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YEAR IN REVIEW

Year in review 2013: Chronic obstructive pulmonary disease, asthma and airway biology FANNY W.S. KO,1 TOW K. LIM,2 ROBERT J. HANCOX3 AND IAN A. YANG4 1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China, 2Department of Medicine, National University Hospital, Singapore, 3Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, Dunedin, Otago, New Zealand, and 4Thoracic Medicine, The Prince Charles Hospital and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia

Key words: airway biology, asthma, chronic obstructive pulmonary disease, diagnosis, treatment. Abbreviations: COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; GERD, gastro-oesophageal reflux disease; ICS, inhaled corticosteroid; IL, interleukin; NK, natural killer; NIV, non-invasive ventilation; PR, pulmonary rehabilitation; SNP, single nucleotide polymorphism.

INTRODUCTION Chronic obstructive pulmonary disease (COPD) and asthma, as airway diseases, contribute significantly to global mortality and morbidity. Studies worldwide, including those published in the past year in Respirology, are continuing to improve diagnosis and management of airway diseases and provide a better understanding of disease pathogenesis.

COPD Fanny WS Ko Comorbidities The latest Global Initiative for Chronic Obstructive Lung Disease guidelines highlight that comorbidities occur frequently in COPD patients, including cardiovascular disease (CVD), skeletal muscle dysfunction, metabolic syndromes, osteoporosis, depression and lung cancer. Given that they can occur in patients with mild, moderate and severe airflow limitation and influence mortality and hospitalizations independently, comorbidities should be actively looked for and treated appropriately if present.1 Concerning cardiovascular comorbidity, by analysing the baseline (1988–1994) and follow-up data in over 9000 subjects in the Third National Health and Nutrition Examination Survey in United States, Correspondence: Ian A. Yang, Department of Thoracic Medicine, The Prince Charles Hospital, Rode Rd, Chermside, Brisbane, Qld. 4032, Australia. Email: [email protected] Received 8 December 2013; accepted 27 December 2013. © 2014 The Authors Respirology © 2014 Asian Pacific Society of Respirology

Mannino et al.2 found that 12.0% and 10.3% of the subjects had obstructive lung function and overt CVD, respectively. The relationship between CVD and airflow obstruction is of interest, in which subjects with obstructive lung function were more likely to have overt CVD and the presence of an obstructive respiratory impairment increased the risk of mortality to that seen for overt CVD alone. However, it appears that in stable chronic heart failure patients, having COPD as the comorbidity did not affect survival. Boschetto et al.3 followed up 180 stable chronic heart failure patients over a mean period of 3 years and found that 30% of these subjects had COPD as comorbidity. Despite the fact that presence of COPD in patients with chronic heart failure did not influence survival on follow-up, patients with both chronic heart failure and COPD had a shorter 6-min walk distance, lower arterial oxygen tension, glomerular filtration rate and higher N-terminal pro-B-type natriuretic peptide in the baseline observation when compared with patients with chronic heart failure but no COPD. Among the gastrointestinal diseases, gastrooesophageal reflux disease (GERD) is a common disease in the adult population with an estimated prevalence of 20%. Kamble et al. assessed the incidence and pattern of GERD in 50 patients with mild-to-moderate COPD using dual-probe 24-h oesophageal pH monitoring and found that that 78% of the subjects had GERD. Among these subjects, prevalence of GERD was higher in patients with reflux symptoms than those without (81% vs 66.7%).4 How GERD relates to COPD is not fully understood. COPD patients may have abnormal thoracoabdominal functional anatomy that in turn causes higher gastric and lower intrathoracic pressures. Previous studies also suggest that GERD may lead to exacerbation of COPD.5 In a group of 329 miners undergoing assessments as part of the compensation scheme, Siva et al. found presence of peptic ulcer disease was associated with poorer lung function.6 Positive Helicobacter pylori serology was found to be present in more COPD patients than controls (54.7% vs 23.5%).6 H. pylori infection is well known to cause peptic ulcer disease/ Respirology (2014) 19, 438–447 doi: 10.1111/resp.12252

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gastritis. However, the relationship between HP infection and reflux disease is more complex. A recent study from Japan analysed the data over 10 000 healthy subjects who had underwent upper gastrointestinal endoscopy and found that reflux oesophagitis was associated with H. pylori non-infection, while non-erosive reflux disease was associated with H. pylori infection. Eradication of H. pylori may even have disadvantageous effects on reflux oesophagitis but not on non-erosive reflux disease.7 It would be of interest to assess the relationship between H. pylori and reflux disease in COPD patients. Apart from cardiovascular and gastrointestinal diseases, lung cancer is also an important comorbidity in COPD patients. Researchers from China assessed the medical records of over 3000 patients hospitalized for lung cancer and found that prevalence of spirometrydefined COPD in hospitalized lung cancer patients was 21.6%. However, a diagnosis of COPD was only made by physicians in 7.1% in the subjects. Among the patients with diagnosed COPD, treatment conformity to Global Initiative for Chronic Obstructive Lung Disease COPD guidelines for stable and acute exacerbation of COPD was 27.1% and 46.8%, respectively.8 COPD is substantially underdiagnosed and undertreated in this hospitalized lung cancer population, and more work should be targeted to manage concomitant COPD in patients with lung cancer.

Inflammation Inflammation of the airway plays an important role in the pathogenesis and progression of COPD. Imbalance of oxidants and anti-oxidants can lead to inflammation in the airway. A recent cross-sectional study from India found that COPD patients had high levels of malondialdehyde, an oxidant, and low levels of anti-oxidants compared with controls.9 A significant increase in the levels of malondialdehyde and decrease in catalase activity and erythrocyte glutathione concentration was observed from Global Initiative for Chronic Obstructive Lung Disease stages II–IV. Immune dysregulation can also lead to inflammation in the airway. The increasing recognition that COPD shares features with autoimmune disease has led to interest in a potential role for regulatory T cells, which are intimately involved in the control of autoimmunity.10 Cytotoxic T lymphocyte-associated antigen-4 is a member of the immunoglobulin gene superfamily and plays an important role in the downregulation of the T-cell response, T-cell homeostasis and maintenance of peripheral tolerance. Shen et al.11 found that levels of cytotoxic T lymphocyteassociated antigen-4 were elevated in COPD patients, inversely correlated with lung function and positively correlated with serum C-reactive protein levels in COPD patients. Mean platelet volume has been investigated as an indicator of inflammation in different diseases including CVD, peripheral artery disease, cerebrovascular disease, rheumatoid arthritis and ulcerative colitis. Wang et al.12 found that mean platelet volume level was decreased during acute exacerbation of COPD when compared with the stable state. © 2014 The Authors Respirology © 2014 Asian Pacific Society of Respirology

439 In addition, mean platelet volume was also lower in COPD patients in stable phase compared with controls. More research is needed to assess whether blood biomarkers including those related to oxidative stress, regulatory T cells and platelet function can serve to assess the inflammation and guide management in COPD patients. Apart from biomarkers from blood, exhaled breath condensate and induced sputum may also contribute information concerning the inflammation in the airway. Warwick et al. collected exhaled breath condensate and induced sputum from patients with asthma exacerbations, COPD exacerbations and control subjects with symptoms of respiratory tract infection.13 The same samples were collected from these subjects after recovery. It was found that exhaled breath condensate pH was significantly lower during exacerbation compared with recovery. Interleukin-10, neopterin and tumour necrosis factor-α levels were significantly increased in induced sputum supernatant during exacerbation. Noninvasive biomarker assessment thus may provide some useful information in the inflammation occurring in the airway during COPD exacerbation, when invasive investigations may pose significant risk.

Monitoring Monitoring the clinical status of COPD patients, including oxygenation and nutrition, may help us to consider offering appropriate management for patients (such as oxygen therapy and nutritional supplement). A study from Trauer et al. followed up 35 community-living patients with stable COPD with partial arterial oxygen concentration 56–70 mm Hg to death from any cause, first exacerbation and first admission. These patients had failed to qualify for home oxygen therapy based on established criteria in Australia. It was found that neither resting partial arterial oxygen concentration nor proportion of ambulatory oximetry below 90% saturation effectively predicted their survival.14 Weight loss and muscle weakness accompanying COPD results in loss in respiratory and peripheral muscle functions, exercise capacity, reduced healthrelated quality of life, and increased mortality. Günay et al. assessed the nutritional status of stable COPD patients who were candidates for outpatient pulmonary rehabilitation (PR) by subjective global assessment.15 They found that the most malnourished group had significantly lower lung function, higher dyspnoea scores and lower exercise capacity (by incremental shuttle walking test and endurance shuttle walking test). Research on intervention on COPD patients by optimizing the oxygen saturation of and nutritional status would be of practical value and interest for management of COPD patients. Risk factor interventions Smoking is the most important risk factor for COPD. Other risk factors include biomass exposure. Measures in tackling these risk factors at their roots may help to decrease the development and progression of Respirology (2014) 19, 438–447

440 COPD. A review by Zhou and Chen16 has discussed interventions based around minimizing risk factors for COPD including patient education, smoking control, reducing exposure to occupational dusts and/or hazardous gases, use of clean fuels, improved ventilation in the kitchen to reduce contamination of indoor and outdoor gases, and prevention of respiratory tract infections in China. Physicians can also help by advising smoking cessation to their patients. Tang et al.17 examined the awareness of chest physicians in Guangzhou, China about harmful effects of tobacco and the degree to which they advise their patients to quit smoking. It was found that physicians more aware of the health hazards of smoking provided more smoking cessation advice. Awareness correlated with hospital levels and smoking status. Physician’s advice correlated with their smoking status and educational background, but not with the levels of hospital, position or department affiliation. This study highlights the importance of reflecting on the relationship between physician awareness and counselling to patient from both an historical and cultural perspective. Such reflection opens new possibilities for future research.18

COPD management TK Lim Pharmacotherapy New evidence is emerging on the optimal pharmacotherapy of COPD. Fukuchi et al. in a large randomized trial showed that a fixed combination of budesonide/ formoterol is superior to formoterol alone in preserving lung function and delaying exacerbations.19 These findings are consistent with the notion that in patients with COPD, a fixed combination of inhaled steroids and long-acting bronchodilators is superior to the individual components taken alone.20 There is some evidence that budesonide/formoterol may be safer than fluticasone/salmeterol with regard to the risk of chest infections in COPD.21 There is also concern about cardiovascular risks especially with recent usage of long-acting bronchodilators in COPD.22 Despite a large cohort study, it remains unclear whether ipratropium bromide also increases this risk.23 However, in a secondary analysis of the Lung Health Study, de Jong et al. found no increased cardiovascular risks in smokers with mild-tomoderate pulmonary obstruction who used shortacting anticholinergic bronchodilators.24 Elderly patients with COPD have low bone mineral density that is often blamed on chronic inhaled steroid treatment.25 However, there is little evidence linking inhaled steroid therapy to low bone mineral density in COPD.26 Systemic inflammation is a significantly independent predictor of low bone mineral density in patients with clinically stable COPD.10 Maltioudakis et al. in a long-term controlled study showed that low-dose inhaled steroid treatment preserves bone mineral density in bronchitic patients presumably through systemic anti-inflammatory effects.27 Respirology (2014) 19, 438–447

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Ventilation Mechanical ventilation, especially non-invasive ventilation (NIV) via face masks, is a life-saving treatment modality for severe acute exacerbations of COPD. Delays in weaning patients with COPD from NIV are a common problem and may result in prolonged and inappropriate occupancy of intensive care beds.5 Lun et al. in a small controlled study were unable to detect any difference in the need to resume NIV between immediate step off versus gradual step down of NIV.28 Their results are comparable with that from a larger Spanish randomized trial.1 Prompt cessation of NIV without the need to ‘cycle’ would be a simpler and more cost-effective option. Failure to wean from invasive mechanical ventilation is an even more serious problem. Hannan et al. reported high weaning success rate in a specialized centre.29 However, this might not be an option for most of our patients. Long-term ventilator dependency is best avoided in patients with COPD by utilizing NIV initially to avoid intubation and, later on, in difficult patients, as an effective liberating mode from invasive ventilation in conjunction with early aggressive rehabilitation.30,31 Pulmonary Rehabilitation Several papers in Respirology described methods to promote and enhance pulmonary rehabilitation (PR) in COPD. Revitt et al. in a before versus after study showed how a short course of PR improved exercise capacity and health status in patients who have had an acute exacerbation of COPD within 4 weeks.32 The number of readmissions was also significantly lowered, offering the possibility that this strategy might be also cost-effective.32 Puhan described how early PR following recovery from acute exacerbations might be applied in practice.33 Pleguezuelos et al. reported the effects of PR with a whole body vibration technique that appeared to improve walking capacity, muscle strength and efficiently in severe COPD.34 Collins et al. in a meta analysis of nutritional support found that both inspiratory and expiratory muscle strength and handgrip strength were significantly improved and associated with weight gains of >2 kg.35 Nutritional support also led to improved exercise performance and enhancement of PR programmes.35 Gurgun et al. confirmed these findings even in advanced COPD patients with muscle wasting by conducting a randomized trial that added nutritional support to PR. The combination of nutritional support with PR resulted in improvements in lean body mass and mid-thigh thickness, and thus may retard muscle wasting in our most frail patients.36 Barriers to widespread deployment and uptake of PR exist in different clinical settings. Johnston et al. described how PR had been implemented in only a minority of patients admitted to their tertiary care hospital with an exacerbation of COPD due to gaps in both referral to and subsequent attendance at a program.37 Similarly, in a primary care setting, Monteagudo et al. implemented an integrated education programme that did not achieve the expected changes in quality of life measured or in the clinical evolution or heath status over 12 months.38 By con© 2014 The Authors Respirology © 2014 Asian Pacific Society of Respirology

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trast, Johnston et al. showed that even in regional and remote settings, focused programs increased healthcare practitioner knowledge and confidence in delivering management for people living with COPD and facilitated the establishment of effective PR programmes where access to such programmes is limited.39

ASTHMA Robert Hancox Asthma control and prevalence Despite the widespread availability of international and national asthma guidelines, poor asthma control remains a problem in the Asia-Pacific region. A survey of people with asthma from several countries across the region found that many respondents had frequent exacerbations. Although there were substantial differences between countries, suboptimal management of asthma was common. Many patients overestimate their level of asthma control, although only 2% of respondents across the region met Global Initiative for Asthma criteria for well-controlled asthma, half of all respondents said that their asthma was wellcontrolled.40 Fear of the adverse effects of inhaled corticosteroids (ICS) is widespread. Clearly, there is a lot of work to be done to meet the asthma educational and treatment needs across the region. Another survey in Jinan, China found the prevalence of asthma to be only 1.1%, much lower than most countries and demonstrating that there are substantial differences in the prevalence of asthma across the Asia-Pacific region.41 Unfortunately, the issues of suboptimal treatment and poor asthma control were common in this survey too. Underuse of ICS is likely to be due to the high cost of these medications as well as the fear of possible steroid side-effects. Our attempts to improve asthma control with better education and treatment need to be informed by a deeper understanding of patients’ perspectives. Grover and colleagues used a qualitative approach to investigate both parents’ and children’s views on asthma in two hospitals in New Delhi.42 Poor understanding of the asthma and its treatment, and the cost of medicines were among the issues identified. Parents also expressed fatalistic views about their children’s asthma, while children were reluctant to use medications in front of others. Few parents or children had been involved in planning the asthma management and most seemed to accept the dominant role of the doctor—somewhat different to what we might expect from research in Western populations. Optimizing asthma medicines Low adherence to medication remains a barrier in achieving good asthma control in all societies. Patel and colleagues compared self-reports of inhaler use with covert electronic monitoring of inhaler actuations during a randomized trial of ICS and long-acting beta-agonists.43 Overall, inhalers were used less often than patients reported, but underreporting of inhaler © 2014 The Authors Respirology © 2014 Asian Pacific Society of Respirology

441 use by frequent users was found as well as overreporting of adherence by patients who underused inhalers. Self-reports of inhaler adherence are likely to be inaccurate. Combining medications into one inhaler is likely to improve adherence. Atienza and colleagues provide further evidence that a single inhaler containing budesonide and formoterol can be used for both maintenance and reliever treatment.44 Over 12 months, the single inhaler regime provided better asthma control than standard treatment with a maintenance budesonide and formoterol inhaler plus terbutaline as a reliever. Single inhaler therapy was associated with fewer severe exacerbations, increased time to exacerbation, fewer courses of oral steroids, fewer admissions and better lung function. The benefits may be due in part to the additional budesonide taken with the reliever at the time of increased symptoms. Chen and colleagues provided further evidence that ICS taken at the time of worsening asthma exacerbations is effective. They studied the addition of nebulized budesonide to bronchodilators in children attending an emergency department with acute exacerbations. No difference in response was observed in the first hour, but from 2 h onwards, budesonide use was associated with clinical improvement, better lung function and a lower need for oral corticosteroid treatment.45

Adverse effects of asthma treatment Unfortunately, ICS do have some adverse effects. A concern arising from large studies of patients with COPD is that they may increase the risk of pneumonia.46 Zhang and colleagues studied oropharyngeal flora in children with asthma and found that colonization with Streptococcus pneumoniae was nearly four times among those treated with ICS.47 Those using higher doses of ICS were most likely to be colonized. Although it is possible that colonization reflects asthma severity rather than treatment, the findings provide further evidence that corticosteroid treatment may increase the risk of respiratory infections.46 An interesting case–cross-over design from the large Korean national database confirmed that recent use of ICS was associated with an increased risk of hospitalization or emergency department presentation with pneumonia.48 Unexpectedly, however, use of ICS with a long-acting beta-agonist was associated with a lower risk of pneumonia. The reasons for this apparent protective effect of the long-acting beta-agonist and ICS combination are not clear and warrant further study. Asthma phenotypes A topical issue is phenotyping of airways disease. It is now widely accepted that the clinical syndrome of asthma comprises more than one distinct entity. Distinguishing between different forms of asthma is important because it may identify different aetiologies and treatments. One well-recognized but poorly understood phenotype is cough-variant asthma. Bao and colleagues found that adding the oral betaRespirology (2014) 19, 438–447

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agonist, procaterol, to ICS treatment improved cough symptoms.49 This indicates that the combination of inhaled steroid and beta-agonist bronchodilator works in this subgroup of asthmatics, even though airflow limitation is not a prominent feature of the disease. James and colleagues investigated risk factors and features of respiratory symptoms in the Busselton Health Study. They found different risk factors for cough and sputum production than for symptoms of wheeze.50 The findings suggest that recent increases in the prevalence of doctor-diagnosed asthma in Busselton may be due to diagnostic transfer from other airways diseases. Appropriate management of diagnosed asthma is likely to require careful characterization of the phenotype. One approach to phenotyping is to assess airway inflammation using induced sputum. A poorly understood inflammatory phenotype is reported to be neutrophilic asthma. Brooks and colleagues assessed sputum neutrophil counts in different age groups in Australian and New Zealand samples. Increasing age was associated with higher neutrophils in both asthmatic and non-asthmatics, and neutrophils tended to be higher in asthma.51 Those aged under 20, however, had high variability in neutrophil counts, tended to have higher neutrophil counts than older age groups. They suggest that diagnosing neutrophilic asthma requires age-specific reference ranges. Another approach to investigating airway inflammation is to measure exhaled nitric oxide. Most measurements use a single exhalation flow rate (50 mL/s) to do this, but measurement at different flows can help to reveal nitric oxide levels in different parts of the lung. Fujisawa and colleagues measured nitric oxide at four different flows to distinguish between central airway and small airway/alveolar levels in a twocompartment mathematical model. Small airway/ alveolar nitric oxide was better correlated with peripheral airway obstruction in their sample of stable adults with asthma.52 Takami and colleagues investigated differences between asthma and non-asthmatic wheeze in 5- to 6-year-old children. Contrary to expectations, they were unable to distinguish between the two groups physiologically in terms of change in airway resistance in response to methacholine. An important observation was the methacholine reactivity was strongly related to baseline respiratory resistance regardless of an asthma diagnosis.53

physiology. Although a ‘one-airway’ approach has been advocated by the Allergic Rhinitis in Asthma guidelines, allergic rhinitis is often overlooked by clinicians treating asthma. Hojo and colleagues assessed a simplified screening questionnaire for both asthma and allergic rhinitis among adults with asthma. The test had good sensitivity and reasonable specificity for allergic rhinitis when assessed against a gold-standard diagnosis based on allergy testing and specialist assessment.55 Airway infections in the setting of an asthma or COPD exacerbation were investigated by Wark and colleagues. Extensive testing revealed that respiratory virus infection—particularly rhinovirus—was common. Bacteria were also commonly found, and co-infection with both virus and bacteria was associated with more severe exacerbations and was more likely to result in readmission after discharge.56 The association between obesity and asthma has been the subject of considerable research and debate in recent years. One possible cause for the appearance of this association could be changes in our diet that influence the airway as well as increase the risk of obesity.57 Berthon and colleagues found that asthmatics ate more fat and less fibre than non-asthmatics.58 Asthmatics also had higher leptin levels than healthy controls. Among the asthmatics, more fat and lower fibre consumption were associated with lower forced expiratory volume in 1 s and sputum eosinophilia. This study represents an early, but important, observation in our attempts to understand the influence of diet on our lungs.57 Exposure to smoke and pollution have long-been implicated as a cause of respiratory symptoms. Bui and colleagues studied exposure to wood smoke and heavy traffic in middle-aged subjects in Tasmania, Australia. Although neither exposure was associated with a diagnosis of asthma, both exposures were significantly associated with increased asthma severity among those with the disease.59 The associations between exposure and severity were similar in participants who were atopic and non-atopic. The findings add to the accumulating evidence that pollution impacts on asthma symptoms, even though they did not support some previous reports that pollution increases the prevalence of asthma.

Comorbidities and precipitating factors Another phenotype of breathing disorder that may co-exist with, or be mistaken for, asthma is vocal cord dysfunction. Vocal cord dysfunction is very often associated with gastro-oesophageal reflux. Woolnough and colleagues investigated the response to acid suppression using a proton-pump inhibitor in patients with proven or suspected vocal cord dysfunction. Unfortunately, acid suppression made only a minor difference to respiratory symptoms among these patients.54 Allergic rhinitis is another disease that is associated with asthma because of a common atopic patho-

Genomics and airway diseases Gene-environment interaction influences susceptibility to airway diseases such as asthma and COPD. Genome-wide association studies of single nucleotide polymorphisms (SNP) and other genomic markers are providing information for understanding susceptibility to asthma60 and allergy.61 In asthma, further studies of candidate genes are being undertaken. An updated meta-analysis of 26 case–control studies found an association between deletion polymorphisms in the anti-oxidant GSTM1 and GSTT1, and asthma risk.62 SNP and copy number variation in the Baculoviral inhibitor of apoptosis protein

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repeat-containing 4 gene, encoding an X-linked inhibitor of apoptosis protein, were not associated with risk of developing asthma.63 Genetic markers for COPD susceptibility would provide useful markers for at-risk individuals.64 Recent genome-wide association studies has found associations with susceptibility to COPD of SNP in the nicotinic acetylcholinergic receptor, hedgehog interacting protein and family with sequence similarity 13 member A, among others.64 A genetic association study in Korea found that in hedgehog interacting protein SNP was associated with lung function in COPD,65 although not susceptibility. Much of the heritability of COPD still remains to be explained.66 Microsatellite markers in the surfactant protein B gene have previously been linked with increased susceptibility to COPD. A genetic association study of a Chinese Kazakh population observed an increased frequency of a microsatellite allele in COPD.67 In a large UK birth cohort, SNP in the mucin gene MUC5AC (mucin 5AC, oligomeric mucus/gel forming) was associated with bronchitis, wheeze, asthma and hay fever.68 SNP in ERBB1, encoding the epidermal growth factor receptor, was associated with chronic bronchitis and interacted with the MUC5AC SNP,68 providing evidence of the interaction between respiratory mucus, regulation by epidermal growth factor receptor and phenotypes related to bronchitis.

Risk factors for airway diseases In addition to genetic determinants, risk factors for asthma include atopy, respiratory viruses and other exposures including air pollution, whereas early life exposure to microbial products may be protective.69 In an ovalbumin-/ozone-induced mouse model of asthma, ozone exposure increased airway inflammation, airway remodelling and p38 mitogen-activated protein kinase (MAPK) activation, whereas the combination of dexamethasone and a p38 MAPK inhibitor was able to reduce these effects of ozone injury,70 which could be a novel method to overcome corticosteroid insensitivity. Gender differences in the development of asthma have long been observed. In an ovalbumin-induced mouse model of asthma, female mice had greater inflammatory markers in the airways (eosinophils, lymphocytes and Th2 cytokines) compared with male mice.71 The authors postulated that differences in hormonal production and inflammation could underpin gender differences in asthma susceptibility. Age is another factor that influences asthma incidence. In the induced sputum of older people with asthma, airway eosinophilia correlated with bronchial hyperresponsiveness as a physiological measure, whereas neutrophilia correlated with airflow obstruction possibly due to loss of elastic recoil.72 Cell biology and disease pathogenesis The immunopathogenesis of asthma is typically characterized by infiltration by eosinophils, mast cells and Th2 lymphocytes, and increased immunoglobulin E production, together with involvement of the bronchial epithelium,73–75 although other cells such as © 2014 The Authors Respirology © 2014 Asian Pacific Society of Respirology

443 macrophages could also play a role.76 Imbalance between histone acetylases and deacetylases have been also implicated in airway diseases. Sirtuins are proteins that have histone deacetylase activity. The sirtuin 1 activator, SRT1720, was found to inhibit the development of inflammation in an ovalbumininduced mouse model of asthma.77 Treatment with SRT1720 reduced bronchoalveolar lavage levels of interleukin (IL)-5 and IL-13, but not IL-4, and reduced airway eosinophilia in this mouse model. These findings suggest that sirtuin 1 activators may have an antiinflammatory action in asthma models, warranting further investigation for therapeutic effects in asthma. Lung inflammation in patients with COPD consists mainly of cellular infiltration by neutrophils, macrophages and lymphocytes; patterns of response to bacterial infection are also characteristic for neutrophils and monocytes.78 CD8+ T lymphocytes are of major interest in the pathogenesis of COPD and have been implicated in enhanced apoptosis of bronchial epithelial cells in the airways of patients with COPD. Increased expression of granzyme B, a serine protease that may induce apoptosis, was found in the small airways of patients with emphysema, in some CD8+ T cells and also in non-CD8+ cells with properties of macrophages.79 This appeared to be a relatively early event in milder disease severity stages, indicating a possible role in small airway remodelling even before clinical COPD is manifest. In addition to CD8+ T cells, natural killer (NK) cells are a small subset of effector lymphocytes that could play a role in COPD. NK and NKT-like cells were found to be increased in number in the bronchoalveolar lavage fluid of patients with COPD and displayed increased cytotoxic function and decreased expression of the inhibitory receptor, CD94.80 Invariant NKT cells has also been found to be activated by a glycolipid component of Aspergillus fumigatus, leading to bronchial hyperresponsiveness in a mouse model of asthma through an IL-33-dependent pathway.81 Furthermore NK cells induce eosinophil apoptosis in asthma in a process regulated by lipoxin A4.82 NK and NKT cells are therefore likely to play an important role in both COPD and asthma. Peroxisome proliferator-activated receptor-γ has been implicated in the regulation of inflammation. In rat and human bronchial epithelial cells, cigarette smoke-induced inflammation and toll-like receptor 4 expression were reduced in the presence of peroxisome proliferator-activated receptor-γ agonists (rosiglitazone or other ligands).83 These results support the potential utility of peroxisome proliferator-activated receptor-γ agonists as antiinflammatory agents in airway diseases and warrant further investigation.

Personalized treatment based on airway biology and clinical phenotypes Clinical and molecular phenotypes of asthma and COPD are becoming more refined, with the hope of achieving more personalized therapy for people with airway diseases. For example, aspirin-intolerant asthma is a clinical phenotype of asthma, with defined Respirology (2014) 19, 438–447

444 characteristics of asthma, rhinosinusitis, nasal polyps and sensitivity to aspirin and non-steroidal antiinflammatory agents. Alterations in arachidonic acid metabolism have been postulated to be involved. Fibroblasts from nasal mucosa of people with aspirinintolerant asthma demonstrated lower expression of prostaglandin E2 and cyclooxygenase, which could then contribute to reduced anti-inflammatory effects in the nose in response to exposure to aspirin.84 Another example of a special clinical setting is asthma in pregnancy. Viral exacerbations are important complications of asthma during pregnancy. Peripheral blood mononuclear cells from pregnant women with asthma were tested for responses to ex vivo challenges with influenza virus.85 The peripheral blood mononuclear cells were shown to have enhanced IL-17 secretion with phytohaemagglutinin stimulation and reduced secretion of interferongamma and IL-10, indicating reduced antiviral and regulatory responses. These observations go some way towards explaining the severe symptoms experienced by pregnant women with asthma who have viral respiratory infections. Combination ICS/long-acting beta-agonist inhalers have been shown to be more beneficial in asthma than the two monocomponents separately. An in vitro study of an air-liquid interface model of Calu-3 cells, a bronchial epithelial cell line, found that the rate of transport of fluticasone proprionate across the cultured cells was slowed in the presence of salmeterol.86 This slower transit was associated with increased epithelial resistance, implying decreased epithelial permeability, which could prolong the duration of anti-inflammatory effects of the inhaled steroid.87 In addition to the direct airway effects of combination inhalers, systemic anti-inflammatory effects have also been studied. Circulating lymphocytes from subjects with mild asthma or healthy controls were stimulated with lipopolysaccharide or phytohaemagglutinin.88 The combination of formoterol and budesonide synergistically activated the glucocorticoid receptor in peripheral lymphocytes within 30 min. Furthermore, formoterol potentiated the anti-inflammatory effects of budesonide in terms of lipopolysaccharide-induced IL-1β, IL-6, IL-8 and tumour necrosis factor-alpha secretion from lymphocytes. These systemic anti-inflammatory effects would be beneficial by reducing recruitment of activated immune cells to the airways. Novel therapies provide insight into mechanisms of disease pathogenesis. Tripterygium wilfordii is a plant used in traditional Chinese medicines for asthma. The major active component within this plant, triptolide, inhibited IL-13 gene expression in peripheral blood mononuclear cells and the Hut-78 lymphocyte cell line by inhibiting nuclear translocation of the transcription factors GATA3 and Nuclear Factor Of Activated T-Cells, Cytoplasmic, CalcineurinDependent 2.89

Future cell-based therapies for lung diseases There is an ever-increasing interest in pulmonary stem cells, given their potential for regeneration and Respirology (2014) 19, 438–447

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targeted therapy for chronic lung diseases, as shown by the Invited Series, ‘Stem cells and the lung’, published in Respirology. Lung-resident mesenchymal stem cells are pluripotent cells that are relatively immunoprivileged, may have immunosuppressive functions and regulate tissue stem cell function.90 Induced pluripotent stem cells can generate alveolar epithelial type I and type II cells, and can be cultured in vitro on decellularized lung tissue scaffolds as a form of lung bioengineering.91,92 As cells with tissue renewal capability, lung stem cells offer promise for future lung regenerative medicine for chronic lung diseases.93 To reach this full potential, a better understanding is required of how ageing and stem cell exhaustion can impair the repair response to lung injury.94

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