Giacomo Sgalla

Three-dimensional characterization of fibroblast foci in idiopathic pulmonary fibrosis

In idiopathic pulmonary fibrosis (IPF), the fibroblast focus is a key histological feature representing active fibroproliferation. On standard 2D pathologic examination, fibroblast foci are considered small, distinct lesions, although they have been proposed to form a highly interconnected reticulum as the leading edge of a “wave” of fibrosis. Here, we characterized fibroblast focus morphology and interrelationships in 3D using an integrated micro-CT and histological methodology. In 3D, fibroblast foci were morphologically complex structures, with large variations in shape and volume (range, 1.3 × 104 to 9.9 × 107 μm3). Within each tissue sample numerous multiform foci were present, ranging from a minimum of 0.9 per mm3 of lung tissue to a maximum of 11.1 per mm3 of lung tissue. Each focus was an independent structure, and no interconnections were observed. Together, our data indicate that in 3D fibroblast foci form a constellation of heterogeneous structures with large variations in shape and volume, suggesting previously unrecognized plasticity. No evidence of interconnectivity was identified, consistent with the concept that foci represent discrete sites of lung injury and repair.

Novel drug targets for idiopathic pulmonary fibrosis

ABSTRACT Idiopathic Pulmonary Fibrosis (IPF) is a progressive, fatal lung disorder of unknown cause with a highly variable and unpredictable clinical course. The advances made in deciphering IPF pathobiology over the last decades have led to the approval of two anti-fibrotic molecules, pirfenidone and nintedanib, that showed to be effective in significantly reducing the rate of progression of the disease. Such pharmacological breakthroughs represent a dramatic change in the management of these patients and are reflected in updated international guidelines. However, the need to find a cure for this devastating disease remains unmet and the development of novel therapeutic agents remains hurdled by several factors. Here, we review the latest insights into therapeutic approaches for IPF and the available evidence for the most promising novel compounds currently under development, and discuss the challenges and evolution of IPF clinical research over the next few years.

Levels of circulating endothelial cells are low in idiopathic pulmonary fibrosis and are further reduced by anti-fibrotic treatments

BackgroundIt has been suggested that circulating fibrocytes and endothelial cells actively participate in the intense remodelling of the pulmonary vasculature in patients with idiopathic pulmonary fibrosis (IPF). Indeed, fibrotic areas exist that have fewer blood vessels, whereas adjacent non-fibrotic tissue is highly vascularized. The number of circulating endothelial cells (CEC) and endothelial progenitor cells (EPC) might reflect the balance between vascular injury and repair. Thus, fibrocytes as well as endothelial cells could potentially be used as biomarkers of disease progression and treatment outcome.MethodsPeripheral blood samples were collected from 67 patients with a multidisciplinary diagnosis of IPF and from 45 age-matched and sex-matched healthy volunteers. Buffy coat was isolated according to standard procedures and at least 20 million cells were stained with different monoclonal antibodies for the detection of CEC, EPC and circulating fibrocytes. For the detection of CEC and EPC, cells were stained with anti-CD45, anti-CD34, anti-CD133, anti-CD14, anti-CD309 and with the viability probe Far-Red LIVE/DEAD. For the detection of circulating fibrocytes, cells were first stained with LIVE/DEAD and the following monoclonal antibodies: anti-CD3, anti-CD19, anti-CD45, anti-CD34 and anti-CD14, then cells were fixed, permeabilized and stained with fluorochrome-conjugated anti-collagen I monoclonal antibodies.ResultsPatients with IPF displayed almost undetectable levels of circulating fibrocytes, low levels of CEC, and normal levels of EPC. Patients treated with nintedanib displayed higher levels of CEC, but lower levels of endothelial cells expressing CD309 (the type II receptor for vascular endothelial growth factor). Treatment with both nintedanib and pirfenidone reduced the percentage of CEC and circulating fibrocytes.ConclusionsLevels of CEC were reduced in patients with IPF as compared to healthy individuals. The anti-fibrotic treatments nintedanib and pirfenidone further reduced CEC levels. These findings might help explain the mechanism of action of these drugs and should be explored as predictive biomarkers in IPF.

Mindfulness-based stress reduction in patients with interstitial lung diseases: a pilot, single-centre observational study on safety and efficacy

Background Chronic, progressive respiratory symptoms are associated with great psychological and emotional impact in patients suffering from interstitial lung disease (ILD). This single-centre pilot study evaluated for the first time the safety, feasibility and efficacy of a Mindfulness Based Stress Reduction Program (MBSR) in a group of patients with ILD. Methods Prospective observational study set in a university hospital ILD outpatient clinic. Nineteen patients with different ILDs were recruited 2 months prior to the start of the 8-week MBSR program and followed up for 12 months. Primary outcomes were program safety and feasibility, while secondary outcomes were changes in moods and stress (assessed by Profile Of Mood State (POMS) and Perceived Stress Scale (PSS) questionnaires), symptoms (Shortness Of Breath (SOB) and Cough And Sputum Assessment (CASA-Q) questionnaires), lung function and exercise tolerance at 12 months. Results Two patients (10.5%) dropped out in the observational period before the start of the MBSR intervention because of non-respiratory causes. All 17 patients who entered the 8-week MBSR program managed to complete it with an adherence average of eight sessions of nine. No adverse events related to the mindfulness training were reported. Statistically significant improvements in the POMS total score and in several individual items of POMS and PSS were observed throughout the study. However, respiratory questionnaire scores, lung function and exercise tolerance did not show a significant difference over time. Conclusions An MBSR program appears to be safe and feasible in patients with ILD, and might affect perceived moods and stress producing a positive and lasting improvement in several stress-related negative domains. These findings pave the way to larger (possibly multicentre), randomised, controlled confirmatory trials.

The safety of new drug treatments for idiopathic pulmonary fibrosis.

ABSTRACT Introduction: The management of idiopathic pulmonary fibrosis (IPF) has been transformed by the recent approval of two anti-fibrotic drugs, nintedanib and pirfenidone. An increasing number of patients with IPF are receiving treatment with these novel therapies, and the risk of adverse events that may be associated with their use must be carefully evaluated. Areas covered: Safety data about nintedanib and pirfenidone is critically evaluated, including data from randomized clinical trials and post-marketing reports. Management strategies to minimize the occurrence of side effects are summarized. Expert opinion: The safety profile of the two anti-fibrotic drugs approved for clinical use in IPF patients appears to be comparable. Data from clinical trials and initial post-marketing surveillance indicate that most of the observed side effects are mild and easily manageable. However, approximately 1/5 of patients may discontinue treatment as a consequence of side effects. Careful patient counselling, and regular follow-up during therapy could reduce the rate of discontinuations. Ongoing post-marketing surveillance may further inform our understanding of the safety profile of these therapies.

Idiopathic pulmonary fibrosis: pathogenesis and management

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the aberrant accumulation of fibrotic tissue in the lungs parenchyma, associated with significant morbidity and poor prognosis. This review will present the substantial advances achieved in the understanding of IPF pathogenesis and in the therapeutic options that can be offered to patients, and will address the issues regarding diagnosis and management that are still open.Main bodyOver the last two decades much has been clarified about the pathogenic pathways underlying the development and progression of the lung scarring in IPF. Sustained alveolar epithelial micro-injury and activation has been recognised as the trigger of several biological events of disordered repair occurring in genetically susceptible ageing individuals. Despite multidisciplinary team discussion has demonstrated to increase diagnostic accuracy, patients can still remain unclassified when the current diagnostic criteria are strictly applied, requiring the identification of a Usual Interstitial Pattern either on high-resolution computed tomography scan or lung biopsy.Outstanding achievements have been made in the management of these patients, as nintedanib and pirfenidone consistently proved to reduce the rate of progression of the fibrotic process. However, many uncertainties still lie in the correct use of these drugs, ranging from the initial choice of the drug, the appropriate timing for treatment and the benefit-risk ratio of a combined treatment regimen. Several novel compounds are being developed in the perspective of a more targeted therapeutic approach; in the meantime, the supportive care of these patients and their carers should be appropriately prioritized, and greater efforts should be made toward the prompt identification and management of relevant comorbidities.ConclusionsBuilding on the advances in the understanding of IPF pathobiology, the further investigation of the role of gene variants, epigenetic alterations and other molecular biomarkers reflecting disease activity and behaviour will hopefully enable earlier and more confident diagnosis, improve disease phenotyping and support the development of novel agents for personalized treatment of IPF.

Nintedanib for the treatment of idiopathic pulmonary fibrosis

ABSTRACT Introduction: Idiopathic Pulmonary Fibrosis (IPF) is an interstitial lung disease characterized by the progressive loss of pulmonary function, ultimately leading to respiratory failure and death. Two novel compounds, nintedanib and pirfenidone, have shown efficacy in reducing the rate of decline of lung function in IPF patients. The multiple tyrosine kinase inhibitor nintedanib has extensively being studied as a potential angiogenesis inhibitor in clinical against various neoplastic disorders. Afterwards, this compound was successfully tested in IPF. Areas covered: Herein, the authors review the working mechanisms of nintedanib, its pharmacological profile, and its efficacy and safety for patients with IPF. Expert opinion: Nintedanib has shown to be safe and effective in patients with IPF, with a favorable long-term safety profile. There is a lack of comparative trials of pirfenidone and nintedanib, and the choice of treatment is left to the physicians’ judgement. Future directions of nintedanib use are represented by the treatment of progressive fibrosing interstitial lung disease other than IPF, IPF with advanced functional impairment, and lung fibrosis secondary to connective tissue diseases. A promising safety profile for the combinational use of nintedanib and pirfenidone in IPF has also recently emerged.

Chapter 4 – Management of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and inevitably fatal lung disease. Although the etiology and pathogenesis of IPF remain incompletely understood, two drugs (e.g., pirfenidone and nintedanib) have proven effective in slowing down functional decline and disease progression and are now approved worldwide for treatment. Yet, as outlined by the recent guideline document on treatment of IPF, every therapeutic decision needs to be tailored to the individual patient, after discussing potential benefits and pitfalls. Comorbidities, which almost invariably complicate IPF, impact significantly clinical course and prognosis of the disease, making a holistic approach to the best care for these patients. Randomized-controlled trials remain a valid choice for selected IPF patients and their completion is critically important to achieving the ultimate goal of improving both survival and quality of life of patients suffering from this devastating disease.

“Velcro-type” crackles predict specific radiologic features of fibrotic interstitial lung disease

Background“Velcro-type” crackles on chest auscultation are considered a typical acoustic finding of Fibrotic Interstitial Lung Disease (FILD), however whether they may have a role in the early detection of these disorders has been unknown. This study investigated how “Velcro-type” crackles correlate with the presence of distinct patterns of FILD and individual radiologic features of pulmonary fibrosis on High Resolution Computed Tomography (HRCT).MethodsLung sounds were digitally recorded from subjects immediately prior to undergoing clinically indicated chest HRCT. Audio files were independently assessed by two chest physicians and both full volume and single HRCT sections corresponding to the recording sites were extracted. The relationships between audible “Velcro-type” crackles and radiologic HRCT patterns and individual features of pulmonary fibrosis were investigated using multivariate regression models.Results148 subjects were enrolled: bilateral “Velcro-type” crackles predicted the presence of FILD at HRCT (OR 13.46, 95% CI 5.85–30.96, p < 0.001) and most strongly the Usual Interstitial Pneumonia (UIP) pattern (OR 19.8, 95% CI 5.28–74.25, p < 0.001). Extent of isolated reticulation (OR 2.04, 95% CI 1.62–2.57, p < 0.001), honeycombing (OR 1.88, 95% CI 1.24–2.83, < 0.01), ground glass opacities (OR 1.74, 95% CI 1.29–2.32, p < 0.001) and traction bronchiectasis (OR 1.55, 95% CI 1.03–2.32, p < 0.05) were all independently associated with the presence of “Velcro-type” crackles.Conclusions“Velcro-type” crackles predict the presence of FILD and directly correlate with the extent of distinct radiologic features of pulmonary fibrosis. Such evidence provides grounds for further investigation of lung sounds as an early identification tool in FILD.

Clinical trials in idiopathic pulmonary fibrosis: where we have been and where we are going

Idiopathic pulmonary fibrosis (IPF) is the most common and most lethal diffuse fibrosing lung disease, with an increasing incidence and a mortality rate that exceeds that of many types of cancer. At present, there is no effective standard treatment recommended by guideline documents. As such, the unmet medical need is high. Recently, several high-quality clinical trials, evaluating safety and efficacy of different novel molecules, have been concluded. The results have mostly been disappointing, although some compounds have shown promising results. In particular, pirfenidone seems to be the most advanced molecule for IPF treatment, having been approved in Europe, Japan and India. Nintedanib, a triple kinase inhibitor, has almost completed enrolment of Phase III trials, based on promising Phase II results. Randomized controlled trials still represent a valid choice for IPF patients, and their completion is critically important to achieving the ultimate goal of curing IPF. Future approaches will probably include the evaluation of currently available agents alone and in combination, the identification of novel drugs with pleiotropic actions, and trials with validated, weighted composite endpoints.