Year in review 2017: Chronic obstructive pulmonary disease and asthma.

Abstract

Currently, the World Health Organization estimates that chronic obstructive pulmonary disease (COPD) affects 65 million individuals worldwide and asthma affects 235 million.1 In 2015, mortality from COPD exceeded 3 million deaths, while mortality from asthma included approximately 400 000 deaths.2 Unquestionably, COPD and asthma pose a significant global burden to which many of our healthcare resources are devoted. The various publications that we highlight in this review will contribute to our understanding of the underlying mechanisms, diagnosis and clinical management of COPD and asthma. There has been a strong research emphasis on management strategies for COPD during 2017. Although clinical management often focuses on prolongation of life, there is increasing emphasis on quality of life. Hospitalization, especially with complications that increase length of stay, can have profound negative consequences for COPD patients. Specifically, they have greater risk for post-operative respiratory complications that increases with age.3 In 2017, evidence was published in Respirology demonstrating that bronchodilator use can prevent or minimize the onset of respiratory complications following non-pulmonary surgery.4 If such complications can be prevented, this will have not only a major impact on length of stay and costs, but also on quality of life. Pulmonary rehabilitation (PR) provides the foundation for community management of COPD. Evidence-based guidelines and original research published in Respirology emphasize the impact of home- or community-based programmes.5, 6 Such programmes not only promote greater access for COPD patients, but also improve function and quality of life with provision of exercise alone. Although cost and long-term adherence data are lacking, there is a growing interest in out of hospital care that improves the efficiency of care delivery by maximizing resources. Asthma research published in Respirology during 2017 has emphasized changes over the lifespan. To differentiate age-related findings, we have provided separate reviews of publications related to paediatric and adult asthma. As with COPD, clinical assessment and management of asthma have been the focus of numerous studies. Not only do severity and risk increase with age,7 but disease severity in childhood has been demonstrated to predict respiratory capacity later in life.8, 9 Novel treatment strategies include a focus on the microbiome, with administration of probiotics for both prevention and treatment.10, 11 Research regarding microbiota is of growing interest to multiple disciplines, and although meta-analysis of human trials is inconclusive,12, 13 use of probiotics remains a promising line of enquiry. Pharmacological management remains the foundation of asthma care. Hence, costs are of great worldwide interest. Of particular note is a study published in Respirology reporting the cost of asthma care in Australia and New Zealand.14 Use of inhaled corticosteroids alone was found to achieve similar outcomes at less cost than combination therapy. With annual global asthma costs estimated to exceed $8 billion,15 efficacy and cost are critically important for long-term population management. In 2017, Respirology published a wide range of articles in the area of COPD. In particular, we welcome the publication of the executive summary of the global strategy for the diagnosis, management and prevention of COPD (Global Initiative for Chronic Obstructive Lung Disease, GOLD) 2017 report in Respirology.16 In the accompanying editorial, Nishimura17 highlights important changes in the classification and management of COPD. Based on the current advances in research published during 2017, including the use of animal models,18 future COPD management will involve new biomarkers for accurate phenotyping, precision health and novel therapeutic products.19, 20 COPD pathology is thought to be primarily due to inflammation. However, Eapen et al.21 found a reduction in total cellularity in both large (endobronchial biopsies) and small airways (resected lung tissues) with a corresponding reduction in key innate inflammatory cell populations in mild-moderate COPD patients. Colonizing microbes were also found to contribute to pathogenesis, with a possible mechanism through perpetuation of negative immune responses over time.22 Although cigarette smoking is the most significant risk factor, only a fraction of smokers develop COPD, so genetic associations should also be considered when assessing potential risk factors. Qiu et al.23 found that rare variants (Glu116Lys) in mitogen-activated protein kinase 7 (MAP2K7) in southern and eastern Chinese were associated with elevated risk of COPD. Epigenetic regulation of gene expression was also shown to be modified in COPD. Barnawi et al.24 found that sphingosine-1 phosphate receptor 5 (S1PR5) gene-associated cytosine-phospho-guanine (CpG) island is differentially methylated in alveolar macrophages from patients with COPD compared with controls. Aberrant DNA methylation caused by cigarette smoke may play a role in the defective phagocytosis of apoptotic airway epithelial cells.24 Apart from genetic associations, researchers also looked at other factors leading to development and progression of COPD. Mahmood et al.25 found that activation of the Smad pathway in bronchoscopic airway biopsies was linked to epithelial mesenchymal transition activity and loss of lung function. Lee et al.26 found that COPD patients exhibited significantly lower progranulin (PGRN) serum levels and higher peripheral blood mononuclear cells intracellular PGRN levels. As PGRN protects alveolar epithelial cells from apoptosis induced by cigarette smoke, changes may be associated with development and progression of disease. It is not entirely clear what drives COPD exacerbations. Pouwels et al.27 found that increased damage-associated molecular patterns (DAMP) signalling contributed to activation of neutrophils during exacerbations. Ishii et al.28 found that in Japanese COPD patients, the G allele of the cSNP rs2075803 and the GA haplotype (rs2075803 = G, rs2258983 = A) of SIGLEC9 were associated with more frequent exacerbations and more severe emphysema (assessed as percentage of the low-attenuation area on computerized tomography (CT) of the thorax). Co-morbidities including osteoporosis are common in COPD, although mechanisms have not been clearly elucidated. Hu et al.29 found that peripheral neutrophils expressed a high level of receptor activator of NF-kB ligand (mRANKL) in male COPD patients with osteoporosis/osteopenia and this correlated with lung function. When and how to start treatment are important questions in the management of COPD.16 A meta-analysis by Chen et al.30 provided support for starting with a long-acting inhaled anti-muscarinic drug as first-line maintenance therapy in COPD instead of a long-acting inhaled beta-agonist. This approach is also advocated by the GOLD 2017 report and discussed in an editorial by Calverley.16, 31 A systematic review of the impact of inhaled corticosteroid treatment on the risk of lung cancer in COPD by Raymakers et al.32 found that randomized studies demonstrated no evidence of benefit, although descriptive studies showed some protection at high doses. Finally, a prospective cohort study by Shin et al.4 reported post-operative respiratory complications in nearly 25% of COPD patients following extra-pulmonary surgery. These complications were related to the severity of airflow obstruction and may have been prevented by perioperative use of bronchodilator therapy.4 Smoking cessation is the most important intervention for COPD, but understanding of the neural mechanisms of tobacco dependence is needed. Zhou et al.33 reported that tobacco smoking may result in lower brain insula-based resting-state functional connectivity in smokers compared with control subjects. Pilcher et al.34 found that O2 delivered via high-flow nasal cannulae in acute COPD exacerbations reduced CO2 slightly at 30 min. High-flow nasal oxygen is an emergent and potentially important treatment modality in COPD which deserves further research.35 Furthermore, for monitoring CO2, Schwarz et al.36 showed that measuring transcutaneous CO2 is more accurate than end-tidal CO2. Antenora et al.37 used non-invasive bedside ultrasound during COPD exacerbations to detect diagrammatic dysfunction (DD) that was related to failure of non-invasive ventilation (NIV) and hospital mortality. Similarly, Okura et al.38 found that even in non-hypercapnic, stable COPD patients, DD was related to severity of nocturnal O2 desaturations, so these patients may be at risk to develop frank ventilatory failure. In their editorial, Lopez-Campos et al.39 reviewed recent advances in instituting high-pressure nocturnal NIV during stable phase COPD, and described the mechanisms which might account for its beneficial effects. (Fig. 1) Thus, the effective treatment of DD may be an important strategy in both stable phase COPD and during acute exacerbations. In 2017, Respirology published the Australian and New Zealand Pulmonary Rehabilitation Guidelines.5 The expert panel made nine evidence-based recommendations that included providing PR at home and in community centres, in addition to hospitals, regardless of whether multidisciplinary education is also abvailable.5 However, Franssen and Spruit40 cautioned that the definition of PR used was somewhat narrow, and may not have adequately reflected the contribution of other interventions such as education. Despite the benefits of exercise, Clarenbach et al.41 reported significant 4-year decreases in physical activity among COPD patients that were primarily determined by airflow limitations. In addition, Braeken et al.42 identified acute exacerbations as a principle barrier to adherence during PR. Lack of access is also a barrier to participation in PR.5 As an alternative to hospital-based PR, Tsai et al.6 conducted a randomized controlled trial of home-based telerehabilitation for COPD patients that significantly improved exercise capacity, while decreasing anxiety and depression. These promising results were recognized in an editorial by Holland and Cox,43 who recommended research to identify which patients need and will benefit from telerehabilitation programmes. To evaluate physiological stress as a barrier to exercise, Robles et al.44 compared cardiorespiratory responses with strength training using single versus double extremity exercises. They reported no differences, although exercises with both arms elevated above shoulder level significantly increased heart rate, blood pressure and perceived exertion.44 However, in the accompanying editorial, Vaes45 noted that this was a single, small study and may not have been representative of the population. Clinical assessment was also the focus of several studies. Al-Kassimi et al.46 demonstrated that a CT scan or carbon monoxide transfer coefficient could be used to identify the non-emphysematous COPD phenotype that displays the clinical features of asthma but has a higher serum IgE, basement membrane thickening on bronchial biopsy, and histological and lung function improvement after inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) therapy. Houben-Wilke et al.47 reported echocardiographic abnormalities in more than 50% of COPD patients, the majority of which had not been documented in the clinical record. Nakahara et al.48 reported that hypoxaemia during exercise could predict pulmonary hypertension in COPD patients that were not hypoxaemic at rest. For more subjective measurement, Zhou et al.49 conducted a systematic review of 43 studies to evaluate the Clinical COPD Questionnaire, concluding that it was valid and reliable, with a minimum clinically important difference of 0.4.49 Chan et al.50 validated a new assessment tool in a large group of Asian COPD patients. The proposed BOSA index is calculated using a 10-point scale based on body mass index, airflow obstruction (forced expiratory volume in 1 s (FEV1) % predicted), St George’s Respiratory Questionnaire and age.50 Finally, Nakken et al.51 evaluated the agreement between surrogate and patient reports of problems with activities of daily living. Although the majority of proxies were spouses or partners of the patients, they were unable to accurately identify the most problematic activities that patients reported. Agreement was moderate for problems with showering/bathing, and only fair for walking, stair climbing and dressing/undressing.51 Improvements in estimated global asthma mortality in 5- to 34-year-olds have been observed since 1993, primarily due to the progressive increase in ICS therapy.52 However, there has been no appreciable change in asthma mortality rates from 2006 through 2012,52 and asthma remains a global problem. In 2017, severe asthma was the focus of a wide variety of papers in Respirology ranging from reviews of the current state of severe asthma management and targeted therapies53-55 to experimental trials of probiotics for asthma control in murine models.10, 11 Among patients with severe asthma, co-morbidities are common and may complicate management. As part of an invited review series in Respirology in 2017, Porsbjerg and Menzies-Gow56 discussed the prevalence and impact of common co-morbidities in patients with severe asthma, and linked those co-morbidities to specific asthma phenotypes in order to assist clinicians with assessment. In a systematic review and meta-analysis, Clark et al.57 evaluated the use of multidimensional assessment in patients with severe asthma and the co-morbidities that were commonly included in assessments. Although psychological dysfunction (anxiety and depression) was the most commonly assessed co-morbidity, respiratory infections were actually the most prevalent co-morbidity followed by sinusitis, gastro-oesophageal reflux disease (GORD) and obesity57 (Fig. 2). Accurate and timely diagnosis is critical for disease management. Bush et al.53 provided an excellent review of childhood asthma management using a unique, multidomain approach to identify severe, steroid-resistant asthma. Other strategies include measurement of FeNO, a non-invasive, repeatable, well-tolerated and reproducible marker that supports the diagnosis of asthma in children. In 2017, Visitsunthorn et al.58 investigated the association between levels of FeNO and asthma exacerbation in children. Asthma exacerbation within the next 12 months was significantly more common in paediatric patients with higher FeNO levels, and the optimal cut-off point in FeNO levels for prediction of exacerbation was 31 ppb.58 In addition, Kim et al.59 reported that high bronchodilator response as well as high FeNO levels were associated with increased risk for loss of asthma control among children with atopic asthma. By comparison, Matsunaga et al.60 assessed the effect of physical activity on asthma control in children and adolescents aged 7–17 years with a diagnosis of atopic asthma, and found no association between physical activity, asthma control level, spirometric measurements and quality of life. Among asymptomatic children, Habukawa et al.61 reported that a recently developed technology for analysing lung sounds using ic700 (index of chest wall at 700 Hz, sound intensity at 700 Hz) was useful in assessing the effects of ICS treatment, identifying those at high risk for asthma attack and predicting attack symptoms.61 Children with persistent asthma and reduced growth of lung function have been found to be at increased risk for fixed airflow obstruction in early adulthood.8 In 2017, Owens et al.9 demonstrated that reduced lung function in infancy is predictive of persistent asthma and reduction in lung function in young adults. Furthermore, Balakrishnan et al.62 examined the relationship between farming exposure and pulmonary function in a rural paediatric population of farm and non-farm dwelling children, and found higher FEV1 and forced vital capacity (FVC) among children living on a farm. Lastly, Movin et al.63 used growth mixture modelling to investigate the association between childhood asthma and heterogeneous sex-specific classes of growth trajectories during adolescence. Girls with asthma were more likely than girls without asthma to belong to a class with later growth, although no differences were found between boys with and without asthma.63 In 2017, McDonald et al.55 summarized round table discussions with Australian experts on severe asthma regarding how treatment can be optimized to improve patient outcomes, while Fricker et al.54 reviewed the use of biomarkers for targeted therapy.54 Asthma is becoming common in older subjects and recently developed treatments for asthma are guided by phenotype.64 Asthmatic subjects aged 65 years or older were found to have lower odds of atopic and eosinophilic phenotypes compared with younger subjects, although they had higher odds of irreversible airway obstruction and severe asthma.7 Blood cell count is often used as a substitute for sputum cytology to identify inflammatory phenotypes in asthma. de Farias et al.65 reported that nasal lavage cytometry showed better accuracy than blood cell count for characterizing asthma inflammation and recommended the use of nasal lavage cytology as an easy and accurate substitute for induced sputum cytology. Additionally, Bjerregaard et al.66 demonstrated that patients with sputum eosinophilia during an acute exacerbation had lower FEV1 than patients with non-eosinophilic inflammation, suggesting that eosinophilic asthma exacerbations may be clinically more severe than non-eosinophilic exacerbations. The mannitol challenge test is an easy to administer, inexpensive, indirect bronchial challenge test that has one standardized protocol. White et al.67 assessed the diagnostic utility of mannitol challenge testing for asthma and reported high specificity and good positive predictive value in symptomatic wheezing populations, but low positive predictive value in a non-clinical population. Although wheezing is associated with asthmatic patients, Musa et al.68 reported that adults with sickle cell anaemia had higher prevalence of wheezing and lower FEV1% predicted and FVC% predicted than controls without sickle cell anaemia. In fact, wheezing and FEV1% predicted were significantly associated with sickle cell anaemia status.68 In a study by Papaporfyriou et al.,69 levels of activin A, a pleiotropic cytokine, were evaluated in sputum and bronchoalveolar lavage of asthmatic patients. Activin A levels were higher in severe refractory asthma and associated with transforming growth factor-β1, eosinophils in sputum and/or in bronchoalveolar lavage and reticular basement membrane thickness.69 Utilizing impulse oscillometry, peripheral airway dysfunction was found to be impaired in adults with asthma.70 The association between asthma and abnormalities in impulse oscillometry measures was stronger in men than in women, and most apparent in those with childhood-onset asthma.70 The Global Initiative for Asthma encourages patients with asthma to engage in regular physical activity for its general health benefits.71 In a population-based cohort study over a mean follow-up of 11.6 years, slightly less decline in lung function was observed in physically active participants with asthma than in inactive participants, particularly for FEV1, FEV1/FVC ratio and peak expiratory flow. Furthermore, it has been observed that childhood asthma is a significant risk factor for persistent asthma in adults.72 In 2017, Omori et al.73 showed that remitted childhood asthma was independently associated with airflow obstruction in middle-aged adults. In addition, ever-smokers with remitted childhood asthma were reported to have significantly lower FEV1/FVC than never-smokers with remitted childhood asthma.73 Reddel et al.14 investigated whether there were differences in asthma management and outcomes between New Zealand and Australia. New Zealand achieved better adherence and similar outcomes with wider use of less expensive ICS monotherapy, despite a higher proportion of participants using costlier ICS/LABA in Australia than in New Zealand. According to longitudinal administrative data from Singapore, asthma control measured by the Asthma Control Test was associated with higher asthma drug costs, but significantly lower total asthma costs, especially for obese patients.74 However, in Singapore, the incremental cost-effectiveness of bronchial thermoplasty combined with optimized asthma therapy was not found superior to optimized asthma therapy alone for difficult-to-treat and severe asthma patients.75 Due to the complexity of asthma phenotypes, studies in different animal models form the basis of our current understanding of the pathophysiology of asthma, and are central to the preclinical development of drug therapies. As part of the invited review series in Respirology, Maltby et al.76 provided an insightful appraisal of mouse models of severe asthma used to understand mechanisms of steroid resistance, tissue remodelling and disease exacerbation. Although no single mouse model provides a comprehensive model of severe asthma in humans, they suggested that mouse models provide evidence for steroid resistance under certain conditions. Murine models have also been used to study the underlying mechanism in the association between intrauterine growth restriction (IUGR) and asthma. Wang et al.77, 78 demonstrated that persistent structural airway changes lead to bronchoconstriction and disease susceptibility in both rat and mouse models of IUGR. Current therapy for asthma is primarily focused on symptom relief. In approximately 10% of patients, symptoms cannot be controlled by maximal, optimally delivered therapy. In the search for alternative drugs for uncontrolled severe asthma, the phosphatidylinositol-3-kinase (PI3K) pan-inhibitor LY294002 was found to attenuate not only IL-25 (an epithelial-derived cytokine)-induced asthma-like AHR and inflammation, but also airway remodelling in the IL-25-induced murine intranasal challenge model of asthma.79 The data suggest that disruption of PI3K signalling for downstream effects of IL-25 might ameliorate ongoing airway inflammation and AHR, and alter the process of chronic airway remodelling.79 Furthermore, it was observed that simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, partially attenuated airway inflammation and reversed the overabundance of bronchial smooth muscle cells, thereby ameliorating AHR through an activated autophagic process in ovalbumin-sensitized and -challenged murine models of asthma.80 Finally, Suzaki et al.81 investigated the use of a periostin-neutralizing antibody in differentiated airway epithelial cells. IL-13-induced periostin production was found to be regulated by Janus kinase (JAK)/signal transducer and activator of transcription factor 6 (STAT6) and MEK/extracellular regulated protein kinase (ERK) pathways.81 Although inhibition of periostin attenuated IL-13-driven MUC5AC mucin production, periostin only weakly stimulated mucus secretion.81 In 2017, two studies examining the effect of microbiota on airway inflammation were reported in Respirology. Juan et al.10 demonstrated that oral administration of Clostridium butyricum CGMCC0313-1 (a specific butyrate-producing bacterial strain) reduced ovalbumin-induced allergic airway inflammation in mice. In another paper, Fonseca et al.11 found that oral administration of Saccharomyces cerevisiae UFMG A-905 (a baker’s yeast) was effective in prevention of allergic asthma characterized by bronchial hyperresponsiveness, bronchoalveolar eosinophils and airway and lung inflammation. However, although these findings are of interest, future studies are warranted to ascertain the specific differences in microbiota composition between healthy humans and asthmatic patients in order to identify the ‘ideal probiotic’ able to prevent or fight airway microbial dysbiosis in asthma.