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The development of a progressive phenotype of interstitial lung disease (ILD) is still unpredictable. Whereas tools to predict mortality in ILD exist, scores to predict disease progression are missing. The aim of this study was to investigate whether baseline serum KL-6 as an established marker to assess disease activity in ILD, alone or in combination with clinical variables, could improve stratification of ILD patients according to progression risk at any time. Consecutive patients with fibrotic ILD, followed at our institution between 2008 and 2015, were investigated. Disease progression was defined as relative decline of ≥10% in forced vital capacity (FVC) or ≥15% in diffusing capacity of the lung for carbon monoxide (DLco)% from baseline at any time. Serum KL-6 was measured using an automated immunoassay (Fujirebio Europe, Gent, Belgium). A stepwise logistic regression was performed to select variables to be included in the score. A total of 205 patients (49% idiopathic pulmonary fibrosis (IPF), 51% fibrotic nonspecific interstitial pneumonia (NSIP)) were included, of them 113 (55%) developed disease progression during follow up. Male gender (G) and serum KL-6 strata (K) were significant predictors of progression at regression analysis and were included in the GK score. A threshold of 2 GK score points was best for discriminating patients at high risk versus low risk to develop disease progression at any time. Serum KL-6 concentration, alone or combined in a simple score with gender, allows an effective stratification of ILD patients for risk of disease progression at any time. [ABSTRACT FROM AUTHOR]

Background: Declines in percent predicted FVC (% predicted FVC), declines in 6-min walk distance (6MWD), and respiratory hospitalizations are events associated with disease progression and mortality in idiopathic pulmonary fibrosis. The incidence of multiple events in the same patient over 12 months of pirfenidone treatment is unknown.Methods: Patients who received pirfenidone 2,403 mg/d (n = 623) or placebo (n = 624) in the ASCEND (study 016; NCT01366209) and CAPACITY (studies 004 and 006; NCT00287716 and NCT00287729) phase III trials were included in this post hoc analysis. Disease progression events were defined as relative decline in % predicted FVC ≥ 10%, absolute decline in 6MWD ≥ 50 m, respiratory hospitalization, or death from any cause. The incidence of disease progression events over 12 months was assessed.Results: The most frequent disease progression events were declines in % predicted FVC (pirfenidone vs placebo; 202 vs 304 events) and declines in 6MWD (pirfenidone vs placebo; 265 vs 348 events). Fewer patients who received pirfenidone had more than one progression event compared with placebo (17.0% vs 30.1%; P < .0001). Death following one or more progression event occurred less frequently in the pirfenidone group than in the placebo group (2.1% vs 6.3%; P = .0002).Conclusions: Pirfenidone significantly reduced the incidence of multiple progression events and death after a progression event over 12 months of treatment compared with placebo. These findings suggest that continued treatment with pirfenidone confers a benefit despite the occurrence of any single disease progression event.Trial Registry: ClinicalTrials.gov; Nos. NCT01366209, NCT00287716, and NCT00287729; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular comorbidities are frequent in patients with idiopathic pulmonary fibrosis (IPF), and many patients with IPF receive treatment with statins to reduce cardiovascular risk. Objectives: We investigated whether statin use at baseline was associated with differences in disease progression in placebo-treated patients or influenced the treatment effect of nintedanib in the INPULSIS® trials. Methods: Post-hoc subgroup analyses of patients receiving versus not receiving statins at baseline using pooled data from the INPULSIS® trials. Results: At baseline, 312 patients received statins and 749 did not. The annual rates of decline in forced vital capacity (FVC) in patients treated with nintedanib and placebo, respectively, were –78.9 and –187.6 mL/year in patients who received statins at baseline, and –127.9 and –237.9 mL/year in patients who did not. The effect of nintedanib was consistent across subgroups (p = 0.9590). Conclusions: In the INPULSIS® trials, there was a numerically lower FVC decline in placebo-treated patients with IPF who received statins at baseline versus those who did not. Use of statins at baseline did not influence the treatment effect of nintedanib. Prospective data are needed to assess the impact of statins on the course of IPF. [ABSTRACT FROM AUTHOR]

Background: RECAP (NCT00662038) was an open-label extension study in patients with idiopathic pulmonary fibrosis (IPF) who completed either the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) 016 phase 3 trial or the Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY) 004/006 phase 3 trials. Objective: To obtain long-term safety data for pirfenidone in patients with IPF in RECAP. Methods: Of the 1,334 patients who participated in the phase 3 trials, 1,058 entered RECAP. The final analysis from enrollment (September 2008) to June 2015 is presented. Results: Mean (SD) and median (range) pirfenidone exposures in RECAP were 122 (98) weeks and 88 (>0 to 349) weeks, respectively, with a mean daily dose of 2,091.1 mg. Cumulative total exposure was 2,482 patient exposure years (PEY). The treatment-emergent adverse event (TEAE) rate was 701.9 per 100 PEY. The serious TEAE rate was 53.5 per 100 PEY, with the most common serious TEAE being IPF (11.1 per 100 PEY). Of the 231 deaths (9.3 per 100 PEY), the most common cause was IPF (5.4 per 100 PEY). The treatment discontinuation rate due to a TEAE was 17.9 per 100 PEY; discontinuations were due to IPF (7.2 per 100 PEY), pneumonia, respiratory failure, acute respiratory failure, rash (0.5 per 100 PEY each), and nausea (0.4 per 100 PEY). For patients from CAPACITY 004/006 who entered RECAP, the mean change in percent predicted forced vital capacity from RECAP baseline at 180 weeks was -9.6%. Median on-treatment survival from the first pirfenidone dose in RECAP was 77.2 months. Conclusions: RECAP provides long-term follow-up and safety data for pirfenidone that were consistent with the known profile, with no new safety signals observed. [ABSTRACT FROM AUTHOR]

IL-9, mainly produced by T helper 9 (Th9) cells, promotes allergic airway inflammation and remodeling through the interaction with its receptor (IL-9R). Th9 cells and IL-9 have also been implicated in tissue fibrosis and autoimmunity pathways. However, the role of IL-9/IL-9R in the pathogenesis of interstitial lung disease (ILD) is unknown. To evaluate IL-9/IL-9R expression in bronchoalveolar lavage fluid (BALF) lymphocytes of patients with various ILDs. Consecutive patients with ILD, who underwent BAL for diagnostic purposes, were studied. As control group, consecutive patients without evidence of ILD were included. Immunocytochemical staining of BALF lymphocytes for IL-9 and IL-9R was performed and evaluated by two independent readers. 45 patients, of them 8 had idiopathic pulmonary fibrosis (IPF), 12 nonspecific interstitial pneumonia (NSIP), 10 sarcoidosis, 9 hypersensitivity pneumonitis (HP), 6 cryptogenic organizing pneumonia (COP), and 24 controls were studied. In the ILD group, the highest BALF lymphocyte count was seen in HP followed by NSIP, COP, sarcoidosis, and IPF (p < 0.05 for HP vs IPF). The highest percentages of IL-9 and IL-9R positive lymphocytes were seen in COP. Conversely, NSIP showed the lowest rate of IL-9, and sarcoidosis the lowest rate of IL-9R positive lymphocytes. Only in NSIP, a direct correlation between IL and 9 and IL-9R positive lymphocytes was seen (r = 0.639, p = 0.025). BALF lymphocytes IL-9 and IL-9R expression differs between various ILDs and could reflect different pathogenetic mechanisms. [ABSTRACT FROM AUTHOR]

This article reviews major biomarkers in serum and bronchoalveolar lavage fluid (BALF) with respect to their diagnostic and prognostic value in connective tissue disease- associated interstitial lung disease (CTD-ILD). In some CTD such as systemic sclerosis (SSc), the incidence of ILD is up to two-third of patients, and currently ILD represents the leading cause of death in SSc. Because of the extremely variable incidence and outcome of ILD in CTD, progress in the discovery and validation of biomarkers for diagnosis, prognosis, patients' subtyping, response to treatment, or as surrogate endpoints in clinical trials is extremely important. In contrast to idiopathic interstitial pneumonias, autoantibodies play a crucial role as biomarkers in CTD-ILD because their presence is strictly linked to the pathogenesis and tissue damage. Patterns of autoantibodies, for instance, anticitrullinated peptide antibodies in rheumatoid arthritis or aminoacyl-tRNA synthetases (ARS) in polymyositis/dermatomyositis, have been found to correlate with the presence and occasionally with the course of ILD in CTD. Besides autoantibodies, an increase in serum or BALF of a biomarker of pulmonary origin may be able to predict or reflect the development of fibrosis, the impairment of lung function, and ideally also the prognosis. Promising biomarkers are lung epithelium-derived proteins such as KL-6 (Krebs von den Lungen-6), SP-D (surfactant protein-D), SP-A (surfactant protein-A), YKL- 40 (chitinase-3-like protein 1 [CHI3L1] or cytokines such as CCL18 [chemokine (C-C) motif ligand 18]). In the future, genetic/epigenetic markers, such as human leukocyte antigen (HLA) haplotypes, single nucleotide polymorphisms, and micro-RNA, may help to identify subtypes of patients with different needs of management and treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis. Methods: In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire [SGRQ]), and total lung capacity. Results: A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P=0.06 with the closed testing procedure for multiplicity correction; P=0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P=0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (−0.66 vs. 5.46, P=0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group. Conclusions: In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683.) [ABSTRACT FROM PUBLISHER]

Abstract: The diagnosis of sarcoidosis cannot be established by the presence of granuloma in a single organ, such as the skin. Therefore, the patient with potential cutaneous sarcoidosis should undergo a systemic evaluation for two reasons: to help confirm the diagnosis, and to identify other potential problems. This article reviews the recommended testing in patients with suspected or known sarcoidosis. The evaluation leads to a wide number of organs being assessed by either history, physical examination or routine laboratory investigations. The major organs routinely assessed are the lungs, the eyes, the liver and the heart. [Copyright &y& Elsevier]

Rare diffuse infiltrative lung diseases are a challenge for clinicians, radiologists, and pathologists for at least three reasons: (a) their low incidence and prevalence hamper the acquisition of expertise and frequently the diagnosis is delayed; (b) therapeutic actions are mainly empirical and based on steroid use, and (c) pathogenetic events are difficult to explain and only recently new therapeutic measures taking advantage of innovative genetic and/or immunopathogenetic studies have been suggested. In this review rare diffuse lung disorders are briefly discussed (pulmonary alveolar proteinosis, inherited lipidoses, acute eosinophilic pneumonia, amyloidosis, pulmonary ossification, pulmonary alveolar microlithiasis). The list is obviously not exhaustive and arbitrarily chosen. The intent is, however, to emphasize that in this difficult field multidisciplinary expertise and the knowledge of the most recent pathogenetic mechanisms have the main role in diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is characterized by uncontrolled progressive lung fibrosis with a median survival of 3 to 5 years. Although currently available pharmacotherapy cannot cure the disease, antifibrotics including pirfenidone and nintedanib were shown to slow disease progression and improve survival in IPF. Nevertheless, there is a knowledge gap on the safety of antifibrotics in patients after liver transplantation receiving concomitant immunosuppressive therapy. This case report of a 68-year-old male patient with IPF illustrates how a complex medical history has led to diagnostic and therapeutic challenges considerably affecting clinical decisions and impacting the patient's journey. The increasing severity of lung function impairment due to the progressive natural history of IPF ultimately led to severe respiratory failure. Double lung transplantation (LTx) was performed as the only therapeutic option in end-stage disease with the potential to improve quality of life and survival. To the best of our knowledge, this is the first case report describing the feasibility and safety of antifibrotic therapy with pirfenidone for IPF in a 68-year-old patient with a history of liver transplantation receiving concomitant immunosuppressive therapy with tacrolimus who underwent successful double lung transplantation when alternative medical interventions had been exhausted. [ABSTRACT FROM AUTHOR]

Sarcoidosis may have more than a single causative agent, including infectious and non-infectious agents. Among the potential infectious causes of sarcoidosis, Mycobacterium tuberculosis and Propionibacterium acnes are the most likely microorganisms. Potential latent infection by both microorganisms complicates the findings of molecular and immunologic studies. Immune responses to potential infectious agents of sarcoidosis should be considered together with the microorganisms detected in sarcoid granulomas, because immunologic reactivities to infectious agents reflect current and past infection, including latent infection unrelated to the cause of the granuloma formation. Histopathologic data more readily support P. acnes as a cause of sarcoidosis compared with M. tuberculosis, suggesting that normally symbiotic P. acnes leads to granuloma formation in some predisposed individuals with Th1 hypersensitivity against intracellular proliferation of latent P. acnes, which may be triggered by certain host or drug-induced conditions. Detection of bacterial nucleic acids in granulomas does not necessarily indicate co-localization of the bacterial proteins in the granulomas. In the histopathologic diagnosis of sarcoidosis, M. tuberculosis-associated and P. acnes-associated sarcoidosis will possibly be differentiated in some patients by immunohistochemistry with appropriate antibodies that specifically react with mycobacterial and propionibacterial antigens, respectively, for each etiology-based diagnosis and potential antimicrobial intervention against sarcoidosis. [ABSTRACT FROM AUTHOR]

See Letter [ABSTRACT FROM AUTHOR]

Data from controlled clinical studies in patients with more advanced idiopathic pulmonary fibrosis (IPF) could inform clinical practice, but they are limited, since this sub-population is usually excluded from clinical trials. These exploratory post-hoc analyses of the open-label, long-term extension study RECAP (NCT00662038) aimed to assess the efficacy and safety of pirfenidone in patients with more advanced IPF. Patients were categorised according to the extent of lung function impairment at baseline: more advanced (percent predicted FVC <50% and/or DLco <35%) and less advanced (percent predicted FVC ≥50% and DLco ≥35%).Overall, 596 patients with baseline FVC and/or DLco values available were included in the analyses; 187 patients had more advanced disease, and 409 patients had less advanced disease. Mean percent predicted FVC declined throughout 180 weeks of treatment in both more and less advanced disease subgroups. Both subgroups exhibited a similar pattern of adverse events; however, adverse events related to IPF progression were experienced by a higher proportion of patients with more advanced versus less advanced disease. Discontinuation rates due to any reason, adverse events related to IPF progression, or deaths were each higher in the more advanced versus the less advanced disease subgroup.These analyses found that longer-term pirfenidone treatment resulted in a similar rate of lung function decline and safety profile in patients with more advanced versus less advanced IPF, and the data suggest that pirfenidone is efficacious, well tolerated, and a feasible treatment option in patients with more advanced IPF. [ABSTRACT FROM AUTHOR]

Background: The benefits and risks of anti-acid medication in patients with idiopathic pulmonary fibrosis (IPF) remain a topic of debate. We investigated whether use of anti-acid medication at baseline was associated with differences in the natural course of disease or influenced the treatment effect of nintedanib in patients with IPF.Methods: Post-hoc analyses of outcomes in patients receiving versus not receiving anti-acid medication (proton pump or histamine-2 receptor inhibitor) at baseline using pooled data from the two Phase III randomized placebo-controlled INPULSIS® trials of nintedanib in patients with IPF.Results: At baseline, 406 patients were receiving anti-acid medication (244 nintedanib; 162 placebo) and 655 were not (394 nintedanib; 261 placebo). In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was - 252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and - 205.4 mL/year in placebo-treated patients who were not (difference of - 47.5 mL/year [95% CI: -105.1, 10.1]; p = 0.1057). In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were - 124.4 mL/year in the nintedanib group and - 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline and - 107.0 mL/year in the nintedanib group and - 205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869). The proportions of patients who had ≥1 investigator-reported acute exacerbation were 11.7% and 5.0% in placebo-treated patients, and 4.9% and 4.8% of nintedanib-treated patients, among patients who were and were not receiving anti-acid medication at baseline, respectively.Conclusions: In post-hoc analyses of data from the INPULSIS® trials, anti-acid medication use at baseline was not associated with a more favorable course of disease, and did not impact the treatment effect of nintedanib, in patients with IPF.Trial Registration: ClinicalTrials.gov identifiers: NCT01335464 and NCT01335477 . [ABSTRACT FROM AUTHOR]

An abstract of the article "Analysis of Patients With Idiopathic Pulmonary Fibrosis (IPF) With More Severe Lung Function Impairment Treated With Pirfenidone in Recap" by Ulrich Costabel and colleagues is presented

The article focuses on updates on guidelines and therapeutics regarding Idiopathic pulmonary fibrosis (IPF) in 2011. It efficacy of pirfenidone and the closing of studies of warfarin treatment, along with safety data regarding the N-acetylcysteine, azathioprine and prednisone combination therapy. It also mentions diagnosis along with the most effective treatment options available to date and calendar for respiratory physicians and researchers.

Key Points: Question: Does the autotaxin inhibitor ziritaxestat improve outcomes, compared with placebo, in patients with idiopathic pulmonary fibrosis who continue to receive standard of care with pirfenidone, nintedanib, or neither standard of care treatment? Findings: In 2 randomized clinical trials, ISABELA 1 and ISABELA 2, there was no reduction in the 52-week rate of decline for forced vital capacity (a measure of lung function) in the 2 ziritaxestat groups vs placebo, and combined data from both trials showed all-cause mortality rates were numerically higher for ziritaxestat than placebo. Therefore, the trials were stopped early. Meaning: The autotaxin inhibitor ziritaxestat was ineffective as a treatment for idiopathic pulmonary fibrosis. Importance: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective: To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants: The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions: Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures: The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results: At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was –124.6 mL (95% CI, −178.0 to −71.2 mL) with 600 mg of ziritaxestat vs –147.3 mL (95% CI, −199.8 to −94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, −52.3 to 97.6 mL]), and –173.9 mL (95% CI, −225.7 to −122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, −26.7 mL [95% CI, −100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was –173.8 mL (95% CI, −209.2 to −138.4 mL) with 600 mg of ziritaxestat vs –176.6 mL (95% CI, −211.4 to −141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, −46.9 to 52.4 mL]) and –174.9 mL (95% CI, −209.5 to −140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, −47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance: Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration: ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444 These 2 randomized clinical trials compare the efficacy and safety of 2 doses of the autotaxin inhibitor ziritaxestat vs placebo in patients with idiopathic pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

The article presents an overview of a 2002 study on how can bronchoalveolar lavage be helpful to elucidate pulmonary complications arising from changes in the vaginal wall. It provides information on a case of a patient who was admitted to hospital with acute respiratory failure. Details of the results of the study are given.

Background: In the INBUILD trial in patients with progressive fibrosing interstitial lung diseases (ILDs), nintedanib reduced the rate of decline in forced vital capacity compared with placebo, with side-effects that were manageable for most patients. We used data from the INBUILD trial to characterize further the safety and tolerability of nintedanib.Methods: Patients with fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF), who had experienced progression of ILD within the 24 months before screening despite management deemed appropriate in clinical practice, were randomized to receive nintedanib 150 mg twice daily or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg twice daily. We assessed adverse events and dose adjustments over the whole trial.Results: A total of 332 patients received nintedanib and 331 received placebo. Median exposure to trial drug was 17.4 months in both treatment groups. Adverse events led to treatment discontinuation in 22.0% of patients treated with nintedanib and 14.5% of patients who received placebo. The most frequent adverse event was diarrhea, reported in 72.3% of patients in the nintedanib group and 25.7% of patients in the placebo group. Diarrhea led to treatment discontinuation in 6.3% of patients in the nintedanib group and 0.3% of the placebo group. In the nintedanib and placebo groups, respectively, 48.2% and 15.7% of patients had ≥ 1 dose reduction and/or treatment interruption. Serious adverse events were reported in 44.3% of patients in the nintedanib group and 49.5% of patients in the placebo group. The adverse event profile of nintedanib was generally consistent across subgroups based on age, sex, race and weight, but nausea, vomiting and dose reductions were more common among female than male patients.Conclusions: The adverse event profile of nintedanib in patients with progressive fibrosing ILDs other than IPF is consistent with its established safety and tolerability profile in patients with IPF and characterized mainly by gastrointestinal events, particularly diarrhea. Management of adverse events using symptomatic therapies and dose adjustment is important to minimize the impact of adverse events and help patients remain on therapy. Trial registration Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178 A video abstract summarizing the key results presented in this manuscript is available at: https://www.globalmedcomms.com/respiratory/cottin/INBUILDsafety . [ABSTRACT FROM AUTHOR]

Background: Regardless of the causative antigen, hypersensitivity pneumonitis (HP) is usually classified as ‘acute’, ‘subacute’ or ‘chronic’. Considerable confusion still surrounds this classification because there are no widely accepted criteria to distinguish the various stages. The objective of this study wasto determine whether the current classification of HP truly reflects categories of patients with distinct clinical features. Methods: Data obtained from a large prospective multicenter cohort study (the HP Study) were used to divide a cohort of patients with HP into a limited number of categories (clusters) with maximally differing clinical patterns, without prejudgment. The results of this cluster analysis were compared with the current classification of HP (acute, subacute or chronic). Results: 168 patients were included in the analysis. A 2-cluster solution best fitted the data. Patients in cluster 1 (41 patients) had more recurrent systemic symptoms (chills and body aches) and normal chest radiographs than those in cluster 2 (127 patients) who showed significantly more clubbing, hypoxemia, restrictive patterns on pulmonary function tests and fibrosis on high-resolution computed tomography (HRCT). All p values were <0.0001, using Fisher’s exact test. Nodular opacities were seen on HRCT as often in cluster 1 as in cluster 2. There was considerable disagreement between the current classification of HP and the results of our analysis. Conclusion: The current classification of acute, subacute and chronic HP is not supported by our analysis. Subacute HP is particularly difficult to define. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Changes in the bronchoalveolar lavage fluid (BALF) cell profile may reflect immunologic reactions of the lung in pulmonary malignancies. Objective: Our aim was to analyse the BALF cell profile in peripheral lung cancer. Methods: This study was a retrospective analysis of BALF samples containing tumor cells from patients with confirmed peripheral lung cancer (140 cases). Routine analysis and lymphocyte phenotyping by an immunoperoxidase technique with the monoclonal antibodies CD3, CD20, CD4, CD8, CD57, CD1, CD25, CD71 and HLA-DR were performed. The data were compared with those from healthy persons. Results: We found a significantly lower proportion of macrophages (60%), and significantly elevated proportions of lymphocytes (24%) and neutrophils (13%) in cases with cancer when compared with controls. The proportion of eosinophils was higher in the cancer patients (2.4%), though not significantly. Regarding the lymphocyte phenotypes, we found a significantly elevated proportion of T cells (86%), a relatively low CD4/CD8 ratio (1.7 ± 1.3), and a relatively higher percentage of HLA-DR+ lymphocytes (6.6%) in patients with cancer. There were no significant differences between smokers and nonsmokers in the cancer patients. In more than half of the cases, a positive staining for epithelial membrane antigen was found. Conclusion: Our observations confirm the possible participation of lymphocytes (activated and suppressor subtypes) and eosinophils in the response against tumor in peripheral airways. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease. Diagnosis of IPF requires considerable expertise and experience. Since the publication of the international IPF guideline in the year 2011 and the update 2018 several studies and technical advances have occurred, which made a new assessment of the diagnostic process mandatory. The goal of this guideline is to foster early, confident, and effective diagnosis of IPF. The guideline focusses on the typical clinical context of an IPF patient and provides tools to exclude known causes of interstitial lung disease including standardized questionnaires, serologic testing, and cellular analysis of bronchoalveolar lavage. High-resolution computed tomography remains crucial in the diagnostic workup. If it is necessary to obtain specimens for histology, transbronchial lung cryobiopsy is the primary approach, while surgical lung biopsy is reserved for patients who are fit for it and in whom a bronchoscopic diagnosis did not provide the information needed. After all, IPF is a diagnosis of exclusion and multidisciplinary discussion remains the golden standard of diagnosis. [ABSTRACT FROM AUTHOR]

Background: Genetic variants of TOLLIP and MUC5B, both on chromosome 11, have been reported to be associated with the development and/or prognosis of idiopathic pulmonary fibrosis (IPF). This retrospective study was conducted to investigate the association of MUC5B and TOLLIP SNPs with disease outcome in IPF. 62 IPF patients and 50 healthy controls (HC) from our Institution were genotyped for SNPs within MUC5B (rs35705950) and TOLLIP (rs3750920 and rs5743890). Correlation of SNPs genotypes with survival, acute exacerbation (AE) or disease progression (defined as a decline of ≥ 5% in FVC and or ≥ 10% in DLco in one year) was investigated.Results: The MUC5B rs35705950 minor allele (T) was more frequent in IPF subjects than in HC (35% vs 9% p < 0.001). TOLLIP SNPs alleles and genotype distribution did not differ between IPF and HC and did not vary according to gender, age, BMI and lung functional impairment at baseline. The minor allele (C) in TOLLIP rs5743890 was associated with worse survival and with disease progression in all performed analyses. The MUC5B rs35705950 or the TOLLIP rs3750920 minor allele, were not associated with disease progression or AE.Conclusion: We confirm that the minor allele of MUC5B rs35705950 is associated with IPF. The minor allele of TOLLIP rs5743890 appears to be a predictor of worse survival and more rapid disease progression, therefore being of potential utility to stratify IPF patients at baseline. [ABSTRACT FROM AUTHOR]

Background: Immunosuppressive therapy still is the standard treatment for patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). Objectives: This retrospective study aimed to provide data on the tolerability and efficacy of azathioprine in progressive CTD-ILDs. Methods: A total of 56 patients with CTD-ILD treated with azathioprine between 2003 and 2014 were included in the study. The patients were assessed every 3 months during follow-up. Results: The mean treatment duration was 34 months, with a range of 3–105 months. Fifteen patients (27%) discontinued treatment due to side effects, mostly due to elevated liver enzymes, within the first 3 months. Forty-one patients were treated for longer than 3 months, and 27 of those (66%) had stabilization or improvement of pulmonary function during treatment. In patients who remained stable or improved, the mean FVC was 62 ± 17% predicted (% pred) at initiation of treatment and 65 ± 17% pred at the last follow-up visit (p = 0.036), and the mean DLCO was 38 ± 16% pred at initiation of treatment and 39 ± 17% pred at the last follow-up visit (p = 0.06). Conclusions: Azathioprine can stabilize or improve CTD-ILD. While early drug intolerance is frequent, most patients who have tolerated the drug well achieve long-term stabilization or improvement of lung function. [ABSTRACT FROM AUTHOR]

The author presents a perspective on all-cause mortality as a primary endpoint, endorsed by 52 European clinicians. He further mentions the problem of the selection of accurate primary end-points for treatment studies in idiopathic pulmonary fibrosis (IPF). He adds that all-cause mortality would be the most clinically meaningful and preferred primary end-point and also opposes to the idea that mortality data should be required for drug registration in IPF.

Background: A thorough diagnostic process is essential with regard to prognosis and treatment of the more than 200 different types of interstitial lung diseases (ILD). Key to this complex process is a comprehensive medical history. For this, a template is recommended and questionnaires are increasingly used. Yet, the optimal questionnaire has not been established. Objectives: We aimed to compare well-established questionnaires that are used in the diagnostic process of interstitial and rare lung diseases. Methods: Via a structured internet search and ILD expert interviews, we identified 6 different questionnaires for the diagnosis of ILDs: the questionnaires developed by the German Respiratory Society (DGP), American College of Chest Physicians (ACCP), National Jewish Health (NJH), Österreichische Röntgengesellschaft/Gesellschaft für Medizinische Radiologie und Nuklearmedizin (OERG), University of California, Los Angeles Health (UCLA), and University of California, San Francisco Medical Center (UCSF). We compared the forms, lengths, and contents of the 6 questionnaires regarding symptoms, comorbidities, drug history, previous ILD therapies, family history, smoking habits, occupational history, exposures, travel history, and former diagnostic procedures. Results: The questionnaires differed in length and content. The UCLA questionnaire focuses on connective tissue diseases extensively, while the NJH questionnaire captures previous diagnostics in detail. The OERG questionnaire is condensed, while the other 5 questionnaires are very detailed. The UCSF questionnaire contains a personal assessment part for the patient. For the majority of the questions, the patient can choose options from a preselected list of possible answers. The DGP questionnaire offers the patient the opportunity to add additional information in the form of free text to some of the key questions. Conclusions: Questionnaires are an important tool in the diagnostic process of ILDs. Further validation and adjustment to clinical guidelines will help to improve existing questionnaires. Future work must aim to develop an internationally accepted template. [ABSTRACT FROM AUTHOR]

Background: Anti-DFS70 antibodies, corresponding to the dense fine speckled antinuclear antibody (ANA) pattern in HEp-2 substrates, have been observed in chronic inflammatory conditions, cancer and in healthy individuals but in only a small percentage of patients with connective tissue diseases (CTD). Objectives: The study was aimed to investigate the possible role of Anti-DFS70 antibodies to distinguish CTD associated interstitial lung disease (CTD-ILD) from idiopathic interstitial pneumonia (IIP) and to explore potential correlations between anti-DFS70 antibodies and clinical parameters. Methods: Serum samples were collected from 49 healthy controls (HC), 35 scleroderma-ILD (SSc-ILD) patients as negative controls for anti-DFS70 antibody, and 260 patients with the initial diagnosis IIP including 100 nonspecific interstitial pneumonia (NSIP) and 160 idiopathic pulmonary fibrosis (IPF) patients. ANA pattern was identified by indirect immunofluorescence on HEp-2 cells and anti-DFS70 antibodies were measured in serum by ELISA. Results: Serum anti-DFS70 antibodies were less frequently seen in ILD and SSc-ILD patients compared to HCs. Thirty-seven patients (34 initial idiopathic NSIP and 3 initial IPF patients) developed CTD during 24 months of follow-up, most of them combined with ANA positivity and anti-DFS70 antibody negativity. Anti-DFS70 antibody positivity was not significantly different between CTD-ILD and idiopathic ILD. Conclusions: The frequency of serum anti-DFS70 antibody is markedly decreased in patients with ILDs. Anti-DFS70 antibodies may be useful to predict CTD development in ILD patients. [ABSTRACT FROM AUTHOR]

B CLINICAL IMPLICATIONS: b These results suggest that pirfenidone has clinically meaningful benefits on both exercise capacity and dyspnea in patients with IPF and more advanced lung function impairment. [Extracted from the article]

The mechanisms of idiopathic pulmonary fibrosis (IPF), a rare, devastating disease with a median survival of 3–5 years, are not fully understood. Gastroesophageal reflux disease (GERD) is a frequent comorbidity encountered in IPF. Hypothetically, GERD-associated microaspiration may lead to persistent inflammation impairing lung infrastructure, thereby possibly accelerating the progression of IPF. IPF may increase intrathoracic pressure, which can aggravate GERD and vice versa. On the basis of the possible beneficial effects of antireflux or antacid therapy on lung function, acute exacerbation, and survival, the recent international IPF guideline recommends antacid therapies for patients with IPF, regardless of symptomatic GERD. However, due to newer conflicting data, several national guidelines do not support this recommendation. Elucidation of these questions by further clinical and bench-to-bedside research may provide us with rational clinical diagnostic and therapeutic approaches concerning GERD in IPF. The present review aims to discuss the latest data on the controversial association of IPF and GERD. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and objective Pulmonary alveolar proteinosis ( PAP) is a rare disease characterized by alveolar filling. YKL-40, a chitinase-like protein produced by macrophages and epithelial cells, is increased in patients with interstitial lung diseases. We aimed to evaluate the role of YKL-40 as a biomarker for PAP. Methods A total of 34 patients with autoimmune PAP and 50 healthy controls were studied. YKL-40 was measured by ELISA in serum and bronchoalveolar lavage fluid ( BALF). Chitinase coding gene polymorphisms ( CHI3L1−329 and −131) were detected by PCR and pyrosequencing. Correlations between serum YKL-40 levels and disease outcome were analysed. Results Baseline serum and BALF levels of YKL-40 were higher in PAP patients than in controls (286 ± 27 ng/ mL vs 42 ± 4 ng/ mL, P < 0.0001; 323 ± 36 ng/ mL vs 3 ± 1 ng/ mL, P < 0.0001, respectively). Serum YKL-40 levels correlated with diffusing capacity of the lung for carbon monoxide ( DLCO ) at baseline ( P = 0.002) and over time ( P < 0.0001). Patients with disease progression had higher baseline serum YKL-40 levels than those who remained stable or improved ( P < 0.0001). A baseline cut-off level of 300 ng/ mL was predictive of disease progression ( HR (hazard ratio): 7.875, P = 0.001). The presence of the G allele was associated with higher serum and BALF levels of YKL-40. Conclusion YKL-40 is elevated in serum and BALF of PAP patients, and may be of clinical utility to predict outcome in PAP. [ABSTRACT FROM AUTHOR]

Background: Gastroesophageal reflux disease is a potential risk factor for idiopathic pulmonary fibrosis (IPF) progression; however, the impact of antacid therapy (AAT) is under debate. Objective: To evaluate the effect of AAT on IPF progression in pirfenidone-treated patients. Methods: This post hoc analysis included patients with IPF who received pirfenidone in 3 trials (CAPACITY [PIPF-004/PIPF-006] and ASCEND [PIPF-016]). Pulmonary function, exercise tolerance, survival, hospitalizations, and adverse events (AEs) over 52 weeks were analyzed by baseline AAT use. Disease progression was defined as a decrease in forced vital capacity (FVC) of ≥ 10%, a decrease in 6-min walking distance of ≥ 50 m, or death over 1 year. Results: Of 623 patients, 44% received AAT. No significant differences were found at 52 weeks (AAT versus non-AAT, respectively) in disease progression (24.9 vs. 30.6%; p = 0.12), all-cause mortality rate (2.9 vs. 4.0%; p = 0.47), IPF-related mortality rate (1.1 vs. 2.0%; p = 0.37), all-cause hospitalization rate (16.1 vs. 18.3%; p = 0.48), or mean change in percent FVC (-2.7 vs. -3.1%; p = 0.44). A relative, but not absolute, FVC decline of ≥ 10% favored AAT (15 vs. 22%; p = 0.03). Severe gastrointestinal AEs (3.7 vs. 0.9%; p = 0.015) and severe pulmonary infections (3.7 vs. 1.1%; p = 0.035) were more frequent with AAT. Conclusions: AAT and pirfenidone had outcomes comparable to those of pirfenidone alone in patients with IPF, underscoring the need for prospective trials to elucidate the role of AAT with or without antifibrotic drugs as a treatment for IPF. [ABSTRACT FROM AUTHOR]

Background: Transbronchial lung cryobiopsy is an innovative method of obtaining samples from the parenchyma of patients with diffuse parenchymal lung diseases. However, the technique is not yet standardized, and uncertainty exists about the optimal protocol, including the number of samples, the biopsy size, and the choice of the biopsy site. Objectives: To compare the diagnostic yield and complications of cryobiopsy with different strategies adopted to sample lung tissue (number of samples, biopsy site, and sample size). Methods: We prospectively enrolled 46 patients with suspected diffuse parenchymal lung diseases for the diagnosis of which a biopsy was deemed useful. All patients under-went transbronchial lung cryobiopsy, and they were randomly assigned to group A (4 samples obtained from the same segment) or group B (2 samples obtained from one segment and 2 samples obtained from a different segment of the same lobe). Analysis of the samples was performed sequentially (from the first to the last sample), and pathologists reformulated their histopathologic diagnosis with the addition of each sample. Results: The mean diagnostic yield of the procedure combining the 2 groups and performing only the first sampling was 69%. When a second biopsy was performed as well, the mean diagnostic yield improved, but this increase was significant only when the 2 samples were obtained from 2 different segments (96%, group B). Conclusions: This study suggests that the strategy of performing 2 biopsies with a cryoprobe may be associated with an increased diagnostic yield in diffuse parenchymal lung diseases if these samples are obtained from 2 different segments within the same lobe. [ABSTRACT FROM AUTHOR]

Background: Whole lung lavage (WLL) is the current standard of care treatment for patients affected by pulmonary alveolar proteinosis (PAP). However, WLL is not standardized and international consensus documents are lacking. Our aim was to obtain a factual portrayal of WLL as currently practiced with respect to the procedure, indications for its use, evaluation of therapeutic benefit and complication rate.Methods: A clinical practice survey was conducted globally by means of a questionnaire and included 27 centers performing WLL in pediatric and/or adult PAP patients.Results: We collected completed questionnaires from 20 centres in 14 countries, practicing WLL in adults and 10 centers in 6 countries, practicing WLL in pediatric patients. WLL is almost universally performed under general anesthesia, with a double-lumen endobronchial tube in two consecutive sessions, with an interval of 1-2 weeks between sessions in approximately 50 % of centres. The use of saline warmed to 37 °C, drainage of lung lavage fluid by gravity and indications for WLL therapy in PAP were homogenous across centres. There was great variation in the choice of the first lung to be lavaged: 50 % of centres based the choice on imaging, whereas 50 % always started with the left lung. The choice of position was also widely discordant; the supine position was chosen by 50 % of centres. Other aspects varied significantly among centres including contraindications, methods and timing of follow up, use of chest percussion, timing of extubation following WLL and lung isolation and lavage methods for small children. The amount of fluid used to perform the WLL is a critical aspect. Whilst a general consensus exists on the single aliquot of fluid for lavage (around 800 ml of warm saline, in adults) great variability exists in the total volume instilled per lung, ranging from 5 to 40 liters, with an average of 15.4 liters/lung.Conclusions: This international survey found that WLL is safe and effective as therapy for PAP. However these results also indicate that standardization of the procedure is required; the present survey represents the a first step toward building such a document. [ABSTRACT FROM AUTHOR]

Background: KL-6, a human MUC1 mucin, is a sensitive biomarker for interstitial lung diseases including pulmonary alveolar proteinosis (PAP). A correlation between MUC1 gene single nucleotide polymorphism (SNP) rs4072037 genotype and serum KL-6 levels has been reported. This study was aimed at investigating the correlation between MUC1 SNP genotype, severity of disease and disease outcome in PAP.Methods: Twenty four patients with PAP and 30 healthy volunteers were studied. MUC1 rs4072037 was detected by using a real-time polymerase chain reaction (RT-PCR). Genotyping was performed by pyrosequencing. KL-6 levels were measured in serum by Nanopia KL-6 assay (SEKISUI Diagnostics).Results: The frequency of MUC1 rs4072037 alleles was significantly different between PAP patients and healthy volunteers (PAP, A/A 46%, A/G 54%, G/G 0%; healthy controls, A/A 30%, A/G 40%, G/G 30%; p = 0.013). Serum KL-6 levels were significantly higher in PAP patients than in controls (p < 0.0001), and significantly higher in PAP patients with A/A genotype than in those with A/G genotype (p = 0.007). Patients with A/A genotype had higher alveolar-arterial oxygen difference (A-aDO2) and lower DLco compared to those with A/G genotype (p = 0.027 and p = 0.012, respectively). Multivariate analysis, Kaplan-Meier analysis and C statistics showed that the rs4072037 A/A genotype was associated with higher rate of disease progression (HR: 5.557, p = 0.014).Conclusions: MUC1 rs4072037 A/A genotype is associated with more severe pulmonary dysfunction and a higher rate of disease progression in PAP patients. [ABSTRACT FROM AUTHOR]

Background: While respiratory bronchiolitis (RB) is a frequent histopathological finding in smoker's lungs, RB-associated interstitial lung disease (RB-ILD) remains a rare disease. Objectives: We analyzed how the histological finding of RB was associated with clinical information in a series of 684 consecutive surgical lung biopsies. Methods: Retrospective analysis with delineation of clinical manifestations, smoking habits, pulmonary function test, and blood gas analysis in patients with RB in surgical lung biopsy. In 240 of these biopsies, RB was diagnosed, and in 146 of these cases a full clinical dataset was available. Results: The final diagnosis of these 146 patients was consistent with RB-ILD (n = 18), pulmonary Langerhans cell histiocytosis (n = 7), various ILD (n = 9), spontaneous pneumothorax (n = 43), traumatic pneumothorax (n = 5), lung cancer (n = 41), various benign lung tumors (n = 8), and chronic pulmonary effusion (n = 15). Smoking history was positive in 93% of patients, 72% revealed centrilobular emphysema in their biopsy, and 58% described dyspnea as the main symptom. Amongst these diagnoses there were significant differences in age and smoking habits, but only small distinctions in pulmonary function test and blood gas analysis. Out of the patients with RB-ILD, 17% developed lung cancer in the later course. Conclusion: RB is strongly related to smoking, emphysema, and dyspnea and frequently associated with lung cancer. RB-ILD is a rare disease that may represent a considerable risk for lung cancer. Pulmonary function testing and blood gas analysis do not differ between RB-associated diseases. The finding of RB should prompt further diagnostic workup, and in case of RB-ILD, entail regular screening for lung cancer. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background and objective A single nucleotide polymorphism ( SNP) rs35705950 in the promoter of Mucin 5 B ( MUC 5 B) has been reported to be associated with idiopathic pulmonary fibrosis ( IPF) mainly in Caucasian populations. This study was conducted to confirm the association between rs35705950 and IPF in a Japanese population. Methods Genomic DNA was extracted from blood samples in 384 Japanese and 137 German subjects, and rs35705950 was detected by commercially available genotyping assay. Results The genotype distributions of rs35705950 in Japanese patients with IPF, nonspecific interstitial pneumonia ( NSIP) and healthy subjects ( HS) were significantly different from those in the German counterparts ( P < 0.001, P < 0.001 and P = 0.010, respectively). The rs35705950 T allele frequencies in patients with IPF, NSIP and HS were 3.4%, 1.7% and 0.8%, respectively in the Japanese, while they were 33.1%, 27.4% and 4.3%, respectively in the German cohort. The T allele frequencies in patients with IPF were significantly higher than those in HS both in the Japanese ( P = 0.031) and German ( P < 0.001) cohorts. Conclusions The association between rs35705950 and IPF was also present in this Japanese cohort, but was not as strong as the German counterpart. To our knowledge, this is the first study to successfully validate the association between rs35705950 and IPF in a Japanese ethnicity. [ABSTRACT FROM AUTHOR]

Background and objective Pirfenidone is an oral antifibrotic agent that is approved in several countries for the treatment of idiopathic pulmonary fibrosis ( IPF). We performed a comprehensive analysis of safety across four clinical trials evaluating pirfenidone in patients with IPF. Methods All patients receiving pirfenidone 2403 mg/day in the Phase 3 CAPACITY studies ( Studies 004 and 006) and all patients receiving at least one dose of pirfenidone in one of two ongoing open-label studies in patients with IPF ( Studies 002 and 012) were selected for inclusion. Safety outcomes were evaluated from baseline until 28 days after the last dose of study drug. Results A total of 789 patients were included in the analysis. The median duration of exposure to pirfenidone was 2.6 years (range, 1 week-7.7 years), and the cumulative total exposure was 2059 person exposure years ( PEY). Gastrointestinal and skin-related events were the most commonly reported adverse events; these were almost always mild to moderate in severity, and rarely led to treatment discontinuation. Elevations (>3× upper limit of normal) in alanine aminotransferase ( ALT) or aspartate aminotransferase ( AST) occurred in 21/789 (2.7%) patients; the adjusted incidence of AST/ ALT elevations was 1.7 per 100 PEY. Conclusions This comprehensive analysis of safety in a large cohort of IPF patients receiving pirfenidone for a total of 2059 PEY demonstrates that long-term treatment with pirfenidone is safe and generally well tolerated. [ABSTRACT FROM AUTHOR]

The article discusses the efficacy and safety of the drug nintedanib in idiopathic pulmonary fibrosis. Topics covered include results of two replicate phase 3 trials which evaluated the efficacy and safety of 150 milligrams of nintedanib twice daily as compared with placebo which found a significant benefit with nintedanib versus placebo, and the ability of nintedanib to reduce the decline in forced vital capacity.

Background Surfactant protein A (SP-A) and SP-D are clinically established in Japan as serum biomarkers for diagnosing interstitial lung diseases (ILDs). Serum SP-D levels are affected by genetic variants. We conducted the present study to examine whether serum SP-A and/or SP-D levels in healthy subjects (HS) and patients with ILDs differ between populations with different genetic backgrounds. Methods German subjects (n = 303; 138 patients with idiopathic interstitial pneumonias [IIPs] and 165 HS) and Japanese subjects (n = 369; 94 patients with IIPs and 275 HS) were enrolled. Serum SP-A and SP-D levels were measured using an enzyme-linked immunosorbent assay, and four single-nucleotide polymorphisms (SNPs) in the SFTPD gene were genotyped using genomic DNA extracted from blood samples. Results In both the German and Japanese cohorts, serum SP-A and SP-D levels were significantly higher in patients with IIPs than in HS. There were no significant differences in SP-A levels between the German and Japanese cohorts; however, we found that serum SP-D levels were significantly higher in the German cohort, both in patients with IIPs and in HS (p < 0.001 and p = 0.005, respectively). Furthermore, the genotype distributions of the four SNPs in the SFTPD gene (rs721917, rs1998374, rs2243639, and rs3088308) were significantly different between German and Japanese cohorts (p < 0.001, p < 0.001, p = 0.022, and p < 0.001, respectively), and univariate linear regression analyses revealed that the genotypes of rs721917, rs1998374, and rs2243639 significantly correlated with serum SP-D levels (p < 0.001, p < 0.001, and p = 0.011, respectively). Furthermore, multivariate analyses revealed that the genotypes of these three SNPs correlated independently with serum SP-D levels (p < 0.001, p = 0.001, and p = 0.038, respectively), whereas ethnicity did not significantly correlate with serum SP-D levels. Conclusions In patients with IIPs and HS, serum SP-D, but not SP-A, levels were significantly higher in the German than in the Japanese cohort, in part, because of the different frequencies of SFTPD gene polymorphisms. [ABSTRACT FROM AUTHOR]

Abstract: Background and objective: Bronchiolitis obliterans organizing pneumonia (BOOP) is a distinct clinicopathological entity histologically characterized by intra-alveolar granulation tissue and absence of extensive fibrotic lesions. Effective macrolide treatment of BOOP has been reported anecdotally. This study aimed to investigate whether alveolar macrophages (AMs) produce aberrant proinflammatory cytokines in BOOP and whether this can be inhibited by clarithromycin (CAM) or azithromycin (AZM). Methods: AMs collected by bronchoalveolar lavage (BAL) from 6 BOOP patients and 8 non-ILD controls were cultured for 24h in the presence or absence of CAM, AZM, lipopolysaccharide (LPS), or dexamethasone (DEX). Tumor necrosis factor alpha (TNF-α), soluble TNF receptor 1 (sTNFR1), sTNFR2, interleukin 1beta (IL-1β), IL-6, IL-8, IL-10, interferon gamma inducible protein 10 (IP-10) and CC chemokine ligand 18 (CCL18) were measured in the culture supernatant by ELISA. Results: The spontaneous and LPS-stimulated production of all investigated cytokines by AMs was significantly increased in BOOP compared to controls. CAM and AZM induced a dose-dependent suppression of spontaneous TNF-α, sTNFR2, IL-6, IL-8 and CCL18 production (p <0.05). CAM also inhibited the IL-1β production. CAM and AZM significantly and dose-dependently attenuated the LPS-stimulated production of sTNFR1, sTNFR2, IL-8 and CCL18 (p <0.05). CAM also inhibited the LPS-stimulated TNF-α, IL-1β, IL-6 and IL-10 production. Conclusions: AMs from BOOP patients produce abundant proinflammatory cytokines which may be pivotal in the disease pathogenesis. Macrolides inhibit this cytokine production, CAM more efficiently than AZM. [Copyright &y& Elsevier]

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor.Objective: To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression.Design: Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300).Setting: Academic and private hospitals.Participants: Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans.Intervention: Ambrisentan, 10 mg/d, or placebo.Measurements: Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function.Results: The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point.Limitation: The study was terminated early.Conclusion: Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations.Primary Funding Source: Gilead Sciences. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. Objective: To determine whether ambrisentan, an ETA receptorselective antagonist, reduces the rate of IPF progression. Design: Randomized, double-blind, placebo-controlled, eventdriven trial. (ClinicalTrials.gov: NCT00768300). Setting: Academic and private hospitals. Participants: Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. Intervention: Ambrisentan, 10 mg/d, or placebo. Measurements: Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. Results: The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebotreated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. Limitation: The study was terminated early. Conclusion: Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. Primary Funding Source: Gilead Sciences. [ABSTRACT FROM AUTHOR]

Background: Pulmonary alveolar proteinosis (PAP) is a rare disorder characterised by abundant alveolar accumulation of surfactant lipoproteins. Serum levels of KL-6, high molecular weight human MUC1 mucin, are increased in the majority of patients with PAP. The prognostic significance of KL-6 in PAP is still unknown. Aim of the study was to evaluate whether serum KL-6 levels correlate with the outcome of the disease. Patients and methods: From 2006 to 2012, we prospectively studied 33 patients with primary autoimmune PAP. We measured serum KL-6 levels by ELISA (Eisai, Tokyo, Japan), and evaluated the correlation between initial KL-6 levels and clinical variables. Disease progression was defined as deterioration of symptoms, and/or lung function, and/or chest imaging. Main results: The initial serum KL-6 levels were significantly correlated with the baseline PaO2, A-aDO2, DLCO, VC and TLC (p=0.042, 0.012, 0.012, 0.02 and 0.013, respectively). The change over time of serum KL-6 correlated with the change over time of DLCO (p=0.017). The initial serum KL-6 levels were significantly higher in patients with disease progression than in those with remission (p<0.001). At a cut-off level of 1526 U/mL, the initial serum KL-6 level predicted disease progression (Se 81%, Sp 94%). At a cut-off level of 2157 U/mL, the initial serum KL-6 predicted the necessity of repeated whole lung lavage (Se 83%, Sp 96%). In the multivariate analysis, the initial serum level of KL-6 was the strongest predictor of disease progression (HR 9.41, p=0.008). Conclusions: Serum KL-6 seems to predict outcome in PAP. [ABSTRACT FROM AUTHOR]

Background: Diffuse alveolar hemorrhage syndrome is a life threatening condition with diverse etiologies. Sensitive prognostic markers for diffuse alveolar hemorrhage have not been well investigated. Serum KL-6 is a biomarker for various interstitial lung disease associated with disease activity and prognosis. The purpose of the present study was to evaluate the clinical utility of serum KL-6 level as a prognostic marker for diffuse alveolar hemorrhage. Methods: We retrospectively collected 41 consecutive patients clinically diagnosed as having diffuse alveolar hemorrhage who were admitted to the Intensive Care Unit of Hiroshima University Hospital between 2004 and 2011. Correlation between prognosis and age, sex, laboratory findings including serum KL-6, radiological findings, ventilatory modes or therapeutic regimens were evaluated. Results: Baseline and peak serum KL-6 levels were significantly higher in non-survivors compared with survivors. An increase in KL-6 levels during the initial week was associated with a subsequent deterioration of the oxygenation index. Higher baseline KL-6 levels and higher peak KL-6 levels were strongly correlated with death. With a cut-off level of 700 U/mL for peak KL-6, the sensitivity, specificity and accuracy for non-survival were 75%, 85% and 78%, respectively. In the multivariate analysis, only the peak KL-6 level ≥700 U/ml was an independent poor prognostic factor for diffuse alveolar hemorrhage. Conclusions: Peak serum KL-6 level ≥700 U/ml may become a clinically useful marker of poor prognosis for diffuse alveolar hemorrhage. [ABSTRACT FROM AUTHOR]

Background: Interstitial pneumonias (IP) cover a broad spectrum of diseases. Open lung biopsies reveal histological patterns and suggest possible diagnoses. Complete clinical records are necessary for final diagnoses. Especially idiopathic interstitial pneumonias (IIP) according to the ATS/ERS classification can only be diagnosed under these predictions. The aim of this study was to compare the results of histological evaluations with the final diagnosis after interdisciplinary case evaluation. Patients and methods: 88 patients with interstitial pneumonia that underwent open lung biopsies were investigated. Histology and clinical records were available for review. Diagnosis was made in three steps: first on the sole basis of histology, second with clinical information given initially and third, on the basis of an interdisciplinary case evaluation. Results: 63 patients (72%) were diagnosed as idiopathic interstitial pneumonias according to ATS/ERS criteria. Further 10 (11%) cases of hypersensitivity pneumonitis, 7 (8%) Langerhans cell histiocytosis and 8 (9%) interstitial pneumonias of other known causes or associations were detected. Histological patterns alone agreed with the final diagnosis in 67%. In 82% histology and clinical information given to the pathologist could provide correct diagnosis. In the rest of cases, especially in non idiopathic interstitial pneumonias, an interdisciplinary case evaluation was needed. Conclusions: Diagnosis of interstitial pneumonias by open lung biopsies needs sufficient clinical information. Because of the overlap of histological patterns, an interdisciplinary case evaluation that includes at least one clinical expert and one pathologist with excellent expertise and the follow-up of the patients is necessary to find correct diagnosis in all cases. [ABSTRACT FROM AUTHOR]

Background: Bronchiolitis obliterans syndrome (BOS) is a life-threatening complication after lung transplantation that is characterized by progressive fibrosis in the small airways. However, little is known about sensitive markers for detecting BOS. Our study compared the clinical utility of serum KL-6 level, a marker for pulmonary fibrosis, with that of neutrophilia in bronchoalveolar lavage fluid (BALF) for detecting BOS. Methods: Levels of serum KL-6 were evaluated in 152 samples from 53 lung transplant recipients (BOS, 15; non-BOS, 38) and in 27 samples from age- and sex-matched healthy individuals. Pulmonary function tests, arterial blood gas analysis, and BALF cell differentials were simultaneously evaluated. Results: Serum KL-6 levels were significantly increased in the BOS group compared with the non-BOS group and the healthy individuals (p < 0.0001). Receiver operating characteristic curve analysis for detecting BOS showed the largest area under the curve for KL-6 compared with lactate dehydrogenase, C-reactive protein, or neutrophils percentage in BALF. Serum KL-6 correlated with the decline in forced expiratory volume in 1 second (FEV1) from post-lung transplant baseline (r = 0.43; p = 0.0001). Conclusions: Serum KL-6 levels are increased and correlate with the decline from baseline in FEV1 in lung transplant recipients. The diagnostic accuracy of serum KL-6 level is better than that of BALF neutrophilia for detecting BOS. [ABSTRACT FROM AUTHOR]

The article presents two randomized studies on the use of a novel antifibrotic and anti-inflammatory drug, pirfenidone, which reduces deterioration in lung function, in patients with idiopathic pulmonary fibrosis (IPF). Patients with IPF were assigned in a 1:1 ratio and 2:1:2 ratio to 2403 milligrams of pirfenidone per day. Based on results, it was observed that perfenidone offers favorable benefit risk profile and is a good treatment option for IPF.

A response by researcher Maurits Demedts and his colleagues to letters to the editor about their article on acetylcysteine treatment in pulmonary fibrosis in the November 24, 2005 issue is presented.