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BackgroundSince 2015, the European pulmonary hypertension guidelines recommend the use of combination therapy in most patients with pulmonary arterial hypertension (PAH). However, it is unclear to what extent this treatment strategy is adopted in clinical practice and if it is associated with improved long-term survival.MethodsWe analysed data from COMPERA, a large European pulmonary hypertension registry, to assess temporal trends in the use of combination therapy and survival of patients with newly diagnosed PAH between 2010 and 2019. For survival analyses, we looked at annualised data and at cumulated data comparing the periods 2010–2014 and 2015–2019.ResultsA total of 2531 patients were included. The use of early combination therapy (within 3 months after diagnosis) increased from 10.0% in patients diagnosed with PAH in 2010 to 25.0% in patients diagnosed with PAH in 2019. The proportion of patients receiving combination therapy 1 year after diagnosis increased from 27.7% to 46.3%. When comparing the 2010–2014 and 2015–2019 periods, 1-year survival estimates were similar (89.0% (95% CI 87.2–90.9%) and 90.8% (95% CI 89.3–92.4%), respectively), whereas there was a slight but nonsignificant improvement in 3-year survival estimates (67.8% (95% CI 65.0–70.8%) and 70.5% (95% CI 67.8–73.4%), respectively).ConclusionsThe use of combination therapy increased from 2010 to 2019, but most patients still received monotherapy. Survival rates at 1 year after diagnosis did not change over time. Future studies need to determine if the observed trend suggesting improved 3-year survival rates can be confirmed.

Progression of chronic obstructive pulmonary disease (COPD) is accelerated by exacerbations often caused by viral infections. Here, we examined the systematic immune cell composition of COPD patients and their specific CD8+ T cell response to Influenza A Virus. Whole blood of 31 COPD patients, 47 severe asthma patients and 33 healthy control donors was analyzed by flow cytometry to quantify peripheral immune cell composition and HLA-A2 status. CD8+ T cell numbers and responses specific for HLA-A2-restricted IAV epitopes were determined in peripheral blood mononuclear cells (PBMCs) of these patients using tetramers loaded with conserved IAV epitopes. We confirmed upregulation of innate immune responses in COPD patients as evidenced by elevated numbers of eosinophiles, neutrophiles and monocytes. In contrast, cells of the adaptive immune system, i.e. CD3+ T- and CD19+ B-cells, were significantly reduced in the blood of COPD patients compared to healthy controls and asthma patients. COPD patients showed reduced relative and absolute numbers of CD8+ T cells but not of CD4+ T cells compared to asthma patients suggesting specific alterations in MHC class I-mediated immune responses in COPD. Importantly both, the absolute and the relative number of Influenza A Virus specific CD8+ T cells are diminished in COPD patients compared to healthy controls and asthma patients. We are currently testing the functionality of CD8+ T cells in response to PMA / Ionomycin stimulations in COPD and asthma patients. Our study contributes to an improved understanding of the role of specific anti-viral CD8+ T cell responses in COPD representing a relevant biomarker to identify COPD patients that are prone to frequent exacerbations.

Allergic bronchopulmonary aspergillosis (ABPA) is a severe hypersensitivity reaction to aspergillus species colonizing the airways of patients with asthma or cystic fibrosis. Biologicals including anti-IgE and anti-IL-5 antibiodies have strongly changed the treatment of severe asthmatics and have partly been shown to be effective in the treatment of ABPA. Recently, dupilumab, an anti-IL4-Rα antibody has been approved for the treatment of severe asthma. Here, we report the case of a 49-year old women with a history of asthma and ABPA, who suffered from severe uncontrolled asthma with an asthma control test (ACT) of 5 of 25 points despite maximum inhalative therapy, anti-IL5-Rα therapy and continued oral steroid therapy. Two exacerbations were recorded during the last 12 months. Trials of itraconazole and omalizumab showed insufficient efficacy. Lung function showed moderate obstruction with an FEV1 of 2,46l (74%), FVC of 3,43l (89,4%) and elevated FeNO of 56 ppb. Initiation of dupilumab therapy led to a complete resolution of pulmonary symptoms, resolution of exacerbations and complete withdrawal of oral steroids. ACT score increased to 25 of 25 reachable points. Serum levels of total IgE decreased from 7000 IU/ml to 4397 IU/ml, whereas eosinophils increased from

Background: A genetic predisposition has been identified in different forms of pulmonary arterial hypertension (PAH). Most pathogenic variants have been identified in BMPR2 in hereditary PAH. However, many further PAH genes have been described. Objective: The aim of this study was to screen for all known PAH genes in a large cohort of patients with PAH and other forms of PH who have been referred for genetic testing. Methods: DNA from 244 patients was extracted and sequenced using a PAH specific gene diagnostics panel for the genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4. Of these, 180 samples were also sequenced for ATP13A3, AQP1 and SOX17. Results: Of the 244 patients about 50% were classified as IPAH and 17% as HPAH. Further patients with associated PAH such as congenital heart disease or connective tissue disease patients, pulmonary veno-occlusive disease (PVOD) and patients with sarcoidosis associated PH were included. A total of 70 pathogenic variants were identified in 66 patients. The majority of the variants (56%) was located in the gene BMPR2 but the others were found across 10 other PAH genes. Most HPAH patients had pathogenic variants in BMPR2 but also in AQP1, KCNK3, SMAD9 and SOX17. Two sarcoidosis associated PH patients carried pathogenic variants in the genes GDF2 and SOX17. Conclusion: Pathogenic variants were located in BMPR2 and in further PAH genes. Genetic predisposition was not restricted to HPAH, IPAH and PVOD but could also be identified PH with sarcoidosis and other forms of associated PAH. Thus, genetic diagnostics might be useful in a larger patient cohort than currently recommended.

The immunoproteasome is the main protein degrading system in immune cells and is essential for the resolution of viral infections. Immunoproteasome activity is markedly decreased in end-stage COPD lung tissue and expression is reduced in early-stage BAL cells (Kammerl et al. AJRCCM 2016). This supports the concept that altered immunoproteasome function contributes to progression of COPD by increasing susceptibility to infections. Our study aims to evaluate if immunoproteasome activity may serve as a biomarker for COPD in non-invasive samples. Systemic immunoproteasome expression was determined by RT-qPCR, Western blot and proteome analysis in peripheral mononuclear cells of 28 COPD patients (GOLD II-IV) and 24 controls (6 smokers). Activity was analyzed using subunit-specific activity-based probes (ABPs) and native gel analysis. In COPD, expression of the immunoproteasome subunits LMP2, LMP7 and MECL1 was increased and activity was also slightly albeit non-significantly upregulated. We are currently analyzing local immune cells of the lung using induced sputum for immunoproteasome activity. Induced sputum of 13 controls (non-smokers), 9 COPD (status B-D) and 4 asthma patients was collected and immune cell composition analyzed via cytospins. Native proteins were extracted and immunoproteasome activity was analyzed using ABPs. Analysis is still ongoing. Contrarily to our findings from lung tissue and BAL cells, immunoproteasome activity seems to be upregulated systemically in PBMC of COPD patients. However, lung-specific determination of immunoproteasome activity is feasible also in non-invasive sputum samples and might be a more useful approach for biomarker profiling in COPD.

Background: Lung cancer patients often have impaired lung function, which limits treatment options and impairs quality of life. Also, treatment may cause further deteriorations in lung function. Here we present an analysis of pulmonary function tests (PFT) in patients treated for lung cancer and examine correlations with treatment type. Methods: We retrospectively analysed 93 patients treated for lung cancer and correlated PFT results over time with type of treatment. Results: 176 PFTs from 55 men and 38 women treated at the Munich Thoracic Oncology Centre were included. Treatment groups were: chemotherapy n=28, other systemic therapy n=3, radiochemotherapy n= 39, radiation n=8, trimodal therapy n=4, surgery n=7, supportive care n=3. Patients treated with surgery or multimodal treatment had better PFTs (FEV1, %predicted FEV1, diffusion capacity and %predicted diffusion capacity) at first diagnosis than those treated with chemotherapy. There was a significant difference in FEV1 (p=0.008) and %predicted FEV (p=0.014) between the therapeutic groups. PFTs often worsened during treatment. At the time of the first follow up patients treated with surgery or multimodal treatment still had a better lung function than patients treated with chemotherapy. Conclusion: There are clinically relevant differences in PFTs before treatment for lung cancer and during the course of treatment in subgroups of lung cancer patients. Patients treated with systemic treatment alone often have poor lung function and may show further deterioration of PFTs during treatment. Larger studies of the effect of individual systemic agents on lung function in this setting are warranted.

Background: The use of probiotic bacteria has been proposed for prevention of allergic diseases. However, clinical trials have given inconsistent results. This may be explained by the complexity of the crosstalk between probiotic bacteria, the host´s microbiota and immune cells. The identification a biochemically defined, bioactive substances from probiotic bacteria could circumvent these problems. We have previously detected the metabolite D-Tryptophan (D-Trp) that had immunomodulatory properties in in vitro screening assays. Objective: To obtain insight into potential mechanisms of D-Trp, such as a modulation of the murine gut microbiota and the differentiation of primary T cells. Methods: Balb/creceived 50 mM D-Trp via drinking water and AAI was induced by Ovalbumin. Gut microbiota was assessed from caecum by 16S qPCR. Primary, naive splenic CD4 + T cells were isolated from Balb/c mice and differentiated in vitro in the presence of 10 or 50 µM DTrp by using anti-CD3/CD28 microbeads and cytobox Th1, cytobox Th2 (Miltenyi Biotech) or 5 ng/ml Tgf-s for Tregs. Differentiation was assessed by intracellular flow cytometry, cytometric bead array (CBA) and qRT-PCR. Results: Feeding D-tryptophan to mice prior to experimental asthma induction restored the AAI-induced reduction in microbial diversity in the gut. In vitro DTrp addition slightly increased Foxp3 + Tregs and decreased Il4 + Th2 cells dose-dependently . Conclusion: Our findings indicate a potential beneficial effect on the gut microbiota, as well as a reduced Th2 differentiation in vitro. Thus, defined bacterial products might able to modulate the host9s immune system.

Background: Nintedanib is approved for the treatment of IPF and has been shown to slow disease progression by reducing annual lung function decline. Aim: To evaluate the efficacy/tolerability of nintedanib in clinical practice using data from a large cohort of patients treated in the German CUP. Methods: Patients (≥40 years) were required to have a confirmed diagnosis of IPF, 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. Stable disease was defined as 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 at 9 centres. 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 Conclusion: Nintedanib was generally well-tolerated and was associated with FVC stabilization in the majority of patients in this real-life setting. Our findings are in agreement with the previously published data.

Background: Pulmonary hypertension (PH) is a common finding in chronic obstructive pulmonary disease (COPD) and is known to increase mortality. It is unclear which COPD patient goes on to develop PH and why. Aim: To assess COPD patients awaiting lung transplantation for the presence of PH and identify lung function characteristics which point towards an underlying PH. Methods: A retrospective data analysis was conducted on all patients with COPD who received a lung transplant at the LMU hospital Munich from 2012-2014. The mean pulmonary artery pressure (mPAP) was taken from the last right-heart catheterisation - as documented in the lung allocation score (LAS) - prior to transplantation. The pre-transplant lung function tests (body plethysmography, diffusion capacity, blood gas analysis) were compared between patients with PH (mPAP ≥ 25 mmHg) and those without PH (mPAP Results: The study consisted of 37 patients with severe COPD (mean FEV 1 = 20 ± 4.1% predicted ). 13 patients had a mPAP of ≥ 25 mmHg and 24 had a normal mPAP . The prevalence of PH was therefore 54.2%. The mPAP in the COPD-PH group was 28 mmHg ± 3.88. There was no significant difference between the group with and without PH respectively in terms of FEV 1 (20.1 ± 4.5 Vs 20 ± 4.1% predicted) TLCO (17.6 ± 7 Vs 16.4 ± 8.5% predicted), or resting pO 2 (50 ± 7.2 Vs 50 ± 8.2 mmHg) and pCO2 (48.6 ± 13.7 Vs 44.9 ± 8.4 mmHg) in the capillary blood gas analysis. Conclusion: In this population of patients with severe COPD requiring lung transplantation, lung function parameters did not differ significantly in patients with and without pulmonary hypertension. PH, when present, was mild.

Background: Previously, D-Tryptophan has been identified as soluble bacterial molecule with Th2-lowering activity in vitro from prebiotic supernatants using bioassay-guided fractionation. However, the in vivo effects of D-Tryptophan on Th2-mediated disease are unknown. Here, we studied the effects of oral D-Tryptophan supplementation on allergic airway inflammation in mice. Methods: Six - eight weeks old female Balb/c mice received 50mM D-tryptophan (Sigma Aldrich, Germany) dissolved in the filtered drinking water or filtered drinking water as control (n=8 per group) starting at least 3 days before the first sensitization until sacrificing on day 25. An ovalbumin model with 3 intraperitoneal sensitizations (d0, d7, 14) and 3 intranasal challenges (d21, 22, 23) was applied to induce allergic airway inflammation. Results: Oral supplementation of mice with D-tryptophan significantly increased D-tryptophan serum levels indicating enteric uptake and systemic distribution. Pre-treatment of mice with D-tryptophan for 3 days and throughout experimental “asthma” induction lowered total BALF cells (from 9.1±1.9x10 5 to 4.4±0.5x10 5 cells), which was mainly caused by reduced eosinophils. Furthermore, D-Tryptophan treated mice exhibited less airway hyperreactivity than controls. Analysis of splenocytes revealed that D-tryptophan significantly reduced IL-13 and trendwise IL-4 (p=0.07) producing CD3 + CD4 + T cells, while IFNg + , Foxp3 + and IL-10 + T cells remained unchanged. In addition, the percentages of CD40 + and CD86 + DCs were reduced by half. Conclusion: Oral D-tryptophan supplementation reduces allergic airway inflammation in mice. Further studies are needed to provide insights into the mechanism of action.