Asthma is a heterogeneous disease with subsets of children responding very differently to medication. Some children have very few limitations while others have significant limitations and decreased lung function. A small subset of children with asthma have severe or refractory asthma, which represents a group that is at risk for significant morbidity and is also responsible for significant healthcare utilization and costs. This article will look at the definitions, risk factors, and treatments for severe asthma.
The joint European Respiratory Society (ERS)/American Thoracic Society (ATS) Task Force defines severe asthma as treatment requiring either of the following:1
1. High-dose inhaled corticosteroids (ICS, as defined here2) and a second controller medication over the last year.
2. Systemic corticosteroid treatment for at least half the prior year to prevent uncontrolled asthma or remaining uncontrolled despite the therapy.
The World Health Organization (WHO) identifies 3 specific groups that encompass severe asthma, each with its own challenges and treatment issues:3
· Untreated severe asthma.
· Difficult-to-treat asthma.
· Treatment-resistant asthma that is not controlled on high-dose steroids.
Uncontrolled vs severe asthma
Asthma is a complicated chronic illness and management is impacted by many domains. Whereas most asthmatic children can achieve good symptom control by avoiding triggers and regularly using controller medications, some will not achieve optimal results even with maximal therapy.4 One of the goals of the pediatrician is to identify whether a patient on maximal therapy has asthma refractory to treatment or whether symptoms are due to noncompliance, psychosocial factors, persistent environmental triggers, or comorbidities. Table 1 gives the pediatrician areas to examine to identify poorly controlled or undertreated asthma.
Clinical features and risk factors
Children with severe asthma are more likely to have received multiple courses of systemic corticosteroids, visited the emergency department (ED), or experienced a hospital admission for an asthma exacerbation in the prior 12 months. There is concern for an increased risk of asthma mortality in this group as nearly 1 in 3 have a history of intubation for near-fatal respiratory failure.2
Compared with children with nonsevere asthma and adults with severe asthma, elevated serum immunoglobulin E (IgE) and increased eosinophil levels are common. Children with severe asthma are also noted to have increased concentrations of exhaled nitric oxide and a different pattern of aeroallergen sensitization compared with children with nonsevere asthma. Sensitization to pollens and molds is more common in nonsevere asthma while sensitization to indoor allergens is more common among children with severe asthma. Finally, children with severe asthma demonstrate less airflow limitation and air trapping as measured by pulmonary function testing compared with adults with severe asthma.2
Risk factors for severe asthma in children include gender, race, comorbid conditions, and environmental exposures, among others.2
Severe asthma is more common in boys compared with girls and the manifestations of severe asthma also vary by gender. Sex hormones are hypothesized to be the cause of some of these differences.
Examples for boys include:2
· Experiencing more airflow obstruction and incomplete reversal with bronchodilators.
· Have greater amounts of air trapping.
Children with severe asthma are more likely to be African Americans. Although it is unclear if this is related to centers doing this research being located in large urban centers, there is some research in adults indicating asthma among African Americans is phenotypically different.5
African Americans with severe asthma are more likely to have a greater body mass index and more airway obstruction compared with Caucasians with severe asthma. Further, serum IgE levels, allergy testing, and family history were all significantly associated with severe asthma in African Americans, but the same association was not present in Caucasians. The relationship between race and asthma severity is complex and remains an area of active research.5
Comorbid conditions that the pediatrician commonly evaluates in patients with nonsevere asthma are also more frequent in children with severe asthma:2
· Gastroesophageal reflux.
· Sinopulmonary infections.
· Pneumonia requiring antibiotic therapy.
Whether obesity in children with asthma results from decreased activity or increased exposure to corticosteroids or some other physiologic mechanism is unclear.2
Although not studied specifically in severe asthma, environmental tobacco smoke (ETS) is associated with poor asthma control and increased risk of hospitalization. In adults, ETS is associated with increased damage to lungs, decreased levels of antioxidants in the lungs, and other pathophysiologic changes (eg, increased proliferation of epithelial cells, increased apoptosis, and decreased cell death suppression) that can lead to increased airway hyper-responsiveness and use of short-acting bronchodilators.2
1. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation, and treatment of severe asthma. Eur Respir J. 2014;43(2):343-373.
2. Fitzpatrick AM. Severe asthma in Children: lessons learned and future directions. J Allergy Clin Immunol Pract. 2016;4(1):11-9.
3. Bousquet J, Mantzouranis E, Cruz AA, et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010;126(5):926-938.
4. Bateman ED, Boushey HA, Bousquet J, et al; GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med. 2004;170(8):836-844.
5. Gamble C, Talbott E, Youk A, et al. Racial differences in biologic predictors of severe asthma: data from the Severe Asthma Research Program. J Allergy Clin Immunol. 2010;126(6):1149.e1-1156.e1.
6. Fitzpatrick AM, Teague WG, Meyers DA, et al; National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. J Allergy Clin Immunol. 2011;127(2):382-389.e1-13.
7. Abrams EM, Becker AB, Szefler SJ. Current state and future of biologic therapies in the treatment of asthma in children. Pediatr Allergy Immunol Pulmonol. 2018;31(3):119-131.
8. Agumadu VC, Ramphul K, Mejias SG, Sonaye R, Sombans S, Lohana P. A review of three new anti-interleukin-5 monoclonal antibody therapies for severe asthma. Cureus. 2018;10(8):e3216.
9. Di Bona D, Fiorino I, Taurino M, et al. Long-term “real-life” safety of omalizumab in patients with severe uncontrolled asthma: a nine-year study. Respir Med. 2017;130:55-60.
10. Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;(1):CD003559.
11. Busse WW, Morgan WJ, Gergen PJ, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med. 2011;364(11):1005-1015.
12. Teach SJ, Gill MA, Togias A, et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol. 2015;136(6):1476-1485.
13. Farne HA, Wilson A, Powell C, Bax L, Milan SJ. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017;9:CD010834.
14. Abrams EM, Becker AB, Szefler SJ. Current state and future of biologic therapies in the treatment of asthma in children. Pediatr Allergy Immunol Pulmonal. 2018;31(3):119-131.