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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., (© 2021 S. Karger AG, Basel.)

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., (© 2020 S. Karger AG, Basel.)

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., (© 2019 S. Karger AG, Basel.)

Background: Diabetes mellitus is a possible risk factor for the development of idiopathic pulmonary fibrosis (IPF), yet the effect of antidiabetic therapy on the course of IPF is unknown., Objectives: This post hoc analysis assessed the effect of metformin on clinically relevant outcomes in patients with IPF., Methods: For the primary analysis, patients randomized to placebo (n = 624) in 3 phase 3, double-blind, controlled trials of pirfenidone (CAPACITY [NCT00287716 and NCT00287729]; ASCEND [NCT01366209]) were categorized by baseline metformin use. The primary outcome was disease progression (forced vital capacity [FVC] decline ≥10%, 6-min walking distance [6MWD] decline ≥50 m, or death). Other outcomes included mortality, hospitalization, FVC decline (≥10 and ≥5%), and 6MWD decline. Outcomes were also assessed in patients with diabetes and/or hyperglycemia (impaired glucose tolerance [IGT] and diabetes population [IGT-diabetes population]) and all patients included in the 3 studies (intention-to-treat [ITT] population)., Results: Overall, 71 (11.4%) patients were metformin users and 553 (88.6%) were nonmetformin users. Baseline data were similar between groups, except for a higher percentage of males (84.5 vs. 73.2%) and a history of diabetes (98.6 vs. 11.6%) in metformin users versus nonmetformin users. The unadjusted 1-year analyses demonstrated no significant differences in disease progression or other outcomes. A higher proportion of metformin users compared with nonmetformin users had a relative FVC decline of ≥5% (63.4 vs. 50.6%, p = 0.043). Results were similar for the IGT-diabetes population and for the ITT population. Multivariable analyses yielded similar results., Conclusions: Metformin has no effect on clinically relevant outcomes in patients with IPF., (© 2018 S. Karger AG, Basel.)

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., (© 2018 S. Karger AG, Basel.)

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., (© 2018 S. Karger AG, Basel.)

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., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

Background: Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis (IPF) and has been shown to slow disease progression by reducing annual lung function decline., Objective: To evaluate the results of a large cohort of IPF patients treated with nintedanib within a compassionate use program (CUP) in Germany (9 centers)., Methods: Patients (≥40 years) were required to have a confirmed diagnosis of IPF, a forced vital capacity (FVC) ≥50% predicted (pred.) and a carbon monoxide diffusing capacity (DLCO) 30-79% pred. and not to be eligible for pirfenidone treatment. Clinical data, pulmonary function tests and adverse events were recorded up to July 2015., Results: Sixty-two patients (48 male/14 female) with moderate IPF (FVC 64 ± 17% pred. and DLCO 40 ± 10% pred.) were treated with nintedanib. 77% of patients switched from pirfenidone (mean treatment duration 14 ± 2 months) mostly due to disease progression (mean decline in FVC 7.4 ± 3% pred. in the 6 months prior to nintedanib intake). Initiation of nintedanib treatment occurred 69 ± 29 months after IPF diagnosis, and mean treatment duration was 8 ± 4 months. Most patients (63%) stabilized 6 months after treatment start (mean FVC decline 3 ± 1 vs. -17 ± 2% in patients with disease progression; p < 0.01). The most common adverse events were diarrhea (63%) and weight loss (50%). Dose reduction occurred in 34% of cases and treatment discontinuation in 10%., Conclusion: Nintedanib treatment was generally well tolerated and was associated with FVC stabilization in the majority of IPF patients in this CUP setting where most patients were not treatment naïve. Our data are in agreement with the previously published data., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

A 51-year-old active smoker with primary acquired pulmonary alveolar proteinosis (PAP) diagnosed by biopsy and anti-GM-CSF antibodies was treated safely with whole-lung lavage (WLL). This resulted in a rapid improvement of symptoms and arterial blood oxygenation, but not of standard lung function parameters. However, we also performed the multiple-breath nitrogen washout (MBW) test to determine the lung clearance index (LCI) as well as indices of acinar ventilation heterogeneity (S(acin)) and conductive ventilation heterogeneity (S(cond)). At baseline, a distinct abnormality was seen for S(acin) and LCI, while S(cond) was at the upper limit of normal for this subject. S(acin), in particular, was in excess of the S(acin) abnormality corresponding to a 20-pack-year smoking history. Immediately after WLL, S(acin) and S(cond) both fell to within a normal range while LCI also decreased but remained abnormal. The S(acin) decrease was much greater than the S(cond) decrease, which was to be expected after 1 week of smoking cessation at the hospital (smoking was resumed after release from hospital). A follow-up visit 7 weeks after WLL revealed a spectacular improvement on CT scan and improvements in standard lung function. Another follow-up visit 14 weeks after WLL showed further improvements in standard lung function, and both S(acin) and S(cond) remained well within the normal range, and LCI was above the upper limit of normal. We conclude that in this patient, removal of excess surfactant by WLL resulted in a restored ventilation distribution in most of the distal air spaces., (Copyright © 2012 S. Karger AG, Basel.)

Background: Angiogenesis-angiostasis balance and leukocyte recruitment are influenced by different concentrations of distinct chemokines., Objective: To investigate the relative contribution of angiogenic and angiostatic CXC chemokines to the pathogenesis of idiopathic pulmonary fibrosis (IPF) and granulomatous lung diseases, we examined the in vitro production of an angiogenic chemokine (IL-8), and 2 angiostatic chemokines (IP-10 and MIG) by alveolar macrophages., Methods: Alveolar macrophages from 16 patients with granulomatous lung diseases [8 with sarcoidosis, 8 with extrinsic allergic alveolitis (EAA)], 16 patients with IPF, and 8 control subjects were cultured for 24 h. IL-8, IL-18, IP-10 and MIG in the culture supernatants were measured by a fluorescent bead-based multiplex technique., Results: In IPF patients, IL-8 was increased and correlated with bronchoalveolar lavage (BAL) neutrophils, whereas the levels of IP-10 and MIG were normal. In sarcoidosis and EAA patients, IL-8, IP-10, and MIG were all increased and IP-10 and MIG correlated with IL-18, a Th1 cytokine, and the percentage and number of BAL lymphocytes., Conclusions: The difference in the expression of CXC chemokines and a Th1 cytokine may contribute to the different immunopathogenesis, clinical course and responsiveness to treatment of these diseases., (Copyright © 2009 S. Karger AG, Basel.)