Exacerbation-Prone Asthma

Abstract

Patients who are prone to exacerbations of asthma experience significant costs in terms of missed work and school, acute care visits, and hospitalizations. Exacerbations are largely driven by environmental exposures including pollutants, stress, and viral and bacterial pathogens. These exposures are most likely to induce acute severe "asthma attacks" in high-risk patients. These personal risk factors for exacerbations can vary with the phenotype of asthma and age of the patient. In children, allergic sensitization is a strong risk factor, especially for those children who develop sensitization early in life. Airway inflammation is an important risk factor, and biomarkers are under evaluation for utility in detecting eosinophilic and type 2 inflammation and neutrophilic inflammation as indicators of risk for recurrent exacerbations. Insights into inflammatory mechanisms have led to new approaches to prevent exacerbations using mAb-based biologics that target specific type 2 pathways. Challenges remain in developing an evidence base to support precision interventions with these effective yet expensive therapies, and in determining whether these treatments will be safe and effective in young children. Unfortunately, there has been less progress in developing treatments for acute exacerbations. Hopefully, greater understanding of mechanisms relating airway viruses, bacteria, mucin production, and neutrophilic inflammatory responses will lead to additional treatment options for patients experiencing acute exacerbations.

Keywords: Corticosteroids; Exacerbation-prone asthma; Precision interventions; Type 2 inflammation.

Figure 1.

Relationship between bronchodilator reversibility and exacerbation rates. Among children and adults participating in the Severe Asthma Research Program, maximum post-albuterol reversibility was related to exacerbation rates (95% confidence interval, multivariable negative binomial model). Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Figure 2.

Contribution of eosinophil peroxidase to mucus plug formation. When airway eosinophils are activated by inflammatory stimuli in the airway, eosinophil peroxidases catalyze a reaction in which H2O2 and thiocyanate (SCN-, from plasma) form hypothiocyanous acids (HOSCN). In turn, HOSCH can cross-link thiol groups on strands of mucin released from goblet cell. The cross-linked mucins are quite viscous, and can form plugs that obstruct lower airways. This figure has been reproduced with permission.

Figure 3.

Omalizumab reduces seasonal exacerbations. Seasonal rates of exacerbations (95% confidence intervals) are depicted for school-aged children participating in the Inner-City Anti-IgE Therapy for Asthma (ICATA) Study. Children were randomized to guidelines-based treatment (“placebo”) or guidelines-based treatment together with omalizumab. [New England Journal of Medicine, Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH, et al, Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children, Volume 364, Pages 1005-15. Copyright © (2011) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Figure 4.

Early childhood wheezing phenotype and the response to inhaled corticosteroid. Data from five NIH-funded treatment studies were combined, and four classes of early childhood recurrent wheeze were identified by latent class analysis. In the PEAK (Prevention of Early Asthma in Kids) study, exacerbation rates in children treated with placebo (solid bars) and daily ICS (hatched bars) are depicted for each class. This figure has been reproduced with permission.