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Medical Journal Review

August 2015

WAO Reviews - Editors' Choice

The Editors select articles for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases, and whenever possible they seek articles that everyone can access freely. The Editors’ Choice comes to you each month from Juan Carlos Ivancevich, MD, WAO Web Editor-in-Chief, and summary author, John J. Oppenheimer, MD, FACAAI, FAAAAI, the WAO Reviews Editor.

1. Underuse of guideline-recommended long-term asthma management in children hospitalized to the intensive care unit: a multicenter observational study

Hasegawa K, Ahn J, Brown MA, Press VG, Gabriel S et al. Underuse of guideline-recommended long-term asthma management in children hospitalized to the intensive care unit: a multicenter observational study. Annals Allergy Asthma Immunology 2015; 115(1): 10-16.

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As noted in this study’s introduction, at least in the state of New Jersey, there was a reported 6-fold rise in the need for intensive care unit (ICU) use in the treatment of asthma exacerbations between 1992 and 2006.  As it is believed that hospitalizations for asthma exacerbations are a consequence of treatment or maintenance failure, it made sense to explore this knowledge gap, by performing a multicenter study of children hospitalized for asthma exacerbation to investigate the proportion and characteristics of children admitted to the ICU and the frequency of guideline-recommended outpatient management in the pre- and post-hospitalization periods. It was hoped that better understanding of these important issues in long-term asthma care will aid in the development of strategies to improve the long-term prevention-oriented management of these hospitalized children.

To do so, the authors performed a 14-center medical record review study of children aged 2 to 17 years hospitalized for asthma exacerbation during 2012-2013. The primary outcome was admission to the ICU.  Secondary outcomes were 2 preventive factors: use of inhaled corticosteroids (ICS) and evaluation by asthma specialists in the pre- and post-hospitalization periods.

They found that of the 385 children hospitalized for asthma, 130 (34%) were admitted to the ICU. The risk factors for ICU admission were female sex, having public insurance, a marker of chronic asthma severity (ICS use), and no prior evaluation by an asthma specialist. Among children with an ICU admission, guideline-recommended outpatient management was suboptimal, which included lack of use of an ICS as well as not having been seen by an asthma specialist. Sadly, at hospital discharge, among children with ICU admission who had not previously used controller medications only 85% were prescribed ICSs and only 62% were referred to an asthma specialist during the 3-month post-hospitalization period.

The authors go on to note that in conjunction with the earlier studies reporting that longitudinal outpatient care by a specialist is associated with fewer subsequent ED visits or hospitalizations and better asthma control, their results lend significant support to this guideline recommendation in the care of children with high-risk asthma.

2. Clinical Relevance of Cluster Analysis in Phenotyping Allergic Rhinitis in a Real-Life Study

Bousquet PJ, Devillier P, Tadmouri A, Mesbah K, Demoly P, Bousquet J. Clinical relevance of cluster analysis in phenotyping allergic rhinitis in a real-life study. International Archives of Allergy and Immunology 2015; 166(3): 231-240. (doi:10.1159/000381339)

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As pointed out by the authors, novel phenotypic characterization of allergic diseases is needed to distinguish groups of patients presenting with allergic rhinitis (AR). It is hoped that through the identification of phenotypes clinicians can improve management and AR control. Popular epidemiologic approaches, such as the unsupervised statistical techniques, have recently emerged to meet these needs. These approaches consist of applying unsupervised statistical methods to a population with a wide distribution of related symptoms, and then identifying the possible underlying phenotypes.

Ideally each of these phenotypes should be as homogeneous as possible and have as little overlap as possible with each of the other phenotypes. Phenotypes are not known a priori, and there are no predefined views about them. There are different types of clustering approaches such as hierarchical, partitioning and model-based clustering as well as network analysis. Many studies in asthma and allergic diseases have used various clustering methods to stratify patients; with one of the recommended methods being Ward’s hierarchical cluster analysis. Through this method patients in the same cluster are more similar to each other than those in different clusters.

A French observational prospective multicenter study (EVEIL: Echelle visuelle analogique dans la rhinite allergique) was carried out on 990 patients consulting general practitioners (GPs) for AR and treated as per clinical practice. In this study, changes in symptom scores, VAS and QoL were measured at baseline and after 14 days of treatment. The study involved a careful evaluation of demographic and clinical characteristics and was suitable for cluster analysis. In this paper, the authors performed a post hoc analysis using the dataset of the EVEIL study to identify clusters of patients with AR using Ward’s hierarchical method, and to define their clinical relevance at baseline and after 14 days of treatment. The cluster approach was compared to ARIA (Allergic Rhinitis and its Impact on Asthma), which is a hypothesis-driven approach largely used in clinical practice. Through use of the cluster approach, patients were clustered into 4 phenotypes which partly followed the ARIA classes. These phenotypes differed in their disease severity (symptoms and quality of life). It should be noted that physicians in “real-life practice” prescribed medication regardless of the phenotype and severity, except for patients with ocular symptoms, who more frequently were prescribed ocular antihistamines. Interestingly, they found that cluster analysis using demographic and clinical parameters did not appear to add relevant information for disease stratification in allergic rhinitis and prescribed treatments were comparable in hypothesis- and data-driven analyses.

In conclusion the authors note that insufficient numbers of primary care physicians stratify their patients in terms of severity, clinical parameters readily available in their offices are helpful in assessing the response to treatment in AR and cluster analysis did not add to disease stratification.

3. Mast Cells, Mastocytosis, and Related Disorders

Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders. The New England Journal of Medicine 2015; 373(2): 163-172. (doi:10.1056/NEJMra1409760)


This article is a wonderful overview of recent developments regarding the physiology and pathobiology of mast cells. In this review, they examine the role of mast cells in human disease. To do so they explore our understanding of the mechanisms of mast cell activation and appropriate diagnostic testing and treatment, both at present and hopefully for the future.

I would encourage practicing allergists to read this paper and to keep it handy for your care of patients with suspected mast cell disease.

4. The allergy epidemics – 1870-2010

Platts-Mills TAE. The allergy epidemics – 1870-2010. The Journal of Allergy and Clinical Immunology 2015; 136(1): 3-13. (doi:

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This is a fascinating review which explores the rise in prevalence of allergic disease as can only be told by Dr. Platts-Mills. He begins this journey with John Bostock, who in 1828 provided the first description of hay fever, relating his own experience as an allergy sufferer. Dr. Platts-Mills’ major tenet in this paper is that this rise in allergy prevalence appears to be a result of three different illness epidemics. This first rise was in allergic rhinitis and began approximately 1870 and was believed to be a consequence of improved public hygiene. The second epidemic was the rise in pediatric asthma noted between the years of 1960 and 2000. The author suggests that this may be of more complex triggering. Beyond improved hygiene, reduced exercise with increased viewing of television, increase use of antibiotics, air pollution, obesity, increase use of acetaminophen and increase in immunization all potentially play a role. The last and most recent of the epidemics was the rise in prevalence in food allergy. With regard to reasons for this increase, Dr. Platts-Mills acknowledges that there is no clear answer. He suggests, however, that this may be related to in utero exposure, exposure through the skin, and possibly delayed introduction of foods.

I would encourage all allergists to read this document. Beyond being a wonderful thought-provoking review of our field, the article is also a great history lesson.

5. Efficacy of Grass Pollen Allergen Sublingual ImmunotherapyTablets for Seasonal Allergic Rhinoconjunctivitis; A Systematic Review and Meta-analysis

Di Bona D, Plaia A, Leto-Barone MS, La Piana S, Di Lorenzo G. Efficacy of grass pollen allergen sublingual immunotherapy tablets for seasonal allergic rhinoconjunctivitis; A systematic review and meta-analysis. JAMA Internal Medicine 2015; 175(8): 1301-1309. (doi:10.1001/jamainternmed.2015.2840)


In this study the authors build upon their prior work examining the efficacy of grass allergen sublingual immunotherapy (SLIT). In their previously published meta-analysis, they demonstrated that SLIT was effective for seasonal allergic rhinoconjunctivits to grass pollen, with “modest” benefit compared to placebo, as well as the fact that tablet SLIT was more effective than drops (DiBona D, Plaia A, Scafidi et al. J Allergy Clin Immununol. 2010;126:558-66). The authors chose to perform a new meta-analysis, because there have been 5 further trials with grass SLIT since their initial publication. They used standard technique, relying on 2 independent observers using the method of DerSimonian and Laird. The primary end point was the difference in symptom score and medication score between SLIT and placebo. Their data included 13 randomized controlled trials involving 4659 subjects for symptom score and 12 trials involving 4558 subjects for medication score. Overall the authors found a “small” treatment benefit in symptoms score (p<0.001) and medication score (p<0.001).  A secondary outcome in their analysis was adverse events, which occurred in 61.3% of SLIT subjects vs. 20.9% of placebo subjects, with 7 of the subjects receiving SLIT requiring epinephrine.

It should be noted that these studies were designed to examine a combined symptom-medication score, yet this meta-analysis separated the two measures. This is somewhat concerning, as even the authors of this meta-analysis point out, symptomatic medication treatment is likely responsible for most of the relief of the symptoms and the placebo group used significantly more such therapy. One thing is for sure, this article is certain to catalyze significant debate on this topic.