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

Abstract

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. Lim COPD is a disease with a high burden to the society. Jamrozik et al. in their review of the respiratory health issues in the Asia–Pacific region has pointed out COPD as one of the important burdens among other respiratory diseases such as influenza, tuberculosis, pneumonia, lung cancer and asthma.29 Smoking is the most important environmental risk factor for the development of COPD. As about one-third of the world's tobacco is produced and consumed in China, tobacco control is of particular importance in this country. The emphasis of central leadership and multi-sector cooperation are crucially important aspects of tobacco control and its success can bring health benefits.30 The high burden of COPD in Asia can be illustrated by a study from Korea with spirometry performed over 4000 subjects aged ≥40 years.31 It was found that airflow obstruction was 13.4% in this group of subjects. Though over 90% of the COPD patients had mild-to-moderate severity without apparent symptoms, COPD was under-diagnosed and undertreated as only 2.4% and 2.1% had a physician diagnosis and were given treatment for COPD, respectively. More efforts are certainly needed in the Asia–Pacific region and worldwide to improve the public awareness of COPD. Another study in Philippines noted the prevalence of COPD in the rural setting was higher that that determined previously for an urban area.32 Apart from smoking, exposure to wood fuels and high prevalence of tuberculosis may contribute to a high prevalence of COPD in this area. Why certain people develop COPD and others do not when exposed to same environmental risk factors is unknown. Both the genetics and epigenetics factors play an important role in this regard. Epigenetic modification may contribute to the regulation of mucus production, oxidative stress response and steroid sensitivity in the airway.33 Drug targeting epigenetics strategies would potentially be useful in the treatment of COPD.33 AECOPD is defined by Global Initiative for Chronic Obstructive Lung Disease guidelines as an event in the natural course of the disease characterized by a change in the patient's baseline dyspnoea, cough and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medications in a patient with underlying COPD.34 An interesting article from MacDonald et al. has hypothesized to phenotype AECOPD by aetiology.35 The proposed phenotypes are as follows: airway viral infection; bacterial infection; co-infection; depression/anxiety; embolism (pulmonary); failure (cardiac or lung integrity); general environment; and non-specific cause identified. It would be interesting to see if future research finds this classification useful for management of patients with AECOPD. EBC collection and the assessment of its contents have been investigated for its potential as a non-invasive way to monitor airway inflammation.36,37 A previous study noted inflammatory markers in EBC changes during the course of recovery of AECOPD.38 Zakharkina et al. conducted a pilot experiment with an aim to identify the infective aetiologies from EBC and compared the microbiological yield obtained from sputum. It was found that using PCR assays, bacterial nucleic acids can be identified in both the EBC and sputum of patients with AECOPD. However, the results obtained from EBC and sputum did not correlate well.39 Sputum microbiological assessment at the moment is a well-acceptable method for investigation of the infection aetiologies of AECOPD, and Hui et al., in a prospective multi-country study, found that among the 447 patients with AECOPD, the most frequent organisms isolated from sputum were Klebsiella pneumoniae and associated species, followed by Haemophilus influenzae, Pseudomonas aeruginosa, Streptococcus pneumoniae, Acinetobacter baumannii and Moraxella catarrhalis.40 This study also provided data on the antibiotic susceptibility data of the microorganisms identified and this can potentially guide the choice of antibiotics. Why there is increased susceptibility of COPD patients to various bacterial infections is uncertain. Zhang et al. found that cigarette smoke modulates prostaglandin E2 and host defence against Moraxella catarrhalis infection in human airway epithelial cells.41 Further studies are needed to explore the potential of EBC collection in the identification of infective aetiologies for AECOPD and also to assess the mechanisms underlying decrease host defence to microbiological invasion in the COPD airway. Apart from infective aetiologies, outdoor air pollution also contributes to AECOPD. This has been discussed in the review article by Chung et al. who have addressed the impact of outdoor air pollution on lung diseases.6 As a result of global climate change, bushfires are expected to increase in the future. During bushfire smoke episodes, particulate matter concentrations are usually much higher than urban background concentrations, and these outdoor pollution episodes may have harmful effect on COPD patients in causing exacerbations.7 Some hospitalizations for acute exacerbation have resulted in mortality. In 2011, two studies from New Zealand found that the CURB-65 score, a severity score for community-acquired pneumonia, which comprises a simple 6-point score based on confusion, blood urea, respiratory rate, blood pressure and age, is useful for prediction of mortality for patients admitted for AECOPD.42,43 Chang et al. in their prospective study found that CURB-65 could be used to stratify patients with AECOPD, without pneumonic changes on chest radiography, into different management groups and the score predicted 30 days, but not 1 year mortality.42 Edwards et al. also found that the CURB-65 score could predict in-hospital and 30-day mortality; however, this study was limited by its retrospective nature and whether patients had concomitant pneumonia was unknown.43 It appears that the CURB-65 score shows similar characteristics for predicting short-term mortality in AECOPD as it does in pneumonia. A recent large prospective study from UK with over 900 subjects with AECOPD (about two-thirds had no pneumonia and one-third had pneumonic changes on chest radiograph) requiring hospitalization found that mortality rates at 30 days for each CURB-65 score were higher in AECOPD with pneumonia than AECOPD without concomitant pneumonia.44 However, it appeared that extended Medical Research Council Dyspnoea Scale was a significantly better discriminator than either CURB-65 or the traditional Medical Research Council Dyspnoea Scale for predicting in-hospital mortality, and was a stronger prognostic tool than CURB-65 in the subgroup of patients with pneumonic AECOPD.44 More studies are certainly needed to look for the factors that would best predict the mortality and readmission of patients admitted with AECOPD. Patients with severe COPD exacerbations and advancing disease are often depressed and anxious.45 These psychiatric problems in such patients predict the risk of further hospitalizations and mortality.45,46 At the other end of the clinical spectrum of COPD, de Miguel Díez et al. in a large population-based study reported a greater prevalence of anxiety and depression in patients with chronic bronchitis.47 Productive cough may be a manifestation of mild COPD in the community. Thus, detection of these psychiatric problems in mild disease may be an opportunity for early diagnosis and intervention with potential long-term benefits. Heart disease is another common and important co-morbidity in COPD, which has been associated with hospital readmissions and deaths.48 Van Gestel et al. documented autonomic dysfunction using Holter-electrocardiography monitoring in patients with COPD.49 In a cross sectional study they described a pattern of reduced parasympathetic and increased sympathetic tone manifested as increased resting heart rate and reduced heart rate variations that was linked to poorer quality of life. Further studies are indicated to investigate possible connections between these findings and psychiatric problems in advanced COPD. Cvejic et al. in a careful contrast study of stable patients with moderate stage COPD, detected sub-clinical laryngeal dysfunction in up to one third of cases.50 This was attributed to discoordination of the respiratory cycle with deglutition in patients with tachypnoea. Its clinical implications are unclear but Singh, in an editorial review, suggests that this may partly account for COPD exacerbations with no obvious triggers.51 The molecular profiling of exhaled breath in medical diagnosis is still in its infancy. However, Hattesohl et al. was able to distinguish COPD from severe untreated alpha-1 antitrypsin deficiency with a high degree of accuracy by using two different methods to examine specimens from exhaled breaths.52 Further studies are warranted to evaluate the practical utility of this novel approach in an unselected population versus more conventional methods in the early diagnosis of alpha-1 antitrypsin deficiency.53 Long-acting bronchodilators are the corner stone of maintenance pharmacological treatment in COPD. Fukuchi et al. in a subgroup analysis of the UPLIFT trial data from an Asian perspective, found that despite regional variations in patient characteristics and the trends in forced expiratory volume in 1 s, overall, for subjects receiving tiotropium, improvements were observed in lung function, exacerbation frequency, health-related quality of life and mortality.54 There is emerging evidence that a combination of different classes of long acting bronchodilators provide better results than monotherapy in COPD. Wang et al. in a meta-analysis of eligible randomized controlled trials showed that in patients with stable COPD, tiotropium plus formoterol improved lung function and symptom scores compared with tiotropium alone, and there was a trend towards a decrease in adverse events in patients treated with the combination therapy.55 Hoshino et al. used high resolution CT to investigate the mechanisms that underlie the beneficial effects of adding ICS plus long-acting β-agonist to tiotropium on airway function.56 They showed that ‘triple therapy’ was superior to tiotropium alone in improving forced expiratory volume in 1 s. The better airway function was associated with a reduction in airway wall thickness and also less airway collapse. This is consistent with positive effects in preventing airway remodelling. Lee et al. in the first Asian trial of roflumilast, an oral, selective phosphodiesterase 4 inhibitor, reported superior pulmonary function compared with placebo.57 However, just as in studies carried out elsewhere, roflumilast caused gastrointestinal side effects and or weight loss in about 20% of patients versus 2% with placebo. Consideration of adverse effects will have an important impact on the utility of this class of drugs in elderly patients with COPD. There is some evidence that early pulmonary rehabilitation during the recovery phase of COPD exacerbations is beneficial. A Cochrane meta-analysis concludedn that pulmonary rehabilitation is a highly effective and safe intervention to reduce hospital admissions and mortality and to improve health-related quality of life in COPD patients who have recently suffered disease exacerbations.58 However, Ko et al. in a randomized trial of an early but short course pulmonary rehabilitation following COPD exacerbations, was unable to demonstrate reduction in health-care utilization at 1 year despite better health status of the subjects at 6 months.59 As recovery from COPD exacerbations may take many weeks, for sustained benefits, exercise rehabilitations programs probably also need to be of longer duration. In an editorial review, Bourbeau suggested that to be more effective, we need to go beyond exercise training and also equip patients with practical coping skills in self-management and action plans during the recovery phase of illness.60 Lan et al. answered an important question regarding the impact of rehabilitation in underweight patients with COPD.61 They showed, in a controlled study of carefully matched patients, that exercise training resulted in significant weight gains, and improvements in exercise capacity and health-related quality of life even in underweight patients with COPD. This is consistent with the positive impact of exercise on muscle bulk and fibre quality in patients with a wide spectrum of COPD severity and suggests, furthermore, that the lower the body weight the better may be the response to rehabilitation.62,63 The value of non-invasive ventilation in patients with severe COPD who are difficult to wean from mechanical ventilators was demonstrated in a large descriptive study by Heinemann et al.64 A gradual switch over to non-invasive ventilation enabled thee majority of patients to be successfully liberated from ventilators. Even more notable was the finding that patients who received prolonged non-invasive ventilation at home experienced 30% greater absolute survival rates at 1 year than those who did not. The possibility that non-invasive ventilation may improve patient outcomes beyond the acute phase of severe hypercapnic COPD exacerbations is an important question currently undergoing investigation in several randomized trials. One of the most robust methods in the discovery of new knowledge in respiratory medicine is through the execution of formal clinical trials. In this regard Rahman and colleagues described the key elements to be assembled and reviewed the processes involved in the establishment of a respiratory clinical trials unit.17 This will be especially helpful to clinicians who are embarking on investigator-initiated trials in respiratory diseases. Darryl A. Knight One of the highlights in Respirology this year was a review series titled ‘Cutting Edge technologies for translational respiratory research’. Leaders were asked to provide the current state-of-the-art and identify potential future trends in their respective fields of expertise. The series included a provocative article on (stem) cell therapies for lung disease by Moodley and colleagues.65 Based primarily on rodent models, the number of endogenous or resident cells with stem/progenitor cell activity is increasing and studies investigating the impact of underlying disease on stem/progenitor function are appearing in the literature.66 In this regard, a variety of cells including mesenchymal stem cells, induced pluripotent stem cells, placental stem cells and embryonic stem cells have been examined for both their immunomodulatory effects as well as their potential for differentiation into specific lung cells. However, in the midst of this excitement, the authors caution us that large hurdles remain, including bioethics, route and timing of stem cell delivery and specific indications that would require stem cell-based therapy. Akhabir and Sandford reviewed and updated the role of genome-wide association study in discovery of novel asthma susceptibility genes.67 The most robust and reproducible finding to date is the susceptibility locus on chromosome 17q21 harbouring ORMDL3 and GSDMB among others.68 Interestingly, the authors suggest that given the strength of 17q21 as a susceptibility locus and the absence of other regions that have shown similar robustness, the era of genome-wide association study for asthma may be drawing to a close. Al-Heialy and colleagues reviewed the current state of knowledge regarding the increasingly contentious issue of animal models of allergic airway disease and airway remodelling.69 The authors highlight the usefulness and shortcomings of current rodent models in understanding the underlying mechanisms of airway remodelling. However, several prudent messages regarding these models were also delivered. Translating the mechanisms from the traditional models of allergen sensitization and challenge to less common forms of the disease such as irritant-induced asthma is problematic and as such better models of this type of asthma need to be developed. Moreover, extrapolation of the findings with any model to the human condition should be viewed with great care. LeClere and coworkers then took animal models to the extreme, reviewing the equine model of human asthma, heaves.70 Despite the obvious limitation(s) of the model, the authors stressed the many unique features of the heavey horse model that make it more clinically relevant over other more traditional (and smaller) models in relation to asthma. These features include the ability to undertake ongoing studies over several years to evaluate airway remodelling reversibility, the contribution of both the innate and adaptive immune-driven inflammation and the generation of large amounts of tissue following surgery or post-mortem. However, the authors also point out that heaves is not just a model of a human disease, but has considerable impact on animal industry and welfare as well as the veterinary community. It is becoming increasingly recognized that the epithelium plays a prominent role in asthma pathogenesis.71 Thus the paper published by Looi et al. comparing the utility and relative merit of different methods to obtain these cells was timely.72 Although each method has its own strengths and limitation, the authors focused their attention on the use of bronchial brushings to isolate and characterize epithelial cell function. This method is one of the best and safest ways to access clinically relevant cells from children and as such has enormous potential for generating truly meaningful information relating to the development and pathophysiology of asthma. Given that proteases play a major role in pathogenesis of COPD, investigating the mechanisms that contribute to a protease–anti-protease imbalance are of importance to understanding disease pathogenesis.73 This year in Respirology, three papers were published addressing this issue. Hu et al. performed a proteomic analysis on lung tissue from never smokers to smokers with no evidence of COPD and smokers with a confirmed diagnosis of COPD.74 They showed by two-dimensional gel electrophoresis and mass spectrometry that expression of over 24 proteins including cyclophilin A and HSP27 were significantly increased in the lungs of smokers and more so in smokers with COPD. Importantly, these findings were validated by Western blot analysis of whole lung tissue and immunohistochemistry on sections of lung tissue. Given the role these proteins play in regulating cellular oxidative stress and hypoxia, it is not unexpected that would be increased in this cohort of patients. Jouneau et al. examined expression of extracellular matrix metalloproteinase inducers (EMMPRIN; CD147) in smokers and patients with COPD. EMMPRIN is a potent activator of several MMPs, but appea