CF Lung Disease Research Articles

Exercise performance and quality of life in children with cystic fibrosis and mildly impaired lung function: relation with antibiotic treatments and hospitalization.

Patients with mild CF lung disease have good exercise performance although still lower than the normal population. VO2max% is affected by number of antibiotic treatments over a longer period. There is an impact of hospitalization days on quality of life. What is Known: • Children with CF have lower exercise performance; there is an association between hospitalization frequency and exercise performance • Quality of life is diminished in children with CF and influenced by respiratory infections What is New: • Even patients with mild CF lung disease have lower maximal exercise performance (VO 2 max) and a lower anaerobic threshold; VO 2 max is lower in children who had more antibiotic treatments in the last 3 years • School and emotional functioning are diminished in children with mild CF lung disease; hospitalization is negatively correlated with school functioning and physical functioning.

Early follow-up of lung disease in infants with cystic fibrosis using the raised volume rapid thoracic compression technique and computed tomography during quiet breathing.

Among the different techniques used to monitor lung disease progression in infants with CF diagnosed by Newborn screening (NBS), raised volume-rapid thoracic compression (RVRTC) remains a promising tool. However, the need of sedation and positive pressure ventilation considerably limits its clinical use. We recently described a semi-quantitative method to evaluate air trapping by chest tomography during quite breathing without sedation (CTqb score). This parameter is the radiological sign of airway obstruction and could be also used for lung disease follow-up in infants with CF. However, its discriminative power compared with RVRTC and correlation with lung function parameters are not known. To compare the discriminative powers of the CTqb score and RVRTC parameters and to determine their correlation during the first year of life of infants with CF. In this multicenter longitudinal study, infants with CF diagnosed by NBS underwent RVRTC and CT during quite breathing at 10 ± 4 weeks (n = 30) and then at 13 ± 1 months of age (n = 28). All RVRTC parameters and the CTqb score remained stable between evaluations. The CTqb score showed a higher discriminative power than forced expiratory volume in 0.5 s (FEV0.5 ; the main RVRTC parameter) at both visits (66% and 50% of abnormal values vs 30% and 28%, respectively). No correlation was found between CTqb score and, the different RVRTC parameters or the plethysmographic functional residual capacity, indicating that they evaluate different aspect of CF lung disease.

Invasive Pulmonary Fungal Infections in Cystic Fibrosis.

Invasive pulmonary mycosis is after allergic bronchopulmonary aspergillosis (ABPA) a frequent and severe complication of CF lung disease. Among CF caregivers, there is an insecurity when and how to treat infections of the lung parenchyma caused by different fungi in patients with CF. This case series provides a multicenter experience on diagnostic, manifestation, and treatment of non-ABPA cases of pulmonary. Non-ABPA cases of pulmonary mycoses in patients with CF have been collected from the CF Centers in Berlin, Essen, Worms, Frankfurt (Germany), Leeds (UK), and Barcelona (Spain). Non-ABPA was defined as total serum IgE level <500kU/L. Scedosporium and Lomentospora species seem to be more virulent in patients with CF and have been successfully treated with triple antifungal drug regimens in several cases. Rare fungi including yeasts can have pathogenic potential in CF. In this series, antibiotic treatment failure was the main indicator for the initiation of antifungal treatment. For an early and effective treatment of pulmonary mycoses in CF, the identification of biomarkers and of risk factors beyond antibiotic treatment failure is crucial and urgently needed. Furthermore, treatment efficacy studies are necessary for the different causative agents of these infections.

Pediatric lung transplantation and end of life care in cystic fibrosis: Barriers and successful strategies.

Pediatric lung transplantation has advanced over the years, providing a potential life-prolonging therapy to patients with cystic fibrosis. Despite this, many challenges in lung transplantation remain and result in worse outcomes than other solid organ transplants. As CF lung disease progresses, children and their caregivers are often simultaneously preparing for lung transplantation and end of life. In this article, we will discuss the current barriers to success in pediatric CF lung transplantation as well as approaches to end of life care in this population.

WS08.2 Exploring the potential impact of gastro-oesophageal reflux on CF lung disease

WS08.2 Exploring the potential impact of gastro-oesophageal reflux on CF lung disease

WS03.5 Invasive sampling that bypasses the oropharynx provides insights into the lung microbiota of children with CF and mild lung disease

WS03.5 Invasive sampling that bypasses the oropharynx provides insights into the lung microbiota of children with CF and mild lung disease

71 Exocytosis of elastase-rich granules by live airway neutrophils correlates with PRAGMA CF score in early CF lung disease

71 Exocytosis of elastase-rich granules by live airway neutrophils correlates with PRAGMA CF score in early CF lung disease

EPS4.3 Differential sensitivity of outcome measures that assess progression of mild CF lung disease in school age children

EPS4.3 Differential sensitivity of outcome measures that assess progression of mild CF lung disease in school age children

Monocyte derived macrophages from CF pigs exhibit increased inflammatory responses at birth

BackgroundWe sought to address whether CF macrophages have a primary functional defect as a consequence of CFTR loss and thus contribute to the onset of infection and inflammation observed in CF lung disease. MethodsMonocyte derived macrophages (MDMs) were prepared from newborn CF and non-CF pigs. CFTR mRNA expression was quantified by rtPCR and anion channel function was determined using whole cell patch clamp analysis. IL8 and TNFα release from MDMs in response to lipopolysaccharide stimulation was measured by ELISA. ResultsCFTR was expressed in MDMs by Q-rtPCR at a lower level than in epithelial cells. MDMs exhibited functional CFTR current at the cell membrane and this current was absent in CF MDMs. CF MDMs demonstrated an exaggerated response to lipopolysaccharide stimulation. ConclusionsIn the absence of CFTR function, macrophages from newborn CF pigs exhibit an increased inflammatory response to a lipopolysaccharide challenge. This may contribute to the onset and progression of CF lung disease.

Chest imaging in CF studies - Commentary

Chest imaging in CF studies - Commentary

Aspergillosis and the role of mucins in cystic fibrosis.

SummaryThe prevalence of aspergillosis in CF patients has until recently been underestimated, but increasing evidence suggests that it may play an important role in the progression of CF lung disease. In healthy airways, Aspergillus fumigatus can be efficiently removed from the lung by mechanisms such as mucociliary clearance and cough. However, these mechanisms are defective in CF, allowing pathogens such as A. fumigatus to germinate and establish chronic infections within the airways. The precise means by which A. fumigatus contributes to CF lung disease remain largely unclear. As the first point of contact within the lung, and an important component of the innate immune system, it is likely that the mucus barrier plays an important role in this process. Study of the functional interplay between this vital protective barrier, and in particular its principal structural components, the polymeric gel‐forming mucins, and CF pathogens such as A. fumigatus, is at an early stage. A. fumigatus protease activity has been shown to upregulate mucus production by inducing mucin mRNA and protein expression, and A. fumigatus proteases and glycosidases are able to degrade mucins. This may allow A. fumigatus to alter mucus barrier properties to promote fungal colonization of the airways and/or utilize mucins as a nutrient source. Moreover, conidial surface lectin binding to mucin glycans is a key aspect of clearance of Aspergillus from the lung in health but may be an important aspect of colonization, where mucociliary clearance is compromised, as in the CF lung. Here we discuss the nature of the mucus barrier and its mucin components in CF, and how they may be implicated in A. fumigatus infection. Pediatr Pulmonol 2017;52:548–555. © 2016 The Authors. Pediatric Pulmonology. Published by Wiley Periodicals, Inc.

Dysregulated Chemokine Signaling in Cystic Fibrosis Lung Disease: A Potential Therapeutic Target.

CF lung disease is characterized by a chronic and non-resolving activation of the innate immune system with excessive release of chemokines/cytokines including IL-8 and persistent infiltration of immune cells, mainly neutrophils, into the airways. Chronic infection and impaired immune response eventually lead to pulmonary damage characterized by bronchiectasis, emphysema, and lung fibrosis. As a complete knowledge of the pathways responsible for the exaggerated inflammatory response in CF lung disease is lacking, understanding these pathways could reveal new therapeutic targets, and lead to novel treatments. Therefore, there is a strong rationale for the identification of mechanisms and pathways underlying the exaggerated inflammatory response in CF lung disease. This article reviews the role of inflammation in the pathogenesis of CF lung disease, with a focus on the dysregulated signaling involved in the overexpression of chemokine IL-8 and excessive recruitment of neutrophils in CF airways. The findings suggest that targeting the exaggerated IL-8/IL-8 receptor (mainly CXCR2) signaling pathway in immune cells (especially neutrophils) may represent a potential therapeutic strategy for CF lung disease.

Hyperpolarized 129Xe for investigation of mild cystic fibrosis lung disease in pediatric patients

BackgroundCystic fibrosis (CF) is a genetic disease which carries high morbidity and mortality from lung-function decline. Monitoring disease progression and treatment response in young patients is desirable, but serial imaging via CT is often considered prohibitive, and detailed functional information cannot be obtained using conventional imaging techniques. Hyperpolarized 129Xe magnetic resonance imaging (MRI) can depict and quantify regional ventilation, but has not been investigated in pediatrics. We hypothesized that 129Xe MRI is feasible and would demonstrate ventilation defects in mild CF lung disease with greater sensitivity than FEV1. Methods11 healthy controls (age 6–16years) and 11 patients with mild CF (age 8–16years, Forced Expiratory Volume (FEV1) percent predicted >70%) were recruited for this study. Nine CF patients had an FEV1>85%. Each subject was imaged via hyperpolarized 129Xe MRI, and the ventilation defect percentage (VDP) was measured. FEV1 and VDP were compared between the groups. ResultsFEV1 for controls was 100.3%±8.5% (mean±sd) and for CF patients was 97.9%±16.0% (p=0.67). VDP was 6.4%±2.8% for controls and 18.3%±8.6% for CF (p<0.001). When considering the 9 CF patients with normal FEV1 (>85%), the mean FEV1 was 103.1%±12.3% (p=0.57 compared to controls) and VDP was 15.4%±6.3% (p=0.002). ConclusionsHyperpolarized 129Xe MRI demonstrated ventilation defects in CF patients with normal FEV1 and more effectively discriminated CF from controls than FEV1. Thus 129Xe may be a useful outcome measure to detect mild CF lung disease, to investigate regional lung function in pediatric lung diseases, and to follow disease progression.

WS15.4 Variation of lung clearance index (LCI) over 12 months in school-children with clinically stable CF lung disease

WS15.4 Variation of lung clearance index (LCI) over 12 months in school-children with clinically stable CF lung disease

Transmission of Bacteria during Cystic Fibrosis Educational Programs

CF is a progressive, lethal disease characterized by mucous build-up in the airways and a continuous annual deterioration of lung function. The host inflammatory response is considered a central pathological feature and constitutes an important target for non-steroidal anti-inflammatory drug therapy. Airway obstruction and bacterial colonization may cause inflammation, or it may be attributable to dysfunction of the cystic fibrosis transmembrane conductance regulator. Educational programs for this group of patients increase the compliance and quality-of-life, but cystic fibrosis patients have been recommended to abstain from attendance for concerns of microbial cross infection. When guidelines for optimal hand and respiratory hygiene and cough etiquette are observed in professionally supervised CF educational programs, an increased risk of bacterial transmission has not been documented. A recommendation to avoid indoor educational events with fellow CF patients must be weighed against the benefits of educational and rehabilitation programs. Further investigations are required to clarify the relative contribution of microbiological and genetic factors to the progression of CF lung disease.

Preliminary comparison of normalized T1 and non-contrast perfusion MRI assessments of regional lung disease in cystic fibrosis patients

BackgroundPrevious studies have shown that Magnetic Resonance Imaging (MRI) techniques can be used to non-invasively assess lung disease in CF patients. In this study, we compare the sensitivity of normalized T1 (nT1) and non-contrast perfusion MRI techniques to detect regional lung disease in CF patients. Materials and methodsMRI data were obtained for eight adult CF patients without overt pulmonary exacerbation (FEV1=45–127%) and six healthy volunteers on a Siemens Espree 1.5T MRI scanner. Sagittal nT1 and perfusion data were acquired for each subject's left and right lungs. A region-of-interest analysis was used to calculate mean nT1 and perfusion values in the individual lobes of the left and right lungs for each subject. ResultsIn comparison to healthy controls, CF subjects showed a significant decrease in nT1 values in the upper lobe of the left lung as well as in the upper and anterior lobes of the right lung (p<0.001). Similar nT1 differences were observed with in the CF cohort in comparison to their respective posterior lobes (p<0.001). Pulmonary perfusion for the CF subjects was also significantly reduced in the upper lobe of the right lung (p<0.05). Significant correlations with spirometry were also observed for both nT1 (left upper lobe: p<0.01) and perfusion (left and right upper lobes (p≤0.05)). Additionally, significant correlations were observed between nT1 and perfusion in the upper lobes of the left (p=0.05) and right lungs (p=0.005). Conclusions: This pilot study confirms that both the nT1 and non-contrast perfusion MRI techniques can sensitively detect regional lung changes in patients with CF. While both imaging methods were able to detect regional lung disease, the additional nT1 reductions in the CF patients suggests that nT1 may be more sensitive to regional CF lung disease.

IFRD1 gene polymorphisms are associated with nasal polyposis in cystic fibrosis patients

Nasal polyposis (NP) is an inflammatory disease of the upper nasal airways frequently present in CF patients. Interferon-Related Developmental Regulator 1 (IFRD1) gene was reported as a possible modifier of CF lung disease severity. Three IFRD1 SNPs were analyzed to investigate a possible effect on the development of NP in CF patients. The DNA of 143 patients with CF (40 with and 103 without NP) was purified from peripheral blood samples. IFRD1 SNPs (rs7817, rs3807213, rs6968084) were genotyped by restriction enzyme analysis. The T allele of the common polymorphisms rs7817 and the rs7817-rs3807213 haplotype were associated with NP (p = 0.002 and 0.004, respectively). These results showed the association of the IFRD1-rs7817 polymorphism with NP in CF patients.

IFRD1 gene polymorphisms are associated with nasal polyposis in cystic fibrosis patients.

Nasal polyposis (NP) is an inflammatory disease of the upper nasal airways frequently present in CF patients. Interferon-Related Developmental Regulator 1 (IFRD1) gene was reported as a possible modifier of CF lung disease severity. Three IFRD1 SNPs were analyzed to investigate a possible effect on the development of NP in CF patients. The DNA of 143 patients with CF (40 with and 103 without NP) was purified from peripheral blood samples. IFRD1 SNPs (rs7817, rs3807213, rs6968084) were genotyped by restriction enzyme analysis. The T allele of the common polymorphisms rs7817 and the rs7817-rs3807213 haplotype were associated with NP (p = 0.002 and 0.004, respectively). These results showed the association of the IFRD1-rs7817 polymorphism with NP in CF patients.

Tobramycin-Treated Pseudomonas aeruginosa PA14 Enhances Streptococcus constellatus 7155 Biofilm Formation in a Cystic Fibrosis Model System.

Cystic fibrosis (CF) is a human genetic disorder which results in a lung environment that is highly conducive to chronic microbial infection. Over the past decade, deep-sequencing studies have demonstrated that the CF lung can harbor a highly diverse polymicrobial community. We expanded our existing in vitro model of Pseudomonas aeruginosa biofilm formation on CF-derived airway cells to include this broader set of CF airway colonizers to investigate their contributions to CF lung disease, particularly as they relate to the antibiotic response of the population. Using this system, we identified an interspecies interaction between P. aeruginosa, a bacterium associated with declining lung function and worsening disease, and Streptococcus constellatus, a bacterium correlated with the onset of pulmonary exacerbations in CF patients. The growth rate and cytotoxicity of S. constellatus 7155 and P. aeruginosa PA14 were unchanged when grown together as mixed biofilms in the absence of antibiotics. However, the addition of tobramycin, the frontline maintenance therapy antibiotic for individuals with CF, to a mixed biofilm of S. constellatus 7155 and P. aeruginosa PA14 resulted in enhanced S. constellatus biofilm formation. Through a candidate genetic approach, we showed that P. aeruginosa rhamnolipids were reduced upon tobramycin exposure, allowing for S. constellatus 7155 biofilm enhancement, and monorhamnolipids were sufficient to reduce S. constellatus 7155 biofilm viability in the absence of tobramycin. While the findings presented here are specific to a biofilm of S. constellatus 7155 and P. aeruginosa PA14, they highlight the potential of polymicrobial interactions to impact antibiotic tolerance in unanticipated ways. Deep-sequencing studies have demonstrated that the CF lung can harbor a diverse polymicrobial community. By recapitulating the polymicrobial communities observed in the CF lung and identifying mechanisms of interspecies interactions, we have the potential to select the best therapy for a given bacterial community and reveal potential opportunities for novel therapeutic interventions. Using an in vitro model of bacterial infection on CF airway cells, we tested how a particular polymicrobial community grows, damages human cells, and responds to antibiotics in single and mixed infections. We describe here the mechanism of an interspecies interaction between two pathogens in the CF lung, P. aeruginosa and S. constellatus, which is potentiated by a commonly prescribed antibiotic, tobramycin.

Long-term improvement of lung clearance index in patients with mild cystic fibrosis lung disease: Does hypertonic saline play a role?

To assess whether long-term inhalation with hypertonic saline is able to halt the progression of mild CF lung disease, we analysed longitudinal data of lung clearance index (LCI) and spirometry. A total of 34 patients with mild lung disease (FEV1≥70% of predicted) had at least one LCI result before and ≥2 LCI measurements after start of hypertonic saline (HS) therapy. After a mean follow-up of 39.7 (SD 7.4) months after starting HS, LCI improved significantly from 7.89 (SD 1.35) at baseline to 6.96 (SD 1.03), and 19/34 patients had a normal LCI value at the last measurement. No decrease in mean FEV1 was observed. Thus, ventilation inhomogeneity can improve in patients with mild lung disease.