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Medical Journal Review

July 2018

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 from Juan Carlos Ivancevich, MD, WAO Web Managing Editor, and summary author, John J. Oppenheimer, MD, FACAAI, FAAAAI, WAO Reviews Editor.

The pediatric asthma yardstick: Practical recommendations for a sustained step-up in asthma therapy for children with inadequately controlled asthma
Chipps BE, Bacharier LB, Farrar JR, Jackson DJ, Murphy KR et al
Annals of Allergy Asthma and Immunology 2018; 120(6): 559-579. DOI:10.1016/j.anai.2018.04.002

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This is the newest addition to the American College of Allergy, Asthma and Immunology’s yardstick series. The intent of this paper is to present patient profiles regarding step-up strategies based on current guideline documents, but modified by more recent data and the authors’ combined clinical experience, with the goal of providing clinicians who treat children with asthma both practical and clinically relevant recommendations for each step-up and each intervention. This is a complete and well thought out document that looks at all levels of asthma severity and its care, from intermittent use of short-acting beta agonists (SABAs) to the use of new biologic agents. It is a must read for those caring for asthmatic children.

Combined analysis of asthma safety trials of long-acting β2-agonists
Busse WW, Bateman ED, Caplan AL, Kelly HW, O’Bryne PM et al
New England Journal of Medicine 2018; 378(26): 2497-2505. DOI:10.1056/NEJMoa1716868


Since early post marketing studies, there has been concern of a signal of increased mortality when using long-acting beta agonists (LABAs) in asthmatic patients. As a consequence, all such agents received a boxed warning, and in 2010 the Food and Drug Administration (FDA) mandated that the four companies marketing LABAs for asthma perform prospective, randomized, controlled trials comparing the safety of combination therapy with a LABA plus an inhaled glucocorticoid with that of an inhaled glucocorticoid alone in adolescents and adults. In the design and implementation of these studies the FDA and the manufacturers harmonized their trial methods to allow an independent joint oversight committee to provide a final combined analysis of the four trials.

In this study by Busse and colleagues, the joint oversight committee present the combined analysis of the four trials comparing an inhaled glucocorticoid plus a LABA (combination therapy) with an inhaled glucocorticoid alone, with the primary outcome being a composite of asthma-related intubation or death. They found that among the 36,010 patients in the intention-to-treat population, there were three asthma related intubations (two in the inhaled-glucocorticoid group and one in the combination-therapy group) and two asthma-related deaths (both in the combination therapy group) in 4 patients. Furthermore, secondary analysis of serious asthma-related events (a composite of hospitalization, intubation, or death), 108 of 18,006 patients (0.60%) in the inhaled-glucocorticoid group and 119 of 18,004 patients (0.66%) in the combination-therapy group had at least one composite event (relative risk in the combination-therapy group, 1.09; 95% confidence interval [CI], 0.83 to 1.43; P = 0.55); 2,100 patients in the inhaled-glucocorticoid group (11.7%) and 1,768 in the combination-therapy group (9.8%) had at least one asthma exacerbation (relative risk, 0.83; 95% CI, 0.78 to 0.89; P<0.001).

The authors conclude that combination therapy with a LABA plus an inhaled glucocorticoid did not result in a significantly higher risk of serious asthma-related events than treatment with an inhaled glucocorticoid alone, but resulted in significantly fewer asthma exacerbations. This combined analysis provides strong evidence to support the recent FDA decision to remove the boxed safety warning for combination therapy with a LABA plus an inhaled glucocorticoid for the treatment of asthma. The rationale for removing this warning is detailed in an accompanying editorial by Seymour et al. (Seymour SM, Lim R, Xia C, Andraca-Carrera E, Chowdhury BA. Inhaled corticosteroids and LABAs — removal of the FDA’s boxed warning. N Engl J Med 2018;378:2461-3).

Association of food allergy and other allergic conditions with autism spectrum disorder in children
Xu G, Snetselaar LG, Jing J, Buyun L, Strathearn L, Bao W
Journal of the American Medical Association 2018; 1(2): e180279. DOI:10.1001/jamanetworkopen.2018.0279

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Although immunologic dysfunction has recently emerged as a factor associated with autism spectrum disorder (ASD), little is known about the association between food allergy and ASD. Thus, the objective of this study was to examine the association of food allergy as well as other allergic conditions with ASD in US children, through a population-based, cross-sectional study which used data from the National Health Interview Survey collected between 1997 and 2016. This analysis included 199,520 children of whom 8,734 (weighted prevalence, 4.31%) had food allergy, 24,555 (12.15%) had respiratory allergy, and 19,399 (9.91%) had skin allergy. A diagnosis of ASD was reported in 1,868 children (0.95%). The weighted prevalence of reported food, respiratory, and skin allergies was higher in children with ASD (11.25%, 18.73%, and 16.81%, respectively) compared with children without ASD (4.25%, 12.08%, and 9.84%, respectively). In analyses adjusting for age, sex, race/ethnicity, family highest education level, family income level, geographical region, and mutual adjustment for other allergic conditions, the associations between allergic conditions and ASD remained significant. The odds ratio (OR) of ASD increased in association with food allergy (OR, 2.29; 95%CI, 1.87-2.81), respiratory allergy (OR, 1.28; 95%CI, 1.10-1.50), and skin allergy (OR, 1.50; 95%CI, 1.28-1.77) when comparing children with these conditions and those without. The authors recommend that further investigation be undertaken to better understand the causality and underlying mechanisms.

A nasal brush-based classifier of asthma identified by machine learning analysis of nasal RNA sequence data
Pandey G, Pandey OP, Rogers AJ, Ahsen ME, Hoffman GE et al
Scientific Reports 2018/ 8(1): 8826. DOI:10.1038/s41598-018-27189-4

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This is an interesting study in which the authors sought to identify a nasal brush based classifier of mild/moderate asthma. One hundred ninety (190) subjects with mild/moderate asthma and controls underwent nasal brushing and RNA sequencing of nasal samples, following which a machine learning-based pipeline identified an asthma classifier consisting of 90 genes interpreted via an L2-regularized logistic regression classification model. This classifier demonstrated strong predictive value and sensitivity across eight test sets, including (A) a test set of independent asthmatic and control subjects profiled by RNA sequencing (positive and negative predictive values of 1.00 and 0.96, respectively; AUC of 0.994), (B) two independent case-control cohorts of asthma profiled by microarray, and (C) five cohorts with other respiratory conditions (allergic rhinitis, upper respiratory infection, cystic fibrosis, smoking), where the classifier had a low to zero misclassification rate. The authors suggest that if validated in a large, prospective cohort, this classifier could be developed into a nasal biomarker of asthma.

The impact of cold on the respiratory tract and its consequences to respiratory health
D’Amato M, Molino A, Calabrese G, Cecchi L, Annesi-Maesano I, D’Amato G
Clinical and Translational Allergy 2018; 8:20. DOI:10.1186/s13601-018-0208-9

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In this review, the authors examine the consequences of repeated exposure to cold air by exploring the mechanisms by which such exposure could modify airway function and affect health outcomes of patients with pre-existing airway disease. The authors conclude that there is a need to better define the consequences of repeated exposure to cold air and the mechanisms by which such exposure could modify airway function and affect the outcomes of patients with pre-existing airway disease.