Year in review 2015: Interstitial lung disease, pulmonary vascular disease, pulmonary function, sleep and ventilation, cystic fibrosis and paediatric lung disease

The diagnosis and treatment of interstitial lung diseases (ILD) have undergone revolution in 2015, with the new antifibrotic treatments pirfenidone and nintedanib now incorporated into clinical practice guidelines for the treatment of idiopathic pulmonary fibrosis (IPF).1 This follows their pivotal phase III trials in 20142, 3 that showed, for the first time, slowing of disease progression in this devastatingly fatal disease. While pirfenidone had been licenced in Japan since 2008 and Europe since 2011, both drugs gained Federal Drug Administration (FDA) approval in the United States in 2014, heralding a new era in the management of IPF worldwide. This change in the paradigm of IPF management prompted a comprehensive and timely review series this year in Respirology, focusing on the idiopathic interstitial pneumonias (IIP),4-8 an important subset of ILD. In this series, Jacob et al.5 highlight the three cardinal features of classical usual interstitial pneumonia (UIP) on high-resolution computed tomography (HRCT) scan as honeycomb cysts, traction bronchiectasis and volume loss of the lung parenchyma. They also discuss the current conundrum of ‘possible UIP’: as clinicians, we are currently faced with guidelines that recommend a surgical lung biopsy for further characterization if the HRCT is not classical. However, in reality, only a minority of patients undergo this procedure. With Fell et al.9 showing in patients without definite honeycomb change, that an age greater than 70 years has a positive predictive value of 95% for UIP on lung biopsy; and sub-analysis from the INPULSIS trials showing that patients with possible UIP respond equally well to nintedanib, the clinical utility of the term ‘possible UIP’ comes into question. In a comprehensive review of the histopathology of IIP, Tabaj et al.7 also highlight the challenge posed on histopathology by the ‘certainty’ categories of UIP based on key features as stated in the 2011 IPF guidelines.10 In practice, while these categories provide a common lexicon for clinical trial enrolment, they may lead to confusion and/or oversimplification. These authors note the potential for transbronchial cyrobiopsy, a new diagnostic procedure for ILD patients, to obtain larger tissue fragments with little reported artefact than previously possible with conventional transbronchial biopsy. With promising results demonstrated in the diagnosis of ILD, this may become a feature of future ILD diagnostic algorithms.11 In a critical review of the revised IIP classification,12 Neurohr et al.6 emphasize the importance of a multidisciplinary approach to IIP diagnosis, integrating clinical, physiological, radiological and histopathological data. They also discuss the importance of the newly recognized category of ‘unclassifiable IIPs’ introduced in the 2013 IIP update, in which a disease behaviour classification has been proposed to allow a pragmatic management approach with suggested goals and monitoring strategies. With the rapid changes occurring in ILD diagnosis and management, this review series encapsulates the current standards and complexities involved in the care of ILD patients. The lack of standardized approach to IPF diagnosis and management is highlighted by Troy et al.13 who report a wide variation in diagnostic and therapeutic approach to IPF in 144 Australian and New Zealand respiratory physicians surveyed in 1999 and again in 2012–2013. In the latter survey, 34% of physicians responded that they would refer patients to subspecialist ILD clinics or multidisciplinary meetings and 33% would commence corticosteroids and/or azathioprine. While no antifibrotic therapies were available at the time of this survey, the results of the PANTHER-IPF trial14 showing increased harm with this immunosuppressive regime were available, and thus, they illustrate the fast pace at which IPF management is changing and delay with which recommendations are being translated to clinical practice. The authors argue that there is a need to standardize the approach to diagnosis and treatment of IPF patients. The need for novel tools to enhance our diagnosis of ILDs is apparent and was explored by Bhattachryya et al.15 who reported an algorithm to visually transform the breath sounds of patients with diffuse parenchymal lung disease compared with normal subjects. While this study showed 100% accuracy in differentiating the normal (n = 20) from the abnormal (n = 8), the accompanying editorial by Joshi16 concludes that this algorithm is unlikely to be of any additional value above traditional auscultation. Their transformation of sound to an interpretable visual image, however, shows ingenuity and promise for future medical and educational applications. Diagnostic challenges facing respiratory physicians extend to the granulomatous lung diseases (GLD) with a diverse range of aetiologies reported. In a single-centre retrospective study of 190 GLD patients with surgical lung biopsies, Nazarullah et al.17 found that infectious aetiologies were common (54.7%) and associated with necrosis at biopsy. The most common non-infectious aetiology was, unsurprisingly, sarcoidosis that was associated with the classical non-necrotizing granulomas in comparatively healthy patients. As many GLD are diagnosed without lung biopsy, it is unlikely that this study provides a true representation of the aetiology of GLD. It does, however, provide a basis for assessing GLD when biopsy is required. Accurate ILD diagnosis is critical to prognosis and management; however, it is clear that disease heterogeneity with regard to both the clinical course and treatment response exists and remains a significant clinical challenge. Research into the pathogenesis of IPF, the commonest of the IIPs, has resulted in the expansion of identified biomarkers with potential utility for screening, diagnosis, prognostication and monitoring. Hambly et al.8 review this highly relevant topic of personalized medicine for the IPF patient in a timely review in this journal. While the exact pathological process by which IPF develops remains elusive, there has been a shift in the pathogenic paradigm from inflammation-driven fibrogenesis to aberrant wound healing following repetitive alveolar epithelial cell injury. This view is supported by increased risk of death and hospitalization with immunosuppressive therapy in the PANTHER-IPF trial.14 It is clear that the progressive fibrosis in IPF is dependent on a complex plethora of intricate signalling pathways and effector cells, increasing the difficulty of developing reliable biomarkers and effective treatments. One proposed mechanism for the development of pulmonary fibrosis is mutations in the telomerase enzymes. Telomeres are located at the end of chromosomes, acting as disposable buffers that become truncated during cell division. Telomere shortening is a hallmark of ageing, and at a critical length, cell renewal capacity becomes limited. Mutations in telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) have been reported in 8–15% of familial pulmonary fibrosis,18, 19 establishing a pathogenic link between short telomeres and pulmonary fibrosis. Dai et al.20 report six patients with novel heterozygous mutations in the telomerase genes (two in TERC and four in TERT) in 100 sporadic IPF patients from Nanjing, China. These authors also confirm that telomere length is shorter in IPF than healthy aged-matched controls and is shortest in those with a TERT/TERC mutation. In a further study, the same authors21 demonstrate that shorter telomere length is associated with increased mortality, independent of age, gender, forced vital capacity (FVC) or diffusion capacity for carbon monoxide (DLco). As noted by Chambers22 in the accompanying editorial, there appears to be a strong causal link between short telomeres and premature senescence of cells in IPF pathogenesis, supporting the potential utility for peripheral blood telomere length as a diagnostic and/or prognostic biomarker. Short telomeres however are not specific for the diagnosis of IPF and have also been identified in the chronic obstructive pulmonary disease (COPD) population.23 Nonetheless, these studies provide additional weight to the telomere-IPF hypothesis. Single nucleotide polymorphisms (SNP) in the promoter region of the Mucin 5B (MUC5B) gene have been consistently observed in familial and sporadic IPF.24 In genome-wide association studies in American and European cohorts, it is the dominant genetic finding and is noted in 31–42% of patients with IPF. Polymorphisms have also been found in 19–20% of control subjects,25-29 although their prevalence varies with ethnicity. Horimasu et al.30 have shown in a Japanese population of 384 patients, that SNPs in MUC5B were more common in IPF (3.4%) compared with non-specific interstitial pneumonia (NSIP) (1.7%) and healthy controls (0.8%). This association however was not as strong as the German counterparts where MUC5B occurred in 33.1% in IPF, 27.4% in NSIP and 4.3% in healthy controls. This study highlights the importance in considering ethnic differences for future potential biomarkers. 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