Allergic Asthma Therapy and Management

AFFILIATIONS:

¹University of Florida College of Medicine, 1600 SW Archer Rd, Gainesville, FL 32610
²University of Florida Health Jacksonville, Division of General Academic Pediatrics, Department of Pediatrics, 8399 Bayberry Rd, Jacksonville, FL 32256

CITATION:

Reich DA, Arango CA. Allergic Asthma Therapy and Management. Consultant. 2023;63(1):4-7. doi:10.25270/con.2022.11.000002

Received June 20, 2022. Accepted August 22, 2022. Published online November 15, 2022.

DISCLOSURES:

The authors report no relevant financial disclosures.

CORRESPONDENCE:

Carlos A. Arango, MD, Associate Professor, Division of General Academic Pediatrics, Department of Pediatrics, 8274 Bayberry Rd, Jacksonville, FL 32256 (carlos.arango@jax.ufl.edu)

Etiology

Asthma is a chronic disease that is common in pediatric patients and has an estimated childhood prevalence of 8.3% in the United States, according to the CDC.^1,2 The underlying origin of asthma is multi-factorial. In addition to one’s genetic predisposition, this disorder can be further influenced by extrinsic variables such as nutrition, environmental allergens, and infections.^3,4 Allergic asthma comprises up to 90% of asthmatic cases in the pediatric population.⁵ Among this population, studies have shown that as much as one in every two patients experience inadequate control of their condition.¹

Suboptimal control of asthma poses the risk of increased exacerbation rates, airflow limitations (measured by forced expiratory volume [FEV1]), negative impact on one’s quality of life, and significant costs for both the patient and the health care system.^6,7 The CDC reported that in 2017, there were more than 1.5 million emergency department visits and over 180,000 hospitalizations due to asthma in the United States.⁸ In this review, we provide some insights and updates into the pathophysiology, diagnostic, and treatment strategies currently available for clinicians.

Pathophysiology and Targeted Therapy

Allergic asthma is an eosinophilic-mediated process involving secretion of various cytokines, including interleukin (IL)-4, IL-5, and IL-13.⁹ Several ILs in combination with eosinophils and immunoglobulin E (IgE) account for the type 2 inflammatory response found in allergic asthma.¹⁰ Allergen immunotherapy (AIT) is an up-and-coming therapy that is being used to manage specific conditions of allergic asthma with potentially greater efficacy. Some studies suggest these therapies may have a more favorable cost-effectiveness profile than standard therapy alone.^5,11 Specifically, biological agents such as benralizumab, dupilumab, and omalizumab have been developed to target specific receptors that mediate the allergic response underlying this disorder.¹² Many of the therapies used for allergic asthma focus on blunting the inflammatory response to minimize both the frequency and severity of asthma exacerbations. Different management options allow for a more patient-centered approach since the inflammatory response experienced by various patients suffering from allergic asthma might be a result of different cytokines and thus, require specialized treatment.

Once the diagnosis of asthma has been established with blood and/or skin tests and pulmonary function testing, the physician may consider measuring the patient’s eosinophil level via a complete blood count if symptoms are severe.^13,14 Patients with a total eosinophil count of above 300 eosinophils/μL may be considered as reasonable candidates for treatment with eosinophil-directed biological agents.^14,15 Indeed, studies have shown that patients who have higher baseline eosinophil counts are predicted to experience a greater benefit in FEV1 level when compared with those patients with lower baseline eosinophil counts (below 300 eosinophils/μL).^15-17

Biologic Options

Novel monoclonal antibodies including benralizumab, dupilumab, and omalizumab are designed to target the IL-5 receptor, IL-4 receptor, and IgE receptor, respectively.¹² (Table 1). Despite requiring a higher up-front cost when compared with the standard therapies such as intermittent inhaled corticosteroids, oral systemic corticosteroids, short acting beta-agonists, long acting beta-agonists, or a combination, these biologics offer potential cost-savings through decreased hospitalization and emergency care rates.^12,18 A 2020 systematic review found that all three of these drugs reduced the annualized asthma exacerbation rate, but only omalizumab significantly improved quality of life.¹² Among these three biologics, omalizumab is currently the most used and concomitantly, the most studied.¹⁹ Therefore, discussion on the biologic options will emphasize omalizumab, while calling attention to the need for further investigation into benralizumab and dupilumab.

Table 1. Three common biologic agents used to treat allergic asthma.

Omalizumab

Omalizumab is among the most studied biologics and has been shown to improve nearly all outcome measures (including symptom relief, exacerbations, or quality of life) in allergic asthma via blunting the IgE mediated response.^19-24 This drug uses a humanized mouse monoclonal antibody that inhibits the human IgE from binding to the Fc receptor of mast cells and basophils, thus inhibiting the inflammatory cascade that usually results from IgE activation.⁵

A 2021 meta-analysis that evaluated the efficacy of omalizumab found that the drug can promote improvement in lung function (250 mL increase in FEV1), decrease the severe exacerbation rate by 59%, and reduce emergency room/unscheduled physician visits.²⁵ Importantly, the authors found perceived improvement in quality of life by the patients, with 82% of patients reporting good/excellent asthmatic management when using the global evaluation of treatment effectiveness scale.^18,25 A post hoc analysis in 2020 reported similarly advantageous effects of omalizumab for its ability to improve lung function, including improved FEV1 and forced vital capacity, in adolescents with moderate-to-severe uncontrolled asthma when compared with a placebo group.¹ In such forms of allergic asthma that are inadequately controlled with beta-agonists and/or steroids, omalizumab provides an opportunity for clinicians to intervene early and improve the quality of life for these patients that do not respond well to standard therapy.^1,26 An important factor that further validates the use of omalizumab treatment is its ability to potentially improve lung function and reduce the exacerbation rate in patients with multiple comorbidities.²⁷ Omalizumab not only showed efficacy in treating allergic asthma in patients with multiple comorbidities, but it may also be efficacious in improving the outcomes for coexisting conditions, such as allergic rhinitis, food allergies, and atopic dermatitis.¹⁹

The safety profile for omalizumab has been favorable, with few signs of severe drug-to-drug interactions or other potentially life-threatening warnings.^18,19,28-31 To date, there are estimated to be more than 1.3 million patient/years analyzed, and anaphylaxis has been reported in 0.1 to 0.2% of these patients.^28,32  The current maintenance dosage for omalizumab is dependent on baseline serum total IgE level and ranges from 75 mg to 375 mg subcutaneous injections administered every two to four weeks.³³ A 2018 study from Domingo and colleagues proposes a protocol for withdrawal, which can be safely performed two to four years after treatment begins.²² Further investigation into the optimal dosage and taper protocol is still warranted.

It is important to consider the long-term cost profile of disease altering biologics, such as omalizumab. Contrary to the generalization of biologics being on the pricier end of treatment options, a study from Japan in 2022 found that adding omalizumab to patients suffering from severe allergic asthma is more cost-effective when compared with the standard of care.¹⁸ Given omalizumab’s ability to decrease acute exacerbations and other asthmatic complications, it is logical that long-term usage of this drug has the potential to be cost-effective, despite a relatively expensive up-front cost.¹²

Benralizumab

Benralizumab is another biological agent that specifically targets the IL-5 receptor, resulting in symptomatic relief for patients with severe allergic asthmatics. Benralizumab targets the IL-5 receptor found on eosinophils and basophils, thus triggering apoptosis via antibody-mediated cytotoxicity.^34,35 As a result, eosinophilic action is blunted and allergic inflammation subsequently diminished.  According to a 2020 systematic review, benralizumab can safely be added onto the standard of care for children older than 12 years of age to reduce exacerbation rates.¹² A 2021 study from the United Kingdom assessed benralizumab’s effectiveness on patients with severe eosinophilic asthma and found similarly advantageous results, including improvements in exacerbation history, spirometry measurements, perceived asthma severity, and quality of life according to asthma-specific questionnaires.³⁵  Being that benralizumab acts on the eosinophilic IL-5 receptor, patients with higher levels of eosinophils are predicted to benefit more from benralizumab add-on treatment when compared with patients with lower baseline eosinophil levels.¹⁶  The main limitations for mainstream usage of this drug derives from the scarcity of in-vivo research and unknown full-safety and efficacy profile. Specifically, questions remain on this drug’s ability to help eosinophilic asthmatics in the long-term and calls for lengthened and more extensive research trials.^16,34

Dupilumab

The third and final biologic to be discussed is dupilumab, which has been studied primarily for its’ ability to treat atopic dermatitis by blunting the allergic response signaling pathways from IL-4 and IL-13 cytokines.^15,21,36-39 In 2018, the FDA approved the use of dupilumab for eosinophilic asthma therapy and since then, the monoclonal antibody has been used as an add-on treatment for certain asthmatic patients suffering from severe symptoms that are not well controlled with the standard of care.⁴⁰ A 2018 study from Castro and colleagues found dupilumab to have similar results as benralizumab by increasing lung function on spirometry, eliciting better perceived control of their asthma, and reducing asthma exacerbations in patients 12 years and older suffering from severe allergic asthma.¹⁵ Additionally, those patients with higher baseline levels of eosinophils experienced greater benefits from dupilumab therapy when compared with those with lower baseline levels.¹⁵ To date, the safety profile of dupilumab seems to be respectable, with the most common adverse event being a non-life threatening injection site reaction.¹⁵  However, there is still need for further evaluation into a larger subset of patients and for longer time periods to truly understand the full and long-term safety profile of this biologic.³⁸

Flavonoids and Glycyrrhizin

Various alternative remedies have been proposed as effective treatment options of allergic asthma, but have yet to undergo extensive research, including randomized control trials. For example, some preliminary research has been published regarding the use of plant metabolites, flavonoids, and their efficacy in mitigating allergic symptoms.⁴¹ It is believed that flavonoids may play a role in treating allergic asthma via blunting the exaggerated inflammatory response that causes the hallmark symptoms of an asthma exacerbation. Although initial results are promising, there remains a dearth of evidence supporting the optimal metrics relating to dosing, timing, and formulation of flavonoid treatment.⁴¹ Another product that contains flavonoids as well as glycyrrhic acid is licorice. Often used in traditional Eastern medicine (especially China), licorice is incorporated into over half of traditional Chinese prescriptions.^41,42 The belief behind using licorice is that it may repress the body’s overall inflammatory response and decrease drug toxicity.⁴² This compound requires further investigation into its efficacy and safety in-vivo.

Polyvalent Mechanical Bacterial Lysate and Nanoparticle Technology

Sublingual administration of Polyvalent Mechanical Bacterial Lysate (PMBL) is a new and understudied treatment option for allergic asthmatics that has the potential to decrease exacerbation rates in children with allergic asthma. A 2018 study found PMBL to decrease the average number of asthma exacerbations in adolescents via non-specific effects and general anti-inflammatory action.⁶

Preliminary work into nanoparticle technology has shown promising results by using unmethylated CpG-oligonucleotide therapy, which can treat asthma by suppressing allergic Th2 responses.⁴³

Conclusion

Asthma is a condition that affects the quality of life for patients worldwide and has even been severe enough to be called an “epidemic” by the New England Journal of Medicine in 2006.⁴⁴ Prevalence trends are increasing with a currently estimated total of more than 300 million people affected globally.⁴⁵ Such exorbitant values warrant the need for more safe and effective management options to help those individuals suffering from this condition. Although medicine has come a long way to develop novel technology and pharmaceuticals for treating allergic asthma, there remains a great opportunity to improve our arsenal of tools to combat this chronic condition.