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Medical Journal Review

January 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 each month from Juan Carlos Ivancevich, MD, WAO Web Editor-in-Chief, and summary author, John J. Oppenheimer, MD, FACAAI, FAAAAI, WAO Reviews Editor.

1. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study

Reddel HK, Busse WW, Pederson S, Tan WC, Chen Y-Z et all. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study. Lancet 2017; 389(10065): 157-166. (doi: http://dx.doi.org/10.1016/S0140-6736(16)31399-X)

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There is a surprising paucity of data regarding the use of inhaled corticosteroids (ICS) in mild asthma when comparing efficacy in intermittent vs. mild persistent disease severity. To better understand this issue, Reddel and colleagues performed a post-hoc analysis of the 3 year Inhaled Steroid Treatment as Regular Therapy (START) study. In this study, over 7000 subjects with mild asthma diagnosed within the previous 2 years with no prior regular use of ICS were randomized to receive either once daily ICS or placebo. The coprimary outcomes of this study were time to first severe asthma-related event [SARE (hospitalization, emergency treatment or death)] and change from baseline in lung function after bronchodilator. In the analysis of this study, subjects were stratified based upon symptom frequency at baseline.

The authors found that when comparing ICS vs. placebo, time to first SARE was longer across symptom frequency subgroups (hazard ratios 0+54 [95% CI 0+34–0+86] for 0–1 symptom days per week, 0+60 [0+39–0+93] for >1 to ≤2 symptom days per week, 0+57 [0+41–0+79] >2 symptom days per week, pinteraction=0+94), and the decline in post-bronchodilator lung function was less at 3 years’ follow-up (pinteraction=0+32). Furthermore,  when comparing ICS vs placebo, severe exacerbations requiring oral or systemic corticosteroids were reduced (rate ratio 0+48 [0+38–0+61] 0–1 symptom days per week, 0+56 [0+44–0+71] >1 to ≤2 symptom days per week, and 0+66 [0+55–0+80] >2 symptom days per week, pinteraction=0+11), pre-bronchodilator lung function was higher, and symptom-free days were more frequent (p<0+0001 for all three subgroups), with no interaction by symptom frequency (pre-bronchodilator pinteraction=0+43; symptom-free days pinteraction =0+53). The authors conclude that these findings challenge long-standing assumptions regarding the risks of mild asthma and suggest that decisions about use of ICS treatment in mild (including intermittent) asthmatics should be made on the basis of population risk reduction rather than on symptom frequency. This is a very interesting article that may be the catalyst for a change in future guideline recommendations.

2. Fish oil-derived fatty acids in pregnancy and wheeze and asthma in offspring.

Bisgaard H, Stockholm J, Chawes BL, Vissing NH, Bjarndottir E et al. Fish oil-derived fatty acids in pregnancy and wheeze and asthma in offspring. New England Journal of Medicine 2016; 375:2530-2539. (doi:10.1056/NEJMoal503734)

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The incidence of asthma and wheezing disorders have more than doubled in westernized countries over the last several decades. Many theories to explain this increase have been put forth. One recent epidemiologic association regarding the increase in lower respiratory disease is the increase use of vegetable oils in cooking and of grain in the feeding of livestock, resulting in an increase intake of n−6 polyunsaturated fatty acids and a decrease in the intake of n−3 polyunsaturated fatty acids, especially the long-chain polyunsaturated fatty acids (LCPUFAs). Furthermore, observational studies have suggested an association between a diet that is deficient in n−3 LCPUFA during pregnancy and an increased risk of asthma and wheezing disorders in offspring,

To better understand this potential connection, Bisgaard and colleagues performed a

double-blind, randomized, controlled trial of n−3 LCPUFA supplementation during the third trimester of pregnancy to assess the effect on the risk of persistent wheeze and asthma in offspring. They assigned 736 pregnant Danish women at 24 weeks of gestation to receive either 2.4 g of n−3 LCPUFA (fish oil) or placebo (olive oil) daily. These offspring were then followed prospectively for the first 3 years of life with comprehensive clinical phenotyping, during which time both the investigators and the participants were unaware of group assignments. The primary end point was persistent wheeze or asthma, with the secondary end points including lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.

A total of 695 children were included in the trial, and 95.5% completed the 3-year, double-blind follow-up period. The risk of persistent wheeze or asthma in the treatment group was 16.9%, versus 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.97; P = 0.035), indicating a relative reduction of 30.7%.

The authors also performed a pre-specified subgroup analysis that indicated the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P = 0.011).

Taken together, these findings show that n−3 LCPUFA supplementation during pregnancy was associated with a significantly diminished burden of wheezing and asthma in children in this Danish birth cohort. The authors recommend that this work should be replicated in other populations to ensure its efficacy beyond this Danish population.

3. ARIA 2016: Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle.

Bousquet J, Hellings PW, Agache I, Bedbrook A, Bachert C et al. ARIA 2016: Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle. Clinical and Translational Allergy 2016; 6:47. (doi:10/1186/s13601-016-0137-4)

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The well-known Allergic Rhinitis and its Impact on Asthma (ARIA) initiative began during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA is now focusing on the use of emerging technologies for individualized and predictive medicine. To do so, they are exploring use of mobile technology to develop and implement care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves.

They have already developed an app (Android and iOS) which is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals.

The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease sufferers.

4. Cross-reactive LTP sensitization in food-dependent exercise-induced urticaria/anaphylaxis: a pilot study of a component-resolved and in vitro depletion approach

(Goncalves Solha Pereira) da Silva DM, Silva Vieira TM, Alves Pereira AM, de Sousa Moreira AMA, Dias Delgado JL. Cross-reactive LTP sensitization in food-dependent exercise-induced urticaria/anaphylaxis: a pilot study of a component-resolved and in vitro depletion approach. Clinical and Translational Allergy 2016; 6:46. (doi:10/1186/s13601-016-0136-5)

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In patients with food-dependent exercise-induced anaphylaxis (FDEIA) challenge tests carry potential risk and unfortunately have a poor negative predictive value. Thus, da Silva and colleagues explored the usefulness of an in vitro immunodepletion assay and allergen microarray test in the identification of IgE-mediated cross-reactive food allergens in patients with suspected FDEIA or food-dependent exercise-induced urticaria and panallergen sensitization. They studied three patients with a history of food dependent exercise induced urticaria/anaphylaxis and food panallergen sensitization, performing a diagnostic work-up with skin prick tests, specific IgE (sIgE) and ImmunoCAP ISAC tests. For the in vitro immunodepletion procedure, patients’ serum was pre-incubated with the suspected native allergen (peach, walnut, or wheat) in solid phase (ImmunoCAP). The eluted serum, containing unbound IgE, was collected and samples were

re-tested using Immunocap ISAC 112 and compared with baseline results.

The authors found that all three patients were sensitized to lipid transfer proteins. The first was sensitized to Pru p 3, Cor a 8, Jug r 3, and Ara h 9; after pre-incubation with peach there was 100% depletion of sIgE to all components. The second patient was sensitized to Pru p 3, Cor a 8, Jug r 3, and Ara h 9; immunodepletion with walnut depleted sIgE to Ara h 9 by 67%, Pru p 3 and Pla a 3 (60%), Art v 3 (75%), Jug r 3 (88%), and Cor a 8 (100%). The third patient was sensitized to Pru p 3, Jug r 3, Ara h 9, and Tri a 14; immunodepletion with wheat depleted Tri a 14 only (100%).

The authors conclude that in vitro immunodepletion appears to be a useful diagnostic tool in food dependent exercise induced urticaria/anaphylaxis with panallergen sensitization, and may be particularly helpful in identifying the culprit allergen and guiding dietary elimination recommendations.

5. Cured meat intake is associated with worsening asthma symptoms

Li Z, Rava M, Bedard A, Dumas O, Garcia-Aymerich J et al. Cured meat intake is associated with worsening asthma symptoms. Thorax 2016; published online before print (20 December). (doi:10.1136/thoraxjnl-2016-208375)

Abstract

Although cured meat has been reported to be a carcinogenic factor and may be associated with risk of COPD, its association with asthma has not been studied.

In this study, Li et al. investigated the association between cured meat intake and worsening asthma symptoms in adults, considering the role of BMI as a potential mediator. To do so, they analyzed data from the French prospective EGEA study, applying a mediation analysis in the counterfactual framework, a marginal structural model (MSM), to estimate the direct effect of baseline cured meat intake (<1, 1–3.9, ≥4 servings/week) on change in asthma symptom score (worsening or not), as well as the indirect effect mediated by BMI.

They found that higher cured meat intake was associated with worsening asthma symptoms over time, through a direct effect and to a lesser extent an effect mediated by BMI. Specifically, of the 971 participants 20% reported worsening asthma symptoms during the mean follow-up time of 7 years. Using the MSM, they reported a positive direct effect of cured meat intake on worsening asthma symptoms (multivariable OR=1.76, 95% CI 1.01 to 3.06 for ≥4 vs <1 serving/week). Furthermore, they found an indirect effect mediated by BMI (OR=1.07; 95% CI 1.01 to 1.14), accounting for 14% of the total effect.

As to the mechanism of why cured meat intake may worsen asthma, the authors share several theories: (1) cured meats are rich in nitrite, which may lead to nitrosative and oxidative stress related lung damage and asthma; (2) the positive relation between cured meat intake and C-reactive protein indicates that cured meat might increase the systemic inflammation, which may have an influence on asthma; (3) the high content of salt and saturated fat in cured meat might also contribute in part to the association with. As noted by the authors, further studies need to be undertaken to improve our understanding regarding potential mechanistic processes.  Until then, be careful in the deli.