Genetic and geographic influence on phenotypic variation in European sarcoidosis patients.

Introduction: Sarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures. Methods: After obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations. Results: In the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement. Discussion: The observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene-environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.

Health and functional status of tiotropium/olodaterol-treated patients with COPD: results from the AERIAL® non-interventional study.

Patients with COPD often have reduced physical activity, which can impair health status. Real-world data can provide valuable information on the health and functional status of patients with COPD treated with tiotropium/olodaterol. AERIAL® (ClinicalTrials.gov NCT03165045) was a German, non-interventional study of patients with COPD receiving treatment with tiotropium/olodaterol under real-world conditions for ∼6 weeks. The primary end-point was the proportion of patients achieving a decrease of ≥0.4 points in Clinical COPD Questionnaire (CCQ) score. The CCQ-4 subdomain was used to assess functional status, and the Physician's Global Evaluation (PGE) scale was used to assess the patients' general condition. Safety was assessed, as well as patient satisfaction and willingness to continue treatment. Out of 1351 screened patients, 1322 were treated and 1140 comprised the full analysis set. The primary end-point was met: 66.3% of patients achieved a ≥0.4-point decrease in overall CCQ score (mean±sd decrease 0.78±0.95). Mean±sd decreases in CCQ symptoms and functional state subdomains were 0.84±1.06 and 0.75±1.05 points, respectively. PGE scores improved. One fatality (not treatment-related) and 23 drug-related adverse events were recorded, most commonly nausea and vertigo. >85% of patients were satisfied/very satisfied with tiotropium/olodaterol overall and with the Respimat® device, both in terms of inhalation and handling. Most patients (95.2%) expressed willingness to continue treatment. Patients with COPD treated with tiotropium/olodaterol via Respimat® in routine clinical practice had clinically relevant improvements in health and functional status compared with baseline.

Arkadia/RNF111 is a SUMO-targeted ubiquitin ligase with preference for substrates marked with SUMO1-capped SUMO2/3 chain.

Modification with SUMO regulates many eukaryotic proteins. Down-regulation of sumoylated forms of proteins involves either their desumoylation, and hence recycling of the unmodified form, or their proteolytic targeting by ubiquitin ligases that recognize their SUMO modification (termed STUbL or ULS). STUbL enzymes such as Uls1 and Slx5-Slx8 in budding yeast or RNF4 and Arkadia/RNF111 in humans bear multiple SUMO interaction motifs to recognize substrates carrying poly-SUMO chains. Using yeast as experimental system and isothermal titration calorimetry, we here show that Arkadia specifically selects substrates carrying SUMO1-capped SUMO2/3 hybrid conjugates and targets them for proteasomal degradation. Our data suggest that a SUMO1-specific binding site in Arkadia with sequence similarity to a SUMO1-binding site in DPP9 is required for targeting endogenous hybrid SUMO conjugates and PML nuclear bodies in human cells. We thus characterize Arkadia as a STUbL with a preference for substrate proteins marked with distinct hybrid SUMO chains.

Assessment of physical functioning and handling of tiotropium/olodaterol Respimat® in patients with COPD in a real-world clinical setting.

Background: Patients with chronic obstructive pulmonary disease (COPD) show signs of reduced physical activity from the early stages of the disease, impacting morbidity and mortality. Data suggest treatment with tiotropium, a long-acting muscarinic antagonist, and olodaterol, a long-acting ß2-agonist (LABA), as monotherapies and in combination, increases exercise capacity. This study assessed the effects of fixed-dose tiotropium/olodaterol (delivered via Respimat®) on physical function in Global Initiative for Chronic Obstructive Lung Disease A-D patients requiring long-acting dual bronchodilation treatment in a real-world setting. Methods: This open-label, single arm, noninterventional study measured changes in physical function in COPD patients treated with tiotropium/olodaterol 5/5 µg for approximately 6 weeks (between Visit 1 [baseline] and Visit 2). Primary end point was therapeutic success, defined as a minimum 10-point increase in Physical Functioning Questionnaire (PF-10) score. Secondary end points included change in PF-10 from Visit 1 to Visit 2, the patient's general condition (measured by Physician's Global Evaluation score) at Visit 1 and Visit 2, and patient satisfaction with treatment delivered via the Respimat® device (assessed by Patient Satisfaction Questionnaire) at study end. Results: Therapeutic success was observed in 51.5% of 1578 patients (95% confidence interval [CI] 49.0, 54.0) after approximately 6 weeks of treatment with tiotropium/olodaterol. Mean change in PF-10 score between Visit 1 and Visit 2 was 11.6 points (95% CI 10.7, 12.6). Patient general condition improved as indicated by a general improvement in scores between visits. Most patients were very satisfied or satisfied with tiotropium/olodaterol treatment (82.5%), inhalation (87.5%), and handling of Respimat® (85.2%). One percent of patients reported an investigator-defined drug-related adverse events (AE). Conclusion: Tiotropium/olodaterol treatment improved physical functioning in COPD patients. An associated increase in patient general condition was observed. Most patients were very satisfied or satisfied with tiotropium/olodaterol treatment, inhaling, and handling of the Respimat® device. No unexpected drug-related AE occurred.

Methods to study SUMO dynamics in yeast.

Covalent modification of proteins with the small ubiquitin-related modifier (SUMO) is found in all eukaryotes and is involved in many important processes. SUMO attachment may change interaction properties, subcellular localization, or stability of a modified protein. Usually, only a small fraction of a protein is modified at a given time because sumoylation is a highly dynamic process. The sumoylated state of a protein is controlled by the activity of the sumoylation enzymes that promote either their mono- or poly-sumoylation (SUMO chain formation), by SUMO proteases that reverse these modifications, and by SUMO-targeted ubiquitin ligases (STUbL, ULS) that mediate their degradation by the proteasome. While some organisms, such as humans, express multiple isoforms, budding yeast SUMO is encoded by a single and essential gene termed SMT3. The analysis of the simpler SUMO system in budding yeast has been instrumental in the identification of enzymes acting on this modification and controlling its dynamics. Sumoylation of proteins changes dramatically during the cell division cycle and under various stress conditions. Here we summarize various approaches that employ Saccharomyces cerevisiae as a model system to study the dynamics of sumoylation and how it is controlled.

Definition, clinical classification and initial diagnosis of pulmonary hypertension: Updated recommendations from the Cologne Consensus Conference 2018.

In the summer of 2016, delegates from the German Society of Cardiology (DGK), the German Respiratory Society (DGP), and the German Society of Pediatric Cardiology (DGPK) met in Cologne, Germany, to define consensus-based practice recommendations for the management of patients with pulmonary hypertension (PH). These recommendations were built on the 2015 European Pulmonary Hypertension guidelines, aiming at their practical implementation, considering country-specific issues, and including new evidence, where available. To this end, a number of working groups was initiated, one of which was specifically dedicated to the definition, clinical classification and initial diagnosis of PH. While the European guidelines provide a detailed clinical classification and a structured approach for diagnostic testing, their application in routine care may be challenging, particularly given the changing phenotype of PH patients who are nowadays often elderly and may present with multiple potential causes of PH, as well as comorbid conditions. Specifically, the working group addresses the thoroughness of diagnostic testing, and the roles of echocardiography, exercise testing, and genetic testing in diagnosing PH. Furthermore, challenges in the diagnostic work-up of patients with various causes of PH including "PAH with comorbidities", CTEPH and coexisting conditions are highlighted, and a modified diagnostic algorithm is provided. The detailed results and recommendations of the working group on definition, clinical classification and initial diagnosis of PH, which were last updated in the spring of 2018, are summarized in this article.

Phenotypes of organ involvement in sarcoidosis.

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.

Ultrafast isomerization in acetylene dication after carbon K-shell ionization.

Ultrafast proton migration and isomerization are key processes for acetylene and its ions. However, the mechanism for ultrafast isomerization of acetylene [HCCH]2+ to vinylidene [H2CC]2+ dication remains nebulous. Theoretical studies show a large potential barrier ( > 2 eV) for isomerization on low-lying dicationic states, implying picosecond or longer isomerization timescales. However, a recent experiment at a femtosecond X-ray free-electron laser suggests sub-100 fs isomerization. Here we address this contradiction with a complete theoretical study of the dynamics of acetylene dication produced by Auger decay after X-ray photoionization of the carbon atom K shell. We find no sub-100 fs isomerization, while reproducing the salient features of the time-resolved Coulomb imaging experiment. This work resolves the seeming contradiction between experiment and theory and also calls for careful interpretation of structural information from the widely applied Coulomb momentum imaging method.The timescale of isomerization in molecules involving ultrafast migration of constituent atoms is difficult to measure. Here the authors report that sub-100 fs isomerization time on acetylene dication in lower electronic states is not possible and point to misinterpretation of recent experimental results.

Cardiovascular magnetic resonance-guided diagnosis of cardiac affection in a Caucasian sarcoidosis population.

BACKGROUND: Clinically evidenced cardiac involvement in systemic sarcoidosis occurs in approximately 5% of patients, whereas post-mortem examinations identify cardiac sarcoidosis in over 60% of cases. OBJECTIVE: Given the inconsistency of diagnostic approaches, we took aim at prospectively investigating the prevalence of cardiac sarcoidosis by cardiovascular magnetic resonance (CMR) in a primary Caucasian population and at correlating the results with standard clinical parameters. METHODS: 188 patients with histologically proven sarcoidosis were included, provenient from the local pneumological department and a national sarcoidosis self-help association. All of them underwent CMR-imaging. Complementary 12-lead ECG, Holter monitoring, laboratory and pulmonary function testing were performed. RESULTS: CMR-based diagnosis of cardiac sarcoidosis was made in 29 patients (15.4%), of whom 17 patients (9% of total cohort) exhibited increased relative gadolinium enhancement - reflecting acute inflammatory processes -, while 11 patients (5.9% of total cohort) showed late gadolinium enhancement as a marker for nonviable tissue damage. Both abnormalities were present in 1 patient (0.5%). Correlation analysis evinced significant association between CMR-diagnosed cardiac sarcoidosis and reduction in LVEF, increase in diastolic interventricular septal thickness, diastolic dysfunction as well as limited electrocardiographic abnormalities. Neither laboratory values nor pulmonary function parameters correlated with presence or activity of cardiac sarcoidosis. CONCLUSIONS: Among our predominantly Caucasian sarcoidosis study population, CMR-detected cardiac affection occurred in 15.4% and was missed by internationally valid standard clinical testing in all but one case. It reinforces CMR's diagnostic value as modality of choice to evaluate cardiac sarcoidosis. The estimation of its prognostic potential and its value in assessing the incidence of cardiac sarcoidosis however requires further longitudinal investigation.

Solution Equilibrium Titration for High-Throughput Affinity Estimation of Unpurified Antibodies and Antibody Fragments.

The generation of therapeutic antibodies with extremely high affinities down to the low picomolar range is today feasible with state-of-the art recombinant technologies. However, reliable and efficient identification of lead candidates with the desired affinity from a pool of thousands of antibody clones remains a challenge. Here, we describe a high-throughput procedure that allows reliable affinity screening of unpurified immunoglobulin G or antibody fragments. The method is based on the principle of solution equilibrium titration (SET) using highly sensitive electrochemiluminescence as a readout system. Because the binding partners are not labeled, the resulting KD represents a sound approximation of the real affinity. For screening, diluted bacterial lysates or cell culture supernatants are equilibrated with four different concentrations of a soluble target molecule, and unbound antibodies are subsequently quantified on 384-well Meso Scale Discovery (MSD) plates coated with the respective antigen. For determination of KD values from the resulting titration curves, fit models deduced from the law of mass action for 1:1 and 2:1 binding modes are applied to assess hundreds of interactions simultaneously. The accuracy of the method is demonstrated by comparing results from different screening campaigns from affinity optimization projects with results from detailed affinity characterization.

Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk.

RATIONALE: Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far. OBJECTIVES: To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci. METHODS: Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms. MEASUREMENTS AND MAIN RESULTS: Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3. CONCLUSIONS: Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics.

Characterization and screening of IgG binding to the neonatal Fc receptor.

The neonatal Fc receptor (FcRn) protects immunoglobulin G (IgG) from degradation and increases the serum half-life of IgG, thereby contributing to a higher concentration of IgG in the serum. Because altered FcRn binding may result in a reduced or prolonged half-life of IgG molecules, it is advisable to characterize Fc receptor binding of therapeutic antibody lead candidates prior to the start of pre-clinical and clinical studies. In this study, we characterized the interactions between FcRn of different species (human, cynomolgus monkey, mouse and rat) and nine IgG molecules from different species and isotypes with common variable heavy (VH) and variable light chain (VL) domains. Binding was analyzed at acidic and neutral pH using surface plasmon resonance (SPR) and biolayer interferometry (BLI). Furthermore, we transferred the well-accepted, but low throughput SPR-based method for FcRn binding characterization to the BLI-based Octet platform to enable a higher sample throughput allowing the characterization of FcRn binding already during early drug discovery phase. We showed that the BLI-based approach is fit-for-purpose and capable of discriminating between IgG molecules with significant differences in FcRn binding affinities. Using this high-throughput approach we investigated FcRn binding of 36 IgG molecules that represented all VH/VL region combinations available in the fully human, recombinant antibody library Ylanthia®. Our results clearly showed normal FcRn binding profiles for all samples. Hence, the variations among the framework parts, complementarity-determining region (CDR) 1 and CDR2 of the fragment antigen binding (Fab) domain did not significantly change FcRn binding.

Impact of untreated obstructive sleep apnea on left and right ventricular myocardial function and effects of CPAP therapy.

BACKGROUND: Obstructive sleep apnea (OSA) has deteriorating effect on LV function, whereas its impact on RV function is controversial. We aimed to determine the effect of OSA and continuous positive airway pressure (CPAP) treatment on left and right ventricular (LV, RV) function using transthoracic echocardiography (TTE) and 2 dimensional speckle tracking (2D ST) analysis of RV deformation capability. METHODS AND RESULTS: 82 patients with OSA and need for CPAP therapy were prospectively enrolled and underwent TTE at study inclusion and after 6 months of follow up (FU). Multivariate regression analysis revealed an independent association between baseline apical right ventricular longitudinal strain (RV-Sl), BMI and the severity of OSA (apical RV-Sl: P = 0.0002, BMI: P = 0.02). After CPAP therapy, LV functional parameters (LVEF: P<0.0001, LV performance index: P = 0.03, stroke volume: P = 0.042), and apical RV-Sl (P = 0.001) improved significantly. The effect of CPAP therapy was related to severity of OSA (LVEF: AHI 5-14, 66.4 ± 8.8%, 68.5 ± 10.6% [P = ns]; AHI 15-30:59.8 ± 7.7%, 68.6 ± 9.3% [P = 0.002]; AHI>30:54.1 ± 12.4%, 68.2 ± 13.6%[P<0.0001]; apical RV-Sl: AHI 5-14: -17.3 ± 8.7%, -16.0 ± 10.8% [P = ns], AHI 15-30: -9.8 ± 6.0%, -15.4 ± 10.9% [P = 0.028], AHI>30: -6.3 ± 5.7%, -17.9 ± 11.2% [P<0.0001]). CONCLUSIONS: OSA seems to have deteriorating effect on LV and RV function. We found a beneficial effect of CPAP on LV and RV functional parameters predominately in patients with severe OSA. 2D speckle tracking might be of value to determine early changes in global and regional right ventricular function.

Transcatheter valve implantation improves central sleep apnoea in severe aortic stenosis.

AIMS: Severe cardiac disorders predispose to central sleep apnoea (CSA). We sought to examine the relationship between severe aortic stenosis, sleep disordered breathing (SDB), and CSA before and after transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: Twenty-nine patients (81±6 yrs, 41% male, LVEF 48±14%) with severe aortic stenosis and high surgical risk underwent polygraphy before and three months after TAVI. Patients with an apnoea-hypopnoea index (AHI) >5/hr were considered to have SDB. SDB with ≥50% absence of both airflow and ventilatory effort was defined as CSA. Twenty-one of 29 patients (72%) had SDB (6/6/9 mild, moderate, and severe, respectively), 12 (41%) with CSA (0/4/8) and 9 (31%) with obstructive sleep apnoea (7/2/0). There was a strong correlation of CSA with LVEDP before TAVI (r=0.74, p=0.024), but not with LVEF, systolic pulmonary artery pressure or NT pro-BNP. After TAVI, AHI improved significantly, particularly in the CSA group (from 43.5±17.5 to 19.4±12.9/hr, p<0.001). Prevalence and severity of SDB were reduced from 72% to 59% (6/6/9 to 7/8/2 patients), triggered by the significant improvement of CSA. CONCLUSIONS: Patients with severe aortic stenosis display a high prevalence of SDB, particularly of CSA. Definitive treatment with TAVI greatly resolved SDB in the CSA subgroup.

An automated immunoassay for early specificity profiling of antibodies.

Antibody-based therapeutics are of great value for the treatment of human diseases. In addition to functional activity, affinity or physico-chemical properties, antibody specificity is considered to be one of the most crucial attributes for safety and efficacy. Consequently, appropriate studies are required before entering clinical trials. High content protein arrays are widely applied to assess antibody specificity, but this commercial solution can only be applied to final therapeutic antibody candidates because such arrays are expensive and their throughput is limited. A flexible, high-throughput and economical assay that allows specificity testing of IgG or Fab molecules during early discovery is described here. The 384-well microtiter plate assay contains a comprehensive panel of 32 test proteins and uses electrochemiluminescence as readout. The Protein Panel Profiling ( 3P) was used to analyze marketed therapeutic antibodies that all showed highly specific binding profiles. Subsequently, 3P was applied to antibody candidates from early discovery and the results compared well with those obtained with a commercially available high content protein chip. Our results suggest that 3P can be applied as an additional filter for lead selection, allowing the identification of favorable antibody candidates in early discovery and thereby increasing the speed and possibility of success in drug development.

Toll-like receptor-9 polymorphisms in sarcoidosis and chronic obstructive pulmonary disease.

The etiology of inflammatory diseases of the lung like sarcoidosis and chronic obstructive pulmonary disease (COPD) is multifactorial. The main trigger for developing a COPD is tobacco smoking while exogenous factors causing sarcoidosis are unclear. In both diseases there is an underlying genetic susceptibility determining both the onset and the course of the diseases. Toll-like receptor (TLR)-9 plays an important role in innate immunity by recognizing bacterial CpG-DNA motifs. It is unclear whether single nucleotide polymorphisms (SNPs) in TLR-9 are able to alter the course of sarcoidosis or COPD, or raise the susceptibility for developing one of the disorders. We examined two SNPs in the promoter region of the TLR-9 gene (T1486C and T1237C) in 175 COPD patients (59% with a stable course of the disease, 41% with an instable course with more than 3 exacerbations over the last 3 years) and 166 sarcoidosis patients (19% with an acute and 81% with a chronic course of the disease lasting >2 years) comparing each group to 233 healthy controls. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis was used for genotyping. The C-allele frequency of T1486C was significantly elevated in COPD patients (p = 0.008). For T1237C there were no significant associations comparing the COPD cohort with the controls. In the sarcoidosis cohort, we could observe a significantly higher prevalence of the C-allele for T1237C in the chronic sarcoidosis cohort in comparison to the control group (p = 0.026). For T1486 there no statistical association was observed. This is the first study showing an association between a SNP (T1486C) in the TLR-9 gene and the onset of COPD. Moreover, we could demonstrate that T1237C is able to alter the course of sarcoidosis as a disease-modifying gene. This study underlines that SNPs in TLR-9 might be involved in acquiring and maintaining lung diseases such as sarcoidosis and COPD.

Pulmonary aspergillosis: therapeutic management and prognostic factors from 16 years of monocenter experience.

Twenty three patients of the University Hospital Bonn were reviewed following surgical procedures for pulmonary aspergilloma, including the choice of antifungal therapy, diagnostic findings, decision-making in treatment, and treatment outcomes of the past 16 years. We used pathological records to identify aspergilloma patients. A review of patients' records and follow-up phone calls to patients, families, or general practitioners were done. Data collected from 1995 to 2011 included patients with aspergilloma (n = 15), multiple aspergillomas (n = 2) and chronic necrotizing pulmonary aspergillosis (n = 6). Classification and diagnosis were based on pathological records. The decision to use systemic antimycotic therapy was based on perioperative findings suspecting parenchymal involvement of the fungal infection. Seventeen patients received systemic antimycotic chemotherapy. Compared with the use of Amphotericin B, newer drugs such as voriconazol, caspofungin, or posaconazol showed no better result in the morbidity and mortality of the patients. Postoperative complications requiring extended therapy and/or prolonged ICU stay (>48 h) were seen in 12 (52.2%) patients. During follow-up there were ten deaths; one death (4.4%) from aspergillus-associated sepsis, nine deaths from patients' underlying diseases (n = 4 within <3 months, n = 6 within >3 months of follow-up). In conclusion, in our cohort, immunocompromised patients with no documented preexisting lung-cavities were most likely to develop pulmonary aspergilloma. Postoperative morbidity (52.2%) was high, but related mainly to patient co-morbidity; postoperative mortality was reasonably low. Patients showing classical symptoms or immunocompromised patients should be considered for surgery. Encapsulated Aspergilloma without invasion of surrounding parenchyma requires no antifungal chemotherapy.

Pulmonary arterial hypertension in patients with sarcoidosis: the Pulsar single center experience.

Sarcoidosis is a systemic granulomatous disease with unknown etiology. Lungs and lymph nodes are commonly affected. Also, cases of pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are described. However, the exact prevalence of PAH in patients with sarcoidosis is unclear. A 111 patients with proven sarcoidosis were recruited from January 2010 to October 2010. All patients were studied prospectively by transthoracic echocardiography (TTE) for the presence of PH. In assumed PH, a right heart catheterization (RHC) followed if there were no other reasons for PH. In 23 of the 111 patients (21%) PH was assumed in TTE. Three patients presented with severe mitral insufficiency III° and IV°, in eight patients PH was supposed to be caused by chronic heart failure or relevant diastolic dysfunction > II°, two patients declined undergoing RHC. Of the ten patients investigated with RHC, four showed a precapillary pulmonary arterial hypertension and in one patient a postcapillary hypertension was diagnosed. All four patients with precapillary PH had a radiologic stage III and IV. In three of the four patients a significantly reduced transfer factor for carbon monoxide (TLCO) <50% was found. All patients with precapillary PH had a chronic course of sarcoidosis lasting ≥13 years. This is the first study which prospectively investigated a large cohort of patients with sarcoidosis for the prevalence of PH and PAH. The prevalence of precapillary PH was found to be at least 3.6% (4/111) and therefore exceeds the prevalence of PAH in the normal population by far. A chronic and progressive lung involvement due to sarcoidosis seems to be the most evident risk factor for developing a sarcoidosis PH.