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INTRODUCTION: Lung injury in severe COVID-19 pneumonia can rapidly evolve to established pulmonary fibrosis, with prognostic implications in the acute phase of the disease and long-lasting impact on the quality of life of COVID-19 survivors. This is an emerging medical need, and it has been hypothesized that antifibrotic treatments could have a role in ameliorating the fibrotic process in the lungs of these patients.Areas covered: The safety and efficacy of available antifibrotic drugs (nintedanib and pirfenidone) and novel promising agents are being assessed in several ongoing clinical trials that were performed either in critically ill patients admitted to intensive care, or in discharged patients presenting fibrotic sequalae from COVID-19. Literature search was performed using Medline and Clinicaltrials.org databases (2001-2021). Expert opinion: Despite the strong rationale support the use of antifibrotic therapies in COVID-related fibrosis, there are several uncertainties regarding the timing for their introduction and the real risks/benefits ratio of antifibrotic treatment in the acute and the chronic phases of the disease. The findings of ongoing clinical trials and the long-term observation of longitudinal cohorts will eventually clarify the best management approach for these patients.

The approval of antifibrotic agents nintedanib and pirfenidone revolutionized the management of idiopathic pulmonary fibrosis (IPF). These treatments showed acceptable tolerability in randomized-clinical trials; however, they have been associated with a spectrum of potential side effects which require careful assessment of risks and benefits in the individual patient before commencing and during antifibrotic therapy.The accrued evidence on safety of nintedanib and pirfenidone is summarized, from the first randomized clinical trials to the open-label extension studies and post-marketing clinical experiences which helped clarify the long-term tolerability of these drugs.The data collected over the last years confirmed the comparable tolerability profile of nintedanib and pirfenidone. The physician's assessment of expected side effects may help decide the optimal first-line therapy for the individual patient. Patient's counseling during treatment remains essential to manage emerging adverse events and eventually inform the decision of drug discontinuation.

The enthusiasm generated by the approval of pirfenidone and nintedanib as the first effective therapies for IPF led the IPF scientific community to investigate an increasing number of novel agents in well-designed randomized controlled trials, in the hope to find a cure for these patients.This reviews the evidence from IPF phase II trials that were completed or started in 2020. Literature search was performed using Medline and Clinicaltrials.org databases.Randomized clinical trials revolutionized the management of IPF, leading to the discovery of the first therapies capable of slowing down functional deterioration in these patients. The recently published findings of the first successful phase II trials since pirfenidone and nintedanib will hopefully inaugurate a new era in the therapeutic scenario of IPF, where consolidated treatments of proven efficacy and novel targeted agents contribute together to reach the final goal of halting the fibrotic process of this dreadful disease.

The last two decades witnessed an increasing number of well-designed late phase trials in patients with Idiopathic Pulmonary Fibrosis (IPF), leading to the approval of the first effective therapies...

Fibrotic hypersensitivity pneumonitis is a complex interstitial lung disease that is not entirely understood. In its chronic and fibrotic form, hypersensitivity pneumonitis is one of the main mimickers of idiopathic pulmonary fibrosis (IPF). Distinguishing between these two conditions is challenging but is of particular clinical relevance. Two approved therapies are available for IPF, and a considerable number of clinical trials are now exploring newer pharmacological options. This impressive research effort is a consequence of new pathogenetic understanding, updated diagnostic criteria and a long history of pharmacological trials. Conversely, current knowledge gaps on pathogenesis of chronic hypersensitivity pneumonitis, coupled with lack of validated diagnostic criteria, make the management of this disease an unsolved clinical challenge. This also reflects the paucity of therapeutic clinical trials in this field. In this review, we describe the current evidence and the possible future options to approach this complex disease.

In recent decades, the primary focus of pharmaceutical research in interstitial lung diseases (ILD) has been on idiopathic pulmonary fibrosis (IPF). Recently, pharmaceutical development has also focused on other forms of ILDs, including connective tissue diseases associated ILD, fibrotic hypersensitivity pneumonitis, and sarcoidosis.The authors summarize the advances in pharmacotherapy for the treatment of ILD. Specifically, the authors review the most recent studies and discuss the most recent research findings and future prospects.Data collected over the past years have confirmed the efficacy of antifibrotic drugs on slowing disease progression in IPF. The usual strategy for CTD-ILD management is represented by the combined use of corticosteroids and immunosuppressive agents. There is an urgent need for new target therapies. The concept of progressive fibrosing ILD has emerged in the ILD community in recent years, which has led to grouping several diseases with a common disease behavior to find an effective treatment . At present, selecting the best therapy in ILDs should be reasonably performed on a case-by-case basis through a multidisciplinary team discussion in tertiary ILD centers, taking into consideration patients' symptoms, lung functional trends, and radiological changes.

Introduction: Idiopathic Pulmonary Fibrosis (IPF) is a fibrotic interstitial lung disease (ILD) with unknown pathogenesis and poor prognosis. Unpredictable events defined as Acute Exacerbations (AE-IPF) may be experienced up to one in five IPF patients. The hallmark is a rapid respiratory failure not fully explained by heart failure/infections and associated with new lung infiltrates. Guidelines recommended treatment with steroids despite a lack of solid evidence. Aims: To compare survival of AE-IPF patients treated with methylprednisolone to those not treated with steroids. Methods: Retrospective analysis of IPF patients admitted to the pulmonary ward from 1 Jan 2014 through 15 Jan 2020. A case-by-case record review was performed. Survival was analyzed using Cox regression and Kaplan-Meier. Results: We admitted 119 ILD patients due and 73 (61.3%) had IPF. We analyzed 26 (35.6%) AE-IPF subjects. Males were predominant (80.1%) with a mean age of 73.2 years and mostly smokers (63.2%). We administered steroid in 12 subjects (46.2%). 10 AE-IPFs died during hospitalization. No association between steroid and mortality was identified either during in-hospital stay (HR 0.81; CI 0.21-3.10; p=0.76). Conclusions: We found no association between corticosteroid use and improved survival in subjects with AE-IPF. Large, controlled-studies are needed to address this unsolved problem. To date, the decision to use steroids remains difficult

Pirfenidone and nintedanib have been the first agents demonstrating to slow down the progressive functional decline in patients with Idiopathic Pulmonary Fibrosis (IPF). Antibody-based therapies with precise molecular targets have been largely investigated over the last decade in IPF as alternative or complementary treatments, in the hope to ameliorate the relentless fibrotic process of IPF.In this review, we summarize the available evidence on two groups of monoclonal antibodies tested in IPF: those directed against known fibrogenic factors and matrix components, and those developed to antagonize the inflammation and immunity pathways. While the latter have failed to demonstrate any clinical efficacy in IPF so far, the anti-CTGF pamrevlumab has been recently proved to be capable of slowing down functional decline as compared to placebo, prompting further investigation.Despite most trials on antibody-based therapies in IPF provided so far unsatisfying results, the therapeutic development in this field should continue to be pursued to deliver a more personalized treatment approach in the future, which is not currently offered by available treatment options. A more careful trial designing and the use of valid predictive markers of response to treatment are required to enhance effectiveness of future trials.

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.

Objective Sleep disorders have a high prevalence among patients with idiopathic pulmonary fibrosis (IPF). The prevalence of restless legs syndrome (RLS) is not known in these patients, neither is its clinical impact as a comorbidity. We investigated the association of RLS with IPF and characterized the clinical features of RLS in a cohort of IPF patients. Methods Fifty patients with diagnosis of IPF were prospectively enrolled. RLS was diagnosed using the validated 5-item RLS criteria. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index. The prevalence of RLS in the IPF group was compared to that observed in a group of 293 patients referred for suspect of sleep disorders. The relationships between RLS and clinical parameters were determined using multivariate logistic regression. Results Prevalence of RLS in the IPF group was significantly higher than in the control population of patients referred for sleep disorders (IPF: 24%, controls 10%: χ2 6.49, p = 0.011). Higher PSQI score confirmed to be associated with RLS after adjusting for demographics and clinical parameters of disease severity (OR = 1.38, 95%CI 1.08–1.76; p = 0.01). Conclusions RLS is highly prevalent in IPF and significantly worsen sleep quality in these patients. The benefit/risk ratio of a specific therapeutic intervention for RLS in IPF should be assessed in further prospective research.

Background and objectivesEvidence of mediastinal Lymph Node Enlargement (LNE) on CT scan is a common finding in idiopathic pulmonary fibrosis (IPF). We sought to investigate whether the involvement of mediastinal lymph nodes is associated with accelerated disease progression, and explored the changes occurring in mediastinal lymph nodes during the radiological follow up of these patients.MethodsThis retrospective study included IPF patients referred to a single ILD centre in Italy. A consensus-based assessment of mediastinal LNE on chest CT scan was performed by two thoracic radiologists. Kaplan-Meier curves and multivariate Cox proportional hazards regression were used to assess hazard ratios for mortality and disease progression (defined as categorical FVC decline ≥10%). The annualized rates of change in functional parameters for each patient were calculated using mixed linear models.ResultsThe study population consisted of 152 IPF patients, of whom 135 (89%) received antifibrotic treatment for IPF during the study follow up. Patients having evidence of 3 or more enlarged mediastinal lymph nodes on baseline CT scan showed increased rates of mortality (HR 5.03, 95% CI 1.86–13.62,p ≤ 0.001) and significant disease progression (HR 2.99, 95% CI 1.22–7.33,p = 0.17) as compared to patients without LNE, after adjusting for GAP stage. Among 62 patients with LNE who underwent a follow up CT scan of the chest and received antifibrotic treatment, 57 (92%) maintained evidence mediastinal LNE over time.ConclusionsDiffuse mediastinal lymph node involvement predicts clinically meaningful functional deterioration in patients with IPF.

The two available therapies for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, slow down but do not halt IPF progression. As such, in the last few years several agents with specific molecular targets have been investigated to find a cure forIPF. Pamrevlumab, a recombinant human antibody that binds to connective tissue growth factor (CTGF) has emerged as a potential therapy for IPF and has advanced to phase 3 clinical trials.The authors offer a backdrop to the current IPF treatment market and describe the chemistry, pharmacokinetics and pharmacodynamics of pamrevlumab. They summarize the preclinical and early clinical evidence on pamrevlumab and propose ways of progressing this agent further as a potential IPF treatment.Pamrevlumab was effective and safe in patients in a placebo-controlled phase 2 trial, demonstrating its potential to become an alternative therapeutic option for IPF; however, the feasibility of intravenous administration in clinical practice may be a hurdle to its use as a first-line treatment. Further studies are necessary to assess its effects when administered with pirfenidone or nintedanib and this could open up a new era of combined therapeutic approaches for IPF.

Background and objective In clinical practice, a working diagnosis of IPF may be performed to provide effective antifibrotic treatment to patients who cannot undergo SLB. In this study, we compared the disease course across IPF diagnostic categories in a real-life clinical setting to clarify the appropriateness of a working diagnosis of IPF and treatment initiation in these patients. Methods Longitudinal data from IPF patients receiving antifibrotic treatment (pirfenidone or nintedanib) were retrospectively collected at three tertiary centres in Italy. Univariate and multivariate analyses were performed to compare time to death and to a composite endpoint of disease progression between two diagnostic subgroups, that is, patients with UIP on HRCT and/or SLB, and patients with possible UIP and no histological confirmation. Results A total of 249 IPF patients were included in the analysis. Among patients with a possible UIP pattern on HRCT, 41 (55%) were prescribed antifibrotic treatment (either nintedanib or pirfenidone) despite absence of histological confirmation. This group demonstrated similar mortality and disease progression as compared to patients with a definite diagnosis of IPF as per diagnostic guidelines (log-rank test P = 0.771 and P = 0.139, respectively). Such findings were confirmed on multivariate analysis (HR: 1.19, 95% CI: 0.49-2.89, P = 0.7 for death; HR: 1.42, 95% CI: 0.83-2.44, P = 0.201 for disease progression). Conclusion In patients receiving antifibrotics following a working diagnosis of IPF, disease progression rates were similar to patients with a confident diagnosis of IPF according to consensus guidelines, supporting the rationale for treatment initiation in these patients by expert multidisciplinary teams.

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.

Accurate diagnosis of idiopathic pulmonary fibrosis (IPF) is essential to ensure prompt initiation of appropriate treatment and enrolment in clinical trials. According to current international guidelines [1], in the appropriate clinical context the identification of the usual interstitial pneumonia (UIP) pattern on chest high-resolution computed tomography (HRCT) allows a confident diagnosis of IPF. Patients referred to tertiary centres for suspected interstitial lung disease (ILD) may provide CT images that do not fulfil recommended scanning protocols [1], therefore triggering the execution of another CT. However, the impact of suboptimal technical quality on the identification of the UIP pattern by thoracic radiologists is unknown. We assessed the quality of chest CT scans performed in the context of an ILD network including a tertiary ILD centre (hub) and the affiliated centres (spokes), and the impact on the identification of the UIP pattern. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Sgalla reports personal fees from Boehringer Ingelheim, outside the submitted work. Conflict of interest: Dr. LARICI has nothing to disclose. Conflict of interest: Dr. Re has nothing to disclose. Conflict of interest: Dr. Farchione has nothing to disclose. Conflict of interest: Dr. Cicchetti has nothing to disclose. Conflict of interest: Dr. Calandriello has nothing to disclose. Conflict of interest: Dr. Comes has nothing to disclose. Conflict of interest: Dr. Golfi has nothing to disclose. Conflict of interest: Dr. Iovene has nothing to disclose. Conflict of interest: Dr. Varone has nothing to disclose. Conflict of interest: Dr. Manfredi has nothing to disclose. Conflict of interest: Dr. Richeldi reports personal fees from Sanofi-Aventis, personal fees from Roche, personal fees from ImmuneWorks, personal fees from Shionogi, personal fees from Boehringer Ingelheim, personal fees from Celgene, personal fees from Nitto, personal fees from Fibrogen, personal fees from Promedior, personal fees from Bristol Myers Squibb, personal fees from DynaMed, outside the submitted work.

Idiopathic pulmonary fibrosis (IPF) is a chronic, debilitating, fibrotic lung disease leading to respiratory failure, and ultimately to death. It is characterized by marked heterogeneity regarding its clinical course. Despite significant progress in the understanding of its pathogenesis, the course of the disease and the response to treatment of an individual patient cannot be reliably predicted today. Areas covered: Non-invasive biomarkers, in particular serum biomarkers, for the (early) diagnosis, differential diagnosis, prognosis, and prediction of therapeutic response are described. The molecules are classified according to their involvement into alveolar epithelial cell injury, fibroproliferation, and matrix remodeling as well as immune regulation. Furthermore, genetic variants of TOLLIP, MUC-5B, and other genes associated with a differential response to treatment and with the development and/or the prognosis of IPF are reported. Expert commentary: The combination of multiple biomarkers may identify comprehensive biomarker signatures in IPF patients. This is a way to apply personalized medicine approach to patient affected by IPF in order to not only improve our ability to diagnose and treat disease but also offer the potential to detect disease at an earlier stage, when it is potentially easier to treat effectively.

Accurate monitoring of disease progression in idiopathic pulmonary fibrosis (IPF) is crucial for predicting prognosis and optimising management, including the initiation of therapies, the appropriate timing of supportive care and the prompt referral for lung transplantation. While forced vital capacity (FVC) via spirometry has been accepted as the most feasible and reliable tool to assess the deterioration in these patients in clinical practice as well as in randomised controlled trials [1, 2], in recent years both visual evaluation and computer-based analysis of high-resolution computed tomography (HRCT) parenchymal patterns have been shown to correlate with disease severity based on FVC and predict outcome in several fibrotic lung diseases, including IPF [3–5]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Sgalla reports personal fees from Boheringer Ingelheim oustide the submitted work. Conflict of interest: Dr. LARICI has nothing to disclose. Conflict of interest: Dr. Sverzellati reports personal fees from Roche, personal fees from Boerhinger Ingelheim, outside the submitted work. Conflict of interest: Dr. Bartholmai reports grants from NIH/NHLBI, personal fees from Promedior, LLC, and from Imbio, LLC, outside the submitted work. In addition, Dr. Bartholmai has a patent SYSTEMS AND METHODS FOR ANALYZING IN VIVO TISSUE VOLUMES USING MEDICAL IMAGING pending. Conflict of interest: Dr. WALSH reports personal fees from Boehringer Ingelheim, personal fees from Roche, personal fees from Intermune, personal fees from Bracco, personal fees from Sanofi-Genzyme, outside the submitted work. Conflict of interest: Dr. Nikolic has nothing to disclose. Conflict of interest: Dr. Barney has nothing to disclose. Conflict of interest: Dr. Fletcher reports funding to attend conferences, speaker fees and fees for advisory boards from Roche and Boehringer Ingelheim. Conflict of interest: Dr. Jones has nothing to disclose. Conflict of interest: Dr. Davies reports other from Synairgen, personal fees from Synairgen, outside the submitted work. Conflict of interest: Dr. Richeldi reports personal fees and other from Boehringer Ingelheim, grants and personal fees from InterMune, personal fees from Cipla, personal fees from Vertex, other from AstraZeneca, other from GlaxoSmithKline, other from Sanofi-Aventis,, other from Celgene, other from Prometic, other from Roche, other from Takeda, during the conduct of the study.

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).Methods: lung 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.Results: 148 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.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing lung disorder of unknown aetiology whose diagnosis involves the careful exclusion of secondary causes for pulmonary fibrosis and the presence of a pattern of usual interstitial pneumonia (UIP) at either high-resolution computed tomography (HRCT) scan or surgical lung biopsy. Despite great efforts made in establishing precise, universally acknowledged diagnostic criteria for IPF, its ascertainment remains a challenge, especially in those individuals presenting with atypical HRCT patterns. With new drugs emerging, establishing a precise diagnosis is becoming a clinically relevant issue. Although regarded as a rare disease, IPF epidemiology is controversial due to studies relying on old data and adopting mixed, incomparable methodologies for cases definition. Overall, the prevalence and incidence appear to be increasing over the last decades, suggesting that in earlier studies they might have been underestimated because of diagnostic uncertainty. IPF is invariably progressive, although its clinical course might greatly vary on an individual basis, with episodes of severe acute respiratory deterioration (acute exacerbations) being unpredictable. A deeper understanding of the mechanisms responsible for an accelerated course of the disease and the identification of biomarkers of progression would lead to a better stratification of the disease, essential for delivering individualized therapeutic strategies.

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.

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.

Background: Immunosuppressive therapy has been - until the recent release of new guidelines on diagnosis and management - the recommended treatment for idiopathic pulmonary fibrosis. However, its efficacy in patients with idiopathic pulmonary fibrosis has always been a matter of debate. Case presentation: We report the occurrence of idiopathic pulmonary fibrosis in a white man receiving chronic immunosuppressive treatment following a heart transplant. Conclusions: This case report suggests that the immune mechanisms targeted by azathioprine and cyclosporine do not play a role in the pathogenesis of idiopathic pulmonary fibrosis.

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.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing lung disorder of unknown aetiology whose diagnosis involves the careful exclusion of secondary causes for pulmonary fibrosis and the presence of a pattern of usual interstitial pneumonia (UIP) at either high-resolution computed tomography (HRCT) scan or surgical lung biopsy. Despite great efforts made in establishing precise, universally acknowledged diagnostic criteria for IPF, its ascertainment remains a challenge, especially in those individuals presenting with atypical HRCT patterns. With new drugs emerging, establishing a precise diagnosis is becoming a clinically relevant issue. Although regarded as a rare disease, IPF epidemiology is controversial due to studies relying on old data and adopting mixed, incomparable methodologies for cases definition. Overall, the prevalence and incidence appear to be increasing over the last decades, suggesting that in earlier studies they might have been underestimated because of diagnostic uncertainty. IPF is invariably progressive, although its clinical course might greatly vary on an individual basis, with episodes of severe acute respiratory deterioration (acute exacerbations) being unpredictable. A deeper understanding of the mechanisms responsible for an accelerated course of the disease and the identification of biomarkers of progression would lead to a better stratification of the disease, essential for delivering individualized therapeutic strategies.

Background: It 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.Methods: Peripheral 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.Results: Patients 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.Conclusions: Levels 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.

Interstitial lung diseases (ILDs) represent a heterogeneous group of clinical entities among which disease of unknown causes may mimic ILDs due to known causes. Clinical, radiographic and histopathology presentation can largely overlap between different entities and a multidisciplinary approach is proven to be essential in composing the puzzle to reach the most likely clinical diagnosis in each single patients. The definition of specific radiographic (on chest high-resolution computed tomography, HRCT) and histopathology (on lung surgical lung biopsy, SLB) patterns has provided a common terminology in the field of ILDs in the tentative of classifying entities presenting with distinctive features. These patterns have been proposed in the classification of idiopathic interstitial pneumonias (IIPs), and then have been applied to describe ILDs due to secondary known causes, particularly those related to connective-tissue diseases. Among all these patterns, the usual interstitial pneumonia (UIP) pattern has received more emphasis, in particular since it identifies patients with idiopathic pulmonary fibrosis (IPF), as outlined in the most recent evidence-based international guideline. In this document, specific HRCT and SLB criteria for the definition of a definite UIP pattern have been proposed and since then they have been widely used as reference standard both in clinical practice and in the definition of eligibility criteria for randomized clinical trials. However, while a definite UIP pattern can be diagnostic for IPF in the proper clinical context, it is well known that the same pattern can be present in fibrotic lung diseases other than IPF, with important consequences in terms of therapeutic management and prognosis. This chapter will provide an overview on how the UIP pattern is defined, both on radiologist’s view and on pathologist’s view, along with elements that might be helpful in distinguishing an idiopathic UIP pattern from similar appearance in secondary diseases.