Key concepts in the management of severe asthma in children include verification of the correct diagnosis, evaluation of co-morbid diseases and assessment of compliance with controller medications. Establishing a treatment strategy based on combination therapy with proper medication delivery should be tailored to maximize patient and family adherence (1). In this case, the patient met diagnostic criteria for asthma based on symptoms and reversible airflow obstruction on pulmonary function testing.
In the difficult-to-manage asthma patient, a thorough investigation to rule out alternative diagnosis or identify co-existing conditions is necessary. Cystic fibrosis or other causes of bronchiectasis can mimic asthma symptoms. Foreign body aspiration should always be considered, particularly in the younger patient (2). Conditions such as allergic rhinitis and eczema indicate an atopic phenotype that contributes to asthma. Immunoglobulin E plays a key role in the pathogenesis of allergy-related asthma (3). Gastroesophageal reflux disease and asthma often co-exist, and some individuals may benefit form GERD therapy (4).
Our patient’s parents were upfront in reporting intermittent use of controller medications and ongoing cigarette smoke exposure. Nonadherence to appropriate medical therapy can be an enormous problem in asthma. Factors associated with poor compliance include concerns of side effects, financial constraints and psychosocial problems. Assessing compliance and addressing barriers to adherence regularly is an important aspect of managing the difficult pediatric asthma patient (5). Cigarette smoke has been associated with an increase in prevalence of asthma, and ongoing environmental smoke exposure has been associated with increased exacerbations (6).
Obstructive sleep apnea is a co-morbid condition that can contribute to severity of asthma symptoms in patients of all ages. In pediatric patients, obstructive sleep apnea is frequently associated with a clinical history of snoring, obesity and enlarged adenoid and tonsilar tissue. It is the least likely of the above choices in this patient due to lack of snoring, normal physical size and normal tonsils on physical exam.
According to the 2007 National Asthma Education and Prevention Program (NAEPP) Guidelines for the Diagnosis and Management of Asthma (7), the goal of asthma therapy is to reduce patient impairment and risk from the disease. A stepwise approach is recommended to gain adequate disease control, and then to maintain this level of control long term. Frequent monitoring and follow-up is necessary.
Inhaled corticosteroids reduce airway hyperresponsiveness, inhibit airway reaction to allergen exposure and inhibit the inflammatory response that is central to the pathogenesis of asthma. They have been proven superior to alternative controller medications in multiple large clinical trials. They are the standard of care for initial treatment in patients with persistent asthma of all ages.
Patients older than 12-years who fail to achieve optimal control on low-dose inhaled corticosteroids alone benefit from the addition of long-acting beta agonists. Expert analysis of available data reported in the NAEPP guidelines indicates the superiority of combined inhaled corticosteroids and long-acting beta agonists therapy to merely increasing the inhaled corticosteroids dose, or to combining inhaled corticosteroids with leukotriene inhibitors. Key components of this recommendation were observed improvement in symptoms, lung function and reduction in the need for rescue short-acting beta agonist use.
In children age 5-11, there is insufficient data to definitely conclude whether or not the addition of long-acting beta agonists to low-dose inhaled corticosteroids is superior to increasing inhaled corticosteroid strength. Therefore, the current NAEPP recommendations consider the combination of low-dose inhaled corticosteroids and adjunctive therapy to be equivalent to medium-dose inhaled corticosteroid therapy.
For children 4 years of age and younger, the NAEPP recommends increasing inhaled corticosteroids to medium-strength dosing and assuring that an adequate dose is effectively delivered before adding alternative therapies. Despite a lack of strong clinical evidence, the addition of long-acting beta agonists or leukotriene inhibitors is the treatment of choice, based on expert consensus, for the pediatric patient younger than 4 years of age with poorly controlled symptoms on medium-dose inhaled corticosteroids alone.
For pediatric patients still failing to reach optimal control on combination inhaled corticosteroid and long-acting beta agonist therapy, leukotriene receptor antagonists, cromolyn sodium or nedocromil, theophylline and immune modulators are all possible additional therapies.
Our patient had persistent asthma that was very poorly controlled. He initially was treated with a burst of oral corticosteroids for symptomatic relief. The inhaled corticosteroid component of his combination therapy was increased in strength, and a leukotriene inhibitor was added to his regimen. The patient and his family were counseled on the need for compliance with his daily controller medications. Extensive smoking cessation education was provided to the father. The patient returned in 2 months with improved, however still poorly controlled symptoms. Pulmonary function testing was significantly improved (FEV1 86% predicted). Regular nasal corticosteroids were added to help with allergic rhinitis. In addition, a proton pump inhibitor was added as an empiric trial of anti-reflux therapy.
Approximately 6 months later, the patient was still noticing substantial symptoms related to environmental allergen exposure. Pulmonary function testing continued to indicate mild obstructive disease. An IgE level was significantly elevated at 665 IU/ml (normal< 250 IU/ml). Formal allergy testing was obtained, and positive skin responses were found for several environmental aeroallergens. The patient was subsequently started on Omalizumab at standard dosing based on weight and baseline IgE level.
Omalizumab is a recombinant humanized anti-IgE antibody that was developed for treatment of allergic diseases. It binds circulating IgE, and also prevents IgE binding to mast cells and basophils (8).
Clinical studies have demonstrated that Omalizumab therapy can help reduce inhaled corticosteroids dose requirement and allow patients to potentially discontinue this treatment altogether (9,10). It also has been shown to result in fewer acute exacerbations and improve quality of life measures (11). Omalizumab was formally approved by the FDA in 2003 for use in asthmatic patients with documented perennial aeroallergen and inadequate control with inhaled corticosteroids. It has been approved in pediatric asthmatics age 12 and older. It has not been evaluated in patients with cystic fibrosis. Dosing is based on body weight and baseline serum IgE level. Omalizumab is an expensive therapy, with average yearly cost of $4000 to $20,000 depending on dose (8).
The current 2007 NAEPP Asthma guidelines recommend that Omalizumab be considered for adjunctive therapy in all patients 12 years of age and older who fail to achieve optimum control on high-dose inhaled corticosteroids AND long-acting beta agonist combination therapy (7).
After initiation of Omalizumab, there may be a period of several weeks before any noticeable clinical improvement is achieved. Patients who will respond to therapy should be expected to show improvements within the first 12 weeks of therapy (12), and therefore patients should be treated for at least 3 months duration prior to assuming a treatment failure. There is no available data on duration of therapy or weaning therapy once a patient reaches adequate asthma control. Dosing should be adjusted for weight as a patient grows over time.
Our patient has maintained on regular Omalizumab treatment for over 2 years, and asthma symptoms have been well-controlled during this time. There have been no severe exacerbations of his disease. After 18 months of therapy, his regimen was decreased to low-dose inhaled corticosteroid monotherapy. He has been able to participate in sports without difficulty, and he is active on the family farm. Pulmonary function testing has been normal, with no evidence of obstruction. At his most recent visit, we were able to discontinue inhaled corticosteroids completely. Short-acting beta agonist use has been very infrequent (less than one dose per month). Omalizumab has been weaned to every other month dosing.
Anaphylaxis from Omalizumab is a rare but documented reaction (13,14). Symptoms including bronchospasm, urticarial rash, angioedema of the throat and/or tongue, hypotension and syncope have been documented as presenting symptoms. Anaphylaxis has occurred with the initial dose of the drug, but also with those on chronic therapy as far as 1 year after initial treatment. For this reason, patients, caregivers and physicians should be aware of this potentially deadly reaction. It is recommended that Omalizumab be administered in a healthcare setting and that patients should be observed for at least 2 hours following drug administration. Providing patients and caregivers with subcutaneous epinephrine is widely accepted.
Recommended Resources:
- National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR3):Guidelines for the Diagnosis and Management of Asthma. National Institue of Healthy; 2007. NIH publication no. 08-4051.
- Strunk RC, Bloomberg GR. Omalizumab for asthma. The New England journal of medicine 2006;354(25):2689-2695.
