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

Abstract

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.

Figure 1.

Comparison of physiological characteristics among adults with normal airways (n = 51), nonsevere asthma (n = 109), and severe asthma (n = 61), showing total lung capacity (box height), FEV₁, and residual lung volume (RV). Note prominent air trapping (elevated RV) and airflow limitation (reduced FEV₁) in severe asthma. Lung volumes are adjusted for differences due to height, age, sex, and race.

Figure 2.

Chest multidetector computed tomography (MDCT) images and bronchial biopsy from subjects with mild and severe asthma. Chest MDCT scans were performed in (A) mild asthma and (B) severe asthma. A screen capture of the cross-sectional MDCT image demonstrates an outline of a central airway and reported average wall thickness. Note that the average wall thickness is significantly greater in the subject with severe asthma. Quantitative CT using the Pulmonary Workstation software (VIDA) allows accurate assessment of air trapping (defined as voxels within the lung field falling below −856 Hounsfield units) as demonstrated by sphericals proportional to area of air trapping (volume rendered view). Each lobe is color-coded. Note the increase in air trapping in all lobes of (D) the subject with severe asthma compared with (C) the subject with mild asthma. Representative images from hematoxylin-eosin sections from an endobronchial biopsy from (E) a subject with mild asthma and (F) a subject with severe asthma are demonstrated. The epithelial layer (Epi) and lamina reticularis (LR) are indicated. This histopathology demonstrates key features of airway remodeling that can now be correlated with quantitative imaging of the airways (airway wall thickness) and lungs (air trapping).

Figure 3.

Cluster analysis of all adults with asthma in the Severe Asthma Research Program. BMI = body mass index; COPD = chronic obstructive pulmonary disease.