Expression and production of the SERPING1-encoded endogenous complement regulator C1-inhibitor in multiple cohorts of tuberculosis patients.

BACKGROUND: To facilitate better discrimination between patients with active tuberculosis (TB) and latent TB infection (LTBI), whole blood transcriptomic studies have been performed to identify novel candidate host biomarkers. SERPING1, which encodes C1-inhibitor (C1-INH), the natural inhibitor of the C1-complex has emerged as candidate biomarker. Here we collated and analysed SERPING1 expression data and subsequently determined C1-INH protein levels in four cohorts of patients with TB. METHODS: SERPING1 expression data were extracted from online deposited datasets. C1-INH protein levels were determined by ELISA in sera from individuals with active TB, LTBI as well as other disease controls in geographically diverse cohorts. FINDINGS: SERPING1 expression was increased in patients with active TB compared to healthy controls (8/11 cohorts), LTBI (13/14 cohorts) and patients with other (non-TB) lung-diseases (7/7 cohorts). Serum levels of C1-INH were significantly increased in The Gambia and Italy in patients with active TB relative to the endemic controls but not in South Africa or Korea. In the largest cohort (n = 50), with samples collected longitudinally, normalization of C1-INH levels following successful TB treatment was observed. This cohort, also showed the most abundant increase in C1-INH, and a positive correlation between C1q and C1-INH levels. Combined presence of increased levels of both C1q and C1-INH had high specificity for active TB (96 %) but only very modest sensitivity 38 % compared to the endemic controls. INTERPRETATION: SERPING1 transcript expression is increased in TB patients, while serum protein levels of C1-INH were increased in half of the cohorts analysed

Delineating associations of progressive pleuroparenchymal fibroelastosis in patients with pulmonary fibrosis

BACKGROUND: Computer quantification of baseline computed tomography (CT) radiological pleuroparenchymal fibroelastosis (PPFE) associates with mortality in idiopathic pulmonary fibrosis (IPF). We examined mortality associations of longitudinal change in computer-quantified PPFE-like lesions in IPF and fibrotic hypersensitivity pneumonitis (FHP). METHODS: Two CT scans 6-36 months apart were retrospectively examined in one IPF (n=414) and one FHP population (n=98). Annualised change in computerised upper-zone pleural surface area comprising radiological PPFE-like lesions (Δ-PPFE) was calculated. Δ-PPFE >1.25% defined progressive PPFE above scan noise. Mixed-effects models evaluated Δ-PPFE against change in visual CT interstitial lung disease (ILD) extent and annualised forced vital capacity (FVC) decline. Multivariable models were adjusted for age, sex, smoking history, baseline emphysema presence, antifibrotic use and diffusion capacity of the lung for carbon monoxide. Mortality analyses further adjusted for baseline presence of clinically important PPFE-like lesions and ILD change. RESULTS: Δ-PPFE associated weakly with ILD and FVC change. 22-26% of IPF and FHP cohorts demonstrated progressive PPFE-like lesions which independently associated with mortality in the IPF cohort (hazard ratio 1.25, 95% CI 1.16-1.34, p<0.0001) and the FHP cohort (hazard ratio 1.16, 95% CI 1.00-1.35, p=0.045). INTERPRETATION: Progression of PPFE-like lesions independently associates with mortality in IPF and FHP but does not associate strongly with measures of fibrosis progression

Precision medicine: integration of genetics and functional genomics in prediction of bronchiolitis obliterans after lung transplantation

PURPOSE OF REVIEW: Lung transplantation (LTx) can be a life saving treatment in end-stage pulmonary diseases, but survival after transplantation is still limited. Posttransplant development of chronic lung allograft dysfunction with bronchiolits obliterans syndrome (BOS) as the major subphenotype, is the main cause of morbidity and mortality. Early identification of high-risk patients for BOS is a large unmet clinical need. In this review, we discuss gene polymorphisms and gene expression related to the development of BOS. RECENT FINDINGS: Candidate gene studies showed that donor and recipient gene polymorphisms affect transplant outcome and BOS-free survival after LTx. Both selective and nonselective gene expression studies revealed differentially expressed fibrosis and apoptosis-related genes in BOS compared with non-BOS patients. Significantly, recent microarray expression analysis of blood and broncho-alveolar lavage suggest a role for B-cell and T-cell responses prior to the development of BOS. Furthermore, 6 months prior to the development of BOS differentially expressed genes were identified in peripheral blood cells. SUMMARY: Genetic polymorphisms and gene expression changes are associated with the development of BOS. Future genome wide studies are needed to identify easily accessible biomarkers for prediction of BOS toward precision medicine.status: publishe

[89Zr]Zr-rituximab PET/CT activity in patients with therapy refractory interstitial pneumonitis: a feasibility study

Recent studies on immune-mediated inflammatory lung diseases show encouraging treatment results with rituximab, a monoclonal antibody (mAb) against CD20-expressing B lymphocytes. The present pilot study aimed to explore the possibility to image CD20-expression in the lungs as future early predictor of treatment response. We describe a series of 10 patients with therapy refractory interstitial pneumonitis who were treated with rituximab (1000 mg at day 0 and day 14) and underwent PET/CT after the administration of [89Zr]Zr-N-suc-DFO-rituximab abbreviated as [89Zr]Zr-rituximab. [89Zr]-rituximab PET/CT of the chest was performed on day 3 and 6. [89Zr]Zr-rituximab PET/CT showed visual and quantifiable increased pulmonary activity in four patients. Other patients demonstrated no increased activity in the lungs. One patient developed a severe allergic reaction during infusion of the first 10% unlabeled rituximab after which rituximab infusion was ceased. Subsequent administration of [89Zr]Zr-rituximab, however, did not result in any adverse reaction. This patient demonstrated the highest uptake of [89Zr]Zr-rituximab in mediastinal lymph nodes and lung parenchyma compared to the other 9 patients who did receive the full dose rituximab before [89Zr]Zr-rituximab. This pilot study demonstrates that [89Zr]Zr-rituximab PET/CT imaging in patients with therapy refractory interstitial pneumonitis is feasible and shows lung-specific uptake in some patients. Further research with larger sample size should establish if the [89Zr]Zr-rituximab uptake correlates with treatment response to rituximab. The higher uptake in the absence of a full 1000 mg rituximab preload may suggest that future studies should consider [89Zr]Zr-rituximab imaging at low mAb dose before treatment with rituximab

Altered splenic [89Zr]Zr-rituximab uptake in patients with interstitial lung disease not responding to rituximab: could this indicate a splenic immune-mediated mechanism?

Rituximab (RTX) for immune-mediated inflammatory disease (IMID) with interstitial pneumonitis (IP) results in non-response in about a third of patients for reasons not well understood. Complete peripheral B-cell depletion in IMID-IP does not seem to correlate with successful treatment outcome. A hypothesis is that splenic B cells might play a role in B-cell recovery and attraction of naïve B cells in non-responsive patients. The aim of this post hoc analysis of clinical trial data is to search for indicators in [89Zr]Zr-rituximab PET/CT data from the spleen that might explain non-responsiveness. PET/CT data of 20 patients with IMID-IP, who were enrolled in a phase II trial and treated with RTX were analyzed. Clinical outcome was categorized into responders (RSP) and non-responders (NR) after 6 months of initial RTX by two independent pulmonologists. Patients were examined separately to search for associations between clinical outcome, splenic activity on PET/CT, lymphocyte counts and other biomarkers. Treatment failure was found in 6/20 patients (30%) while all patients exhibited B-cell depletion from the circulation. NR patients demonstrated significantly higher splenic activity than RSP patients (non-preload protocol: SUV 4.9±1.96 and SUV 2.3±1.08 respectively, P=0.025). No correlations between treatment outcome and serum lymphocyte subsets were found. Our findings suggest a potential splenic mechanism in IMID-IP patients non-responding to RTX and warrant further consideration and investigation

[89Zr]Zr-rituximab PET/CT activity in patients with therapy refractory interstitial pneumonitis : a feasibility study

Recent studies on immune-mediated inflammatory lung diseases show encouraging treatment results with rituximab, a monoclonal antibody (mAb) against CD20-expressing B lymphocytes. The present pilot study aimed to explore the possibility to image CD20-expression in the lungs as future early predictor of treatment response. We describe a series of 10 patients with therapy refractory interstitial pneumonitis who were treated with rituximab (1000 mg at day 0 and day 14) and underwent PET/CT after the administration of [89Zr]Zr-N-suc-DFO-rituximab abbreviated as [89Zr]Zr-rituximab. [89Zr]-rituximab PET/CT of the chest was performed on day 3 and 6. [89Zr]Zr-rituximab PET/CT showed visual and quantifiable increased pulmonary activity in four patients. Other patients demonstrated no increased activity in the lungs. One patient developed a severe allergic reaction during infusion of the first 10% unlabeled rituximab after which rituximab infusion was ceased. Subsequent administration of [89Zr]Zr-rituximab, however, did not result in any adverse reaction. This patient demonstrated the highest uptake of [89Zr]Zr-rituximab in mediastinal lymph nodes and lung parenchyma compared to the other 9 patients who did receive the full dose rituximab before [89Zr]Zr-rituximab. This pilot study demonstrates that [89Zr]Zr-rituximab PET/CT imaging in patients with therapy refractory interstitial pneumonitis is feasible and shows lung-specific uptake in some patients. Further research with larger sample size should establish if the [89Zr]Zr-rituximab uptake correlates with treatment response to rituximab. The higher uptake in the absence of a full 1000 mg rituximab preload may suggest that future studies should consider [89Zr]Zr-rituximab imaging at low mAb dose before treatment with rituximab

Altered splenic [89Zr]Zr-rituximab uptake in patients with interstitial lung disease not responding to rituximab: could this indicate a splenic immune-mediated mechanism?

Rituximab (RTX) for immune-mediated inflammatory disease (IMID) with interstitial pneumonitis (IP) results in non-response in about a third of patients for reasons not well understood. Complete peripheral B-cell depletion in IMID-IP does not seem to correlate with successful treatment outcome. A hypothesis is that splenic B cells might play a role in B-cell recovery and attraction of naïve B cells in non-responsive patients. The aim of this post hoc analysis of clinical trial data is to search for indicators in [89Zr]Zr-rituximab PET/CT data from the spleen that might explain non-responsiveness. PET/CT data of 20 patients with IMID-IP, who were enrolled in a phase II trial and treated with RTX were analyzed. Clinical outcome was categorized into responders (RSP) and non-responders (NR) after 6 months of initial RTX by two independent pulmonologists. Patients were examined separately to search for associations between clinical outcome, splenic activity on PET/CT, lymphocyte counts and other biomarkers. Treatment failure was found in 6/20 patients (30%) while all patients exhibited B-cell depletion from the circulation. NR patients demonstrated significantly higher splenic activity than RSP patients (non-preload protocol: SUV 4.9±1.96 and SUV 2.3±1.08 respectively, P=0.025). No correlations between treatment outcome and serum lymphocyte subsets were found. Our findings suggest a potential splenic mechanism in IMID-IP patients non-responding to RTX and warrant further consideration and investigation

MUC5B promoter variant rs35705950 and rheumatoid arthritis associated interstitial lung disease survival and progression.

BackgroundThe major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD.MethodsThrough an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline.ResultsOut of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern.ConclusionIn this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD