Year in review 2014: Interstitial lung disease, physiology, sleep and ventilation, acute respiratory distress syndrome, cystic fibrosis, bronchiectasis and rare lung disease

Toby M. Maher 2014 was a seminal year for interstitial lung disease (ILD) with the announcement of three positive phase III clinical trials assessing treatments for the most devastating of the ILDs, idiopathic pulmonary fibrosis (IPF).1, 2 Both pirfenidone and nintedanib were shown to be effective in slowing the progression of IPF with the consequence that both drugs have now been approved by the Federal Drugs Administration in the United States. While nintedanib is only now starting to be prescribed for patients, pirfenidone has been licensed in Europe since 2011 and Japan since 2008.3 With these new treatments, real-world experience of prescribing together with long-term safety studies will be important in defining the true costs and benefits of these first effective anti-fibrotic drugs. With this in mind, Valeyre et al. published an informative analysis of all patients treated to date in the CAPACITY studies4 and the open-label, rollover RECAP studies.5 This cohort included 789 subjects with a median pirfenidone exposure of 2.6 years (range 7 days to 7.7 years) and a cumulative exposure of 2059 patient-years. The adverse events noted mirrored those seen in shorter clinical trials with upper gastrointestinal disturbance and photosensitive rash predominating. Minor derangement of liver function tests was observed in 2.7% of the study population. Reassuringly, no hitherto unrecognized, rare adverse events were identified in this study population. The advent of effective therapies for IPF, a disease that had until recently been considered by many to be untreatable, has led to a considerable increase in clinical trial activity targeted at identifying novel approaches to inhibiting fibroproliferation.6 Chambers et al. reported a phase 1b trial of placenta-derived mesenchymal stromal cells (MSC) in IPF.7 Eight subjects received escalating doses of MSC administered via a peripheral vein. In general, the treatment was well-tolerated and appeared to be safe. The study was not powered to determine efficacy, but at 6 months all subjects remained alive with stable disease. As noted by Glassberg and Toonkel in the accompanying editorial, the study raises at least as many questions as it answers but it has, at least, paved the way for larger and longer efficacy trials.8 ILD other than IPF are frequently characterized by progressive, life-threatening fibrosis. In contrast to IPF,9 many of these other ILDs are characterized by chronic inflammation or immune dysregulation, and it is this that appears to drive the development of fibrosis.10 As such, the mainstay of treatment for conditions such as connective tissue disease (CTD) associated ILD or chronic hypersensitivity pneumonitis is immunosuppression. Following on from a smaller study,11 Keir et al. reported the potential beneficial effects of the anti-CD20 antibody, rituximab.12 Although a retrospective report based on the open-label, clinical use of rituximab in a broad range of disorders, the results of treatment were sufficiently encouraging to support the funding and initiation of a double-blind clinical comparison of rituximab and cyclophosphamide as first-line treatment for CTD-ILD (NCT 01862926). Another important aspect of treating progressive fibrotic ILD is managing disease complications; one of the most serious of which is pulmonary hypertension (PH). In IPF, the phosphodiesterase (PDF)-5 inhibitor sildenafil,13 but not the endothelin receptor antagonist bosentan,14 appears to be effective in alleviating the symptoms of PH. Zimmermann et al., in a small study of 10 patients with before and after cardiac catheter data, were able to demonstrate that PDE-5 inhibitors improve pulmonary haemodynamics in individuals with ILD associated PH.15 The advent of high-resolution computed tomography (CT) scanning and the introduction, at the turn of this century, of international consensus diagnostic guidelines were important factors leading to improved clinical understanding of the natural history of many of the ILD.16 However, improved collaboration between dedicated ILD centres continues to result in the recognition of new disease entities (such as pleuroparenchymal fibroelastosis17) and has led to a better appreciation of the clinical association between chronic lung diseases such as emphysema and progressive fibrosis. Whether combined emphysema and pulmonary fibrosis (CPFE) constitutes a novel disease syndrome remains hotly contested. However, as described by Sugino et al., the combination of both emphysema and fibrosis confers a much worse prognosis than either entity alone.18 In future, real-world registry data, such as that which will be generated by the Australian IPF Registry, may help answer important questions about the nature of CPFE, the occurrence of other disease complications and changes in survival following the introduction of anti-fibrotic therapy.19 Despite the central role played by CT in the diagnosis of ILD, there is sufficient diagnostic uncertainty to warrant some form of lung biopsy in upwards of 20% of patients. While an important diagnostic modality, surgical lung biopsy, even when undertaken laparoscopically, carries an appreciable risk of morbidity and mortality. Cryobiopsy of lung parenchyma has recently been developed as a technique to try and obviate the need for surgical biopsy. The procedure, undertaken bronchoscopically, entails freezing lung tissue with an ultra-low temperature cryoprobe before removing a core of tissue with dedicated biopsy forceps. Cryobiopsy samples are significantly bigger than those obtained by trans-bronchial biopsy. Fruchter et al., in a study of 75 patients, were able to demonstrate that cryobiopsy can be safely undertaken in patients with ILD and was sufficient to enable a reliable diagnosis in at least 70% of subjects.20 In a separate study, Pajares et al. undertook a randomized assessment of cryobiopsy compared with transbronchial biopsy in patients with a range of ILD.21 Diagnostic yield was significantly better (74.4% compared with 34.1%, P < 0.001) in the cryobiopsy group without any major increase in adverse events. Further studies are required to define the exact place of cryobiopsy in the ILD diagnostic algorithm; nonetheless, it can be hoped that the procedure may, in the future, prevent some patients from needing to undergo surgical lung biopsy.22, 23 While the impact of IPF has been increasingly recognized over the last decade, the importance of ILD and pulmonary fibrosis in other diseases is frequently overlooked.24 Assayag et al. undertook a systematic review of previous reports of rheumatoid arthritis-associated ILD (RA-ILD).25 They found that RA-ILD was universally associated with a poor prognosis with a median survival from diagnosis ranging from 3.2–8.1 years. Predictors of mortality included male gender, age, extent of fibrosis and presence of a usual interstitial pneumonia pattern. ILD, of whatever cause, is not only frequently life shortening, but importantly it leads to significant curtailment of physical activity with consequent impairment of quality of life (QoL). In separate studies, Holland et al. and de Boer et al. demonstrated a clear association between dyspnoea and anxiety and depression in ILD26 and health-related QoL and psychological factors in sarcoidosis.27 Better recognition of the link between dyspnoea and psychological morbidity can only lead to improved delivery of care for both these groups of patients.28 Dyspnoea in ILD most commonly arises due to diffusion block associated with expansion of the interstitial space by either fibrosis or inflammation. However, in advanced disease the onset of PH (either due to ablation of the vascular bed or in some subjects due to chronic hypoxia) inevitably exacerbates dyspnoea and further curtails exercise capacity.29 Traditionally, invasive measurement of pulmonary pressure has been required to confirm a diagnosis of PH in ILD. Non-invasive assessment of early PH would, however, permit earlier treatment (or even prevention).30 With this goal in mind, van der Plas et al. demonstrated that cardiopulmonary exercise (CPEx) parameters, especially ventilatory equivalent at anaerobic threshold, correlated well with invasive measures of pulmonary pressure and associate with an increased mortality risk.31, 32 Although simpler than cardiac catheterization, CPEx still requires specialized equipment. For this reason, de Boer et al. compared the modified shuttle walk test with CPEx in patients with sarcoidosis. Peak VO2 during CPEx correlated strongly with walk distance in a modified shuttle walk.33 Whether this in turn enables simple, clinic-based prediction of the development of PH in this patient cohort remains to be defined. The observation by Mendoza et al. that quadriceps strength and thus endurance is impaired in patients with fibrotic ILD suggests that multiple comorbidities are likely to be involved in reducing walk distance in patients with chronic disease.34 Another comorbidity that has been linked to IPF is that of lung cancer. Detection of cancer in individuals with progressive fibrotic lung disease is frequently challenging. Dai et al. assessed the relationship between the serum cancer markers CEA and CA-125 in a retrospective single-point-in-time study of patients with ILD.35 Interestingly, both markers were increased in ILD patients compared with control and were further increased in those with coexistent ILD and cancer. The sensitivity and specificity for the markers was, however, relatively low, thus limiting their clinical utility. In contrast to fibrotic ILD, Ungprasert et al. demonstrated in a systematic review that patients with sarcoidosis do not appear to be at increased risk of malignancy.36 Neil D. 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