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Asthma and allergic disease impact millions of patients and are associated with high costs. Up to 30% of all medical care involves wasted spending. Across the spectrum of care provided by the allergist-immunologist, there are opportunities to improve value and reduce medical waste. Several examples highlight this reality. Evidence suggests that most patients may receive cost-effective care in the management of chronic spontaneous urticaria without the need for laboratory testing. For patients with asthma, although a single maintenance and reliever therapy approach may be cost-effective, insurance-mandated therapy changes are not, and may harm patients. Biologics may be very effective in improving asthma control but are too expensive for this indication-as demonstrated by cost-effectiveness analyses and highlighted by the Institute of Clinical and Economic Review, which concluded that the value-based price for asthma biologics ranges between $6500 and 14,3000 per year. Early introduction may prevent food allergy, but screening before first introduction is neither necessary nor cost-effective, although early salvage food oral immunotherapy may result in improved quality of life and cost savings. Evidence does not support the presence of allergic disease as a risk factor for anaphylaxis to coronavirus disease 2019 vaccination, and risk-stratified vaccination approaches do not appear cost-effective. Allergen immunotherapy is a very cost-effective treatment option. The practice of allergy-immunology has continued to evolve in recent years and can provide a leading example of high-value practice.

Purpose To describe the socioeconomic and healthcare-related effects of the COVID-19 pandemic, and willingness to receive a free COVID-19 vaccine, among African American/Black (AA/B) and Hispanic/Latinx (H/L) adults with asthma currently enrolled in a large trial. Methods The present analysis is a sub-study of the PeRson EmPowered Asthma RElief (PREPARE) study, a pragmatic study of 1201 AA/B and H/L adults with asthma. A monthly questionnaire was completed by a subset of PREPARE participants (n = 325) during May–August, 2020. The 5-item questionnaire assessed self-reported impact of COVID-19 on respondents’ ability to obtain asthma medications, medical care quality, employment, income and ability to pay bills; and willingness to get a free COVID-19 vaccine. Bivariate analysis and multivariate logistic regression were performed to investigate factors associated with vaccine hesitancy. Results Of 325 survey respondents (25% AA/B, 75% H/L), the majority reported no impact of COVID-19 on medical care or ability to get asthma medications. Approximately half of employed respondents experienced a lower level of employment or job loss, and approximately half reported having difficulty paying bills during the pandemic. Thirty-five percent of respondents reported unwillingness and 31% reported being somewhat likely to receive a free COVID-19 vaccine. AA/B race/ethnicity and poorer reported physical health were associated with a higher likelihood of COVID-19 vaccine hesitancy. Conclusion AA/B and H/L adults with asthma may experience changes in the quality of their asthma care and increased socioeconomic stressors as a result of the COVID-19 pandemic and may be hesitant or unwilling to receive a COVID-19 vaccine.

Background Hypogammaglobulinemia (serum IgG levels Research Question To determine the relationship between hypogammaglobulinemia and the risk of hospitalization in patients with COPD. Study Design and Methods Serum IgG levels were measured on baseline samples from four COPD cohorts (n = 2,259): Azithromycin for Prevention of AECOPD (MACRO, n = 976); Simvastatin in the Prevention of AECOPD (STATCOPE, n = 653), Long-Term Oxygen Treatment Trial (LOTT, n = 354), and COPD Activity: Serotonin Transporter, Cytokines and Depression (CASCADE, n = 276). IgG levels were determined by immunonephelometry (MACRO; STATCOPE) or mass spectrometry (LOTT; CASCADE). The effect of hypogammaglobulinemia on COPD hospitalization risk was evaluated using cumulative incidence functions for this outcome and deaths (competing risk). Fine-Gray models were performed to obtain adjusted subdistribution hazard ratios (SHR) related to IgG levels for each study and then combined using a meta-analysis. Rates of COPD hospitalizations per person-year were compared according to IgG status. Results The overall frequency of hypogammaglobulinemia was 28.4%. Higher incidence estimates of COPD hospitalizations were observed among participants with low IgG levels compared with those with normal levels (Gray's test, P Interpretation Hypogammaglobulinemia is associated with a higher risk of COPD hospital admissions.

Background Although inhaled therapy reduces exacerbations among patients with COPD, the effectiveness of providing inhaled treatment per risk stratification models remains unclear. Research Question Are inhaled regimens that align with the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy associated with clinically important outcomes? Study Design and Methods We conducted secondary analyses of Long-term Oxygen Treatment Trial (LOTT) data. The trial enrolled patients with COPD with moderate resting or exertional hypoxemia between 2009 and 2015. Our exposure was the patient-reported inhaled regimen at enrollment, categorized as either aligning with, undertreating, or potentially overtreating per the 2017 GOLD strategy. Our primary composite outcome was time to death or first hospitalization for COPD. Additional outcomes included individual components of the composite outcome and time to first exacerbation. We generated multivariable Cox proportional hazard models across strata of GOLD-predicted exacerbation risk (high vs low) to estimate between-group hazard ratios for time to event outcomes. We adjusted models a priori for potential confounders, clustered by site. Results The trial enrolled 738 patients (73.4% men; mean age, 68.8 years). Of the patients, 571 (77.4%) were low risk for future exacerbations. Of the patients, 233 (31.6%) reported regimens aligning with GOLD recommendations; most regimens (54.1%) potentially overtreated. During a 2.3-year median follow-up, 332 patients (44.9%) experienced the composite outcome. We found no difference in time to composite outcome or death among patients reporting regimens aligning with recommendations compared with undertreated patients. Among patients at low risk, potential overtreatment was associated with higher exacerbation risk (hazard ratio, 1.42; 95% CI, 1.09-1.87), whereas inhaled corticosteroid treatment was associated with 64% higher risk of pneumonia (incidence rate ratio, 1.64; 95% CI, 1.01-2.66). Interpretation Among patients with COPD with moderate hypoxemia, we found no difference in clinical outcomes between inhaled regimens aligning with the 2017 GOLD strategy compared with those that were undertreated. These findings suggest the need to reevaluate the effectiveness of risk stratification model-based inhaled treatment strategies.

Asthma disproportionately affects African American/Black (AA/B) and Hispanic/Latinx (H/L) patients and individuals with low socioeconomic status (SES), but the relationship between SES and asthma morbidity within these racial/ethnic groups is inadequately understood.To determine the relationship between SES and asthma morbidity among AA/B and H/L adults with moderate to severe asthma using multidomain SES frameworks and mediation analyses.We analyzed enrollment data from the PeRson EmPowered Asthma RElief randomized trial, evaluating inhaled corticosteroid supplementation to rescue therapy. We tested for direct and indirect relationships between SES and asthma morbidity using structural equation models. For SES, we used a latent variable defined by poverty, education, and unemployment. For asthma morbidity, we used self-reported asthma exacerbations in the year before enrollment (corticosteroid bursts, emergency room/urgent care visits, or hospitalizations), and Asthma Control Test scores. We tested for mediation via health literacy, perceived stress, and self-reported discrimination. All models adjusted for age, sex, body mass index, ethnicity, and comorbidities.Among 990 AA/B and H/L adults, low SES (latent variable) was directly associated with hospitalizations (β = 0.24) and worse Asthma Control Test scores (β = 0.20). Stress partially mediated the relationship between SES and increased emergency room/urgent care visits and worse asthma control (β = 0.03 and = 0.05, respectively). Individual SES domains were directly associated with asthma morbidity. Stress mediated indirect associations between low educational attainment and unemployment with worse asthma control (β = 0.05 and = 0.06, respectively).Lower SES is directly, and indirectly through stress, associated with asthma morbidity among AA/B and H/L adults. Identification of stressors and relevant management strategies may lessen asthma-related morbidity among these populations.

Summary Background Occurrence of severe asthma exacerbations are the cornerstone of the evaluation of asthma management, but severe asthma exacerbations are rare events. Therefore, trials that assess drug efficacy on exacerbations are done late in clinical development programmes. We aimed to establish an endpoint capturing clinically relevant deteriorations (diary events) that, when combined with severe exacerbations, create a composite outcome (CompEx). CompEx needs to strongly mirror results seen with the severe exacerbation-validated outcome, to allow the design of clinical trials of shorter duration and that include fewer patients than trials assessing severe exacerbations. Methods Data from 12 asthma trials of 6 months or 12 months duration and, with standardised collection of exacerbations and diary card variables, were used to construct and test CompEx. The study populations had a mean age of 35–53 years, 59–69% were female, and had a mean FEV 1 percentage of predicted normal of 63–84%. With data from five trials, we established a series of diary events based on peak expiratory flow (P), reliever use (R), symptoms (S), awakenings (A), and threshold values for change from baseline and slopes to assess trends. For the development phase, we evaluated different variable combinations and deterioration criteria to select the most robust algorithm to define a diary event for the composite outcome. We defined a composite outcome, CompEx, as first occurrence of a diary event or a severe exacerbation. We assessed the performance of CompEx in seven trials by comparing the event frequency, treatment effect (hazard ratio; HR), and the sample size needed for future trials for the CompEx versus episodes of severe exacerbations. Findings CompEx (based on PRS) was the algorithm that best fulfilled our two-set criteria. When censored at 3 months, CompEx resulted in 2·8 times more events than severe exacerbations, and while preserving the treatment effect observed on severe exacerbations (CompEx over severe exacerbation average HR 1·01). The increased number of events, together with the sustained treatment effect, resulted in a large net gain in power, with a 67% mean reduction in the number of patients required in a drug trial for severe exacerbations. In six of seven comparisons tested, CompEx reduced the sample size needed by at least 50%. Validation of independent test populations confirmed the ability of CompEx to increase event frequencies, preserve treatment effect, and reduce the number of patients needed. Interpretation CompEx is a composite outcome for evaluation of new asthma therapies. CompEx allows design of shorter trials that require fewer patients than studies of severe exacerbations, while preserving the ability to show a treatment effect compared with severe exacerbations. Funding AstraZeneca.

Background Asthma prevalence, morbidity, and mortality disproportionately impact African American/Black (AA/B) and Hispanic/Latinx (H/L) communities. Adherence to daily inhaled corticosteroid (ICS), recommended by asthma guidelines in all but the mildest cases of asthma, is generally poor. As-needed ICS has shown promise as a patient-empowering asthma management strategy, but it has not been rigorously studied in AA/B or H/L patients or in a real-world setting. Design and Aim The PeRson EmPowered Asthma RElief (PREPARE) Study is a randomized, open-label, pragmatic study which aims to assess whether a patient-guided, reliever-triggered ICS strategy called PARTICS (Patient-Activated Reliever-Triggered Inhaled CorticoSteroid) can improve asthma outcomes in AA/B and H/L adult patient populations. In designing and implementing the study, the PREPARE research team has relied heavily on advice from AA/B and H/L Patient Partners and other stakeholders. Methods PREPARE is enrolling 1200 adult participants (600 AA/Bs, 600H/Ls) with asthma. Participants are randomized to PARTICS + Usual Care (intervention) versus Usual Care (control). Following a single in-person enrollment visit, participants complete monthly questionnaires for 15 months. The primary endpoint is annualized asthma exacerbation rate. Secondary endpoints include asthma control; preference-based quality of life; and days lost from work, school, or usual activities. Discussion The PREPARE study features a pragmatic design allowing for the real-world assessment of a patient-centered, reliever-triggered ICS strategy in AA/B and H/L patients. Outcomes of this study have the potential to offer powerful evidence supporting PARTICS as an effective asthma management strategy in patient populations that suffer disproportionately from asthma morbidity and mortality.

BACKGROUND: Little is known about specialist-specific variations in guideline agreement and adoption. OBJECTIVE: To assess similarities and differences between allergists and pulmonologists in adherence to cornerstone components of the National Asthma Education and Prevention Program’s Third Expert Panel Report (EPR-3). METHODS: Self-reported guideline agreement, self-efficacy and adherence were assessed in allergists (n=134) and pulmonologists (n=99) in the 2012 National Asthma Survey of Physicians. Multivariate models were used to assess if physician and practice characteristics explained bivariate associations between specialty and “almost always” adhering to recommendations (i.e., ≥75% of the time). RESULTS: Allergists and pulmonologists reported high guideline self-efficacy and moderate guideline agreement. Both groups “almost always” assessed asthma control (66.2%, SE 4.3), assessed school/work asthma triggers (71.3%, SE 3.9), and endorsed inhaled corticosteroids use (95.5%, SE 2.0). Repeated assessment of inhaler technique, use of asthma action/treatment plans and spirometry were lower (39.7%, SE 4.0, 30.6%, SE 3.6, 44.7%, SE 4.1, respectively). Compared to pulmonologists, more allergists almost always performed spirometry (56.6% vs 38.6%, P=.06), asked about nighttime awakening (91.9% vs 76.5%, P=.03) and ED visits (92.2% vs 76.5%, P=0.03), assessed home triggers (70.5% vs 52.6%, P=.06) and performed allergy testing (61.8% vs 21.3%, P

Background Underuse of guideline-recommended inhaled corticosteroids (ICS) controller therapy is a risk factor for greater asthma burden. ICS concomitantly-used with rescue inhalers [Patient-Activated Reliever-Triggered ICS(‘PARTICS’)] reduced asthma exacerbations in efficacy trials, but whether PARTICS is effective in pragmatic trials is unknown. Objective We conducted this pilot to determine the feasibility of executing a large-scale pragmatic PARTICS trial and to improve study protocols. Methods Four sites recruited 33 Hispanic or Black persistently asthmatic adults, randomized them ∼3:1 to intervention or usual care, and followed them for 12 weeks. All participants received asthma guideline-based educational videos; intervention participants received video-based instructions on implementing PARTICS plus usual medications. The study involved one randomization visit and monthly questionnaires. Timely questionnaire responses (+/-2 weeks) were monitored. Participants underwent qualitative phone interviews to assess self-reported adherence to PARTICS and understand barriers to completing study procedures. Results Timely questionnaire response rates were 61%, 64%, 70% at 4, 8 and 12 weeks, respectively. Self-reported adherence to PARTICS was 76% [95%CI 58-94%(n=21)], 88% [95%CI 72-100%(n=16)], and 62% [95%CI 36-88%(n=13)] at weeks 1, 6, and 12, respectively. Barriers to completing study procedures included difficulties with questionnaire access, remembering to use ICS and rescue inhalers together, and obtaining refills. Only 22% of participants recognized their short-acting bronchodilator as “reliever” or “rescue”. Conclusion Recruitment was feasible within the allocated period. Adherence to PARTICS was incomplete, questionnaire completion was suboptimal, and common rescue inhaler nomenclature usage was limited. We have modified the full study protocol to attempt to improve adherence to PARTICS and minimize barriers to study procedures.

Summary Background Lung transplant is the only available therapy for patients with advanced lung disease. The goal of this study was to examine the prevalence, origin, management and outcome of lung cancer in recipients of lung transplant at our institution. Methods After institutional review board approval, we conducted a retrospective chart review of all lung transplantations in our institution from January 1990 until June 2012. Results The prevalence of lung cancer in the explanted lung was 6 (1.2%) of 462 and all cases were in subjects with lung fibrosis. All 4 subjects with lymph node involvement died of causes related to the malignancy. Nine (1.9%) of 462 patients were found to have bronchogenic carcinoma after lung transplant. The most common location was in the native lung in recipients of a single lung transplant (6 out of 9 patients). In one case, the tumor originated in the allograft and was potentially donor related. The median time to diagnosis after lung transplant was 28 months with a range from 9 months to 10 years. Median survival was 8 months, with tumors involving lymph nodes or distant metastases associated with a markedly worse prognosis (median survival 7 months) than stage I disease (median survival 27 months). Conclusions The prevalence of lung cancer in lung transplant recipients is low. Using accepted donor screening criteria, donor derived malignancy is exceptionally rare. While stage I disease is associated with improved survival in this cohort, survival is still not comparable to that of the general population, likely influenced by the need for aggressive immune suppression.

Introduction The Expert Panel Report-3 (EPR-3) guideline recommends a stepwise approach to attain asthma control. We examined the association between asthma control and EPR-3 step in a managed-care population with asthma. Methods Retrospective analysis of patient survey responses from the Observational Study of Asthma Control and Outcomes. Eligible patients with persistent asthma aged ≥12 years received 4 identical surveys (Waves [W]1–4), which included the 5-item Asthma Control Questionnaire (ACQ-5), over 15 months. Unadjusted mean ACQ-5 scores were compared across EPR-3 steps (S)2–6 (S1 results excluded due to group heterogeneity). Adjusted regression analyses (± baseline-controlled [W1 ACQ-5 score]) were conducted for W2 only (reference category: S2). Results Mean (SD) ACQ-5 scores were higher/worse for patients in higher EPR-3 steps: S2(n=994), 0.84(0.79); S3(n=1314), 0.87(0.77); S4(n=1138), 1.03(0.90); S5(n=937), 1.11(0.91); S6(n=79), 1.50(1.21). Similarly, in regression analyses uncontrolled for baseline, ACQ-5 scores were statistically significantly worse in higher EPR-3 steps (S4–S6) vs S2 (Table) (R2=0.13). Statistical significance did not persist in baseline-controlled analyses, and for each one-point increase in baseline ACQ-5 score, W2 score was 0.61 points higher (Table). This result, in addition to significantly higher R2 (R2=0.45), suggests that baseline ACQ-5 score is more predictive of future scores than EPR-3 step categorization. Conclusions A statistically significant relationship was observed between ACQ-5 score and EPR-3 S4–6. However, baseline ACQ-5 score was more predictive of asthma control than EPR-3 step categorization. Individual baseline characteristics (e.g. asthma phenotype, disease severity, comorbidities) may have a more important association with asthma control than treatment step.

The presence of interstitial pneumonitis (IP) on surveillance lung biopsy specimens in lung transplant recipients is poorly described, and its impact on posttransplant outcomes is not established. The following study assessed the association of posttransplant IP with the development of bronchiolitis obliterans syndrome (BOS).We examined all recipients of primary cadaveric lung transplants at our institution between January 1, 2000, and December 31, 2007 (N = 145). Patients had bronchoscopies with BAL, and transbronchial biopsies performed for surveillance during posttransplant months 1, 3, 6, and 12 as well as when clinically indicated. Patients were given a diagnosis of IP if, in the absence of active infection and organizing pneumonia, they showed evidence of interstitial inflammation and fibrosis on two or more biopsy specimens.IP was a significant predictor of BOS (OR, 7.84; 95% CI, 2.84-21.67; Plt; .0001) and was significantly associated with time to development of BOS (hazard ratio, 3.8; 95% CI, 1.93-7.39; P = .0001) within the first 6 years posttransplant. The presence of IP did not correlate with a significantly higher risk of mortality or time to death. There was no association between the presence of IP and the development of or time to acute rejection.The presence of IP on lung transplant biopsy specimens suggests an increased risk for BOS, which is independent of the presence of acute cellular rejection.

Background Formal economic evaluation using a model-based approach is playing an increasingly important role in health care decision making. Objective To develop a model by using an objective measure of lung function— prebronchodilator FEV 1 as a percent of predicted (FEV 1 % predicted)—as the primary independent factor to predict the frequency of adverse events related to the exacerbation of asthma on a population level. Methods We developed a Markov simulation model of childhood asthma by using data from the Childhood Asthma Management Program. 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 the Childhood Asthma Management Program with covariates of age, prebronchodilator FEV 1 % 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. Conclusions Our findings suggest that longitudinal intervention effects may be modeled through FEV 1 % predicted to estimate hospitalizations, ED visits, and need for oral corticosteroid therapy in childhood asthma for planning and evaluation purposes.

SummaryBackgroundAcute exacerbations are a significant source of morbidity and mortality associated with chronic obstructive pulmonary disease. Among individuals 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.MethodsCase-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.ResultsPhysician-diagnosed asthma was a significant predictor of frequent exacerbations. Within a subset of our cohort, the modified Medical Research Council dyspnea score and FEF 25–75% predicted were also significant clinical predictors of frequent exacerbator status (p

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 children with asthma. 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 (ICSs). Methods To assess the impact of parent-reported IUS exposure on airway responsiveness in childhood asthma, we performed a repeated-measures analysis of methacholine PC 20 data from the Childhood Asthma Management Program, a 4-year, multicenter, randomized, double-masked, placebo-controlled trial of 1041 children age 5 to 12 years comparing the long-term efficacy of ICS with mast cell stabilizing agents or placebo. Results Although improvement was seen in both groups, children with asthma and IUS exposure had on average 26% less of an improvement in airway responsiveness over time compared with unexposed children ( P = .01). Moreover, while children who were not exposed to IUS who received budesonide experienced substantial improvement in PC 20 compared with 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). Conclusion In utero smoke exposure reduces age-related improvements in airway responsiveness among children with asthma. 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.

Background CT scan measures of emphysema and airway disease have been correlated with lung function in cohorts of subjects with a range of COPD severity. The contribution of CT scan-assessed airway disease to objective measures of lung function and respiratory symptoms such as dyspnea in severe emphysema is less clear. Methods Using data from 338 subjects in the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study, densitometric measures of emphysema using a threshold of −950 Hounsfield units (%LAA-950) and airway wall phenotypes of the wall thickness (WT) and the square root of wall area (SRWA) of a 10-mm luminal perimeter airway were calculated for each subject. Linear regression analysis was performed for outcome variables FEV 1 and percent predicted value of FEV 1 with CT scan measures of emphysema and airway disease. Results In univariate analysis, there were significant negative correlations between %LAA-950 and both the WT ( r = −0.28, p = 0.0001) and SRWA ( r = −0.19, p = 0.0008). Airway wall thickness was weakly but significantly correlated with postbronchodilator FEV 1 % predicted (R = −0.12, p = 0.02). Multivariate analysis showed significant associations between either WT or SRWA (β = −5.2, p = 0.009; β = −2.6, p = 0.008, respectively) and %LAA-950 (β = −10.6, p = 0.03) with the postbronchodilator FEV 1 % predicted. Male subjects exhibited significantly thicker airway wall phenotypes (p = 0.007 for WT and p = 0.0006 for SRWA). Conclusions Airway disease and emphysema detected by CT scanning are inversely related in patients with severe COPD. Airway wall phenotypes were influenced by gender and associated with lung function in subjects with severe emphysema.

Although inhaled corticosteroids (ICSs) generally protect against severe exacerbations in asthma, they may result in elevated IgE levels, which are associated with exacerbations.To determine whether variation in the low-affinity IgE receptor gene, FCER2, is associated with severe exacerbations defined as emergency department visits and/or hospitalizations in patients with asthma on ICSs.We resequenced, then genotyped 10 FCER2 single nucleotide polymorphisms (SNPs) in 311 children randomized to inhaled budesonide as part of the Childhood Asthma Management Program. We evaluated the association of FCER2 variants with IgE levels and presence or absence of severe exacerbations over the 4-year clinical trial. We also evaluated differences in cellular expression of the novel FCER2 SNP, T2206C.In white subjects, 3 FCER2 SNPs were significantly associated (P.05) with elevated 4-year IgE level; each was also associated with increased severe exacerbations. Final multivariable models demonstrated associations between T2206C and severe exacerbations in both white and African American children (hazard ratio, 3.95; 95% CI, 1.64-9.51; and hazard ratio, 3.08; 95% CI, 1.00-9.47), despite ICS use. Interaction models supported a true gene-environment effect in white subjects (interaction P = .004). T2206C was also associated with decreased FCER2 expression (P = .02).FCER2 predicts the likelihood of treatment protocol success in asthma. The associations of T2206C with IgE level, severe exacerbations, and FCER2 expression may provide a mechanistic basis for the observed findings.Genetic variation in FCER2 may help form a prognostic model for ICS response in asthma.

Background The effects of inhaled corticosteroid (ICS) preparations on bone health have been debated. Multiple analyses have been published examining the question, with mixed results. Objectives We examined how assumptions about the effect of ICS on bone mineral density (BMD) influence the cost-effectiveness of ICS in asthma. Methods We developed a mathematical simulation model to estimate clinical outcomes and costs for a cohort with mild/moderate asthma. The analysis conformed to reference case recommendations of the US Panel on Cost-Effectiveness in Health and Medicine. Sensitivity analysis evaluated the stability of our results to uncertainty in treatment duration, age at treatment, and ICS dose. Results Assuming a dose of 200 μg twice per day of ICS, a literature-based average effect of ICS on BMD and a 10-year time horizon, we observed a minimal increase in the costs attributed to hip fracture and incremental cost effectiveness ratio of $26,000 per quality-adjusted life-year and $14.00 per symptom-free day gained. Over an extended the time horizon (lifetime), the incremental cost effectiveness ratio increased to $42,000/quality-adjusted life-year. Only under a scenario of high-dose ICS, a lifetime horizon, and a large effect of ICS on BMD did the potential impact of ICS on BMD dramatically affect the economic attractiveness of therapy. Conclusion To minimize any potential impact, use of the lowest effective dose of ICS and measures to target and intervene in high-risk individuals are warranted. However, ICS therapy in mild/moderate asthma compares favorably with commonly accepted interventions over a wide range of assumptions regarding this treatment and its effects on BMD.

In last month’s Journal, Szefler et al presented an article from the National Heart, Lung, and Blood Institute Childhood Asthma Research and Education (CARE) Network on the characterization of response to 2 common therapies for childhood asthma. The article establishes a definition of response as the percent change in prebronchodilator FEV1 7.5%. The importance of the article is that it selected a working definition of response and then attempted to assess whether predictors of response could be determined. The article by Szefler et al takes a systematic look at one definition of response and serves as an example for future discussion of how one characterizes a responder. A limitation in the interpretation of the asthma literature is the inconsistency in the definition of response. The heterogeneity and variability of asthma make it difficult to achieve consensus for this term. This is compounded by the lack of a standardized means to assess asthma control, a measure of response. Should response to an intervention be defined primarily by objective parameters, subjective symptom reports, or a composite measure? Is the observed response to an intervention clinically as well as statistically significant, and how has the choice of primary outcome and sample size influenced these results? In addition, which parameters should be more appropriately thought of as markers of disease severity than measures of response? If these issues are difficult for the specialist and researcher to resolve, how can we provide guidance to our primary care colleagues when they read the asthma literature? The definition of responder is increasingly important as the number of assessment tools multiplies beyond traditional clinical trials to include observational investigations, studies of patients with specific phenotypes

In 1998, the economic burden of asthma in the United States was estimated to be 12.7 billion dollars. Yet few studies have examined the relationship between the total costs of asthma-related care and measures of asthma morbidity. Understanding the relationship between total costs of asthma-related care and morbidity can assist in designing the most cost-effective asthma care strategies to improve patient outcomes and minimize total costs.To investigate correlates of asthma costs for children with mild-to-moderate persistent asthma and, specifically, to characterize how closely the percentage of predicted forced expiratory volume in 1 second (FEV1) and symptom days were correlated with costs of illness.A total of 638 parents and children with mild-to-moderate persistent asthma in 4 managed care delivery systems in 3 different US geographic regions were enrolled. Symptom burden and annual resource utilization were determined from reports of physician visits, hospitalizations, emergency department visits, medication use, and parental missed workdays. Spirometry was conducted on children who were 5 years and older. To characterize the relationship between symptom days and the percentage of predicted FEV1 with costs, we specified a multivariate regression model.The median total annual asthma-related cost for the group was 564 dollars (interquartile range [IQR], 131 dollars-1602 dollars). Indirect costs represented 54.6% of total costs. Medicines accounted for 52.6% of direct costs. The mean percentage of predicted FEV1 was 101.6% (range, 39.3%-183.5%; IQR, 91.6%-111.3%), with 91.4% of patients with a percentage of predicted FEV1 of more than 80%. Based on multivariate modeling, increasing asthma severity, use of peak expiratory flow rate meters, younger age, low-income status and nonwhite race, and longer duration of asthma were significantly associated with increasing cost. Symptom days (P0.001) predicted annual costs better than percentage of predicted FEV1 (P0.16) in this group of children.For the large number of children with mild-to-moderate persistent asthma and normal or near-normal lung function, symptom days are predictive of health care costs. For these insured children receiving care from 3 large managed care providers, low-income status and nonwhite race were the strongest correlates for increased asthma-related costs.

Studies examining the influence of provider behavior and patterns of care delivery on the use of anti-inflammatory asthma therapy have been limited to selected populations or have been unable to assess the appropriateness of therapy for individuals. We have previously reported the influence of sociodemographic variables and asthma severity on reported use of asthma medications in the United States.We sought to examine the influence of patterns of care delivery and clinician behavioral factors on the use of anti-inflammatory medication by patients with asthma.We performed a cross-sectional national random digit dial household telephone survey in 1998 of adult patients and parents of children with current asthma. Respondents were classified as having current asthma if they had a physician's diagnosis of asthma and were either taking medication for asthma or had asthma symptoms during the past year.One or more persons met the study criteria for current asthma in 3273 (7.8%) households in which a screening questionnaire was completed. Of the 2509 persons (721 children16 years of age) with current asthma interviewed, 507 (20.1%) reported current use of anti-inflammatory medication. In a multiple logistic regression model controlling for asthma symptoms, reported anti-inflammatory use was significantly associated with patients reporting their physician having an excellent ability to explain asthma management (odds ratio [OR], 1.47; 95% CI, 1.09-1.98), scheduling regular visits to a physician for asthma (OR, 1.30; 95% CI, 1.02-1.64), having a written asthma action plan (OR, 1.63; 95% CI, 1.29-2.06), and being of white, non-Hispanic ethnicity (OR, 1.53; 95% CI, 1.19-1.98), along with markers of greater asthma morbidity, missing 6 or more days from work or school in the past year (OR, 1.29; 95% CI, 1.01-1.65), and hospitalization for asthma in the past year (OR, 1.74; 95% CI, 1.19-2.53). Anti-inflammatory use was less likely to be reported with younger age (OR, 0.82; 95% CI, 0.73-0.94), lower long-term asthma symptom burden (OR, 0.82; 95% CI, 0.71-0.94), use of 4 or fewer reliever inhaler canisters in the past year (OR, 0.50; 95% CI, 0.43-0.58), and smoking (OR, 0.50; 95% CI, 0.37-0.68).How asthma care is delivered influences the use of anti-inflammatory medication. Strategies to increase regular evaluation by a physician interested in asthma, particularly for minority patients, and to increase a physician's ability to communicate asthma management to patients might improve use of anti-inflammatory therapy among patients with asthma.

The preponderance of epidemiologic evidence demonstrates disparities in asthma burden when comparing females and males. Males develop asthma at a younger age than do females [1], and the incidence of asthma generally is reported to be higher in boys throughout preadolescence, resulting in a 2:1 male predominance in childhood [2,3]. The increased risk for asthma and wheeze among boys reverses at puberty, however, after which the incidence rate of asthma in girls increases, resulting in a 2:1 female predominance among adults [4–6]. These findings are demonstrated by De Marco and colleagues in a retrospective analysis of data from the European Respiratory Health Survey (Fig. 1). In infancy, girls have a lower risk for developing asthma than do boys, with a rate ratio (RR) for girls compared with boys ranging from 0.74 to 0.56 among children 10 years old or younger. At the time of puberty, the risk equalizes in both sexes (RR, 0.84; 95% confidence interval [CI], 0.66–1.12), and after puberty the risk is significantly higher in women than in men, ranging from 1.38 to 5.91 [7]. Among adults aged 25 to 74, being female has been shown to be the strongest predictor of incident cases of asthma [8]. There is evidence for a disparate increase in the prevalence of asthma between men and women. Between 1982 and 1992, the prevalence among US women increased 82% (from 2.9% to 5.4%) compared with an increase of 29% among men (4.0% to 5.1%) [9]. Other investigators suggest that the reversal in the prevalence rates of asthma among young adults is caused by a higher remission rate among boys and a higher incidence rate among girls [10–14].

Background: In patients with asthma, treatment for associated conditions, such as rhinitis, is recommended. It is unknown whether this treatment can reduce the risk for emergency department (ED) visits for asthma. Objectives: We sought to determine whether treatment with intranasal steroids or prescription antihistamines in persons with asthma is associated with a reduced risk for ED visits caused by asthma. Methods: We performed a retrospective cohort study of members of a managed care organization aged greater than 5 years who were identified during the period of October 1991 to September 1994 as having a diagnosis of asthma by using a computerized medical record system. The main outcome measure was an ED visit for asthma. Results: Of the 13,844 eligible persons, 1031 (7.4%) had an ED visit for asthma. The overall relative risk (RR) for an ED visit among those who received intranasal corticosteroids, adjusted for age, sex, frequency of orally inhaled corticosteroid and β-agonist dispensing, amount and type of ambulatory care for asthma, and diagnosis of an upper airways condition (rhinitis, sinusitis, or otitis media), was 0.7 (95% confidence interval [CI], 0.59-0.94). For those receiving prescription antihistamines, the risk was indeterminate (RR, 0.9; 95% CI, 0.78-1.11). When different rates of dispensing for intranasal steroids were examined, a reduced risk was seen in ED visits in those with greater than 0 to 1 (RR, 0.7; 95% CI, 0.57-0.99) and greater than 3 (RR, 0.5; 95% CI, 0.23-1.05) dispensed prescriptions per year. Conclusions: Treatment of nasal conditions, particularly with intranasal steroids, confers significant protection against exacerbations of asthma leading to ED visits for asthma. These results support the use of intranasal steroids by individuals with asthma and upper airways conditions. (J Allergy Clin Immunol 2002;109:636-42.)

Increasing morbidity due to asthma and antimicrobial resistance among human pathogens are both major public-health concerns. Numerous studies describe the overuse of antibiotics in general populations and underuse of anti-inflammatory medications by asthmatic patients. However, little is known about the relationship between asthma medication and antibiotic use in asthmatics. Specifically, we tested the hypothesis that higher use of bronchodilator and anti-inflammatory medication by asthmatics, as a marker of problematic asthma, is associated with greater antibiotic use. We also test the hypothesis that physicians who are low prescribers of anti-inflammatory medications are high prescribers of antibiotics.We conducted a retrospective cohort study evaluating asthma medication and antibiotic use by children and adults with asthma and the prescribing of these medications by primary-care physicians.Subjects were continuously enrolled asthma patients aged 6 to 55 years receiving care in an urban, group-model, health maintenance organization.None.Main outcome measures were (1) antibiotic use by asthmatics stratified by low, moderate, and high bronchodilator use; (2) antibiotic use by asthmatics stratified by no, intermittent, and long-term anti-inflammatory use; and (3) correlation between physician-level anti-inflammatory agent to bronchodilator ratio (AIF:BD) and their rate of antibiotic prescribing. We found that (1) high bronchodilator users received 1.72 antibiotics per person-year (95% confidence interval [CI], 1.62 to 1.83), whereas low bronchodilator users received 1.23 antibiotics per person-year (95% CI, 1.19 to 1.27; p0.0001); (2) long-term users of anti-inflammatory agents received 1.85 antibiotics per person-year (95% CI, 1.76 to 1.95), whereas those not receiving an anti-inflammatory agent received 0.95 antibiotics per person-year (95% CI, 0.90 to 1.00; p0.0001); and (3) despite variations in physician AIF:BDs and antibiotic prescribing, respectively, these measures were not correlated.Antibiotic use and asthma medication use are positively associated in a cohort of asthma patients. Greater effort is needed to define the appropriate role of antibiotics in asthma management.

Background: Asthma is the most common chronic disease among children and the most frequent cause of hospitalization. Appropriate pharmacotherapy is a cornerstone of published national guidelines for the care of children with asthma. Objective: The goal was to compare the baseline pharmacotherapy and health care utilization from 1996 to 1997 in children with asthma at managed care organizations (MCOs). Methods: A common protocol was used to extract the study sample from 3 MCOs with automated claims and pharmacy databases. Children were selected if they were 3 to 15 years old as of June 1997 with 1 or more encounters (outpatient, emergency department visit, hospitalization) with an asthma diagnosis in the previous year. Results: Of the 13,352 children studied, less than 40% were given controllers during the 12-month interval, with ranges of 15% to 77% by level of bronchodilator use, 31% to 44% by age, and 38% to 42% by MCO. Among children given 6 or more bronchodilators, controller dispensing ranged from 73% to 89% among the 3 MCOs. Variability was most evident for inhaled corticosteroids, for which dispensing ranged from 51% to 70%. Rates of asthma hospitalization and emergency department visits also differed among the MCOs, ranging from 21 to 37 per 1000 person-years and 37 to 142 per 1000 person-years, respectively. Conclusion: Five years after dissemination of national guidelines for care, the pattern of asthma therapy does not reflect guideline recommendations. Variation among health care organizations with respect to asthma therapy and utilization of health services exists. In addition, controller medications may not be used by all children who could benefit from them. (J Allergy Clin Immunol 2000;106:1108-14.)

Objectives: We wished to determine whether early rejection after lung transplantation as assessed by surveillance transbronchial biopsy predicts for survival. Methods: Between 1990 and 1997, 96 consecutive patients had lung transplantation: 89 had a minimum 1-month follow-up. For 71 consecutive patients we have 1-year follow-up and for 69 patients we have the results of the first 3 biopsies. Cytomegalovirus status, bronchiolitis obliterans prevalence, and use of total lymphoid irradiation are noted. Biopsies were done at 1 week and 1, 3, and 6 months. Standard immunosuppression consisted of induction antilymphocyte globulin and high-dose methylprednisolone induction for 1 week and standard maintenance triple therapy. Acute rejection treatment was with pulse methylprednisolone. Bronchiolitis obliterans syndrome was treated with total lymphoid irradiation and a change to tacrolimus and mycophenolate. Blinded grading using International Society for Heart and Lung Transplantation classification was done retrospectively. Results: Survival at 1 month and 1, 2, and 3 years for the 96-patient cohort with 1-year follow-up was 93%, 74%, 62%, and 56%. Survival was not significantly different for subsets with rejection on any combination of the first 3 biopsies (1/3, 2/3, 3/3) or absence of rejection on the first 3 biopsies. Ninety-one positive biopsy results were graded. Eighteen of 71 patients had one or more moderate or severe rejection episodes without survival difference relative to the others. There was no statistically significant association between acute rejection on the first 3 surveillance biopsy results and bronchiolitis obliterans. Conclusions: Intensive induction and maintenance immunotherapy with surveillance transbronchial biopsies and aggressive treatment of acute rejection is associated with a survival similar to that of patients without early acute rejection. This regimen appears to uncouple the association between early acute rejection and bronchiolitis obliterans. Further study may elucidate this mechanism. (J Thorac Cardiovasc Surg 2000;119:27-38)

The ability to predict and prevent future exacerbations has been a consistent focus of asthma research. Although some progress has been made on identifying factors associated with an increased risk of exacerbation at the population and individual levels, no measure or instrument is available for widespread use in the asthma community. In this issue of the Journal, Thamrin et al present a statistical method used to calculate the future exacerbation risk for a patient (as defined by deterioration in percent predicted peak expiratory flow [PEF]) based on the history of fluctuations in lung function (percent predicted PEF). The authors challenge us to reframe our analytic approach to asthma. Frey et al have suggested that a patient with asthma should be thought of as a complex, nonlinear dynamic systems network; such a network exhibits fluctuations over time in physiologic and clinical variables. However, such a system also exhibits memory effects, and although changes can occur over time, the recent past will include most of the pertinent information needed to predict the short-term future risk. Viewingasthma through this framework, it follows that the single best individual parameter to predict the risk of an exacerbation over the next year is the history of an exacerbation in the prior year. The natural history of asthma in any given patient is a summation of personal characteristics (eg, demographics, inflammatory profile, and lungmechanics), genetics, both the physical (exposure to environment [environmental tobacco smoke, pollution, and allergens]) and psychosocial (access to care) environment, and therapy (including adherence). The complex interaction of these factors results in the overall clinical phenotype expressed by a patient, and this helps explain why the recent past is a strong predictor of future events. Modeling asthma as a complex, nonlinear dynamic system also fits with our increasing recognition of the heterogeneity of asthma. Patients with asthma present differently in regard to symptoms, physiologic measures, inflammatory indices, and perception of obstruction; measuring a single parameter at a single point might not

Classifying asthma severity or activity has evolved, but there are no published weighted composite measures of asthma disease activity that account for the relative importance of the many individual clinical variables that are widely used.We sought to develop a weighted and responsive measure of asthma disease activity.Discriminant and multiple regression analyses based on 2 previously conducted clinical trials were used to develop the Asthma Disease Activity Score (ADAS-6).The ADAS-6 demonstrated content validity because its components assess different manifestations of asthma: FEV(1) (percent predicted), Asthma Quality of Life Questionnaire-Symptom domain, rescue β-agonist use, nocturnal awakenings, peak expiratory flow diurnal variability, and rescue β-agonist use diurnal variability. The ADAS-6 demonstrated cross-sectional and longitudinal validity. It was discriminating: it distinguished levels of disease activity and response to different treatment intensities (P.0001). Similar results were obtained with an independent clinical trial. The ADAS-6 was highly responsive to treatment effects, with a standardized effect size exceeding that of other widely used outcome measures. Using ADAS-6 as the primary end point in the montelukast pivotal trials would have significantly reduced the sample size needed to detect a comparable change in outcome. Furthermore, increments in the ADAS-6 predicted the risk of future asthma attacks. A simplified Asthma Disease Activity Score 4-variable version (ADAS-4) demonstrated similar measurement properties.The ADAS-6 and ADAS-4 are novel, weighted, and responsive measures of asthma disease activity. Use of these measures in clinical trials might better separate treatment effects, predict future asthma attacks, and substantially reduce sample size.

OBJECTIVE: To forecast the discounted costs and clinical consequences of inhaled corticosteroids (ICS) in a population of adults with mild-to-moderate asthma. METHODS: We developed a Markov, state-transition simulation of asthma patient care and its pharmacoeconomic impact. We employed this framework to compare quick relievers (e.g., b-agonists) on an as-needed basis to quick relievers plus ICS therapy targeted to one of three severity sub-populations. State-space dimensions included patient age, clinical history, and lung dysfunction (measured via forced expiratory volume in one second, FEV1). Risk functions were estimated from symptom, exacerbation, and hospitalization rates obtained from literature reviews and analyses of primary, cross-sectional data. Systematic review of published trials yielded 16 eligible studies and produced the following outcome ranges for sensitivity analysis: 1%–21% improvement in FEV1; monthly costs of $14–$76; and 0%–4% probability of major toxicity. Societal costs were derived from published economic studies of inpatient and outpatient asthma. We collected preference weights (using standard gambles, time trade-offs, and the Health Utilities Index) in a cross-sectional study of 100 adult asthmatics. RESULTS: The table reports outcomes over a 10-year period. Results were driven by the impact of ICS on quality of life, rather than on mortality. Findings were stable over most input data ranges. However, at efficacy levels below 3% and toxicity rates greater than 2.9%, the cost-effectiveness estimate exceeded $100,000/QALY. CONCLUSION: Results suggest that inhaled steroids deliver good comparative value in mild-to-moderate adult asthma. More research is needed, however, on the impact of ICS toxicity on patient preferences. Strategy Cost QALY $QALY Quick Relievers alone $5,185 6.77 — +ICS in moderate disease $5,961 6.84 $10,300 +ICS in mild disease $7,616 6.93 dominated +ICS in mild/mod. disease $8,392 7.00 $15,000

Rationale A decision to implement innovative disease management interventions in health plans often requires evidence of clinical benefit and financial impact. The Pediatric Asthma Care PORT II trial evaluated the outcomes of two asthma care strategies in children (ages 3 – 17) – a peer leader based physician behavior change intervention (PLE) and a practice-based redesign (Planned Asthma Care Intervention (PACI)). The purpose of this study is to estimate the cost-effectiveness of the interventions. Methods This was a three-arm cluster randomized trial conducted in 41 primary care practices within 3 managed care organizations. 638 children with mild to moderate persistent asthma were observed for up to two years. Practices were randomized to PLE (N=226), PACI (N=213) or usual care (N=199). The primary outcome was average symptom-free days (SFD) estimated from GEE models. Costs for the interventions, asthma-related hospitalizations, ED visits, office visits and medications were included. Non-medical costs were excluded. Results Mean annual costs per patient were: PACI=$1436, PLE=$970 and Usual Care=$388. The incremental difference in annual SFD for the interventions compared to usual care was 6.5 (95% CI −3.6 to 16.9 days) for PLE and 13.3 (95% CI 2.1 to 24.7 days) for PACI. Compared to usual care the incremental cost-effectiveness ratio (ICER) was $90 per SFD gained for PLE and $79 per SFD gained for PACI. In subgroup analyses, ICERs varied by child's age and baseline medication use. Conclusions The cost-effectiveness ratios of these interventions are greater than those of other asthma interventions tested in other settings.