Year‐in‐review 2010: Asthma, COPD, cystic fibrosis and airway biology

Respiratory diseases are estimated to affect a billion people around the world, and account for 12 million deaths a year. In order to raise awareness of respiratory conditions, the Forum of International Respiratory Societies (FIRS), which includes the Asia Pacific Society of Respirology, declared 2010 the Year of the Lung.1 One of the highlight events of the year was World Spirometry Day on October 14, when over 100 000 free spirometry tests were performed at 412 events worldwide. The Year of the Lung also involved intense lobbying of legislative bodies to promote issues such as air quality and anti-tobacco initiatives, and to encourage direction of research funding towards respiratory conditions. One of the important goals of the Year of the Lung was to focus awareness on respiratory research. In this review, we describe important global advances in 2010 in asthma, COPD, cystic fibrosis and airway biology, and highlight the contribution of research in these areas from Respirology. Helen Reddel In 2010, in a series of thought-provoking editorials, pro/con debates and reviews, Respirology provided a forum for discussion about important issues in asthma management. The discussion commenced with a Think Tank Review by Hancox and colleagues,2 which focussed on several 'inconvenient truths' about asthma, and linked these to current controversies in areas such as epidemiology, safety of long-acting β2-agonists (LABA) and clinical practice guidelines. Subsequently, in the first of several pro/con debates, O'Byrne and Colice argued, respectively, for and against the proposition that the current stepwise approach to asthma pharmacotherapy in guidelines encourages over-treatment.3 The discussion focussed on factors which currently encourage clinicians to increase medication doses when asthma is not completely controlled rather than considering more basic factors such as poor adherence or poor inhaler technique. The authors emphasized the importance of treating medication changes as therapeutic trials, to avoid an inevitable upward progression of medication use. Discussion about the safety of LABA continued unabated in 2010, with a robust pro/con debate in Respirology about whether more evidence on this topic is needed.4 On the pro side, Drazen, Kazani and Ware argued that the current level of uncertainty about safety was unacceptable, and proposed a randomized controlled trial of 50 000 patients. On the con side, Sears argued that no safety signal was seen when concomitant inhaled corticosteroid use was mandatory. As moderator, Taylor commented that it was unlikely that the outcomes of any further safety study would be regarded as final, and recommended ongoing vigilance for adverse effects of β2-agonists.4 In a third pro/con debate,5 Bardin, as moderator, asked whether allergy still had a role in asthma exacerbations, reminding readers that for much of the 20th century, they were mostly assumed to be caused by allergens. On the pro side, Custovic and Simpson provided evidence of synergistic effects between viruses, atopy and allergen exposure, and argued that previous evidence may have been diluted by the phenotypic heterogeneity of asthma. On the con side, Le Souëf argued that allergy, rather than being causally related to asthma, was a marker for more important deficits in the immune system that allowed respiratory viruses to induce exacerbations. The complexity of the relationships between socioeconomic factors and the prevalence of asthma was demonstrated in a population-based study published in Respirology, in which Chittleborough and colleagues reported that gender interactions varied according to which socioeconomic variable, for example employment, educational status or income, was considered.6 Recent years have seen increasing awareness of the need for use of objective measures in epidemiological studies. The Tennessee Children's Respiratory Initiative, the design of which was reported in Respirology,7 recruited over 650 families during acute viral respiratory illness of infancy. These children will be followed to age 6 years with standardized assessments, to identify modifiable factors important in the development of asthma. One of the challenges in such studies is in the way asthma should be defined. The scale of this issue for paediatric epidemiological studies was highlighted by Van Wonderen and colleagues in a systematic review8 which identified no fewer than 60 definitions of childhood asthma; the choice of definition had a major impact on predictive models for asthma prevalence. Paediatric epidemiological studies often depend on parent-reported wheezing, but wheezing is poorly defined, and the range of human hearing varies among individuals. In Respirology, Habukawa and colleagues9 demonstrated a lack of correlation between airway hyperresponsiveness, spirometry and wheezing sounds, using sound spectography during methacholine challenge. The frequency of both inspiratory and expiratory breath sounds increased during challenge testing and decreased following administration of salbutamol. The importance of objective measures for asthma studies in adults was also highlighted in 2010 by Luks and colleagues;10 following their earlier demonstration that 30% of doctor diagnoses of asthma were incorrect,11 the authors demonstrated that a correct diagnosis could be confirmed in over 90% of patients with a simple bronchodilator reversibility test or single methacholine challenge, even in those taking regular controller medications. For patients presenting primarily with cough, a standard objective measure has been capsaicin challenge,12 which stimulates C-fibre cough receptors. As cough may also be stimulated via rapidly adapting mechanoreceptors, Kamimura and colleagues13 investigated three modes of mechanical stimulation (tracheal compression, neck retroflexion, tuning fork). Induction of an itchy sensation and cough with all tests was significantly more likely in patients reporting phonation-induced cough. Further major work on asthma phenotypes was published in 2010, including a cluster analysis of 726 patients with mild, moderate and severe asthma, published from the Severe Asthma Research Program.14 Eighty per cent of patients were able to be classified into one of five clusters on the basis of just three clinical variables—pre- and post-bronchodilator FEV1% predicted, and age of onset of asthma. Even more interesting will be future work from this programme on predictors of clinical course and response to treatment. The interaction between asthma and obesity is complex. In Respirology, Arshi and colleagues15 studied the relationship between obesity and asthma in children, finding insulin resistance in almost half of the children with allergic asthma but none of the BMI-matched healthy controls, with some interesting patterns emerging in the relationships between insulin resistance and blood levels of several adipokines. With increasing awareness of phenotypic differences in asthma, increasing importance is placed on the identification of predictors of response to different asthma medications, and, as a corollary, on phenotype-based approaches to asthma management. In a novel triple cross-over study, Lemanske and colleagues16 investigated the predictors of response to add-on therapy with LABA, montelukast or higher dose inhaled corticosteroid, for children with persistent asthma who were uncontrolled on inhaled corticosteroids alone. Almost all of the children demonstrated a differential response between treatments, but, contrary to prior assumptions, baseline characteristics mostly failed to predict the most effective treatment for individual patients. Polymorphisms of the β2-adrenoceptor gene did not predict response to add-on LABA in this study. In Respirology, Asano and colleagues17 showed the impact for β2-adrenoceptor genetic association studies of reporting β2-agonist response as a proportion of the patients' maximal reversibility capacity after administration of both β2-agonist and anticholinergic agents, rather than as the absolute difference after administration of β2-agonist alone. In Respirology, Sandrini and colleagues18 provided a clinical update on the use of fractional exhaled concentration of nitric oxide (FeNO), describing its transition from research tool to clinical biomarker. An example of FeNO-guided treatment was reported by Cowan and colleagues,19 who examined the protective effects of non-steroid medications (cromoglycate, formoterol and montelukast) on exercise-induced bronchoconstriction and airway hyperresponsiveness to mannitol in adults with exercise-related cough, wheeze or dyspnoea and low FeNO. A second arm of the study confirmed that in patients with high FeNO, airway hyperresponsiveness and exercise-induced bronchoconstriction were improved by 2 weeks of inhaled corticosteroids. A potential limitation of phenotype-guided treatment is variation in the phenotypic marker itself, but few publications have examined this. Al-Samri and colleagues20 examined the repeatability of inflammatory phenotypes over a year in patients with moderate and severe asthma. Only one-third of patients demonstrated a stable inflammatory phenotype, with variation greatest for eosinophil counts. In Respirology, Korn and colleagues21 reported another potential source of variation relevant to phenotype-guided management, with clinically important differences in FeNO levels recorded from different brands of analysers. In addition to clinical trials of conventional pharmacotherapy, 2010 saw the continuation of interest in novel treatment approaches for asthma, with studies providing further evidence for the importance of selection of patients and outcome measures in the design of clinical trials.22 A sham-controlled study of bronchial thermoplasty in patients with severe asthma23 identified improvements in asthma exacerbations, that is, the 'future risk' component of asthma control,24 with less impact on conventional assessment of clinical asthma control. The demonstration in this study of a substantial placebo effect also highlighted the need for careful selection of control interventions for non-pharmacological studies, and for investigators to consider the potential impact of information provided to study participants, as was recently demonstrated by Wise and colleagues in a pharmacological study.25 An alternative approach was taken by Mendes and colleagues26 who examined the effect of 3 months of aerobic training for patients with asthma, and reported significant improvements in health-related quality of life, symptom-free days, and depression and anxiety levels, compared with breathing techniques. In Respirology, Anderson provided a comprehensive overview of asthma vaccine strategies,27 describing the limitations attendant upon focussing on a Th1-Th2 asthma paradigm—just as early vaccine research was limited by the dominant assumption in the 19th century that immunity is always protective. The most promising vaccine area with current methods appears to be in primary prevention or early treatment of allergic asthma, with fewer prospects for improvement in more advanced or severe disease. There is increasing interest in reducing the morbidity and health-care costs due to asthma exacerbations, either by preventing their occurrence, or by reducing their severity. Although most attention focuses on strategies for reducing exacerbations in individual patients, a striking example of the impact of policy changes on population-level asthma outcomes was seen during 2010, when Mackay and colleagues28 reported that the implementation of legislation banning smoking in public places in Scotland had led to a reduction in paediatric asthma hospitalizations of 18% per year, adjusted for confounders, contrasting with an increase of 5% per year in the preceding 6 years. 2010 also saw the publication of evidence about the rapid impact of even low levels of traffic-related air pollution on Emergency Department presentations for asthma amongst children.29 Despite improvements in the need for intensive care admission for asthma in many countries, life-threatening exacerbations have not been eliminated, and they remain a difficult area to study because of ethical concerns about randomized controlled trials in such contexts. Well-conducted retrospective audits can provide insight into factors that may contribute to improved outcomes. In Respirology, Murase and colleagues30 examined the impact of the introduction of non-invasive ventilation (NIV) for life-threatening asthma in a large teaching hospital in Japan. The introduction of NIV for acute severe asthma in 2003 was associated with a significant reduction in the number of patients requiring endotracheal intubation and mechanical ventilation, and a significant reduction in hospital stay. Michiaki Mishima and TK Lim Blood eosinopenia has long been known as a marker of acute infection, and has recently been shown to be a better predictor of sepsis than CRP in critically ill patients.31 Holland and colleagues examined the usefulness of eosinopenia (≤40/mm3), for predicting the severity of COPD exacerbations, and reported that the eosinophil count might be a useful marker of exacerbation severity, independent of the total WCC and pH.32 As the full blood count performed in most patients on admission to hospital routinely includes the eosinophil count, there is no extra cost for this potentially beneficial test. FeNO has been implicated as a pulmonary biomarker in various respiratory diseases, including COPD.33 Antus and colleagues evaluated the benefit of measuring FeNO in COPD patients hospitalized with an exacerbation of the disease,34 and concluded that FeNO levels may predict the overall response to treatment in COPD patients with acute exacerbations. The PiKo-6 is an inexpensive device for measuring FEV1, FEV6 and FEV1/FEV6, and is easy to use. As FEV6 is a reasonable surrogate for FVC, as measured by spirometry, FEV1/FEV6 is sensitive test for the diagnosis of airway obstruction.35 Wada and colleagues investigated the usefulness of a combination of an electronic FEV1/FEV6 meter (PiKo-6) with a symptom-based COPD diagnosis questionnaire from the International Primary Care Airways Group (IPAG) as a screening method in patients with cardiovascular diseases.36 They concluded that the combination of the PiKo-6 with a COPD questionnaire may be a useful and feasible method of identifying undiagnosed COPD patients attending a cardiovascular outpatient clinic. Lung uptake of iodine-123 metaiodobenzylguanidine (123I-MIBG) is used as an indicator of pulmonary endothelial function.37 Decreased lung uptake of 123I-MIBG has been demonstrated in patients with COPD as compared with normal subjects. Koizumi and colleagues demonstrated that early lung uptake of 123I- MIBG is inversely correlated with increased pulmonary artery pressure during exercise in patients with COPD.38 It has yet to be determined whether the presence of productive cough is a risk factor for the development of COPD.39 Lu and colleagues assessed the prevalence of COPD in the absence of chronic bronchitis based on a population survey in China, and identified the determinants of chronic bronchitis in patients with COPD.40 They concluded that there is a high prevalence of COPD in the absence of chronic bronchitis in China, and that chronic bronchitis is not essential to the diagnosis of COPD. Yamane and colleagues reported that productive cough is an independent risk factor for the development of COPD in former smokers in Japanese men with normal spirometry.41 In particular, the authors recommended that former smokers who complain of this symptom should be regarded as being at high risk for the development of COPD. The data suggested that stage 0, as originally defined in the Global Initiative for Chronic Obstructive Lung Disease 2001 guidelines, may be relevant for the identification of subjects at risk of developing COPD. Viruses are important aetiological agents for acute exacerbations of COPD (AECOPD), and their prevalence has been reported to vary from region to region.42 Mohan and colleagues conducted a systematic review which examined the prevalence of respiratory viral infections in AECOPD, and concluded that viruses are strongly associated with AECOPD, with the highest detection rates of viruses being in Europe.43 The geographical epidemiology of viruses may have important therapeutic implications for management of AECOPD. COPD is associated not only with an abnormal inflammatory response in the lung but also with systemic inflammation. He and colleagues explored whether local and systemic inflammation occurs concurrently in patients with COPD using induced sputum and peripheral blood samples.44 They reported that an increase in the inflammatory cell population and IL-6 and CRP levels may occur earlier in the airway than in peripheral blood, and may reflect the degree of airflow limitation better than do peripheral blood measurements. Systemic inflammation may be present in patients with severe or very severe COPD. COPD is one of the leading causes of mortality and morbidity. From the National Hospital Discharge Survey, Holguin and colleagues evaluated whether or not COPD in adults ≥25 years old was associated with increased prevalence and in-hospital mortality of several comorbidities.45 During 1979 to 2001, there were an estimated 47 404 700 hospital discharges, and any mention of COPD in the discharge diagnosis was associated with higher hospitalization rates and higher in-hospital mortality from other comorbidities. On imaging, some patients are found to have combined pulmonary fibrosis and emphysema (CPFE). In a retrospective study of 47 patients with CPFE and 82 patients with emphysema-predominant COPD, Kitaguchi and colleagues reported that the CPFE group had milder airflow limitation and lower diffusing capacity than the COPD group, and 47% of the CPFE patients had lung cancer.46 They also reported that during 6-min walk testing, for equivalent levels of FEV1 or 6MWD, desaturation in CPFE patients tended to be more severe than in COPD patients. Hannink and colleagues reported that COPD and heart failure are both common diseases with major impact, and that they seem to coexist more frequently than expected from their separate population prevalences.47 However, the authors also commented that the estimates of combined prevalence must be interpreted carefully because of imperfections and difficulties in assessment of both diseases. Parappil and colleagues reported that comorbid diabetes may prolong length of stay and increase the risk of death in patients admitted with AECOPD.48 However, further studies may be required to elucidate the reasons for these poorer outcomes, in particular whether premorbid or inpatient glycaemic control is responsible, as these are potentially modifiable factors. Systemic corticosteroids are prescribed routinely in the treatment of acute severe exacerbations of COPD. They speed up recovery of symptoms and restitution of physiology, reduce treatment failure rates and shorten hospital stays.49 However, one out of five patients experiences side-effects, the most common being hyperglycaemia.49 Kim and colleagues reported in Respirology, for the first another potentially of chronic From a retrospective study of patients who were was in It was as high as in patients for which is than the of treatment for COPD exacerbations. In an and suggested that the of in patients who only inhaled corticosteroids in the They further recommended screening for with a towards treatment in However, further studies are on the of different management strategies to treatment in patients with COPD. As there is also uncertainty the dose and of systemic corticosteroid treatment for COPD exacerbations, it may be more to to avoid high doses per or treatment and in care for patients with very advanced COPD, alternative for symptom control such as may be less and more than high dose systemic NIV is the current standard of care for patients with life-threatening acute exacerbations of COPD who do not to and bronchodilator treatment. However, there is uncertainty about the method of NIV in this A trial of NIV with did not reduction in intubation In the presence of severe airway ventilation and ventilation have different of and a more stable ventilation, heterogeneity and of and in a that the of NIV which pressure to a ventilation the of both modes of ventilation and may provide NIV hospital mortality in COPD, a study of 100 patients by and colleagues that the outcome following first treatment with NIV was very As in the by and more effective treatment is for advanced COPD. One such NIV at was explored in another study by and who showed improvement in the of patients with persistent controlled trials of NIV have reported for and quality of at this NIV should not be regarded as an treatment for stable COPD. and colleagues the to an exercise programme for patients with and the often areas of programme and of to With to baseline exercise and in another in Respirology, showed that the 6-min walk test should be or several as there is a significant of the 6-min walk test is important as and colleagues showed that it can be used to predict the with the being the primary and for exercise in order to a strategies to exercise during exercise including have been used in patients with COPD. and colleagues evaluated the effects of NIV during exercise with the on in patients with They concluded that it was and did not exercise to clinical outcomes during is and conducted a systematic review and on the impact of on patients with COPD They were not able to any significant in exercise capacity quality of There is evidence for the of in is an important which will the of this important it can be with In the years the cystic fibrosis gene was in there have been advances in this genetic The focus on and clinical outcomes and the evidence and of care with review an for care The associated with the improvements in outcomes and the future have been recently by and There is a awareness of early airway infection, inflammation and lung in and children with The clinical outcome measures to early both from a clinical and from a research remain and colleagues low may be in the to early with a to They highlight of with and early seen on treatment was this may is as yet and the evidence for effective very limited in children and is issues such as the degree of lung and respiratory affect the quality of the it more difficult to these in in in children have recently been reported using in children as as years of and the development of low dose may provide in the the frequency of such tests and the clinical further and colleagues that doses are and increase with increasing age in children with and may be higher in children who with With in patients with care to be taken to avoid Lung testing a component of clinical care in patients with and finding that can be used to early lung response to including and childhood are The measures resistance of the respiratory system and in the way of from the it as an for airway and response to bronchodilator in and colleagues have shown that the resistance estimated from early pressure as as that estimated from pressure may both be in patients with bronchodilator response may be using and colleagues recently demonstrated that abnormal lung measured in children years lung in children and and colleagues have reported changes in lung with use of inhaled and with lung tests as clinical trial to a number of challenges including local with and potentially large which have been investigated and recently by and a major associated with increased morbidity and mortality for children and adults with and, is difficult to has a large with a that between different and an with of For a readers should to a review The of to in the lung to has recently been associated with the of high levels of that a to the resistance The is for but that have a more of a population of has been shown to increase following to high doses of and with increasing in from some patients with the and increasing will be to developing strategies to chronic infections in the The treatment for or prevention of of has not been 2010 has seen the publication of the of randomized controlled trials different treatment The study demonstrated a benefit in using rather than of inhaled children free of at at therapy using inhaled and for 3 weeks 3 months did not reduce the risk of or chronic with in children with The investigators also reported the of increased in respiratory in the treatment group compared

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