Year in review 2016: Interstitial lung disease, pulmonary vascular disease, pulmonary function, paediatric lung disease, cystic fibrosis and sleep

Adelle S. Jee and Tamera J. Corte The year 2016 has been pivotal for researchers and clinicians with an interest in interstitial lung disease (ILD). The advent of anti-fibrotic therapy for idiopathic pulmonary fibrosis (IPF), the most common idiopathic ILD, has led to major changes to the approach towards the diagnosis and management of ILD. In appreciation of such changes, Respirology commissioned a timely series of reviews of the idiopathic interstitial pneumonias (IIPs), an important subgroup of the ILD. We review the original manuscripts from 2016, as well as highlighting some key points from this IIP review series. The increasing complexity of ILD classification and diagnostic approach underscores the importance of diagnosis by multidisciplinary discussion, including input from experienced pulmonologists, chest radiologists and lung pathologists. Jo et al. have recently demonstrated the impact of a dedicated ILD multidisciplinary team (ILD-MDT) review on clinical care. In the present study, the ILD-MDT at two specialist ILD referral centres led to a change in ILD diagnosis in 53% of patients with suspected ILD.1 The proportion of unclassifiable ILD was reduced from 42% to 12% following ILD-MDT. Importantly, 37% of patients referred with IPF had their diagnosis changed to another ILD and 8% had their diagnosis changed to IPF.1 As pharmacotherapies become increasingly targeted and the dangers of administering immunosuppression to IPF patients recognized, the ramifications of accurate diagnosis only further argue for the necessity of ILD-MDTs in the diagnostic approach to ILD.1 Accurate interpretation of HRCT findings remains pivotal in the assessment of ILD, and has major implications for diagnosis and management. In an interesting response to the review by Jacob et al. on this topic, Spagnolo et al. discuss the diagnostic challenges posed by an HRCT pattern of ‘possible’ usual interstitial pneumonia (UIP).2 The authors described the high proportion of patients with biopsy-proven UIP—thus affecting the diagnosis of IPF—despite HRCT abnormalities atypical for UIP in their study cohort.2 They suggest that in the appropriate clinical setting, an atypical or possible UIP pattern on HRCT should not exclude a diagnosis of IPF and that there is a need to continue to evolve the diagnostic criteria for IPF using real-life clinical data with the aim of safely reducing the number of patients undergoing surgical lung biopsy, without reducing diagnostic accuracy.2 The need for a gold standard to investigate for pulmonary embolism (PE) in patients with ILD is apparent. V/Q-SPECT (ventilation/perfusion single-photon emission computed tomography) and computed tomography pulmonary angiography (CTPA) are the two major modalities utilized in clinical practice to assess for PE. Leuschner et al. reported a cohort of ILD patients with suspected PE, and found a high rate of discordance between positive results as detected by V/Q-SPECT and CTPA.3 With studies now demonstrating increased mortality in IPF patients treated with warfarin without other indications for anticoagulation, and concerns that anticoagulation may provoke exacerbations of IPF, there is need for further validation of these findings.4, 5 Despite advances in medical imaging technology, up to 20% of patients still require some form of lung biopsy during the diagnostic workup of suspected ILD.6 Transbronchial cryobiopsy (TBCB) is a promising method of obtaining lung samples of a good size (average 40–50 mm2), with lower morbidity and mortality than surgical lung biopsy.7 The most common complications are pneumothorax (5–30%) and pulmonary haemorrhage (moderate in 40–56%).8-10 Echevarria-Uraga et al. described a series of 100 consecutive TBCB procedures whereby an angioplasty balloon was used for selective bronchial blockade to reduce bleeding (observed rate 13%), whilst preserving its high yield.10 Whilst TBCB continues to hold significant promise, its exact role in the diagnostic algorithm of ILD remains unclear. There is an ongoing and global search for a biomarker or panel of biomarkers that will allow early and specific diagnosis, and accurate prognostication of ILD patients. Whilst there are a wide variety of markers under development, the prognostic value of mucin 5B (MUC5B) and matrix metalloproteinase-7 (MMP-7) have more recently been validated in larger cohorts.11 van der Vis et al. investigated the prognostic implications of MUC5B allele carriage. Unlike prior studies, the authors separated truly sporadic IPF from familial interstitial pneumonia (IP), as well as idiopathic non-specific interstitial pneumonia (iNSIP) and connective tissue disease-associated ILD (CTD-ILD).12 The authors reported that MUC5B minor allele carriage conferred survival benefit in familial IP but not sporadic IPF, and was associated with worse survival in iNSIP.12 Zhang et al. analysed another biomarker, soluble L1-cell adhesion molecule (sL1-CAM), in bronchoalveolar lavage fluid (BALF) and serum in IPF patients.13 Compared with lung cancer and ‘chronic cough’ patients with no evidence of lung disease, sL1-CAM levels were higher in both BALF and serum in patients with IPF.13 It remains too early to determine the clinical utility of sL1-CAM or other candidate biomarkers, and it is essential that larger, longitudinal studies are performed to validate the most promising biomarkers from such exploratory studies. The new anti-fibrotic therapies, nintedanib and pirfenidone, have revolutionized the management of IPF and the tolerability and reduction in functional decline observed in clinical trials appear to have been borne out in real-life experience.14, 15 In the recent review by Borie et al., the authors highlight the myriad of unanswered questions with regard to anti-fibrotic therapy including when treatment should be stopped and how treatment failure is defined.14 With limited data to answer such questions, continuing efforts to formally study patients commencing anti-fibrotic therapy as well as to develop novel therapies and continue to enrol patients in clinical trials remain pertinent. ILD patients have significant symptom burden, and cough and dyspnoea have been demonstrated to negatively impact quality of life, be associated with depression and anxiety and even linked to increased mortality.16 Olukogbon et al. measured the breathing patterns in IPF patients and found that resting ventilation rate increased with worsening disease severity and declining lung function.17 These changes were also associated with increased dyspnoea and cough severity, thus providing a quantifiable link between symptoms and disease severity.17 A deeper understanding of tidal breathing patterns may inform the development of targeted approaches to breathlessness and a mechanism for monitoring disease progression in the future.17 Current approaches to breathlessness remain empirical and whilst there is growing evidence that pulmonary rehabilitation improves dyspnoea scores and quality of life, further research is still required to clarify the long-term benefits, optimal timing and protocols for exercise training programmes and the role of ambulatory oxygen in patients with exercise-induced hypoxia.18 Hanada et al. studied the effect of corticosteroids in 47 ILD patients on muscle strength and found an inverse correlation between total steroid dose and peripheral muscle strength.19 In COPD, the evidence suggests that skeletal muscle dysfunction is associated with impaired exercise capacity, quality of life and increased mortality. In ILD, there is little data exploring the role of skeletal muscle strength on longer term symptoms and outcomes. However, corticosteroids are often used in the treatment for non-IPF ILD. In an accompanying editorial, Mathur highlights the importance of further study to determine how best to balance corticosteroid dose to treat the underlying ILD pathology whilst not inducing myopathic changes.20 It appears that there is a close association between gastro-oesophageal reflux disease (GORD) and IPF, although the underlying pathogenic mechanisms of bile acid microaspiration remain unclear.21 Chen et al. investigated the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor whose expression has been detected in human alveolar epithelial cells and pulmonary endothelial cells, and demonstrated activation of alveolar epithelial cells and lung fibroblasts via FXR-dependent and -independent pathways in experimental models.22 in vitro studies are required to determine the role of FXR in disease pathogenesis. Cardiovascular disease is also highly prevalent in IPF, and studies have a possible pathogenic role of the and a cohort of patients with pulmonary and found that and receptor were associated with Whilst it is too early to for clinical continue search for of patients with remains the only treatment for ILD to medical therapy and it remains to be the impact of more anti-fibrotic will have on the number of IPF patients and and the indications and of cells have been as a novel in IPF, with demonstrating and in experimental of pulmonary However, with some studies progression of fibrosis cells are in disease, the and timing of this treatment remains to be et al. 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