Ronald L. Sorkness

Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program

RATIONALE The Severe Asthma Research Program cohort includes subjects with persistent asthma who have undergone detailed phenotypic characterization. Previous univariate methods compared features of mild, moderate, and severe asthma. OBJECTIVES To identify novel asthma phenotypes using an unsupervised hierarchical cluster analysis. METHODS Reduction of the initial 628 variables to 34 core variables was achieved by elimination of redundant data and transformation of categorical variables into ranked ordinal composite variables. Cluster analysis was performed on 726 subjects. MEASUREMENTS AND MAIN RESULTS Five groups were identified. Subjects in Cluster 1 (n = 110) have early onset atopic asthma with normal lung function treated with two or fewer controller medications (82%) and minimal health care utilization. Cluster 2 (n = 321) consists of subjects with early-onset atopic asthma and preserved lung function but increased medication requirements (29% on three or more medications) and health care utilization. Cluster 3 (n = 59) is a unique group of mostly older obese women with late-onset nonatopic asthma, moderate reductions in FEV(1), and frequent oral corticosteroid use to manage exacerbations. Subjects in Clusters 4 (n = 120) and 5 (n = 116) have severe airflow obstruction with bronchodilator responsiveness but differ in to their ability to attain normal lung function, age of asthma onset, atopic status, and use of oral corticosteroids. CONCLUSIONS Five distinct clinical phenotypes of asthma have been identified using unsupervised hierarchical cluster analysis. All clusters contain subjects who meet the American Thoracic Society definition of severe asthma, which supports clinical heterogeneity in asthma and the need for new approaches for the classification of disease severity in asthma.

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy. ERS/ATS guidelines revise the definition of severe asthma, discuss phenotypes and provide guidance on patient management http://ow.ly/roufI

Severe asthma: lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program.

The National Heart, Lung, and Blood Institute Severe Asthma Research Program (SARP) has characterized over the past 10 years 1,644 patients with asthma, including 583 individuals with severe asthma. SARP collaboration has led to a rapid recruitment of subjects and efficient sharing of samples among participating sites to conduct independent mechanistic investigations of severe asthma. Enrolled SARP subjects underwent detailed clinical, physiologic, genomic, and radiological evaluations. In addition, SARP investigators developed safe procedures for bronchoscopy in participants with asthma, including those with severe disease. SARP studies revealed that severe asthma is a heterogeneous disease with varying molecular, biochemical, and cellular inflammatory features and unique structure-function abnormalities. Priorities for future studies include recruitment of a larger number of subjects with severe asthma, including children, to allow further characterization of anatomic, physiologic, biochemical, and genetic factors related to severe disease in a longitudinal assessment to identify factors that modulate the natural history of severe asthma and provide mechanistic rationale for management strategies.

Evaluation of Structure-Function Relationships in Asthma using Multidetector CT and Hyperpolarized He-3 MRI

RATIONALE AND OBJECTIVES Although multiple detector computed tomography (MDCT) and hyperpolarized gas magnetic resonance imaging (HP MRI) have demonstrated ability to detect structural and ventilation abnormalities in asthma, few studies have sought to exploit or cross-validate the regional information provided by these techniques. The purpose of this work is to assess regional disease in asthma by evaluating the association of sites of ventilation defect on HP MRI with other regional markers of airway disease, including air trapping on MDCT and inflammatory markers on bronchoscopy. MATERIALS AND METHODS Both HP MRI using helium-3 and MDCT were acquired in the same patients. Supervised segmentation of the lung lobes on MRI and MDCT facilitated regional comparisons of ventilation abnormalities in the lung parenchyma. The percentage of spatial overlap was evaluated between regions of ventilation defect on HP MRI and hyperlucency on MDCT to determine associations between obstruction and likely regions of gas trapping. Similarly, lung lobes with high defect volume were compared to lobes with low defect volume for differences in inflammatory cell number and percentage using bronchoscopic assessment. RESULTS There was significant overlap between sites of ventilation defect on HP MRI and hyperlucency on MDCT suggesting that sites of airway obstruction and air trapping are associated in asthma. The percent (r=0.68; P= .0039) and absolute (r=0.61; P= .0125) number of neutrophils on bronchoalveolar lavage for the sampled lung lobe also directly correlated with increased defect volume. CONCLUSIONS These results show promise for using image guidance to assess specific regions of ventilation defect or air trapping in heterogeneous obstructive lung diseases such as asthma.

Pin1 regulates TGF-β1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis

Eosinophilic inflammation is a cornerstone of chronic asthma that often culminates in subepithelial fibrosis with variable airway obstruction. Pulmonary eosinophils (Eos) are a predominant source of TGF-beta1, which drives fibroblast proliferation and extracellular matrix deposition. We investigated the regulation of TGF-beta1 and show here that the peptidyl-prolyl isomerase (PPIase) Pin1 promoted the stability of TGF-beta1 mRNA in human Eos. In addition, Pin1 regulated cytokine production by both in vitro and in vivo activated human Eos. We found that Pin1 interacted with both PKC-alpha and protein phosphatase 2A, which together control Pin1 isomerase activity. Pharmacologic blockade of Pin1 in a rat asthma model selectively reduced eosinophilic pulmonary inflammation, TGF-beta1 and collagen expression, and airway remodeling. Furthermore, chronically challenged Pin1(-/-) mice showed reduced peribronchiolar collagen deposition compared with wild-type controls. These data suggest that pharmacologic suppression of Pin1 may be a novel therapeutic option to prevent airway fibrosis in individuals with chronic asthma.

Asthma outcomes: Pulmonary physiology

BACKGROUND Outcomes of pulmonary physiology have a central place in asthma clinical research. OBJECTIVE At the request of National Institutes of Health (NIH) institutes and other federal agencies, an expert group was convened to provide recommendations on the use of pulmonary function measures as asthma outcomes that should be assessed in a standardized fashion in future asthma clinical trials and studies to allow for cross-study comparisons. METHODS Our subcommittee conducted a comprehensive search of PubMed to identify studies that focused on the validation of various airway response tests used in asthma clinical research. The subcommittee classified the instruments as core (to be required in future studies), supplemental (to be used according to study aims and in a standardized fashion), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011. RESULTS A list of pulmonary physiology outcomes that applies to both adults and children older than 6 years was created. These outcomes were then categorized into core, supplemental, and emerging. Spirometric outcomes (FEV(1), forced vital capacity, and FEV(1)/forced vital capacity ratio) are proposed as core outcomes for study population characterization, for observational studies, and for prospective clinical trials. Bronchodilator reversibility and prebronchodilator and postbronchodilator FEV(1) also are core outcomes for study population characterization and observational studies. CONCLUSIONS The subcommittee considers pulmonary physiology outcomes of central importance in asthma and proposes spirometric outcomes as core outcomes for all future NIH-initiated asthma clinical research.

Similar colds in subjects with allergic asthma and nonatopic subjects after inoculation with rhinovirus-16.

BACKGROUND Rhinovirus infections are frequent causes of asthma exacerbations. OBJECTIVE This study was conducted to test whether subjects with and without allergic asthma have different responses to infection and to identify baseline patient risk factors that predict cold outcomes. METHODS Twenty subjects with mild persistent allergic asthma and 18 healthy subjects were experimentally inoculated with rhinovirus-16. Subjects were evaluated at baseline, during the acute infection, and during recovery for asthma and cold symptoms by using a validated questionnaire. Sputum and nasal lavage fluid were evaluated for viral shedding, cytokines, and cellular inflammation. RESULTS There were no group-specific significant differences in peak cold symptom scores (10.0 +/- 5.8 vs 11.1 +/- 6.2, asthmatic vs healthy subjects), peak nasal viral titers (log(10) 4.3 +/- 0.8 vs 3.7 +/- 1.4 50% tissue culture infective dose/mL, respectively), or changes in peak flow during the study (10% +/- 10% vs 8% +/- 6%, respectively). Rhinovirus-16 infection increased peak asthma index values in the asthmatic group (median, 6 --> 13; P = .003) but only marginally in the healthy group (median, 4 --> 7; P = .09). More asthmatic subjects had detectable eosinophils in nasal lavage and sputum samples at baseline and during infection, but otherwise, cellular and cytokine responses were similar. Baseline sputum eosinophilia and CXCL8 (IL-8) levels were positively associated with cold symptoms, whereas CCL2 (monocyte chemotactic protein 1) levels were inversely associated with nasal viral shedding. CONCLUSIONS These findings suggest that subjects with mild allergic asthma and healthy subjects have similar cold symptoms and inflammatory and antiviral responses. In addition, eosinophilia and other selective baseline measures of airway inflammation in subjects with or without asthma might predict respiratory outcomes with rhinovirus infection.

Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations

Rationale: Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation‐prone asthma (EPA) remain incompletely defined. Objectives: To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA. Methods: Baseline data from the NHLBI Severe Asthma Research Program (SARP)‐3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), or exacerbation prone (≥3). Replication of a multivariable model was performed with data from the SARP‐1 + 2 cohort. Measurements and Main Results: Of 709 subjects in the SARP‐3 cohort, 294 (41%) had no exacerbations and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP‐3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP‐3 multivariable model, blood eosinophils, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval], 1.6 [1.2‐2.1] for every log unit of eosinophils, 1.3 [1.1‐1.4] for every 10 body mass index units, and 1.2 [1.1‐1.4] for every 10% increase in bronchodilatory responsiveness). Chronic sinusitis and gastroesophageal reflux were also associated with exacerbation frequency (1.7 [1.4‐2.1] and 1.6 [1.3‐2.0]), even after adjustment for multiple factors. These effects were replicated in the SARP‐1 + 2 multivariable model. Conclusions: EPA may be a distinct susceptibility phenotype with implications for the targeting of exacerbation prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 01760915).

Imaging of lung ventilation and respiratory dynamics in a single ventilation cycle using hyperpolarized He‐3 MRI

To image respiratory dynamics and three‐dimensional (3D) ventilation during inhalation, breath‐hold, and exhalation for evaluation of obstructive lung disease using a single dose of hyperpolarized (HP) He‐3 during MRI.

Pulmonary 3He magnetic resonance imaging of childhood asthma.

BACKGROUND Magnetic resonance imaging (MRI) with (3)He does not require ionizing radiation and has been shown to detect regional abnormalities in lung ventilation and structure in adults with asthma, but the method has not been extended to children with asthma. Measurements of regional lung ventilation and microstructure in subjects with childhood asthma could advance our understanding of disease mechanisms. OBJECTIVE We sought to determine whether (3)He MRI in children can identify abnormalities related to the diagnosis of asthma or prior history of respiratory illness. METHODS Forty-four children aged 9 to 10 years were recruited from a birth cohort at increased risk of asthma and allergic diseases. For each subject, a time-resolved 3-dimensional image series and a 3-dimensional diffusion-weighted image were acquired in separate breathing maneuvers. The numbers and sizes of ventilation defects were scored, and regional maps and statistics of average (3)He diffusion lengths were calculated. RESULTS Children with mild-to-moderate asthma had lower average root-mean-square diffusion length (X(rms)) values (P = .004), increased regional SD of diffusion length values (P = .03), and higher defect scores (P = .03) than those without asthma. Children with histories of wheezing illness with rhinovirus infection before the third birthday had lower X(rms) values (P = .01) and higher defect scores (P = .05). CONCLUSION MRI with (3)He detected more and larger regions of ventilation defect and a greater degree of restricted gas diffusion in children with asthma compared with those seen in children without asthma. These measures are consistent with regional obstruction and smaller and more regionally variable dimensions of the peripheral airways and alveolar spaces.