[German Guideline for Idiopathic Pulmonary Fibrosis]. / S2K-Leitlinie zur Diagnostik der idiopathischen Lungenfibrose.

Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease. Diagnosis of IPF requires considerable expertise and experience. Since publication of the international IPF guideline in the year 2011 and Update 2018 several studies and technical advances occurred, which made a new assessment of the diagnostic process mandatory. In view of the antifibrotic drugs which have been approved for the treatment of IPF patients, the goal of this guideline is to foster early, confident and effective diagnosis of IPF. The guideline focusses on the typical clinical setting of an IPF patient and provides tools to exclude known causes of interstitial lung disease including standardised questionnaires, serologic testing and cellular analysis of bronchoalveolar lavage. High resolution computed tomography remains crucial in the diagnostic work-up. If it is necessary to obtain specimen 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 bronchoscopic diagnosis did not provide the information needed. Despite considerable progress, IPF remains a diagnosis of exclusion and multidisciplinary discussion remains the golden standard of diagnosis.

[Chronic fibrosing lung diseases : Idiopathic pulmonary fibrosis from the perspective of its differential diagnosis]. / Chronisch-fibrosierende Lungenerkrankungen : Die idiopathische pulmonale Fibrose im Spiegel ihrer Differenzialdiagnosen.

Fibrosing lung diseases describe a heterogeneous group of interstitial lung diseases (ILD) of highly variable etiology, but with a unifying terminal process of irreversible, fibroproliterative destruction of the alveolar surface, loss of compliance and progressive impairment of gas exchange. In view of the heterogeneity, the disastrous prognoses in some cases and the treatment consequences, a thorough differential diagnosis is essential in all patients. Antifibrotic therapies are currently only indicated in idiopathic pulmonary fibrosis (IPF). The only curative therapeutic option is lung transplantation. Therefore, suitable patients should be promptly evaluated.

Biomarkers in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, debilitating, fibrotic lung disease leading to respiratory failure and ultimately to death. Being the prototype of interstitial lung diseases, IPF is characterized by marked heterogeneity regarding its clinical course. Despite significant progress in the understanding of its pathogenesis, we still cannot reliably predict the course of the disease and the response to treatment of an individual patient. Non-invasive biomarkers, in particular serum biomarkers, for the (early) diagnosis, differential diagnosis, prognosis and prediction of therapeutic response are urgently needed. Numerous molecules involved in alveolar epithelial cell injury, fibroproliferation and matrix remodeling as well as immune regulation have been proposed as potential biomarkers. Furthermore, genetic variants of TOLLIP, MUC5B, and other genes are associated with a differential response to treatment and with the development and/or the prognosis of IPF. Additionally, the bacterial signature in IPF lungs, as shown from microbiome analyses, as well as mitochondrial DNA seem to have promising roles as biomarkers. Moreover, combination of multiple biomarkers may identify comprehensive biomarker signatures in IPF patients. However, there is still a long way until these potential biomarkers complete or substitute for the clinical and functional parameters currently available for IPF.

The low density lipoprotein receptor-related protein (LRP) 1 and its function in lung diseases.

The low density lipoprotein receptor-related protein (LRP) 1 is a ubiquitously expressed, versatile cell surface transmembrane receptor involved in embryonic development and adult tissue homeostasis. LRP1 binds and endocytoses a broad spectrum of over 40 ligands identified thus far, including lipoproteins, extracellular matrix proteins, proteases and protease/inhibitor complexes and growth factors. Interactions with other membrane receptors and intracellular adaptors/scaffolding proteins allow LRP1 to modulate cell migration, survival, proliferation and (trans) differentiation. Because LRP1 displays a wide-range of interactions and activities, its expression and function is temporally and spatially tightly controlled. It is not, therefore, surprising that deregulation of LRP1 production and/or activity is observed in several diseases. In this review, we will systematically examine the evidence for the role of LRP1 in human pathologies placing special emphasis on LRP1-mediated pathogenesis of the lung.

[Position Paper: Significance of the Forced Vital Capacity in Idiopathic Pulmonary Fibrosis]. / Positionspapier zur Bedeutung der forcierten Vitalkapazität für Patienten mit idiopathischer Lungenfibrose (IPF).

Spirometry is a highly standardized method which allows to measure the forced vital capacity (FVC) with high precision and reproducibility. In patients with IPF FVC is directly linked to the disease process which is characterized by scaring of alveoli and shrinkage of the lungs. Consequently, there is ample evidence form clinical studies that the decline of FVC over time is consistently associated with mortality in IPF. As for the first time effective drugs for the treatment of IPF are available it becomes obvious that in studies which could demonstrate that the drug reduces FVC decline, a numerical effect on mortality was also observed, while in one study where a significant effect on FVC decline was missed, there was also no change in mortality. Based on these studies FVC decline is a validated surrogate of mortality in IPF. It is concluded that FVC decline is not only accepted as an endpoint of clinical treatment trials in IPF but is also valid as a patient related outcome parameter which should be considered for the assessment of the efficacy of an IPF drug.

[German guideline for diagnosis and management of idiopathic pulmonary fibrosis]. / S2K-Leitlinie zur Diagnostik und Therapie der idiopathischen Lungenfibrose.

Idiopathic pulmonary fibrosis is a fatal lung disease with a variable and unpredictable natural history and limited treatment options. Since publication of the ATS-ERS statement on IPF in the year 2000 diagnostic standards have improved and a considerable number of randomized controlled treatment trials have been published necessitating a revision. In the years 2006 - 2010 an international panel of IPF experts produced an evidence-based guideline on diagnosis and treatment of IPF, which was published in 2011. In order to implement this evidence-based guideline into the German Health System a group of German IPF experts translated and commented the international guideline, also including new publications in the field. A consensus conference was held in Bochum on December 3rd 2011 under the protectorate of the "Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin (DGP)" and supervised by the "Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften" (AWMF). Most recommendations of the international guideline were found to be appropriate for the german situation. Based on recent clinical studies "weak negative" treatment recommendations for pirfenidone and anticoagulation were changed into "weak positive" for pirfenidone and "strong negative" for anticoagulation. Based on negative results from the PANTHER-trial the recommendation for the combination therapy of prednisone plus azathiorpine plus N-acetlycsteine was also changed into strong negative für patients with definite IPF. This document summarizes essential parts of the international IPF guideline and the comments and recommendations of the German IPF consensus conference.

[Interstitial lung disease]. / Interstitielle Lungenerkrankungen.

This concise article summarizes recent advances in the field of interstitial lung disease (ILD) with particular focus on clinically relevant findings. As a novel treatment option for idiopathic pulmonary fibrosis (IPF), pirfenidone has been granted marketing authorization in the European Union for the treatment of mild to moderate IPF. In contrast, the FDA refused to approve pirfenidone for the US market. Promising study results for the treatment of IPF were published for the triple tyrosine kinase inhibitor intedanib, other drugs such as the endothelin receptor antagonist (ERA) macitentan are currently investigated in clinical trials. Further studies that investigated the ERA bosentan, the phosphodiesterase 5 inhibitor sildenafil, or the tyrosine kinase inhibitor imatinib in IPF failed to show a benefit for the pertinent primary endpoint. Additionally, an evidence-based guideline for the diagnosis and management of IPF has very recently been published. The European Respiratory Society established a guideline for the management of lymphangioleiomyomatosis (LAM), while another study showed the cost effectiveness of HRCT screening for LAM in selected female patients suffering from spontaneous pneumothorax. Data from a scleroderma-ILD study show the prognostic relevance of antitopoisomerase antibodies in the progression of this form of ILD. Bosentan treatment did not significantly enhance exercise capacity in patients with scleroderma-ILD in the absence of pulmonary hypertension. With regard to sarcoidosis with mediastinal lymphadenopathy the diagnostic sensitivity can be significantly improved by endobronchial ultrasonography-guided transbronchial needle aspiration vs. conventional needle aspiration. As a possible future treatment option for sarcoidosis vasointestinal peptide has been successfully evaluated in a phase 2 tolerability trial.

[Pulmonary hypertension in COPD and interstitial lung diseases]. / Pulmonale Hypertonie bei COPD und interstitiellen Lungenerkrankungen.

Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) and of interstitial lung diseases (ILD) such as idiopathic pulmonary fibrosis and sarcoidosis. When present in these patients, PH is usually mild to moderate. When severe PH is diagnosed in COPD and ILD patients, other potentially better treatable underlying causes should be ruled out. In COPD patients, PH is associated with an increased risk of severe exacerbations and a reduced life expectancy. Similarly, in patients with ILD, the presence of PH correlates with a poor prognosis. Doppler echocardiography is the best non-invasive method for the diagnosis of PH, but is frequently inaccurate in patients with advanced lung diseases. Thus, when clinical suspicion remains high, right heart catheterization in a reference center is required to ultimately confirm the presence of PH. Treatment of PH in COPD and ILD is primarily based on long term oxygen therapy. Drugs approved for pulmonary arterial hypertension, such as prostanoids, phosphodiesterase inhibitors, and endothelin receptor antagonists, may represent promising options for COPD and ILD patients, however, their use may be hampered by potentially deleterious effects on gas exchange and their efficacy yet remains to be proven in appropriately designed and controlled clinical trials. Lung transplantation may be considered in all patients with an advanced disease.

Role of coagulation and fibrinolysis in lung and renal fibrosis.

Elevated procoagulant and suppressed fibrinolytic activities are regularly encountered in different forms of clinical and experimental fibrosis of the lungs and the kidneys. Although primarily serving to provide a provisional matrix of repair largely consisting of fibrin and fibronectin, the involved procoagulant serine proteases and protease inhibitors may also exert distinct cellular downstream signaling events modifying the fibrotic response. In this review, evidence for an impaired regulation of coagulation and fibrinolysis factors in clinical and experimental lung and renal fibrosis is provided and the role of PAR (protease activated receptor) induced profibrotic and HGF (hepatocyte growth factor) elicited antifibrotic cellular events is worked out. In view of experiments obtained in animal models of lung and renal fibrosis, the potential therapeutic usefulness of anticoagulant or profibrinolytic strategies is discussed.

Cellular origin of pro-coagulant and (anti)-fibrinolytic factors in bleomycin-injured lungs.

Excessive pro-coagulant and decreased fibrinolytic activities in the alveolar compartment have been repeatedly documented for inflammatory and fibrotic lung diseases. The current authors determined the contribution of different resident lung cells to the altered local production of coagulation- and fibrinolysis-system components in bleomycin-injured mouse lungs via cell-specific and quantitative assessment of mRNA levels of various pro-coagulant and (anti)-fibrinolytic factors. Laser-assisted microdissection technology was used to sample specific cell populations in combination with subsequent mRNA analysis by real-time quantitative reverse transcriptase-PCR. Additionally, western blot analysis, immunohistochemistry and activity assays were performed. Following bleomycin challenge, the strongest induction of tissue factor and plasminogen activator inhibitor (PAI)-1 mRNA expression was observed in alveolar macrophages (approximately 250- and 60-fold induction, respectively). These factors were also upregulated in alveolar type II cells, but to an approximately six-fold lesser extent. In contrast, PAI-2 expression was induced exclusively in alveolar macrophages. A slight increase of urokinase-type plasminogen activator (uPA) expression was also observed in alveolar macrophages (two-fold induction), but uPA activity was reduced due to a disproportionate increase of PAI production. Alveolar macrophages and, to a lesser extent, alveolar type II cells are the main sources of locally produced pro-coagulant and anti-fibrinolytic factors in bleomycin-injured lungs.

Safety and tolerability of bosentan in idiopathic pulmonary fibrosis: an open label study.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease for which no effective treatment exists. In the present study, 12 IPF patients underwent analysis of gas exchange properties using the multiple inert gas elimination technique on day 1 before and after the administration of 125 mg bosentan, a dual endothelin antagonist. Following this, patients received chronic administration for 12 weeks (62.5 mg b.i.d. in week 1, 125 mg b.i.d. thereafter). The primary objective was to determine the effect of bosentan on gas exchange (day 1) and on oxygen saturation and minute ventilation (week 2). With one exception, where redistribution of total pulmonary blood flow from normal ventilation/perfusion (V'/Q') areas (93% before, 72% after bosentan) to low V'/Q' areas (0% before, 22.2% after) was encountered, no patient showed any change in gas exchange (mean+/-SD shunt flow (% of cardiac output) 8.5+/-3.4% before, 6.1+/-2.3% after bosentan; day 1) or oxygen saturation and minute ventilation (week 2). Similarly, none of the secondary parameters was significantly changed either at week 2 or at the end of the study period (week 12). Five patients developed respiratory infections and two died because of pneumonia; this was judged as being unrelated to bosentan intake. In conclusion, bosentan administration does not seem to induce clinically relevant gas exchange abnormalities in idiopathic pulmonary fibrosis patients.

Minimal immunoreactive plasma beta-endorphin and decrease of cortisol at standard analgesia or different acupuncture techniques.

BACKGROUND AND OBJECTIVE: Acupuncture has been claimed to be associated with activation of the endogenous antinociceptive system. The analgesic effects of acupuncture have been ascribed to beta-endorphin interacting with opioid receptors. However, firstly, the release of beta-endorphin into the blood has been proven to be induced by stress, i.e. under dysphoric conditions, and, secondly, if released under stress, beta-endorphin has been shown not to be analgesic. Our aim was to test whether beta-endorphin immunoreactive material is released into the cardiovascular compartment during acupuncture comparing the most frequently used types of acupuncture with standard pain treatment under apparently low stress conditions. METHODS: This prospective study included 15 male patients suffering from chronic low back pain. beta-Endorphin immunoreactive material and cortisol were measured in the plasma of patients who underwent, in random order, therapy according to a standard pain treatment, traditional Chinese acupuncture, sham acupuncture, electro acupuncture and electro acupuncture at non-acupuncture points before, at and after the treatment. Statistical analysis was performed using two-way ANOVA with repeated measures. RESULTS: A decrease in plasma cortisol concentration measured over the five treatment protocols was highly significant (P < 0.001). The beta-endorphin immunoreactive material concentrations in plasma were minimal at all times and in all treatment conditions. The influence of treatments by various acupuncture procedures on cortisol and beta-endorphin immunoreactive material plasma concentrations over the three time points was not significantly different. CONCLUSIONS: beta-endorphin immunoreactive material in blood is not released by any type of acupuncture as tested under low stress conditions.

Surfactant protein C mutations in sporadic forms of idiopathic interstitial pneumonias.

Interstitial pneumonias have recently been associated with mutations in the gene encoding surfactant protein C (SFTPC). In particular, SFTPC mutations have been reported in a number of familial forms of pulmonary fibrosis and in infants with interstitial lung diseases. The present study searched for SFTPC mutations in adult patients with sporadic idiopathic interstitial pneumonia. In total, 35 adult patients with sporadic idiopathic interstitial pneumonia and 50 healthy subjects were investigated for SFTPC mutations by direct DNA sequencing. Of the patients with sporadic idiopathic interstitial pneumonia, 25 suffered from idiopathic pulmonary fibrosis and 10 patients from nonspecific interstitial pneumonia. Only two frequent nonsynonymous variants, T138N and S186N, were detected. Allele frequencies of both variations as well as of other identified noncoding alterations did not differ significantly between the diverse patient groups and control subjects. In conclusion, mutations in the gene encoding surfactant protein C are not common in sporadic cases of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia, suggesting that the mutated gene does not play an important role in the pathogenesis of these forms of idiopathic interstitial pneumonia.

[Differential therapy of pulmonary fibrosis]. / Differenzielle Therapie bei Lungenfibrosen.

Pulmonary fibrosis is the final outcome of a numerous and heterogeneous group of pulmonary disorders grouped together under the family of diffuse parenchymal lung diseases. Safe identification of the underlying condition is difficult but is the prerequisite for any therapeutic attempt. In principle, diffuse parenchymal lung diseases may be divided into those forms being triggered by an initial inflammatory process (e. g. sarcoidosis, hypersensitivity pneumonitis), and those being most likely triggered by epithelial injury (idiopathic pulmonary fibrosis). Steroids and immunosuppressants do have their role in treatment of the former group, although the efficacy on long-term outcome is not entirely clear. In contrast, steroids and immunosuppressants are only rarely helpful in the latter condition. Novel therapeutic strategies for the treatment of idiopathic pulmonary fibrosis are currently under preclinical or clinical assessment and include antioxidative agents and agents that block alveolar coagulation or different growth factors.

Alveolar antioxidant status in patients with acute respiratory distress syndrome.

In the acutely inflamed lung, oxidant stress occurs within the alveolar compartment. Under these conditions, the regulation of low molecular weight antioxidants in the epithelial lining fluid is poorly understood. Therefore, antioxidant levels were measured in the bronchoalveolar lavage fluid (BALF) of patients with acute respiratory distress syndrome (ARDS; n=40) and in healthy volunteers (n=20). Reduced glutathione (GSH), oxidised glutathione (GSSG; enzymatic assay), retinol (vitamin A), alpha-tocopherol (vitamin E), ascorbic acid (vitamin C), uric acid (all by HPLC), plasmalogens (1-alkenyl-2-acyl phospholipids), polyunsaturated fatty acids (PUFA; both by gas-liquid chromatography), and F2-isoprostanes (ELISA) were quantified. All values are expressed as concentrations in cell-depleted BALF. GSSG (ARDS: 0.13+/-0.02 microM; control: 0.03+/-0.01 microM; mean+/-sem) and F2-isoprostanes (ARDS: 78+/-10 pM; control: 26+/-5 pM) were increased in ARDS, thus indicating oxidant stress. GSH levels in patients did not change significantly, whereas concentrations of vitamins A and C, vitamin E (ARDS: 77+/-15 nM; control: 26+/-3 nM) and uric acid (ARDS: 11.8+/-2.2 microM; control: 0.7+/-0.0 microM) were significantly elevated in ARDS. PUFA of total lipids, which may act as sacrificial antioxidants, increased by a factor of approximately 3 in patients, but plasmalogens showed a significant decrease. In conclusion, low molecular weight antioxidants are elevated in the alveolar compartment of patients with acute respiratory distress syndrome. Further research is warranted to elucidate the molecular mechanisms underlying this finding.