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Ömer Kalayci: Adult and pediatric severe asthma – Differences in treatment

Summary of a presentation given on June 19 at EAACI 2017

Pediatric severe asthma is an orphan disease, and its prevalence may be even lower than most textbooks indicate. According to a study among Turkish children, the prevalence of this severe phenotype is 1,8 % (Prosperi 2013). Therefore, it is not surprising that clinical studies on severe asthma in children are scarce. The 2017 GINA guidelines recommend that when the disease reaches treatment step 4, children (age 6 –12) should be referred to a specialist for individualized treatment. The question is, how to find the right treatment for a particular phenotype.

Phenotype-based treatment – first steps

Several studies tried to find data that would help physicians find the most efficacious phenotype-based treatment. For example, Lemanske and colleagues investigated which step-up therapy is best for children with uncontrolled asthma, and whether there are phenotypic or genotypic characteristics that could be used to predict a better response (Lemanske 2010). The children received either increased fluticasone, fluticasone plus long-acting beta-agonist (LABA), or fluticasone plus leukotriene-receptor antagonist (LTRA). The study failed to show any patient characteristics that would predict the best response. A more recent study had more success. Fitzpatrick and colleagues treated children with persistent asthma with inhaled corticosteroids (ICS), or a LTRA, or as -needed ICS (Fitzpatrick 2016). The strongest difference in the treatment regimes was seen in children with both aeroallergen sensitization and blood eosinophilia (≥300/µL). The data suggest that children with high blood eosinophils are much more likely to respond to ICS treatment. This is one of the few examples of phenotype-based treatment in children with asthma.  

Yet, there are concerns about the side effects of high doses of ICS. According to a study by Kelly and colleagues, children that have been treated with 400 μg budesonide were 1,2 cm shorter when they reached their adult height compared to children in a placebo group (Kelly 2012). In a meta-analysis listed in the recent GINA guidelines, it was shown that ICS treatment in adults increased the risk of adrenal insufficiency by factor 7.8 (Broersen 2015). Children might be even more vulnerable. Therefore, practitioners have good reason to be careful when using corticosteroids in pediatric asthma patients. In adults, the next step-up after ICS treatment is to add LABA, but physicians have concerns about using LABA in children. In a recent study with over 6000 children, a combination of fluticasone and salmeterol slightly was safe as the ICS alone and reduced the risk of severe exacerbation in children with asthma (Stempel 2016). According to Ömer Kalayci, it could be an option in children above four years of age to add LABA to the treatment regimen instead of increasing the dose of ICS to high levels.

A new cluster in pediatric patients

Recently, Ömer Kalayci and colleagues identified five clusters of pediatric patients with severe asthma (Deliu M et al. submitted): (1) early-onset difficult asthma, (2) early-onset mild atopic asthma, (3) early-onset mild non-atopic asthma, (4) late-onset asthma, and (5) early-onset asthma with a high number of asthma attacks. Cluster 1, 2 and 4 had significantly higher numbers of eosinophils in the blood. Cluster 5 had not been identified before, and comprised only 13 of the 613 patients. These patients were similar to type 2 brittle asthma in adults and were difficult to treat because they had normal pulmonary function, but suffered from sudden exacerbations that started without warning signs.

In recent years, there have been impressive developments in asthma treatment when information about blood and/or sputum eosinophils is available (Muraro 2016). Anti-IgE (omalizumab) and anti-IL-5 (mepolizumab, reslizumab) antibodies can be used to manage severe asthma, and other agents may be in the pipeline. An antibody shutting down the IL-33 pathway seems to be an interesting candidate. The endotype-driven approach for non-type 2 immune response asthma is lagging behind, however. Among the biologicals, only omalizumab is approved for use in pediatric patients over six years of age. In a randomized trial of omalizumab for inner-city children, the drug proved to be effective in reducing exacerbation (Busse 2011). The strongest effect of omalizumab was seen in patients who were in treatment step 5, which suggests that children with severe asthma respond better to the IgE-targeted treatment (Teach 2015).

Omalizumab, and then?

Many studies have shown that a high count of eosinophils in the blood is associated with a better response to omalizumab. Judging from these studies, it can be said that a high level of information (allergic sensitization, blood and/or sputum eosinophilia) and the presence of a more severe disease can be predictors of a better response to omalizumab. But what is the next treatment step after omalizumab? At this point, the physician should consider admitting the patient in order to eliminate remediable causes of asthma, to increase treatment adherence, to treat psychosocial factors and to observe whether the symptoms are truly genuinely related to asthma. A treatment with an antifungal medication, such as amphotericin B seems to be less promising, while macrolides such as azithromycin might offer another treatment option. According to a study with around 400 adults, azithromycin was effective in patients with eosinophilic asthma. However, this observation from Australian researchers has only been published as an abstract and still needs to be validated. In conclusion, for the small subset of patients who are unresponsive to asthma treatment, there is very little the physician can do but wait for the approval of new biologicals or other future supplementary treatments.

Summary:

  • Appropriate phenotyping leads to good control in most children.
  • ICS doses should be monitored.
  • LABA are generally safe.
  • There exists a problematic exacerbating phenotype whose treatment is unclear.
  • Anti-IgE treatment may be beneficial in severe treatment resistant asthma (STRA).
  • Further phenotyping may be necessary in children unresponsive to anti-IgE treatment

Ömer Kalayci is Professor at the Hacettepe University School of Medicine, Ankara, Turkey

References:

Broersen LHA, Pereira AM, Jørgensen JOL et al. Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis. J Clin Metab 2015; 100: 2171–2180

Busse WW, Morgan WJ, Gergen PJ. Et al. Randomized Trial of Omalizumab (Anti-IgE) for Asthma in Inner-City Children. N Engl J Med 2011; 364: 1005–1015

Fitzpatrick AM, Jackson DJ, Mauger DT et al. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol. 2016; 138:1608–1618.e12

Kelly W, Sternberg A, Lescher R et al. Effect of Inhaled Glucocorticoids in Childhood on Adult Height. N Engl J Med 2012; 367: 904–912

Lemanske R, Mauger DT, Sorkness CA et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 2010; 362: 975–85.

Muraro MD, Lemanske RF, Hellings PW et al. Precision medicine in patients with allergic diseases: Airway diseases and atopic

dermatitis—PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy

of Allergy, Asthma & Immunology. J Allergy Clin Immunol 2016; 137: 1347–58

Prosperi MC, Sahiner UM, Belgrave D et al. Challenges in identifying asthma subgroups using unsupervised statistical learning techniques. Am J Respir Crit Care Med. 2013; 188: 1303–1312

Stempel DA, Szefler SI, Pedersen S et al. Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma. N Engl J Med 2016; 375: 840–9.

Teach SJ, Gill MA, Togias A et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. JACI 2015; 136: 1476–1485

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