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Medical Journal Review

December 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.

Testosterone attenuates group 2 innate lymphoid cell-mediated airway inflammation
Cephus JY, Stier MT, Fuseini H, Yung JA, Toki S et al
Cell Reports 2017; 21(9): 2487-2499.  doi: 10.1016/j.celrep.2017.10.110.

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It has long been known that hormones play a role in inflammatory disease, as exemplified in asthma where the prevalence of disease is 2-fold greater in women compared to men. It is also known that group 2 innate lymphoid cells (ILC2) is increased in patients with asthma, and in this paper, Cephus and colleagues investigate how testosterone attenuates ILC2 function. First they demonstrated that in patients with moderate to severe asthma, women have an increased number of circulating ILC2 compared to men. Furthermore they found that ILC2 from adult female mice have increased IL-2-mediated ILC2 proliferation versus ILC2 from adult male mice, as well as pre-pubescent females and males. Also, 5a-dihydrotestosterone, a hormone downstream of testosterone, was shown to decrease lung ILC2 numbers and IL-5 and IL-13 expression from ILC2. In vivo, testosterone attenuated Alternaria extract-induced IL-5+ and IL-13+ ILC2 numbers and lung eosinophils by intrinsically decreasing lung ILC2 numbers, as well as by decreasing expression of IL-33 and thymic stromal lymphopoietin (TSLP), ILC2-stimulating cytokines. Overall, these findings provide a foundational understanding of sexual dimorphism in ILC2 function and reinforce the importance of further research on this topic.

Virus-triggered exacerbation in allergic asthmatic children: neutrophilic airway inflammation and alteration of virus sensors characterize a subgroup of patients
Deschildre A, Pichavant M, Engelmann I, Langlois C, Drumez E et al.
Respiratory Research 2017; 18(1): 191.  doi: 10.1186/s12931-017-0672-0.

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While viruses are a known trigger of asthma exacerbations, they are also detected outside of an exacerbation.  Prior research has demonstrated an alteration of anti-viral response in asthmatic patients; yet the mechanism(s) responsible for this defect remain unclear. To better understand this issue, Deschildre and colleagues compared in virus-infected and non-infected allergic asthmatic children, aged 6 to 16 years, admitted to hospital for a severe exacerbation, the innate immune response with attention to the expression of pattern recognition receptor (PRR) and their function.

Viruses were identified in 46 out of 72 children (median age 8.9 years) during exacerbation, and among them, in 17 at steady state. IFN-β, IFN-γ and IL-29 levels in sputum and plasma were similar between infected and non-infected patients at both times, as well as the expression of TLR3, RIG-I and MDA5 in blood monocytes and dendritic cells. On the other hand, there were differences in airway inflammation in infected patients, with significantly higher IL-5 concentration and eosinophil counts. Compared to patients only infected at exacerbation, the re-infected children significantly exhibited lower levels of IFN-γ in plasma and sputum at exacerbation associated with modifications in PRR expression and function in blood mononuclear cells. These re-infected patients also presented an airway neutrophilic inflammation at steady state.

Overall this study indicates that asthmatic children have impaired anti-viral response during virus-induced exacerbation which is more pronounced in a subgroup of patients prone to re-infection by virus. This subgroup is characterized by altered PRR function as well as a disparate pattern of airway inflammation.

Predicting the atopic march: Results from the Canadian Healthy Infant Longitudinal Development Study
Tran MM, Lefebvre DL, Dharma C, Dai D, Lou WY et al; Canadian Health Infant Longitudinal Development Study Investigators
Journal of Allergy and Clinical Immunology 2017; pii: S0091-6759(17)31480-X. Published online ahead of print, 1 November.  doi: 10.1016/j.jaci.2017.08.024.


The progression from atopic dermatitis during infancy to asthma and allergic rhinitis in later childhood is termed the “atopic march”. In a Canadian birth cohort Tran et al., examined whether concomitant allergic sensitization enhances subsequent development of these allergic diseases at age 3 years. At age 1, children underwent skin prick testing and were considered sensitized if they produced a wheal 2 mm or larger than that elicited by the negative control to any of 10 inhalant or food allergens and were assessed for atopic dermatitis.  At age 3 years, children were assessed for asthma, allergic rhinitis, food allergy, and atopic dermatitis. From the 2311 children available for study, atopic dermatitis without allergic sensitization was not associated with an increased risk of asthma at age 3 years after adjusting for common confounders (relative risk [RR], 0.46; 95% CI, 0.11-1.93), while atopic dermatitis with allergic sensitization increased the risk of asthma more than 7-fold (RR, 7.04; 95% CI, 4.13-11.99). Atopic dermatitis and allergic sensitization had significant interactions on both the additive (relative excess risk due to interaction, 5.06; 95% CI, 1.33-11.04) and multiplicative (ratio of RRs, 5.80; 95% CI, 1.20-27.83) scales in association with asthma risk. There was also a positive additive interaction between atopic dermatitis and allergic sensitization in their effects on food allergy risk (relative excess risk due to interaction, 15.11; 95% CI, 4.19-35.36). Overall, this data indicates that atopic dermatitis without concomitant allergic sensitization was not associated with an increased risk of asthma, but atopic dermatitis with concomitant allergic sensitization had strong interactive effects on both asthma and food allergy risk at age 3 years.

Expression of TNFα receptors on immunocompetent cells is increased in atopic dermatitis
Lopatnikova JA, Alshevskaya AA, Krugleeva OL, Nepomnyschic VM, Gladkikh VS et al.
International Archives of Allergy and Immunology 2017; 174(3-4): 151-160.  doi: 10.1159/000481135.


Tumor necrosis factor-α (TNFα) has been shown to be actively involved in the inflammatory process of atopic dermatitis (AD), but the role of TNFα membrane receptors (TNFR) and their regulatory function in AD remains unclear. In this study, Lopatnikova and colleagues examined the association of TNFRα expression on immunocompetent cells with disease severity before and after therapy in AD patients. They found that TNFR1 and TNFR2 expression in lymphocyte and monocyte populations of AD patients was higher than in healthy individuals. Serum TNFα concentration, both soluble receptors, the number of TNFR2/T cells, and the percentage of TNFR2+ monocytes were all found to be strongly associated with the AD severity via SCORAD index. Overall, this demonstrated that AD patients had increased TNFR expression on immune cells, and changes in the parameters of TNFRα expression compared to HI were associated with the disease severity index SCORAD.

Effect of an intervention to promote breastfeeding on asthma, lung function, and atopic eczema at age 16 years: Follow-up of the PROBIT randomized trial
Flohr C, Henderson AJ, Kramer MS, Patel R, Thompson J et al.
JAMA Pediatrics 2018; 172(1): e174064. doi: 10.1001/jamapediatrics.2017.4064. 

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In this study, Flohr et al., investigated whether an intervention to promote prolonged and exclusive breastfeeding protects against asthma, atopic eczema, and loss of lung function in adolescence via follow-up analysis of the Promotion of Breastfeeding Intervention Trial (PROBIT). POBIT is a cluster randomized trial in 30 Belarusian maternity hospitals, which recruited 17,046 healthy term infants who were randomized to receive a breastfeeding promotion intervention versus usual care. Spirometry and flexural eczema on standardized skin examination by study pediatricians were the primary outcomes. While secondary outcomes included self-reported asthma diagnosis ever, and wheezing and flexural eczema symptoms in the previous year.

The authors found that the intervention group, 0.3%(21 of 7064) had flexural eczema on skin examination and mean (SD) forced expiratory volume in the first second of expiration/forced vital capacity (FEV1/FVC) ratio z score was −0.10 (1.82), compared with 0.7%(43 of 6493) and 0.35 (1.34), respectively, in the control group. Through modified intention-to-treat analysis, which accounted for clustering by polyclinic, they found a 54%lower risk of flexural eczema on skin examination in the intervention compared with the control group (odds ratio [OR], 0.46; 95%CI, 0.25 to 0.86). Self-reported flexural eczema symptoms in the past year (OR, 0.57; 95%CI, 0.27 to 1.18), asthma (OR, 0.76; 95%CI, 0.47 to 1.23), and wheezing in the past year (OR, 0.66; 95%CI, 0.37 to 1.18) were less frequently reported in the intervention compared with the control group, but 95%CIs were wide and included the null.  There was no significant difference in the FEV1/FVC ratio z score (β −0.15; 95%CI, −0.76 to 0.45). Furthermore, all results were similar with additional adjustment for baseline characteristics, via instrumental variable analysis, and with multiple imputation among all 17,046 randomized participants.