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

Abstract

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. The search for biomarkers extends to sarcoidosis: Plate et al.31 studied the role of a functional polymorphism in the factor 2 receptor (F2R) gene promoter in sarcoidosis. SNPs in the F2R have been shown to confer higher promoter activity and hence higher PAR-1 expression. In this study, the authors found that this SNP was less common in sarcoidosis compared with controls and speculate that increased proteinase-activated receptor-1 (PAR-1) expression may be associated with protection from the development of sarcoidosis. This same allele has also been found to protect against frequent exacerbations of COPD, and they speculate that the effect of PAR-1 in sarcoid may be related to early inflammatory stages in sarcoid as the allele did not distinguish between persistent and quiescent sarcoid. As there was no replication cohort, however, these observations are exploratory and require further confirmation. The recent landmark clinical trials in IPF herald a new era in IPF management,1, 32 however, they also highlight the considerable barriers encountered during the often arduous journey from drug development to the translation of new drugs into clinical care practices. In a review series edited by Kolb and Ask,33 Rose et al.34 emphasize that increasing insights into complex biological and disease mechanisms have resulted in the need for highly differentiated medications and greater transitional research expertise. As the cost of drug development increases and traditional government funding for academic research diminishes, the authors propose that there is a need for new research paradigms with collaboration between academia and the pharmaceutical industry. Through successful collaboration, industry may be able to gain specific scientific expertise, while academia gains access to financial resources and novel technology. While these collaborations as well as government financial and regulatory incentives aide the development of new drugs, attention is drawn to the delays in access attributed to delays in regulatory approval and drug reimbursement. Feltmate et al.35 illustrate that this journey for pirfenidone, which despite regulatory approval in Japan in 2008, did not receive reimbursement until 2012. In the United States, access to pirfenidone was delayed even further, only gaining regulatory approval in 2014 after the results of ASCEND, with reimbursement negotiations still ongoing. There is a universal need to ensure timely access to new drugs, which is only possible through a shift in government approval timelines and streamlining of the reimbursement review process. Although efforts to improve access to new medications persist, debate continues regarding which IPF patients warrant a trial of antifibrotic therapy. As with most clinical trials, the populations studied in INPULSIS and ASCEND were highly selected and homogenous, as evidenced by the use of a central review panel and a 65% screen failure rate in ASCEND. Despite the lack of evidence, it is tempting to broaden the use of these medications beyond those included in the narrow clinical trial cohorts, as there are few alternatives in this devastating disease. Moodley et al.36 draw attention to this issue in a pro-con debate. Although it is enticing to provide a therapeutic option for patients with severe disease, older patients or patients without true IPF, the authors note that there is an opposing view to maintain the use of these medications to the specific indication studied. Sub-analysis from the INPULSIS trials has suggested that nintedanib is equally efficacious across multiple subgroups including the spectrum of disease severity, age and ‘possible IPF’ subgroups. It is important to note that no patients with severe IPF were included in these studies and enthusiasm to treat this group must be tempered by the lack of supporting evidence and potential for adverse events. In an effort to increase evidence-based therapy for patients with severe IPF, Sakamoto et al.37 studied the efficacy of pirfenidone combined with inhaled N-acetylcysteine (NAC) in a small retrospective case–control study of 34 advanced IPF patients from a Japanese centre. Patients included in this study had Japanese Respiratory Society stage 3 or 4 disease (equating to resting partial pressure of oxygen (PaO2) < 69 Torr) and a fall in FVC of >10% in the preceding 6 months. The authors describe combination treatment with inhaled NAC and pirfenidone (n = 24) was associated with a reduced annual FVC decline (−610 mL) and improved progression free survival (304 days) compared with pirfenidone alone (n = 10) (annual FVC decline of −1320 mL; progression free survival 168 days). While this study is small, and the groups were not closely matched with regard to disease severity, there is biological plausibility for the use of inhaled NAC in IPF. Velez and Nambiar,38 in the accompanying editorial remind the reader that this is an important step towards addressing the current gaps in the management of severe, progressive disease and the use of combination therapy. Strides in the improved management of ILD extend to acute eosinophilic pneumonia (AEP) with Jhun et al.39 showing that rapid corticosteroid tapering may be an acceptable alternative for patients with mild AEP. This single centre, prospective cohort study of 59 patients divided patients into milder AEP based on the presence of initial peripheral blood eosinophilia (n = 14) compared with a normal initial peripheral eosinophil count (n = 45). Patients in the eosinophilia group had lower rates of fever, dyspnoea, tachypnoea, need for oxygen and anorexia, consistent with milder disease. In this group, steroids were stopped at the time of clinical stabilization (median duration 4 days) with no resultant treatment failure, while the control group received a 2-week course with only one patient experiencing minor relapse. It is important to note that there are no controlled trials regarding treatment duration in AEP and both arms of this study are not consistent with many expert-based recommendations.40 While this study supports individualization of therapy based on disease severity and response to steroid, caution is advised as this study was small and short (5-day follow-up) with limited generalizability given the homogenous cohort of young, military, Korean men included in this study. Another disease where the use of corticosteroid treatment requires clarification is autoimmune pancreatitis (AIP) in immunoglobulin G4-related disease (IgG4-RD) and its associated lung disease. In a retrospective analysis of 34 patients with AIP, Ogoshi et al.41 found a high frequency of diverse lung lesions (40%) including ground glass attenuation, bronchial wall thickening, nodules and consolidation. These lesions exhibited improvement with steroids and, unlike AIP, had a low probability of relapse in this study. Lower physical activity levels are universally a poor prognostic sign.42 Patients with ILD have lower physical activity than healthy-aged matched controls due to a number of contributing factors that may vary over the course of disease. Nakayama et al.43 investigated physical activity in patients with mild IPF (mean FVC 89%, DLco 79%) using an accelerometer and found that most patients spent 90% of the day at lower than slow walking intensity and only 1 h per day in light intensity activity. They also found that physical activity was not linked to the severity of the lung disease as judged by pulmonary function tests, but rather with breathlessness (modified Medical Research Council scale), and exercise capacity (6 minute walk test (6MWT) distance). The authors speculate that the cause of reduced physical activity may differ in early disease compared with late disease. In a cross-sectional study performed in Canada, Mendes et al.44 assessed the muscle size and function of 26 patients with advanced ILD awaiting lung transplantation. They report muscle atrophy and weakness of thigh and calf muscles, with relative preservation of upper limb muscle size and function. This pattern is similar to that found in muscle disuse atrophy. The authors surmise that it is likely that muscle disuse is a contributing factor to the decreased exercise capacity demonstrated in ILD patients. Given these findings, Holland,45 in the accompanying editorial, emphasizes the importance of exercise training as improvements in skeletal muscle function may contribute to improved exercise capacity, symptoms and quality of life. The accurate assessment of physical activity and understanding the physiological basis of functional impairment in ILD are important, particularly as pharmacological therapies slowing disease progression may result in IPF patients living longer. The incremental shuttle walk test (ISWT), a measure of exercise capacity, is also used to calculate walking speeds for the endurance shuttle walk test (ESWT) and to prescribe exercise programmes. While it has been extensively investigated in COPD, little data exist regarding the properties and reliability of ISWT in ILD patients. While guidelines based on COPD patients suggest the need for two ISWTs, the necessity of a practice test in ILD patients who are frequently limited by exertional desaturation and severe breathlessness was investigated by Johnson-Warrington et al.46 These authors found that, similar to COPD patients, there was a significant learning effect in the ILD population, with 72.1% of patients walking further on their second test with a mean change in distance of 29 m. This difference would have resulted in 60% of patients performing ESWT at an incorrect level and thus supports the performance of a practice ISWT in ILD. It has been an exciting year in ILD with significant progress made not only in the diagnosis and treatment but also in the emerging field of genetics and biomarkers as well as functional assessment. This, however, is only the beginning, and we wait with anticipation the new discoveries that will be made in the year to come. Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between the pulmonary arterial and venous circulations, thus bypassing the pulmonary capillary beds and producing anatomical right to left shunts. PAVMs have been reported in up to 1 in 2600 population; paradoxical embolic phenomenon may result in cerebral infarct or abscess formation.47 Whereas, in the Western literature, PAVMs are mostly associated with hereditary haemorrhagic telangiectasia (HHT), it was interesting to read that Kim et al. reported a much lower association in a small population of Korean patients (13.3%).48 Furthermore, a small Japanese study reported an association of HHT in only 51% of patients with PAVMs. As Kim et al. acknowledged the small sample size and the retrospective nature of their study, with perhaps under-diagnosis of HHT limit the overall conclusion, but it begs the question as to whether there really is a prevalence difference in Western and Asian HHT patients. Porres-Aguilar and Mukherjee wrote a very comprehensive update on portopulmonary hypertension (PoPH).49 PoPH describes a group of patients with portal hypertension (with or without liver disease) that develop pulmonary arterial hypertension. Around 4% of patients being worked up for liver transplant (LT) will have PoPH diagnosed. Echocardiography remains a compulsory screening tool in symptomatic patients. Right heart catheterization in those with echocardiographic signs of pulmonary hypertension (PH) will secure the diagnosis while giving important prognostic information, especially with regard to risks associated with LT. There is growing evidence that pulmonary vasodilator therapy may be improving the terrible outcome and may allow some patients access to otherwise contraindicated LT. Connective tissue disease associated pulmonary arterial hypertension (PAH) includes a diverse collection of conditions with different pathogenesis and response to treatment. The most prevalent condition, scleroderma-associated PAH, is resistant to immunosuppressive therapy and shows a modest response to pulmonary vasodilators. Systemic lupus erythematosus and mixed connective tissue disease-associated PAH may respond to immunosuppression and/or pulmonary vasodilators. Less is known about rheumatoid arthritis (RA)-associated PAH. Sadeghi et al. described the largest cohort of patients with RA-PAH fully characterized by right heart catheterization (RHC).50 Compared with matched patients with idiopathic PAH, RA-PAH patients were older, had better haemodynamics and equivalent survival, although they tended to be less aggressively treated. Venous thromboembolism (VTE) is the third largest cause of cardiovascular disease in the developed world. There is good evidence that treating surgical patients with VTE prophylaxis prevents VTE events.51 There is less evidence for medical patients, although the American College of Chest Physicians recommends prophylaxis. An editorial by Lutz Beckert and Anthony Rahman discusses this issue in the context of a large Taiwanese, retrospective, case-controlled study reported by Chen et al.52, 53 In this study, almost 20 000 patients admitted with pneumococcal pneumonia were compared with 75 000 age-matched controls. Although there were significant differences in baseline comorbidities, after correction for these differences, there appeared a higher incidence of short-term and long-term deep vein thrombosis and pulmonary embolism (PE) in the pneumonia group. The observation of the highest increased risk within the first 4 weeks after diagnosis is particularly important and similar to that observed in surgical patients. It remains unknown whether the outcome of the study by Chen et al. would be the same with a pathogen other than Streptococcus pneumoniae. Pneumococcal infection has been associated with an inflammatory profile that promotes intravascular coagulation, perhaps as a host-protective mechanism.54 The authors of paper and editorial recommend that patients admitted with pneumococcal pneumonia receive prophylaxis as per American College of Chest Physicians guidelines. Currently, there is no convincing evidence supporting treatment of pulmonary hypertension associated with chronic respiratory diseases (CRD-PH). Hence, all recent guidelines recommend that treatment is aimed at the underlying lung disease only. In the latest European guidelines, however, it is acknowledged that patients with severe PH should be referred to specialist centres and considered for registries and clinical trials. It is therefore of great interest that Tanabe et al. report an improvement in outcome in 70 patients with mixed CRD and severe PH (defined as mean PAP > 35 mm Hg) treated with the phosphodiesterase inhibitor, sildenafil.55 The study had severe limitations as it was retrospective, small and non-placebo controlled. However, it supports a potential benefit of sildenafil seen in the IPFnet study in patients with evidence of right ventricular (RV) dysfunction and adds to the need for a prospective randomized placebo-controlled study.56 Since the first measures of pulmonary function over 300 years ago,57 spirometry has become and remained the cornerstone for the diagnosis and management of respiratory disease. While the scientific developments in spirometry have slowed,58 the science of lung function measurement continues to advance, and many new techniques, as well as refinements of older methodologies, continue to develop allowing us to better understand pulmonary function in health and disease. In Respirology in 2015, the forced oscillation technique (FOT) was utilized to evaluate pulmonary function in a relatively large cohort of healthy unsedated infants (6–10 weeks of age).59 The attraction of the FOT is that it is non-invasive and does not require controlled respiratory manoeuvres, which allows measurements to be performed in spontaneously breathing humans of any age.60 While the FOT has been used in a number of studies to date, the novelty of the study performed by Gray and colleagues59 was that it provided normative data in infants of African ancestry, allowing investigation of the impact of specific prenatal exposures to also be performed.61 The study reported that male infants had higher airway resistance and lower compliance than females59. Furthermore, maternal smoking during pregnancy resulted in a lower compliance compared with those not exposed, while no effect of maternal human immunodeficiency virus (HIV) infection or ethnicity was observed.59 The lung clearance index (LCI) is starting to grow in popularity as it has been shown to be a reliable measurement62-64 more sensitive than spirometry for detecting airway changes in mild lung disease.65 In a study by Benseler and colleagues,66 the effect of equipment dead-space on LCI measured by the multiple breath washout technique was investigated. Utilizing healthy children as well as those with cystic fibrosis (CF), the authors demonstrated that when equipment dead-space is large relative to the lung volume of the subject, the LCI was increased. The authors present a correction factor to adjust for this effect of equipment dead-space.66 However, research is now needed to assess whether this adjustment improves the accuracy of LCI across longitudinal studies.66 The multiple breath nitrogen technique can also be utilized to assess inhomogeneity of ventilation in the peripheral airways supplying two indices for where gas transport is either convection-dependent (Scond) or diffusion-dependent (Sacin).67 Using this technique, Farah et al.,67 investigated whether small airway dysfunction was associated with measures of airway inflammation in 53 individuals with stable asthma who were on inhaled corticosteroid (ICS) therapy. Multivariate analysis (accounting for age, gender, disease duration, body mass index and ICS dose) demonstrated that Sacin (%predicted) was correlated with percent neutrophils, while Scond (%predicted) was associated with percent eosinophils and ICS dose. While these data are interesting and support the potentially differing roles of neutrophils and eosinophils in peripheral airway function in asthma, the relationships were relatively weak, and further investigation is needed to determine any causative effect. In 2014, Respirology initiated an invited review series that bought together World leaders in respiratory physiology and medicine to investigate the central question ‘what is the most appropriate lung function test for a particular lung disease’.58, 68 In 2015, this series was completed with the publication of four reviews that highlighted the best diagnostic lung function tests for HIV,69 CF70 and obesity,71 as well as discussed the utilization of statistical models for respiratory disease diagnosis and prognosis.72 In the review by Calligaro and Gray,69 the authors examine the non-infectious pulmonary complications associated with HIV infection, namely, increased respiratory symptoms, accelerated emphysema and reduced diffusion capacity and how they influence lung function in both adults and children. They also discuss the complex pathogenic mechanisms causing airflow obstruction and impairment in diffusion capacity associated with HIV, antiretroviral therapy, repeated respiratory infections (particularly pneumocystis and bacterial pneumonia) and the role of the lung microbiome.69 Due to the complexity and heterogeneity of airways disease in CF, the review by Horsley and Siddiqui70 highlighted the limitations of utilizing a single lung function test to provide a comprehensive assessment of lung physiology across the spectrum of CF patients. Nevertheless, forced expired volume in one-second (FEV1) remains important for assessing the severity of impairment, monitoring lung function decline and is a strong predictor of survival.70 However, FEV1 is relatively insensitive to the early development and progression of small airways disease. As such, additional measurements such as computed tomography, the multiple breath washout test, FOT and cardiopulmonary exercise testing may offer additional information to understand and clinically phenotype patients.70 Obesity is associated with a number of detrimental changes to lung volumes, gas exchange and airway function that are relatively well documented.73-75 In the review by Brazzale and colleagues,71 the authors succinctly discuss what is known regarding the physiological effects of obesity and weight loss on all aspects of pulmonary function. The authors also present the strengths and limitations of a variety of lung function tests (i.e. lung volume measurements, volume corrected measures of respiratory mechanics and cardiopulmonary exercise testing) that can be utilized to bet