Survival-Adjusted FEV1 and BMI Percentiles for Patients with Cystic Fibrosis before the Era of Triple CFTR Modulator Therapy in Germany.

BACKGROUND: Pulmonary disease is the major cause for morbidity and mortality in cystic fibrosis (CF). In CF, forced expiratory volume in 1 s (FEV1) referenced against a healthy population (FEV1%predicted) and body mass index (BMI) do not allow for the comparison of disease severity across age and gender. OBJECTIVES: We aimed to determine updated FEV1 and BMI percentiles for patients with CF and to study their dependence on mortality attrition. METHODS: Age- and height-adjusted FEV1 and BMI percentiles for CF patients aged 6-50 years were calculated from 4,947 patients of the German CF Registry for the period 2016-2019 utilizing quantile regression and a Generalized Additive Model for Location, Scale and Shape (GAMLSS). Further, survival-adjusted percentiles were estimated. RESULTS: In patients with CF, FEV1 increased throughout childhood until maximal median values at 16 years in females (2.46 L) and 18 years in males (3.27 L). During adulthood, FEV1 decreased substantially. At 17 years of age, the 25th BMI percentile of patients with CF (females 18.50 and males 18.15 kg/m2) was below the 10th BMI percentile of the German reference cohort. From the age of 20 years, survival (96.3%) decreased tremendously. At 50 years of age (survival 15.0%), the 50th CF-specific FEV1 or BMI percentile among the survivors corresponded to the 92.5th percentile among the total CF birth cohort. CONCLUSIONS: Continuously updated disease-specific FEV1 and BMI percentiles with correction for survival may serve as age-independent measure of disease severity in CF (accessible via https://cfpercentiles.statup.solutions).

Bronchoscopic Measurement of Collateral Ventilation: State of the Art.

Endoscopic lung volume reduction procedure with valves is a well-studied treatment option for advanced lung emphysema to target lung hyperinflation in carefully selected patients with COPD. Before valve implantation, collateral ventilation (CV) of the target lobe needs to be assessed to obtain an optimal treatment effect. The analysis of CV according to current standards occurs via an in vivo assessment with the Chartis®system (PulmonX Inc., Redwood City, CA, USA) and a computed tomography (CT) scan of the thorax with interlobar fissure analysis. The focus of this review is to provide detailed information about the Chartis®procedure and interpretation of Chartis® phenotypes. As a main tool in the assessment of CV and being a safe procedure, the Chartis® assessment should be performed by default to confirm interlobar fissure analysis in most emphysema patients. Based on the obtained results, lung volume reduction therapy options should be discussed in an interdisciplinary emphysema conference.

Macrophage PD-1 associates with neutrophilia and reduced bacterial killing in early cystic fibrosis airway disease.

BACKGROUND: Macrophages are the major resident immune cells in human airways coordinating responses to infection and injury. In cystic fibrosis (CF), neutrophils are recruited to the airways shortly after birth, and actively exocytose damaging enzymes prior to chronic infection, suggesting a potential defect in macrophage immunomodulatory function. Signaling through the exhaustion marker programmed death protein 1 (PD-1) controls macrophage function in cancer, sepsis, and airway infection. Therefore, we sought to identify potential associations between macrophage PD-1 and markers of airway disease in children with CF. METHODS: Blood and bronchoalveolar lavage fluid (BALF) were collected from 45 children with CF aged 3 to 62 months and structural lung damage was quantified by computed tomography. The phenotype of airway leukocytes was assessed by flow cytometry, while the release of enzymes and immunomodulatory mediators by molecular assays. RESULTS: Airway macrophage PD-1 expression correlated positively with structural lung damage, neutrophilic inflammation, and infection. Interestingly, even in the absence of detectable infection, macrophage PD-1 expression was elevated and correlated with neutrophilic inflammation. In an in vitro model mimicking leukocyte recruitment into CF airways, soluble mediators derived from recruited neutrophils directly induced PD-1 expression on recruited monocytes/macrophages, suggesting a causal link between neutrophilic inflammation and macrophage PD-1 expression in CF. Finally, blockade of PD-1 in a short-term culture of CF BALF leukocytes resulted in improved pathogen clearance. CONCLUSION: Taken together, these findings suggest that in early CF lung disease, PD-1 upregulation associates with airway macrophage exhaustion, neutrophil takeover, infection, and structural damage.

Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis.

RATIONALE: Neutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In adolescents and adults with CF, airway neutrophils actively exocytose the primary granule protease elastase (NE), whose extracellular activity correlates with lung damage. During childhood, free extracellular NE activity is measurable only in a subset of patients, and the exocytic function of airway neutrophils is unknown. OBJECTIVES: To measure NE exocytosis by airway neutrophils in relation to free extracellular NE activity and lung damage in children with CF. METHODS: We measured lung damage using chest computed tomography coupled with the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis scoring system. Concomitantly, we phenotyped blood and BAL fluid leukocytes by flow and image cytometry, and measured free extracellular NE activity using spectrophotometric and Förster resonance energy transfer assays. Children with airway inflammation linked to aerodigestive disorder were enrolled as control subjects. MEASUREMENTS AND MAIN RESULTS: Children with CF but not disease control children harbored BAL fluid neutrophils with high exocytosis of primary granules, before the detection of bronchiectasis. This measure of NE exocytosis correlated with lung damage (R = 0.55; P = 0.0008), whereas the molecular measure of free extracellular NE activity did not. This discrepancy may be caused by the inhibition of extracellular NE by BAL fluid antiproteases and its binding to leukocytes. CONCLUSIONS: NE exocytosis by airway neutrophils occurs in all children with CF, and its cellular measure correlates with early lung damage. These findings implicate live airway neutrophils in early CF pathogenesis, which should instruct biomarker development and antiinflammatory therapy in children with CF.

Interleukin-1 is associated with inflammation and structural lung disease in young children with cystic fibrosis.

BACKGROUND: Little is known about the role of interleukin (IL)-1 in the pathogenesis of cystic fibrosis (CF) lung disease. This study investigated the relationship between IL-1 signalling, neutrophilic inflammation and structural lung changes in children with CF. METHODS: Bronchoalveolar lavage fluid (BALf) from 102 children with CF were used to determine IL-1α, IL-1ß, IL-8 levels and neutrophil elastase (NE) activity, which were then correlated to structural lung changes observed on chest computed tomography (CT) scans. RESULTS: IL-1α and IL-1ß were detectable in BAL in absence of infection, increased in the presence of bacterial infection and correlated with IL-8 (p < 0.0001), neutrophils (p < 0.0001) and NE activity (p < 0.01 and p < 0.001). IL-1α had the strongest association with structural lung disease (p < 0.01) in the absence of infection (uninfected: p < 0.01 vs. infected: p = 0.122). CONCLUSION: Our data associates IL-1α with early structural lung damage in CF and suggests this pathway as a novel anti-inflammatory target.

Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis.

Neutrophil elastase (NE) is a key risk factor for severity of cystic fibrosis (CF) lung disease. Recent studies identified increased NE activity on the surface of airway neutrophils from CF-like mice and patients with CF. However, the role of surface-bound NE in CF lung disease remains unknown. We determined the relationship between surface-bound NE activity and severity of lung disease in CF.Surface-bound NE activity was measured on sputum neutrophils from 35 CF patients and eight healthy controls using novel lipidated Förster resonance energy transfer reporters and correlated with free NE activity, neutrophil counts, interleukin-8, myeloperoxidase and antiproteases in sputum supernatant, and with lung function parameters.Surface-bound NE activity was increased in CF compared to healthy controls (p<0.01) and correlated with free NE activity (p<0.05) and other inflammation markers (p<0.001). Surface-bound and free NE activity correlated with forced expiratory volume in 1 s % predicted (p<0.01 and p<0.05), but only surface-bound NE activity correlated with plethysmographic functional residual capacity % pred (p<0.01) in patients with CF.We demonstrate that surface-bound NE activity on airway neutrophils correlates with severity of lung disease in patients with CF. Our results suggest that surface-bound NE activity may play an important role in the pathogenesis and serve as novel biomarker in CF lung disease.

One time quantitative PCR detection of Pseudomonas aeruginosa to discriminate intermittent from chronic infection in cystic fibrosis.

BACKGROUND: Chronic airway infection with Pseudomonas aeruginosa is a major risk factor of progression of lung disease in patients with cystic fibrosis (CF). Chronic P. aeruginosa infection evolves from intermittent infection that is amenable to antibiotic eradication, whereas chronically adapted P. aeruginosa becomes resistant to antibiotic therapy. Discrimination of intermittent versus chronic infection is therefore of high therapeutic relevance, yet the available diagnostic methods are only partly satisfactory. The aim of the present study was, therefore, to evaluate the usage of quantitative PCR (qPCR) to measure pathogen abundance and to discriminate between intermittent and chronic Pseudomonas infection in patients with CF. METHOD: Using an established qPCR protocol, we analyzed the abundance of P. aeruginosa in 141 throats swabs and 238 sputa from CF patients with intermittent or chronic infection with P. aeruginosa, as determined by standard culture based diagnostics. RESULTS: We observed a large increase of abundance of P. aeruginosa in throat swabs and sputum samples from patients with chronic compared to intermittent infections with P. aeruginosa. The data show that abundance of P. aeruginosa as measured by qPCR is a valuable tool to discriminate intermittent from chronic infection. Of note, P. aeruginosa burden seems more sensitive than mucoidity phenotype to discriminate chronic from intermittent strains. Furthermore we observed that molecular detection in throat swabs was linked to a viable culture in the sputum when sputum was available. This result is of special interest in young patients with cystic fibrosis that often cannot expectorate sputum. We also observed that qPCR in comparison to culture detected the infection earlier. CONCLUSION: The results suggest that qPCR detection and quantification of P. aeruginosa is a precious tool to be added to the diagnostic toolbox in cystic fibrosis.

Modeling 18F-FDG kinetics during acute lung injury: experimental data and estimation errors.

BACKGROUND: There is increasing interest in Positron Emission Tomography (PET) of 2-deoxy-2-[18F]flouro-D-glucose ((18)F-FDG) to evaluate pulmonary inflammation during acute lung injury (ALI). We assessed the effect of extra-vascular lung water on estimates of (18)F-FDG-kinetics parameters in experimental and simulated data using the Patlak and Sokoloff methods, and our recently proposed four-compartment model. METHODOLOGY/PRINCIPAL FINDINGS: Eleven sheep underwent unilateral lung lavage and 4 h mechanical ventilation. Five sheep received intravenous endotoxin (10 ng/kg/min). Dynamic (18)F-FDG PET was performed at the end of the 4 h period. (18)F-FDG net uptake rate (Ki), phosphorylation rate (k(3)), and volume of distribution (F(e)) were estimated in three isogravitational regions for each method. Simulations of normal and ALI (18)F-FDG-kinetics were conducted to study the dependence of estimated parameters on the transport rate constants to (k(5)) and from (k(6)) the extra-vascular extra-cellular compartment. The four-compartment model described 85.7% of the studied (18)F-FDG-kinetics better than the Sokoloff model. Relative to the four-compartment model the Sokoloff model exhibited a consistent positive bias in Ki (3.32 [1.30-5.65] 10(-4)/min, p<0.001) and showed inaccurate estimates of the parameters composing Ki (k(3) and F(e)), even when Ki was similar for those methods. In simulations, errors in estimates of Ki due to the extra-vascular extra-cellular compartment depended on both k(5) and k(5)/k(6), with errors for the Patlak and Sokoloff methods of 0.02 [-0.01-0.18] and 0.40 [0.18-0.60] 10(-3)/min for normal lungs and of -0.47 [-0.89-0.72] and 2.35 [0.85-3.68] 10(-3)/min in ALI. CONCLUSIONS/SIGNIFICANCE: (18)F-FDG accumulation in lung extra-vascular fluid, which is commonly increased during lung injury, can result in substantial estimation errors using the traditional Patlak and Sokoloff methods. These errors depend on the extra-vascular extra-cellular compartment volume and its transport rates with other compartments. The four-compartment model provides more accurate quantification of (18)F-FDG-kinetics than those methods in the presence of increased extra-vascular fluid.