Homer A Boushey

University of California, San Francisco, San Francisco, California, United States

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Publications (230)2232.43 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Asthma is heterogeneous, and airway dysbiosis is associated with clinical features in patients with mild-to-moderate asthma. Whether similar relationships exist among patients with severe asthma is unknown. We sought to evaluate relationships between the bronchial microbiome and features of severe asthma. Bronchial brushings from 40 participants in the Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) study were evaluated by using 16S ribosomal RNA-based methods. Relationships to clinical and inflammatory features were analyzed among microbiome-profiled subjects. Secondarily, bacterial compositional profiles were compared between patients with severe asthma and previously studied healthy control subjects (n = 7) and patients with mild-to-moderate asthma (n = 41). In patients with severe asthma, bronchial bacterial composition was associated with several disease-related features, including body mass index (P < .05, Bray-Curtis distance-based permutational multivariate analysis of variance; PERMANOVA), changes in Asthma Control Questionnaire (ACQ) scores (P < .01), sputum total leukocyte values (P = .06), and bronchial biopsy eosinophil values (per square millimeter, P = .07). Bacterial communities associated with worsening ACQ scores and sputum total leukocyte values (predominantly Proteobacteria) differed markedly from those associated with body mass index (Bacteroidetes/Firmicutes). In contrast, improving/stable ACQ scores and bronchial epithelial gene expression of FK506 binding protein (FKBP5), an indicator of steroid responsiveness, correlated with Actinobacteria. Mostly negative correlations were observed between biopsy eosinophil values and Proteobacteria. No taxa were associated with a TH2-related epithelial gene expression signature, but expression of TH17-related genes was associated with Proteobacteria. Patients with severe asthma compared with healthy control subjects or patients with mild-to-moderate asthma were significantly enriched in Actinobacteria, although the largest differences observed involved a Klebsiella genus member (7.8-fold increase in patients with severe asthma, adjusted P < .001). Specific microbiota are associated with and may modulate inflammatory processes in patients with severe asthma and related phenotypes. Airway dysbiosis in patients with severe asthma appears to differ from that observed in those with milder asthma in the setting of inhaled corticosteroid use. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    The Journal of allergy and clinical immunology 07/2015; 22. DOI:10.1016/j.jaci.2015.05.044 · 11.48 Impact Factor
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    ABSTRACT: Age and gender are associated with differences in asthma prevalence and morbidity. Determine if age and gender associate with distinct phenotypes and a variable response to therapy in mild-moderate asthmatics. We utilized Asthma Clinical Research Network data to determine the impact of age and gender on phenotypes and treatment failures among subjects participating in 10 trials from 1993 to 2003. 1,200 subjects were identified [median age = 30.4 years, male = 520 (43.3%), female = 680(56.7%)] and analyzed. A higher proportion of subjects ≥30 years old experienced treatment failures (17.3% vs. 10.3%; OR=1.82, CI=1.30-2.54; P < 0.001); and rates increased proportionally with increasing age above 30 across the cohort [OR per year = 1.02, CI=1.01-1.04), OR per 5-year = 1.13 (CI 1.04-1.22), P<0.001]. Lower lung function and longer duration of asthma were associated with a higher risk of treatment failure. A higher proportion of subjects ≥30 years old receiving controller therapy experienced treatment failures. When stratified by specific therapy, treatment failures increased consistently for every year above age 30 in subjects on inhaled corticosteroids [OR per year = 1.03 (CI 1.01-1.07)]. Females had a slightly higher FEV1% predicted (84.5% vs. 81.1%; P <0.001) but similar asthma control measures. There was not a statistically significant difference in treatment failures between females and males (15.2% vs. 11.7%, P =0.088). Older age is associated with an increased risk of treatment failure, particularly in subjects taking inhaled corticosteroids. There was no significant difference in treatment failures between genders.
    American Journal of Respiratory and Critical Care Medicine 06/2015; 192(5). DOI:10.1164/rccm.201503-0426OC · 13.00 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2015; 135(2):AB102. DOI:10.1016/j.jaci.2014.12.1265 · 11.48 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2015; 135(2):AB154. DOI:10.1016/j.jaci.2014.12.1444 · 11.48 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2015; 135(2):AB169. DOI:10.1016/j.jaci.2014.12.1488 · 11.48 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2015; 135(2):AB273. DOI:10.1016/j.jaci.2014.12.1834 · 11.48 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2015; 135(2):AB109. DOI:10.1016/j.jaci.2014.12.1291 · 11.48 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2015; 135(2):AB273. DOI:10.1016/j.jaci.2014.12.1833 · 11.48 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2015; 135(2):AB154. DOI:10.1016/j.jaci.2014.12.1443 · 11.48 Impact Factor
  • Yvonne J Huang · Homer A Boushey
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    ABSTRACT: The application of recently developed sensitive, specific, culture-independent tools for identification of microbes is transforming concepts of microbial ecology, including concepts of the relationships between the vast complex populations of microbes associated with ourselves and with states of health and disease. Although most work initially focused on the community of microbes (microbiome) in the gastrointestinal tract and its relationship to gastrointestinal disease, interest has expanded to include study of the relationships of the airway microbiome to asthma and its phenotypes and to the relationships between the gastrointestinal microbiome, development of immune function, and predisposition to allergic sensitization and asthma. Here we provide our perspective on the findings of studies of differences in the airway microbiome between asthmatic patients and healthy subjects and of studies of relationships between environmental microbiota, gut microbiota, immune function, and asthma development. In addition, we provide our perspective on how these findings suggest the broad outline of a rationale for approaches involving directed manipulation of the gut and airway microbiome for the treatment and prevention of allergic asthma. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
    Journal of Allergy and Clinical Immunology 01/2015; 135(1):25-30. DOI:10.1016/j.jaci.2014.11.011 · 11.48 Impact Factor
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    ABSTRACT: Asthma is a chronic lung disease that has a high prevalence. The therapeutic intervention of this disease can be made more effective if genetic variability in patients' response to medications is implemented. However, a clear picture of the genetic architecture of asthma intervention response remains elusive. We conducted a genome-wide association study (GWAS) to identify drug response-associated genes for asthma, in which 909 622 SNPs were genotyped for 120 randomized participants who inhaled multiple doses of glucocorticoids. By integrating pharmacodynamic properties of drug reactions, we implemented a mechanistic model to analyze the GWAS data, enhancing the scope of inference about the genetic architecture of asthma intervention. Our pharmacodynamic model observed associations of genome-wide significance between dose-dependent response to inhaled glucocorticoids (measured as %FEV1) and five loci (P=5.315 × 10(-7) to 3.924 × 10(-9)), many of which map to metabolic genes related to lung function and asthma risk. All significant SNPs detected indicate a recessive effect, at which the homozygotes for the mutant alleles drive variability in %FEV1. Significant associations were well replicated in three additional independent GWAS studies. Pooled together over these three trials, two SNPs, chr6 rs6924808 and chr11 rs1353649, display an increased significance level (P=6.661 × 10(-16) and 5.670 × 10(-11)). Our study reveals a general picture of pharmacogenomic control for asthma intervention. The results obtained help to tailor an optimal dose for individual patients to treat asthma based on their genetic makeup.The Pharmacogenomics Journal advance online publication, 20 January 2015; doi:10.1038/tpj.2014.83.
    The Pharmacogenomics Journal 01/2015; 15(5). DOI:10.1038/tpj.2014.83 · 4.23 Impact Factor
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    ABSTRACT: ß2-agonists are the most common form of treatment of asthma but there is significant variability in response to these medications. A significant proportion of this responsiveness may be heritable. To investigate whether a genome-wide association study (GWAS) could identify novel pharmacogenetic loci in asthma. We performed a GWAS of acute bronchodilator response (BDR) to inhaled ß2-agonists. 444,088 single nucleotide polymorphisms (SNPs) were examined in 724 individuals from the SNP Health Association Resource (SHARe) Asthma Resource Project (SHARP). The top 50 SNPs were carried forward to replication in a population of 444 individuals. The combined p-value for 4 SNPs reached statistical genome-wide significance after correcting for multiple comparisons. Combined p-values for rs350729, rs1840321, rs1384918, rs1319797 were 2.21x10-10, 5.75 x10-8, 9.3x10-8, and 3.95x10-8 respectively. The significant variants all map to a novel genetic region on chromosome 2 near the ASB3 gene, a region associated with smooth muscle proliferation. As compared to the wild-type the presence of the mutant alleles reduced the degree of bronchodilator response by 20% in the original population and by a similar percentage in the confirmatory population. These GWAS findings for bronchodilator response in asthmatics suggest that a gene associated with smooth muscle proliferation may influence a proportion of the smooth muscle relaxation that occurs in asthma.
    American Journal of Respiratory and Critical Care Medicine 01/2015; 191(5). DOI:10.1164/rccm.201408-1426OC · 13.00 Impact Factor
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    ABSTRACT: Importance In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency.Objective To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels.Design, Setting, and Participants The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute’s AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized.Interventions Oral vitamin D3 (100 000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained.Main Outcomes and Measures The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care).Results Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]).Conclusions and Relevance Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma.Trial Registration clinicaltrials.gov Identifier: NCT01248065
    JAMA The Journal of the American Medical Association 05/2014; 311(20):2083. DOI:10.1001/jama.2014.5052 · 35.29 Impact Factor
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    ABSTRACT: Background: Wheezing illnesses cause major morbidity in infants and are frequent precursors to asthma. Objective: We sought to examine environmental factors associated with recurrent wheezing in inner-city environments. Methods: The Urban Environment and Childhood Asthma study examined a birth cohort at high risk for asthma (n = 560) in Baltimore, Boston, New York, and St Louis. Environmental assessments included allergen exposure and, in a nested case-control study of 104 children, the bacterial content of house dust collected in the first year of life. Associations were determined among environmental factors, aeroallergen sensitization, and recurrent wheezing at age 3 years. Results: Cumulative allergen exposure over the first 3 years was associated with allergic sensitization, and sensitization at age 3 years was related to recurrent wheeze. In contrast, first-year exposure to cockroach, mouse, and cat allergens was negatively associated with recurrent wheeze (odds ratio, 0.60, 0.65, and 0.75, respectively; P <= .01). Differences in house dust bacterial content in the first year, especially reduced exposure to specific Firmicutes and Bacteriodetes, was associated with atopy and atopic wheeze. Exposure to high levels of both allergens and this subset of bacteria in the first year of life was most common among children without atopy or wheeze. Conclusions: In inner-city environments children with the highest exposure to specific allergens and bacteria during their first year were least likely to have recurrent wheeze and allergic sensitization. These findings suggest that concomitant exposure to high levels of certain allergens and bacteria in early life might be beneficial and suggest new preventive strategies for wheezing and allergic diseases.
    Journal of Allergy and Clinical Immunology 05/2014; 134(3). DOI:10.1016/j.jaci.2014.04.018 · 11.48 Impact Factor
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    ABSTRACT: Specific bacterial species are implicated in the pathogenesis of exacerbations of chronic obstructive pulmonary disease (COPD). However, recent studies of clinically stable COPD patients have demonstrated a greater diversity of airway microbiota, whose role in acute exacerbations is unclear. In this study temporal changes in the airway microbiome before, at the onset of, and after an acute exacerbation were examined in 60 sputum samples collected from subjects enrolled in a longitudinal study of bacterial infection in COPD. Microbiome composition and predicted functions were examined using 16S rRNA-based culture-independent profiling methods. Shifts in the abundance (≥2-fold, p<0.05) of many taxa at exacerbation and after treatment were observed. Microbiota members increased at exacerbation were primarily of the Proteobacteria phylum, including non-typical COPD pathogens. Changes in bacterial composition after treatment for exacerbation differed significantly among the therapy regimens clinically prescribed (antibiotics only, oral corticosteroids only, or both). Treatment with antibiotics alone primarily decreased the abundance of Proteobacteria, with prolonged suppression of some microbiota members observed. In contrast, treatment with corticosteroids alone led to enrichment for Proteobacteria and members of other phyla. Predicted metagenomes of particular microbiota members involved in these compositional shifts, indicated exacerbation-associated loss of functions involved in the synthesis of antimicrobial and anti-inflammatory products, alongside enrichment in functions related to pathogen-elicited inflammation. These trends reversed upon clinical recovery. Further larger studies will be necessary to determine whether specific compositional or functional changes detected in the airway microbiome could be useful indicators of exacerbation development or outcome.
    Journal of Clinical Microbiology 05/2014; 52(8). DOI:10.1128/JCM.00035-14 · 3.99 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2014; 133(2):AB240. DOI:10.1016/j.jaci.2013.12.853 · 11.48 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2014; 133(2):AB400. DOI:10.1016/j.jaci.2013.12.1056 · 11.48 Impact Factor
  • Yvonne J Huang · Homer A Boushey
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    ABSTRACT: That the subglottic airways are not sterile, as was once believed, but are populated by a distinct "bronchial microbiome," is now accepted. Also accepted is the concept that asthma is associated with differences in the composition of this microbiome. What is not clear is whether the differences in microbial community composition themselves mediate pathologic changes in the airways or whether they reflect differences in systemic immune function driven by differences in the development of the gastrointestinal microbiome in early life, when the immune system is most malleable. Recognition of the probable existence of a "common mucosal immune system" allowed synthesis of these apparently opposing ideas into a single conceptual model. Gastrointestinal microbiome-driven differences in systemic immune function predispose to sensitization to allergens deposited on mucosal surfaces, whereas possibly similar, but not identical, differences in immune function predispose to less effective responses to microbial infection of the airways, resulting in persistence of the inflammation underlying the structural and functional abnormalities of asthma. In this model, allergic sensitization and asthma are thus seen as commonly overlapping but not necessarily coincident consequences of abnormalities in microbial colonization, development of immune function, and encounter with agents infecting the respiratory tract.
    Annals of the American Thoracic Society 01/2014; 11(Supplement_1):S48-S51. DOI:10.1513/AnnalsATS.201306-187MG
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    ABSTRACT: Acute respiratory illness (ARI) is the leading cause of asthma exacerbations yet the mechanisms underlying this association remain unclear. To address the deficiencies in our understanding of the molecular events characterizing ARI-induced asthma exacerbations, we undertook a transcriptional profiling study of the nasal mucosa over the course of ARI amongst individuals with a history of asthma, allergic rhinitis and no underlying respiratory disease. Transcriptional profiling experiments were performed using the Agilent Whole Human Genome 4X44K array platform. Time point-based microarray and principal component analyses were conducted to identify and distinguish ARI-associated transcriptional profiles over the course of our study. Gene enrichment analysis was conducted to identify biological processes over represented within each ARI-associated profile and gene expression subsequently confirmed by quantitative PCR. We found that ARI is characterized by dynamic, time-specific transcriptional profiles whose magnitudes of expression are influenced by underlying respiratory disease and the mucosal repair signature evoked during ARI. Most strikingly, we report that asthmatics that experience ARI-induced exacerbations are characterized by a reduced but prolonged inflammatory immune response, inadequate activation of mucosal repair and the expression of a newly described exacerbation-specific transcriptional signature. Findings from our study represent a significant contribution towards clarifying the complex molecular interactions which typify ARI-induced asthma exacerbations.
    Genome Medicine 01/2014; 6(1):1. DOI:10.1186/gm520 · 5.34 Impact Factor
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    ABSTRACT: Background: Differences in pathophysiology may underlie asthma heterogeneity, and bronchial microbiota composition has been associated with the degree of airway hyperresponsiveness among patients with mild to moderate asthma. In this study, we investigated relationships between the bronchial airway microbiome and disease features in severe asthma. Methods: Bacterial microbiota represented in protected bronchial brushings from 30 severe asthma subjects were profiled using a 16S rRNA-based phylogenetic microarray (PhyloChip; Second Genome Inc., San Bruno, CA). Clinical, physiologic, and airway inflammation measures were analyzed for relationships to airway bacterial community structure and composition. Results: Airway bacterial community structure was associated with between-visit differences in Asthma Control Questionnaire (ACQ) scores (P < 0.01), sputum neutrophilia (P < 0.08), and body mass index (BMI) (P < 0.03). The specific microbiota associated with change in ACQ score and with sputum neutrophilia differed markedly from those associated with BMI. Proteobacteria composed more than 70% of bacterial taxa correlated with sputum neutrophilia (Benjamini-Hochberg-adjusted P < 0.05), including such bacterial families as Bacillaceae, Helicobacteraceae, and Moraxellaceae. Proteobacteria constituted 93% of taxa positively correlated with ACQ score difference, whereas Actinobacteria composed 80% of taxa negatively correlated with this variable. In contrast, Bacteroidetes accounted for 54% of the taxa strongly associated with BMI, including a greater relative abundance of Prevotellaceae and Porphyromonadaceae among subjects with BMI greater than or equal to 30. Conclusions: Distinct airway bacterial community composition was associated with specific clinical and inflammatory features of severe asthma in this group of patients. We speculate that particular microbiota members may be involved in the induction or modulation of specific inflammatory processes that contribute to severe asthma and corresponding clinical phenotype.
    Annals of the American Thoracic Society 01/2014; 11(Supplement_1):S78. DOI:10.1513/AnnalsATS.201306-163MG

Publication Stats

13k Citations
2,232.43 Total Impact Points


  • 1981–2015
    • University of California, San Francisco
      • • Cardiovascular Research Institute
      • • Department of Medicine
      • • Division of Hospital Medicine
      San Francisco, California, United States
  • 2009
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 2007
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2006
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2004
    • CSU Mentor
      Long Beach, California, United States
    • California State University
      • Department of Nursing
      Long Beach, California, United States
  • 2001
    • Children's Hospital of Wisconsin
      Madison, Wisconsin, United States
  • 1997–2001
    • Thomas Jefferson University
      Philadelphia, Pennsylvania, United States
  • 1998
    • ASTHMA, Inc. Clinical Research Center
      Seattle, Washington, United States
  • 1985–1998
    • Cardiovascular Research Foundation
      New York, New York, United States
  • 1996
    • Harvard University
      Cambridge, Massachusetts, United States