<i>Respirology</i> year‐in‐review 2007: Clinical science

Respirology continues to serve as the pre-eminent regional respiratory journal for Asian and Pacific countries and submissions have continued to increase, as has the quality of published papers. Rather than reporting mostly descriptive data, many authors have endeavoured to also examine disease mechanisms with the aim of improving our understanding of the underlying disease process. We are starting to move from descriptions of the disease and where it occurs to a more developed style able to provide mechanistic information that may ultimately contribute to the development of treatment solutions and better disease management. The shift in emphasis reflects a growing maturity of Respirology and indicates that as an academic journal it can contribute significantly to future dissemination of new scientific knowledge related to respiratory diseases. It is expected that this ‘maturity’ will encourage authors to send their ‘good’ papers first to Respirology and indeed the journal is now receiving many manuscripts from areas outside of our traditional support base. In this review we highlight important findings in clinical sciences from articles published in Respirology in 2007. We hope it will provide an overview of new information reported in the journal that will facilitate gains in our understanding of respiratory diseases. Characterization of different disease phenotypes remains a research priority in asthma.1 Ceylan et al. studied the association of nasal polyps with asthma and found that patients with polyps had increased asthma severity, suggesting the presence of a ‘united airway’ and implying close links between inflammatory diseases affecting the upper and lower airways.2 Severe or ‘difficult’ asthma was evaluated in a study conducted in a specialist asthma clinic, and again the severe phenotype was linked to an impaired quality of life.3 The study also showed that the severity of impairment is likely to be underestimated by clinicians managing patients in busy outpatient departments. An interesting study by Talay et al. found increased Gram-negative bacterial colonization in older asthmatics with more severe disease.4 Although all patients were current non-smokers, previous smoking was not reported and the cohort may have been biased by the inclusion of ex-smokers having COPD, a group with known increased bacterial colonization.5 Studies of environmental factors that influence the development of asthma have suggested that exposure to endotoxin may bias the immune response away from asthma. This hypothesis was assessed in a longitudinal Canadian study, conducted over a period of 2 years.6 The data demonstrated a reduced risk of asthma in a farming environment, with odds ratios of 0.22 (parental asthma) and 0.39 (no parental asthma). This study expands the findings from previous observational studies in the field. Asthma outcomes and management were evaluated in an Australian study that covered all states (metropolitan and rural) by Marks and colleagues.7 They obtained responses to a detailed questionnaire from 70% of the study group initially identified for inclusion, and showed that asthma control was generally poor. Rather disturbingly, they found that only 35% of adult asthmatics with daily symptoms were taking inhaled corticosteroids. Although the study was conducted in one country and may not necessarily be representative of the Asia–Pacific region, it nevertheless indicates that asthma management and treatment may be suboptimal in many countries. An intriguing study performed by Lancsar and coworkers assessed patient preferences in relation to three options: current inhaled steroid medication, a hypothetical preventer and no medication.8 This entailed a discrete choice experiment in 57 adults with mild–moderate asthma who were using ≤500 μg beclomethasone (BDP) or equivalent medication. The results suggested that patients prefer anti-inflammatory medications that maximize physical activities, have few side-effects and do not require daily PEF measurements. The results provide a timely reminder that asthma patients may have priorities that are different from those traditionally espoused by medical professionals. Finally, two studies evaluated the efficacy and side-effects of a new inhaled corticosteroid, ciclesonide.9,10 Hydrofluoroalkane-ciclesonide, 800 μg daily was more efficacious than chlorofluorocarbon-BDP, 800 μg daily in reducing asthma symptoms and increasing PEF. Side-effects were similar in the two treatment groups and occurred in few patients. Interstitial lung disease (ILD) remains under researched and continues to present ongoing clinical, therapeutic and prognostic challenges to respiratory physicians. Although some basic research indicates the nature of the underlying lung fibrotic process, there is limited information to help the clinician choose an effective treatment and provide the patient with an accurate indication of their disease course and ultimate prognosis. However, several studies published in Respirology in 2007 have added valuable information regarding prevalence, putative causes and diagnosis of ILD. Anantham and coworkers studied the incidence of sarcoidosis in a large Singapore hospital.11 They detected a higher incidence and more severe disease in patients of Indian ethnicity, a finding that is comparable to observations made in African-American populations. A study conducted in Turkey found the highest frequency of onset of sarcoidosis in spring, again suggesting a role for an infectious agent and further studies appear warranted.12 Patients with IPF are prone to acute exacerbations that have been mostly ascribed to infections. Infections with Chlamydophila (previously Chlamydia) pneumoniae are thought to be an important cause of both asthma and COPD exacerbations and were evaluated in patients with acute ILD.13 The authors used acute and convalescent serology to detect infections, and only a small number of cases were associated with significant rises in antibody titres, suggesting a limited role for this organism in acute ILD. The study did not use PCR methods to assess C. pneumoniae in sputum and may have failed to detect mild infections. PET is now widely used to stage lung cancer but may also have utility in ILD, reflecting the high inflammatory burden. Nusair and coworkers used PET to evaluate whether IPF can be distinguished from other ILD by this method.14 The findings were disappointing and did not allow differentiation of IPF from other ILD. Larger study populations and use of newer technologies may be required in assessing the utility of PET in ILD. Real-time endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) is a new technique with a sensitivity >90% for diagnosis of mediastinal and hilar malignancies. A study by Oki et al. found EBUS-TBNA to be highly sensitive in the context of suspected sarcoidosis with mediastinal and/or hilar lymphadenopathy.15 The procedure was safe and devoid of significant morbidity, and larger studies are warranted. A feature of papers published in Respirology in 2007 has been an emphasis on characterizing pleural effusions associated with a variety of medical conditions. Porcel and coworkers studied 230 consecutive patients with pulmonary embolism and detected pleural fluid in about one-third.16 All effusions were exudates, often with high erythrocyte counts. Surprisingly, the presence of pleural fluid was not related to radiological evidence of pulmonary infarction (50% in those with signs of infarction, 46% in patients without, P = 0.7). The prevalence of pleural effusion post orthotopic heart transplantation (OHT) was evaluated in another study.17 The authors reported that pleural effusions were common within 12 months following OHT (85%) and that most were small, bilateral and tended to resolve. Peng and coworkers evaluated symptomatic large pleural effusions more than 30 days after coronary artery bypass grafting.18 The prevalence of effusions was low (approximately 3%) and again most resolved with medical management. Diagnostic and therapeutic modalities for simplifying traditional diagnostic pathways in pleural effusions of unknown origin continue to evolve. Lee and coworkers reported a prospective evaluation of flex-rigid pleuroscopy for diagnosis of indeterminate pleural effusion.19 Patients who had received no diagnosis after at least one thoracocentesis and one closed needle pleural biopsy were studied. Flex-rigid pleuroscopy yielded a diagnosis in 49/51 patients and morbidity was minimal. In a report by Luh and Tsao treatment of spontaneous haemopneumothorax was evaluated using video-assisted thoracic surgery (VATS).20 The source of bleeding was identifiable by VATS in >80% of patients and thoracotomy was required intra- or postoperatively to control ongoing bleeding in only about 25% of patients. Finally, an interesting study by Wang et al. assessed lung function after drainage of pleural fluid.21 The investigators postulated that paradoxical movement of a hemidiaphragm secondary to a large pleural effusion contributes significantly to reduced pulmonary function and hence possibly also to breathlessness. The researchers showed elegantly that ‘pendulum’ breathing was present in a subgroup of patients, and that thoracocentesis leads to small, but significant improvements in FEV1, FVC, blood gases and the Borg dyspnoea scale. There were no improvements after thoracocentesis if paradoxical movements were absent. Based on recent estimates, more than a million people die annually of lung cancer. This is of particular importance and relevance for Asia-Pacific countries where smoking remains a major public health problem that shows no signs of abating. Lung cancer was well covered by Respirology in 2007, chiefly through a number of outstanding reviews coordinated by Neil Watkins and Wah-Kit Lam. Michael Alberts discussed follow up and surveillance of patients following surgery for lung cancer.22 A suggested surveillance approach that was clinically reasonable and cost-effective was outlined but it was emphasized that current recommendations are primarily based on expert opinion. This key aspect awaits further studies. A review by Hicks et al. outlined the role of imaging in the diagnosis of non-small cell lung cancer (NSCLC).23 PET FDG, and particularly PET/CT, provides significantly superior staging information and EBUS with biopsy offers a minimally invasive approach with a good safety profile. The authors concluded that few patients should reach the point of definitive treatment without clear definition of the extent of disease. This sentiment was echoed in the review of invasive modalities in staging NSCLC.24 The optimum approach and appropriate use of invasive modalities will depend on the individual case and the clinician's assessment. Adjuvant and neo-adjuvant chemotherapy is being used in later-stage NSCLC (Stages II and III) and has provided evidence of improved survival. Brahmer and Ettinger compiled a comprehensive review of data supporting the standard use of adjuvant therapy and presented information supporting the use of neo-adjuvant therapy in selected patients with NSCLC.25 Future directions were reviewed by Lam and Watkins.26 They emphasized that basic research is increasingly being translated into clinical benefits for patients. New targeted treatments directed at apoptotic and developmental pathways have therapeutic potential, and molecular profiling may allow individualized prognostic and therapeutic treatment plans that are tailored to the disease characteristics in each patient. The authors pointed out that Asia is facing a major epidemic of lung cancer and that a concerted effort should be made to devise and organize antismoking strategies and programmes. Diagnosis of early lung cancer remains a key goal. Yonemori and coworkers developed and validated a diagnostic prediction model for solitary pulmonary nodules.27 The model consisted of two biochemical and three radiographic components. In a validation model it had diagnostic accuracy of >85% but the model was still inferior to the opinion of an experienced radiologist (90%). Hsu and coworkers evaluated the performance of transbronchial needle aspiration (TBNA) for diagnosing hilar-mediastinal lesions suspected on PET/CT.28 A respectable sensitivity, specificity and diagnostic accuracy (82%, 100% and 84%, respectively) for PET/CT-guided TBNA were reported. Limitations were the retrospective study design and possible selection bias, and prospective multicentre studies are now indicated. Surgical strategies for NSCLC in octogenarians were evaluated by Ikeda et al.29 Patients were aged (mean 83 years) but judged to be operable with evidence of only limited disease. Generally, survival was comparable to that of younger patients but postoperative complications were more frequent (>25%). Again early diagnosis was paramount and predicted survival. COPD represents an increasing disease burden for all communities and common descriptors, models and effective strategies to reduce morbidity and mortality are needed. Publications in Respirology in 2007 have covered the full spectrum of COPD management, from nomenclature to rehabilitation, as well as models of COPD. A guest editorial by Miravitlles and Morera argued for incorporating ‘tobacco smoking’ into the description of COPD.30 Their argument was partly based on the fact that biomass smoke exposure causes a lung disease different from that caused by tobacco smoking. They argue that re-thinking the definition may stimulate the development of appropriate strategies for the management of COPD. Aliverti et al. reviewed a human model of the pathophysiology of COPD.31 Expiratory flow limitation (EFL) imposed during exercise in normal subjects caused a reduction in maximum work (to about two-thirds of the control value), due to dyspnoea without prominent dynamic hyperinflation. During the EFL exercise, the Borg scale breathing effort increased progressively over control values. There was strong evidence for inspiratory and expiratory muscle recruitment during EFL exercise and the amplitude of oesophageal pressure swings accounted for most of the variance in Borg scale ratings. A major effect of EFL is a reduction of expiratory flow and increased inspiratory flow. Therefore EFL causes a load that decreases the shortening velocity of expiratory muscles, while increasing the shortening velocity of inspiratory muscles. A progressive rise in end tidal PaCO2 throughout the EFL exercise probably causes increased central drive to inspiratory muscles. In addition, the dead space : tidal volume ratio increased as the EFL exercise workload increased. EFL also limits cardiac output by decreasing venous return and also reduces pulmonary capillary blood volume. Although this useful model mimics many of the findings in COPD and exercise, one major limitation is that it is an acute and temporary intervention. Dynamic hyperinflation (an increase in end expiratory lung volume (EELV)) occurs during exercise in COPD patients, and partly causes decreased exercise times and the sensation of increased dyspnoea. Fujimoto et al. examined whether incremental hyperventilation caused dynamic hyperinflation as measured by plethysmography, in ex-smokers without COPD and in patients with COPD, and examined the effects of short-acting β-agonist and anticholinergic bronchodilators in an open study.32 Patients with COPD showed a significant increase in EELV, and a decrease in inspiratory capacity with metronome-paced hyperventilation. Ex-smokers without COPD showed lesser effects than COPD patients. Both short-acting bronchodilator treatments significantly increased inspiratory capacity and reduced EELV. Therefore metronome-paced hyperventilation appears to be simpler than exercise tests for determining whether patients are likely to suffer dynamic hyperinflation during exercise, and is a potential model for testing therapeutic agents. Xu et al. have examined a large population in China by direct interview to look at the relationships between cigarette smoking, indoor pollution and COPD.33 The striking 90% response rate to this survey exceeds that of many Western population surveys. They found a dose–response for the development of COPD on exposure to active cigarette smoking even when other factors such as socioeconomic status were adjusted for. Women had a greater odds ratio for developing COPD than men. In this study there were no overall links between indoor pollution, passive smoking and COPD prevalence. However, in non-smoking women who were exposed to pollution from the burning of coal for winter heating, there was a small increase in COPD prevalence. The study limitations were that the COPD was not characterized by spirometry and direct pollution measures were not available. Interactions between indoor pollution factors and COPD causation probably require objective measurement, but biological effects may be dependent on ethnic variation. Lindberg et al. undertook a randomized double-blind placebo-controlled study in 90 patients who had COPD with acute FEV1 reversibility of between 9% and 25% in response to inhaled terbutaline.34 They compared the effects of budesonide/formoterol, fluticasone/salmeterol, salbutamol and placebo. The primary outcome was change in FEV1 at 5 min with the secondary outcomes being changes in inspiratory capacity and perception. Not surprisingly, given the selection of the patients and the pharmacology of the agents used, budesonide/formoterol promoted a greater increase in FEV1 at 5 min than fluticasone/salmeterol, but the effect was similar to that of salbutamol. Changes in inspiratory capacity were equivalent across active treatments and greater than placebo. It is arguable whether some of these patients had a component of asthma, given the bronchodilator response. Perhaps they should have been classified as a group with overlapping asthma and COPD. It is noteworthy that all of the subjects were taking inhaled corticosteroids at a mean dose >600 μg/day. Acute exacerbations of COPD (AECOPD) were studied for types of pathogens by Lin et al.35 and Alamoudi.36 Potentially pathogenic bacteria were identified in the sputum of 66.5% of AECOPD, with Klebsiella pneumoniae being more prevalent in mild COPD, while Pseudomonas aeruginosa was associated with long hospital stays, increased mortality and an increased risk for intubation.35 In the study of Alamoudi et al. 69.8% of 139 AECOPD had positive sputum cultures.36 Regional knowledge of likely pathogenic bacteria is helpful in the management of AECOPD, but needs to be supported by regional knowledge of antibiotic et al. examined hospital for COPD patients in were higher than compared with There was a between and smoking, as well as a lower number of of may the between the and may have several but there are at the for better of and for that provide within the to hospital after AECOPD in were associated with a low and use of An open study suggested that reduced after AECOPD as compared with standard The study should be with an appropriate prospective design if it is to influence changes in current A COPD population was examined for the effect of high exercise in a pulmonary conducted by et The were at the work rate in exercise testing than the patients the high This is of for these patients on the of their and Patients who the high showed a significant increase in with a mean of be a significant for a number of the patients. improved in both these changes can be to larger with the high in pulmonary is The study observations that exercise, at high or at lower provide outcomes for patients with COPD. et al. in dyspnoea and quality of in patients with Women had a lower exercise were more and had lower on more and The quality of showed greater for women in physical activities, and than for patients. findings were present after for and of It has been reported that can influence quality of and whether the findings from this study are outside is is it that women appear to have more this diagnosis or factors affecting the of women compared with et al. examined the of in COPD patients compared with a group of This study, in of the COPD patients were on showed more severe and of in COPD patients. This study the to about in COPD patients, and the severity of the to management of this into the comprehensive of COPD patients. the COPD population more people die from disease and lung cancer than respiratory al. reviewed the risk factors in COPD It is known that is associated with risk of disease even after for other known This association is also present in and it has been argued that this provides a possible for environmental and of disease. There are effects in COPD, muscle and It has been demonstrated that of are associated with increased mortality in COPD. In COPD patients there is an association between and the of and corticosteroids are used for reducing exacerbations in severe COPD and this also reduces mortality has been in patients aged over who use inhaled corticosteroids after exacerbations of COPD. The use of has no benefits to disease mortality has not been assessed in studies of patients receiving is the treatment to survival of COPD patients. and the nomenclature and presented the results of in a of patients with expiratory central The the and of the as at the severity of the of the that was reduced during and the of the should be of this will provide a common for the of patients with expiratory central and a common standard for changes in severity of with or after is probably improved both by and in some by treatment of the underlying for Patients with dynamic may most likely from treatment of the underlying such as COPD, such as or A study of the of survival in patients positive pressure for thoracic and respiratory was reported by et A of was associated with survival. The of was not a of survival. This retrospective study needs to be but the potential of PaCO2 to about the of for thoracic This will widely in on health et al. examined the outcomes of in patients with They reviewed the of patients, patients with and 12 patients with who had as well as patients with that more the onset of patients had higher PaCO2 and a lower but higher FEV1 than patients with The survival for patients was it was months in the group with progressive disease and months in the patients with In by was on the of symptoms and a PaCO2 during the or at the that a inspiratory pressure of of should the for in this the mean at the onset of was or 30 of The investigators the point of being of the for early of respiratory as a for two studies the use of PaCO2 as an early of the for a study suggesting that there is a higher risk of in patients with findings during and there was a for days of therapy to reduce The prevalence of in the group was The study two to the are required in many to provide information and drive changes in with being to evaluate the effect of A study on a of hospital a respiratory was reported by et had received a hospital It was of that were detected in the who on and this may be by and The findings support the for active and control programmes. et al. report a study of adult patients with pulmonary over a period in were treatment with corticosteroids for from several to a number of associated with pulmonary were COPD, transplantation and infections. using sputum a high in those the mean to diagnosis was no radiological was for The is that there has to be a between and of for in all et al. a retrospective of patients with severe acute respiratory in clinical and data and during the first days of from the of onset were rate and were all of respiratory and during the period from and were of hospital mortality in this of and was also associated with This with of severe in other but the were more Infections in had a significantly lower mortality than and this may be related to An early to and for early and the management of are being A prospective Australian study by Lee and compared a group of patients = a early to and early with a retrospective control group = The for hospital were medical in in in diagnosis in and with the severity in of patients. of

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