Pediatric Asthma – do we need more innovation for treatment?



Asthma is one of the most common diseases in children, and, in many parts of the world, the incidence is still on the rise. Clinical and epidemiological studies have shown that there is no single asthma phenotype or generally applicable definition of asthma over the range from infancy to adulthood. Many pathophysiological aspects of the ‘asthma syndrome’ are still poorly understood and only recently have the use of omics (genomics, transcriptomics, proteomics, lipidomics, metabolomics, and breathomics) in the lungs, blood, and urine helped identify biomarkers that better define various clinical, pathophysiological, and genetic aspects of the disease [1]. The more we learn about the different endotypes of the disease, the more challenged is our current concept of treatment. How should one size fit all?

Asthma treatment has not changed very much over the last 30 yrs, except that chronic eosinophilic inflammation has gained more attention, and thus, anti-inflammatory drugs have become the main treatment pillar. Inhaled corticosteroids (ICS) are the most used anti-inflammatory drugs followed by leukotriene receptor antagonists. These drugs reduce symptoms and exacerbations, improve quality of life, restore lung function, and reduce inflammation; however, they are not really disease modifying and do not alter the natural course of the disease [2]. Most children with the ‘asthma syndrome’ do well on acceptable doses of ICS in combination with as-needed short-acting bronchodilators. Some do better with high doses of ICS or ICS plus long-acting beta-2 agonist (LABA) or leukotriene receptor antagonist (LTRA) and about 4–5% have therapy-resistant asthma [3]. For this rather small subgroup, which however accounts for more than half of the total healthcare costs in children with asthma, a few innovative drugs have been made available recently [4].

Omalizumab, a recombinant humanized monoclonal antibody against free IgE improves asthma control, reduces exacerbations and is associated with reduction in ICS in allergic children and adolescents between 6 and 20 yrs old who have therapy-resistant asthma [5-7]. The clinical benefits are modest, the long-term safety and efficacy have not been determined, and the costs are high. Anti-interleukin antibodies such as anti-IL-5 and anti-IL-5R (mepolizumab, reslizumab, benralizumab) [8], anti-IL-4R (dupilumab), anti-IL-13 (lebrikizumab, tralokinumab), anti-IL-4/IL-13 (pitrakinra), or anti-TNF-α (golinumab, etanercept) have been tested mainly in adults showing variable effects on asthma control, exacerbations, and lung function and often clear benefits for specific targets of the underlying pathophysiologic abnormalities such as eosinophilic inflammation parameters. Experimental data have emerged on the use of antisense oligonucleotide therapy to reduce the levels of mRNA for cytokine receptor production: for example, TPI ASM-8 (Topigen) targets CCR3 involved in eosinophilic chemoattraction and post-allergen bronchial hyperresponsiveness [9]. For these novel treatment options, a precise characterization of those patients who might benefit most is mandatory and the search for specific biomarkers is continuing.

In some children with severe therapy-resistant asthma, a trial of immunomodulating or immunosuppression agents such as oral macrolides, cyclosporine, or methotrexate might be warranted [3]. Other immunomodulating treatment options might involve the combined use of steroids and vitamin D to modulate Th1/Th2 differentiation, to target T regs and Th17, and to increase the sensitivity to glucocorticoids in steroid-resistant asthma [9]. Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) have the potential to alter the course of asthma, yet in fact might even prevent asthma in children with allergic rhinoconjunctivitis. Novel accelerated immunotherapy schedules might increase adherence to this type of more curative treatment [10].

The above-mentioned approaches in asthma management, particularly in severe therapy-resistant asthma, are important steps in improving quality of life in these patients. Some of the more novel molecular phenotype-/endotype-related avenues will certainly better address the complexity of gene by environmental-by-developmental interactions important in childhood asthma. They are, however, expensive and so far represent only the tips of the many different pathophysiological and immunologic icebergs active in the asthma syndrome. Scientifically, these therapeutic approaches including and involving as many as possible of the various facets of an individual ‘omics repertoire’ are intriguing but most likely unaffordable and impossible in real life.

In my opinion, for the near future, we need to pursue two main strategies of innovative asthma management. First, foster personalized, self-managed asthma using web-based tele-management that includes education, self-monitoring of symptoms, and lung function and electronic reminder devices. This approach will lead to patient empowerment and aims at increasing adherence to the personalized treatment, the individual patient goals and necessary changes in lifestyle (i.e., reduction in smoking and of second- and third-hand smoke exposure). In addition, educational programs should be offered to primary and secondary care physicians with the aim to adhere to national asthma guidelines and to be familiar with the aspects of the approach of self-managed asthma.

The second strategy is to shift asthma management from treatment to prevention. For a long time, the main focus in primary prevention of allergy and asthma was on allergen avoidance. So far, most primary prevention attempts, particularly reduction in exposure to house-dust mites, dogs, cats, or food allergens, have failed. In fact, more and more evidence suggests that exposure to allergens very early in life, if not before birth, is crucial for induction of tolerance. The two main risk factors for the development of childhood asthma and the progression into adulthood asthma are early-life respiratory viral infections and atopic sensitization [11]. The two most relevant viruses in this context are rhinovirus and respiratory syncytial virus, and it appears that viral and atopic inflammation have synergistic effects. In terms of being a true risk factor for later asthma, the viral infection has to be sufficiently severe, involves the lower airways and affects children who are presensitized against inhalant allergens [12]. Vaccines against these viral infections or, more likely, targeting key cell populations of the viral- and atopy-induced inflammation in the airway mucosa could serve as primary prevention. OM-85 has been shown to be effective in preventing wheezing associated with viral respiratory infections possibly through its ability to upregulate the antiviral Th-1 response and to increase virus clearance [13].

A promising strategy for preventing sensitization could be the use of combined allergen-specific sublingual immunotherapy in the first years of life to induce tolerance. Alternatively, sensitization and asthma are reduced in children growing up on traditional farms [14], and several immunomodulating substances have been identified in stables and cowsheds [15]. These are potential candidates for orally or intranasally applied compounds that could lead to the prevention of asthma in the sense of true innovation in asthma management.