Pediatric Asthma: Guidelines-Based Care, Omalizumab, and Other Potential Biologic Agents

Synopsis

Over the past several decades, the evidence supporting rational pediatric asthma management has grown exponentially. As more is learned about the various phenotypes of asthma, the complexity of management will continue to grow. This review focuses on the evidence supporting the current guidelines-based pediatric asthma management and explores the future of asthma management with respect to phenotypic heterogeneity and biologics.

Introduction

Asthma affects more than 6 million children, making it one of the most common chronic diseases of childhood, and the prevalence continues to increase.¹ Asthma accounts for over 14 million school absences each year and is the leading cause of hospitalizations among children.^2–4 Fortunately, advances in medical therapy have reduced the number of asthma-related deaths and improved overall quality of life for many asthmatics.^{1, 2} Effective management guidelines now exist, with substantial supporting evidence from clinical trials in asthmatic children.⁵ Over the past decade, however, there has been a rapid increase in novel therapies for asthma management and few of these have been studied in children.

Further complicating pediatric asthma management is the diagnosis of asthma itself. There is significant heterogeneity amongst children who wheeze, and only a subset of all children who wheeze will go on to develop asthma.^6–8 Several studies have looked at both children who wheeze and those that subsequently develop asthma and have clustered children into distinct phenotypes.^6–9 This phenotypic variability is only the tip of the iceberg in the heterogeneity amongst asthmatics, as can be seen with range of responses to guidelines based therapy. Although this heterogeneity causes some difficulty in the diagnosis and management of asthma in children, it also poses the unique opportunity for targeted asthma therapy. In the era of biologics, targeted therapy may become increasingly important and fundamental to management.

This review will focus on (1) potential opportunities for prevention of pediatric asthma (2) the evidence supporting the current guidelines based therapies with an emphasis on phenotypic heterogeneity, and (3) promising novel therapeutics that have not yet been incorporated into standard care.

Prevention

Prevention is the holy grail of any chronic disease management, including for asthma. With tools such as the Asthma Predictive Index to predict which children will develop asthma, prevention may be a possibility for the future.¹⁰ One phenotype that has been targeted for prevention already is the allergic atopic phenotype. There is a strong association between allergen sensitization and asthma, and early exposure to allergens in sensitized atopic children has been shown to reduce lung function.^{11, 12} Prophylactic interventions have thus been aimed at reducing allergen exposure and inducing tolerance. The Inner City Asthma Study showed that reducing cockroach and dust mite allergen in the home significantly reduced asthma symptoms in inner-city asthmatic children.¹³ Jacobsen et al showed that treatment with subcutaneous allergen immunotherapy prevents the development of asthma in atopic children.^{14, 15} Subsequent trials have supported these findings, and similar results have been obtained using sublingual immunotherapy.^16–19

There is also a strong association between RSV bronchiolitis and the development of asthma.^{11, 20–24} Palivizumab, an anti-RSV monoclonal antibody, has been shown to reduce wheezing in premature infants, suggesting that perhaps it may prevent the development of asthma in this population.^{25, 26} The impact of palivizumab on wheezing in term infants remains to be determined.

Lastly, given the growing evidence for the role of gut flora in the development of allergic and atopic disease, probiotics have become of interest in preventing not only asthma, but other allergic diseases as well. Unfortunately, the data have not supported the use of probiotics in the prevention of asthma thus far. Multiple studies have had limited if any positive results and a recent meta-analysis of trials of probiotic supplementation in pregnancy and infancy found no evidence that probiotics prevented the development of asthma.^{27, 28} Some studies suggest that there may be a role for probiotics in preventing asthma in children that are otherwise atopic, although further work is needed in this area.²⁹

Medication Adherence

Once the diagnosis of asthma is established, ensuring medication adherence becomes a fundamental component of asthma manegement.^{5, 30, 31} Poor adherence leads to increased morbidity and unnecessary escalation of treatment regimens.^{32, 33} In children with asthma, noncompliance with inhalers is a significant problem in all disease severity categories, with some studies citing rates of adherence below 60%.^{31, 34–36}

The reasons for non-adherence are many and differ depending on the child and family.^{30, 36–38} Cost, lack of knowledge about asthma, and patient motivation have been cited in multiple studies as the most critical barriers to adherence.^{37, 38} In several analyses, education of the parent or caregiver on the importance of medication and impact on the underlying disease was found to be a major factor toward improving child medication adherence.^{37, 38} Providers also play a key role, as appointment time constraints, changes in providers, and barriers to scheduling appointments have all been shown to worsen medication noncompliance.^{37, 38} Implementation of the guidelines-based therapy and the development of novel therapies for the refractory asthmatic discussed below will only be of benefit if clinicians address adherence as a primary component of asthma management.

Inhaled Corticosteroids

Based on several large trials, inhaled corticosteroids have become the first-line agent in the management of asthma and remain the preferred treatment choice for all levels of persistent asthma in children.^{39, 40} Unfortunately, in spite of improving asthma control, inhaled corticosteroids have not been shown to alter the progression of asthma. In a large randomized controlled trial from the CAMP Group, budesonide was not shown to preserve lung function when compared with placebo.^{41, 42} The PEAK Trial demonstrated that inhaled corticosteroids decreased wheezing episodes and need for supplemental inhalers in young children with a positive modified Asthma Predictive Index, but this effect did not last once the inhaled corticosteroids were discontinued.⁴⁰ Similarly, inhaled corticosteroids have not been shown to alter the progression of intermittent to persistent wheezing in infants.⁴³ Additionally, there is evidence to suggest that well-controlled asthmatic children on inhaled corticosteroids with normal spirometry continue to have abnormalities in lung clearance indices, suggesting abnormalities persist despite not being detectable using standard office measurements.⁴⁴

Interestingly, newer data suggest that inhaled corticosteroids may hold greater benefit in certain subpopulations. Numerous studies have shown heterogeneity in response to inhaled corticosteroids.^{40, 45–47} For example, some studies have shown that treatment with fluticasone propionate has greatest benefit in children with frequent symptoms, family history asthma, and those with a positive asthma predictive index.^{40, 45} Another study found better outcomes with inhaled corticosteroids in Caucasians, males, and those with aeroallergen sensitization.⁴⁷ More recently, benefit from fluticasone propionate has been associated with a specific CYP3A4 genetic polymorphism.⁴⁶

Furthermore, the newer generation inhaled corticosteroids may improve control for the asthmatic population as a whole. Newer generation inhaled corticosteroids, ciclosenide and mometasone, generate smaller particle size and thus better reach the peripheral airways at lower doses. Although there is evidence to suggest that children on traditional long-term inhaled corticosteroids may have increased risk for delayed growth, studies support that most children achieve their predicted adult heights when treated with recommended doses.^{42, 48} Nevertheless, studies suggest that the newer generation inhaled corticosteroids have a smaller side-effect profile due to lower daily doses.^{30, 49–54} A 2013 Cochrane Review, however, found no difference in control of asthma symptoms, exacerbations, or side effects between ciclosenide, budesonide, and fluticasone.⁵⁵ An additional potential benefit of these newer agents, however, is that both ciclosenide and mometasone are effective as once daily dosing, and thus may improve medication adherence.^{30, 53, 56}

Alternatives to Inhaled Corticosteroids

Other agents, including cromolyn and leukotriene receptor antagonists, have also shown some benefit in children but largely have not performed as well as inhaled corticosteroids and thus are not considered first-line therapy.^{5, 57–63} As with inhaled corticosteroids, there may be some phenotypic variability in response to leukotriene receptor antagonists. Evidence suggests that the differential response to inhaled corticosteroids and leukotriene receptor antagonists is greatest in children with lower lung function, allergic airway inflammation, and elevated FeNO, and children with higher ratios of urinary leukotriene E4 to FeNO may respond better to leukotriene receptor antagonists.^{57, 61, 64–69} The data are somewhat inconsistent and thus these biomarkers have not yet made it into the guidelines for clinical practice.⁵

Theophylline, an agent with a long history in the mangement of asthma, has been shown to be inferior to inhaled corticosteroids and inferior to montelukast as add-on therapy.^{70, 71} One small trial showed that the addition of theophylline to inhaled corticosteroids resulted in improvement in peak expiratory flow, but did not improve FEV1 or bronchial reactivity.⁷² Given the lack of substantial supporting evidence, potential toxicity, and need for frequent monitoring, theophylline is not part of first-line therapy for children with asthma and is not recommended for children under 5.⁵

Step-Up Therapy

If inhaled corticosteroids do not adequately manage a child’s asthma, the guidelines suggest that the next step in therapy be the addition of a long-acting beta agonist.⁵ The addition of a long-acting beta agonist to inhaled corticosteroids has been shown to improve lung function for most children, but many studies have shown there is significant variability in response and resulting asthma control.^{68, 73–78} The Best Add-On Giving Effective Response (BADGER) study showed that while the addition of long-acting beta agonists to low dose inhaled corticosteroids were the most likely to reduce exacerbations, and improve FEV₁ and the number of asthma control days when compared with medium dose inhaled corticosteroids or the addition of a leukotriene receptor antagonist, the study also demonstrated that there was significant variability amongst the children with regard to these results.⁷⁸ As many as 26.7% of children in the study responded better to a medium dose of inhaled corticosteroids and 29.2% to leutkotriene receptor antagonists.⁷⁸ In a recent study post-hoc analysis of the BADGER study, Rabinovitch et al. identified phenotypic variables that would differentiate these populations of children.⁶⁸ The authors found that higher impulse oscillometry reactance area, suggesting peripheral airway obstruction, corresponded to better response to the addition of long-acting beta agonists to low dose inhaled corticosteroids than increasing the dose of inhaled corticosteroids or adding a leukotriene receptor antagonist.⁶⁸ Additionally, they found that higher urinary leukotriene E₄ levels predicted better response to the addition of leukotriene receptor antagonists.⁶⁸ Thus, just as with inhaled corticosteroids and leukotriene receptor antagonists as discussed before, there is likely phenotypic variability in response to long-acting beta agonists. Further work is needed to justify the use of these markers to differentiate asthma phenotypes in clinical practice.

Novel Uses for Old Therapies

Macrolides have been broadly studied in adult chronic pulmonary diseases as well as children with cystic fibrosis, and have shown significant benefits in some patients.^{30, 79–82} The observed improvement is thought to be related to the immunomodulatory role of macrolides and resulting decrease in airway neutrophils.^{30, 79–82} Initial optimism surrounding the benefit of macrolides in management of refractory asthma was humbled by the discovery that many macrolides decrease the clearance of steroids.^{30, 83, 84} More recently, several small studies have suggested that the use of macrolides in children with asthma may reduce bronchial hyper-responsiveness, airway neutrophils, and shorten the duration of symptoms.^{85, 86} There is also some evidence to suggest that asthmatics with colonization by Chlamydia pneumonia or Mycoplasma pneumonia may have more benefit from macrolides.^{30, 87, 88} Some have argued that given the relatively low-risk of macrolides, a trial of therapy in refractory asthmatics is reasonable, although this recommendation has yet to become part of the US guidelines for pediatric asthma management.^{5, 30} NHLBI AsthmaNet is currently investigating whether azithriymycin initiated at start of upper respiratory infection in preschool wheezers will alter the development of lower respiratory illness and exacerbation (NCT01272635).

Vitamin D is also known to have immunomodulatory effects and may play a role in the management of asthma.^{30, 89, 90} Vitamin D has been shown in vitro to stimulate T-regulatory cells and the production of IL-10 in response to steroids, which then inhibits allergen-specific TH2 cells.^{30, 89} Furthermore, a study from the Childhood Asthma Management Program found that children with vitamin D deficiency were more likely to have poorer lung function and less response to inhaled corticosteroids.⁹⁰ Whether supplementation of vitamin D impacts asthma outcomes remains to be determined and is currently being evaluated in adults in NHLBI AsthmaNet (NCT01248065).

The Era of Biologics

A subset of asthmatics remains severely symptomatic despite the above therapy, and prior to the introduction of biologics, these patients were relegated to long-term oral corticosteroids. With the advent of biologics, there is now hope that these severe steroid-dependent asthmatics may have alternative options for treatment.

Furthermore, biologics provide the perfect opportunity to selectively choose therapy based on asthma phenotype. The first of these agents to make it to the national guidelines is omalizumab. Omalizumab, an anti-IgE monoclonal antibody, is now recommended by the most recent guidelines from the National Asthma Education and Prevention Program for children 12 years of age and older with moderate-to-severe asthma. These recommendations are supported by over a decade of work showing that omalizumab reduces the frequency of asthma exacerbations, Emergency Department visits, hospitalizations, and decreases the need for rescue medications and steroids in children with asthma.^91–97 There is limited data at this point on the safety and efficacy of long-term use; some of the longest studies have shown that the medication was tolerated for at least 3 years with improvement in both symptoms and lung function.⁹⁸ Additionally, data is limited for children under 12 years of age.

Omalizumab has been further studied in specific patient populations and shown significant benefit for asthmatics of certain phenotypes. A major randomized controlled trial of omalizumab in inner city children with asthma of any severity demonstrated significant reduction in asthma exacerbations and symptoms.⁹⁹ Omalizumab had the greatest benefit in children with sensitization and exposure to cockroach and dust mites.⁹⁹ Post-hoc analysis further supported the concept that anti-IgE therapy may be of particular benefit in those with seasonal exacerbations.⁹⁹ Studies of omalizumab in other clinical phenotypes that are thought to be Th2 driven, including patients with chronic rhinosinusitis and those with nasal polyps, have shown promise as well.^{100, 101} Given the substantial cost of omalizumab, many have argued for the importance of identifying populations that will have significant benefit and using the drug selectively in those groups.^{99, 102, 103} Traditionally, the populations identified have been those with elevated IgE levels and more severe asthma, although recent work has begun to investigate the impact of anti-IgE on specific biomarkers in allergic asthmatics including FeNO, eosinophilia, periostin.^{99, 104–107}

While omalizumab is the only biologic that has been approved for asthma in children, there are several others that have shown promise in clinical trials in adults and thus may eventually find their way into pediatric asthma management as well. Additionally, there are ongoing clinical trials for many of biologics in adolescents ages 12 and older. Many of these newer biologics target T cells or T cell cytokines. The role of T cells in asthma has been well-established and is discussed in detail elsewhere.¹⁰⁸ Here we discuss several of the newer biologics, but this list is only intended to be illustrative of the numerous and varied biologics in existence for asthma and is not meant to be a comprehensive list of all biologics trialed in asthma to date.

One such biologic is keliximab, a monoclonal antibody to the CD4 receptor. In phase II trails, keliximab seemed to improve peak expiratory flow, but resulted in diminished CD4 counts.^{109, 110} Several of the other biologics under investigation target the cytokines involved in TH-2-mediated allergic and asthmatic inflammation, including IL-2, IL-5, IL-4, and IL-13. IL-2 leads to the activation of TH2 cells, and symptomatic asthmatics have long been known to have increased levels of the IL-2 receptor.¹¹¹ Daclizumab, a monoclonal antibody to the IL-2 receptor, has been shown in phase II trials to improve lung function in adults with moderate to severe asthma on inhaled corticosteroids.¹¹² No trials have been done on daclizumab in children or adolescents with asthma.

IL-4 and IL-13 are directly involved in IgE-mediated mast cell degranulation and mucus hypersecretion and plays a role in airways remodeling in asthma.¹¹³ Dupilumab, a human monoclonal antibody to IL-4, has been shown to reduce the frequency of asthma exacerbations and improve lung function in adults with persistent moderate-to-severe asthma and elevated sputum eosinophils.¹¹⁴ No trials have been done on dupilumab in children or adolescents with asthma. Pitrakinra, a recombinant form of IL-4 that blocks the IL-4 receptor signaling, decreased asthma exacerbations and symptoms in patients with specific IL-4 receptor polymorphisms.¹¹⁵ No trials have been done on pitrakinra in children or adolescents. Lebrikizumab, a monoclonal antibody to IL-13, has been shown in a phase II trial to improve lung function in adult asthmatics, particularly those with elevated serum periostin levels.¹¹⁶ Periostin, a matricellular protein, is secreted by bronchial epithelial cells in response to IL-13 and results in airway remodeling.¹¹⁷ Lebrikizumab is currently being studied in children under several different clinical trials, including adolescents age 12–17 on both an inhaled corticosteroid and a second controller agent, steroid-dependent children ages 12 and older, and steroid-dependent children ages 12 and older with a trial design focused on changes in biomarkers. Another anti-IL-13 antibody, tralokinumab, was found in phase IIa trials to also improve lung function, and most dramatically in those with high levels of airway eosinophils.¹¹⁸ Tralokinumab is currently undergoing pharmokinectic studies in children ages 12–17.

There are several new monoclonal antibodies targeting IL-5, a cytokine linked directly with sputum eosinophilia and airway hyper-responsiveness in asthma.¹¹⁹ Mepolizumab, a monocloncal antibody to IL-5, has been shown to reduce exacerbations and improve quality of life scores in adults with eosinophilic asthma in phase III clinical trials.^120–122 Numerous studies have shown, however, that mepolizumab has no impact FeNO or FEV1.^120–124 There are numerous ongoing clinical trials of mepulizumab recruiting children ages 12 and older, designed to examine dosing, efficacy, safety, longterm safety, and steroid-sparing effect. Reslizumab, another monoclonal antibody to IL-5, has shown promise in phase II trials in improving asthma quality of life scores and lung function.^{125, 126} Interestingly, the greatest benefit was seen in those patients with asthma and nasal polyps.¹²⁶ The efficacy and safety of reslizumab in children ages 12 and older with eosinophilic asthma is currently being examined in the several clinical trials.

Potential Therapeutic Targets

In addition to the above-mentioned cytokines, numerous other cytokines have been suggested as targets for biologics in the treatment of asthma (Table 1).^{127, 128} Studies in mice suggest that IL-9 may play a role in airway hyperresponsivness, airway eosinohilia and mucus secretion.¹²⁹ Medi-528, a monoclonal antibody to IL-9, is under investigation, and has reached phase 2 trials with some promise.¹³⁰ Work is also ongoing to develop an anti-IL-25 antibody for use in allergic asthmatics, as IL-25 plays a role in the activation of TH2 lymphocytes, and the development of allergic asthmatic traits.¹³¹ IL-33 was also recently identified as important potential target, as it was found to promote airway remodeling in pediatric patients with steroid resistant asthma.¹³² Pre-clinical studies have shown that anti-IL-33 can prevent the development of allergic asthma in mice.¹³³ TNF-α, which has shown great success in many chronic inflammatory diseases, is known to be up-regulated in the airways of severe asthmatics.^{134, 135} Unfortunately, anti-TNF agents, such as infliximab and golimumab, have had not had much success in asthma secondary to significant risk with limited benefit.^{136, 137}

Table 1.

Potential therapeutic targets and ongoing studies to establish their role in asthma.

Therapeutic Target	Role in Asthma	Current Investigation
IL-9	AHR, airway eosinophilia, mucus secretion129	Medi-528, phase II trials130
IL-25	Activation of TH2 cells, allergic asthma131	Pre-clinical studies131, development of anti-IL-25 antibody
IL-33	Airway remodeling132	Pre-clinical studies133
Tyrosine Kinase Inhibitors	Inflammatory gene expression30, 138	Masitinib138, phase III clinical trial currently recruiting (NCT01449162)
CCR3	Airway eosinophilia, airway remodeling142, 143	GW766994, phase II clinical trial (NCT01160224)
CCR4	Airway inflammation127, 144	AMG 761, phase I clinical trial (NCT01514981)

AHR: airway hyperresponsiveness.

Tyrosine kinase inhibitors, which have become part of the standard of care in the management of many malignancies, have recently come under investigation for use in asthma given their role in inflammatory gene expression.^{30, 138} A preliminary study of masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, showed promise in reducing asthma symptoms in severe steroid-dependent asthmatics.¹³⁸ Further work is needed to determine if the benefits outweigh the potential side effects of such therapy, and a phase III clinical trial of masitinib in severe steroid-dependent asthmatics is currently underway.

Chemokines involved in the homing of inflammatory cells have also attracted attention as being potential targets in the treatment of asthma.¹²⁷ CCR3 and eotaxin are involved eosinophil infiltration in the airways, and their presence and level in induced sputum correlates with asthma severity.^{139, 140} Furthermore, additional work suggests the CCR3 may play a role in smooth muscle remodeling in asthmatic airways.¹⁴¹ There has been some investigation into CCR3 and eotaxin antagonists, and results of a clinical trial of a CCR3 receptor antagonist in adults with mild-moderate asthma are currently pending publication.^{142, 143} CCR4 is overexpressed in TH2 lymphocytes in asthma, and RS-1748, a CCR4 antagonist, has been shown to reduce airway inflammation in animal models.^{127, 144} Another CCR4 antagonist, AMG 761, is currently undergoing phase I clinical trials in asthmatics. Other chemokines may eventually be targeted for asthma therapy as well.

There are many other potential targets under investigation including phospholipase A2, 5′-lipoxygensase, phosphodiesterase-4, thymic stromal lymphopoietin, OX40 ligand, and tissue kallikrein-1, and discussion of these targets is beyond the scope of this review and are discussed in more detail elsewhere.^{30, 127}

Conclusions

The management of asthma is becoming much more patient-specific, as more and more is learned about biology behind the development and progression of asthma. The future of asthma management will likely involve phenotypic characterization and potentially even genotypic characterization in certain cases to determine appropriate therapy. Until that time, the therapies sufficient for the majority of pediatric asthmatic patients and the focus should remain on ensuring adherence to the guidelines through education of both patients and providers.