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Medical Journal Review

July 2017

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.

Computational analysis of multimorbidity between asthma, eczema and rhinitis
Aguilar D, Pinart M, Koppelman GH, Saeys Y, Nawijn MC et al
PLoS ONE 2017; 12(6): e0179125. DOI: https://doi.org/10.1371/journal.pone.0179125

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The mechanisms explaining allergic multimorbidity (co-existence of asthma, eczema and rhinitis) are largely unknown. In this study, Aguilar and colleagues explored the mechanisms underlying multimorbidity at a molecular level by identifying the proteins and cellular processes that are common to them. To do so, this in silico study based on computational analysis of the topology of the protein interaction network was performed to characterize the molecular mechanisms of multimorbidity of asthma, eczema and rhinitis.

In the first step, proteins associated to either disease were identified using data mining approaches, and their overlap was calculated. Next, a functional interaction network was built, allowing identification of cellular pathways involved in allergic multimorbidity. Finally, a network-based algorithm generated a ranked list of newly predicted multimorbidity-associated proteins. From this they found that asthma, eczema and rhinitis shared a larger number of associated proteins than expected by chance, and their associated proteins demonstrated a significant degree of interconnectedness in the interaction network. There were 15 pathways involved in the multimorbidity of asthma, eczema and rhinitis, including IL4 signaling and GATA3-related pathways.

These results indicate the existence of an allergic multimorbidity cluster between asthma, eczema and rhinitis, and suggest that type 2 signaling pathways represent a relevant multimorbidity mechanism of allergic diseases.

Etiologies of chronic cough in pediatric cohorts, CHEST Guideline and Expert Panel Report
Chang AB, Oppenheimer JJ, Weinberger M, Grant CC, Rubin BK, Irwin RS
CHEST 2017; Article in press (published online June 20) DOI:http://dx.doi.org/10.1016/j.chest.2017.06.006

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In children (aged ≤14-years) there is no published systematic review regarding the etiologies of chronic cough nor the relationship between obstructive sleep apnea (OSA) and chronic cough. Therefore, the CHEST expert cough panel performed systematic reviews based on key questions (KQs) using the PICO format. The KQs were: among children with chronic (>4 weeks) cough: (1) Are the common etiologies different from adults? (2) Are the common etiologies age and/or setting dependent? and; (3) Is obstructive sleep apnea (OSA) an etiology of chronic cough in children? The authors found moderate level evidence from 10 prospective studies that the etiologies of cough in children are different from adults, and are setting dependent. Furthermore, data from 3 studies found that common etiologies of cough in young children were different from older children. However, data relating sleep abnormalities to chronic cough in children were only found in case studies. As there are few data relating OSA with chronic cough in children, the panel suggested that presently these children should be managed in accordance with pediatric sleep guidelines and reinforced the need for further research regarding this potential association.

Influences of environmental bacteria and their metabolites on allergies, asthma and host microbiota
Jatzlauk G, Bartel S, Heine H, Schloter M, Krauss-Etschmann S
Allergy 2017; published online ahead of print (June 10) DOI:10.1111/all.13220

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The prevalence of allergic diseases and asthma has dramatically increased over the last decades, resulting in a high burden for patients and health care systems, yet there is an unmet need regarding the develop of  preventative strategies for these diseases.

Epidemiological studies show that reduced exposure to environmental bacteria in early life (eg, birth by cesarean section, being formula-fed, growing up in an urban environment or with less contact to various persons) is associated with an increased risk to develop allergies and asthma later in life. On the other hand, a reduced risk for asthma is consistently found in children growing up on traditional farms, thereby being exposed to a wide spectrum of microbes. A detailed mechanistic understanding how environmental microbes influence the development of the human microbiome and the immune system is important to enable the development of novel preventative approaches that are based on the early modulation of the host microbiota and immunity. Thus, this review of our current knowledge and experimental evidence for the potential of bacteria and their metabolites to be used for the prevention of asthma and allergic diseases is very timely.

Allergic Rhinitis and its Impact on Asthma (ARIA) Guidelines – 2016 Revision
Bro┼╝ek J, Bousquet J, Agache I, Agarwal A, Bachert C et al
Journal of Allergy and Clinical Immunology 2017; Article in press (published online June 20)

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This is a targeted update of the ARIA guidelines. The ARIA guideline panel identified new clinical questions and selected questions requiring an update. Through this systematic review using GRADE they make the following recommendations:

1. In patients with seasonal allergic rhinitis, they suggest either a combination of an intranasal corticosteroid (INCS) with an oral H1-antihistamine or an intranasal corticosteroid alone (conditional recommendation | low certainty of evidence)

2. In patients with perennial allergic rhinitis, they suggest an INCS alone rather than a combination of an INCS with an oral H1-antihistamine (conditional recommendation | very low certainty of evidence)

3. A combination of INCS with an intranasal antihistamine (INAH) may have an advantage over INCS alone as their mechanisms of action are different. The antihistaminic effect of INAH could be additive to anti-inflammatory effects of INCS.

Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias
Gauthier M, Chakraborty K, Oriss TB, Raundhal M, Das S et al
JCI Insight 2017; 2(13): e94580. DOI:10.1172/jci.insight.94580

Full Text Available

Previous studies have demonstrated that Th1/type 1 inflammation marked by increased IFN-γ levels in the airways can be seen in 50% of patients with severe asthma, despite high dose corticosteroid (CS) treatment. Gauthier and colleagues hypothesized that a downstream target of IFN-γ, CXCL10, which recruits Th1 cells via the cognate receptor CXCR3, is an important contributor to Th1-high asthma and CS unresponsiveness. In this study they demonstrate that high levels of CXCL10 mRNA are closely associated with IFN-γ levels in the BAL cells of 50% of severe asthmatics and as well as in the airways of a severe asthma mouse model, in the context of high-dose CS treatment. The inability of CS to dampen IFN-γ or CXCL10 expression was not because of impaired nuclear translocation of the glucocorticoid receptor (GR) or its transactivational functions. Rather, in the presence of CS and IFN-γ, STAT1 and GR were recruited on critical regulatory elements in the endogenous CXCL10 promoter in monocytes, albeit without any abatement of CXCL10 gene expression.

These findings suggest that the IFN-γ–CXCL10 axis plays a central role in persistent type 1 inflammation that may be facilitated by CS therapy through GR-STAT1 cooperation converging on the CXCL10 promoter. Taken together, this study demonstrates that elevated CXCL10 signature in a subgroup of severe asthmatics correlates with markers of poor disease control.