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Purpose: The clinical manifestations of sarcoidosis vary widely, depending on the intensity of the inflammation and the organ systems affected. Hence, sarcoidosis patients may suffer from a great variety of symptoms. The aim of this study was to compare the self-reported burden of sarcoidosis patients in Denmark, Germany and the Netherlands, especially the prevalence of fatigue and small fiber neuropathy (SFN)-related symptoms, as well as differences in treatment strategies. Methods: A cross-sectional web-based anonymous survey about complaints was conducted among sarcoidosis patients. Patients were invited to take part through the sarcoidosis patient societies as well as through outpatient sarcoidosis clinics in these countries. Results: The questionnaire was completed by 1072 sarcoidosis patients (152 Danish, 532 German and 388 Dutch). Almost all patients reported having sarcoidosis-associated symptoms (organ-related as well as non-specific, non-organ related). Fatigue was reported by almost all respondents (90%), followed by pulmonary symptoms (72.4%). More than 50% of the respondents were being treated with prednisone, which was comparable in all three countries. In contrast, second- and third-line treatment differed substantially between Denmark, Germany and the Netherlands. Conclusion: Sarcoidosis patients in Denmark, Germany and the Netherlands present with similar self-reported symptoms, organ-related as well as non-specific, non-organ related. Fatigue (90%) and symptoms associated with SFN (86%) were highly prevalent in all three countries. [ABSTRACT FROM AUTHOR]

Background: The receptor for advanced glycation end product (RAGE) is a transmembrane receptor accelerating a pro-inflammatory signal. RAGE signalling is promoted by decreased soluble isoform of RAGE (sRAGE), which is a decoy receptor for RAGE ligands, and RAGE SNP rs2070600 minor allele. In Caucasian and Japanese cohorts, low circulatory sRAGE levels and presence of the minor allele are associated with poor survival of idiopathic pulmonary fibrosis (IPF) and increased disease susceptibility to interstitial lung disease, respectively. However, whether sRAGE and RAGE SNP rs2070600 are associated with acute exacerbation of IPF (AE-IPF) is unclear., Methods: This retrospective cohort study evaluated the association between the onset of AE-IPF and serum sRAGE levels in 69 German and 102 Japanese patients with IPF. The association of AE-IPF with RAGE SNP rs2070600 in 51 German and 84 Japanese patients, whose DNA samples were stored, was also investigated., Results: In each cohort, the incidence of AE-IPF was significantly and reproducibly higher in the patients with sRAGE < 467.1 pg/mL. In a pooled exploratory analysis, the incidence of AE-IPF was lowest in the patients with higher sRAGE levels and rs2070600 minor allele, although no significant difference in the incidence was observed between the patients with and without the rs2070600 minor allele., Conclusions: Low sRAGE levels were associated with increased incidence of AE-IPF in two independent cohorts of different ethnicities. The combination of rs2070600 and sRAGE levels may stratify patients with IPF for the risk of AE., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Ethics Committees of Ruhrlandklinik (IRB 06-3170) and Hiroshima University Hospital (IRB33 and M326). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The present recommendations on the therapy of sarcoidosis of the German Respiratory Society (DGP) was written in 2023 as a German-language supplement and update of the international guidelines of the European Respiratory Society (ERS) from 2021. It contains 5 PICO questions (Patients, Intervention, Comparison, Outcomes) agreed in the consensus process, which are explained in the background text of the four articles: Confirmation of diagnosis and monitoring of the disease under therapy, general therapy recommendations, therapy of cutaneous sarcoidosis, therapy of cardiac sarcoidosis., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany.)

Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease with a median survival of 2 - 4 years after diagnosis. Since the publication of the German IPF guideline in 2013 new treatment trials have been published, necessitating an update of the pharmacological therapy of IPF. Different from the previous guideline, the GRADE system was discarded and replaced by the Oxford evidence classification system which allows a more differentiated judgement. The following pharmacological therapies were rated not suitable for the treatment of IPF patients (recommendation A; evidence 1-b): triple therapy with prednisolone, azathioprine and acetyl-cysteine; imatinib; ambrisentan; bosentan; macitentan. A less clear but still negative recommendation (B, 1-b) was attributed to the treatment of IPF with the phosphodiesterase-5-inhibitor sildenafil and acetyl-cysteine monotherapy. In contrast to the international guideline antacid therapy as a general treatment for IPF was rated negative, based on conflicting results of recent analyses (recommendation C; evidence 4). An unanimous positive recommendation was granted for the antifibrotic drugs nintedanib and pirfenidone for the treatment of IPF (A, 1-a). For some open questions in the management of IPF patients for which firm evidence is lacking the guideline also offers recommendations based on expert consensus., Competing Interests: Interessenkonflikt: Jürgen Behr erhielt Honorare für Vortrags- und Beratertätigkeiten von Actelion, Bayer, Boehringer-Ingelheim, Gilead, InterMune/Roche, Novartis. Forschungsunterstützung erfolgte durch Actelion und Boehringer-Ingelheim. Andreas Günther erhielt Honorare für Vortrags- und/oder Beratertätigkeiten von Roche, Boehringer-Ingelheim, Teva und Novartis sowie Drittmittel im Rahmen von Kooperationsprojekten mit Roche, Inventiva und Sanofi Aventis.Francesco Bonella erhielt Honorare für Vortrags- und Beratertätigkeiten von InterMune/Roche und Boehringer-Ingelheim sowie Drittmittel für Forschungsvorhaben durch die Firmen InterMune/Roche, Boehringer-Ingelheim und Serendex/Savara.Dirk Koschel erhielt Honorare für Vortrags- und Beratertätigkeiten von InterMune/Roche und Boehringer-Ingelheim.Michael Kreuter erhielt Honorare für Vortrags- und Beratertätigkeiten von InterMune/Roche und Boehringer-Ingelheim sowie Drittmittel für Forschungsvorhaben durch die Firmen InterMune/Roche und Boehringer-Ingelheim.Antje Prasse erhielt Honorare für Vortrags- und Beratertätigkeiten von InterMune/Roche, Boehringer-Ingelheim, Bayer und Actelion sowie Drittmittel für Forschungsvorhaben durch die Firmen Roche und Boehringer-Ingelheim.Joachim Müller-Quernheim: Honorare für Vorträge und/oder Beratung von Roche und Norvatis. Einnahmen der Klinik im Rahmen von Studien von Boehringer-Ingelheim, Actelion, Roche und Bristol-Myers Squibb.Ulrich Costabel erhielt Honorare für Vortrags- und Beratertätigkeiten von InterMune/Roche und Boehringer-Ingelheim, für Vortragstätigkeit von AstraZeneca, für Beratertätigkeit von Bayer, GSK, UCB Celltech, Biogen, Fibrogen sowie Drittmittel für Forschungsvorhaben durch die Firmen InterMune/Roche und Boehringer-Ingelheim.Klaus Geißler, Nicolas Schönfeld und Helmut Sitter geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Health status and quality of life are impaired in patients with interstitial lung disease (ILD). To assess these parameters in ILD patients no valid and reliable questionnaire exists in German language so far. The K-BILD questionnaire is a brief and valid tool to evaluate health status in ILD patients, with no validated German version. Method: The linguistic validation of K-BILD was carried out in a multistage process in collaboration with the developer of the questionnaire and bilingual, professional translators. Review by the developers and back translations as well as clinical assessment by ILD patients ensured that the translated questionnaire reflected the intention of the original K-BILD. Results: A German version of K-BILD with 15 questions concerning the health status was composed. The questions cover the three domains breathlessness and activities, psychological aspects and chest symptoms. Problems in understanding or difficulties in replying to the questions were not stated by the ILD patients. Conclusion: The German version of the K-BILD questionnaire allows the clinical and scientific use to measure reliable health quality in ILD patients., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The majority of cases with severe pulmonary alveolar proteinosis (PAP) are caused by auto-antibodies against GM-CSF. A multitude of genetic and exogenous causes are responsible for few other cases. Goal of this study was to determine the prevalence of GATA2 deficiency in children and adults with PAP and hematologic disorders., Methods: Of 21 patients with GM-CSF-autoantibody negative PAP, 13 had no other organ involvement and 8 had some form of hematologic disorder. The latter were sequenced for GATA2., Results: Age at start of PAP ranged from 0.3 to 64 years, 4 patients were children. In half of the subjects GATA2-sequence variations were found, two of which were considered disease causing. Those two patients had the typical phenotype of GATA2 deficiency, one of whom additionally showed a previously undescribed feature - a cholesterol pneumonia. Hematologic disorders included chronic myeloic leukemia, juvenile myelo-monocytic leukemia, lymphoblastic leukemia, sideroblastic anemia and two cases of myelodysplastic syndrome (MDS). A 4 year old child with MDS and DiGeorge Syndrome Type 2 was rescued with repetitive whole lung lavages and her PAP was cured with heterologous stem cell transplant., Conclusions: In children and adults with severe GM-CSF negative PAP a close cooperation between pneumologists and hemato-oncologists is needed to diagnose the underlying diseases, some of which are caused by mutations of transcription factor GATA2. Treatment with whole lung lavages as well as stem cell transplant may be successful.

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.

Background and Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with an estimated median survival of only 3 years after diagnosis. Pirfenidone is the only medication approved in the European Union for the treatment of adults with mild to moderate lung fibrosis. We analyzed data on safety and efficacy of pirfenidone in the treatment of patients with IPF in our centre., Patients and Methods: From 2006 to 2012, 45 patients (28 inside clinical trials, 17 outside) with mild to moderate IPF were treated with pirfenidone. Clinical data, results of lung function tests, and radiological findings as well as data about side effects were collected routinely., Results: The mean duration of treatment per patient was 48 [range 3-321] weeks. 16 patients (35 %) received pirfenidone as monotherapy and 29 (65 %) in combination with corticosteroids and/or N-acetylcysteine (NAC). At the end of the follow-up period 28 of 40 patients (70 %) with treatment duration > 3 months were in a stable condition. 26 patients (58 %) suffered from side effects, mostly gastrointestinal (17 [38 %]). Pirfenidone was discontinued by six patients (13 %) because of side effects. The median survival after the start of pirfenidone was 3.8 years., Conclusion: Pirfenidone alone or in combination with NAC and/or corticosteroids was generally well tolerated. Severe side effects were rare. The course of the disease was stable during treatment with pirfenidone in two out of three patients. Our results are in line with the previous published safety and efficacy data on pirfenidone as treatment for IPF., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: KL-6 is a high-molecular-weight glycoprotein classified as human Mucin-1 (MUC1). KL-6 has been reported to be a sensitive biomarker for interstitial lung diseases (ILDs) in the Japanese population. It is also known that polymorphisms in the MUC1 gene affect serum levels of KL-6. This study was conducted to evaluate serum levels of KL-6 and MUC1 polymorphisms in both German and Japanese populations., Methods: Serum levels of KL-6 were measured in 267 patients with ILDs (152 German and 115 Japanese) and 186 healthy subjects (HS) (76 German and 110 Japanese). In addition, rs4072037 single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction. The optimal cutoff values for discriminating patients with ILDs from HS was determined by receiver operating characteristic analysis based on ethnicity and rs4072037 genotypes., Results: The serum KL-6 levels in patients with ILDs were significantly higher compared with HS in both the German and the Japanese cohorts (both p<0.001). The discriminating cutoff value of serum KL-6 in the German cohort was significantly higher than the value in the Japanese cohort. The difference in the serum levels of KL-6 was significantly associated with the rs4072037 genotype distribution., Conclusions: Even in the German cohort, the serum KL6 levels were significantly higher in patients with ILDs than HS. Because of differences in the genotype distribution of rs4072037, the KL-6 cutoff value for the German cohort that discriminated patients with ILDs from HS was significantly higher than the value in the Japanese cohort., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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., Virtual Slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5031706258025129.

Background: Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by the intra-alveolar accumulation of surfactant lipids and proteins. The aim of the study is to describe the epidemiologic, clinical, physiologic, and laboratory features of PAP in a large single-center cohort of patients with PAP., Study Population: Over 30 years, 70 patients with PAP were managed at our institution, 64 with primary and 6 with secondary PAP., Results: The mean age at diagnosis was 43 years with a male to female ratio of 1.3. BAL was the most commonly applied diagnostic method, performed in 83% of cases. A history of smoking was seen in 79%, and of dust exposure in 54%, most commonly to aluminum, silica and sawdust. GM-CSF autoantibody correlated with clinical outcome and KL-6 with diffusing capacity. The number of whole lung lavages (WLL) necessary to reach remission was higher in current smokers., Conclusions: This study shows that the use of BAL for the diagnosis of PAP can reduce the need of histological confirmation. A history of dust or fume inhalation is strongly associated with PAP, also with the autoimmune form. Smoking seems to influence the response to treatment, increasing the number of WLL necessary to reach remission., (Copyright © 2011 Elsevier Ltd. All rights reserved.)