Year in review 2011: Asthma, chronic obstructive pulmonary disease and airway biology

A recent estimate by the World Health Organization estimated that over half a billion people across the globe suffer from asthma and chronic obstructive pulmonary disease alone and the incidence is increasing. Last year, 2010, was the year of the lung, and one of its primary objectives was to increase awareness and promote increased research funding for respiratory diseases. This has had some tangible positive effects. This year the European Respiratory Society's research framework highlighted the disparity between funding for Respiratory Research in Europe versus the impact to the disease. The European Respiratory Society also provided a series of recommendations to tackle this disparity, which are germane to us all. A major challenge is and has been the lack of any cures for these diseases and as such greater emphasis needs to be directed towards developing ways to restore pulmonary structure and function. However, such high impact discoveries must first be disseminated and subjected to peer review before being translated into practice or policy. In this review, we describe some important advances in asthma and chronic obstructive pulmonary disease clinical and basic research and highlight specific contributions to these areas published in Respirology. Ian A. Yang Despite stability in prevalence rates and reduction in hospital admissions for asthma in some countries,1 asthma remains an important cause of morbidity. A study of adolescents and young adults in Australia found that asthma was a major cause of physical disability in this age group.2 In 2011, there were significant developments in monitoring and treatment of asthma, leading towards future paradigms of personalized therapy for people with asthma. Asthma control is the extent to which the various manifestations of asthma have been reduced or removed by treatment, in terms of clinical asthma control (e.g. symptoms, quality of life) and risk of future adverse events (e.g. exacerbations, decline in lung function, medication side effects).3 In a study published in Respirology, Lai and colleagues studied measures of asthma control in a cross-sectional study of 4805 subjects.4 Asthma control, based on the Global Initiative for Asthma symptom levels and the Asthma Control Test, correlated with health-care utilization for asthma exacerbations, with nocturnal awakening showing the strongest association with hospitalization. Thus, identifying suboptimal asthma control is a key principle of asthma management, in order to prevent exacerbations. Spirometry is an essential tool in the diagnosis and monitoring of asthma; however, there is still relatively little use of spirometry in primary care. In Respirology, Oei and colleagues studied spirometry for monitoring asthma control, as measured by the Asthma Control Test, in 195 patients from 31 general practices over 12 months.5 Spirometry with follow-up medical review improved asthma control better than spirometry only or usual care without spirometry. Although an unblinded study, these results suggest that spirometry and assessment of symptoms should both be used in primary care to adjust asthma medications and achieve asthma control. Multiple trigger factors are implicated in asthma exacerbations. As well as allergens and viral infections, air pollution is a significant environmental trigger for people with asthma, as shown in two reviews in Respirology. Chung et al. provide evidence for outdoor air pollution as a critical susceptibility and exacerbation factor for chronic respiratory disease in Asia.6 Bushfire smoke is a frequent contributor to particulate matter with a median aerodynamic diameter <10 µm (PM10). A substantial number of studies have demonstrated an increase in asthma or respiratory-related hospital presentations and admissions, although the effects are not consistent in all studies.7 Exposure to bushfire smoke has clinical implications for people with asthma, who should have an action plan for what to do in the event of serious exposure. Lawson and colleagues, in another study in Respirology, showed that peak flow and wheeze in children worsened with increasing endotoxin exposure in the household environment, and that environmental tobacco smoke exposure further increased this effect, particularly in girls.8 Understanding the plethora of asthma trigger factors will help individualize trigger avoidance in people with asthma. Treatment based on biological and clinical stratification9 and asthma endotypes10 shows promise to develop a more personalized approach to asthma management. Assessing phenotypes of airway inflammation can usefully tailor treatment.11 A randomized controlled trial of 220 non-smoking, pregnant women with asthma found that titrating the dose of inhaled corticosteroids (ICS) based on fraction of exhaled nitric oxide (FeNO), a non-invasive marker of airway eosinophilic inflammation, improved quality of life and reduced asthma exacerbations during pregnancy.12 FeNO may also help to better define small airways obstruction.13 Nevertheless, FeNO alone may be less useful in other groups such as smokers with asthma, who have less eosinophilia and more neutrophilia in their airways. In Respirology, Hillas and coworkers used both FeNO and exhaled breath condensate (EBC) pH as non-invasive biomarkers, and correlated these to inflammatory profiles of induced sputum.14 In smokers with asthma, FeNO increased with sputum eosinophils but did not accurately predict sputum neutrophils, whereas EBC pH reduced with increasing sputum neutrophils. Using both methods was more useful than either alone, to define airway inflammation in smokers with asthma. Other novel measurements may be useful as biomarkers for asthma control. In Respirology, Jayaram and colleagues measured concentrations of zinc (total and labile) in induced sputum from 163 subjects (114 with asthma).15 People with asthma had lower median airway concentrations of zinc, which correlated with worse asthma symptoms and lower lung function. Zinc has anti-inflammatory and anti-oxidant properties, making it a potentially interesting biomarker, pending further validation. A wide range of asthma comorbidities and differential diagnoses should be assessed in people with difficult-to-control asthma.11 In a Clinical Note in Respirology, Lau and co-authors reported a Churg-Strauss-like syndrome in a female with asthma, severe eosinophilia, positive anti-neutrophil cytoplasmic antibody serology but no vasculitis on lung biopsy.16 High dose steroids were required; however, omalizumab was not beneficial as a steroid-sparing agent, and mycophenolate was needed as immunosuppression to achieve symptom control in this severe eosinophilic syndrome. A timely invited review in Respirology by Rahman and colleagues provides practical advice about setting up a respiratory clinical trials unit, to initiate and undertake studies of treatment.17 On the other hand, pragmatic real-world trials raise different issues in interpretation of results, compared with randomized controlled trials, as shown in trials of leukotriene receptor antagonists.18 Bronchodilator reversibility remains in important phenotype to diagnose asthma, which then facilitates initiation of therapy. In Respirology, Mahut and colleagues demonstrated that specific airway resistance, used to diagnose bronchodilator responsiveness in children, does not completely correlate with forced expiratory volume in 1 s measurements; hence, both measurements may be useful.19 Hall and coworkers showed that respiratory function laboratories vary significantly in their use of spacer devices to deliver bronchodilators for testing.20 Bronchodilators and inhaled steroids are the mainstay of pharmacological treatment for all severities of asthma. However, several issues remain to be resolved with both classes of inhalers. Bronchoprotection, in the form of bronchodilators, in addition to anti-inflammatory treatments, is likely to be important for the long-term treatment of asthma, as bronchoconstriction itself leads to airway wall remodelling in asthma.21 However, the safety of long-acting β-agonists remains an unresolved issue, and will be tested in large prospective trials planned by the Food and Drug Administration.22 Non-adherence in ICS was identified as a major precipitant in 24% of asthma exacerbations, in a prospective cohort using electronic recording of prescription filling.23 Interestingly, a pharmacogenetic study found that response to ICS was associated with a genetic variation in the glucocorticoid-induced transcript 1 gene (GLCCI1), a marker of glucocorticoid-induced apoptosis,24 although this only explained 6.6% of the variability in response. Few studies have compared two different ICS with the use of a single ICS. In a 2-month open pilot study of 36 patients published in Respirology, Kurashima et al. found that mometasone 100 µg bd added to salmeterol/fluticasone propionate 50/250 µg was superior to salmeterol/fluticasone propionate 50/500 µg bd alone, in patients with asthma that was uncontrolled on the lower salmeterol/fluticasone propionate dose.25 Combined use of ICS for small airways (e.g. mometasone) and large airways (e.g. fluticasone) could be a novel therapeutic option for severe asthma; however, further studies are required. Biological therapies for severe asthma remain an important area of discovery, and require further translation from clinical trials to clinical practice. Omalizumab, a recombinant humanized monoclonal anti-immunoglobulin E, reduced exacerbations and improved quality of life in adults with uncontrolled asthma on ICS/long-acting β-agonist.26 Similarly, in children and young adults, omalizumab reduced asthma symptoms and exacerbations, particularly in allergic patients sensitized to cockroach allergen and house dust mite.27 Lebrikizumab, a monoclonal antibody to interleukin-13 (IL-13), a pro-inflammatory Th2 cytokine, was tested in a 24-week randomized controlled trial of 219 adults with uncontrolled asthma despite ICS.28 Lebrikizumab improved lung function, particularly in those patients with high serum periostin, a matricellular protein secreted by bronchial epithelial cells after induction by IL-13. This prediction of treatment response to anti-IL13 biological therapy raises hope for the practical development of biomarkers for individualized treatment of severe asthma. Finally, in a comprehensive invited review for Respirology, McDonald and colleagues describe how to set up a severe asthma service.11 They outline a detailed, systematic, evidence-based approach to confirming the diagnosis of asthma, management of comorbidities and triggers, ensuring optimal adherence and self-management, and trialling add-on therapies for severe asthma. Importantly, they provide practical advice about resources required and implementation of the multidisciplinary approach to managing severe asthma. This timely advice provides practical solutions to helping people with difficult-to-treat asthma, and puts us on the path to individualizing therapy. Fanny W.S. Ko and T.K. 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