Disease trajectories in interstitial lung diseases - data from the EXCITING-ILD registry.

BACKGROUND: Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with different disease trajectories. Progression (PF-ILD) occurs in up to 50% of patients and is associated with increased mortality. METHODS: The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for disease trajectories in different ILD. The course of disease was classified as significant (absolute forced vital capacity FVC decline > 10%) or moderate progression (FVC decline 5-10%), stable disease (FVC decline or increase < 5%) or improvement (FVC increase ≥ 5%) during time in registry. A second definition for PF-ILD included absolute decline in FVC % predicted ≥ 10% within 24 months or ≥ 1 respiratory-related hospitalisation. Risk factors for progression were determined by Cox proportional-hazard models and by logistic regression with forward selection. Kaplan-Meier curves were utilised to estimate survival time and time to progression. RESULTS: Within the EXCITING-ILD registry 28.5% of the patients died (n = 171), mainly due to ILD (n = 71, 41.5%). Median survival time from date of diagnosis on was 15.5 years (range 0.1 to 34.4 years). From 601 included patients, progression was detected in 50.6% of the patients (n = 304) with shortest median time to progression in idiopathic NSIP (iNSIP; median 14.6 months) and idiopathic pulmonary fibrosis (IPF; median 18.9 months). Reasons for the determination as PF-ILD were mainly deterioration in lung function (PFT; 57.8%) and respiratory hospitalisations (40.6%). In multivariate analyses reduced baseline FVC together with age were significant predictors for progression (OR = 1.00, p < 0.001). Higher GAP indices were a significant risk factor for a shorter survival time (GAP stage III vs. I HR = 9.06, p < 0.001). A significant shorter survival time was found in IPF compared to sarcoidosis (HR = 0.04, p < 0.001), CTD-ILD (HR = 0.33, p < 0.001), and HP (HR = 0.30, p < 0.001). Patients with at least one reported ILD exacerbation as a reason for hospitalisation had a median survival time of 7.3 years (range 0.1 to 34.4 years) compared to 19.6 years (range 0.3 to 19.6 years) in patients without exacerbations (HR = 0.39, p < 0.001). CONCLUSION: Disease progression is common in all ILD and associated with increased mortality. Most important risk factors for progression are impaired baseline forced vital capacity and higher age, as well as acute exacerbations and respiratory hospitalisations for mortality. Early detection of progression remains challenging, further clinical criteria in addition to PFT might be helpful.

Hospitalisation patterns in interstitial lung diseases: data from the EXCITING-ILD registry.

BACKGROUND: Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with more than 200 entities and relevant differences in disease course and prognosis. Little data is available on hospitalisation patterns in ILD. METHODS: The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for hospitalisations. Reasons for hospitalisation were classified as all cause, ILD-related and respiratory hospitalisations, and patients were analysed for frequency of hospitalisations, time to first non-elective hospitalisation, mortality and progression-free survival. Additionally, the risk for hospitalisation according to GAP index and ILD subtype was calculated by Cox proportional-hazard models as well as influencing factors on prediction of hospitalisation by logistic regression with forward selection. RESULTS: In total, 601 patients were included. 1210 hospitalisations were recorded during the 6 months prior to registry inclusion until the last study visit. 800 (66.1%) were ILD-related, 59.3% of admissions were registered in the first year after inclusion. Mortality was associated with all cause, ILD-related and respiratory-related hospitalisation. Risk factors for hospitalisation were advanced disease (GAP Index stages II and III) and CTD (connective tissue disease)-ILDs. All cause hospitalisations were associated with pulmonary hypertension (OR 2.53, p = 0.005). ILD-related hospitalisations were associated with unclassifiable ILD and concomitant emphysema (OR = 2.133, p = 0.001) as well as with other granulomatous ILDs and a positive smoking status (OR = 3.082, p = 0.005). CONCLUSION: Our results represent a crucial contribution in understanding predisposing factors for hospitalisation in ILD and its major impact on mortality. Further studies to characterize the most vulnerable patient group as well as approaches to prevent hospitalisations are warranted.

Krebs von den Lungen-6 as a Potential Predictive Biomarker in Fibrosing Interstitial Lung Diseases.

BACKGROUND: As fibrosing interstitial lung diseases (fILDs) are associated with high mortality, monitoring of disease activity under treatment is highly relevant. Krebs von den Lungen-6 (KL-6) is associated with the presence and severity of different fILDs, mainly in Asian patient populations. OBJECTIVES: Our aim was to evaluate KL-6 as a predictive biomarker in fILDs in Caucasian patients. METHODS: Consecutive patients with fILDs were recruited prospectively and serum concentrations of KL-6 were measured at baseline (BL), after 6 and 12 months (6 Months, 12 Months). Clinical characteristics including pulmonary function tests were assessed at 6-monthly visits and correlated with KL-6 BL levels as well as with KL-6 level changes. RESULTS: A total of 47 fILD patients were included (mean age: 65 years, 68% male). KL-6 levels at BL were significantly higher in fILD patients than in healthy controls (n = 44, mean age: 45, 23% male) (ILD: 1,757 ± 1960 U/mL vs. control: 265 ± 107 U/mL, p < 0.0001). However, no differences were noted between ILD subgroups. KL-6 decreased significantly under therapy (6M∆BL-KL6: -486 ± 1,505 mean U/mL, p = 0.032; 12M∆BL-KL6: -547 ± 1,782 mean U/mL, p = 0.041) and KL-6 level changes were negatively correlated with changes in pulmonary function parameters (forced vital capacity [FVC]: r = -0.562, p < 0.0001; DLCOSB: r = -0.405, p = 0.013). While neither absolute KL-6 levels at BL nor KL-6 level changes were associated with ILD progression (FVC decline ≥10%, DLCOSB decline ≥15% or death), patients with a stable FVC showed significantly decreasing KL-6 levels (p = 0.022). CONCLUSIONS: A decline of KL-6 under therapy correlated with a clinically relevant stabilization of lung function. Thus, KL-6 might serve as a predictive biomarker, which however must be determined by larger prospective cohorts.

How Informed Are German Patients with Pulmonary Sarcoidosis about Their Disease?

BACKGROUND: Sarcoidosis is a multisystemic disease with a heterogenous course of disease. Comprehensive information about the complexity and treatment indications is essential for improving patient knowledge and adhering to therapy. OBJECTIVES: The aim of our study was to investigate the level and resources of information in patients with sarcoidosis and to analyze differences in patient subgroups including age and gender. METHODS: We conducted a questionnaire-based online survey in Germany and three semi-structured focus group interviews. The interviews were evaluated independently by two investigators using a structured qualitative content analysis. RESULTS: A total of 402 completed questionnaires were analyzed, 65.8% of participants were women, and the mean age was 53 years. The majority of patients felt well informed about their disease in general (59.4%), but 40.6% were inadequately informed. The most relevant information gaps related to the future perspective (70.6%) as well as fatigue and diffuse pain (63.9%). Most patients received information from their treating pulmonologist (72.1%). 94% used the internet, especially homepages of patient support groups (75.2%). Male participants more often reported being well informed about their disease and were more satisfied with the information (p = 0.001). During the interviews, patients expressed their wish for more comprehensive information and highlighted the importance of psychological co-care as well as the future perspective. CONCLUSIONS: A relevant proportion of patients with sarcoidosis are inadequately informed about their own disease, particularly with regard to factors impeding quality of life such as fatigue. Efforts are needed to improve the level and quality of information.

[Interstitial lung diseases : Classification, differential diagnosis and treatment approaches in a heterogeneous group of chronic lung disorders]. / Interstitielle Lungenerkrankungen : Klassifikation, Differenzialdiagnostik und therapeutische Ansätze bei einer heterogenen Gruppe chronischer Lungenerkrankungen.

Interstitial lung diseases (ILD) comprise a heterogeneous group of chronic lung disorders of different etiologies that can not only affect the interstitium but also the alveolar space and the bronchial system. According to the "Global Burden of Disease Study" there has been an increase in incidence over the last decades and it is expected that the number of ILD-associated deaths will double over the next 20 years. ILD are grouped into those of unknown cause, e.g. idiopathic pulmonary fibrosis (IPF), and ILD of known cause, which include drug-induced and connective tissue disease-associated ILD as well as granulomatous ILD such as sarcoidosis and hypersensitivity pneumonitis. In addition, some ILD present a progressive fibrosing phenotype, which influences therapeutic decisions. Predominantly inflammatory entities are treated with immunosuppressives, whereas predominantly fibrosing ILD are treated with antifibrotic drugs; in some cases, a combination of both is necessary. The spectrum of differential diagnoses in ILD is broad, but definite diagnosis is essential for treatment selection; therefore, the multidisciplinary ILD board plays a pivotal role.

Ligand-activated RXFP1 gene therapy ameliorates pressure overload-induced cardiac dysfunction.

Recurrent episodes of decompensated heart failure (HF) represent an emerging cause of hospitalizations in developed countries with an urgent need for effective therapies. Recently, the pregnancy-related hormone relaxin (RLN) was found to mediate cardio-protective effects and act as a positive inotrope in the cardiovascular system. RLN binds to the RLN family peptide receptor 1 (RXFP1), which is predominantly expressed in atrial cardiomyocytes. We therefore hypothesized that ventricular RXFP1 expression might exert potential therapeutic effects in an in vivo model of cardiac dysfunction. Thus, mice were exposed to pressure overload by transverse aortic constriction and treated with AAV9 to ectopically express RXFP1. To activate RXFP1 signaling, RLN was supplemented subcutaneously. Ventricular RXFP1 expression was well tolerated. Additional RLN administration not only abrogated HF progression but restored left ventricular systolic function. In accordance, upregulation of fetal genes and pathological remodeling markers were significantly reduced. In vitro, RLN stimulation of RXFP1-expressing cardiomyocytes induced downstream signaling, resulting in protein kinase A (PKA)-specific phosphorylation of phospholamban (PLB), which was distinguishable from ß-adrenergic activation. PLB phosphorylation corresponded to increased calcium amplitude and contractility. In conclusion, our results demonstrate that ligand-activated cardiac RXFP1 gene therapy represents a therapeutic approach to attenuate HF with the potential to adjust therapy by exogenous RLN supplementation.

NmPin from the marine thaumarchaeote Nitrosopumilus maritimus is an active membrane associated prolyl isomerase.

BACKGROUND: Peptidyl-prolyl isomerases (PPIases) are present in all forms of life and play a crucial role in protein folding and regulation. They catalyze the cis-trans isomerization of the peptide bond that precedes proline residues in numerous proteins. The parvulins, which is one family of PPIases, have been extensively investigated in several eukaryotes. However, nothing is known about their expression, function and localization in archaea. RESULTS: Here, we describe the endogenous expression, molecular structure, function and cellular localization of NmPin, a single-domain parvulin-type PPIase from Nitrosopumilus maritimus. This marine chemolithoautotrophic archaeon belongs to the globally abundant phylum Thaumarchaeota. Using high resolution NMR spectroscopy we demonstrate that the 3D structure of NmPin adopts a parvulin fold and confirmed its peptidyl-prolyl isomerase activity by protease-coupled assays and mutagenesis studies. A detailed topological analysis revealed a positively charged lysine-rich patch on the protein surface, which is conserved in all known parvulin sequences of thaumarchaeotes and targets NmPin to lipids in vitro. Immunofluorescence microscopy confirms that the protein is attached to the outer archaeal cell membrane in vivo. Transmission electron microscopy uncovered that NmPin has a uniform distribution at the membrane surface, which is correlated with a native cell shape of the prokaryote. CONCLUSION: We present a novel solution structure of a catalytically active thaumarchaeal parvulin. Our results reveal that a lysine-rich patch in NmPin mediates membrane localization. These findings provide a model whereby NmPin is located between the archaeal membrane and the surface layer and hence suggest proteins of the S-layer as the key target substrates of this parvulin.

Single-domain parvulins constitute a specific marker for recently proposed deep-branching archaeal subgroups.

Peptidyl-prolyl cis/trans isomerases (PPIases) are enzymes assisting protein folding and protein quality control in organisms of all kingdoms of life. In contrast to the other sub-classes of PPIases, the cyclophilins and the FK-506 binding proteins, little was formerly known about the parvulin type of PPIase in Archaea. Recently, the first solution structure of an archaeal parvulin, the PinA protein from Cenarchaeum symbiosum, was reported. Investigation of occurrence and frequency of PPIase sequences in numerous archaeal genomes now revealed a strong tendency for thermophilic microorganisms to reduce the number of PPIases. Single-domain parvulins were mostly found in the genomes of recently proposed deep-branching archaeal subgroups, the Thaumarchaeota and the ARMANs (archaeal Richmond Mine acidophilic nanoorganisms). Hence, we used the parvulin sequence to reclassify available archaeal metagenomic contigs, thereby, adding new members to these subgroups. A combination of genomic background analysis and phylogenetic approaches of parvulin sequences suggested that the assigned sequences belong to at least two distinct groups of Thaumarchaeota. Finally, machine learning approaches were applied to identify amino acid residues that separate archaeal and bacterial parvulin proteins from each other. When mapped onto the recent PinA solution structure, most of these positions form a cluster at one site of the protein possibly indicating a different functionality of the two groups of parvulin proteins.