Year in review 2011: Acute lung injury, interstitial lung diseases, physiology, sleep and lung cancer

Yuanlin Song ALI and acute respiratory distress syndrome remain severe respiratory diseases with a high morbidity and mortality.1 For this reason ALI/acute respiratory distress syndrome are an important topic of on-going research. During 2011 Respirology published a number of important papers focusing on risk factor identification, biomarker screening, imaging for lung injury assessment and potential novel treatments. Robinson et al. comprehensively summarized the effects of natural disasters on human lung health.2 It is not surprising that most natural disasters are associated with respiratory disease due to inhalation of various particles and noxious gases. This is especially the case with ambient matter with a diameter less than 10 µm; a size of particle that can penetrate the distal airway and which can then injure airway and alveolar epithelial cells. These particles may well increase cell permeability partially through induction of occludin internalization.3 Effective prevention, which relies on prompt and early intervention immediately after disasters, is very important to ensure safety and lung health. An alert system following disaster may minimize hazardous exposure and reduce subsequent morbidity and mortality in the general population. Quantification of lung injury enables optimization of treatment and provides an indication of prognosis. There are, however, currently very few practical tools that enable clinicians to make an accurate disease severity assessment in individuals with ALI. Lung infection is a major risk factor for ALI. Tagami et al. found plasma neutrophil elastase level correlates with pulmonary vascular permeability index.4 This observation could be useful for assessing endothelial permeability changes in severe pneumonia patients. In another study, Bastin et al. found that a progressive drop in pH in exhaled breath condensation fluid during single lung ventilation is inversely correlated with increased lung injury.5 The exact mechanism of exhaled breath condensation pH changes and association with ALI warrants further investigation. Imaging analysis demonstrates that CT can be used to measure tissue density and perfusion in normal and acute respiratory distress syndrome lungs through intravenous injection of contrast fluid.6 This imaging approach is thus useful for detecting heterogeneous blood perfusion in acute respiratory distress syndrome patients. There have been several studies in the last few years showing promising treatment strategies that are inspiring in the field. Lung injury repair is the essential component in disease recovery, for which stem cell therapy has shown significant promise through induction of immune modulation and antimicrobial peptide production.7–9 These findings suggest the emergence of an era of tissue and organ regeneration for various organ injuries, including ALI and acute respiratory distress syndrome. Toby M. Maher The last few years have seen a rapid increase in clinical trials for interstitial lung diseases in general and idiopathic pulmonary fibrosis in particular. The licensing for the treatment of idiopathic pulmonary fibrosis (IPF) of the novel anti-fibrotic agent pirfenidone in Europe, India and Japan has brought a ray of hope to suffers of this deadly and progressive disease.10 However, it is clear that further treatment developments are required and the results of on-going trials are eagerly anticipated. In 2011 Respirology published several important studies in IPF. Malouf et al. reported the results of an investigator-led study of the macrocyclic proliferation signal inhibitor and immunosuppressant evorolimus.11 In a six-centre Australian study the authors administered placebo or evorolimus (at a dose of 4 mg twice daily) to 104 individuals with IPF for 3 years. Unfortunately, evorolimus was poorly tolerated because of side effects and, at 3 years, patients in the treatment arm had fared worse than those receiving placebo. Three year transplant-free survival was 36% in the everolimus group versus 51% in the placebo arm (P = 0.11). This result, together with the recently announced PANTHER study data suggest that aggressive immunosuppression in IPF is deleterious and should be avoided. Furthermore, as was cogently argued in the accompanying editorial by Lee and Collard,12 it is important that in the search for an effective treatment for IPF investigators remain mindful of a therapy's potential for harm. Pre-clinical studies are therefore an important testing ground for potential future treatment developments. Wang et al. presented interesting data on the use of a novel single chain Fv antibody targeting connective tissue growth factor.13 The authors were able to demonstrate in vitro, in fibroblasts, and in vivo, in the murine bleomycin model, that connective tissue growth factor inhibition attenuates fibrogenesis. Notwithstanding important limitations in animal models of fibrosis14 these data suggest that further exploration of anti-connective tissue growth factor approaches as a treatment for IPF are merited. In a disease, such as IPF, lacking definitive therapies it is important that clinicians also focus on interventions that improve quality of life and reduce disease-related symptoms. Pulmonary rehabilitation is now well established as an effective therapy for individuals with COPD. Whilst the evidence base is less well developed for IPF there is a growing consensus that pulmonary rehabilitation is also of value for individuals with IPF. Kozu et al. have made an important contribution to this area with a study of 65 subjects with IPF.15 The authors measured the effect of an individual's baseline disability on their response to rehabilitation. Subjects were divided by MRC dyspnoea score at enrolment. Only those with a score of 3 or less showed improvements in the 6-minute walk distance and QoL (as measured by the Short Form-36 questionnaire). Subjects with grade 4 or grade 5 dyspnoea failed to show any physiological or symptomatic improvements following rehabilitation and in some cases deteriorated over the course of the program. These finding suggest that although pulmonary rehabilitation is an effective intervention in IPF it should be used during the earlier rather than later stages of the disease. As discussed in the accompanying editorial it may be that for severe disease, novel approaches are required in delivering rehabilitation therapy for it to benefit this patient group.16 The disease course of IPF is characterized by the development of a number of important complications. These include symptoms such as dyspnoea and cough and secondary conditions such as pulmonary arterial hypertension, lung cancer and an increased incidence of ischaemic heart disease. These issues were all explored in a number of insightful papers published in Respirology during 2011. In a cohort of 242 subjects with well-defined IPF Ryerson et al. made the interesting and novel observation that the symptom of cough predicted a group of patients with more progressive disease and did so independent of baseline disease severity.17 The only limitation to the usefulness of this finding was the high baseline incidence of cough (84%) in subjects with IPF. Secondary pulmonary hypertension (PH) in individuals with IPF is another determinant of poor outcome, and despite the negative outcomes of recent trials remains an attractive target for treatment.18,19 Right heart catheter remains the diagnostic gold standard for PH. However, in a group of patients with rapidly progressive disease and often associated co-morbidities it is an investigation with major limitations. It is unsurprising therefore that a number of groups have sought to find effective non-invasive alternatives to right heart catheterization. In recent studies published in Respirology, Swigris et al. have shown that delayed heart rate recovery following a 6-minute walk defines a group of patients more likely to have PH.20 Similarly, Boutou et al. showed that in maximal exercise tests, maximum work rate, peak O2 uptake, anaerobic threshold and peak O2 pulse were all reduced in those with a systolic pulmonary artery pressure > 50 mm Hg.21 Although both studies demonstrate that currently available non-invasive tests can be used to identify groups of patients with IPF with a higher likelihood of having PH, none have the discriminatory power to be used in isolation as a stand-alone diagnostic test for IPF-related PH. Instead, it seems likely that integrating the results of several non-invasive tests (such as serum brain natriuretic peptide, echocardiography, 6-minute walk data and lung function variables such as DLco and Kco) will provide the best means for discriminating individuals with IPF related PH from those with IPF alone. Such an approach may thus enable enrichment of appropriate clinical trials and selection of individuals most likely to benefit from treatment for PH without necessarily requiring right heart catheterization. Individuals with IPF have been shown to have an increased incidence of coronary artery disease. However, identifying symptoms arising from cardiac disease in an individual with significant exercise limitation due to advanced respiratory disease is frequently challenging. With this in mind Nathan et al. assessed the value of CT in identifying individuals with IPF and significant coronary artery disease.22 Moderate to severe calcification of the coronary arteries had a sensitivity of 81% and specificity of 85% for detecting coronary artery disease considered significant at angiography in a cohort of 57 patients with IPF who underwent left heart catheterization. This study suggests that CT may be an effective non-invasive test for identifying individuals with IPF who would benefit from further cardiac investigation and intervention. Toby M. Maher Sarcoidosis remains an enigmatic disease with protean manifestations. All practising respiratory physicians will be au fait with the challenges inherent in confirming a diagnosis of sarcoidosis, defining organ involvement, deciding need for treatment and assessing disease activity and complications.23 A number of papers published in Respirology during 2011 have sought to address these issues. Okumus et al. in a well-organized study conducted by the Turkish Thoracic Society's Clinical Problems Study Group, sought to define the patterns of extra pulmonary involvement seen in patients with sarcoidosis in Turkey.24 In keeping with studies in other populations the authors found that extra thoracic symptoms occur frequently and that the commonest non-pulmonary sites involved were the skin (16.4%) and the lymph nodes (13.3%). Umeda et al. assessed the use of 18F-fluorodeoxyglucose-positron emission tomography for determining individuals with persistent or progressive disease.25 The authors were able to demonstrate that, by undertaking two scans, at 60 and 180 min post-18F-fluorodeoxyglucose administration, and calculating the retention index (a measure of change in intensity of 18F-fluorodeoxyglucose uptake across the two time points) that it was possible to identify individuals with persistent disease from those with disease that improved at follow up. Whilst the study is too small to drive a change in clinical practice it suggests that 18F-fluorodeoxyglucose-positron emission tomography may enable better stratification of patients at presentation than current techniques such as gallium scanning and it might be of use in identifying individuals most likely to benefit from therapy. PH occurs in sarcoidosis through a number of mechanisms and frequently portends a poor prognosis. In a detailed review Corte et al. describe potential mechanisms for the development of PH in sarcoidosis and provide a helpful practical overview of current treatment options for this challenging to manage disease complication.26 Amanda Piper Obstructive sleep apnoea syndrome (OSAS) is a common medical condition with potentially serious clinical consequences. It is strongly associated with body weight,27 and given the increasing prevalence of obesity in the general population, the health burden of this disorder will undoubtedly increase over the coming years. 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