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Medical Journal Review

April 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. Systematic Review of Pathways for the Delivery of Allergy Services

Diwakar L, Cummins C, Lilford R, Roberts T
BMJ Open 2017; 7: e012647 (DOI:10.1136/bmjopen-2016-012647)

Full Text

It is well known that the incidence and prevalence of allergies worldwide has been increasing. Allergy services globally are unable to keep up with this increase in demand. Thus, this systematic review was undertaken to understand the delivery of allergy services worldwide, challenges faced and future directions for service delivery.

Through this analysis, 205 publications were screened and 27 selected for review. Only 3 were prospective studies, and none included a control group. The authors found no eligible publications from North America, Africa, Australia and most parts of Asia, with the majority related to allergy services in the United Kingdom. Overall, they found that allergy services globally appear not to have kept pace with increasing demand. They further found that primary care practitioners are not being adequately trained in allergy and that there is a paucity of appropriately trained specialists, especially in pediatric allergy. There appear to be considerable barriers to service improvement, including lack of political will and reluctance to allocate funds from local budgets. As a result, the authors stress the need for well-planned, prospective studies in this area.

2. Inhaled Corticosteroids and Respiratory Infections in Children with Asthma: A Meta-analysis

Cazeoro C, Silva C, Mayer S, Mariany V, Wainwright CE, Zhang L. Pediatrics 2017; 139(3): e20163271 (DOI:10.1542/peds.2016-3271)


Inhaled corticosteroids (ICS) are known to be associated with an increased risk of pneumonia in patients with chronic obstructive pulmonary disease.

To determine if there was also an association between ICS use and risk of pneumonia and other respiratory infections in children with asthma, Cazeiro and colleagues performed a meta-analysis of randomized trials that compared ICS with placebo for at least 4 weeks duration in children with asthma. Using risk difference as effect measure, the meta-analysis including all 31 trials revealed no significant difference in the risk of pneumonia between the ICS and placebo groups (risk difference: –0.1%; 95% CI: –0.3% to 0.2%). Furthermore no significant association was found between ICS and risk of pharyngitis (RR: 1.01;95% CI: 0.87 to 1.18), otitis media (RR: 1.07; 95% CI: 0.83 to 1.37), and sinusitis (RR: 0.89; 95% CI: 0.76 to 1.05).

The authors stress that these data add to the already considerable body of evidence suggesting a good safety profile of ICS in children with asthma.

3. Addition of Anti-leukotriene Agents to Inhaled Corticosteroids for Adults and Adolescents with Persistent Asthma

Chauhan BF, Jeyaraman MM, Singh MA, Lys J, Abou-Setta AM et al. Cochrane Database of Systematic Reviews 2017, Issue 3, Article No. CD010347 (DOI:10.1002/14651858.CD010347.pub2)


A daily low dose of inhaled corticosteroids (ICS) is the recommended initial reliever treatment for adults and teenagers with asthma. In those patients with inadequate asthma control despite use of ICS, treatment options include adding an anti-leukotriene (LTRA), a long-acting 2-agonist, or by increasing the dose of ICS. This Cochrane analysis asks the question: “Is adding an anti-leukotriene to ICS better than using an ICS alone for adults and adolescents 12 years of age and older with persistent asthma?”

Using standard Cochrane procedures the authors found 37 studies (representing 6128 adults and adolescents) suffering from mild to moderate asthma. Through this they found that in adolescents and adults with asthma not controlled with daily low-dose ICS, adding an anti-leukotriene agent to ICS reduced by half the number of patients with asthma exacerbations requiring an oral corticosteroid. The combination also improved lung function and asthma control. In general, the addition of anti-leukotrienes to ICS therapy was not associated with increased side effects, if the dose of ICS was maintained. The overall confidence in the evidence was moderate or low for most outcomes.

4. A Systematic Review and Meta-analysis of Complementary and Alternative Medicine in Asthma

Kohn CM and Paudyal P. European Respiratory Review 2017; 26: 160092 (DOI:10.1183/16000617.0092-2016)

Full Text

As we all know, conventional medications in asthma are not curative and patients have significant concerns regarding their side-effects. It is thus not surprising that many of our patients turn to complementary and alternative medicine (CAM) for a more holistic approach for the care of their asthma. In this study, Kohn and Paudyal systematically reviewed the available evidence regarding the effectiveness of CAM in the management of asthma in adults.

Through use of the Cochrane protocol, 23 eligible trials were identified covering 19 different CAMs. They found that there was limited evidence regarding the effectiveness of CAM in adult asthma as most CAMs were only assessed in a single trial. CAMs with multiple trials provided null or inconsistent results. Many of the trials were rated as having high risk of bias.

As a result, the authors conclude that existing evidence is insufficient to recommend any of the oral and topical CAMs in the management of asthma in adults.

5. Natural Killer Cell-mediated Inflammation Resolution Is Disabled in Severe Asthma

Duvall MG, Barnig C, Cernadas M, Ricklefs I, Nandini K et al. Science Immunology 2017; 2(9): eaam5446 (DOI: 10.1126/sciimunol.aam5446)


Severe asthma is typically characterized by chronic airway inflammation that is refractory to corticosteroids and associated with excess morbidity. Patients were recruited into the National Heart, Lung, and Blood Institute–sponsored Severe Asthma Research Program and comprehensively phenotyped by bronchoscopy and analysis of bronchoalveolar lavage (BAL) cells.

The authors found that compared with healthy individuals (n = 21), patients with asthma (n = 53) had fewer BAL natural killer (NK) cells. Patients with severe asthma (n = 29) had a marked increase in the ratios of CD4+ T cells to NK cells and neutrophils to NK cells. BAL NK cells in severe asthma were skewed toward the cytotoxic CD56dim subset, with significant increase of BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56dim NK cells and CCR6−CCR4− T helper 1–enriched CD4+ T cells correlated inversely with lung function [forced expiratory volume in 1 s (FEV1) % predicted] in asthma. Relative to cells from healthy controls, peripheral blood NK cells from asthmatic patients had impaired killing of K562 myeloid target cells despite releasing more cytotoxic mediators. Ex vivo exposure to dexamethasone markedly decreased blood NK cell lysis of target cells and cytotoxic mediator release. NK cells expressed airway lipoxin A4/formyl peptide receptor 2 receptors, and in contrast to dexamethasone, lipoxin A4–exposed NK cells had preserved functional responses.

Overall, these findings indicate that the immunology of the severe asthma airway is characterized by decreased NK cell cytotoxicity with increased numbers of target leukocytes, which is exacerbated by corticosteroids that further disable NK cell function. The authors suggest that it is through these failed resolution mechanisms that persistent airway inflammation occurs in severe asthma.