Severe asthma: an expanding and mounting clinical challenge

Abstract

Although all patients with asthma have variable airflow obstruction, airway inflammation, and bronchial hyperresponsiveness, some have disease that is severe in many aspects: persistent airflow obstruction, ongoing symptoms, increased frequency of exacerbations, and, most importantly, a diminished response to medications. A number of definitions have emerged to characterize the clinical features of severe asthma, but a central feature of this phenotype is the need for high doses of medications, especially corticosteroids, in attempts to achieve disease control. The prevalence of severe asthma is also undergoing reevaluation from the usual estimate of 10% to larger numbers on the basis of medication needs and the lack of disease control achieved. At present, the underlying mechanisms of severe asthma are not established but likely reflect a heterogeneous pattern, rather than a single unifying process. Guideline-directed treatment for severe asthma has limits with usual approaches centered on high doses of inhaled corticosteroids, long-acting β-agonists, and trials with omalizumab, the monoclonal antibody to IgE. With the development of approaches to recognize asthma phenotypes with distinct pathogenesis and hence unique therapeutic targets, it is hoped that a personalized strategy in treatment directed toward disease-specific features will improve outcomes for this high-risk, severely affected population of patients.

Keywords: Asthma; anti-IgE; bronchodilators; corticosteroids; immunomodulators.

Figure 1

Inflammatory and remodelling responses in asthma with activation of the epithelial mesenchymal trophic unit. Epithelial damage alters the set point for communication between bronchial epithelium and underlying mesenchymal cells, leading to myofibroblast activation, an increase in mesenchymal volume, and induction of structural changes throughout airway wall. Adapted from J Allergy Clin Immunol 2003; 111: 215–25. From: Holgate and Polosa. Lancet 2006; 368:780–93.

Figure 2

Relative Change in Forced Expiratory Volume in 1 Second (FEV₁) in the Intention-to-Treat Population. At week 12, the increase from baseline in FEV₁ was higher by 5.5 percentage points (95% CI, 0.8 to 10.2) in the lebrikizumab group than in the placebo group (mean [±SE] change, 9.8±1.9% vs. 4.3±1.5%; P = 0.02) (Panel A). In the subgroup of patients with high periostin levels (high Th2), the relative increase from baseline FEV1 was higher by 8.2 percentage points (95% CI, 1.0 to 15.4) in the lebrikizumab group than in the placebo group (mean change, 14.0±3.1% vs. 5.8±2.1%; P = 0.03) (Panel B). Among patients in the low-periostin subgroup (low Th2), the relative increase from baseline FEV₁ was higher by 1.6 percentage points (95% CI, –4.5 to 7.7) in the lebrikizumab group than in the placebo group (mean change, 5.1±2.4% vs. 3.5±2.1%; P = 0.61) (Panel C). From Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365:1088–1098.

Figure 3

Healthcare utilization events during the posttreatment period. Severe exacerbations (exacerbation requiring treatment with systemic corticosteroids or doubling of the inhaled corticosteroids dose), emergency department visits, and hospitalizations occurring in the post-treatment period. Open bars, sham; shaded bars, bronchial thermoplasty. All values are means 6 SEM statistical significance. From: Castro M, et al. Am J Respir Crit Care Med 2010; 181:116–124.

Figure 4

Personalized treatment algorithm for difficult to control asthma patients.