Paolo Spagnolo

Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis

BACKGROUND Gastro-oesophageal reflux disease is a potential risk factor for the development and progression of idiopathic pulmonary fibrosis (IPF). We aimed to investigate the effect of antacid therapy on disease progression in patients randomly assigned to placebo through analysis of three large, phase 3 trials of pirfenidone in IPF. METHODS Patients with IPF from the placebo groups of three trials of pirfenidone (CAPACITY 004, CAPACITY 006, and ASCEND) were included in this post-hoc analysis. We analysed effects of antacid therapy use from baseline for pulmonary function, exercise tolerance, survival, hospital admission, and adverse events for 52 weeks with and without adjustment for potential confounders. The primary endpoint, disease progression by 1 year, was defined as a decrease in predicted forced vital capacity (FVC) by 10% or more, a decrease in 6 min walk distance (6MWD) by 50 m or more, or death. We did survival analyses with the Kaplan-Meier estimator and evaluated using the log-rank test. FINDINGS Of 624 patients, 291 (47%) received antacid therapy and 333 (53%) did not. At 52 weeks, we noted no significant difference between groups for disease progression (114 [39%] for antacid therapy vs 141 [42%] for no antacid therapy, p=0·4844). Rates also did not differ for all-cause mortality (20 [7%] vs 22 [7%], p=0·8947), IPF-related mortality (11 [4%] vs 17 [5%]; p=0·4251), absolute FVC decrease by 10% or more (49 [17%] vs 64 [19%]; p=0·4411), or mean observed change in FVC (% predicted -4·9% [SD 6·4] vs -5·5% [7·2], p=0·3355; observed volume -0·2 L [0·3] vs -0·2 L [0·3], p=0·4238). The rate of hospital admission was non-significantly higher in the antacid therapy group (65 [22%] vs 54 [16%]; p=0·0522). When stratified by baseline FVC (<70% or ≥70%), disease progression, mortality, FVC, 6MWD, and hospital admission did not differ between groups. Adverse events were similar between treatment and no treatment groups; however, overall infections (107 [74%] vs 101 [62%]; p=0·0174) and pulmonary infections (20 [14%] vs 10 [6%]; p=0·0214) were higher in patients with advanced IPF (ie, FVC <70%) who were treated with antacids than not treated with antacids. INTERPRETATION Antacid therapy did not improve outcomes in patients with IPF and might potentially be associated with an increased risk of infection in those with advanced disease. FUNDING F Hoffmann-La Roche.

Long-term macrolide treatment for chronic respiratory disease

Long-term macrolide treatment was first shown to alter the natural history of diffuse panbronchiolitis (DPB) in the late 1980s. Since then, macrolides have been demonstrated to exert anti-inflammatory and immunomodulatory activity in addition to being antimicrobial. Indeed, their spectrum of action extends to the regulation of leukocyte function and production of inflammatory mediators, control of mucus hypersecretion, resolution of inflammation and modulation of host defence mechanisms. As such, the potential benefit of macrolide antibiotics has been evaluated in a variety of chronic respiratory diseases. The best studied condition is cystic fibrosis, of which there have been six randomised controlled trials showing evidence of benefit. However, most of the studies were limited by small numbers of patients and short follow-up. More recently, landmark studies have demonstrated the efficacy of azithromycin in reducing the risk of acute exacerbations in patients with chronic obstructive pulmonary disease, but the optimal duration and dosing of macrolide treatment remain uncertain. With the exception of patients with DPB and cystic fibrosis, until clear evidence of efficacy is available, the long-term use of macrolides should be limited to highly selected patients after careful evaluation of benefit and harm, or in the context of randomised controlled clinical trials.

Recent advances in the genetics of sarcoidosis

Sarcoidosis is a heterogeneous inflammatory disorder of unknown origin that may affect virtually any organ, although intrathoracic engagement is almost universal. Sarcoidosis may present rather dramatically as an acute disease, which usually resolves either spontaneously or with treatment, while other patients have an insidious onset and a chronic/progressive disease course. The different clinical phenotypes have led to the suggestion that sarcoidosis may consist of several separate entities. Yet, the characteristic immune response eventually leading to granuloma formation indicates that a number of features are common to all subgroups of the disease. Through a classical candidate gene approach, several genes of importance for sarcoidosis have been identified, and in some cases such gene variants associate with distinct clinical phenotypes. More recently, another approach to the search for sarcoidosis-associated genes has been applied, that is, through genome-wide association studies (GWAS). GWAS have led to the identification of a number of new genetic associations, although several of them need to be validated. Conversely, some of the previously identified human leucocyte antigen (HLA) associations with sarcoidosis have already been replicated in different cohorts and found to be quite strong, particularly in specific patient subgroups. In highly specialised centres such HLA associations already represent a useful aid in clinic practice for improving patient management. For the future, there is an urgent need for a better understanding, in particular, of gene–gene as well as gene–environmental interactions, both likely to be of importance for developing sarcoidosis.

Idiopathic pulmonary fibrosis: An update

Abstract Idiopathic pulmonary fibrosis (IPF) is the most common and lethal form of idiopathic interstitial pneumonia. The disease, which occurs primarily in middle-aged and older adults, is thought to arise following an aberrant reparative response to alveolar epithelial cell injury characterized by secretion of excessive amounts of extracellular matrix components, resulting in scarring of the lung, architectural distortion, and irreversible loss of function. A complex interplay between environmental and host factors is thought to contribute to the development of the disease, although the cause of IPF remains elusive and its pathogenesis incompletely understood. Over the last decade, disease definition and diagnostic criteria have evolved significantly, and this has facilitated the design of a number of high-quality clinical trials evaluating novel therapeutic agents for IPF. This massive effort of the medical and industry community has led to the identification of two compounds (pirfenidone and nintedanib) able to reduce functional decline and disease progression. These promising results notwithstanding, IPF remains a major cause of morbidity and mortality and a largely unmet medical need. A real cure for this devastating disease has yet to emerge and will likely consist of a combination of drugs targeting the plethora of pathways potentially involved in disease pathogenesis.

Update on therapeutic management of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive diffuse parenchymal lung disease of unknown origin, with a mortality rate exceeding that of many cancers. The diagnostic process is complex and relies on the clinician integrating clinical, laboratory, radiological, and histological data. In the last decade, major advances in our understanding of the pathogenesis of IPF have shifted the paradigm from a primarily inflammatory process evolving to fibrosis to a condition driven by aberrant wound healing following alveolar epithelial cell injury that results in scarring of the lung, architectural distortion, and irreversible loss of function. Improved understanding of disease pathogenesis has led to the identification of several therapeutic targets and the design of high-quality clinical trials evaluating novel compounds. However, the results of these studies have been mostly disappointing, probably due to the plethora of mediators, growth factors, and signaling pathways involved in the fibrotic process. Most recently, pirfenidone and nintedanib, two compounds with pleiotropic anti-fibrotic properties, have been proven effective in reducing functional decline and disease progression in IPF. This is a major breakthrough. Nevertheless, we still have a long way to go. In fact, neither pirfenidone nor nintedanib is a cure for IPF, and most patients continue to progress despite treatment. As such, comprehensive care of patients with IPF, including management of concomitant conditions and physical debility, as well as timely referral for lung transplantation, remains essential. Several agents with a high potential are currently being tested, and many more are ready for clinical trials. Their completion is critical for achieving the ultimate goal of curing patients with IPF.

Sex differences in emphysema phenotype in smokers without airflow obstruction

Data on sex differences in emphysema are limited to chronic obstructive pulmonary disease. We aimed to verify whether such differences also exist in smokers without airflow obstruction, weighting their influence on the relationship between emphysema and clinical features. We evaluated both clinical and multidetector computed tomography (MDCT) data of 1,011 heavy smokers recruited by a lung cancer screening project. MDCT scans were analysed with software allowing lobar quantification of emphysema features. For these measures, multiple regression models were applied to assess the effect of patients sex, after allowance for age, body mass index (BMI), smoking history, forced expiratory volume in 1 s (FEV1) and forced vital capacity. The final study cohort consisted of 957 smokers without airflow obstruction. Compared with males, females exhibited an emphysema phenotype less extensive in each pulmonary lobe, characterised by smaller emphysematous areas and less concentrated in the core of the lung. However, in females, the increase of emphysema with age was more pronounced and displayed a more significant relationship with FEV1% decline; conversely, in males there was a stronger association with the decrease in BMI. Males and females respond differently to the type and location of lung damage due to tobacco exposure. In smokers, sex influences the relationship between emphysema and clinical features.

Idiopathic pulmonary fibrosis: Recent advances on pharmacological therapy

Idiopathic pulmonary fibrosis (IPF) is the most common and lethal of the idiopathic interstitial pneumonias with an estimated 5-year survival of approximately 20%. In the last two decades our understanding of disease pathogenesis has substantially evolved and novel compounds have been developed consequent to the increasing knowledge of the mechanisms underlying disease pathobiology. The disease appears to be driven - following chronic injury - by abnormal/dysfunctional alveolar epithelial cells that promote fibroblast recruitment and proliferation, resulting in scarring of the lung and irreversible loss of function. With very few exceptions, clinical trials evaluating novel potential therapies have provided disappointing results. More recently, pirfenidone and nintedanib, two compounds with pleiotropic mechanisms of action, have proven effective in slowing functional decline and disease progression in IPF patients with mild to moderate functional impairment, highlighting the importance of timely diagnosis and administration of treatment in early stages of disease. However, due to the complexity and uncertainties intrinsic to IPF, it is essential that each therapeutic strategy be tailored to the individual patient, after evaluation of potential benefits and risks. This article provides an overview of the most recent clinical trials in IPF and discusses how their results are going to change the clinical and clinical research landscape in IPF. A number of agents with high potential are currently being tested and many more are ready for clinical trials. Their completion is critical for achieving the ultimate goal of curing patients with IPF.

Genetic determinants of pulmonary fibrosis: evolving concepts.

Interstitial lung diseases encompass a wide range of diffuse lung disorders that are often complicated by the development of pulmonary fibrosis and that can occur in isolation or in systemic diseases. In the past decade, availability of high-throughput genotyping and large collaborative clinical networks has led to the identification of many genetic variants associated with sporadic and familial fibrotic interstitial pneumonias. Susceptibility to idiopathic pulmonary fibrosis seems to involve a combination of polymorphisms related to epithelial cell injury and dysfunction and abnormal wound healing, whereas chronic inflammation seems important in the development of pulmonary fibrosis in sarcoidosis or collagen vascular diseases such as systemic sclerosis or rheumatoid arthritis; however, each of the disease-associated variants typically has a small effect and they are therefore not helpful in prediction of risk. Genetic studies have substantially expanded understanding of the pathogenesis of pulmonary fibrosis. Future challenges will be to assess how multiple susceptibility alleles interact with each other and environmental factors to determine disease risk and several different phenotypes, to define the mechanism of action and cellular pathways involving susceptibility alleles, and to identify which of the gene products and molecular mechanisms implicated in disease pathobiology are good therapeutic targets.

Rare lung disease and orphan drug development

Rare diseases are a major health-care burden worldwide. Very little is known about the cause, behaviour, and treatment of these disorders, and thus non-specialist health-care providers and patients are left without sufficient knowledge to manage these diseases. Up to 3 million Europeans are estimated to have a rare lung disease. Several organisations-many of which are patient led-attempt to raise the profile of rare lung diseases to improve understanding and management of these disorders. Incentives have now been introduced in the USA and Europe that encourage the pharmaceutical industry to invest in targets that might otherwise not appeal because of small target populations. Despite many intrinsic challenges and obstacles, considerable progress is constantly being made in the research and development of drugs for rare disorders.

Differential diagnosis of usual interstitial pneumonia: when is it truly idiopathic?

Idiopathic pulmonary fibrosis (IPF), the most common and lethal of the idiopathic interstitial pneumonias, is defined by a radiological and/or pathological pattern of usual interstitial pneumonia (UIP). However, UIP is not synonymous with IPF as other clinical conditions may be associated with UIP, including chronic hypersensitivity pneumonitis, collagen vascular disease, drug toxicity, asbestosis, familial IPF and Hermansky–Pudlak syndrome. Differentiating IPF (“idiopathic UIP”) from conditions that mimic IPF (“secondary UIP”) has substantial therapeutic and prognostic implications. A number of radiological and histological clues may help distinguish IPF from other conditions with a UIP pattern of fibrosis, but their appreciation requires extensive expertise in interstitial lung disease as well as an integrated multidisciplinary approach involving pulmonologists, radiologists and pathologists. In addition, multidisciplinary discussions may decrease the time to initial IPF diagnosis and, thus, enable more timely management. This concept was strongly emphasised by the 2011 ATS/ERS/JRS/ALAT guidelines. This article highlights, with the aid of a clinical case, the difficulties in making a diagnosis of IPF in clinical practice. Yet, an accurate diagnosis is critical, particularly given the availability of drugs that may reduce the pace of functional decline and disease progression in IPF.