Showing papers by "William W. Busse published in 2017"
TL;DR: This work will review common inciting factors for asthma exacerbations and approaches to prevent and treat these events, particularly with human rhinovirus.
234 citations
University of Wisconsin-Madison1, National Institutes of Health2, University of Texas Southwestern Medical Center3, Columbia University4, Cincinnati Children's Hospital Medical Center5, Henry Ford Health System6, University of Colorado Denver7, Children's National Medical Center8, Boston University9, Children's Memorial Hospital10
TL;DR: In children with allergic asthma, treatment with omalizumab decreased the duration of RV infections, viral shedding, and the risk of RV illnesses, providing direct evidence that blocking IgE decreases susceptibility to RV infections and illness.
Abstract: Rationale: Allergic inflammation has been linked to increased susceptibility to viral illnesses, but it is unclear whether this association is causal.Objectives: To test whether omalizumab treatmen...
185 citations
TL;DR: The results do not support restriction of inhaled corticosteroids to patients with symptoms on more than 2 days per week and suggest that treatment recommendations for mild asthma should consider both risk reduction and symptoms.
144 citations
TL;DR: In this hypothesis‐generating analysis, gene expression networks in relation to asthma severity provided potentially new insight into biological mechanisms associated with the development of SA and its phenotypes.
Abstract: Rationale: Severe asthma (SA) is a heterogeneous disease with multiple molecular mechanisms. Gene expression studies of bronchial epithelial cells in individuals with asthma have provided biological insight and underscored possible mechanistic differences between individuals.Objectives: Identify networks of genes reflective of underlying biological processes that define SA.Methods: Airway epithelial cell gene expression from 155 subjects with asthma and healthy control subjects in the Severe Asthma Research Program was analyzed by weighted gene coexpression network analysis to identify gene networks and profiles associated with SA and its specific characteristics (i.e., pulmonary function tests, quality of life scores, urgent healthcare use, and steroid use), which potentially identified underlying biological processes. A linear model analysis confirmed these findings while adjusting for potential confounders.Measurements and Main Results: Weighted gene coexpression network analysis constructed 64 gene ne...
120 citations
TL;DR: The clinical efficacy, safety, and tolerability of omalizumab have been demonstrated in several published clinical trials, which supported the approval of the pediatric indication by the European Medicines Agency and the US Food and Drug Administration in 2009 and 2016, respectively.
Abstract: Asthma is one of the most common chronic diseases of childhood. Allergen sensitization and high frequencies of comorbid allergic diseases are characteristic of severe asthma in children. Omalizumab, an anti-IgE mAb, is the first targeted biologic therapeutic approved for the treatment of moderate-to-severe persistent allergic asthma (AA) that remains uncontrolled despite high-dose inhaled corticosteroids plus other controller medications. Since its initial licensing for use in adults and adolescents 12 years of age and older, the clinical efficacy, safety, and tolerability of omalizumab have been demonstrated in several published clinical trials in children aged 6 to less than 12 years with moderate-to-severe AA. These studies supported the approval of the pediatric indication (use in children aged ≥6 years) by the European Medicines Agency in 2009 and the US Food and Drug Administration in 2016. After this most recent change in licensing, we review the outcomes from clinical trials in children with persistent AA receiving omalizumab therapy and observational studies from the past 7 years of clinical experience in Europe. Data sources were identified by using PubMed in 2016. Guidelines and management recommendations and materials from the recent US Food and Drug Administration's Pediatric Advisory Committee meeting are also reviewed.
116 citations
Colorado School of Public Health1, University of Colorado Denver2, Boston University3, Columbia University Medical Center4, Henry Ford Hospital5, University of Texas Southwestern Medical Center6, Cincinnati Children's Hospital Medical Center7, Boston Children's Hospital8, University of Wisconsin-Madison9, University of Colorado Boulder10
TL;DR: Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner‐city children and methylation‐expression relationships were validated in an independent cohort of children with atopic asthma.
Abstract: Background Given the strong environmental influence on both epigenetic marks and allergic asthma in children, the epigenetic alterations in respiratory epithelia might provide insight into allergic asthma. Objective We sought to identify DNA methylation and gene expression changes associated with childhood allergic persistent asthma. Methods We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma (n = 36) versus healthy control subjects (n = 36). Results were validated in an independent population of asthmatic children (n = 30) by using a shared healthy control population (n = 36) and in an independent population of white adult atopic asthmatic patients (n = 12) and control subjects (n = 12). Results We identified 186 genes with significant methylation changes, differentially methylated regions or differentially methylated probes, after adjustment for age, sex, race/ethnicity, batch effects, inflation, and multiple comparisons. Genes differentially methylated included those with established roles in asthma and atopy and genes related to extracellular matrix, immunity, cell adhesion, epigenetic regulation, and airflow obstruction. The methylation changes were substantial (median, 9.5%; range, 2.6% to 29.5%). Hypomethylated and hypermethylated genes were associated with increased and decreased gene expression, respectively ( P −6 for differentially methylated regions and P −10 for differentially methylated probes). Quantitative analysis in 53 differentially expressed genes demonstrated that 32 (60%) have significant methylation-expression relationships within 5 kb of the gene. Ten loci selected based on the relevance to asthma, magnitude of methylation change, and methylation-expression relationships were validated in an independent cohort of children with atopic asthma. Sixty-seven of 186 genes also have significant asthma-associated methylation changes in nasal epithelia of adult white asthmatic patients. Conclusions Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner-city children.
116 citations
TL;DR: Patients with severe asthma generally benefit from consultations with an asthma specialist to optimise their management, which may include the potential initiation of biologic agents that have made a breakthrough in the treatment of severe disease.
Abstract: Physicians need care pathways to select a biologic in type 2 severe asthma (omalizumab, mepolizumab, reslizumab) http://ow.ly/pygw30gB7Bv
79 citations
TL;DR: This article interprets current evidence for biomarkers of eosinophilic or type 2-high asthma so that clinicians can determine potential treatments for patients based on knowledge of their effectiveness in specific asthma phenotypes and assess clinical data on the efficacy, safety, and mechanisms of action of approved and pipeline biologic therapies.
53 citations
TL;DR: An exacerbation in children treated with guidelines‐based therapy with or without omalizumab was associated with a higher saEPI along with higher markers of allergic inflammation, treatment step, and a recent exacerbation.
Abstract: Background A Seasonal Asthma Exacerbation Predictive Index (saEPI) was previously reported based on 2 prior National Institute of Allergy and Infectious Diseases Inner City Asthma Consortium trials. Objective This study sought to validate the saEPI in a separate trial designed to prevent fall exacerbations with omalizumab therapy. Methods The saEPI and its components were analyzed to characterize those who had an asthma exacerbation during the Preventative Omalizumab or Step-Up Therapy for Fall Exacerbations (PROSE) study. We characterized those inner-city children with and without asthma exacerbations in the fall period treated with guidelines-based therapy (GBT) in the absence and presence of omalizumab. Results A higher saEPI was associated with an exacerbation in both the GBT alone (P Conclusions An exacerbation in children treated with GBT with or without omalizumab was associated with a higher saEPI along with higher markers of allergic inflammation, treatment step, and a recent exacerbation. Those that exacerbated on omalizumab had similar features with the exception of some markers of allergic sensitization, indicating a need to develop better markers to predict poor response to omalizumab therapy and alternative treatment strategies for children with these risk factors. The saEPI was able to reliably predict those children unlikely to have an asthma exacerbation in both groups.
41 citations
University of Wisconsin-Madison1, Wayne State University2, Columbia University3, National Institutes of Health4, University of Texas Southwestern Medical Center5, Cincinnati Children's Hospital Medical Center6, University of Colorado Denver7, Boston University8, Children's Memorial Hospital9, George Washington University10, Johns Hopkins University11
TL;DR: A Trpg and A Limit patterns of obstruction, as defined by using routine spirometric measurements, can identify obstruction phenotypes that are indicators of risk for asthma severity and instability.
Abstract: Background Small-airways instability resulting in premature airway closure has been recognized as a risk for asthma severity and poor control. Although spirometry has limited sensitivity for detecting small-airways dysfunction, a focus on the air-trapping component of obstruction might identify a risk factor for asthma instability. Objective We sought to use spirometric measurements to identify patterns of airway obstruction in children and define obstruction phenotypes that relate to asthma instability. Methods Prebronchodilation and postbronchodilation spirometric data were obtained from 560 children in the Asthma Phenotypes in the Inner City study. An air-trapping obstruction phenotype (A Trpg) was defined as a forced vital capacity (FVC) z score of less than −1.64 or an increase in FVC of 10% of predicted value or greater with bronchodilation. The airflow limitation phenotype (A Limit) had an FEV 1 /FVC z score of less than −1.64 but not A Trpg. The no airflow limitation or air-trapping criteria (None) phenotype had neither A Trpg nor A Limit. The 3 obstruction phenotypes were assessed as predictors of number of exacerbations, asthma severity, and airway lability. Results Patients with the A Trpg phenotype (14% of the cohort) had more exacerbations during the 12-month study compared with those with the A Limit ( P P 1 over time, and the greatest sensitivity to methacholine challenge. Conclusions A Trpg and A Limit patterns of obstruction, as defined by using routine spirometric measurements, can identify obstruction phenotypes that are indicators of risk for asthma severity and instability.
33 citations
University of Cincinnati1, Johns Hopkins University School of Medicine2, Boston University3, Children's Memorial Hospital4, University of Texas Southwestern Medical Center5, Henry Ford Health System6, Columbia University7, Children's National Medical Center8, University of Wisconsin-Madison9, National Institutes of Health10, University of Colorado Denver11
TL;DR: In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children, and mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Diff difficult-to theControl asthma.
Abstract: African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6–17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population.
TL;DR: The population initiating omalizumab in PROSPERO reported poorly controlled asthma and a substantial disease burden.
Abstract: Background Patients included in clinical trials do not necessarily reflect the real-world population. Objective To understand the characteristics, including disease and comorbidity burden, of patients with asthma receiving omalizumab in a real-world setting. Methods The Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab (PROSPERO) was a US-based, multicenter, single-arm, and prospective study. Patients (≥12 years of age) with allergic asthma initiating omalizumab treatment based on physician-assessed need were included and followed for 12 months. Exacerbations, health care use, adverse events, and Asthma Control Test (ACT) scores were assessed monthly. Biomarkers (blood eosinophils, fractional exhaled nitric oxide, and periostin) were evaluated and patient-reported outcomes (Asthma Quality of Life Questionnaire for 12 Years and Older [AQLQ+12] and Work Productivity and Activity Impairment: Asthma questionnaire [WPAI:Asthma]) were completed at baseline and months 6 and 12. The Mini Rhinoconjunctivitis Quality of Life Questionnaire (MiniRQLQ) was completed at baseline and 12 months. Results Most of the 806 enrollees (91.4%) were adults (mean age 47.3 years, SD 17.4), white (70.3%), and female (63.5%). Allergic comorbidity was frequently reported (84.2%), as were hypertension (35.5%) and depression (22.1%). In the 12 months before study entry, 22.1% of patients reported at least 1 asthma-related hospitalization, 60.7% reported at least 2 exacerbations, and 83.3% reported ACT scores no higher than 19 (uncontrolled asthma). Most patients had low biomarker levels based on prespecified cut-points. Baseline mean patient-reported outcome scores were 4.0 (SD 1.4) for AQLQ+12, 2.7 (SD 1.4) for MiniRQLQ, and 47.7 (SD 28.9) for WPAI:Asthma percentage of activity impairment and 33.5 (SD 28.7) for percentage of overall work impairment. Conclusion The population initiating omalizumab in PROSPERO reported poorly controlled asthma and a substantial disease burden. Trial Registration ClinicalTrials.gov Identifier: NCT01922037.
TL;DR: Among patients with severe, uncontrolled asthma, individualized treatment based on asthma phenotype and eosinophil presence should be considered and the efficacy of the anti-IgE antibody omalizumab has been well established.
TL;DR: The efficacy and safety associated with both subcutaneous (SCIT) and sublingual (SLIT) approaches are reviewed and positioned as treatment options for pediatric patients, with specific focus on current literature as it relates to SLIT in children, including those with perennial allergic rhinitis.
TL;DR: A patient who had symptoms of anaphylaxis after eating salmon, but confirmation of the causative allergen was not readily apparent is presented, providing a framework for navigating through a case involving identification of an underlyingAllergen.
TL;DR: A clinical and therapeutic revolution in the treatment of atopic dermatitis, chronic urticaria, chronic sinusitis with polyps, and HES is seen as these agents are replacing the existing broad spectrum therapeutic approaches, often associated with major risks for significant adverse events.
TL;DR: A1 Subcutaneous pollen immunotherapy by needleless device shows promising results in children with wheat allergy and adults with seasonal pollen allergies.
TL;DR: A greater proportion of Asian patients (S2 and S3, for Well-Controlled; all strata, for Totally Controlled) achieved guideline-defined asthma control with FP/SAL versus FP alone.
Abstract: To analyse the efficacy of fluticasone propionate (FP) alone and combined with salmeterol (SAL) in achieving guideline-defined asthma control in Asian patients. A post hoc analysis of the GOAL study in which patients were stratified by prior-medication use into inhaled corticosteroid (ICS)-naive (Stratum [S] 1), low-dose ICS (S2), and medium-dose ICS (S3), and randomised to receive FP/SAL or FP. Doses were stepped-up every 12 weeks until Totally Controlled asthma or maximum dose was reached (PhI) and then maintained until study end (PhII). The primary endpoint was the proportion of patients achieving Well-Controlled asthma during PhI. Additional endpoints included Total Control and adverse events. Asian and non-Asian patients were analysed separately. In Asian patients in PhI, 74% (n = 87/118) in S1 achieved Well-Controlled asthma with FP/SAL versus 74% (n = 89/121) with FP alone (p = 0.839); corresponding values were 76% (n = 81/107) versus 60% (n = 62/104; p = 0.005) in S2, and 58% (n = 59/102) versus 43% (n = 41/95; p = 0.015) in S3. More patients in all three strata achieved Totally Controlled asthma with FP/SAL versus FP alone. Control was achieved more rapidly and with lower ICS doses with FP/SAL versus FP. A high proportion of patients who achieved control during PhI maintained control during PhII. Similar trends were found in non-Asian patients. No new safety concerns were identified. A greater proportion of Asian patients (S2 and S3, for Well-Controlled; all strata, for Totally Controlled) achieved guideline-defined asthma control with FP/SAL versus FP alone. High proportions of Asian patients in S1 achieved Well-Controlled asthma in both treatment groups.