Person:

Fuhlbrigge, Anne

Aim: To identify the clinical and economic circumstances under which a pharmacogenomic test that predicts response to inhaled corticosteroids might be a cost-effective option for individuals with asthma.

Materials & methods: We synthesized published data on clinical and economic outcomes to project 10-year costs, quality-adjusted life-years and cost–effectiveness of pharmacogenomic testing for inhaled corticosteroid response. We assumed the pharmacogenomic test cost was $500 with a sensitivity and specificity of 84 and 98%, respectively. These were varied in sensitivity analyses.

Results: Both strategies, pharmacogenomic testing for inhaled corticosteroid response and no testing conferred 7.1 quality-adjusted life-years. Compared with no testing, pharmacogenomic testing costs less. Conclusion: Pharmacogenomic testing for asthma is cost-saving and noninferior in improving health.

Background: Although ambient air pollution has been linked to reduced lung function in healthy children, longitudinal analyses of pollution effects in asthma are lacking. Objective: To investigate pollution effects in a longitudinal asthma study and effect modification by controller medications. Methods: We examined associations of lung function and methacholine responsiveness (PC20) with ozone, carbon monoxide (CO), nitrogen dioxide (NO2) and sulfur dioxide (SO2) levels in 1,003 asthmatic children participating in a 4-year clinical trial. We further investigated whether budesonide and nedocromil modified pollution effects. Daily pollutant concentrations were linked to zip/postal code of residence. Linear mixed models tested associations of within-subject pollutant concentrations with FEV1 and FVC %predicted, FEV1/FVC and PC20, adjusting for seasonality and confounders. Results: Same-day and 1-week average CO levels were negatively associated with post-bronchodilator %predicted FEV1 (change(95%CI) per IQR: −0.33(−0.49, −0.16), −0.41(−0.62, −0.21), respectively) and FVC (−0.19(−0.25, −0.07), −0.25(−0.43, −0.07)). Longer-term four-month averages of CO were negatively associated with prebronchodilator %predicted FEV1 and FVC (−0.36(−0.62, −0.10), −0.21(−0.42, −0.01)). Four-month averaged CO and ozone levels were negatively associated with FEV1/FVC (p<0.05). Increased four-month average NO2 levels were associated with reduced post-bronchodilator FEV1 and FVC %predicted. Long-term exposures to SO2 were associated with reduced PC20 (%change(95%CI) per IQR:-6(-11,-1.5)). Treatment augmented the negative short-term CO effect on PC20. Conclusions: Air pollution adversely influences lung function and PC20 in asthmatic children. Treatment with controller medications may not protect but worsens the CO effects on PC20. This clinical trial design evaluates modification of pollution effects by treatment without confounding by indication.

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

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.