Year in review 2012: Asthma and chronic obstructive pulmonary disease

Abstract

Asthma and chronic obstructive pulmonary disease (COPD) continue to have considerable impact on disease burden and mortality worldwide. Early diagnosis still remains a challenge, with low uptake of spirometry in many countries. Implementing best practice management for airways disease is a critical goal for health-care systems—the management now includes pharmacological and non-pharmacological approaches to the lung disease, as well as recognition and treatment of comorbidities. Finally, the pathogenesis of airways disease continues to be fertile field of investigation, in order to better prevent disease, slow progression and identify relevant biomarkers. A large number of studies published in Respirology in 2012 have addressed all of these important clinical and scientific issues, and made major contributions to advance this field and hopefully improve outcomes for patients with asthma and COPD. Despite years of research, the origins of asthma remain obscure. Although there is clearly a genetic disposition to developing asthma, gene-association studies have so far failed to reveal clear insights into the development of asthma (reviewed in Respirology in 20111), indicating that asthma is likely to result from a complex interaction between genes and environment. Moreover, marked changes in the prevalence of asthma in recent decades indicate that changing environmental exposures must be to blame. Air pollution is known to exacerbate asthma symptoms and has been one of the factors suspected of causing the disease in the first place. Gowers et al. reviewed the association between air pollution and asthma for the Department of Health in the United Kingdom.2 In fact, they found little evidence for an association between pollution and asthma prevalence. If anything, time trends indicated a negative rather than positive association, but there is some evidence for an increased incidence of asthma in people living very close to roads carrying heavy traffic. The overall impact of this traffic pollution on asthma incidence is not likely to be large. Air pollution of different kind was studied by Havstad et al. who studied the impact of early-life exposure to environmental tobacco smoke on the development of atopy by 2–3 years in a cohort of children.3 Using propensity score matching, they found that tobacco smoke exposure increased the risk of positive skin prick or specific immunoglobulin E (IgE) tests in children whose mothers were not atopic, but paradoxically decreased the risk in those with a positive history of maternal atopy. This interaction between maternal atopy and the effect of environmental tobacco smoke on children's risk for atopy may help to explain some of the conflicting data from previous studies. An accompanying editorial emphasizes that exposing children to tobacco smoke should of course be avoided because of the many other adverse effects,4 but the paper, like that of Gowers et al.,2 demonstrates the need to better understand how genes and environment interact to cause atopy. Other changes in lifestyle and exposures may also help to explain increases in asthma prevalence. The well-recognized association between asthma and obesity was reviewed in Respirology and the mechanism for the association continues to elude researchers.5 Changing dietary exposures could be part of the explanation. A novel association between soft drink consumption, tobacco smoking and airway disease was reported by Shi et al.6 In a large cross-sectional telephone survey of Australian adults, consumption of more than half a litre a day of soft drinks was associated with both asthma and COPD. The association was only apparent among smokers in whom soft drinks and smoking appeared to have additive effects. If these findings are confirmed in other studies, they suggest a lifestyle intervention to prevent airways disease. One of the problems in identifying the origins of asthma is that clinical asthma comprises a number of distinct phenotypes. It has recently been proposed that these phenotypes represent truly different diseases with different causes (also called ‘endotypes’) rather than simply being different and variable expressions of the same underlying pathology.7 Defining asthma phenotypes on the basis of the cellular profile of induced sputum has become increasingly important as studies indicate that eosinophilic airway inflammation responds better to corticosteroid treatment than neutrophilic inflammation.8 Phenotypes are increasingly used to target novel asthma treatments, such as the anti-interleukin (IL)-5 monoclonal antibody targeted to eosinophilic asthma.9 Specific treatments for non-eosinophilic asthma have not been established however. Choi et al. studied sputum inflammatory profiles in patients with refractory asthma requiring high-dose corticosteroid therapy selected from a large asthma cohort.10 Those with persistent airway obstruction had a longer duration of asthma and had predominantly neutrophilic inflammation, whereas refractory asthma without persistent airway obstruction was more likely to be eosinophilic. The authors suggest that this provides a rationale for developing new medications for individualized treatment in these patients. However, two studies in Respirology show that eosinophilic airway inflammation varies over time even in the absence of corticosteroid treatment. Hancox et al. found that the eosinophilic/non-eosinophilic classification was not stable over time in two clinical asthma treatment trails: even though the sputum phenotype was determined at a time when the patients were not taking any steroid treatment, nearly all patients with ‘non-eosinophilic asthma’ had raised sputum eosinophils at some point.11 Similarly, the study of Bacci et al. (discussed in the Airway Biology section) provided evidence that inflammatory phenotypes based on sputum cell analysis are not stable over time.12 Another report last year found that sputum phenotypes are not stable in children either.13 Hence, characterization of asthma and long-term treatment decisions should not be based on a single sputum specimen.14 Induced sputum analysis remains valuable for assessing patients with difficult asthma, but the resources required to obtain and analyse frequent sample will inhibit its widespread use. Although not yet established in the management of asthma, measuring of exhaled nitric oxide (eNO) offers a more practical way to monitor airway inflammation than monitoring of induced sputum.15 Affordable handheld electrochemical nitric oxide analysers are now available, making this a realistic possibility for many services. Kim et al. compared eNO measurements using the handheld Niox Mino (Aerocrine AB, Solna, Sweden) electrochemical analyser with a Sievers (GE Analytical Instruments, Boulder, CO, USA) chemiluminesence analyser.16 Correlation between the two machines was good (r = 0.88), but agreement in absolute values was only moderate: the Mino tended to give about 15% lower readings. The handheld machines are convenient but differences between machines need to be taken into account when interpreting eNO values. Although measuring airway inflammation is appealing, more simple clinical assessments remain the mainstay of asthma management. Ko et al. found that a single measurement of the Asthma Control Test—a score based on a simple 5-item questionnaire—correlated with asthma control assessments by physicians and predicted exacerbations and emergency health-care use over the following 6 months in a cohort of patients attending tertiary care in Hong Kong.17 The baseline Asthma Control Test score was better at predicting exacerbations than lung function, peak flow or eNO measurements. Simple management of asthma was also supported by a large randomized control trial comparing adjustment of inhaled steroid doses using eNO, clinical physician guidance and patient symptom-based adjustment using inhaled corticosteroids (ICS) each time they required β-agonist. No difference was found between the strategies, with the trends favouring patient symptom-led adjustment.9 Improvements in computed tomography (CT) scanning technology and lower radiation doses have enabled the use of high-resolution scans to study airway structure and differentiate between diseases, sites of inflammation and treatment response without the need for tissue biopsies.18 Kurashima et al. found that airway lumens were smaller in the 3rd- to 6th-generation bronchi in asthma but not COPD, whereas both diseases demonstrated airway wall thickening.19 These small airway diameters correlated with lung function in asthma not COPD. Hoshino and Ohtawa used high-resolution CT scans to assess changes in large airway remodelling before and after 24 weeks treatment with combination long-acting β-agonist (LABA) and ICS or ICS alone in a double-blind randomized controlled trial.20 Combination therapy reduced airway wall thickness and increased the airway luminal area to a greater extent than ICS alone. The improvements in airway wall thickness in the combination group correlated with reductions in sputum eosinophils and improvements in forced expiratory volume in 1 s (FEV1). The mechanisms for this positive interaction between ICS and LABA are not known, but the findings offer hope that airway remodelling can effectively treated and/or prevented by combination therapy. An accompanying editorial by King and Farah emphasizes the need for confirmatory and long-term studies as well as investigations of the effects on smaller airways that remain beyond the resolution of the scans.21 The findings of Hoshino and Ohtawa of a positive interaction between LABA and ICS on remodelling is relevant to the current concerns over the safety of LABA in asthma.20 Among the most controversial issues this year is the American Food and Drug Administration requirement that the manufacturers of LABA undertake large safety studies of the combination on LABA with ICS. It is accepted that using LABA without ICS is not acceptable in asthma, but it has been suggested that these large safety studies of combination therapy are futile because they will not be powered to address the question of whether they cause a small excess of asthma deaths.22 In the meantime, a recent meta-analysis demonstrates that withdrawing LABA once asthma control has been achieved, as currently recommended by the Food and Drug Administration, leads to a deterioration in control.23 Cough-variant asthma is another well-recognized but poorly understood phenotype. Ohkura et al. compared coughing during methacholine-induced bronchoconstriction in patients with cough-variant asthma (but normal cough sensitivity to capsaicin challenge) and normal controls.24 Patients with cough-variant asthma had increased cough during even mild methacholine-induced bronchoconstriction. After treatment with inhaled steroids, the number of coughs diminished to be similar to normal controls, indicating that increased cough sensitivity to bronchoconstriction is a feature of this disease variant, but that it responds to anti-inflammatory treatment. For non-asthmatic refractory chronic cough, an exciting discovery this year was that gabapentin is an effective treatment in a double-blind randomized controlled trial.25 Gabapentin is an anticonvulsant that is also used to treat neuropathic pain, suggesting that its effect on chronic cough may be due to suppression of central cough reflexes. The paradigm of Th1- versus Th2-mediated inflammation would suggest that asthma (predominantly a Th2 disease) would be less uncommon in sarcoidosis—regarded as a Th1 disorder. However, Wilsher et al. found that the prevalence of positive specific IgE tests for common aeroallergens (34%) and a history of asthma (21.5%) were similar in patients with sarcoidosis to that reported in the general population.26 In another study from the same group, Young et al. found that 44% of patients with sarcoidosis had airway hyperresponsiveness to histamine (a direct airway challenge), whereas only 11% were hyperresponsive to an indirect challenge using hypertonic saline.27 Hyperresponsiveness to histamine was more common in those with lower baseline FEV1 values and those with fibrotic and reticular patterns on lung CT. The findings suggest that the high prevalence of histamine responsiveness in patients with sarcoidosis is likely to be distinct from asthma (because of the low prevalence of hypertonic saline responsiveness) and is more likely to be due to airway remodelling caused by granulomatous airway inflammation. The development of COPD is related to both genetic and environmental factors. For genetic factors, a recent study by Guan et al. from China found that D2S388-5 microsatellite polymorphism located upstream of the surface lung surfactant protein B gene on chromosome 2 may be associated with susceptibility to COPD in Xinjiang Kazakhs.28 Another genetic factor, nucleotide-binding and oligomerization domain (NOD) 2 genes polymorphism, has also been found to have some potential association with COPD in a study from Japan. The distribution of NOD2 rs1077861 genotypes differed between COPD patients and non-COPD smokers and was associated with a lower FEV1 % predicted value in the TT when compared with the TA/AA genotypes.29 For environmental factors, exposure to noxious particles or gases is associated with the development of COPD.30 A study from Johannessen et al. found that exposure to environmental tobacco smoking during childhood was associated with COPD and respiratory symptoms in adulthood mainly in women in a cross-sectional study in Norway. In men, the most important risk factor is still acting smoking.31 The relationship of air pollution and COPD is reviewed by Ko and Hui.32 Outdoor air pollution (such as ambient air pollution) and indoor pollution (such as second-hand smoking and biomass fuel combustion exposure) are associated with the development of COPD and outdoor air pollution is a significant environmental trigger for acute exacerbation of COPD. Zeng et al. reviewed the aetiology of COPD in non-smoking subjects and risk factors may include genetic factors, long-standing asthma, outdoor air pollution, environmental smoke exposure, biomass smoke, occupational exposure, diet, recurrent respiratory infection in early childhood and tuberculosis.33 Interestingly, statins34 and even soft drink consumption6 have been found to have association with COPD. A cross-sectional study from Japan found that the prevalence of airflow limitation among patients who used statins was approximately five times lower than that among patients who did not use statins. However, statin use was not significantly associated with a lower prevalence of airflow limitation in multivariate analysis.34 Statins thus cannot be advocated for prevention of airflow obstruction at this stage. A study from South Australia assessed the relationship between soft drink consumption and presence of asthma/COPD in over 16 000 subjects.6 and noted the odds ratio for having COPD was 1.79 (95% confidence interval: 1.32–2.43) in multivariate analysis by comparing those who consumed more than half a litre of soft drink per day with those who did not consume soft drinks. The reason behind these associations is unclear and a causative relationship cannot be drawn from these studies. Comorbidities are common in COPD patients and the latest Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline has also emphasized that comorbid illness in COPD patients should be managed appropriately.30 The link between COPD and coronary artery disease is strong and complex. Coronary artery disease has a strong effect on the severity and prognosis of COPD and vice versa, including acute exacerbations.35 Ito and colleagues found that depression and sleep disorders were both common in patients with COPD.36 McSharry et al. found that sleep quality is poor in severe COPD patients with reduced sleep efficiency and reduced percentage of rapid eye movement sleep. There was a significant association between daytime hypoxaemia and sleep efficiency.37 However, depression, but not sleep disorder, is an independent risk factor for exacerbations and hospitalizations among COPD patients.36 The economic burden of COPD is huge and a recent study from Singapore showed that in 2009, COPD admissions represented 3.4% of all hospital discharges. Hospitalization was found to be the major cost driver, accounting for 73% of the total COPD burden, Between 2005 and 2009, attendances at primary care clinics, emergency departments and specialist clinics accounted for 3%, 5% and 17% of overall COPD costs, respectively.38 There are some new developments in the assessment of COPD using tools like CT and exercise tests. Degree of hyperinflation39 and airway dimensions18, 19 in COPD patients can be measured using CT parameters. Tanabe and colleagues applied a novel CT index to assess lung volume. This DLV% index measures the ratio of lung volume region adjacent to the diaphragm dome (D) to total lung volume (LV). Using this index, it was found that a reduced lung volume around the diaphragm correlated with lung hyperinflation and health-related quality of life, independent of emphysema severity.39 A recent study by Galban et al. adapted the parametric response map, a voxel-wise image analysis technique, for assessing COPD phenotype. In their study, whole-lung CT scans acquired at inspiration and expiration of COPD patients were analysed. Parametric response map identified the extent of functional small airways disease and emphysema as well as provided CT-based evidence that supports the concept that functional small airways disease precedes emphysema with increasing COPD severity.40 Phenotyping COPD by image biomarkers is currently under investigation and offers potential development of personalized therapy for COPD patients. There are also different field and laboratory tests for measuring exercise capacity in COPD patients. Hill and colleagues compared the 6-min walk test, incremental shuttle walk test and endurance shuttle walk test with a ramp cycle ergometer test in a group of patients with moderate COPD and found that these tests all elicited a similar peak rate of oxygen uptake and heart rate response. This suggested that that both self- and externally paced field tests can progress to high intensities.41 Field tests can probably offer a reasonable alternative for the evaluation of patients with moderate COPD.42 The revised GOLD was published in late 2011.30 Long-acting bronchodilators were indicated as either the first- or second-choice drugs in the treatment of all categories of patients with COPD. A new generation of rapid-onset and ultra long-acting bronchodilators have emerged as potentially the most effective drugs for symptom control in patients with COPD. Kinoshita et al. reported the efficacy of one such drug, indacaterol, when compared with placebo in 347 patients from 6 Asian regions for 12 weeks.43 They found that indacaterol provided clinically significant bronchodilation and improvements in dyspnoea and health status in Asian COPD patients, consistent with that reported in other populations. Results from several clinical trials indicate that macrolide antibiotics may prevent acute exacerbations of COPD.44, 45 However, the underlying mechanism for this effect is unknown.46 Hodge et al. showed that low-dose azithromycin treatment in patients with COPD improved the phagocytosis and elimination of both apoptotic cells and Gram-negative bacilli by alveolar macrophages and peripheral monocytes.47 This implies a dual beneficial effect of the macrolide in COPD: by reducing the load of pathogenic bacteria and by promoting the airway healing-protection process.48 The long-term safety of this approach and its cost-effectiveness in relation to other treatment options need further evaluation before it becomes a routine. During acute exacerbation of breathlessness, it is difficult for physicians to differentiate COPD from heart failure, common and mutual comorbidities. Abroug and colleagues evaluated the accuracy of N-terminal proB-type natriuretic peptide levels for the diagnosis of left ventricular dysfunction in 120 patients with severe acute exacerbations of COPD and renal dysfunction in 2 intensive care units.49 They found that the N-terminal proB-type natriuretic peptide was more accurate in patients with normal renal function (1000 pg/mL, sensitivity 94% and specificity 82%) than those in renal failure (sensitivity 71% and specificity 82%) which required adjustment of the ‘cut off’ level to a higher titre (2000 pg/mL).49 Zhang et al. in a pragmatic trial of 40 patients with acute COPD and elevated natriuretic peptide levels, presumably from left heart failure, compared treatment with intravenous diuretic versus diuretic plus vasodilator.50 They reported more rapid decline in natriuretic peptide levels with the combination treatment but no difference in symptoms.50 This is a promising approach to the accurate detection and optimal treatment of heart failure during apparent COPD exacerbations. Depression and sleep disorders are common and important comorbidities in severe COPD.37 Ito et al. found, in a comparative study of COPD patients and normal subjects, that only depression but not sleep disorders is associated with the increased risk of exacerbations and hospitalizations.36 The management of anxiety and depression was the subject of a review by Cafarella and colleagues in which they contrasted multiple treatment options available with the paucity of high-quality clinical trials on this important aspect of COPD care.51 Increased mucus production with impaired sputum clearance contributes to symptoms, exacerbations and poor quality of life in patients with COPD. In a review article, Gjoerup et al. concluded that inhaled mannitol treatment may improve the quality of life in patients with non-cystic fibrosis bronchiectasis by facilitating sputum clearance.52 Further studies are however indicted to confirm the effectiveness of this approach. Maintaining physical activity is an important lifelong goal in patients with COPD.30 It improves quality of life and averts the vicious downward spiral of greater inactivity, deconditioning and worsening dyspnoea. While pulmonary rehabilitation is an effective way to promote cardiopulmonary fitness in COPD patients, long-term monitoring and maintenance of physical activity at home is essential to preserve the initial benefits of any exercise programme. In this regard, Depew et al. found that a daily step value <4580 was correlated with severe physical inactivity (physical activity level <1.40).53 This may be a practical minimal threshold of physical activity which patients can self-monitor and aim to achieve with pedometers which are inexpensive and widely available. Non-invasive ventilation is a pivotal intervention for patients with severe, life-threatening acute exacerbations of COPD who fail to respond to initial medical treatment. It may be considered as the current standard of care in this clinical setting.30 Moreover, in patients with acutely exacerbated COPD placed on invasive mechanical ventilation, the appropriate initiation of non-invasive ventilation facilitates weaning and reduces mortality from complications linked to prolonged endotracheal intubation.30 However, there is a need to improve the practical assessment of the response to non-invasive ventilation in the acute setting. In this regard, Smith et al. reviewed the effectiveness of non-invasive ventilation for the relief of dyspnoea during acute COPD.54 However, they were unable to find consistently positive results from four randomized trials.54 The clinical implication may be that relief of dyspnoea may not be a reliable sign of response to non-invasive ventilation and thus, we should continue to rely on objective parameters. As the disease advances, the conventional treatment of COPD become less effective and symptoms become more severe. Physicians caring for such patients need to find early opportunities to hold complex conversations with them about prognosis, personal values and preferences for life-sustaining care including site of final illness. Patel et al., in a timely narrative review of the literature, discusses the various approaches to advanced care planning at the end of life in patients with severe COPD.55 Gene–environment interaction influences susceptibility to airway diseases such as asthma and COPD. Recent genome-wide association studies have found associations of specific single nucleotide polymorphisms with the development of asthma or COPD. Studies in Respirology have also focused on genetic determinants of airway diseases. A meta-analysis of studies of the +252A/G polymorphism in lymphotoxin-α found increased risk of asthma in adult or atopic populations with GG/GA genotypes.56 A genetic association study of 228 COPD patients and 101 non-COPD controls in Japan genotyped single nucleotide polymorphisms in the NOD genes (NOD1 and NOD2), encoding pattern recognition receptors that bind bacterial peptidoglygans.29 The A allele of single nucleotide polymorphism rs1077861 in NOD2 was associated with increased risk of COPD, and enhanced NOD2 gene expression in peripheral blood neutrophils stimulated with tumour necrosis factor-alpha. Genetic studies such as these support gene–environment interaction in inflammation and innate immunity pathways in the development of airway diseases. Cigarette smoking is undoubtedly the major cause of COPD; other causes include air pollution and occupational exposures.33 In the development of childhood asthma, an allergic diathesis and repeated respiratory viral infections are predisposing factors.57 The link between respiratory infections and Th2 immune responses has been demonstrated in ovalbumin-induced asthma in mice, where repeated infections with respiratory syncytial virus in infancy induced allergic airway inflammation and cytokine production by regulatory T cells and reduced tolerance to allergens.58 Bacterial infection may also contribute to asthma pathogenesis and severity, as shown by studies of airway microbiota in asthma.59 In a mouse model of asthma, the bacterial protein, flagellin, acted as an adjuvant for allergic sensitisation to ovalbumin, mediated by Toll-like receptor (TLR)5 which senses flagellin.60 Obesity has been implicated as a risk factor for asthma. In the Respirology Invited Review Series on obesity and respiratory disorders, Claude Farah and Cheryl Salome discussed potential mechanisms for the effects of obesity in asthma,5 including release of pro-inflammatory cytokines from adipose tissue (adipokines) and mechanical changes that alter lung function. Others have found increased macrophage infiltration of visceral adipose tissue in patients with asthma.61 The immunopathogenesis of asthma is typically characterized by eosinophilia, Th2 lymphocytes, IgE production and mast cell activation, together with involvement of the airway epithelium.57, 62, 63 In contrast, non-eosinophilic asthma occurs in some patients. In a study of 40 patients with non-eosinophilic asthma (sputum eosinophil count <3%), 40% of patients also had transient sputum eosinophilia during follow up over 6 months. This was more common when they were treated with the LABA, salmeterol, alone (i.e. without inhaled steroids), compared with fluticasone alone.12 This paper in Respirology therefore further supports the avoidance of LABA monotherapy for treating asthma and the potential instability of airway inflammatory phenotype. The airway inflammation of COPD is characterized by neutrophils, macrophages and CD8+ lymphocytes. A number of studies in Respirology have focused on other mediators of innate immunity. Invariant natural killer T cells are a subset of lymphocytes that recognize glycolipid antigens and function more like innate immunity mediators, but also link to the adaptive immune system. Numbers of invariant natural killer T cells were lower in the peripheral blood of patients with stable COPD and decreased further during acute exacerbations.64 TLR3 is a pattern recognition receptor that recognizes viral double-stranded RNA. A study of lung tissue showed that alveolar macrophages from COPD patients and smokers had increased protein expression of TLR3, compared with non-smokers.65 Cigarette smoke extract exposure in vitro increased TLR3 expression of monocyte-derived macrophages and increased IL-8 and matrix metalloproteinase 9 expression upon exposure to the TLR3 ligand, poly I:C.65 Thus, cigarette smoke could potentiate inflammatory responses to viral and other ligands of pattern recognition receptors in the airways. Other TLR have also been implicated in COPD. Gene expression of TLR5 was downregulated in small airway epithelium of COPD patients and healthy smokers, compared with non-smokers.66 Furthermore, in vitro challenges with flagellin activated gene expression of IL-6 and IL-8 from epithelial cells that had high TLR5 production. Hence, smoking-induced downregulation of TLR5 in the airways could contribute to susceptibility to bacterial infections in the lungs of COPD patients and smokers.66 Airway remodelling is an important feature of chronic asthma. In a study in Respirology, airway epithelial expression of resistin-like molecule-β was increased in patients with severe asthma, compared with mild asthma or healthy volunteers, and was induced following bronchoconstriction with allergen or methacholine challenge.67 Resistin-like molecule-β has previously been shown to be chemotactic for fibroblasts, and is therefore a potential mediator of airway remodelling in asthma. The pathogenesis of COPD is characterized by a response to environmental toxins, leading to lung damage that involves biological pathways, for example inflammation, oxidative stress, protease–antiprotease imbalance, apoptosis.68 These pathways have been explored in a number of studies in Respirology in the past year. Oxidized metabolites of cholesterol may have pro-inflammatory effects in specific organs. Increased protein expression of cholesterol 25-hydroxylase was measured in the lung tissue of COPD patients, with expression mainly in alveolar macrophages and pneumocytes.69 Its metabolite, 25-hydroxycholesterol, was increased in sputum of COPD patients, negatively correlated with impairment of lung function, and correlated with sputum IL-8 and neutrophils. In another study, matrix metalloproteinases and tissue inhibitors of metalloproteinases were measured in serum from 74 COPD patients and 20 non-COPD controls.70 Levels of matrix metalloproteinases 1–3 and matrix metalloproteinases 7–9, as well as tissue inhibitors of metalloproteinases 1 and 4, were increased in COPD, further supporting the involvement of protease–antiprotease imbalance. COPD is characterized by acute exacerbations, particularly as disease progresses. A study of 97 patients hospitalized with an exacerbation of COPD measured inflammatory biomarkers at admission and before discharge.71 Levels of CRP, IL-6 and fibrinogen were elevated at the start of the admission, correlated with exacerbation severity and were reduced by the time of discharge but not back to normal levels. Recovery of biomarkers therefore lags behind clinical recovery and could be useful adjuncts in monitoring COPD exacerbations.71 Molecular studies provide insight into treatment responses in airways disease. In an asthma pharmacogenetics study, single nucleotide polymorphisms in the promoter region of the SPATS2L gene were associated with bronchodilator reversibility in a genome-wide association study of 1644 non-Hispanic white subjects from six clinical trials.72 Although the biological function of SPATS2L is as yet unknown, in vitro knockdown of SPATS2L messenger RNA by short interfering RNA in human airway smooth muscle cells increased protein expression of the β2-adrenergic receptor, suggesting a role for SPATS2L in regulating receptor expression.72 In the Respirology Invited Review Series on translating research into practice, Hiroshi Kubo summarized recent developments in tissue engineering, in relation to the lung.73 The large airways have been modelled for tissue engineering with cells (extracellular matrix cells and epithelial cells, or mesenchymal progenitor cells) placed onto scaffolds (synthetic or natural). In contrast, development of models for the small airways has been more complex, because of the intricate architecture and number of cells involved. Further understanding of the biology of lung endogenous stem cells will help to advance this field, towards the future hope of regenerative medicine for lung diseases.73