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Medical Journal Review

May 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.

1. Obstructive sleep apnoea accelerates FEV1 decline in asthmatic patients
Wang TY, Lo YL, Lin SM, Huang CD, Chung FT et al.
BMC Pulmonary Medicine 2017; 17:55 (DOI: 10.1186/s12890-017-0398-2)

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In this study, the authors examined the impact of Obstructive Sleep Apnea (OSA) on lung function. To do so, they performed a retrospective analysis of 77 patients with asthma and OSA who had undergone regular follow-up over a 5-year period. They found that the decline in FEV1 among asthma patients with severe OSA (AHI > 30/h) was 72.4 ± 61.7 ml/year (N = 34), as compared to 41.9 ± 45.3 ml/year (N = 33, P = 0.020) in those with mild to moderate OSA (5 < AHI ≤ 30) and 24.3 ± 27.5 ml/year (N = 10, P = 0.016) in those without OSA (AHI ≤ 5). For those patients with severe OSA, the decline in FEV1 significantly decreased after continuous positive airway pressure (CPAP) treatment. With use of multivariate stepwise linear regression analysis, only AHI was an independent risk factor for the decline of FEV1.

The authors conclude that OSA is associated with decline in FEV1 asthmatics with OSA and that CPAP treatment may alleviate this decline of FEV1.

2. Vitamin D levels and susceptibility to asthma, elevated immunoglobulin E levels, and atopic dermatitis: A Mendelian randomization study

Manousaki D, Paternoster L, Standl M, Moffatt MF, Farrall M et al.
PLOS Medicine 2017; 14(5): e1002294 (DOI:10.1371/journal.pmed.1002294)

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Prior epidemiologic studies have demonstrated an association between low circulating vitamin D levels and the risk of asthma, atopic dermatitis, and elevated total immunoglobulin E (IgE). In this study by Manousaki and colleagues, the authors aimed to test whether genetically lowered vitamin D levels were associated with risk of asthma, atopic dermatitis, or elevated serum IgE levels, using Mendelian randomization (MR) methodology in attempt to control bias from confounding and reverse causation. The authors mined data from the UK Biobank resource and from the SUNLIGHT, GABRIEL and EAGLE eczema consortia. Using four single-nucleotide polymorphisms (SNPs) strongly associated with 25-hydroxyvitamin D (25OHD) levels in 33,996 individuals, they utilized MR to estimate the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses. None of the four 25OHD-lowering alleles were associated with asthma, atopic dermatitis, or elevated IgE levels (p 0.2). The MR odds ratio per standard deviation decrease in log-transformed 25OHD was 1.03 (95% confidence interval [CI] 0.90±1.19, p = 0.63) for asthma, 0.95 (95% CI 0.69±1.31, p = 0.76) for childhood-onset asthma, and 1.12 (95% CI 0.92±1.37, p = 0.27) for atopic dermatitis, and the effect size on log-transformed IgE levels was −0.40 (95% CI −1.65 to 0.85, p = 0.54). The authors note that the main limitations of this study were that the findings do not exclude an association between the studied outcomes and 1,25-dihydoxyvitamin D, the active form of vitamin D, the study was underpowered to detect effects smaller than an OR of 1.33 for childhood asthma, and the analyses were restricted to white populations of European ancestry.

Overall, they found no evidence that genetically determined reduction in 25OHD levels conferred an increased risk of asthma, atopic dermatitis, or elevated total serum IgE. The authors opine that this suggests that efforts to increase vitamin D are unlikely to reduce risks of atopic disease.

3. Androgen signaling negatively controls group 2 innate lymphoid cells

Laffont S, Blanquart E, Savignac M, Cénac C, Laverny G et al.
Journal of Experimental Medicine 2017; Epub ahead of print, May 8, 2017 (DOI: 10.1084/jem.20161807)


Although asthma is more common in young boys compared to girls, it is well known that in adults, women are more commonly affected than men. The mechanism(s) underlying this sex bias are unknown.

In this paper Laffont and colleagues, using a mouse model, demonstrate that male mice have reduced numbers of group 2 innate lymphoid cells progenitors (ILC2Ps) as well as mature ILC2s in peripheral tissues compared with females. ILCPs are rapid and potent producers of the type 2 cytokines, representing an early source of mediators responsible for the initiation of Th2-dependent immune responses. Thus, it is not surprising that male mice exhibit reduced susceptibility to allergic airway inflammation in response to environmental allergens and less severe IL-33–driven lung inflammation, correlating with an impaired expansion of lung ILC2s. They further demonstrated that orchiectomy, but not ovariectomy, abolished the sex differences in ILC2 development and restored IL-33–mediated lung inflammation. ILC2Ps express the androgen receptor (AR), and AR signaling inhibits their differentiation into mature ILC2s. Finally, they demonstrated that hematopoietic AR expression limits IL-33–driven lung inflammation through a cell-intrinsic inhibition of ILC2 expansion. Thus, androgens play a crucial protective role in type 2 airway inflammation by negatively regulating ILC2 homeostasis, thereby limiting their capacity to expand locally in response to IL-33. This set of experiments provides a very interesting potential explanation for asthma prevalence difference by sex. Further research is sure to follow.

4. Effectiveness and success factors of educational inhaler technique interventions in asthma & COPD patients: a systematic review

Klijn SL, Hiligsmann M, Evers SMAA, Román-Rodríguez M, van der Molen T, van Boven JFM
NPJ  Primary Care Respiratory Medicine 2017; 27(1): 24 (DOI: 10.1038/s41533-017-0022-1)

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As pointed out by the authors, presently when caring for asthmatic patients we have multiple device choices, each of which requires different technique for optimal delivery. This study by Klijn systematically reviewed educational inhalation technique interventions, to assess their overall effectiveness and identify main drivers of success. Although 37 of the 39 of the studies included (95%) statistically significant improvement of inhaler technique, the average follow-up time was relatively short (5 months), 28% lacked clinical relevant endpoints and all lacked cost-effectiveness estimates. Poor initial technique, number of inhalation procedure steps, setting (outpatient clinics performing best), and time elapsed since intervention (all, p < 0.05), were shown to have an impact on effectiveness of the intervention, which explained up to 91% of the variation in effectiveness. Interestingly, other factors such as disease (asthma vs. chronic obstructive pulmonary disease), education group size (individual vs. group training) and inhaler type (dry powder inhalers vs. pressurized metered dose inhalers) did not play a significant role.

In conclusion, this systematic review demonstrated that educational interventions do improve inhaler technique in the short-term, but further long-term studies are needed.

5. Making the most of in vitro tests to diagnose food allergy

Santos AF, Brough HA.
The Journal of Allergy and Clinical Immunology: In Practice 2017; 5(2): 237-248 (DOI:10.1016/j.jaip.2016.12.003)

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This is a wonderful review of the available clinical and experimental diagnostic tools in food allergy. It is well known that in vitro allergy tests are useful in diagnosing IgE-mediated FA and are excellent aids in the decision of whether an oral food challenge (OFC) is necessary to reach an accurate diagnosis.

Although there are validated cutoffs, they are only reliable when applied to a similar patient population to the one where they were studies, as patient-specific factors, such as age and associated atopic dermatitis can modulate the probability of clinical allergy of a given sIgE result. IgE to allergen components may provide more precise information about IgE specificity and basophil activation test (BAT) can assess the function of IgE in its ability to mediate allergen-induced effector cell activation. The authors reinforce that further research is needed to improve our understanding about how the information gained from these tests can be combined for optimal diagnostic accuracy with the goal of reducing the need to perform OFCs.