[CF Lung Disease - a German S3 Guideline: Pseudomonas aeruginosa]. / S3-Leitlinie: Lungenerkrankung bei Mukoviszidose ­ Pseudomonas aeruginosa.

Cystic Fibrosis (CF) is the most common autosomal recessive genetic multisystemic disease. In Germany, it affects at least 8000 people. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the airway epithelial lining fluid which leads to reduction of the mucociliary clearance.Even if highly effective, CFTR modulator therapy has been available for some years and people with CF are getting much older than before, recurrent and chronic infections of the airways as well as pulmonary exacerbations still occur. In adult CF life, Pseudomonas aeruginosa (PA) is the most relevant pathogen in colonisation and chronic infection of the lung, leading to further loss of lung function. There are many possibilities to treat PA-infection.This is a S3-clinical guideline which implements a definition for chronic PA-infection and demonstrates evidence-based diagnostic methods and medical treatment in order to give guidance for individual treatment options.

Every CFTR variant counts - Target-capture based next-generation-sequencing for molecular diagnosis in the German CF Registry.

BACKGROUND: In times of genotype guided therapy options, a total of 3.2 % of people with CF (pwCF) in the German CF Registry[1] only have one or no CFTR-variant detected after genetic analysis. Additionally, genetic data in the Registry can be documented as free text and can therefore be prone to error. In order to allow the greatest possible amount of pwCF access to modern therapies, we conducted a re-evaluation of free text entries and established a custom-whole-CFTR-locus NGS-approach for all pwCF who remained without genetic confirmation afterwards. METHODS: To this end, we assembled 731 free text variants of 655 pwCF in the German CF Registry. All variants were evaluated using ClinVar, HGMD and CFTR1/2, corrected in the Registries' database and uploaded to ClinVar. PwCF whose diagnosis remained uncertain as well as additional pwCF or pwCFTR-RD that were assembled through a nationwide call for testing of unclear cases were offered genetic analysis. Samples were analysed using a target-capture based NGS-custom-design-panel covering the entire CFTR-locus. RESULTS: Evaluation of free text variants led to the discovery of 43 variants not formerly reported in the context of CF. The Registries' dropdown list was extended by 497 variants and over 500 pwCF were provided with their most up-to-date genotype. Samples of 47 pwCF/pwCFTR-RD were sequenced via NGS with an overall success rate of 61.7 %, resulting in implementation of entire CFTR-genotyping into routine diagnostics. CONCLUSION: Entire CFTR-genotyping can greatly increase the genetic diagnostic rate of pwCF/pwCFTR-RD and should be considered after inconspicuous CFTR screening panels in CFTR-diagnostics.

Limited prognostic accuracy of the CRB-65 and qSOFA in patients presenting with pneumonia and immunosuppression.

BACKGROUND: Scores for risk prediction used in immunocompetent patients with sepsis or pneumonia are poorly evaluated in immunocompromised patients. Therefore, we evaluated the prognostic value of the qSOFA- and CRB-65-criteria in immunocompromised patients presenting with pneumonia. METHODS: Retrospective cohort study including consecutive patients hospitalized with pneumonia and immunosuppression without treatment restrictions. The qSOFA and CRB-65 criteria were documented in the emergency department. Outcome was defined as need of mechanical ventilation (MV) or vasopressor support (VS) and/or hospital-mortality. RESULTS: 41 of 198 (21%) patients reached the outcome and 10% died. Both, the CRB-65 and qSOFA- were independently associated with the outcome (all p<0.01), but age was not predictive. ROC curve analysis showed moderate predictive potential for both scores (CRB-65: AUC 0.63 and qSOFA: 0.69). With scores of 0, the negative predictive values were below 90% (CRB-65: 9/60 and qSOFA: 12/105 missed patients). With scores > 1, the positive predictive values were 36% (CRB-65) and 58% (qSOFA), respectively. CONCLUSIONS: Both, the qSOFA and the CRB-65 only showed moderate prognostic value, and negative predictive values were inadequate to exclude organ failure or death in patients with immunosuppression. In this population, age was not a predictive parameter. Patients with > 1 positive vital sign criterion measured by both scores should be assessed for organ failure.

Prognostic value of blood pressure drops during the first 24 h after hospital admission for risk stratification of community-acquired pneumonia: a retrospective cohort study.

OBJECTIVES: Current risk stratification in community-acquired pneumonia (CAP) does not incorporate the dynamic nature of CAP evolution. Study aim was to evaluate the predictive value of early blood pressure (BP) drop and its consideration within the CRB-65 score. METHODS: We performed a retrospective cohort study including consecutive adult hospitalized CAP patients 2013-2014 without documented treatment limitations or direct ICU admission. The CRB-65 score was calculated initially and re-calculated including any BP below the threshold (BP drop) within the first 24 h (CRB-65[BP24]). The primary endpoint was need for mechanical ventilation or vasopressors (MVVS) occurring after 24 h. Prognostic values were evaluated by uni- and multivariate and ROC curve analyses. RESULTS: 28/294 patients (9.5%) met the primary endpoint. Only 3 (11%) of them showed an initial BP of < 90 mmHg systolic or ≤ 60 mmHg diastolic, but 21 (75%) developed a BP drop within the first 24 h. 24/178 (13%) with and only 4/116 (3%) without any low BP during the first 24 h needed MVVS (p = 0.004). After multivariate analysis, the predictive value of BP drop was independent of other score parameters and biomarkers (all p < 0.01). In ROC analysis, the new CRB-65(BP24) showed a better prediction than the CRB-65 score (AUC 0.69 vs. 0.62, p = 0.04). 7/13 patients (54%) with MVVS despite an admission CRB-65 of 0 or 1 showed a BP drop. CONCLUSIONS: In the evaluated cohort, BP drop within the first 24 h was significantly associated with more need for MVVS in CAP, and its consideration improved the prognostic value of the CRB-65 score.

Neutrophil elastase-mediated increase in airway temperature during inflammation.

BACKGROUND: How elevated temperature is generated during airway infections represents a hitherto unresolved physiological question. We hypothesized that innate immune defence mechanisms would increase luminal airway temperature during pulmonary infection. METHODS: We determined the temperature in the exhaled air of cystic fibrosis (CF) patients. To further test our hypothesis, a pouch inflammatory model using neutrophil elastase-deficient mice was employed. Next, the impact of temperature changes on the dominant CF pathogen Pseudomonas aeruginosa growth was tested by plating method and RNAseq. RESULTS: Here we show a temperature of ~38°C in neutrophil-dominated mucus plugs of chronically infected CF patients and implicate neutrophil elastase:α1-proteinase inhibitor complex formation as a relevant mechanism for the local temperature rise. Gene expression of the main pathogen in CF, P. aeruginosa, under anaerobic conditions at 38°C vs 30°C revealed increased virulence traits and characteristic cell wall changes. CONCLUSION: Neutrophil elastase mediates increase in airway temperature, which may contribute to P. aeruginosa selection during the course of chronic infection in CF.

Fibrinogen plasma concentration is an independent marker of haemodynamic impairment in chronic thromboembolic pulmonary hypertension.

Fibrinogen has a crucial role in both inflammation and coagulation, two processes pivotal for the pathogenesis of pulmonary hypertension. We therefore aimed to investigate whether fibrinogen plasma concentrations a) are elevated in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) and b) may serve as a novel biomarker for haemodynamic impairment. In a dual-centre, retrospective analysis including 112 patients with PAH (n = 52), CTEPH (n = 49) and a control cohort of patients with suspected PAH ruled out by right heart catheterisation (n = 11), we found fibrinogen plasma concentrations to be increased in patients with PAH (4.1 ± 1.4 g/l) and CTEPH (4.3 ± 1.2 g/l) compared to control patients (3.4 ± 0.5 g/l, p = 0.0035 and p = 0.0004, respectively). In CTEPH patients but not in PAH patients fibrinogen was associated with haemodynamics (p < 0.036) and functional parameters (p < 0.041). Furthermore, fibrinogen was linked to disease severity (WHO functional class, p = 0.017) and independently predicted haemodynamic impairment specifically in CTEPH (p < 0.016). Therefore, fibrinogen seems to represent an important factor in CTEPH pathophysiology and may have the potential to guide clinical diagnosis and therapy.