055
PMCID: PMC3476046  PMID: 17904628
Omalizumab; cost-effectiveness; asthma; anti-IgE
11.  Clinical Predictors of Frequent Exacerbations in Subjects with Severe Chronic Obstructive Pulmonary Disease (COPD) 
Respiratory medicine  2010;105(4):588-594.
Background
Acute exacerbations are a significant source of morbidity and mortality associated with chronic obstructive pulmonary disease. Among patients with COPD, some patients suffer an inordinate number of exacerbations while others remain relatively protected. We undertook a study to determine the clinical factors associated with "frequent exacerbator" status within a population of subjects with severe COPD.
Methods
Case-control cohort recruited from two Boston-area practices. All subjects had GOLD stage 3 or 4 (FEV1 ≤50% predicted) COPD. "Frequent exacerbators" (n=192) had an average of ≥2 moderate-to-severe exacerbations per year while "non-exacerbators" (n=153) had no exacerbations in the preceding 12 months. Multivariate logistic regression was performed to determine the significant clinical predictors of "frequent exacerbator" status.
Results
Physician-diagnosed asthma was a significant predictor of frequent exacerbations. Within a subset of our cohort, the modified Medical Research Council dyspnea score and FEF25–75 % predicted were also significant clinical predictors of frequent exacerbator status (p<0.05). Differences in exacerbation frequency were not found to be due to increased current tobacco use or decreased rates of maintenance medication use.
Conclusions
Within our severe COPD cohort, a history of physician-diagnosed asthma was found to be a significant clinical predictor of frequent exacerbations. Although traditional risk factors such as decreased FEV1% predicted were not significantly associated with frequent exacerbator status, lower mid-expiratory flow rates, as assessed by FEF 25–75 % predicted, were significantly associated with frequent exacerbations in a subset of our cohort.
doi:10.1016/j.rmed.2010.11.015
PMCID: PMC3046312  PMID: 21145719
12.  Decreased response to inhaled steroids in overweight and obese asthmatic children 
Background
The mechanisms and consequences of the observed association between obesity and childhood asthma are unclear.
Objectives
To determine the effect of obesity on treatment responses to inhaled corticosteroids in asthmatic children.
Methods
We performed a post hoc analysis to evaluate the interaction between body mass index (BMI) and treatment with inhaled budesonide on lung function in the Childhood Asthma Management Program (CAMP) trial. Participants were then stratified into overweight/obese and non-overweight, and their response to inhaled budesonide was analyzed longitudinally over the 4 years of the trial.
Results
There was a significant interaction between BMI and budesonide for pre-BD FEV1/FVC (P=0.0007) and bronchodilator response (BDR) (P=0.049), and a non-significant trend for an interaction between BMI and budesonide on pre-BD FEV1 (P=0.15). Non-overweight children showed significant improvement with inhaled budesonide in lung function (FEV1, FEV1/FVC, and BDR) during the early (years 1–2) and late stages (years 3–4) of the trial. Overweight/obese children had improved FEV1 and BDR during the early but not the late stage of the trial, and showed no improvement in FEV1/FVC. When comparing time points where both groups showed significant response, the degree of improvement among non-overweight children was significantly greater than in overweight/obese children at most visits. Non-overweight children had a 44% reduction in the risk of ER visits or hospitalizations throughout the trial (P=0.001); there was no reduction in risk among overweight/obese (P=0.97).
Conclusions
Compared to children of normal weight, overweight/obese children in CAMP showed a decreased response to inhaled budesonide on measures of lung function and ER visits/hospitalizations for asthma.
doi:10.1016/j.jaci.2010.12.010
PMCID: PMC3056233  PMID: 21377042
Asthma; obesity; pediatric asthma; childhood obesity; budesonide
13.  In Utero Smoke Exposure and Impaired Response to Inhaled Corticosteroids in Children with Asthma 
Background
Few studies have examined the effects of in utero smoke exposure (IUS) on lung function in children with asthma, and there are no published data on the impact of IUS on treatment outcomes in asthmatic children.
Objectives
To explore whether IUS exposure is associated with increased airway responsiveness among children with asthma, and whether IUS modifies the response to treatment with inhaled corticosteroids (ICS).
Methods
To assess the impact of parent-reported IUS exposure on airway responsiveness in childhood asthma we performed a repeated-measures analysis of methacholine PC20 data from the Childhood Asthma Management Program (CAMP), a four-year, multicenter, randomized double masked placebo controlled trial of 1041 children ages 5–12 comparing the long term efficacy of ICS with mast cell stabilizing agents or placebo.
Results
Although improvement was seen in both groups, asthmatic children with IUS exposure had on average 26% less of an improvement in airway responsiveness over time compared to unexposed children (p=.01). Moreover, while children who were not exposed to IUS who received budesonide experienced substantial improvement in PC20 compared to untreated children (1.25 fold-increase, 95% CI 1.03, 1.50, p=.02) the beneficial effects of budesonide were attenuated among children with a history of IUS exposure (1.04 fold-increase, 95% CI 0.65, 1.68, p=.88).
Conclusions
IUS reduces age-related improvements in airway responsiveness among asthmatic children. Moreover, IUS appears to blunt the beneficial effects of ICS use on airways responsiveness. These results emphasize the importance of preventing this exposure through smoking cessation counseling efforts with pregnant women.
doi:10.1016/j.jaci.2010.06.016
PMCID: PMC2937829  PMID: 20673983
asthma; in utero smoke exposure; airway responsiveness; inhaled corticosteroids
14.  Serum Vitamin D Levels and Severe Asthma Exacerbations in the Childhood Asthma Management Program Study 
Background
Asthma exacerbations, most often due to respiratory tract infections, are the leading causes of asthma morbidity and comprise a significant proportion of asthma-related costs. Vitamin D status may play a role in preventing asthma exacerbations.
Objectives
To assess the relationship between serum vitamin D levels and subsequent severe asthma exacerbations.
Methods
We measured 25-hydroxyvitamin D (25(OH)D) levels in serum collected from 1,024 mild to moderate persistent asthmatic children at the time of enrollment in a multi-center clinical trial of children randomized to receiving budesonide, nedocromil, or placebo (as-needed beta-agonists), the Childhood Asthma Management Program. Using multivariable modeling we examined the relationship between baseline vitamin D level and the odds of any hospitalization or emergency department (ED) visit over the 4 years of the trial.
Results
35% of all subjects were vitamin D insufficient, as defined by a level ≤ 30 ng/ml 25(OH)D. Mean vitamin D levels were lowest in African-American subjects, and highest in whites. After adjusting for age, sex, BMI, income, and treatment group, insufficient vitamin D status was associated with a higher odds of any hospitalization or ED visit (odds ratio [OR] 1.5 [95% confidence interval [CI]: 1.1 – 1.9] P =0.01).
Conclusion
Vitamin D insufficiency is common in this population of North American children with mild to moderate persistent asthma, and is associated with higher odds of severe exacerbation over a four year period.
doi:10.1016/j.jaci.2010.03.043
PMCID: PMC2902692  PMID: 20538327
Asthma; Vitamin D; inhaled corticosteroids; asthma exacerbations
15.  Patterns of inhaled corticosteroid use and asthma control in the Childhood Asthma Management Program Continuation Study 
Background
Daily controller medication use is recommended for children with persistent asthma to achieve asthma control.
Objective
To examine patterns of inhaled corticosteroid (ICS) use and asthma control in an observational study of children and adolescents with mild-to-moderate asthma (the Childhood Asthma Management Program Continuation Study).
Methods
We assessed patterns of ICS use during a 12-month period (consistent, intermittent, and none) and asthma control (well controlled vs poorly controlled). Multivariate logistic regression examined the association between pattern of ICS use and asthma control.
Results
Of 914 patients enrolled, 425 were recommended to continue receiving ICS therapy in the Childhood Asthma Management Program Continuation Study. Of these patients, 46% reported consistent ICS use and 20% reported no ICS use during year 1. By year 4, consistent ICS use decreased to 20%, whereas no ICS use increased to 57%; poorly controlled asthma was reported in 18% of encounters. In multivariate models controlling for age, sex, forced expiratory volume in 1 second, and asthma severity assessment, patients reporting consistent ICS use during a 12-month period were more likely to report poor asthma control (odds ratio, 1.6; 95% confidence interval, 1.2–2.1) compared with those reporting no ICS use.
Conclusions
In this observational study of children and adolescents with mild-to-moderate asthma, most did not report continued use of ICS. Patients recommended to continue receiving ICS therapy and reporting consistent ICS use were less likely to report well-controlled asthma even after controlling for markers of asthma severity. Although residual confounding by severity cannot be ruled out, many children and adolescents may not achieve well-controlled asthma despite consistent use of ICS.
doi:10.1016/j.anai.2009.11.004
PMCID: PMC3040975  PMID: 20143642
16.  Identifying the components of asthma health status in children with mild to moderate asthma 
Background
Weak and inconsistent correlations between measurements of asthma health status suggest that the disease is composed of non-overlapping components.
Objective
Factor analysis was used to explore the relationships between measures of asthma morbidity and to identify heterogeneous components of asthma health status in 5 to 12 year old children. Results were compared across time (baseline and 48 month visit) and treatment arms.
Methods
Analyses were conducted in 7 different study windows in a database from a large clinical trial of children with mild to moderate asthma (n=1041). Measurements of lung function, symptoms and health care utilizations from daily diary cards, serum IgE levels, total eosinophil count, skin test positivity, and airway hyper-responsiveness were included. Data on fractional exhaled nitric oxide (FENO) and sputum eosinophil cationic protein (ECP) was included in a subgroup of patients.
Results
In each of the study windows, factor analysis identified 5 factors which explained between 50% and 60% of the common variance. Factors identified included: (1) inflammatory markers, (2) symptoms/medication use, (3) asthma exacerbations, and measures of lung function which subdivided into (4) Forced Expiratory Volume (FEV1 ) and Forced Vital Capacity (FVC), (5) Bronchodilator response and the FEV1/FVC ratio. Exploratory analyses suggest that FENO comprise the atopy/inflammatory marker factor, and sputum measurements comprise a 6th, separate factor.
Conclusion
The consistent identification of a five factor structure across time and treatment arms suggests that each of these factors provides independent information in the assessment of asthma.
Clinical Implications
This study confirms the importance of a multidimensional approach to asthma in the clinical setting.
doi:10.1016/j.jaci.2008.02.015
PMCID: PMC3036169  PMID: 18466785
factor analysis; asthma health status; components; associations; morbidity
17.  Clinical Predictors and Outcomes of Consistent Bronchodilator Response in the Childhood Asthma Management Program 
Background
Among asthmatics, bronchodilator response (BDR) to inhaled ß2- adrenergic agonists is variable, and the significance of a consistent response over time is unknown.
Objective
We assessed baseline clinical variables and determined the clinical outcomes associated with a consistently positive BDR over 4 years in children with mild-moderate persistent asthma.
Methods
In the 1,041 participants in the Childhood Asthma Management Program (CAMP), subjects with a change in FEV1 of 12% or greater (and 200mLs) after inhaled ß2 agonist at each of their yearly follow-up visits (consistent BDR) were compared with those who did not have a consistent BDR.
Results
We identified 52 children with consistent BDR over the 4-year trial. Multivariable logistic regression modeling demonstrated that baseline pre-bronchodilator FEV1 (OR=0.71, p<0.0001), log 10 IgE level (OR=1.97, p=0.002), and lack of treatment with inhaled corticosteroids (OR=0.31, p=0.009) were associated with a consistent BDR. Individuals who had a consistent BDR had more hospital visits (p=0.007), required more prednisone bursts (p=0.0007), had increased nocturnal awakenings due to asthma (p<0.0001), and missed more days of school (p=0.03) than non-responders during the 4-year follow-up.
Conclusions
We have identified predictors of consistent BDR and determined that this phenotype is associated with poor clinical outcomes.
doi:10.1016/j.jaci.2008.09.004
PMCID: PMC2947830  PMID: 18848350
asthma; consistent bronchodilator response; outcomes
18.  Predictors of poor response during asthma therapy differ with definition of outcome 
Pharmacogenomics  2009;10(8):1231-1242.
Aims
To evaluate phenotypic and genetic variables associated with a poor long-term response to inhaled corticosteroid therapy for asthma, based independently on lung function changes or asthma exacerbations.
Materials & methods
We tested 17 phenotypic variables and polymorphisms in FCER2 and CRHR1 in 311 children (aged 5–12 years) randomized to a 4-year course of inhaled corticosteroid during the Childhood Asthma Management Program (CAMP).
Results
Predictors of recurrent asthma exacerbations are distinct from predictors of poor lung function response. A history of prior asthma exacerbations, younger age and a higher IgE level (p < 0.05) are associated with recurrent exacerbations. By contrast, lower bronchodilator response to albuterol and the minor alleles of RS242941 in CRHR1 and T2206C in FCER2 (p < 0.05) are associated with poor lung function response. Poor lung function response does not increase the risk of exacerbations and vice versa (p = 0.72).
Conclusion
Genetic and phenotypic predictors of a poor long-term response to inhaled corticosteroids differ markedly depending on definition of outcome (based on exacerbations vs lung function). These findings are important in comparing outcomes of clinical trials and in designing future pharmacogenetic studies.
doi:10.2217/PGS.09.86
PMCID: PMC2746392  PMID: 19663668
asthma; corticosteroid; exacerbation; lung function; pharmacogenetics
19.  Airway Responsiveness in Mild to Moderate Childhood Asthma 
Rationale: Airway responsiveness is a prognostic marker for asthma symptoms in later life.
Objectives: To evaluate characteristics responsible for persistence of airway responsiveness in children with asthma.
Methods: A total of 1,041 children, initially aged 5–12 years, with mild to moderate persistent asthma enrolled in the Childhood Asthma Management Program (CAMP) were studied prospectively for 8.6 ± 1.8 years with methacholine challenges yearly.
Measurements and Main Results: Least squares geometric mean models were fit to determine effects of sex and age on airway responsiveness (provocative concentration producing 20% decrease in FEV1 [PC20]). Multiple linear regression analysis was performed to determine factors at baseline and over time, which were associated with PC20 at end of follow-up. A total of 7,748 methacholine challenges were analyzed. PC20 increased with age, with boys having greater increase after age 11 years than girls (P < 0.001). The divergence coincided with the mean age for Tanner stage 2. Postpubertal girls had greater airway responsiveness, even after adjustment for FEV1 and other potential confounders. Although multivariable regression analyses noted a variety of factors that influenced airway responsivness in both sexes, a history of hay fever (β= −0.30, P = 0.005), respiratory allergy (β= −0.32, P = 0.006), or recent inhaled corticosteroid usage (β= −0.18, P = 0.02) were associated with decrements in final log PC20 only in girls.
Conclusions: Airway responsiveness (PC20) is more severe in the postpubertal female with asthma than in males. Although there are factors associated with airway responsiveness in both males and females, sex-specific factors may contribute to new insights into asthma pathogenesis.
doi:10.1164/rccm.200708-1174OC
PMCID: PMC2542438  PMID: 18420965
methacholine; PC20; FEV1; bronchoconstriction
20.  Practice-Level Effects of Interventions to Improve Asthma Care in Primary Care Settings: The Pediatric Asthma Care Patient Outcomes Research Team 
Health Services Research  2005;40(6 Pt 1):1737-1757.
Objective
To assess the practice-level effects of (1) a physician peer leader intervention and (2) peer leaders in combination with the introduction of asthma education nurses to facilitate care improvement. And, to compare findings with previously reported patient-level outcomes of trial enrollees.
Study Setting
Data were included on children 5–17 years old with asthma in 40 primary care practices, affiliated with managed health care plans enrolled in the Pediatric Asthma Care Patient Outcomes Research Team (PORT) randomized trial.
Study Design
Primary care practices were randomly assigned to one of two care improvement arms or to usual care. Automated claims data were analyzed for 12-month periods using a repeated cross-sectional design. The primary outcome was evidence of at least one controller medication dispensed among patients with persistent asthma. Secondary outcomes included controller dispensing among all identified asthmatics, evidence of chronic controller use, and the dispensing of oral steroids. Health service utilization outcomes included numbers of ambulatory visits and hospital-based events.
Principal Findings
The proportion of children with persistent asthma prescribed controllers increased in all study arms. No effect of the interventions on the proportion receiving controllers was detected (peer leader intervention effect 0.01, 95 percent confidence interval [CI]: −0.07, 0.08; planned care intervention effect −0.03, 95 percent CI: −0.09, 0.02). A statistical trend was seen toward an increased number of oral corticosteroid bursts dispensed in intervention practices. Significant adjusted increases in ambulatory visits of 0.08–0.10 visits per child per year were seen in the first intervention year, but only a statistical trend in these outcomes persisted into the second year of follow-up. No differences in hospital-based events were detected.
Conclusions
This analysis showed a slight increase in ambulatory asthma visits as a result of asthma care improvement interventions, using automated data. The absence of detectable impact on medication use at the practice level differs from the positive intervention effect observed in patient self-reported data from trial enrollees. Analysis of automated data on nonenrollees adds information about practice-level impact of care improvement strategies. Benefits of practice-level interventions may accrue disproportionately to the subgroup of trial enrollees. The effect of such interventions may be less apparent at the level of practices or health plans.
doi:10.1111/j.1475-6773.2005.00451.x
PMCID: PMC1361234  PMID: 16336546
Asthma care; randomized controlled trial; chronic care model; physician behavior change
22.  TLC-Asthma: An Integrated Information System for Patient-centered Monitoring, Case Management, and Point-of-Care Decision Support 
A great deal of successful work has been done in the area of EMR development, implementation, and evaluation. Less work has been done in the area of automated systems for patients. Efforts to link data at multiple levels – the patient, the case manager, and the clinician have been rudimentary to-date.
In this paper we present a model information system that integrates patient health information across multiple domains to support the monitoring and care of children with persistent asthma. The system has been developed for use in a multi-specialty group practice and includes three primary components: 1) a patient-centered telephone-linked communication system; 2) a web-based alert reporting and nurse case-management system; and 3) EMR-based provider communication to support clinical decision making at the point-of-care.
The system offers a model for a new level of connectivity for health information that supports customized monitoring, IT-enabled nurse case-managers, and the delivery of longitudinal data to clinicians to support the care of children with persistent asthma.
Systems like the one described are well -suited, perhaps essential, technologies for the care of children and adults with chronic conditions such as asthma.
PMCID: PMC1480156  PMID: 14728122

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