Publications by authors named "Wendy C Moore"

81 Publications

PrecISE: Precision Medicine in Severe Asthma An Adaptive Platform Trial with Biomarker Ascertainment.

J Allergy Clin Immunol 2021 Mar 2. Epub 2021 Mar 2.

Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC.

Severe asthma accounts for almost half of the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Further, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The NIH Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Further, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.
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http://dx.doi.org/10.1016/j.jaci.2021.01.037DOI Listing
March 2021

Mixed Sputum Granulocyte Longitudinal Impact on Lung Function in the Severe Asthma Research Program.

Am J Respir Crit Care Med 2021 Feb 5. Epub 2021 Feb 5.

The University of Arizona Arizona Health Sciences Center, 12217, Division of Genetics, Genomics and Precision Medicine, Tucson, Arizona, United States.

Rationale: Reports indicate longitudinal variability in sputum differential cell counts while others describe stability. Highly variable sputum eosinophil percents are associated with greater lung function loss than persistently elevated eosinophil percents, but elevated neutrophils are linked to more severe asthma.

Objectives: To examine sputum granulocyte stability or variability longitudinally and associations with important clinical characteristics.

Methods: The Severe Asthma Research Program (SARP 3) cohort underwent comprehensive phenotype characterization at baseline and annually over three years. Adult subjects with acceptable sputum were assigned to one of 3 longitudinal sputum groups: Eosinophils predominantly <2%, predominantly >2%, or highly variable (>2SD determined from independent, repeated baseline eosinophil %s). Subjects were similarly assigned to 1 of 3 longitudinal neutrophil groups with a 50% cut-point.

Measurements And Main Results: The group with predominantly <2% sputum eosinophils had highest lung function (pre bronchodilator FEV1%predicted, p<0.01 and FEV1/FVC ratio, p<0.001) at baseline and throughout three years compared to other eosinophil groups. Healthcare utilization did not differ although the highly variable eosinophil group reported more asthma exacerbations at year 3. Longitudinal neutrophil groups showed few differences. However, combination of predominantly >2% eosinophil and >50% neutrophil groups resulted in the lowest prebronchodilator FEV1%predicted (p=0.049) compared to predominantly <2% eosinophils +<50% neutrophils.

Conclusions: Subjects with predominantly >2% sputum eosinophils in combination with predominantly >50% neutrophils showed greater loss of lung function, whereas those with highly variable sputum eosinophils had greater healthcare utilization.
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http://dx.doi.org/10.1164/rccm.202009-3713OCDOI Listing
February 2021

Responsiveness to Parenteral Corticosteroids and Lung Function Trajectory in Adults with Moderate to Severe Asthma.

Am J Respir Crit Care Med 2020 Dec 8. Epub 2020 Dec 8.

Brigham and Women's Hospital, 1861, Pulmonary and Critical Care Division, Boston, Massachusetts, United States.

Rationale: It is unclear why select patients with moderate to severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of severe decline in lung function.

Objective: To evaluate corticosteroid response phenotypes as longitudinal predictors of lung decline.

Methods: Adults with in the NHLBI Severe Asthma Research Program (SARP3; (1, 2)) who had undergone a course of intramuscular triamcinolone at baseline and ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/year; mild decline, >0.5 to 2.0% loss/year; no change, 0.5% loss/year to <1% gain/year; improve, ≥1% gain/year. Regression models were used to develop predictors of severe decline.

Measurements And Main Results: Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV1% predicted (tdFEV1; derived by baseline subtraction) was related to the 4-yr change in lung function or slope category in univariable models (p < 0.001). For each 5% decrement in the tdFEV1, there was a 50% increase in the odds of being in the severe decline group (OR 1.5, 95% CI 1.3 to 1.8), when adjusted for baseline FEV1, exacerbation history, blood eosinophils and BMI.

Conclusions: Failure to improve the post-bronchodilator FEV1 after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk of severe decline in lung function.
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http://dx.doi.org/10.1164/rccm.202002-0454OCDOI Listing
December 2020

The precision interventions for severe and/or exacerbation-prone asthma (PrecISE) adaptive platform trial: statistical considerations.

J Biopharm Stat 2020 Sep 17:1-12. Epub 2020 Sep 17.

University of Chicago, Chicago, IL.

The Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) study is an adaptive platform trial designed to investigate novel interventions to severe asthma. The study is conducted under a master protocol and utilizes a crossover design with each participant receiving up to five interventions and at least one placebo. Treatment assignments are based on the patients' biomarker profiles and precision health methods are incorporated into the interim and final analyses. We describe key elements of the PrecISE study including the multistage adaptive enrichment strategy, early stopping of an intervention for futility, power calculations, and the primary analysis strategy.
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http://dx.doi.org/10.1080/10543406.2020.1821705DOI Listing
September 2020

Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways.

J Allergy Clin Immunol 2020 Aug 11. Epub 2020 Aug 11.

Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Ariz.

Background: The Chr17q12-21.2 region is the strongest and most consistently associated region with asthma susceptibility. The functional genes or single nucleotide polymorphisms (SNPs) are not obvious due to linkage disequilibrium.

Objectives: We sought to comprehensively investigate whole-genome sequence and RNA sequence from human bronchial epithelial cells to dissect functional genes/SNPs for asthma severity in the Severe Asthma Research Program.

Methods: Expression quantitative trait loci analysis (n = 114), correlation analysis (n = 156) of gene expression and asthma phenotypes, and pathway analysis were performed in bronchial epithelial cells and replicated. Genetic association for asthma severity (426 severe vs 531 nonsevere asthma) and longitudinal asthma exacerbations (n = 273) was performed.

Results: Multiple SNPs in gasdermin B (GSDMB) associated with asthma severity (odds ratio, >1.25) and longitudinal asthma exacerbations (P < .05). Expression quantitative trait loci analyses identified multiple SNPs associated with expression levels of post-GPI attachment to proteins 3, GSDMB, or gasdermin A (3.1 × 10 
Conclusions: By using a unique set of gene expression data from lung cells obtained using bronchoscopy from comprehensively characterized subjects with asthma, we show that SNPs in GSDMB associated with asthma severity, exacerbations, and GSDMB expression levels. Furthermore, its expression levels correlated with asthma exacerbations and antiviral pathways. Thus, GSDMB is a functional gene for both asthma susceptibility and severity.
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http://dx.doi.org/10.1016/j.jaci.2020.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876167PMC
August 2020

The CHRONICLE Study of US Adults with Subspecialist-Treated Severe Asthma: Objectives, Design, and Initial Results.

Pragmat Obs Res 2020 16;11:77-90. Epub 2020 Jul 16.

Institute for Translational Medicine and Science, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.

Background: Approximately 5-10% of patients with asthma have severe disease. High-quality real-world studies are needed to identify areas for improved management.

Objective: Aligned with the International Severe Asthma Registry, the CHRONICLE study (ClinicalTrials.gov: NCT03373045) was developed to address this need in the US.

Study Design: Learnings from prior studies were applied to develop a real-world, prospective, noninterventional study of US patients with confirmed severe asthma who are treated by subspecialist physicians and require biologic or maintenance systemic immunosuppressant therapy or who are uncontrolled by high-dosage inhaled corticosteroids and additional controllers. Target enrollment is 4000 patients, with patient observation for ≥3 years. A geographically diverse sample of allergist/immunologist and pulmonologist sites approach all eligible patients under their care and report patient characteristics, treatment, and health outcomes every 6 months. Patients complete online surveys every 1-6 months.

Initial Results: From February 2018 to February 2019, 102 sites screened 1428 eligible patients; 936 patients enrolled. Study sites (40% allergist/immunologist, 42% pulmonologist, 18% both) were similar to other US asthma subspecialist samples. Enrolled patients were 67% female with median ages at enrollment and diagnosis of 55 (range: 18-89) and 26 (0-80) years, respectively. Median body mass index was 31 kg/m; 3% and 29% were current or former smokers, respectively, and >60% reported ≥1 exacerbation in the prior year and suboptimal symptom control.

Conclusion: CHRONICLE will provide high-quality provider- and patient-reported data from a large, real-world cohort of US adults with subspecialist-treated severe asthma.
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http://dx.doi.org/10.2147/POR.S251120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371434PMC
July 2020

Levodopa inhalation powder in a patient with persistent asthma.

Parkinsonism Relat Disord 2020 09 14;78:44-45. Epub 2020 Jul 14.

Wake Forest School of Medicine, Pulmonary, Critical Care, Allergy, and Immunologic Medicine, United States.

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http://dx.doi.org/10.1016/j.parkreldis.2020.07.011DOI Listing
September 2020

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and receptors in type 1, type 2 and type 17 inflammation in cross-sectional asthma study.

Thorax 2020 09 1;75(9):808-811. Epub 2020 Jun 1.

Department of Internal Medicine, Pulmonary Section, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) reportedly promotes, or conversely, resolves inflammation in asthma. In this study of TRAIL and cell receptors in sputum, bronchoalveolar lavage and biopsy from subjects in the Severe Asthma Research Program at Wake Forest, the high TRAIL group had significant increases in all leucocytes, and was associated with increased type 1, type 2 and type 17 cytokines, but not type 9 interleukin 9. Two variants at loci in the TRAIL gene were associated with higher sputum levels of TRAIL. Increased TRAIL decoy receptor R3/DcR1 was observed on sputum leucocytes compared with death receptor R1/DR4, suggesting reduced apoptosis and prolonged cellular inflammation.
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http://dx.doi.org/10.1136/thoraxjnl-2019-214496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476262PMC
September 2020

Biologic and maintenance systemic corticosteroid therapy among US subspecialist-treated patients with severe asthma.

Ann Allergy Asthma Immunol 2020 09 15;125(3):294-303.e1. Epub 2020 Apr 15.

AstraZeneca, Gaithersburg, Maryland. Electronic address:

Background: Severe asthma (SA) often requires subspecialist management and treatment with biologic therapies or maintenance systemic corticosteroids (mSCS).

Objective: To describe contemporary, real-world biologic and mSCS use among US subspecialist-treated patients with SA.

Methods: CHRONICLE is an ongoing, noninterventional study of US adults with SA treated by allergists/immunologists or pulmonologists. Eligible patients are receiving biologics or mSCS or are uncontrolled on high-dosage inhaled corticosteroids with additional controllers. Biologic and mSCS use patterns and patient characteristics were summarized for patients enrolled between February 2018 and February 2019.

Results: Among protocol-eligible patients, 58% and 12% were receiving biologics and mSCS, respectively, with 7% receiving both. Among 796 enrolled, most were women (67%), non-Hispanic white (71%), of suburban residence (50%), and had elevated body mass index (median: 31). Respiratory and nonrespiratory comorbidities were highly prevalent. With biologics (n = 557), 51% were anti-immunoglobulin E and 48% were anti-interleukin (IL)-5/IL-5Rα; from May 2018, 76% of initiations were anti-IL-5/IL-5Rα. In patients receiving mSCS, median prednisone-equivalent daily dose was 10 mg. Multivariate logistic regression found that patients of hospital clinics, sites with fewer nonphysician staff, and with a recorded concurrent chronic obstructive pulmonary disease diagnosis were less likely to receive biologics and more likely to receive mSCS.

Conclusion: In this real-world sample of US subspecialist-treated patients with SA not controlled by high-dosage inhaled corticosteroids with additional controllers, mSCS use was infrequent and biologic use was common, with similar prevalence of anti-immunoglobulin E and anti-IL-5/IL-5Rα biologics. Treatment differences associated with patient and site characteristics should be investigated to ensure equitable access to biologics and minimize mSCS use.

Trial Registration: ClinicalTrials.gov Identifier: NCT03373045.
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http://dx.doi.org/10.1016/j.anai.2020.04.004DOI Listing
September 2020

genotype identifies glucocorticoid responsiveness in severe asthma.

Proc Natl Acad Sci U S A 2020 01 13;117(4):2187-2193. Epub 2020 Jan 13.

Lerner Research Institute and the Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195;

Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive (1245A) allele limits conversion, whereas the adrenal permissive (1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEVPP). (1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEVPP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined ( = 318). Validation was performed in a second cohort (SARP I&II; = 184). DHEA-sulfate is associated with FEVPP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEVPP compared with noGC patients (54.3% vs. 75.1%; < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEVPP difference in GC vs. noGC patients (73.4% vs. 78.9%; = 0.39). Results were independently confirmed: FEVPP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 ( < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 ( = 0.92). The adrenal restrictive (1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.
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http://dx.doi.org/10.1073/pnas.1918819117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995013PMC
January 2020

Severe asthma during childhood and adolescence: A longitudinal study.

J Allergy Clin Immunol 2020 01 14;145(1):140-146.e9. Epub 2019 Oct 14.

Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, Ohio. Electronic address:

Background: Morbidity and mortality associated with childhood asthma are driven disproportionately by children with severe asthma. However, it is not known from longitudinal studies whether children outgrow severe asthma.

Objective: We sought to study prospectively whether well-characterized children with severe asthma outgrow their asthma during adolescence.

Methods: Children with asthma were assessed at baseline with detailed questionnaires, allergy tests, and lung function tests and were reassessed annually for 3 years. The population was enriched for children with severe asthma, as assessed by the American Thoracic Society/European Respiratory Society guidelines, and subject classification was reassessed annually.

Results: At baseline, 111 (59%) children had severe asthma. Year to year, there was a decrease in the proportion meeting the criteria for severe asthma. After 3 years, only 30% of subjects met the criteria for severe asthma (P < .001 compared with enrollment). Subjects experienced improvements in most indices of severity, including symptom scores, exacerbations, and controller medication requirements, but not lung function. Surprisingly, boys and girls were equally likely to has resolved asthma (33% vs 29%). The odds ratio in favor of resolution of severe asthma was 2.75 (95% CI, 1.02-7.43) for those with a peripheral eosinophil count of greater than 436 cells/μL.

Conclusions: In longitudinal analysis of this well-characterized cohort, half of the children with severe asthma no longer had severe asthma after 3 years; there was a stepwise decrease in the proportion meeting severe asthma criteria. Surprisingly, asthma severity decreased equally in male and female subjects. Peripheral eosinophilia predicted resolution. These data will be important for planning clinical trials in this population.
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http://dx.doi.org/10.1016/j.jaci.2019.09.030DOI Listing
January 2020

Development and initial validation of the Asthma Severity Scoring System (ASSESS).

J Allergy Clin Immunol 2020 01 8;145(1):127-139. Epub 2019 Oct 8.

Department of Medicine, University of Wisconsin, Madison, Wis.

Background: Tools for quantification of asthma severity are limited.

Objective: We sought to develop a continuous measure of asthma severity, the Asthma Severity Scoring System (ASSESS), for adolescents and adults, incorporating domains of asthma control, lung function, medications, and exacerbations.

Methods: Baseline and 36-month longitudinal data from participants in phase 3 of the Severe Asthma Research Program (NCT01606826) were used. Scale properties, responsiveness, and a minimally important difference were determined. External replication was performed in participants enrolled in the Severe Asthma Research Program phase 1/2. The utility of ASSESS for detecting treatment response was explored in participants undergoing corticosteroid responsiveness testing with intramuscular triamcinolone and participants receiving biologics.

Results: ASSESS scores ranged from 0 to 20 (8.78 ± 3.9; greater scores reflect worse severity) and differed among 5 phenotypic groups. Measurement properties were acceptable. ASSESS was responsive to changes in quality of life with a minimally important difference of 2, with good specificity for outcomes of asthma improvement and worsening but poor sensitivity. Replication analyses yielded similar results, with a 2-point decrease (improvement) associated with improvements in quality of life. Participants with a 2-point or greater decrease (improvement) in ASSESS scores also had greater improvement in lung function and asthma control after triamcinolone, but these differences were limited to phenotypic clusters 3, 4, and 5. Participants treated with biologics also had a 2-point or greater decrease (improvement) in ASSESS scores overall.

Conclusions: The ASSESS tool is an objective measure that might be useful in epidemiologic and clinical research studies for quantification of treatment response in individual patients and phenotypic groups. However, validation studies are warranted.
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http://dx.doi.org/10.1016/j.jaci.2019.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949388PMC
January 2020

Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma.

N Engl J Med 2019 09;381(13):1227-1239

From National Jewish Health (M.E.W., R.C., J.T.O.), Denver, and University of Colorado School of Medicine (M.E.W., S.J.S., R.C., F.H., J.T.O.) and Children's Hospital Colorado (S.J.S.), Aurora - all in Colorado; Wake Forest School of Medicine (V.E.O., W.C.M., S.P.P.), Winston-Salem, North Carolina Clinical Research (C.F.L.), Raleigh, and Duke University Medical Center (N.L., L.Q.), Durham - all in North Carolina; Ann and Robert H. Lurie Children's Hospital of Chicago (J.A.P., R.G.R.), University of Illinois at Chicago (J.A.K., H.K.), Rush University Medical Center (J.M.), University of Chicago (E.N., J.S., S. White), and Northwestern University Feinberg School of Medicine (L.J.S.) - all in Chicago; Penn State University (V.C., S.J.K., D.M.), Hershey, and Allegheny General Hospital (D.G.) and University of Pittsburgh Medical Center (S. Wenzel), Pittsburgh - all in Pennsylvania; Nemours Children's Health System, Jacksonville (J.J.L., K.V.B., J.L.), and University of South Florida Morsani College of Medicine, Tampa (J.-C.C.) - both in Florida; University of Arizona Health Sciences, Tucson (E.R.B., M.K., F.M., D.A.M.); Washington University School of Medicine, St. Louis (L.B.B., A.B., M.C.); University of California, San Francisco (UCSF), San Francisco (M.B., M.D.C., S.C.L., D.L.) and UCSF Benioff Children's Hospital, Oakland (M.B., D.L.) - both in California; Brigham and Women's Hospital and Harvard Medical School (J.-C.C., N.G., E.I.) and Boston Children's Hospital (W.P., W.S.) - all in Boston; University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland (J.F.C., K.R.); University of Wisconsin-Madison, Madison (L.D., D.J.J., R.F.L., C.A.S.) and Aurora Sinai Medical Center, Milwaukee (L.S.-V.) - both in Wisconsin; Columbia University Irving Medical Center, New York, (E.D.); Emory University, Atlanta (A.M.F.); and University of New Mexico, Albuquerque (H.R.).

Background: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients.

Methods: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry.

Results: When quintupling the dose of fluticasone (to 250 μg twice a day) was compared with adding salmeterol (50 μg twice a day) and doubling the fluticasone (to 100 μg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age.

Conclusions: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).
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http://dx.doi.org/10.1056/NEJMoa1905560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026584PMC
September 2019

Clinical significance of the bronchodilator response in children with severe asthma.

Pediatr Pulmonol 2019 11 19;54(11):1694-1703. Epub 2019 Aug 19.

Department of Medicine, Washington University School of Medicine in Saint Louis, St. Louis, Missouri.

Background: Our objective was to determine those characteristics associated with reversibility of airflow obstruction and response to maximal bronchodilation in children with severe asthma through the Severe Asthma Research Program (SARP).

Methods: We performed a cross-sectional analysis evaluating children ages 6 to 17 years with nonsevere asthma (NSA) and severe asthma (SA). Participants underwent spirometry before and after 180 µg of albuterol to determine reversibility (≥12% increase in FEV ). Participants were then given escalating doses up to 720 µg of albuterol to determine their maximum reversibility.

Results: We evaluated 230 children (n = 129 SA, n = 101 NSA) from five centers across the United States in the SARP I and II cohorts. SA (odds ratio [OR], 2.08, 95% confidence interval [CI], 1.05-4.13), second-hand smoke exposure (OR, 2.81, 95%CI, 1.23-6.43), and fractional exhaled nitric oxide (FeNO; OR, 1.97, 95%CI, 1.35-2.87) were associated with increased odds of airway reversibility after maximal bronchodilation, while higher prebronchodilator (BD) FEV % predicted (OR, 0.91, 95%CI, 0.88-0.94) was associated with decreased odds. In an analysis using the SARP III cohort (n = 186), blood neutrophils, immunoglobulin E (IgE), and FEV % predicted were significantly associated with BD reversibility. In addition, children with BD response have greater healthcare utilization. BD reversibility was associated with reduced lung function at enrollment and 1-year follow-up though less decline in lung function over 1 year compared to those without reversibility.

Conclusions: Lung function, that is FEV % predicted, is a predictor of BD response in children with asthma. Additionally, smoke exposure, higher FeNO or IgE level, and low peripheral blood neutrophils are associated with a greater likelihood of BD reversibility. BD response can identify a phenotype of pediatric asthma associated with low lung function and poor asthma control.
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http://dx.doi.org/10.1002/ppul.24473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015037PMC
November 2019

Structural and Functional Features on Quantitative Chest Computed Tomography in the Korean Asian versus the White American Healthy Non-Smokers.

Korean J Radiol 2019 07;20(7):1236-1245

School of Mechanical Engineering, Kyungpook National University, Daegu, Korea.

Objective: Considering the different prevalence rates of diseases such as asthma and chronic obstructive pulmonary disease in Asians relative to other races, Koreans may have unique airway structure and lung function. This study aimed to investigate unique features of airway structure and lung function based on quantitative computed tomography (QCT)-imaging metrics in the Korean Asian population (Koreans) as compared with the White American population (Whites).

Materials And Methods: QCT data of healthy non-smokers (223 Koreans vs. 70 Whites) were collected, including QCT structural variables of wall thickness (WT) and hydraulic diameter (D) and functional variables of air volume, total air volume change in the lung (ΔV), percent emphysema-like lung (Emph%), and percent functional small airway disease-like lung (fSAD%). Mann-Whitney U tests were performed to compare the two groups.

Results: As compared with Whites, Koreans had smaller volume at inspiration, ΔV between inspiration and expiration ( < 0.001), and Emph% at inspiration ( < 0.001). Especially, Korean females had a decrease of ΔV in the lower lobes ( < 0.001), associated with fSAD% at the lower lobes ( < 0.05). In addition, Koreans had smaller D and WT of the trachea (both, < 0.05), correlated with the forced expiratory volume in 1 second (R = 0.49, 0.39; all < 0.001) and forced vital capacity (R = 0.55, 0.45; all < 0.001).

Conclusion: Koreans had unique features of airway structure and lung function as compared with Whites, and the difference was clearer in female individuals. Discriminating structural and functional features between Koreans and Whites enables exploration of inter-racial differences of pulmonary disease in terms of severity, distribution, and phenotype.
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http://dx.doi.org/10.3348/kjr.2019.0083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609438PMC
July 2019

Association of Symptoms of Obstructive Lung Disease and All-Cause Mortality in Older Adult Smokers.

J Am Geriatr Soc 2019 10 27;67(10):2116-2122. Epub 2019 Jun 27.

Section on Pulmonary, Critical Care, Allergy, and Immunologic Disease, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Objectives: This study aims to investigate the impact of respiratory symptoms in current and former smokers with and without obstructive lung disease (OLD) on all-cause mortality.

Design: Secondary analysis in a prospective cohort (the Health, Aging and Body Composition study).

Setting: Memphis, Tennessee, and Pittsburgh, Pennsylvania.

Participants: Black and white men and women with a history of current and former smoking (N = 596; 63% male and 37% female) aged 70-79 years followed for 13 years. Participants were categorized into 4 mutually exclusive groups based on symptom profile and forced expiratory volume in the 1st second to forced vital capacity ratio. The groups were Less Dyspnea-No OLD (N = 196), More Dyspnea-No OLD (N = 104), Less Dyspnea-With OLD (N = 162), and More Dyspnea-With OLD (N = 134).

Measurements: All-cause mortality.

Results: Overall, 53% in Less Dyspnea-No OLD, 63% in More Dyspnea-No OLD, 67% in Less Dyspnea-With OLD, and 84% in More Dyspnea-With OLD died within the 13- year follow up period (log-rank χ  = 44.4, P < .0001). The hazard ratio was highest for participants with OLD, both with (HR =1.91, 95% CI 1.44 - 2.54; P < .0001) and without dyspnea (HR = 1.52, 95% CI 1.15 - 2.02; p = .004). Participants without OLD but with dyspnea had a similar risk of death to subjects who had OLD but fewer symptoms.

Conclusions: OLD is associated with high risk of death with different risk profiles based on symptom group. Patients with symptoms of shortness of breath without OLD should be considered an at-risk group given their similar mortality to those with OLD with minimal symptoms. J Am Geriatr Soc 67:2116-2122, 2019.
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http://dx.doi.org/10.1111/jgs.16052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800777PMC
October 2019

BAL Cell Gene Expression in Severe Asthma Reveals Mechanisms of Severe Disease and Influences of Medications.

Am J Respir Crit Care Med 2019 10;200(7):837-856

Division of Allergy, National Jewish Hospital, Denver, Colorado.

Gene expression of BAL cells, which samples the cellular milieu within the lower respiratory tract, has not been well studied in severe asthma. To identify new biomolecular mechanisms underlying severe asthma by an unbiased, detailed interrogation of global gene expression. BAL cell expression was profiled in 154 asthma and control subjects. Of these participants, 100 had accompanying airway epithelial cell gene expression. BAL cell expression profiles were related to participant (age, sex, race, and medication) and sample traits (cell proportions), and then severity-related gene expression determined by correlating transcripts and coexpression networks to lung function, emergency department visits or hospitalizations in the last year, medication use, and quality-of-life scores. Age, sex, race, cell proportions, and medications strongly influenced BAL cell gene expression, but leading severity-related genes could be determined by carefully identifying and accounting for these influences. A BAL cell expression network enriched for cAMP signaling components most differentiated subjects with severe asthma from other subjects. Subsequently, an cellular model showed this phenomenon was likely caused by a robust upregulation in cAMP-related expression in nonsevere and β-agonist-naive subjects given a β-agonist before cell collection. Interestingly, ELISAs performed on BAL lysates showed protein levels may partly disagree with expression changes. Gene expression in BAL cells is influenced by factors seldomly considered. Notably, β-agonist exposure likely had a strong and immediate impact on cellular gene expression, which may not translate to important disease mechanisms or necessarily match protein levels. Leading severity-related genes were discovered in an unbiased, system-wide analysis, revealing new targets that map to asthma susceptibility loci.
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http://dx.doi.org/10.1164/rccm.201811-2221OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812436PMC
October 2019

The effect of BPIFA1/SPLUNC1 genetic variation on its expression and function in asthmatic airway epithelium.

JCI Insight 2019 04 18;4(8). Epub 2019 Apr 18.

National Jewish Health, Denver, Colorado, USA.

Bacterial permeability family member A1 (BPIFA1), also known as short palate, lung, and nasal epithelium clone 1 (SPLUNC1), is a protein involved in the antiinflammatory response. The goal of this study was to determine whether BPIFA1 expression in asthmatic airways is regulated by genetic variations, altering epithelial responses to type 2 cytokines (e.g., IL-13). Nasal epithelial cells from patients with mild to severe asthma were collected from the National Heart, Lung, and Blood Institute Severe Asthma Research Program centers, genotyped for rs750064, and measured for BPIFA1. To determine the function of rs750064, cells were cultured at air-liquid interface and treated with IL-13 with or without recombinant human BPIFA1 (rhBPIFA1). Noncultured nasal cells with the rs750064 CC genotype had significantly less BPIFA1 mRNA expression than the CT and TT genotypes. Cultured CC versus CT and TT cells without stimulation maintained less BPIFA1 expression. With IL-13 treatment, CC genotype cells secreted more eotaxin-3 than CT and TT genotype cells. Also, rhBPIFA1 reduced IL-13-mediated eotaxin-3. BPIFA1 mRNA levels negatively correlated with serum IgE and fractional exhaled nitric oxide. Baseline FEV1% levels were lower in the asthma patients with the CC genotype (n = 1,016). Our data suggest that less BPIFA1 in asthma patients with the CC allele may predispose them to greater eosinophilic inflammation, which could be attenuated by rhBPIFA1 protein therapy.
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http://dx.doi.org/10.1172/jci.insight.127237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538329PMC
April 2019

Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate.

J Allergy Clin Immunol 2019 08 11;144(2):416-425.e7. Epub 2019 Mar 11.

Department of Medicine, Brigham and Women's Hospital, Boston, Mass. Electronic address:

Background: Loss of bronchoprotection (LOBP) with a regularly used long-acting β-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate.

Objective: We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients.

Methods: We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250 μg of fluticasone twice daily for 2 weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8 weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8 weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC value.

Results: The mean doubling dose reduction in SPMCh PC value was 0.50 and 0.27 with alendronate and placebo, respectively (P = .62). Thirty-eight percent of participants receiving alendronate and 33% receiving placebo had LOBP (P = .81). The after/before ICS plus LABA treatment ratio of B2AR number was 1.0 for alendronate (P = .86) and 0.8 for placebo (P = .15; P = .31 for difference between treatments). The B2AR signaling ratio was 0.89 for alendronate (P = .43) and 1.02 for placebo (P = .84; P = .44 for difference). Changes in lung function and B2AR number and signaling were similar between those who did and did not experience LOBP.

Conclusion: This study did not find evidence that alendronate reduces LABA-associated LOBP, which relates to the occurrence of LOBP in only one third of participants. LOBP appears to be less common than presumed in concomitant ICS plus LABA-treated asthmatic patients. B2AR downregulation measured in PBMCs does not appear to reflect LOBP.
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http://dx.doi.org/10.1016/j.jaci.2019.01.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950766PMC
August 2019

Three Major Efforts to Phenotype Asthma: Severe Asthma Research Program, Asthma Disease Endotyping for Personalized Therapeutics, and Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome.

Clin Chest Med 2019 03;40(1):13-28

Department of Respiratory Medicine F5-152, Amsterdam UMC, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands.

The SARP, ADEPT, and U-BIOPRED programs are all significant efforts in characterizing asthma and reporting clusters that will assist in designing personalized therapies for asthma, and especially severe asthma. Key aspects of the design of these programs are summarized and major findings are reported in this review.
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http://dx.doi.org/10.1016/j.ccm.2018.10.016DOI Listing
March 2019

Multiview Cluster Analysis Identifies Variable Corticosteroid Response Phenotypes in Severe Asthma.

Am J Respir Crit Care Med 2019 06;199(11):1358-1367

14 Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.

Corticosteroids (CSs) are the most effective asthma therapy, but responses are heterogeneous and systemic CSs lead to long-term side effects. Therefore, an improved understanding of the contributing factors in CS responses could enhance precision management. Although several factors have been associated with CS responsiveness, no integrated/cluster approach has yet been undertaken to identify differential CS responses. To identify asthma subphenotypes with differential responses to CS treatment using an unsupervised multiview learning approach. Multiple-kernel -means clustering was applied to 100 clinical, physiological, inflammatory, and demographic variables from 346 adult participants with asthma in the Severe Asthma Research Program with paired (before and 2-3 weeks after triamcinolone administration) sputum data. Machine-learning techniques were used to select the top baseline variables that predicted cluster assignment for a new patient. Multiple-kernel clustering revealed four clusters of individuals with asthma and different CS responses. Clusters 1 and 2 consisted of young, modestly CS-responsive individuals with allergic asthma and relatively normal lung function, separated by contrasting sputum neutrophil and macrophage percentages after CS treatment. The subjects in cluster 3 had late-onset asthma and low lung function, high baseline eosinophilia, and the greatest CS responsiveness. Cluster 4 consisted primarily of young, obese females with severe airflow limitation, little eosinophilic inflammation, and the least CS responsiveness. The top 12 baseline variables were identified, and the clusters were validated using an independent Severe Asthma Research Program test set. Our machine learning-based approaches provide new insights into the mechanisms of CS responsiveness in asthma, with the potential to improve disease treatment.
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http://dx.doi.org/10.1164/rccm.201808-1543OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543720PMC
June 2019

Safety and Tolerability of Comprehensive Research Bronchoscopy in Chronic Obstructive Pulmonary Disease. Results from the SPIROMICS Bronchoscopy Substudy.

Ann Am Thorac Soc 2019 04;16(4):439-446

4 Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan.

Rationale: There is an unmet need to investigate the lower airways in chronic obstructive pulmonary disease (COPD) to define pathogenesis and to identify potential markers to accelerate therapeutic development. Although bronchoscopy is well established to sample airways in various conditions, a comprehensive COPD research protocol has yet to be published.

Objectives: To evaluate the safety and tolerability of a comprehensive research bronchoscopy procedure suitable for multicenter trials and to identify factors associated with adverse events.

Methods: We report the detailed methodology used to conduct the bronchoscopy used in SPIROMICS (the Subpopulations and Intermediate Outcome Measures in COPD Study). The protocol entailed collection of tongue scrapings and oral rinses as well as bronchoscopy with airway inspection, bronchoalveolar lavage (BAL), protected brushings, and endobronchial biopsies. Visual airway characteristics were graded on a scale of 0 (normal appearance) to 3 (severe abnormality) in four domains: erythema, edema, secretions, and friability. Adverse events were defined as events requiring intervention. Logistic regression modeling assessed associations between adverse event occurrence and key variables.

Results: We enrolled 215 participants. They were 61 ± 9 years old, 71% were white, 53% were male, and post-bronchodilator forced expiratory volume in 1 second was 89 ± 19% predicted. Self-reported asthma was present in 22% of bronchoscopy participants. Oral samples were obtained in greater than or equal to 99% of participants. Airway characteristics were recorded in 99% and were most often characterized as free of edema (61.9%). Less than 50% reported secretions, friability, or erythema. BAL yielded 111 ± 57 ml (50%) of the 223 ± 65 ml of infusate, brushes were completed in 98%, and endobronchial biopsies were performed in 82% of procedures. Adverse events requiring intervention occurred in 14 (6.7%) of 208 bronchoscopies. In logistic regression models, female sex (risk ratio [RR], 1.10; 95% confidence interval [CI], 1.02-1.19), self-reported asthma (RR, 1.17; 95% CI, 1.02-1.34), bronchodilator reversibility (RR, 1.17; 95% CI, 1.04-1.32), COPD (RR, 1.10; 95% CI, 1.02-1.20), forced expiratory volume in 1 second (RR, 0.97; 95% CI, 0.95-0.99), and secretions (RR, 1.85; 1.08-3.16) or friability (RR, 1.64; 95% CI, 1.04-2.57) observed during bronchoscopy were associated with adverse events.

Conclusions: A research bronchoscopy procedure that includes oral sampling, BAL, endobronchial biopsy, and brushing can be safely performed. Airway characteristics during bronchoscopy, demographics, asthma or COPD, and lung function may convey increased risk for procedure-related events necessitating intervention.
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http://dx.doi.org/10.1513/AnnalsATS.201807-441OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441692PMC
April 2019

Racial disparities in asthma-related health care use in the National Heart, Lung, and Blood Institute's Severe Asthma Research Program.

J Allergy Clin Immunol 2019 06 8;143(6):2052-2061. Epub 2019 Jan 8.

University of Virginia, Department of Pediatrics, Charlottesville, Va.

Background: Despite advances in asthma care, disparities persist. Black patients are disproportionally affected by asthma and also have poorer outcomes compared with white patients.

Objective: We sought to determine associations between black and white patients and asthma-related health care use, accounting for complex relationships.

Methods: This study was completed as part of the National Heart, Lung, and Blood Institute's Severe Asthma Research Program, a prospective observational cohort. Between November 2012 and February 2015, it enrolled 579 participants 6 years and older with 1 year of observation time and complete data. Inverse probability of treatment weighting was used to balance racial groups with respect to community and family socioeconomic variables and environmental exposure variables. The primary outcome was emergency department (ED) use for asthma. Secondary outcomes included inhaled corticosteroid use, outpatient physician's office visits for asthma, and asthma-related hospitalization.

Results: Black patients had greater odds of ED use over 1 year (odds ratio, 2.19; 95% CI, 1.43-3.35) but also differed in the majority (>50%) of baseline variables measured. After statistical balancing of the racial groups, the difference between black and white patients with respect to ED use no longer reached the level of significance. Instead, in secondary analyses black patients were less likely to see an outpatient physician for asthma management (adjusted odds ratio, 0.57; 95% CI, 0.38-0.85).

Conclusions: The disparity in ED use was eliminated after consideration of multiple variables. Social and environmental policies and interventions tailored to black populations with a high burden of asthma are critical to reduction (or elimination) of these disparities.
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http://dx.doi.org/10.1016/j.jaci.2018.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556425PMC
June 2019

Effects of endogenous sex hormones on lung function and symptom control in adolescents with asthma.

BMC Pulm Med 2018 Apr 10;18(1):58. Epub 2018 Apr 10.

University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.

Background: Although pre-puberty asthma is more prevalent in males, after puberty through middle-age, asthma is more prevalent in females. The surge of sex hormones with puberty might explain this gender switch.

Methods: To examine the effects of sex hormones on lung function and symptoms with puberty, Tanner stage was assessed in 187 children 6-18 years of age (59% severe) enrolled in the NIH/NHLBI Severe Asthma Research Program (SARP). The effects of circulating sex hormones (n = 68; testosterone, dehydroepiandrosterone sulfate (DHEA-S), estrogen, and progesterone) on lung function and 4 week symptom control (ACQ6) in cross-section were tested by linear regression.

Results: From pre-/early to late puberty, lung function did not change significantly but ACQ6 scores improved in males with severe asthma. By contrast females had lower post-BD FEV% and FVC% and worse ACQ6 scores with late puberty assessed by breast development. In males log DHEA-S levels, which increased by Tanner stage, associated positively with pre- and post-BD FEV%, pre-BD FVC %, and negatively (improved) with ACQ6. Patients treated with high-dose inhaled corticosteroids had similar levels of circulating DHEA-S. In females, estradiol levels increased by Tanner stage, and associated negatively with pre-BD FEV% and FVC %.

Conclusions: These results support beneficial effects of androgens on lung function and symptom control and weak deleterious effects of estradiol on lung function in children with asthma. Longitudinal data are necessary to confirm these cross-sectional findings and to further elucidate hormonal mechanisms informing sex differences in asthma features with puberty.

Trial Registration: ClinicalTrials.gov registration number: NCT01748175 .
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http://dx.doi.org/10.1186/s12890-018-0612-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891903PMC
April 2018

Pediatric Perioperative Nurses and the Ethics of Organ Donation After Cardiac Death.

AORN J 2018 04;107(4):e1-e8

Pediatric perioperative nurses are experiencing increased opportunities to participate in donations after cardiac death. An increased public awareness regarding transplantation has inspired more people to donate than in previous years. The demand for transplantable organs has led to opportunities that have increased donor candidates including living donors and cardiac death donors. Cardiac death in children is often sudden and unexpected, and is an emotional time not only for the family members but also for the hospital staff members, including perioperative nurses. However, when perioperative nurses adhere to standards and guidelines, they can perform their responsibilities in an ethical and compassionate manner and assist their team in doing so. This article reviews the guiding principles of pediatric organ donation after cardiac death, the phases of the process, and the ethical and moral issues surrounding donation.
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http://dx.doi.org/10.1002/aorn.12110DOI Listing
April 2018

Baseline Features of the Severe Asthma Research Program (SARP III) Cohort: Differences with Age.

J Allergy Clin Immunol Pract 2018 Mar - Apr;6(2):545-554.e4. Epub 2017 Aug 31.

University of Wisconsin School of Medicine, Madison, Wis.

Background: The effect of age on asthma severity is poorly understood.

Objectives: The objective of this study was to compare the baseline features of severe and nonsevere asthma in the Severe Asthma Research Program (SARP) III cohort, and examine in cross section the effects of age on those features.

Methods: SARP III is a National Institutes of Health/National Heart Lung Blood Institute multisite 3-year cohort study conducted to investigate mechanisms of severe asthma. The sample included 188 children (111 severe, 77 nonsevere) and 526 adults (313 severe, 213 nonsevere) characterized for demographic features, symptoms, health care utilization, lung function, and inflammatory markers compared by age and severity.

Results: Compared with children with nonsevere asthma, children with severe asthma had more symptoms and more historical exacerbations, but no difference in body weight, post-bronchodilator lung function, or inflammatory markers. After childhood, and increasing with age, the cohort had a higher proportion of women, less allergen sensitization, and overall fewer blood eosinophils. Enrollment of participants with severe asthma was highest in middle-aged adults, who were older, more obese, with greater airflow limitation and higher blood eosinophils, but less allergen sensitization than adults with nonsevere asthma.

Conclusions: The phenotypic features of asthma differ by severity and with advancing age. With advancing age, patients with severe asthma are more obese, have greater airflow limitation, less allergen sensitization, and variable type 2 inflammation. Novel mechanisms besides type 2 inflammatory pathways may inform the severe asthma phenotype with advancing age.
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http://dx.doi.org/10.1016/j.jaip.2017.05.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832534PMC
November 2019