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Sarcoidosis is a systemic disease of unknown cause that is characterised by the formation of immune granulomas in various organs, mainly the lungs and the lymphatic system. Studies show that sarcoidosis might be the result of an exaggerated granulomatous reaction after exposure to unidentified antigens in individuals who are genetically susceptible. Several new insights have been made, particularly with regards to the diagnosis and care of some important manifestations of sarcoidosis. The indications for endobronchial ultrasound in diagnosis and for PET in the assessment of inflammatory activity are now better specified. Recognition of unexplained persistent disabling symptoms, fatigue, small-fibre neurological impairment, cognitive failure, and changes to health state and quality of life, has improved. Mortality in patients with sarcoidosis is higher than that of the general population, mainly due to pulmonary fibrosis. Predicted advances for the future are finding the cause of sarcoidosis, and the elucidation of relevant biomarkers, reliable endpoints, and new efficient treatments, particularly in patients with refractory sarcoidosis, lung fibrosis, and those with persistent disabling symptoms.

Idiopathic pulmonary fibrosis is characterized by abundant collagen production and accumulation of alternatively activated macrophages (M2) in the lower respiratory tract. Mechanisms as to how alveolar macrophages are activated by collagen breakdown products are unknown. Alveolar macrophages were obtained by bronchoalveolar lavage from 30 patients with idiopathic pulmonary fibrosis (IPF) and 37 healthy donors (HD). Alveolar macrophages were cultured in the presence of collagen type I, III, IV and V monomers w/wo a neutralizing antibody against scavenger receptor I class A (CD204). Culture supernatants were assayed for the M2 markers CCL18, CCL2, and interleukin-1 receptor antagonist (IL-1ra) by ELISA. Furthermore, expression of phospho-Akt was measured using ELISA and expression of CD204 by RT-PCR and flow cytometry. Stimulation with collagen type I and III monomers significantly up-regulated CCL18, IL-1ra production of alveolar macrophages. Furthermore, expression of CCL2 and CD204 were up-regulated by collagen type I exposure. In addition, collagen type I stimulation increased pospho-Akt expression. Collagen type I effects were abrogated by neutralizing antiCD204 and a non-selective Phosphatidylinositide 3-kinase inhibitor (LY294002). Spontaneous CD204 expression of alveolar macrophages was significantly increased in patients with IPF. In conclusion, our findings demonstrate that monomeric collagen type I via CD204 induces phospho-Akt expression shifting alveolar macrophages to the profibrotic M2 type. Innate immune responses induced by collagen monomers might perpetuate pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a poor prognosis. There is great effort to find predictors of outcome. Conclusive data for any serum biomarker are lacking. We have recently documented that serum CCL18 concentrations correlate with the course of pulmonary function data in patients with pulmonary fibrosis of various causes. To test the value of serum CCL18 concentrations in IPF, we included 72 patients in a prospective study. IPF was defined according to the ATS/ERS criteria. Serum CCL18 concentrations were measured by a commercially available ELISA. Patients were followed for 24 months. Pulmonary function tests were performed at least every 6 months. Baseline serum CCL18 concentrations predicted the change in TLC and FVC at the 6-month follow-up. Receiver operating characteristics (ROC) revealed a significant relation between survival and baseline CCL18 concentrations. By ROC analysis, the cutoff value with the highest diagnostic accuracy was defined as 150 ng/ml (sensitivity, 0.83; specificity, 0.77). There was a significantly higher mortality in patients with serum CCL18 concentrations above 150 ng/ml (P < 0.0001). The hazard proportional ratio adjusted for age, sex, and baseline pulmonary function data was 8.0. There was a higher incidence of disease progression in the group with high serum CCL18 concentrations. Our data demonstrate that serum CCL18 concentrations have a predictive value in IPF and may be a useful tool in the clinical management of patients with IPF and in clinical trials.

Background: Several sarcoidosis patients require treatment with corticosteroids to prevent organ damage and control symptoms. However, corticosteroids are associated with numerous side effects and can be detrimental to patients if used long-term. Roflumilast is approved for the treatment of chronic obstructive pulmonary disease (COPD) and has been studied with positive results in patients with fibrosing sarcoidosis. Due to its mode of action, it targets proinflammatory and profibrotic pathways involved in sarcoidosis and could be a suitable medication for sarcoidosis. Methods: We retrospectively analyzed a cohort of 51 sarcoidosis patients treated with Roflumilast off-label between 2010 and 2020 at the Department of Pneumology, University Hospital Freiburg. Medical records, lung function, and laboratory results were reviewed. Results: Of the 51 patients, 33 patients received Roflumilast for at least 6 months, whereas 18 discontinued treatment, mostly due to mild to moderate gastrointestinal side effects (n = 7). No severe adverse events were observed. Patients on Roflumilast were less likely to have a decrease in FEV1 of more than 10% of their mean FEV1 compared to patients without Roflumilast (OR = 0.2; 95% CI 0.08–0.5). Escalation of therapy was documented in 49/97 (51%) of ambulatory visits for patients taking Roflumilast compared to 100/144 (69%) for patients without Roflumilast (OR = 0.45; 95% CI 0.26–0.76). Conclusions: Sarcoidosis patients receiving Roflumilast had less lung function loss and were less likely to require therapy escalation. Roflumilast could be a therapeutic option in sarcoidosis.

Recently, models of macrophage activation have been revised. Macrophages stimulated with Th2 cytokines have been classified as alternatively activated. This article examines the expression and regulation of CC chemokine ligand 18 (CCL18), a marker of alternative activation, by human alveolar macrophages (AMs). AM were obtained from bronchoalveolar lavage (BAL) fluid of patients with idiopathic pulmonary fibrosis, sarcoidosis, or hypersensitivity pneumonitis (n = 69) and healthy volunteers (n = 22). Expression of CCL18 was determined by quantitative reverse transcriptase-polymerase chain reaction, in situ hybridization, flow cytometry, and immunohistochemistry, respectively. Spontaneous CCL18 production by BAL-derived cells was markedly increased in patients with pulmonary fibrosis and correlated negatively with pulmonary function test parameters. CCL18 gene expression and protein production were up-regulated in normal AMs after Th2 cytokine stimulation and/or coculture with human lung fibroblasts. Native collagen significantly up-regulated CCL18 expression in normal AMs activated with Th2 cytokines via a mechanism mediated by beta2-integrin/ scavenger receptor(s). Culture supernatants of AMs from patients with idiopathic pulmonary fibrosis increased collagen production by normal lung fibroblasts partly mediated via CCL18. Our findings suggest that AMs from patients with pulmonary fibrosis disclose a phenotype of alternative activation and might be a part of a positive feedback loop with lung fibroblasts perpetuating fibrotic processes.

Stefan Schreiber and colleagues report the results of a genome-wide association study for sarcoidosis, a complex chronic inflammatory disorder. Variants near ANXA11 and PLAC9 are associated with elevated risk of the disease, with ANXA11 as the stronger candidate. Sarcoidosis is a complex chronic inflammatory disorder with predominant manifestation in the lung. In the first genome-wide association study (>440,000 SNPs) of this disease, comprising 499 German individuals with sarcoidosis and 490 controls, we detected a series of genetic associations. The strongest association signal maps to the ANXA11 (annexin A11) gene on chromosome 10q22.3. Validation in an independent sample (1,649 cases, 1,832 controls) confirmed the association (SNP rs2789679: P = 3.0 × 10 −13 , rs7091565: P = 1.0 × 10 −5 , allele-based test). Extensive fine mapping located the association signal to a region between exon 5 and exon 14 of ANXA11 . A common nonsynonymous SNP (rs1049550, C > T, R230C) was found to be strongly associated with sarcoidosis. The GWAS lead SNP and additional risk variants in the region (rs1953600, rs2573346, rs2784773) were in strong linkage disequilibrium with rs1049550. Annexin A11 has complex and essential functions in several biological pathways, including apoptosis and proliferation.

Previous studies suggest an important immunoregulatory role of vasoactive intestinal peptide (VIP) in experimental models of chronic noninfectious inflammation. Sarcoidosis is characterized by noncaseating epitheloid cell granulomas, where excessive tumor necrosis factor-alpha production by pulmonary macrophages plays a critical role in granuloma formation and disease progression, which may lead to fatal organ dysfunction. To test whether inhaled VIP has an immunoregulatory role. Sarcoid alveolitis was used as a prototype of immune-mediated chronic lung inflammation. In an open clinical phase II study, we treated 20 patients with histologically proved sarcoidosis and active disease with nebulized VIP for 4 weeks. VIP inhalation was safe, well-tolerated, and significantly reduced the production of tumor necrosis factor-alpha by cells isolated from bronchoalveolar lavage fluids of these patients. VIP treatment significantly increased the numbers of bronchoalveolar lavage CD4(+)CD127(-)CD25(+) T cells, which showed regulatory activities on conventional effector T cells. In vitro experiments demonstrated the capacity of VIP to convert naive CD4(+)CD25(-) T cells into CD4(+)CD25(+)FoxP3(+) regulatory T cells, suggesting the generation of peripheral regulatory T cells by VIP treatment. This study is the first to show the immunoregulatory effect of VIP in humans, and supports the notion of inhaled VIP as an attractive future therapy to dampen exaggerated immune responses in lung disorders. Thus, the inhalation of neuropeptides may be developed into a new therapeutic principle for chronic inflammatory lung disorders in humans.

IntroductionNon-necrotising granulomas are the histological hallmark of sarcoidosis and chronic beryllium disease (CBD). Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), transbronchial lung forceps biopsy (TBLB) and endobronchial biopsy (EBB) are often used as standard methods for obtaining suitable tissue. Transbronchial lung cryobiopsy (TBLC) is a novel biopsy technique well studied in different fibrosing lung diseases; however, data on its use in sarcoidosis are scarce. This study aimed to assess whether TBLC provides additional diagnostic value compared with standard diagnostic methods in detecting non-necrotising granulomas.MethodsWe retrospectively analysed 321 patients diagnosed with sarcoidosis or CBD between 2010 and 2020 in a single tertiary care centre. Patients who underwent intrathoracic biopsy were analysed to assess the diagnostic yield, factors influencing diagnostic success, as well as complications related to each technique.ResultsIntrathoracic biopsy procedures were performed on 264 patients (EBUS-TBNA n=215, EBB n=61, TBLB n=120 and TBLC n=66). The diagnostic yields for single methods ranged from 56.3% (EBB) to 63.6% (TBLC) (p=0.7643). Combination of EBUS-TBNA with TBLC increased the diagnostic yield to 91.7%. Notably, TBLC provided a superior diagnostic yield compared with TBB in cases without radiologically detected parenchymal involvement. Complication rates were numerically higher following TBLC compared with TBLB (16.7% vs 9.2%, p=0.1561).ConclusionsThe addition of TBLC significantly enhances the diagnostic yield in the workup of sarcoidosis and CBD, particularly in cases without radiologically detected parenchymal involvement. This underscores the added value of TBLC in improving diagnostic accuracy in challenging clinical scenarios.

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 (D LCO ) 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 D LCO 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.

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown origin, with a median patient survival time of ~3 years after diagnosis without anti-fibrotic therapy. It is characterized by progressive fibrosis indicated by increased collagen deposition and high numbers of fibroblasts in the lung. It has been demonstrated that CCL18 induces collagen and αSMA synthesis in fibroblasts. We aimed to identify the CCL18 receptor responsible for its pro-fibrotic activities. Methods: We used a random phage display library to screen for potential CCL18-binding peptides, demonstrated its expression in human lungs and fibroblast lines by PCR and immunostaining and verified its function in cell lines. Results: We identified CCR6 (CD196) as a CCL18 receptor and found its expression in fibrotic lung tissue and lung fibroblast lines derived from fibrotic lungs, but it was almost absent in control lines and tissue. CCL18 induced receptor internalization in a CCR6-overexpressing cell line. CCR6 blockade in primary human lung fibroblasts reduced CCL18-induced FGF2 release as well as collagen-1 and αSMA expression. Knockdown of CCR6 in a mouse fibroblast cell line abolished the induction of collagen and α-smooth muscle actin expression. Conclusion: Our data indicate that CCL18 triggers pro-fibrotic processes via CCR6, highlighting its role in fibrogenesis.