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Medical Journal Review

December 2016

WAO Reviews – Editors’ Choice

December 2016

Articles are selected for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases by Juan Carlos Ivancevich, MD, WAO Web Editor-in-Chief, and John J. Oppenheimer, MD - FACAAI - FAAAAI, WAO Reviews Editor. 

1. Exon skipping of Fc ε RI β eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy.

Cruse G, Yin Y, Fukuyama T, Desai A, Arthur GK et al. Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy. Proceedings of the National Academy of Sciences 2016; 113(49): 14115-14120. (doi:10.1073/pnas.1608520113)

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Presently there are no drugs available that can specifically down-regulate mast cell function in vivo when chronically administered. In this study Cruse and colleagues describe an approach for targeting mast cells using antisense oligonucleotide-mediated exon skipping of the β-subunit of the high-affinity IgE receptor (FceRIβ) to eliminate surface high-affinity IgE receptor (FceRI) expression and function, resulting in mast cell unresponsiveness to IgE-mediated activation. As FceRIβ expression is restricted to mast cells and basophils, this approach would selectively target these cell types which are important in allergic disease. It should be noted that this approach of exon skipping has proven successful in clinical trials to treat genetic diseases such as Duchenne muscular dystrophy. The authors conclude by noting that this technique could be a viable approach for treatment of allergic conditions such as asthma and atopic dermatitis, via inhaled or topical application.  This approach is certainly quite exciting and more is sure to come.

2. Pulmonary α-1,3-Glucan-Specific IgA-Secreting B Cells Suppress the Development of Cockroach Allergy

Patel PS, King RG, Kearney JF. Pulmonary α-1,3-Glucan-Specific IgA-Secreting B Cells Suppress the Development of Cockroach Allergy. The Journal of Immunology 2016; 197(8): 3175-3187. (doi:10.4049/?jimmunol.1601039)

Abstract

Several recent epidemiologic studies have demonstrated a higher incidence of allergic conditions among children living in industrialized versus developing countries.  There have been several theories as to why this occurs. One explanation is reduced neonatal exposure to microbes and the resultant lack of immune stimulation. It is also known that sensitivity to cockroach allergen is highly correlated with the development of severe asthma.

In this study, the authors found that an antibody to microbial α-1,3-glucan binds an Enterobacter species as well as cockroach allergen. Furthermore, they found that neonatal, but not adult, mice immunized with this α -1,3-glucan–bearing Enterobacter (MK7) were protected against cockroach allergy. While exposure as neonates to cockroach allergen, α -1,3-glucan–specific IgA-secreting cells are present in the lungs of mice immunized with MK7, no such protection was seen in the lungs of those immunized as adults. Thus indicating that neonatal, but not adult, exposure to α-1,3-glucan results in suppressed development of cockroach allergy via pulmonary α-1,3-glucan–specific IgA-secreting cells.  The authors suggest that therapeutic prophylaxis via a vaccine or probiotic-containing α-1,3- glucans during early life could be used to modulate neonatal B cells, with the potential of long-lived suppression of asthma development secondary to cockroach sensitization.

3. Efficacy and Safety of Anti-Interleukin-5 Therapy in Patients with Asthma: A Systematic Review and Meta-Analysis.

Wang FP, Liu T, Lan Z, Li SY, Mao H. Efficacy and Safety of Anti-Interleukin-5 Therapy in Patients with Asthma: A Systematic Review and Meta-Analysis. PLoS 2016; 11(11):e0166833. (doi:10.1371/journal.pone.0166833).

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In this meta-analysis, the authors examine the literature regarding anti-IL5 agents (mepolizumab, reslizumab, and benralizumab) in the treatment of asthma. Although they identified 3047 studies on the topic, only 20 met criteria for analysis. From this, they found that anti-interleukin-5 therapy is safe and may reduce asthma exacerbation risk, slightly improve FEV1, FEV1%, and quality of life; as well as decrease blood and sputum eosinophil levels. PEF and PC20, however, were not improved and SABA rescue use was not reduced.

The authors conclude that Anti-IL5 therapy may be beneficial as adjunct asthma therapy, particularly in severe and eosinophilic asthma, but further trials are necessary to distinguish which patients will respond to particular antibodies, both within and between classes.

4. Allergy immunotherapy across the life cycle to promote active and healthy ageing: from research to policies: An AIRWAYS Integrated Care Pathways (ICPs) programme item (Action Plan B3 of the European Innovation Partnership on active and healthy ageing) and the Global Alliance against Chronic Respiratory Diseases (GARD), a World Health Organization GARD research demonstration project.

Calderon MA, Demoly P, Casle T, Akdis CA, Bachert C. Allergy immunotherapy across the life cycle to promote active and healthy ageing: from research to policies: An AIRWAYS Integrated Care Pathways (ICPs) programme item (Action Plan B3 of the European Innovation Partnership on active and healthy ageing) and the Global Alliance against Chronic Respiratory Diseases (GARD), a World Health Organization GARD research demonstration project. Clinical and Translational Allergy 2016; 6(41). (doi:10.1186/s13601-016-0131).

Full Text, Open Access

As allergic disease often begins in early life and persist throughout life, it is important that this life-course perspective is considered in the use of allergen immunotherapy (AIT). This paper, by a working group of AIRWAYS integrated care pathways, explored the concept of AIT across the life cycle and proposed a strategic framework to be tested. To do so, the group considered (1) the political background, (2) the rationale for allergen immunotherapy across the life cycle, (3) the unmet needs for the treatment, (particularly in preschool children and old age adults), (4) the strategic framework and the practical approach to synergize current initiatives in allergen immunotherapy, specifically its mechanisms and the concept of active and healthy ageing.

5. A pilot study to investigate the use of serum inhaled corticosteroid concentration as a potential marker of treatment adherence in severe asthma.

George KE, Ryan DM, Keevil B, Niven R, Fowler SJ. A pilot study to investigate the use of serum inhaled corticosteroid concentration as a potential marker of treatment adherence in severe asthma. Journal of Allergy and Clinical Immunology 2016; published online ahead of print, October 11. (doi: 10.1016/j.jaci.2016.08.037)

Summary

It is well known that inhaled corticosteroids (ICS), the mainstay of asthma controller therapy, when used as directed are associated with improved asthma control.  Unfortunately, studies have demonstrated very poor adherence and this lack of adherence is often blamed for loss of asthma control.  Presently there is a need for better measures of adherence.  This pilot study by George and colleagues assessed whether ICS could be directly measured in serum using liquid chromatography tandem mass spectrometry (LC-MS/MS) and whether this could be used as a marker of adherence.

In a series of 19 subjects with severe asthma treated with at least 1000mcg beclomethasone dipropionate equivalent (13 FP and 6 Bud) the authors were able to detect both FP and BUD in the serum of all but one of the participants with good inhaler technique at two hours post inhalation as well as in all but three at eight hours. Two patients with poor inhaler technique were found to have very low concentration levels. The authors conclude by stating that this technique has the potential to be used as a direct measure of adherence but note that further work with increased patient numbers and alternative inhaled corticosteroids and devices are needed.  They also acknowledge that they need to explore the impact of airway obstruction on serum concentrations of ICS, as this may result in decrease drug delivery to the distal lung and resultant systemic absorbtion.