Publications by authors named "Anne L Fuhlbrigge"

76 Publications

Building eConsult (Electronic Consults) Capability at an Academic Medical Center to Improve Efficiencies in Delivering Specialty Care.

J Prim Care Community Health 2021 Jan-Dec;12:21501327211005303

University of Colorado School of Medicine, Aurora, CO, USA.

As the COVID-19 health crisis continues to reshape healthcare, systems across the country face increasing pressure to adapt their models of care to expand access to care, while also improving efficiency and quality in the face of limited resources. Consequently, many have shown a growing interest and receptivity to the expansion of telehealth models to help meet these demands. Electronic consultations (eConsults) are a telehealth modality that allow for a non-face-to-face asynchronous consultation between a primary care provider (PCP) and a specialist aimed at facilitating specialist input without the need for a patient visit. The aim of this case study is to describe eConsults, how they differ from traditional in person models of care and other models of telemedicine and to review the evidence related to the effectiveness of eConsults by PCPs and clinicians from multiple specialties at the University of Colorado School of Medicine. We have worked to develop an infrastructure, delivery system integration, and care model adaptations that aim to improve delivery system performance by ensuring proper care in appropriate settings and lowering costs through reduced utilization. Lastly, we have increased care coordination, improved collaboration and better care transitions through strengthening of relationships between community-based PCPs and academic medical center-based specialists. This work has resulted in cost savings to patients and positive provider satisfaction.
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http://dx.doi.org/10.1177/21501327211005303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010812PMC
April 2021

Oral Corticosteroid Use in Asthma: A Wolf in Sheep's Clothing.

J Allergy Clin Immunol Pract 2021 Jan;9(1):347-348

Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO.

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http://dx.doi.org/10.1016/j.jaip.2020.10.014DOI Listing
January 2021

A randomized, open-label, pragmatic study to assess reliever-triggered inhaled corticosteroid in African American/Black and Hispanic/Latinx adults with asthma: Design and methods of the PREPARE trial.

Contemp Clin Trials 2021 Feb 11;101:106246. Epub 2020 Dec 11.

Division of Critical Care/Pulmonary, Baystate Health, Tolosky Center, 3300 Main Street, Suite 2B, Springfield, MA, United States of America. Electronic address:

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.
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http://dx.doi.org/10.1016/j.cct.2020.106246DOI Listing
February 2021

Impact of season and geography on CompEx Asthma: a composite end-point for exacerbations.

ERJ Open Res 2020 Oct 19;6(4). Epub 2020 Oct 19.

Early Respiratory and Immunology Clinical Development, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

Background: CompEx Asthma, a novel composite end-point combining severe exacerbations (SevEx) with asthma-worsening events, was recently developed. Further characterisation of CompEx Asthma is needed to illustrate the applicability of this end-point. The objective was to evaluate CompEx Asthma as a rate end-point to determine how seasonal and geographical factors impact this novel outcome.

Methods: Seven 24-56-week randomised controlled trials of budesonide/formoterol (BUD/FORM) and benralizumab were analysed. Annualised event rates (AERs) and treatment effects (hazard ratio (HR)) were analysed with Poisson and Andersen-Gill models, respectively. Seasonality was analysed by month and five geographical regions were evaluated.

Results: The studies included 10 815 patients (63% female, mean age 42-49 years). CompEx Asthma AER mirrored seasonal variations in SevEx AER. CompEx Asthma AERs were higher SevEx in BUD/FORM and benralizumab trials (range 2.7-4.5-fold and 1.3-2.0-fold increase, respectively) and were less variable SevEx between regions (ratios of greatest:smallest AERs: 1.36 for CompEx 2.28 for SevEx (BUD/FORM); 1.81 for CompEx 2.22 for SevEx (benralizumab)). Treatment effects for CompEx Asthma and SevEx were generally similar across regions and months. However, in Eastern Europe, where SevEx rates were lowest, treatment effect was greater with CompEx Asthma SevEx, reaching statistical significance in the benralizumab studies (HR (95% CI): 0.67 (0.53-0.85) 0.87 (0.65-1.15)).

Conclusion: This study confirmed the reliability of CompEx Asthma as a rate end-point and allowed detection of variations in seasonal SevEx rates, reduction of variation in rates across regions and potential greater sensitivity to treatment effects.
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http://dx.doi.org/10.1183/23120541.00246-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569167PMC
October 2020

Cost-Effectiveness of Biologics for Allergic Diseases.

J Allergy Clin Immunol Pract 2021 Mar 15;9(3):1107-1117.e2. Epub 2020 Oct 15.

Dartmouth-Hitchcock Medical Center, Section of Allergy and Immunology, Lebanon, NH; Geisel School of Medicine at Dartmouth, Departments of Pediatrics, of Medicine, and of Community and Family Medicine, Hanover, NH.

The introduction of specific humanized monoclonal antibodies over the past 20 years has dramatically changed the treatment of allergic diseases. At present, 5 mAbs are licensed for treating moderate to severe allergic and eosinophilic asthma, atopic dermatitis, chronic spontaneous urticaria, chronic sinusitis with nasal polyps, and eosinophilic granulomatosis with polyangiitis. Given the high costs of biologics, understanding their cost-effectiveness is critical. As new biologics are developed and new indications are approved for existing biologics, the use of biologics for allergic diseases will increase. Conducting cost-effectiveness evaluations in parallel to efficacy and effectiveness trials will help patients, providers, payers, and policymakers in decision making.
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http://dx.doi.org/10.1016/j.jaip.2020.10.009DOI Listing
March 2021

Serum IgG Levels and Risk of COPD Hospitalization: A Pooled Meta-analysis.

Chest 2020 Oct 19;158(4):1420-1430. Epub 2020 May 19.

Department of Medicine, University of Maryland, Baltimore, MD.

Background: Hypogammaglobulinemia (serum IgG levels < 7.0 g/L) has been associated with increased risk of COPD exacerbations but has not yet been shown to predict hospitalizations.

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 < .001); pooled SHR (meta-analysis) was 1.29 (95% CI, 1.06-1.56, P = .01). Among patients with prior COPD admissions (n = 757), the pooled SHR increased to 1.58 (95% CI, 1.20-2.07, P < .01). The risk of COPD admissions, however, was similar between IgG groups in patients with no prior hospitalizations: pooled SHR = 1.15 (95% CI, 0.86-1.52, P =.34). The hypogammaglobulinemia group also showed significantly higher rates of COPD hospitalizations per person-year: 0.48 ± 2.01 vs 0.29 ± 0.83, P < .001.

Interpretation: Hypogammaglobulinemia is associated with a higher risk of COPD hospital admissions.
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http://dx.doi.org/10.1016/j.chest.2020.04.058DOI Listing
October 2020

Association of Guideline-Recommended COPD Inhaler Regimens With Mortality, Respiratory Exacerbations, and Quality of Life: A Secondary Analysis of the Long-Term Oxygen Treatment Trial.

Chest 2020 Aug 9;158(2):529-538. Epub 2020 Apr 9.

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA; Health Services Research & Development Center of Innovation for Veteran-centered and Value-driven Care, VA Puget Sound Healthcare System, Seattle, WA.

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.
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http://dx.doi.org/10.1016/j.chest.2020.02.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417382PMC
August 2020

Precision Medicine in Asthma-Using Phenotypes to Understand Endotypes That Lead Us to New Therapeutic Options.

J Allergy Clin Immunol Pract 2020 02;8(2):496-497

Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Kansas School of Medicine, Kansas City, Kan.

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http://dx.doi.org/10.1016/j.jaip.2019.12.001DOI Listing
February 2020

Adherence to adding inhaled corticosteroids to rescue therapy in a pragmatic trial with adults with asthma: A pilot study.

Ann Allergy Asthma Immunol 2020 05 8;124(5):487-493.e1. Epub 2020 Jan 8.

Brigham and Women's Hospital, Division of Pulmonary and Critical Care Medicine, Boston, Massachusetts.

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 adults with persistent asthma, randomized them approximately 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 1 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%, and 70% at 4, 8, and 12 weeks, respectively. Self-reported adherence to PARTICS was 76% (95% confidence interval [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.

Clinical Trials Registration: pilot study for 'PeRson EmPowered Asthma Relief' (PREPARE, NCT02995733).
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http://dx.doi.org/10.1016/j.anai.2019.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188592PMC
May 2020

Association Between Pulmonary Function and Asthma Symptoms.

J Allergy Clin Immunol Pract 2019 Sep - Oct;7(7):2319-2325. Epub 2019 Apr 26.

University of Colorado Denver, Denver, Colo.

Background: FEV as a percentage of predicted (FEV%pred) is commonly measured in asthma clinical studies; however, reports vary on its association with asthma control instruments evaluating symptoms.

Objective: Assess the association between FEV%pred and Asthma Control Questionnaire (ACQ) scores in a managed-care population with persistent asthma.

Methods: Retrospective analysis of survey responses and spirometry results of patients (aged ≥12 years) with persistent asthma from the Observational Study of Asthma Control and Outcomes was done. Eligible patients received 4 identical surveys including the 5-item ACQ (ACQ-5)/6-item ACQ (ACQ-6) and completed spirometry in parallel. Longitudinal analyses, comparisons of change over time, and fixed- and random-effects regression analyses were conducted, with/without adjustment for covariates.

Results: There were 1748 survey responses with valid spirometry results. In unadjusted models, coefficients for ACQ-5/ACQ-6 scores were not statistically significant and coefficient of determination (R) was low (0.03). When adjusted for covariates, ACQ-5 and ACQ-6 scores were significantly associated with FEV%pred (P < .001) and R increased to 0.11 and 0.12, respectively. In adjusted models, every 1-point increase in ACQ-5 and ACQ-6 scores was associated with a 1.7% and 1.9% decrease, respectively, in FEV%pred. Change in FEV%pred and change in ACQ-5/ACQ-6 scores were not significantly associated in regressions with/without covariates.

Conclusions: The weak and statistically insignificant association between FEV%pred and ACQ-5/ACQ-6 scores in unadjusted models suggests a high degree of unexplained variation between these measures. Results support the use of both symptoms and pulmonary function, rather than relying on one measure alone, to assess asthma control in clinical care and outcomes studies.
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http://dx.doi.org/10.1016/j.jaip.2019.04.019DOI Listing
October 2020

Characteristics at the time of oxygen initiation associated with its adherence: Findings from the COPD Long-term Oxygen Treatment Trial.

Respir Med 2019 03 13;149:52-58. Epub 2019 Feb 13.

University of Colorado School of Medicine, Aurora, CO, USA.

Rationale: Characteristics associated with adherence to long-term oxygen therapy (LTOT) in COPD remain unclear.

Objectives: To identify patient characteristics at the time of oxygen initiation associated with its adherence.

Methods: We conducted a secondary analysis of data from 359 COPD participants assigned to oxygen in the Long-term Oxygen Treatment Trial. Participants were prescribed continuous (n = 214) or intermittent (n = 145) oxygen based on desaturation patterns at study entry. At the time of initial prescription, participants rated their perceived readiness, confidence, and importance to use oxygen on a 0-10 scale (0 = not at all, 10 = very much). During follow-up, they self-reported average hours per day of use (adherence). Adherence was averaged over short-term (0-30 days), medium-term (months 9-12), and long-term (month 13 to last follow-up) intervals. Multivariable logistic regression models explored characteristics associated with high adherence (≥16 h/day [continuous] or ≥8 h/day [intermittent]) during each time interval.

Results: Participant readiness, confidence, and importance at the time of oxygen initiation were associated with high short- and medium-term adherence. For each unit increase in baseline readiness, the odds of high short-term adherence increased by 21% (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.05-1.40) and 94% (OR 1.94, 95% CI 1.45-2.59) in the continuous and intermittent groups, respectively. In both groups, high adherence in the medium-term was associated with high adherence in the long-term (continuous, OR 12.49, 95% CI 4.90-31.79; intermittent, OR 38.08, 95% CI 6.96-208.20).

Conclusions: Readiness, confidence, and importance to use LTOT at initiation, and early high adherence, are significantly associated with long-term oxygen adherence.
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http://dx.doi.org/10.1016/j.rmed.2019.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424633PMC
March 2019

Clinical Differences in COPD Patients with Variable Patterns of Hypoxemia.

Chronic Obstr Pulm Dis 2018 Apr 28;5(3):167-176. Epub 2018 Apr 28.

Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.

Chronic obstructive pulmonary disease (COPD) patients enrolled into the Long-term Oxygen Treatment Trial had hypoxemia at rest, hypoxemia on exertion, or hypoxemia both at rest and on exertion. We hypothesized that patients with different patterns of hypoxemia may have significant differences in clinical features. All patients had COPD and oxygen saturation measured by pulse oximetry (blood oxygenation [SpO]) at rest and during the 6-minute walk test (6MWT). Hypoxemia at rest was defined as resting SpO between 89-93%. SpO < 90% for at least 10 seconds and ³ 80% for at least 5 minutes during ambulation characterized hypoxemia on exertion. Severe exercise hypoxemia (< 80% for > 1 minute) was exclusionary. Of 738 patients studied, 133 (18.0%) had mild-moderate hypoxemia at rest only, 319 (43.2%) had hypoxemia on exertion only, and 286 (38.8%) had hypoxemia at both rest and exertion. Patients with hypoxemia at rest only were more likely to be current smokers, had higher body mass index (BMI) and a higher incidence of self-reported diabetes. Patients with hypoxemia on exertion only were more severely obstructed compared to the other groups. General and disease-specific quality of life scores were similarly impaired in all groups. Quality of well-being scores were more impaired in those with hypoxemia at rest only. COPD patients with mild-moderate hypoxemia have distinct clinical characteristics based on the pattern of oxygen desaturation at rest and with exertion.
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http://dx.doi.org/10.15326/jcopdf.5.3.2017.0175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296792PMC
April 2018

Genomics and response to long-term oxygen therapy in chronic obstructive pulmonary disease.

J Mol Med (Berl) 2018 12 23;96(12):1375-1385. Epub 2018 Oct 23.

Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Ave, Boston, MA, 02115, USA.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, and long-term oxygen therapy has been shown to reduce mortality in COPD patients with severe hypoxemia. However, the Long-term Oxygen Treatment Trial (LOTT), a large randomized trial, found no benefit of oxygen therapy in COPD patients with moderate hypoxemia. We hypothesized that there may be differences in response to oxygen which depend on genotype or gene expression. In a genome-wide time-to-event analysis of the primary outcome of death or hospitalization in 331 subjects, 97 single nucleotide polymorphisms (SNPs) showed evidence of interaction with oxygen therapy at P < 1e-5, including 7 SNPs near arylsulfatase B (ARSB; P = 6e-6). In microarray expression profiling on 51 whole blood samples from 37 individuals, at screening and/or at 12-month follow-up, ARSB expression was associated with the primary outcome depending on oxygen treatment. The significant SNPs were conditional expression quantitative trait loci for ARSB expression. In a network analysis of genes affected by long-term oxygen, two observed clusters including 26 co-expressed genes were enriched in mitochondrial function. Using data from the observational COPDGene Study, we validated the expression of 25 of these 26 genes, plus ARSB. The effect of long-term oxygen therapy in COPD varied based on ARSB expression and genotype. ARSB has previously been shown to be associated with hypoxemia in human bronchial and colonic epithelial cells and in a mouse model. In peripheral blood, long-term oxygen treatment affected expression of mitochondrial-related genes, a biologically relevant pathway in COPD. SNPs and expression of ARSB are associated with response to long-term oxygen in COPD. The ARSB SNPs were expression quantitative trait loci depending on oxygen therapy. Genes differentially expressed by long-term oxygen were enriched in mitochondrial functions. This suggests a potential biomarker to personalize use of long-term oxygen in COPD.
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http://dx.doi.org/10.1007/s00109-018-1708-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240374PMC
December 2018

Susceptibility to exacerbations in Black adults with asthma.

J Asthma 2019 Jul 4;56(7):704-710. Epub 2018 Oct 4.

c Brigham and Women's Hospital , Boston , MA , USA.

Objective: Exacerbations account for much of the morbidity in asthma. In a large intervention study, we sought to test the hypothesis that a Black adult exacerbation-prone phenotype - a group of Black people with asthma who are at high risk of repeat exacerbation within one year - exists in asthma independent of clinical control.

Methods: We analyzed exacerbation risk factors in 536 self-identified Black Americans with asthma eligible for, or on, Step 3 National Asthma Education and Prevention Program (NAEPP) therapy who participated in a randomized 6-18 month trial of tiotropium versus long acting beta agonist as add-on therapy to inhaled corticosteroids. Exacerbations were defined as events treated by oral or systemic corticosteroids. Clinical control was assessed by a validated asthma control questionnaire (ACQ5).

Results: Exacerbations became more likely with loss of clinical control. The mean baseline ACQs for exacerbators and non-exacerbators were 2.41 and 1.91, respectively (p < 0.001). The strongest independent factor associated with exacerbations across all ACQ levels was an exacerbation in the preceding year (adjusted OR 3.26; p < 0.001). The severity of prior exacerbations did not correlate with the likelihood of a future exacerbation. Lower baseline FEV1/FVC was also associated with increased risk of exacerbations.

Conclusions: Even though exacerbations increase with loss of clinical control, an exacerbation susceptibility phenotype exists in Black adults with asthma, independent of clinical control. This phenotype requires precision therapeutic targeting.
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http://dx.doi.org/10.1080/02770903.2018.1486855DOI Listing
July 2019

Challenges in Childhood Asthma Mortality Persist Despite Advances in Care.

J Allergy Clin Immunol Pract 2018 May - Jun;6(3):1037-1038

School of Medicine, University of Colorado, Aurora, Colo. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2017.12.003DOI Listing
September 2019

Correlation or Causation?

J Allergy Clin Immunol Pract 2018 Jan - Feb;6(1):114-115

Department of Medicine, Pulmonary Sciences and Critical Care Division, University of Colorado School of Medicine, Aurora, Colo. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2017.09.017DOI Listing
September 2019

Severe COPD cases from Korea, Poland, and USA have substantial differences in respiratory symptoms and other respiratory illnesses.

Int J Chron Obstruct Pulmon Dis 2017 30;12:3415-3423. Epub 2017 Nov 30.

Channing Division of Network Medicine.

Purpose: Chronic obstructive pulmonary disease (COPD), characterized by irreversible airflow obstruction, is a major cause of morbidity and mortality worldwide. However, geographic differences in the clinical characteristics of severe COPD patients have not been widely studied.

Methods: We recruited a total of 828 severe COPD cases from three continents. Subjects in Poland were enrolled by the Institute of Tuberculosis and Lung Diseases in Warsaw; subjects in Korea participated at several university hospitals in Korea; and subjects in USA were enrolled at two clinics affiliated with academic medical centers. All subjects were over the age of 30 with at least 10 pack-years of cigarette smoking history. Cases manifested severe to very severe airflow obstruction with post-bronchodilator forced expiratory volume in 1 second (FEV) <50% predicted and FEV/forced vital capacity <0.7. All subjects completed a detailed questionnaire and underwent standardized pre-bronchodilator and post-bronchodilator spirometry. Subjects with known tuberculosis (TB)-associated lung parenchymal destruction were excluded. Univariate and multivariate assessments of the impact of the country of origin on respiratory symptoms and respiratory illness were performed.

Results: In both univariate and multivariate analyses, a history of TB (38.7%) and physician-diagnosed asthma (43.9%) were significantly more common in subjects with severe COPD from Korea than USA or Poland, while attacks of bronchitis (64.2%) were more common in subjects with severe COPD from Poland. COPD subjects from Poland had more severe dyspnea (modified Medical Research Council 3.3±1.0) and more frequently reported symptoms of chronic bronchitis (52.2%). A history of TB was also more common in Poland (10.8%) than in USA (0.3%) severe COPD patients.

Conclusion: Respiratory symptoms and other respiratory illnesses associated with severe COPD differed widely among three continents.
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http://dx.doi.org/10.2147/COPD.S145908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716321PMC
August 2018

The Long-Term Oxygen Treatment Trial for Chronic Obstructive Pulmonary Disease: Rationale, Design, and Lessons Learned.

Ann Am Thorac Soc 2018 01;15(1):89-101

9 University of Alabama at Birmingham, Birmingham, Alabama.

The Long-Term Oxygen Treatment Trial demonstrated that long-term supplemental oxygen did not reduce time to hospital admission or death for patients who have stable chronic obstructive pulmonary disease and resting and/or exercise-induced moderate oxyhemoglobin desaturation, nor did it provide benefit for any other outcome measured in the trial. Nine months after initiation of patient screening, after randomization of 34 patients to treatment, a trial design amendment broadened the eligible population, expanded the primary outcome, and reduced the goal sample size. Within a few years, the protocol underwent minor modifications, and a second trial design amendment lowered the required sample size because of lower than expected treatment group crossover rates. After 5.5 years of recruitment, the trial met its amended sample size goal, and 1 year later, it achieved its follow-up goal. The process of publishing the trial results brought renewed scrutiny of the study design and the amendments. This article expands on the previously published design and methods information, provides the rationale for the amendments, and gives insight into the investigators' decisions about trial conduct. The story of the Long-Term Oxygen Treatment Trial may assist investigators in future trials, especially those that seek to assess the efficacy and safety of long-term oxygen therapy. Clinical trial registered with clinicaltrials.gov (NCT00692198).
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http://dx.doi.org/10.1513/AnnalsATS.201705-374SDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822416PMC
January 2018

A novel endpoint for exacerbations in asthma to accelerate clinical development: a post-hoc analysis of randomised controlled trials.

Lancet Respir Med 2017 07 2;5(7):577-590. Epub 2017 Jun 2.

Global Product and Portfolio Strategy, Global Medical Affairs, Gothenburg, Sweden. Electronic address:

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 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.
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http://dx.doi.org/10.1016/S2213-2600(17)30218-7DOI Listing
July 2017

Quantitative computed tomography assessment of bronchiolitis obliterans syndrome after lung transplantation.

Clin Transplant 2017 05 12;31(5). Epub 2017 Apr 12.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Background: Bronchiolitis obliterans syndrome (BOS) is a clinical manifestation of chronic allograft rejection following lung transplantation. We examined the quantitative measurements of the proximal airway and vessels and pathologic correlations in subjects with BOS.

Methods: Patients who received a lung transplant at the Brigham and Women's Hospital between December 1, 2002 and December 31, 2010 were included in this study. We characterized the quantitative CT measures of proximal airways and vessels and pathological changes.

Results: Ninety-four (46.1%) of the 204 subjects were included in the study. There was a significant increase in the airway vessel ratio in subjects who developed progressive BOS compared to controls and non-progressors. There was a significant increase in airway lumen area and decrease in vessel cross-sectional area in patients with BOS compared to controls. Patients with BOS had a significant increase in proximal airway fibrosis compared to controls.

Conclusions: BOS is characterized by central airway dilation and vascular remodeling, the degree of which is correlated to decrements in lung function. Our data suggest that progressive BOS is a pathologic process that affects both the central and distal airways.
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http://dx.doi.org/10.1111/ctr.12943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723437PMC
May 2017

A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation.

N Engl J Med 2016 10;375(17):1617-1627

Background: Long-term treatment with supplemental oxygen has unknown efficacy in patients with stable chronic obstructive pulmonary disease (COPD) and resting or exercise-induced moderate desaturation.

Methods: We originally designed the trial to test whether long-term treatment with supplemental oxygen would result in a longer time to death than no use of supplemental oxygen among patients who had stable COPD with moderate resting desaturation (oxyhemoglobin saturation as measured by pulse oximetry [Spo], 89 to 93%). After 7 months and the randomization of 34 patients, the trial was redesigned to also include patients who had stable COPD with moderate exercise-induced desaturation (during the 6-minute walk test, Spo ≥80% for ≥5 minutes and <90% for ≥10 seconds) and to incorporate the time to the first hospitalization for any cause into the new composite primary outcome. Patients were randomly assigned, in a 1:1 ratio, to receive long-term supplemental oxygen (supplemental-oxygen group) or no long-term supplemental oxygen (no-supplemental-oxygen group). In the supplemental-oxygen group, patients with resting desaturation were prescribed 24-hour oxygen, and those with desaturation only during exercise were prescribed oxygen during exercise and sleep. The trial-group assignment was not masked.

Results: A total of 738 patients at 42 centers were followed for 1 to 6 years. In a time-to-event analysis, we found no significant difference between the supplemental-oxygen group and the no-supplemental-oxygen group in the time to death or first hospitalization (hazard ratio, 0.94; 95% confidence interval [CI], 0.79 to 1.12; P=0.52), nor in the rates of all hospitalizations (rate ratio, 1.01; 95% CI, 0.91 to 1.13), COPD exacerbations (rate ratio, 1.08; 95% CI, 0.98 to 1.19), and COPD-related hospitalizations (rate ratio, 0.99; 95% CI, 0.83 to 1.17). We found no consistent between-group differences in measures of quality of life, lung function, and the distance walked in 6 minutes.

Conclusions: In patients with stable COPD and resting or exercise-induced moderate desaturation, the prescription of long-term supplemental oxygen did not result in a longer time to death or first hospitalization than no long-term supplemental oxygen, nor did it provide sustained benefit with regard to any of the other measured outcomes. (Funded by the National Heart, Lung, and Blood Institute and the Centers for Medicare and Medicaid Services; LOTT ClinicalTrials.gov number, NCT00692198 .).
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http://dx.doi.org/10.1056/NEJMoa1604344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216457PMC
October 2016

Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma.

Am J Respir Crit Care Med 2016 12;194(12):1465-1474

1 Channing Division of Network Medicine and.

Rationale: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease.

Objectives: To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma.

Methods: We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays.

Measurements And Main Results: An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10; odds ratio, 2.8; 95% confidence interval, 2.0-4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene.

Conclusions: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575).
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http://dx.doi.org/10.1164/rccm.201602-0250OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215031PMC
December 2016

Pharmacogenomic test that predicts response to β-agonists in adults with asthma is cost effective.

Per Med 2015 Nov;12(6):574-584

Division of Pulmonary & Critical Care Medicine, Brigham & Women's Hospital & Harvard Medical School, Boston, MA, USA.

Background: Pharmacogenomic tests that predict which asthma patients are likely to respond to β-agonists hold promise to improve care for asthma.

Objective: To identify the clinical and economic circumstances under which a pharmacogenomic test that predicts response to β-agonists might or might not be an appropriate, cost-effective option.

Methods: We synthesized published data on clinical and economic outcomes in adults 18-35 to project 10-year costs, quality-adjusted life years and cost-effectiveness of pharmacogenomic testing for β-agonist response.

Results: Pharmacogenomic testing for β-agonist response conferred a cost-effectiveness ratio of $13,700 per quality-adjusted life year gained compared with no testing.

Conclusion: Pharmacogenomic testing for β-agonist response in individuals with asthma is potentially cost effective and should be pursued by test developers.
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http://dx.doi.org/10.2217/pme.15.23DOI Listing
November 2015

Anticholinergic vs Long-Acting β-Agonist in Combination With Inhaled Corticosteroids in Black Adults With Asthma: The BELT Randomized Clinical Trial.

JAMA 2015 Oct;314(16):1720-30

Brigham and Women's Hospital, Boston, Massachusetts.

Importance: The efficacy and safety of long-acting β-agonists (LABAs) have been questioned. Black populations may be disproportionately affected by LABA risks.

Objective: To compare the effectiveness and safety of tiotropium vs LABAs, when used with inhaled corticosteroids (ICS) in black adults with asthma and to determine whether allelic variation at the Arg16Gly locus of the β2-adrenergic receptor (ADRB2) geneis associated with treatment response.

Design, Setting, And Participants: A multisite (n = 20), open-label, parallel-group, pragmatic randomized clinical trial conducted from March 2011 through July 2013, enrolling black adults with moderate to severe asthma in the United States.

Interventions: Patients eligible for, or receiving, step 3 or step 4 combination therapy per National Heart, Lung, and Blood Institute guidelines, received ICS plus either once-daily tiotropium (n = 532) or twice-daily LABAs (n = 538,) and were followed up for up to 18 months. Patients underwent genotyping, attended study visits at baseline, 1, 6, 12, and 18 months, and completed monthly questionnaires.

Main Outcomes And Measures: The primary outcome was time to asthma exacerbation, defined as a worsening asthma event requiring oral or parenteral corticosteroids. Secondary outcomes included patient-reported outcomes (Asthma Quality of Life Questionnaire, Asthma Control Questionnaire [ACQ], Asthma Symptom Utility Index, and Asthma Symptom-Free Days questionnaire), spirometry (FEV1), rescue medication use, asthma deteriorations, and adverse events.

Results: There was no difference between LABA + ICS vs tiotropium + ICS in time to first exacerbation (mean No. of exacerbations/person-year, 0.42 vs 0.37 (rate ratio, 0.90 [95% CI, 0.73 to 1.11], log-rank P = .31). There was no difference in change in FEV1 at 12 months (0.003 L for LABA + ICS vs -0.018 L for tiotropium + ICS; between-group difference, 0.020 [95% CI, -0.021 to 0.061], P = .33) and at 18 months (-0.053 L vs -0.078 L; between-group difference, 0.025 [95% CI, -0.045 to 0.095], P = .49). There were no differences in ACQ score at 18 months (change in score from baseline, -0.68 for LABA + ICS vs -0.72 for tiotropium + ICS; between-group difference, 0.04 [95% CI, -0.18 to 0.27], P = .70). There were no differences in other patient-reported outcomes. Arg16Gly ADRB2 alleles were not associated with differences in the effects of tiotropium + ICS vs LABA + ICS (hazard ratio for time to first exacerbation, 0.84 [95% CI, 0.47 to 1.51] for Arg/Arg vs 0.85 [95% CI, 0.63 to 1.15] for Arg/Gly or Gly/Gly, P = .97).

Conclusions/relevance: Among black adults with asthma treated with ICS, adding a LABA did not improve time to asthma exacerbation compared with adding tiotropium. These findings were not affected by polymorphisms at the Arg16Gly locus of ADRB2. These findings do not support the superiority of LABA + ICS compared with tiotropium + ICS for black patients with asthma.

Trial Registration: ClinicalTrials.gov identifier: NCT01290874.
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http://dx.doi.org/10.1001/jama.2015.13277DOI Listing
October 2015

Improving Influenza and Pneumococcal Vaccination Rates in Ambulatory Specialty Practices.

Open Forum Infect Dis 2015 Dec 1;2(4):ofv119. Epub 2015 Oct 1.

Department of Medicine Quality Program ; Divisions of Rheumatology, Immunology and Allergy.

Background.  Influenza and pneumococcal vaccinations are recommended for elderly and high-risk patients; however, rates of adherence are low. We sought to implement influenza and pneumococcal vaccine initiatives in 4 different ambulatory specialty practices, using 3 unique approaches. Methods.  Four specialties with high-risk patient populations were selected for intervention: allergy (asthma), infectious disease (ID) (human immunodeficiency virus), pulmonary (chronic lung disease), and rheumatology (immunocompromised). Allergy and ID focused on influenza vaccination, and pulmonary and rheumatology focused on pneumococcal vaccination. We used 3 strategies for quality improvement: physician reminders, patient letters, and a nurse-driven model. Physicians were provided their performance data on a monthly basis and presented trended data on a quarterly basis at staff meetings. Results.  All 4 specialties developed processes for improving vaccination rates with all showing some increase. Higher rates were achieved with pneumococcal vaccine than influenza. Pneumococcal vaccine rates showed steady improvement from year to year while influenza vaccine rates remained relatively constant. Allergy's influenza rate was 59% in 2011 and 64% in the 2014 flu season. Infectious disease influenza rates moved from 74% in the 2011 flu season to 86% for the 2014 season. Pneumococcal vaccine in pulmonary patients' rate was 52% at the start of intervention in February 2009 and 79% as of January 2015. Rheumatology rates rose from 50% in February 2009 to 87% in January 2015. Conclusions.  Integrated routine workflow and performance data sharing can effectively engage specialists and staff in vaccine adherence improvement. Influenza vaccination may require other approaches to achieve the rates seen with pneumococcal vaccine.
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http://dx.doi.org/10.1093/ofid/ofv119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589825PMC
December 2015

Pharmacogenomic test that predicts response to inhaled corticosteroids in adults with asthma likely to be cost-saving.

Pharmacogenomics 2015 16;16(6):591-600. Epub 2015 Apr 16.

Center for Child Health Care Studies, Department of Population Medicine, Harvard Medical School & Harvard Pilgrim Health Care Institute, 133 Brookline Avenue, Boston, MA 02215-5301, USA.

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. Original submitted 19 November 2014; Revision submitted 23 February 2015.
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http://dx.doi.org/10.2217/pgs.15.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545673PMC
February 2016

Classification of childhood asthma phenotypes and long-term clinical responses to inhaled anti-inflammatory medications.

J Allergy Clin Immunol 2014 May;133(5):1289-300, 1300.e1-12

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047642PMC
http://dx.doi.org/10.1016/j.jaci.2014.02.006DOI Listing
May 2014

Inhaled corticosteroids in children: effects on bone mineral density and growth.

Lancet Respir Med 2014 Jun 8;2(6):487-96. Epub 2014 Apr 8.

Department of Pediatrics: Pediatrics/Pulmonary, University of New Mexico, Albuquerque, NM, USA.

Potent, topically active corticosteroids with minimum systemic activity have fewer adverse effects than do systemic corticosteroids, and can control both asthma and allergic rhinitis when given in recommended doses. However, study findings show that children with asthma receiving budesonide and beclometasone dipropionate have decreased linear growth, and that children who receive long-term inhaled corticosteroid therapy for asthma have height deficits 1-2 years after treatment initiation that persist into adulthood. The effects of inhaled corticosteroids on growth seem to be dependent on both dose and duration; the degree of systemic effects is dependent on pharmacokinetic properties (ie, absorption, distribution, and elimination), whereas the effective dose delivered is dependent on the delivery system and potency of the molecule. The effects of corticosteroids on bone mineral density in children seem to be more amenable to intervention; long-term therapy with inhaled corticosteroid therapy is safer than frequent bursts of oral corticosteroids on bone mineral accretion in this regard. Importantly, adequate nutrition (particularly sufficient intake of calcium and vitamin D) should prevent or blunt the effects of corticosteroids on bone mineral density. The potential adverse effects of inhaled corticosteroids need to be weighed against the large and well established benefit of these drugs to control persistent asthma. To minimise any adverse effects, treatment with inhaled corticosteroids should always aim to reach the lowest effective dose that gives the patient good asthma control.
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http://dx.doi.org/10.1016/S2213-2600(14)70024-4DOI Listing
June 2014

Interstitial pneumonitis and the risk of chronic allograft rejection in lung transplant recipients.

Chest 2013 May;143(5):1430-1435

Department of Medicine; Lung Transplant Program, Division of Pulmonary and Critical Care Medicine, Boston, MA; Harvard Medical School, Boston, MA. Electronic address:

Background: 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).

Methods: 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.

Results: IP was a significant predictor of BOS (OR, 7.84; 95% CI, 2.84-21.67; P < .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.

Conclusions: 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.
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http://dx.doi.org/10.1378/chest.12-0354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653348PMC
May 2013

Diagnostic accuracy of the bronchodilator response in children.

J Allergy Clin Immunol 2013 Sep 14;132(3):554-559.e5. Epub 2013 May 14.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.

Background: The bronchodilator response (BDR) reflects the reversibility of airflow obstruction and is recommended as an adjunctive test to diagnose asthma. The validity of the commonly used definition of BDR, a 12% or greater change in FEV1 from baseline, has been questioned in childhood.

Objectives: We sought to examine the diagnostic accuracy of the BDR test by using 3 large pediatric cohorts.

Methods: Cases include 1041 children with mild-to-moderate asthma from the Childhood Asthma Management Program. Control subjects (nonasthmatic and nonwheezing) were chosen from Project Viva and Home Allergens, 2 population-based pediatric cohorts. Receiver operating characteristic curves were constructed, and areas under the curve were calculated for different BDR cutoffs.

Results: A total of 1041 cases (59.7% male; mean age, 8.9 ± 2.1 years) and 250 control subjects (46.8% male; mean age, 8.7 ± 1.7 years) were analyzed, with mean BDRs of 10.7% ± 10.2% and 2.7% ± 8.4%, respectively. The BDR test differentiated asthmatic patients from nonasthmatic patients with a moderate accuracy (area under the curve, 73.3%). Despite good specificity, a cutoff of 12% was associated with poor sensitivity (35.6%). A cutoff of less than 8% performed significantly better than a cutoff of 12% (P = .03, 8% vs 12%).

Conclusions: Our findings highlight the poor sensitivity associated with the commonly used 12% cutoff for BDR. Although our data show that a threshold of less than 8% performs better than 12%, given the variability of this test in children, we conclude that it might be not be appropriate to choose a specific BDR cutoff as a criterion for the diagnosis of asthma.
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http://dx.doi.org/10.1016/j.jaci.2013.03.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759549PMC
September 2013