Abstract
Focus on drug development for asthma has been on development of immunomodulator therapies, with the hopes that they can eventually alter the natural course of asthma. This review focuses on the currently available immunomodulating therapies for children. Allergen immunotherapy has been long used as an approach in allergic asthma in children and has the potential ability to alter the natural course of asthma over time. Omalizumab, a humanized anti-IgE specific form of IgG, is the best studied of a new crop of antiallergic mediator immunotherapy. Other, newer modalities, such as anti-IL-5 (mepolizumab, reslizumab, and benralizumab) and combined anti-IL 4/13 (dupilumab), have additionally shown promise; however, these have not been extensively studied in children. We will review mechanism of action, pharmacology, and current literature regarding efficacy of these new therapies for childhood asthma. It is our hope that, with future studies, one or more of these agents may be helpful in altering the onset and progression of severe asthma in children.
Keywords
allergen immunotherapy, asthma, benralizumab, dupilumab, early asthma, inhaled corticosteroids, mepolizumab, omalizumab, reslizumab, severe asthma
Introduction
Attention in asthma management is now being directed toward the development of immunomodulators, medications that can potentially stimulate or impair features of the immune system. Based on current therapeutic strategies, the available medications, such as inhaled corticosteroids (ICS), long-acting β-adrenergic agonists, and leukotriene modifiers, have been shown to reduce asthma symptoms and exacerbations but have not been shown to alter the natural history of asthma. This review will focus on the class of immunomodulators, beginning with allergen immunotherapy (AIT) in its subcutaneous and sublingual forms, followed by experience with anti-IgE (omalizumab), and subsequently by recent experience with the introduction and evaluation of anti-IL5 and anti-IL4/13. Aside from AIT, the other immunomodulators have limited data in children. However, all of these agents hold promise in the possibility of altering the course of asthma, and further studies will be needed to assist the clinician in selecting these medications and the appropriate time for introduction in the management of children with asthma.
Allergen Immunotherapy
Indications and Patient Selection
AIT remains the only treatment modality available that can alter the natural course, and potentially have a curative approach in some patients, for asthma and other allergic conditions through its sustained disease-modifying effects. The therapeutic preparation for AIT is extracted from source materials, such as pollen and animal pelts. Two forms of AIT administration are currently in wide-scale clinical practice: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). SLIT has been increasing in use over the last two decades, especially in Europe. AIT is addressed both by the Global Initiative for Asthma (GINA) and National Institute of Health National Heart, Lung, and Blood Institute Expert Panel 3 (NIH NHLBI EPR-3) guidelines for the management of asthma when there is clear evidence between symptoms and exposure to an allergen to which the patient is sensitized.
AIT should be reserved only for patients who have both documented evidence of sensitivity to an allergen, either through immediate hypersensitivity skin testing or in vitro testing for serum specific IgE antibodies, and symptoms that correlate with exposure to said allergen. Skin-prick testing has been shown to have greater sensitivity than serum-specific IgE measurements based on nasal and bronchial challenge test results. Patient-specific factors to consider when deciding whether to start AIT include the patient’s preference, adherence, current medication requirements, level of asthma disease control, seasonality of disease, response to avoidance measures, medication adverse effects, coexisting allergic rhinitis, cost, impact on quality of life, and geographic location. Patients whose symptoms are not well controlled by medications or avoidance measures, who are requiring multiple medications or high doses of medications to maintain asthma control, who may be experiencing side effects from their medications, or who wish to avoid long-term pharmacotherapy could be appropriate candidates for AIT.
Administration
SCIT may be administered via a conventional, cluster, or rush schedule. In conventional SCIT, the allergen is administered via once-weekly injections at increasing concentrations until a maintenance dose is achieved, followed by injections typically at 4-week intervals. In a cluster schedule, multiple injections, usually 2–3, are administered on nonconsecutive days, while in a rush protocol, multiple injections are administered on consecutive days, allowing the patient to reach maintenance typically in 1–3 days. As opposed to SCIT, SLIT’s safety profile allows it to be administered with either a shortened or absent build-up phase. A typical course of immunotherapy is 3–5 years in duration, as studies with SCIT have demonstrated prolonged remission after 3–4 years of treatment. Three years of SCIT may be sufficient in asthmatic children, as a prospective study did not show a significant clinical benefit, including change in asthma symptoms, ICS dose, quality of life, and bronchial hyperreactivity, from an additional 2 years of SCIT. SLIT has a similar course, with its use for allergic rhinitis from house dust mites showing sustained remission for 7 and 8 years after 3 and 4–5 years of treatment, respectively. The decision to stop or continue immunotherapy is based on the severity of the disease, benefits sustained from treatment, and convenience of treatment.
Mechanism of Action
The goal of AIT is to induce immune tolerance to specific allergens via downregulation of T H 2-mediated responses, through both induction of allergen-specific T regulatory (T reg ) cells and an ultimate shift toward a T H 1-mediated response ( Fig. 48.1 ).
Very early into the course of AIT desensitization, mast cells and basophils bearing the high-affinity IgE receptor, FcεRI, decrease their susceptibility to degranulation in response to the specific allergen. With continued AIT desensitization, the proportion of IL-4-secreting T H 2 cells decreases, while T reg cells for the same allergic epitope increase in number and function. These inducible CD4+CD25+ T reg cells secrete IL-10 and transforming growth factor beta (TGF-β), regulatory cytokines that function to mediate allergen-specific peripheral T-cell tolerance. IL-10 directly inhibits T-cell cytokine production, including IL-4 and IL-5 by T H 2 cells, through suppression of the CD28 costimulatory pathway. Cytokine production is also inhibited by IL-10 through the inhibition of the costimulatory molecules CD80 and CD86 on antigen-presenting cells, which eliminates the ability of these cells to provide the accessory signals necessary for T helper cell activation.
IL-10 has regulatory effects on B-cells, mast cells, and eosinophils. IL-10 acts on B-cells to decrease antigen-specific IgE production and undergo class switching with IgG4 production. Allergen-specific IgG4 competes with allergen-specific IgE for allergen binding, thus preventing the IgE-mediated release of inflammatory mediators from mast cells and basophils. The binding of allergens to IgG4 also inhibits IgE-facilitated allergen presentation to T-cells. In addition to the IgG4 isotype switching, TGF-β produced by T reg cells will induce the production of IgA at mucosa surfaces, which will also compete with IgE for allergen binding. Allergen-specific IgE levels often transiently increase after AIT but then gradually decrease with continued treatment late into the AIT course, likely secondary to IL-10 and T reg cells. Acting on mast cells, IL-10 and T reg cells modulate the threshold for mast cell activation, decrease IgE-mediated histamine release, and inhibit FcεRI-dependent mast cell degranulation. IL-10 also downregulates eosinophil function, proinflammatory cytokine release, and activity.
Impact on Asthma Control
Meta-analyses of randomized controlled trials using SCIT to treat asthma in children and adults have demonstrated a significant reduction in asthma symptoms, asthma medication use, and allergen-specific and nonspecific bronchial hyperreactivity. The effect on lung function has been mixed in these studies, with one meta-analysis showing no consistent effect on lung function, while another showed an improvement in peak expiratory flow rates. Specific individual studies in children have demonstrated similar results with improvement in asthma symptom-medication scores with the use of SCIT, medication use, decreased allergen-specific bronchial hyperreactivity when used in combination with ICSs, and improvement in peak expiratory flow rates.
Meta-analyses of randomized controlled trials examining the impact of SLIT on the treatment of asthma in children and adults have been limited in their ability to draw such significant conclusions as seen with SCIT, primarily secondary to wide but varied use of largely unvalidated symptom and medication scores, and significant heterogeneity between studies. Meta-analyses examining symptom and medication scores in both pediatric and adult patients with both asthma and comorbid allergic rhinitis treated with SLIT have demonstrated a consistent reduction in combined asthma and allergic rhinitis symptom and medication scores, but differing results regarding its ability to impact asthma symptoms and medication use alone. There is evidence that the benefit of SLIT for asthma may be more impactful in the pediatric than adult population. A meta-analysis investigating the use of SLIT exclusively in pediatric patients with allergic asthma as young as 3 years old showed a significant reduction in both asthma symptom scores and rescue medication use compared with placebo. In a real-life randomized open controlled trial of SLIT in patients with allergic rhinitis with or without asthma, the use of SLIT compared with conventional medical therapy alone showed a significantly more pronounced reduction in combined rhinitis and asthma symptoms scores in patients less than 18 years of age than in adults. Studies in children and adults have demonstrated a decrease in the number of patients with a positive methacholine challenge in those treated with SLIT in addition to standard medical therapy, versus those without SLIT.
Most important would be SCIT and SLIT’s ability to reduce ICS doses, especially in a pediatric population. Randomized trials of adults, adolescents, and pediatric patients with mild and moderate persistent allergic asthma have demonstrated that the addition of house dust mite SCIT and SLIT to ICSs resulted in a reduction in ICS dose while still maintaining asthma control. Post hoc analysis of adolescent and adult patients treated with house dust mite SLIT with more severe disease, represented by only partly controlled asthma and higher ICS dose, demonstrated a greater significant impact on asthma control, ICS reduction, and quality of life than the less severe population. In a trial of adults with house dust mite allergy–related asthma poorly controlled on ICSs or combination therapy, the addition of house dust mite SLIT increased the time to first moderate or severe asthma exacerbation during an ICS reduction period compared to placebo.
Persistent Clinical Effects After Discontinuation
AIT’s ability to have persistent effects on asthma control or even resolution of the disease (stemming from its alteration of the underlying immunological response long after discontinuation of therapy) separates it uniquely from other therapies. A prospective study using house dust mite SCIT in asthmatic children showed that 3 years after discontinuation of SCIT, more than 50% of treated patients had remission of their asthma, compared with 3.3% of controls. Patients treated with SCIT had significantly reduced doses of ICSs, lower asthma symptom scores, higher quality-of-life scores, less bronchial hyperreactivity, and higher forced expiratory volume in 1 second (FEV 1 ) compared with controls at the 3-year time mark. Some of the impact of SCIT in childhood persists into adulthood, as demonstrated by a retrospective study that showed 9 years after the discontinuation of therapy, that asthmatic children who were not treated with SCIT had a three times higher risk of frequent asthma symptoms than those treated with house dust mite or grass pollen SCIT. This study, however, did not show any difference in lung function or medication use between the groups 9 years after discontinuation of SCIT. Similar findings have been demonstrated with the use of house dust mite SLIT in asthmatic children, with a reduction in the presence of asthma, number of patients using asthma medications, use of bronchodilator, and peak expiratory flow rate 5 years after the discontinuation of SLIT compared with controls.
Prevention of Asthma and Allergic Sensitivity Development
Perhaps the most profound effect of AIT is its ability to prevent progression of allergic sensitization and the development of asthma in children with allergic rhinoconjunctivitis. Treatment with both SCIT and SLIT against house dust mite, grass, and birch in monosensitized children with allergic rhinoconjunctivitis with or without asthma for 3 years has been shown to prevent or reduce the development of new aeroallergen sensitizations. The preventative effects of SCIT in the development of new aeroallergen sensitizations has been observed even 12 years after the discontinuation of therapy.
The use of SCIT in children with seasonal allergic rhinoconjunctivitis to grass and/or birch pollen without asthma for 3 years in a randomized open trial resulted in significantly fewer patients developing asthma or having asthma symptoms after 3 years of treatment compared with controls, with the preventative effect persisting at 2 years and 7 years after discontinuation of SCIT. Similar prevention of the development of asthma in children with allergic rhinoconjunctivitis has been demonstrated with the use of SLIT to dust mites, grasses, or birch for 3 years in addition to standard medical therapy, compared with medical therapy alone. Those children who had bronchial hyperresponsiveness with allergic rhinoconjunctivitis or who were younger at baseline were most at risk of developing asthma, suggesting a potential benefit of the initiation of AIT in these groups for the prevention of asthma.
Safety
According to the GINA, the benefits of AIT compared with other pharmacologic and avoidance options must be weighed against several factors, including the risk of adverse events. SCIT carries the risk of localized injection site reactions, large local reactions, anaphylaxis, and even death. Annual survey reports show the rate of a severe reaction of any severity is 11.8 reactions per 10,000 injection visits, with the rate of a severe life-threatening reaction being 0.1 reactions per 10,000 injection visits. Overall, 95% of reactions were only mild to moderate in severity. SCIT meta-analysis data estimated the risk of a near-fatal injection was once per 1 million injections and a fatal injection to occur once per 2.5 million injections. Patients with severe or uncontrolled asthma are at increased risk for systemic reactions to SCIT, including fatal and near-fatal reactions, secondary to bronchoconstriction. As such, poorly controlled asthma is a major contraindication to AIT. Given the risk of these reactions, practice parameters recommend that SCIT only be administered in a supervised medical facility by a professional trained in the prescribing and administration of SCIT and patients be monitored for 30 minutes following the injection, as the risk of a life-threatening anaphylactic reaction after 30 minutes is rare.
Unlike SCIT, the safety of SLIT is far superior, with no confirmed reports of SLIT-related fatalities to date, but anaphylactic reactions have been reported. A comprehensive review showed the risk of a severe reaction to SLIT was 1.4 events per 100,000 doses. The most common adverse reactions for SLIT are typically localized oral-mucosal pruritis or mild local edema, which occur within the first 30 minutes of administration, resolved spontaneously, and did not persist with continued therapy. SLIT’s favorable safety profile allows administration outside of a supervised medical setting.
Clinical Application. AIT offers the potential for remission of disease activity but requires careful consideration for benefit-risk assessment, especially for the SCIT form of administration and for those with moderate to severe asthma. Experience with SLIT is more limited in terms of allergens currently approved for administration, but it does offer the benefit of a safer form of AIT administration.
Omalizumab
Mechanism of Action
Omalizumab is the best studied of the new class of biologic medications for asthma. IgE is known to be important in the T H 2-related asthma response and binds to high-affinity receptors on basophils, mast cells, and neutrophils, leading to the release of inflammatory mediators, which are part of the allergic cascade that leads to asthma-related symptoms ( Fig. 48.2 ).
Eosinophils also contain a high-affinity IgE receptor. IgE also has the ability to facilitate antigen presentation to T cells, allowing small amounts of antigen to provoke a T H 2-related asthma response. Omalizumab is a humanized, anti-IgE-specific form of IgG for the treatment of asthma. It binds to circulating IgE, preventing it from binding with both high- and low-affinity receptors on effector cells, leading to a reduction in the release of allergic mediators. Importantly, it does not cross-link bound IgE, which could amplify the allergic cascade and increase the risk of anaphylaxis. IgE levels are decreased in the airway mucosa, as well as in the blood after 16 weeks of treatment, indicating good penetration to the affected tissues. Reports have shown that treatment with omalizumab reduces cellular activation, leading to basophil and mast cell degranulation, as well as modifying dendritic cell antigen presentation mechanisms. In addition, there is early evidence that omalizumab may also downregulate bronchial smooth muscle proteins, indicating a possible role in disease-modifying remodeling. There is evidence that omalizumab actually decreases IgE production over time, indicating that indefinite treatment may not be required. One evaluation of shorter-term therapy showed that after 7 months of treatment, withdrawing omalizumab led to a recurrence of symptoms. One study recommended a minimum duration of treatment of 12–16 weeks to fully assess treatment response. Another study evaluated patients 3 years after the discontinuation of omalizumab therapy (which they had received for 6 years), and found that most patients continued to have reduced asthma symptoms at that time.
Pharmacology
Pharmacodynamics
In vitro allergen-stimulated basophil histamine release is reduced by approximately 90% in treated subjects. Serum-free IgE values are reduced within 1 hour of the first dose, and this is maintained between doses, and immediately after treatment discontinuation, IgE levels return to pretreatment levels without any evidence of rebound.
Pharmacokinetics
Bioavailability.
After subcutaneous administration, average bioavailability is approximately 62%. It is absorbed slowly and reaches peak serum concentrations after approximately 7–8 days. Pharmacokinetics are linear at doses greater than 0.5 mg/kg.
Distribution.
Omalizumab forms complexes of limited size with IgE, without evidence of precipitation of these complexes. The apparent volume of distribution following subcutaneous administration is approximately 78 ± 32 mL/kg.
Elimination.
Clearance occurs via IgG elimination processes as well as via complex formation with IgE. Liver elimination occurs via degradation in the reticuloendothelial system and endothelial cells, and intact IgG is excreted in bile. Serum elimination half-life averages 26 days, clearance averages 2.4 ± 1.1 mL/kg per day, and the doubling of body weight doubles clearance. There is no evidence for a need for dose adjustment, due to factors such as age (above 6 years), race/ethnicity, gender, and there is no available data at this time regarding dosing in renal or hepatic impairment.
Mode of Administration
Omalizumab is administered via subcutaneous administration every 2–4 weeks, depending on the weight and IgE level of the patient. Clinicians should not administer more than 150 mg per injection site, and be prepared and equipped to identify and treat anaphylaxis should this occur. Observation for 2 hours postinjection for the first three injections and 30 minutes postinjection thereafter has been recommended.
Dosing Strategies
Dosing tables exist, based on a combination of total IgE and weight, to guide omalizumab dosing, and reducing doses below those recommended has been shown to increase free IgE and thus could cause a reduction in asthma control. European guidelines specify a maximum dose of 600 mg every 2 weeks and do not support dosing in IgE levels above 1500 IU/mL. US guidelines specify a maximum dose of 300 mg for every 4-week dosing or 375 mg for every 2-week dosing, and do not support dosing in IgE levels above 700 IU/mL if administered every 4 weeks, 1300 IU/mL if administered every 2 weeks. Country-specific dosing tables are available and should be consulted to determine patient-specific dosing. Unfortunately, a significant proportion of asthmatic children and adolescents that may benefit from omalizumab therapy may not qualify due to elevated IgE levels, and though current dosing tables are close to optimal, it may be possible to treat patients with higher baseline IgE levels than currently recommended. This area will need to be continually studied in order to fully optimize treatment for all asthmatic children and adolescents.
Clinical Studies
Adult Studies
Omalizumab has been shown to be effective in the adult population across a wide range of clinical outcomes, including asthma exacerbations, ED (emergency department) visits/hospitalizations, exhaled nitric oxide, asthma control test (ACT), quality-of-life scores, unscheduled physicians visits, decreasing ICS requirements, and airway wall thickness. Omalizumab has also been shown to be effective in nonatopic asthmatic adults, though not all data supports its use in this population.
Child Studies
The studies described previously were largely conducted on adolescents and adults 12 years of age or older. The remainder of the literature in children focuses on the 6–18-year-old population. Omalizumab has also been shown to improve exacerbation rates, decrease inhaled and oral corticosteroid doses, and improve asthma-related quality-of-life scores, ACT, asthma control, and lung function. Omalizumab has also been found to be a potential alternative to treatment in patients who have poor adherence to ICSs. In addition, omalizumab has been shown to improve interferon alpha (IFN-α) responses to rhinoviral infection in children.
Safety
Early concerns with the use of omalizumab included concerns of anaphylaxis, serum sickness, and even risk for malignancy. Omalizumab has a mostly good safety and tolerability profile and no significant development of omalizumab specific antibodies, although urticaria is a potential side effect. One meta-analysis of 2749 patients receiving omalizumab therapy showed similar rates of minor adverse effects in treatment and placebo groups and a slightly lower incidence and profile of serious adverse effects in the omalizumab groups. The safety and tolerability of omalizumab in children remains stable over longer time frames (52 weeks) as well. Anaphylaxis does remain a risk with omalizumab injection (see the notes on monitoring given previously), however, and clinicians should be aware that it may be characterized by delayed onset (>2 hours after dose) and protracted progression of symptoms ; patients should be trained in the recognition of anaphylaxis and use of epinephrine autoinjector use, and be sent home with an epinephrine autoinjector. Pain and swelling at the injection site occurs in 5%–20% of patients. The EXCELS study evaluated 7857 patients, of whom 5007 were treated with omalizumab, and found that omalizumab was not associated with any increased risk of malignancy. However, there is evidence that omalizumab may increase the risk of cardiovascular and cerebrovascular events.
Clinical Application—Current and Future Considerations
Age
Currently omalizumab is approved in the US and Europe in children greater than 6 years of age, adolescents, and adults. Further study is needed to determine safety and efficacy in children younger than 6 years of age.
Biomarkers
Omalizumab has effects on several biomarkers. It is known to decrease serum free IgE, and it also reduces sputum and tissue eosinophils and airway lymphocytes and reduces basophil numbers.
Target Response Expected
There is evidence that patients with high baseline levels of fractional exhaled nitric oxide (FeNO), eosinophils, and serum periostin have the greatest improvement in exacerbation frequency with omalizumab compared with placebo. In addition, the response to inhaled allergens in asthma is diminished by omalizumab, and this decrease is paralleled by a reduction in eosinophils and IgE bearing cells. However, it is important to recognize that monitoring IgE alone does not predict clinical response in omalizumab treated patients.
Other Diseases
Omalizumab has been studied in various other diseases as well, has been shown to be effective in allergic rhinitis and allergic bronchopulmonary dysplasia (ABPA), and has been found equivocal in nasal polyposis. In addition, it has been utilized successfully for the treatment of chronic urticaria.
Cost Effectiveness
Omalizumab currently remains a high-cost therapy for asthma treatment. Studies have shown it to be cost effective with regard to decreasing exacerbations and improving health-related quality of life when used in severe asthmatic adults. The selection of patients to receive omalizumab therapy should focus on those children who have severe allergic asthma in order to maximize cost efficiency.
Mepolizumab
Mechanism of Action and Target Effects
Mepolizumab is a humanized murine monoclonal IgG1κ antibody directed against interleukin-5 (IL-5). The IL-5 receptor is composed of the IL-5Rα chain, which binds IL-5, and the common β chain (βc), which mediates the signal transduction ( Fig. 48.3 ). Mepolizumab binds to IL-5, preventing its interaction with the IL-5 receptor and subsequent signaling.
