Role of Immunotherapy in Asthma
Immunotherapy plays a critical role in asthma management through two distinct pathways: allergen immunotherapy (subcutaneous) for allergic asthma at Steps 2-4, and biologic immunotherapy (anti-IgE, anti-IL-5/IL-5R agents) for severe persistent asthma at Steps 5-6 when conventional therapy fails.
Allergen Immunotherapy (Subcutaneous)
Indications for Referral
Consider subcutaneous allergen immunotherapy for patients with persistent allergic asthma when there is a clear relationship between asthma symptoms and unavoidable aeroallergen exposure with documented specific IgE antibodies 1. This applies specifically to Steps 2-4 of asthma management 1.
Specific Clinical Scenarios
Allergen immunotherapy is appropriate when patients experience 1:
- Poor response to pharmacotherapy or avoidance measures
- Unacceptable medication side effects
- Desire to avoid long-term pharmacotherapy
- Coexisting allergic rhinitis
- Long duration of symptoms (perennial or major portion of the year)
Preventive Role
In children with allergic rhinitis, allergen immunotherapy can potentially prevent asthma development and reduce new allergen sensitivities 1. The efficacy has been demonstrated in multiple double-blind, placebo-controlled studies for pollens, animal allergens, fungi, and dust mites 1.
Biologic Immunotherapy
Anti-IgE Therapy (Omalizumab)
Patient Selection Criteria
Omalizumab is indicated for patients aged 12 years and older with severe persistent allergic asthma (Steps 5-6) whose symptoms remain inadequately controlled despite high-dose inhaled corticosteroids plus long-acting beta-agonists 2, 3, 4. Patients must have 1, 4:
- Documented atopy with positive skin testing or RAST to perennial aeroallergens
- Elevated serum IgE levels
- Sensitivity to relevant allergens (dust mite, cockroach, cat, or dog)
Clinical Benefits
Omalizumab prevents exacerbations, improves symptoms, and reduces inhaled steroid requirements in moderate-to-severe asthma 1. In the INNOVATE trial, omalizumab reduced clinically significant asthma exacerbations by 26.2% when added to existing therapy 5.
Critical Safety Requirements
Omalizumab must be administered in a healthcare setting by providers trained to recognize and treat anaphylaxis, with observed anaphylaxis risk of approximately 0.09% 2, 3, 4. The FDA has issued a black-box warning for anaphylaxis 4. Patients should be observed after injection and prescribed an epinephrine autoinjector 4.
Mechanism of Action
Omalizumab inhibits IgE binding to high-affinity receptors (FcεRI) on mast cells, basophils, and dendritic cells, resulting in FcεRI down-regulation 6. Serum free IgE levels decrease by greater than 96% within 1 hour of the first dose 6.
Anti-IL-5 Pathway Biologics
Mepolizumab
Mepolizumab (anti-IL-5 ligand antibody) is indicated for severe eosinophilic asthma at Steps 5-6 1. It demonstrates effectiveness in reducing exacerbations and oral corticosteroid requirements 7, 8. In real-world studies, mepolizumab showed the greatest improvement in FEV1 among biologics 8.
Benralizumab
Benralizumab (anti-IL-5 receptor antibody) provides rapid eosinophil depletion and is effective for severe eosinophilic asthma 9, 10. Real-world data shows benralizumab produces the greatest reduction in blood eosinophil counts 8 and can result in immediate improvements in lung function and symptom relief 10.
Comparative Effectiveness
Indirect treatment comparisons suggest dupilumab (anti-IL-4/IL-13) demonstrates superior efficacy compared to anti-IL-5 agents and omalizumab, with 54% greater reduction in exacerbations versus benralizumab, 28% versus mepolizumab, and 26% versus omalizumab 9. However, the 2020 NAEPP guidelines note that biologics were not systematically reviewed, and specific recommendations for Steps 5-6 were not made 1.
Combination Biologic Therapy
In select cases of severe asthma with both elevated IgE and eosinophilic phenotype, combination therapy with omalizumab plus anti-IL-5 agents may be necessary 11, 10. Case reports demonstrate successful dual targeting with omalizumab and mepolizumab or benralizumab, allowing significant oral corticosteroid reduction and preventing need for lung transplantation 11, 10.
Clinical Outcomes with Specialist Care
Allergist-immunologist management reduces asthma emergency department visits, hospitalizations, and improves asthma-related quality of life 1. Specialist care increases appropriate use of controller medications, particularly inhaled corticosteroids, which reduce asthma symptoms, exacerbations, hospitalizations, and asthma death 1.
When to Refer to Specialist
Consultation with an asthma specialist is recommended 1:
- Step 4 or higher required (mandatory)
- Step 3 (consider consultation)
- Patients with potentially fatal asthma (prior severe, life-threatening episode or intubation)
- Patients requiring emergency department care for acute episodes
- Uncontrolled asthma despite appropriate therapy
Common Pitfalls
Do not use long-acting beta-agonists as monotherapy for asthma control—they must always be combined with inhaled corticosteroids 1. The FDA issued a boxed warning for montelukast in March 2020 due to neuropsychiatric risks 1. Clinicians administering immunotherapy must be prepared and equipped to identify and treat anaphylaxis 1.