News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2017)

There is currently a strong need to prevent exacerbations in patients with uncontrolled asthma. Gibson et al (Lancet 2017;390:659-68; https://doi.org/10.1016/S0140-6736(17)31281-3) performed a randomized, double-blind, placebo-controlled trial to assess the effect of the macrolide antibiotic azithromycin on asthma exacerbation frequency. Four hundred twenty patients with severe asthma that was uncontrolled by inhaled corticosteroids or long-acting bronchodilators were assigned to receive 500 mg of oral azithromycin or placebo 3 times per week for 48 weeks. Azithromycin treatment decreased the frequency of all asthma exacerbations (mean exacerbations per person-year, 1.07 vs 1.86) and severe exacerbations (mean severe exacerbations per person-year, 0.61 vs 1.07). Importantly, the exacerbation rate was decreased in both patients with eosinophilic asthma and those with noneosinophilic asthma. Additionally, the azithromycin treatment group had a significant improvement in asthma-related quality-of-life measures and fewer respiratory tract infections. These results demonstrate that azithromycin decreases asthma exacerbations and might be of therapeutic benefit as an additional therapy for patients with severe asthma. Figure Attribution: accessed by Wikimedia Commons, made by user By Yikrazuul (Own work) [Public domain].Azithromycin decreases asthma exacerbations Azithromycin decreases asthma exacerbations We asked first author Peter Gibson, MBBS, FRACP, of the University of Newcastle, Newcastle, New South Wales, Australia, to comment on the study. He writes, “The clinically important benefit of azithromycin in reducing asthma exacerbations occurred in both eosinophilic and noneosinophilic phenotypes and in addition to maintenance inhaled corticosteroid/long-acting bronchodilator therapy. This study identifies an additional treatment option for adult asthma that might work on a different mechanistic pathway to current therapy.” Hereditary angioedema (HAE) is a genetic disorder notable for paroxysmal attacks of angioedema caused by loss of activity of the complement C1 inhibitor. In a phase 2, randomized, double-blind, placebo-controlled trial of 32 subjects with a crossover design, Riedl et al (Lancet 2017; https://doi.org/10.1016/S0140-6736(17)31963-3) assessed the effect of the prophylactic use of recombinant C1 esterase inhibitor on HAE attack frequency. Patients were randomized to one of 6 possible treatment sequences, which each consisted of three 4-week treatment periods with a 1-week washout period. Patients received recombinant human C1 esterase inhibitor (50 IU/kg) twice weekly, once weekly with placebo once weekly, or placebo twice weekly. Recombinant C1 esterase inhibitor twice weekly and once weekly decreased the frequency of HAE attacks per 4-week period compared with placebo by 4.4 (P < .0001) and 2.8 (P = .0004) attacks, respectively. In total, these findings demonstrate that recombinant C1 esterase inhibitor used twice weekly decreases HAE attack rates and might be a promising prophylactic strategy for HAE. We asked first author Marc Riedl, MD, MS, of the University of California San Diego, to comment on the study. He writes, “Recombinant C1INH has previously been shown effective and FDA-approved for acute treatment of HAE attacks. This rigorous study provides evidence that recombinant C1INH has prophylactic benefits when administered once or twice weekly. The data are particularly timely as HAE patients have limited prophylactic treatment options that have further been reduced by critical shortages of plasma-derived C1INH products. Based on this trial as well as existing safety data, recombinant C1INH may be a useful treatment option to consider when HAE prophylaxisis indicated.” Atopic dermatitis (AD) commonly begins early in life and is associated with progression to other allergic diseases. Roduit et al (JAMA Pediatr;171:655-62; https://doi.org/10.1001/jamapediatrics.2017.0556) undertook a prospective study to determine whether patients with AD could be stratified on the basis of both the onset and nature course of the disorder. Symptoms were recorded through the first 6 years of life of 1038 children in the European Protection Against Allergy Study in Rural Environments (PASTURE) birth cohort. Latent class statistical analysis revealed 3 distinct phenotypes of AD. Two phenotypes had disease onset before 2 years of age (early transient and early persistent) and a late phenotype with onset after 2 years of age. Both the early transient and early persistent phenotypes had increased risk for food allergy, and the persistent early phenotype also had an increased risk of having asthma. Additionally, having 2 parents with a history of allergies increased strongly the risk of early persistent AD compared with that in children with no parental history of allergy. Finally, the late phenotype was associated with allergic rhinitis but not food allergy or asthma. In summation, the authors have identified phenotypes of AD dependent on the time of onset and progression with unique risks for other allergic symptoms and suggest that children with onset of AD before age 2 years might have higher risk of respiratory and food allergy. Figure Attribution: accessed by Wikimedia Commons, made by user 7mike5000 (Own work) [CC BY-SA 3.0].Children with onset of AD before age 2 years might have higher risk of having respiratory and food allergy Children with onset of AD before age 2 years might have higher risk of having respiratory and food allergy We asked first author Caroline Roduit, MD, MPH, PhD, of the University Children’s Hospital, Zurich, Switzerland, to comment on the article. Dr Roduit writes, “The latent class analysis method confirms that phenotypes of atopic dermatitis could be defined by the time of onset but also the progression of the disease during childhood. Children with an early persistent phenotype of atopic dermatitis are most at risk for developing other allergic diseases and might require special attention for allergy prevention.” Human population-based genetic studies are commonly used for determining the underlying causes of human disease and rely on the accepted dogma that all of a person’s cells have the same genetic coding. Growing evidence has demonstrated that this is not true, especially in neurons. The DNA in each nerve cell has hundreds of mutations of the A-T and C-G nucleotides that constitute the genetic code for the neuron. Thus no 2 neurons are alike. McConnell et al (Science 2017; https://doi.org/10.1126/science.aal1641) have formed a consortium to combine cutting-edge technologies, including single-cell genome-wide RNA sequencing and bioinformatics analyses to explore genetic diversity found within individual cells and potential links to human disease. This line of study raises the intriguing hypothesis that somatic mutations can lead to disease-causing phenotypes in subsets of cells.Somatic mutations can lead to disease-causing phenotypes in subsets of cells Somatic mutations can lead to disease-causing phenotypes in subsets of cells Environmental exposures are classically thought to change gene expression and thus cell function through epigenetic modification. Klosin et al (Science 2017;356:320-3; https://doi.org/10.1126/science.aah6412) provide evidence that these epigenetic modifications can be inherited in subsequent generations with long-term effects. Using the nematode Caenorhabditis elegans as a model organism, they identified that high temperature exposure induced expression of genes that were endogenously repressed. Importantly, genetic changes were still present more than 10 generations later and were conveyed through both ova and sperm to offspring that had no exposure to high temperature. It will be of great interest to see whether these findings can be replicated in higher-order animals, including mammals.Genetic changes were still present more than 10 generations laterNews items were written by medical writer Jared Travers, PhD.Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com. Genetic changes were still present more than 10 generations later News items were written by medical writer Jared Travers, PhD. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com.