Angira Dasgupta

How to Diagnose and Phenotype Asthma

Asthma has been described as a chronic disease of the airways characterized by variable airflow obstruction, airway hyperresponsiveness, and airway inflammation. This review discusses the diagnosis and phenotyping of asthma, with a special emphasis on phenotyping based on the nature of cellular inflammation and radiological imaging and how this could be used to direct the treatment of asthma and, in the future, to apply specifically directed therapies to specific phenotypes.

Targeted therapy of bronchitis in obstructive airway diseases.

Guidelines for the management of obstructive airway diseases do not emphasize the measurement of bronchitis to indicate appropriate treatments or monitor response to treatment. Bronchitis is the central component of airway diseases and contributes to symptoms, physiological and structural abnormalities. It can be measured directly and reliably by quantitative assay of spontaneous or induced sputum. The measurement is reproducible, valid, and responsive to treatment and to changes in disease status. Bronchitis may be eosinophilic, neutrophilic, mixed, or paucigranulocytic (eosinophils and neutrophils not elevated). Eosinophilic bronchitis is usually a Th2 driven process and therefore a sputum eosinophilia of greater than 3% usually indicates a response to treatment with corticosteroids or novel therapies directed against Th2 cytokines such as IL-4, IL-5 and IL-13. Neutrophilic bronchitis which is a non-Th2 driven disease is generally a predictor of response to antibiotics and may be a predictor to therapies targeted at pathways that lead to neutrophil recruitment such as IL-8 (eg anti-CXCR2), IL-17 (eg anti-IL17) etc. Paucigranulocytic disease may not warrant anti-inflammatory therapy. Several novel monoclonals and small molecule antagonists have been evaluated in clinical trials with variable results and several more are likely to be discovered in the near future. The success of these agents will depend on appropriate patient selection by accurate phenotyping or characterization of bronchitis.

A pilot randomised clinical trial of mepolizumab in COPD with eosinophilic bronchitis.

Airflow limitation in chronic obstructive pulmonary disease (COPD) is associated with influx of various inflammatory cells (e.g. eosinophils, neutrophils, lymphocytes, macrophages) into the airways. Approximately one-third of stable COPD patients and one in five COPD exacerbations are associated with eosinophilic bronchitis that usually responds to inhaled or ingested corticosteroids [1]. Specific anti-eosinophil agents like mepolizumab, a humanised monoclonal antibody against interleukin 5 (IL-5), reduce severe asthma exacerbations and improve lung function [2–4]. The improvement in forced expiratory volume in 1 s (FEV1) is also associated with a decrease in biomarkers of airway remodelling, such as sputum hyaluronan and versican, over a 6-month treatment period [5]. It is not known if the same benefits are observed in patients with COPD and eosinophilia in whom the airflow obstruction is due to cigarette smoke-related bronchitis and emphysema. Eosinophils may not directly contribute to luminal obstruction in COPD although they may predict steroid response http://ow.ly/b3Au308wA0m

Sample sizes for clinical trials using sputum eosinophils as a primary outcome

Clinical trials do not report sputum eosinophil data in a consistent method and this makes it difficult to compare across studies and to evaluate the sample sizes estimated in these studies. The objectives of the paper are: 1) to systematically review reporting of effect size and sample calculations in randomised controlled trials using sputum eosinophil count as a primary outcome and 2) to illustrate sample size estimation under different methods of data representation using data from an effective anti-eosinophil treatment strategy (mepolizumab). Randomised controlled trials in adults (excluding allergen provocation models) of treatment of asthma and chronic obstructive pulmonary disease for the past 10 years were searched in Ovid MEDLINE and 20 studies were identified that met all the inclusion criteria. Only nine studies discussed sample size calculation. Change from baseline was used as an outcome in 11 studies and was expressed as change in absolute percentage count, percentage change from baseline or as fold changes. Assuming a minimal clinically important reduction of 15% in absolute terms, 18 subjects in each arm will be required to achieve 80% power using an ANCOVA analysis, which we recommend, to detect significance with an alpha error of 0.05. Systematic review and illustration of sample size calculations in RCTs using sputum eosinophil count as a primary outcome http://ow.ly/mK9g3

The use of cellular and molecular biomarkers to manage COPD exacerbations

ABSTRACT Introduction: Chronic obstructive pulmonary disease (COPD) exacerbations are a common cause of respiratory morbidity and mortality, and have various etiologies. Multiple cellular and molecular biomarkers have been associated with exacerbations. Quantitative sputum cell counts are able to identify the presence and type of bronchitis, which is an important contributor to exacerbations. Their utility to monitor bronchitis and to help treat exacerbations has been evaluated, yet they are not used in routine clinical practice. Areas covered: This review will provide a brief summary of biomarkers utilized in COPD, with a focus on the application of cellular markers for the management of exacerbations. A case study will demonstrate the application of these methods. With quantitative sputum cell counts, the presence of eosinophilic bronchitis predicts corticosteroid-responsiveness, while neutrophilic bronchitis identifies infection and suggests the need for antibiotics. Gastroesophageal reflux-related aspiration and heart failure can also be identified by examining sputum. Expert commentary: Quantitative sputum cytometry is an essential tool in the management of exacerbations of COPD, particularly those prone to frequent exacerbations. Treatment based on sputum cell counts is superior to current guideline-based recommendations to prevent future exacerbations and hospitalizations in observational and single-centre controlled trials. Large multicentre clinical trials are necessary to confirm this.

Changing Pattern of Sputum Cell Counts During Successive Exacerbations of Chronic Obstructive Pulmonary Disease

Abstract Background: Chronic Obstructive Pulmonary Disease exacerbations are associated with worsening of airway inflammation, the nature of which may be neutrophilic, eosinophilic, or both. Objective: The primary objective was to examine the cellular nature of airway inflammation in successive COPD exacerbations in order to ascertain if they changed in individual patients. The secondary objective was to estimate the relative risk indicating the extent to which a particular type of exacerbation changed as a function of the most recent exacerbation. Design: This was a retrospective survey performed on a computerised sputum cell count database of a referral respiratory service in Hamilton, Canada. Recurrent event analyses were used to model the incidence of exacerbations and subtypes of exacerbations. Results: 359 patients and 148 patients had sputum examined during stable condition and during exacerbations, respectively. It was found 65 patients had sputum examined during both situations. The exacerbations were eosinophilic in 15.9%, neutrophilic in 18%, combined in 2.6%, of unknown clinical significance in 19.6% and normal in 19.6%. There were missing counts for 24.3% samples. In 85.2% of patients, a different subtype of bronchitis was noted in successive exacerbations. The relative risk of a subsequent neutrophilic or eosinophilic exacerbation was 6.24 (p = 0.02) and 2.8 (p = 0.24) when the previous exacerbation was neutrophilic or eosinophilic respectively. Conclusions: This non-intervention study suggests that the cellular nature of bronchitis is largely unpredictable and needs to be examined at each COPD exacerbation This has important implications in choosing the appropriate therapy. Future intervention studies would provide further evidence.

The effects of rituximab on serum IgE and BAFF

BackgroundThere are few treatment options for patients with severe atopic asthma. Antagonism of IgE is an effective strategy. We investigated, by utilizing serum samples from a clinical trial of Rituximab in patients with Idiopathic Thrombocytopenic Purpura, if B cell depletion would decrease serum IgE and therefore be a potential therapeutic option.FindingsIn a placebo-controlled randomized clinical trial of Rituximab, an anti-CD20 molecule, there were no significant differences in serum levels of IgE or BAFF levels between the two treatment groups at 3 or 6 months irrespective of the baseline serum IgE levels.ConclusionsSince Rituximab did not significantly decrease serum IgE levels, this proof of concept study suggests that Rituximab may not be a useful treatment strategy for patients with severe IgE mediated disease.

Selected ReportsAsthma Associated With Incontinentia Pigmenti and Fanconi Anemia: Variable Airflow Limitation Without Cellular Bronchitis

Airway inflammation is considered a central component of asthma and, therefore, international guidelines recommend antiinflammatory medications. We describe the clinical history of a 34-year-old woman with airway hyperresponsiveness and asthma who had a reduced ability to mount an inflammatory response due to two unrelated and rare genetic conditions: Fanconi anemia and incontinentia pigmenti. Absence of eosinophils in blood and sputum led to a successful reduction in the dose of corticosteroids without loss of asthma control demonstrating the clinical utility of monitoring treatment using biomarkers and the importance of recognizing the components of airway diseases that contribute to symptoms.

Asthma Associated With Incontinentia Pigmenti and Fanconi Anemia: Variable Airflow Limitation Without Cellular Bronchitis

Airway inflammation is considered a central component of asthma and, therefore, international guidelines recommend antiinflammatory medications. We describe the clinical history of a 34-year-old woman with airway hyperresponsiveness and asthma who had a reduced ability to mount an inflammatory response due to two unrelated and rare genetic conditions: Fanconi anemia and incontinentia pigmenti. Absence of eosinophils in blood and sputum led to a successful reduction in the dose of corticosteroids without loss of asthma control demonstrating the clinical utility of monitoring treatment using biomarkers and the importance of recognizing the components of airway diseases that contribute to symptoms.