Abstract
Biologic agents, including anti-immunoglobulin E (omalizumab) and anti-interleukin 5 (mepolizumab), target different mediators involved in the inflammatory process and may work synergistically to decrease symptoms in patients with severe asthma. Here we describe a 12-year-old female on 2 biologic agents, omalizumab and mepolizumab, to control severe persistent asthma. Omalizumab was started years earlier with an initial response; however, her asthma again became uncontrolled and mepolizumab was added. Both biologics were administered concomitantly for over 6 months with marked improvement of asthma symptoms without significant side effects. A combination of biologic agents may be a potential therapy for pediatric patients with severe persistent asthma that remains uncontrolled on a single agent.
Keywords: biologic therapy, combination, mepolizumab, omalizumab, pediatric, severe asthma
Background
Asthma is defined by the World Health Organization as a chronic disease characterized by recurrent attacks of wheezing and breathlessness.1 The backbone of asthma therapy consists of an inhaled corticosteroid with or without a long-acting beta-agonist as maintenance therapy and oral corticosteroids for exacerbations. However, approximately 15% of patients will experience severe persistent asthma that is not controlled on traditional therapy and require frequent oral corticosteroid use, which can lead to long-term complications.2 Biologic agents, including anti-immunoglobulin E (IgE) (omalizumab) and anti-interleukin-5 (IL-5) (mepolizumab) monoclonal antibodies, are available on the market. These drugs target different mediators involved in the inflammatory process and may decrease the frequency of asthma exacerbations requiring oral corticosteroids, hospitalizations, or emergency department visits and improve the patient's overall quality of life.3,4 Several case reports of patients on dual biologic therapy with omalizumab and mepolizumab are available, which suggest it is an effective treatment without significant intolerances. Other cases, with alternate combinations of dual biologic therapies for asthma, including benralizumab, reslizumab, and dupilumab, have been reported in adults since the time our patient was treated.5,6 However, this patient case remains the youngest patient reported to our knowledge to receive any combination of dual biologic therapies, and the only case of this nature that includes specific detail on the practices surrounding administration and monitoring.
Case
Here we describe the case of a 12-year-old female on omalizumab (Xolair, Genentech, Inc, San Francisco, CA) and mepolizumab (Nucala, GlaxoSmithKline LLC, Philadelphia, PA) concomitantly to control her severe persistent asthma, with permission and written informed consent from the patient's mother. Based on a personal history of allergic rhinitis, strong family history of asthma, and presentation concerning for reactive airway disease, the patient was initiated on Step 2 treatment for asthma according to the Global Initiative for Asthma guidelines at the time,7 consisting of a short-acting beta agonist and low-dose inhaled corticosteroid when she was <1 year of age. A timeline of her asthma history can be found in Table 1. This diagnosis was confirmed by pulmonary function testing at age 6. Selected results can be found in Table 2.
Table 1.
Timeline of Asthma History
| Age, yr | Clinically Significant Exacerbations,*(Season) | Pertinent Laboratory Results | Therapies Added | Therapies Discontinued | ||
|---|---|---|---|---|---|---|
| Office Visit | Emergency Room | Inpatient Admission | ||||
| <1 | Unknown, missing documentation from first 6 months of life | None | Levalbuterol (Xopenex, Sunovion Pharmaceuticals Inc., Marlborough, MA) (unknown dose) nebulized as needed; Budesonide (Pulmicort, AstraZeneca Pharmaceuticals LP, Wilmington, DE) 0.5 mg/2 mL nebulized twice daily | None | ||
| 1 | 0 | 0 | 0 | None | Montelukast (Singular, Merck & Co., Inc, Whitehouse Station, NJ) 4 mg by mouth daily | Budesonide (Pulmicort) 0.5 mg/2 mL nebulized twice daily |
| 2 | 0 | 1 (fall) | 0 | None | Albuterol (Nephron Pharmaceuticals Corp, Orlando, FL) (unknown dose) nebulized as needed | None |
| 3 | 0 | 2 (late summer and early fall) | 0 | None | Budesonide (Pulmicort) 0.5 mg/2 mL nebulized twice daily | |
| 4 | 0 | 0 | 0 | None | None | None |
| 5 | 1 (winter) | 0 | 0 | None | None | None |
| 6 | 1 (winter) | 0 | 0 | None | Fall: Mometasone/formoterol (Dulera, Merck & Co., Inc, Whitehouse Station, NJ) 100–5 mcg, 2 puffs inhaled twice daily Montelukast (Singular) 5 mg by mouth daily Winter:† Budesonide (Pulmicort) 0.5 mg/2 mL nebulized twice daily; Formoterol (Foradil, Merck & Co., Inc,Whitehouse Station, NJ) 12 mcg nebulized twice daily | Fall: Budesonide (Pulmicort) 0.5 mg/2 mL nebulized twice daily; Montelukast (Singular) 4 mg by mouth daily Winter:† Mometasone/formoterol (Dulera) 100–5 mcg, 2 puffs inhaled twice daily |
| 7 | 0 | 2 (fall and late winter) | 1 (fall) | Absolute eosinophil count: 360 cells/mL | Mometasone/formoterol (Dulera, ck & Co., Inc, Whitehouse Station, NJ) 200–5 mcg, 2 puffs inhaled twice daily | Budesonide (Pulmicort) 0.5 mg/2 mL nebulized twice daily; Formoterol (Foradil) 12 mcg nebulized twice daily |
| 8 | 0 | 1 (late winter) | 0 | None | None | None |
| 9 | 4 (early fall and winter) | 2 (early fall and winter) | 1 (winter) | IgE: 519 ku/L; FeNO: 22–102 ppb; Serum specific IgE: only positive for food allergens† | Budesonide/formoterol (Symbicort, AstraZeneca Pharmaceuticals LP, Wilmington, DE) 160–4.5 mcg, 2 puffs inhaled twice daily | Mometasone/formoterol (Dulera) 200–5 mcg, 2 puffs inhaled twice daily |
| 10 | 2 (late summer and early fall) | 2 (winter) | 0 | IgE: 318 ku/L, FeNO: 7–21 ppb | Omalizumab (Xolair) 300 mg subcutaneously every 4 wk | None |
| 11 | 2 (early fall and late winter) | 0 | 0 | Absolute eosinophil count: 260 cells/mL; | Mepolizumab (Nucala) 100 mg subcutaneously every 4 wk | None |
FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E
*Clinically significant exacerbations were defined as those that lead to receipt of oral steroids.
† Deterioration presumed to be based on poor technique with inhaler, so the decision was made to switch back to nebulized therapies.
‡ Banana, kiwi fruit, and cow's milk.
Table 2.
Selected Results From Spirometry at the Time of Asthma Diagnosis
| Pulmonary Function Test | Prebronchodilator | Postbronchodilator |
|---|---|---|
| FEV1pp | 69 | 110 |
| FEV1/FVCpp | 90 | 98 |
FEV1pp, forced expiratory volume over 1 second percent predicted; FVCpp, forced vital capacity percent predicted
In terms of her social history, the patient lives at home with her mother, father, 2 sisters, 1 brother, and pet dog. There has never been smoke exposure in the household, and the family has lived at the same residence her whole life. On multiple occasions, the patient did experience worsening asthma symptoms following overnight stays at an aunt's house with extensive carpeting.
Her symptoms are triggered by changes in weather, animal dander, and exercise; she also has comorbid gastroesophageal reflux disease and allergic rhinitis. Her asthma symptoms remained uncontrolled despite consistent documentation by her physician and other care team members of good adherence to her regimen. This consisted of a high-dose inhaled corticosteroid, long-acting beta-agonist combination inhaler, and leukotriene receptor antagonist, as well as medications to control her allergic symptoms. A complete list of her medications at the time of initiation of biologic therapy can be found in Table 3. These medications are her only chronic therapies and all were initiated at least 12 months prior to her starting omalizumab. Despite receiving maximum standard therapies and demonstrating proper inhaler technique with a spacer, she had multiple asthma-related hospital admissions; hence, the decision was made to start a biologic agent.
Table 3.
Medications at the Time Omalizumab Was Initiated
| Medication | Directions |
|---|---|
| Albuterol (ProAir, Teva Respiratory, LLC, Frazer, PA) 90 mcg/actuation | Inhale 2 puffs every 4 hr as needed |
| Azelastine-fluticasone (Dymista, Meda Pharmaceuticals Inc., Somerset, NJ) 137–50 mcg/actuation nasal spray | Administer 1 spray in each nostril twice daily |
| Budesonide-formoterol (Symbicort) 160–4.5 mcg/actuation | Inhale 2 puffs twice daily |
| Cetirizine (Zyrtec, Pfizer Inc, NY, NY) 10 mg tablets | Take 1 tablet by mouth daily |
| Ipratropium-albuterol (Combivent Respimat, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT) 20–100 mcg/actuation | Inhale 1–2 puffs every 6 hr as needed |
| Hydroxyzine (Vistaril, Pfizer Inc, NY, NY) 2 mg/mL oral solution | Take 7.5 mL (15 mg) at bedtime as needed |
| Montelukast (Singulair) 5 mg chewable tablet | Take 1 tablet by mouth daily |
| Ranitidine (Zantac, GlaxoSmithKline, Research Triangle Park, NC) 75 mg | Take 1 tablet by mouth twice daily |
The patient is followed by a pediatric pulmonologist. Her previous laboratory results can be found in Table 1 and were significant for elevations in absolute eosinophil count, IgE, fractional exhaled nitric oxide, and serum-specific IgE. Given her history of severe persistent asthma with elevations in IgE, she was started on omalizumab at 10 years of age, following a 10-month delay due to barriers in insurance coverage. Dosing of omalizumab 300 mg subcutaneously every 4 weeks was based on her age, weight, and IgE. She had improvement of symptoms following initiation of therapy, but after about 10 months of consistent dosing there was an increase in frequency of clinically significant asthma exacerbations requiring treatment with oral steroids or a visit to the emergency room. At this time mepolizumab was considered.
The preference for mepolizumab was based on greater physician and pharmacist experience with off-label use of this agent in the pediatric population, as compared with other IL-5 targeting agents, such as reslizumab (Cinqair, Teva Respiratory, LLC, Frazer, PA), which has only adult data and less convenient administration, and benralizumab (Fasenra, AstraZeneca Pharmaceuticals LP, Wilmington, DE), which like mepolizumab has some adolescent data, but which our institution had less prior experience with off-label use of in pediatric populations, based on that product only being available in a standard adult dose prefilled syringe. The on-site Specialty Pharmacy assisted in overcoming insurance barriers and at 11 years of age the patient ultimately received standard adult dosing of mepolizumab (i.e., 100 mg subcutaneously every 4 weeks).
At the time of this publication, she had received the combination of omalizumab and mepolizumab for nearly 24 months. The patient received both agents during the same visit every 4 weeks. The drugs were given as 3 separate injections (i.e., 150 mg omalizumab + 150 mg omalizumab + 100 mg mepolizumab). This was followed by the standard length of postdose monitoring for these biologic therapies when given in the pediatric outpatient procedure area at our institution. This includes 2 hours of monitoring following the first 3 doses of the drug, and 30 minutes of monitoring following all subsequent doses. In addition to her regularly scheduled appointments with her physician, she receives quarterly follow-up calls from the pediatric pulmonology specialty pharmacist to assess adherence, efficacy, and possible side effects. Since starting mepolizumab, her symptoms have markedly improved and she is able to participate on her school's track team without difficulty. Her albuterol use has decreased significantly, and she now only uses her albuterol inhaler prior to exercise. She has not required any oral corticosteroids since starting mepolizumab and has had only 1 mild self-reported asthma flare. In terms of safety, after starting mepolizumab she experienced only mild, occasional headaches that respond to either acetaminophen or ibuprofen, which the patient's mother provides at home, at her discretion. She reported that headache has improved with subsequent doses and she denies ever having any flu-like symptoms. There have been no major changes in environmental exposures throughout the treatment course. None of her baseline laboratory tests were repeated because this is not standard of care for these drugs, with changes in IgE or eosinophils not correlating well with clinical response.
The original plan for de-escalation of therapy was to discontinue the omalizumab after 6 months of concomitant therapy, based on recommendation from her clinical pharmacist. The intent was to allow 12 to 16 weeks for mepolizumab to achieve steady-state serum concentrations, and sufficient time to evaluate response to therapy. This was also consistent with the timeframe of her initial approval through her insurance. However, the patient's mother was apprehensive about discontinuing either medication, so following discussion with her pediatric pulmonologist and immunologist, the decision was made to continue for an additional 6 months.
Discussion
Biologic agents in asthma are reserved for patients with moderate-to-severe persistent asthma that is not controlled with traditional therapies. Due to the relatively new nature of these drugs, there is a lack of data regarding combining biologic agents. There have been several case reports of patients on omalizumab and mepolizumab simultaneously with consistently positive outcomes. In 2016 a case report was published of a 58-year-old female with refractory allergic bronchopulmonary aspergillosis and an underlying diagnosis of asthma; she showed significant improvement on a combination of omalizumab and mepolizumab.8 In 2017 another case study came out of a 16-year-old female with a history of severe persistent asthma, non-allergic bronchopulmonary aspergillosis bronchiectasis, and allergic rhinitis. They were treated with both omalizumab and mepolizumab with marked relief of asthma symptoms and no perceived side effects.9 Another case report described a 55-year-old female who was treated with both biologics for severe persistent eosinophilic asthma and elevated IgE levels; she was able to reduce her maintenance dose of prednisone from 20 mg daily to 4 mg daily without significant adverse effects.10
This report is unique because it illustrates the use of both IgE and anti-IL-5 therapies for severe persistent asthma in a very young adolescent. Previous case reports have not detailed the practices of administration of dual biologic therapies, leaving gaps in understanding around whether or not multiple injections could be given during the same visit, or what postdose monitoring was recommended. Since the monoclonal antibodies work on different components of the inflammatory pathway, they may work synergistically to improve symptoms of severe, persistent asthma. Similarly, since these agents work in the same pathway they may result in an increase in undesired adverse effects. In this case, it appears that the patient had a significant improvement in her asthma symptoms with no remarkable increase in adverse effects. This case report suggests that dual biologic therapy may be a safe and effective treatment for pediatric patients with uncontrolled severe asthma.
It must also be considered that given the negative results of the aeroallergens in the serum-specific IgE test, perhaps omalizumab was not most efficacious choice of biologics to initiate based on her phenotype, and the improvement of the patient's symptoms were due to the addition of a more appropriate biologic which targeted IL-5. There is some adult data to suggest that in patients who met criteria for both omalizumab and mepolizumab, that mepolizumab may be more effective.11–13 A switch directly from omalizumab to mepolizumab would also have been appropriate to consider for this patient; however, no literature currently indicates whether an overlap of agents provides additional benefit during the 12 to 16 weeks before the add-on therapy has reached steady-state concentrations.
Another alternative consideration is that the patient's symptoms may have improved regardless of the addition of a second biologic agent and it was incidental that a second biologic was added around the same time. However, given the multiple other cases demonstrating similar improvement of allergic symptoms for patients on a combination of biologic agents, the question of synergy using these agents cannot be ignored.
Conclusion and Recommendations
There is limited evidence for the use of combination biologics in the treatment of severe persistent asthma. This report represents the first pediatric patient to receive combination biologic therapies at our institution. Both the pharmacist and immunologist involved in her care had experience with concomitant biologic agents for the management of severe persistent asthma in our adult patients, and applied the same principles.
In general, we reserve combination biologic therapy for patients who have had clinical improvement on 1 biologic agent during the first 6 months of treatment, but are still not meeting goals of therapy, and are deemed too high risk to discontinue the initial agent before achieving steady-state concentrations of an alternate drug. We consider de-escalating to a single agent after 3 to 6 months of combination biologic therapy.
Based on the complexity and severity of disease in patients who we might consider candidates for combination biologic agents, we recommend evaluation by a multidisciplinary team that includes a pharmacist, pulmonologist, and immunologist. We allow administration of both drugs during a single appointment for convenience, and we use our standard postdose monitoring protocols and standard pharmacist telephone follow-up assessments.
ABBREVIATIONS
- FeNO
fractional exhaled nitric oxide
- FEV1pp
forced expiratory volume over 1 second percent predicted
- FVCpp
forced vital capacity percent predicted
- IgE
immunoglobulin E
- IL-5
interleukin-5
Footnotes
Disclosures. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all patient information in this report and take responsibility for the integrity and accuracy of the report.
Ethical Approval and Informed Consent. Given the nature of this study, institution review board/ethics committee review and informed consent were not required. However, the patient's mother did sign an informed consent for the information in this case report to be published during the manuscript preparation process.
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