Cystic Fibrosis Bronchiectasis Research Articles

Increased Airway Smooth Muscle Mass in Children with Asthma, Cystic Fibrosis, and Non-Cystic Fibrosis Bronchiectasis

Structural alterations to airway smooth muscle (ASM) are a feature of asthma and cystic fibrosis (CF) in adults. We investigated whether increase in ASM mass is already present in children with chronic inflammatory lung disease. Fiberoptic bronchoscopy was performed in 78 children (median age [IQR], 11.3 [8.5-13.8] yr): 24 with asthma, 27 with CF, 16 with non-CF bronchiectasis (BX), and 11 control children without lower respiratory tract disease. Endobronchial biopsy ASM content and myocyte number and size were quantified using stereology. The median (IQR) volume fraction of subepithelial tissue occupied by ASM was increased in the children with asthma (0.27 [0.12-0.49]; P < 0.0001), CF (0.12 [0.06-0.21]; P < 0.01), and BX (0.16 [0.04-0.21]; P < 0.01) compared with control subjects (0.04 [0.02-0.05]). ASM content was related to bronchodilator responsiveness in the asthmatic group (r = 0.66, P < 0.01). Median (IQR) myocyte number (cells per mm(2) of reticular basement membrane) was 8,204 (5,270-11,749; P < 0.05) in children with asthma, 4,504 (2,838-8,962; not significant) in children with CF, 4,971 (3,476-10,057; not significant) in children with BX, and 1,944 (1,596-6,318) in control subjects. Mean (SD) myocyte size (mum(3)) was 3,344 (801; P < 0.01) in children with asthma, 3,264 (809; P < 0.01) in children with CF, 3,177 (873; P < 0.05) in children with BX, and 1,927 (386) in control subjects. In all disease groups, the volume fraction of ASM in subepithelial tissue was related to myocyte number (asthma: r = 0.84, P < 0.001; CF: r = 0.81, P < 0.01; BX: r = 0.95, P < 0.001), but not to myocyte size. Increases in ASM (both number and size) occur in children with chronic inflammatory lung diseases that include CF, asthma, and BX.

Genetic mechanisms involved in the repression of flagellar assembly by Pseudomonas aeruginosa in human mucus

Pseudomonas aeruginosa downregulates flagellin transcription when it is grown in purulent mucus from patients with cystic fibrosis (CF) and non-CF bronchiectasis. This response possibly abrogates the potent inflammatory response mediated by the interaction of flagellin with Toll-like receptor 5. The molecular mechanisms involved are thus far unknown. Known flagellar transcriptional regulators were not involved, thus Tn5 mutagenesis was used to ascertain whether novel regulators existed. Five clones with independent Tn5 insertions in flgM showed derepression of flagellin synthesis, suggesting that FlgM was involved in this phenomenon. Furthermore, examination of mucus-grown bacteria showed FlgM accumulation and overexpression of fliA in mucus-grown bacteria reversed the repression of flagellin synthesis. A related study from our laboratory had identified neutrophil elastase in mucus as the molecule responsible for fliC repression, therefore we examined whether loss of the flagellar hook (FlgE), by proteolysis was involved, because the flagellar hook is required for FlgM export. Western immunoblot of membranes from mucus-grown bacteria showed the absence of FlgE, despite the fact that the protein is made and the operon encoding FlgE is upregulated in mucus. A model is proposed wherein neutrophil elastase in mucus proteolytically cleaves the flagellar hook, thus completion of the hook basal body is never sensed, resulting in FlgM accumulation within the cell, causing repression of flagellin synthesis. We speculate that the cyclical bouts of inflammation observed in CF patients may result from flagellin synthesis and its repression, caused by presence of neutrophils at the site of infection.

Bronchiectasis

Bronchiectasis is generally classified into cystic fibrosis and non-cystic fibrosis bronchiectasis. This review article describes non-cystic fibrosis bronchiectasis in adults. Bronchiectasis can be considered a heterogeneous condition characterized by irreversible airway dilatation with chronic bronchial infection/inflammation. It remains a common condition and is a major cause of respiratory morbidity. Many factors are associated with bronchiectasis, but most commonly patients will have idiopathic disease. Important clinical findings include chronic productive cough, rhinosinusitis, fatigue and bi-basal crackles. Patients have usually had symptoms for many years. Diagnosis is confirmed by high-resolution computed tomography scanning using standardized criteria. Spirometry shows moderate airflow obstruction and there is a high prevalence of bronchial hyperreactivity. The most common pathogens are non-typeable Haemophilus influenzae and Pseudomonas aeruginosa. There may be considerable overlap with other chronic airway diseases. Treatment regimens are still not well defined. Patients tend to have ongoing symptoms and decline in respiratory function despite treatment.

Pseudomonas aeruginosa pyocyanin inactivates lung epithelial vaculoar ATPase-dependent cystic fibrosis transmembrane conductance regulator expression and localization

Pseudomonas aeruginosa (PA) is a major pathogen causing morbidity and ultimately mortality in patients afflicted with cystic fibrosis (CF) lung disease. One important virulence factor, pyocyanin (PCN), is a blue, redox-active compound that is secreted in such copious amounts by PA in the CF lungs that it determines the colour of expectorated sputum. In this study, we discovered that physiological concentrations of PCN inactivate the airway epithelial vacuolar ATPase, resulting in reduced expression and trafficking of the cystic fibrosis transmembrane conductance regulator in cultured lung and primary nasal epithelial cells. Our study supports the notion that PCN contributes significantly to the pathogenesis of CF and other bronchiectasis patients infected by PA.

Nebulised gentamicin—suitable for childhood bronchiectasis

Nebulised antibiotic therapy is an established, safe and effective therapy for cystic fibrosis with chronic pseudomonas infection resulting in improved pulmonary function and reduced hospitalisation. Despite similar respiratory disease, this therapy has not been evaluated in children with non cystic fibrosis bronchiectasis. This study evaluates the suitability of a gentamicin solution and nebuliser combination for use in this population. Materials and methods: Four millilitres of gentamicin (80 mg) in saline delivered by a PARI LC plus ® nebuliser and PARI Turboboy N ® compressor was used. The pH, osmolarity, chloride concentration and aerosol particle size was determined. Ten children with non cystic fibrosis bronchiectasis received nebulised antibiotic and had peak gentamicin concentrations measured in sputum and serum. Pulmonary function was measured pre and post nebulisation. Results: The solution had an osmolarity of 199 mOsm/l, pH of 4.1, chloride concentration of 75 mmol/l and the aerosol a mass median aerodynamic diameter of 3.3 μm. Nebulisation was well tolerated, with no significant change in FEV1. Peak serum levels were at the threshold of detectability (0.3 mg/l). Sputum concentrations had a mean of 624 mg/g and lower 95th confidence interval 25 times the minimum inhibitory concentration for the predominant infecting organism, Haemophilus influenzae. Conclusion: Nebulisation of 80 mg of gentamicin in saline achieved bactericidal concentrations in sputum, was well tolerated and had negligible systemic absorption making it a suitable choice for this population.

HRCT lung abnormalities are not a surrogate for exercise limitation in bronchiectasis.

In paediatric bronchiectasis, there has been limited work on the relationship between disease severity as assessed by exercise limitation and high resolution computed tomography (HRCT). An observational study was performed on 36 children who completed a questionnaire, physical examination, spirometry and sputum analysis, followed by a low dose of radiation protocol chest computed tomography (CT) scan and cycle ergometry incremental exercise test. A modified Bhalla score was used to score the HRCT abnormalities. The exercise variables used to assess functional status were heart rate, oxygen consumption, oxygen saturations and time of exercise. The results were compared with established normal paediatric values. The median (range) age of the children was 13 yrs (10.6-17.1). Age, sex, height, weight or pubertal status were equally distributed between the children with cystic fibrosis (CF) or non-CF bronchiectasis. The children with non-CF bronchiectasis had a lower median forced expiratory volume in one second % predicted than the children with CF (69% versus 76%, respectively). The distribution of lung disease differed between the two groups. The children with CF bronchiectasis had predominantly right upper lobe disease, and scored higher for the presence and extent of bronchiectasis. Otherwise, there was no statistical difference in the overall CT score or the individual CT parameters between the groups. There was evidence of exercise limitation in both CF and non-CF bronchiectasis compared to normal children. No consistent relationships were identified between the lung function parameters, HRCT findings or exercise parameters in either disease group. In this study, high resolution computed tomography features were not found to be markers of exercise capacity. As spirometry, high resolution computed tomography features and exercise testing give different information in children with cystic fibrosis and non-cystic fibrosis bronchiectasis, the current authors suggest all three may be required for the comprehensive assessment of respiratory status.

Retrospective review of children presenting with non cystic fibrosis bronchiectasis: HRCT features and clinical relationships

Non cystic fibrosis (CF) bronchiectasis in children presents with a spectrum of disease severity. Our aims were to document the extent and severity of disease in children with non-CF bronchiectasis, to review the inter- and intraobserver agreement for the high-resolution computed tomography (HRCT) features examined, and to assess correlations between HRCT features and clinical measures of severity. We performed a retrospective review of 56 children from the Starship Children's Hospital. HRCT scans were scored by a modified Bhalla system, and the chest X-rays using the Brasfield score. Scores were correlated with demographics, number of hospitalizations, disease duration, pulmonary function, clinical examination, and chronic sputum infection. The bronchiectasis seen was widespread and severe, particularly in Maori and Pacific Island children. The kappa coefficient for intraobserver agreement was better than that for interobserver agreement. Comparisons between HRCT scan and lung function parameters showed that the strongest relationships were between forced expiratory volume in 1 sec (FEV(1)) and forced expiratory flow between 25-75% of forced vital capacity (FEF(25-75)) with the extent of bronchiectasis, bronchial wall thickening, and air trapping. Children with digital clubbing and chest deformity showed significantly higher scores for extent of bronchiectasis, bronchial wall dilatation and thickness, and overall computed tomography (CT) score. No relationship was demonstrated between chronic sputum infection and CT score. The HRCT score demonstrated a stronger correlation between the extent and severity of bronchiectasis, and spirometry values, than the chest X-ray score. In conclusion, pediatric non-CF bronchiectasis in Auckland is extensive and severe. The good intraobserver ratings mean that consistency of scoring is possible on repeated scans. This study cannot comment on the relationships of CT and less severe disease.

Overview of Cystic Fibrosis and Non-CF Bronchiectasis

Overview of Cystic Fibrosis and Non-CF Bronchiectasis

Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis.

Cystic fibrosis is characterized by an early and sustained influx of inflammatory cells into the airways and by release of proteases. Resolution of inflammation is normally associated with the orderly removal of dying apoptotic inflammatory cells through cell recognition receptors, such as the phosphatidylserine receptor, CD36, and alpha v integrins. Accordingly, removal of apoptotic inflammatory cells may be impaired in persistent inflammatory responses such as that seen in cystic fibrosis airways. Examination of sputa from cystic fibrosis and non-cystic fibrosis bronchiectasis patients demonstrated an abundance of apoptotic cells, in excess of that seen in patients with chronic bronchitis. In vitro, cystic fibrosis and bronchiectasis airway fluid directly inhibited apoptotic cell removal by alveolar macrophages in a neutrophil elastase-dependent manner, suggesting that elastase may impair apoptotic cell clearance in vivo. Flow cytometry demonstrated that neutrophil elastase cleaved the phosphatidylserine receptor, but not CD36 or CD32 (Fc gamma RII). Cleavage of the phosphatidylserine receptor by neutrophil elastase specifically disrupted phagocytosis of apoptotic cells, implying a potential mechanism for delayed apoptotic cell clearance in vivo. Therefore, defective airway clearance of apoptotic cells in cystic fibrosis and bronchiectasis may be due to elastase-mediated cleavage of phosphatidylserine receptor on phagocytes and may contribute to ongoing airway inflammation.

Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis

Cystic fibrosis is characterized by an early and sustained influx of inflammatory cells into the airways and by release of proteases. Resolution of inflammation is normally associated with the orderly removal of dying apoptotic inflammatory cells through cell recognition receptors, such as the phosphatidylserine receptor, CD36, and αv integrins. Accordingly, removal of apoptotic inflammatory cells may be impaired in persistent inflammatory responses such as that seen in cystic fibrosis airways. Examination of sputa from cystic fibrosis and non–cystic fibrosis bronchiectasis patients demonstrated an abundance of apoptotic cells, in excess of that seen in patients with chronic bronchitis. In vitro, cystic fibrosis and bronchiectasis airway fluid directly inhibited apoptotic cell removal by alveolar macrophages in a neutrophil elastase-dependent manner, suggesting that elastase may impair apoptotic cell clearance in vivo. Flow cytometry demonstrated that neutrophil elastase cleaved the phosphatidylserine receptor, but not CD36 or CD32 (FcγRII). Cleavage of the phosphatidylserine receptor by neutrophil elastase specifically disrupted phagocytosis of apoptotic cells, implying a potential mechanism for delayed apoptotic cell clearance in vivo. Therefore, defective airway clearance of apoptotic cells in cystic fibrosis and bronchiectasis may be due to elastase-mediated cleavage of phosphatidylserine receptor on phagocytes and may contribute to ongoing airway inflammation.

The Effect of Erythromycin on Mucociliary Transportability and Rheology of Cystic Fibrosis and Bronchiectasis Sputum

Background: Erythromycin has been shown to diminish sputum production in hypersecretory states by a mechanism that is still unclear. Objectives and Methods: We have investigated the effect of erythromycin on the ciliary transportability of cystic fibrosis and non-cystic fibrosis bronchiectasis sputum in vitro using the mucus-depleted bovine trachea. Results: Additional erythromycin in concentrations up to 20 µg/g did not significantly alter the ciliary transportability of sputum from 6 cystic fibrosis and 6 bronchiectasis patients. Sputum viscoelasticity measured with parallel-plate rheology was also little changed. These erythromycin concentrations also had little effect on the beating frequency of bovine tracheal cilia. Conclusions: These results suggest that the presence of erythromycin in sputum neither alters the physical properties of the gel nor the activity of cilia. The clinical effects of erythromycin on pulmonary hypersecretory states therefore have another explanation.

Treatment of Idiopathic Bronchiectasis With Aerosolized Recombinant Human DNase I

To study the safety and efficacy of aerosolized recombinant human DNase I in the treatment of idiopathic bronchiectasis. Double-blind, randomized, placebo-controlled, multicenter study. Three hundred forty-nine adult outpatients in stable condition with idiopathic bronchiectasis from 23 centers in North America, Great Britain, and Ireland. Study patients received aerosolized rhDNase or placebo twice daily for 24 weeks. Primary end points were incidence of pulmonary exacerbations and mean percent change in FEV1 from baseline over the treatment period. Pulmonary exacerbations were more frequent and FEV1 decline was greater in patients who received rhDNase compared with placebo during this 24-week trial. rhDNase was ineffective and potentially harmful in this group of adult outpatients in stable condition with idiopathic bronchiectasis. This contrasts with previously published results that demonstrated efficacy of rhDNase in patients with cystic fibrosis bronchiectasis.

Effects of characterised Pseudomonas aeruginosa exopolysaccharides on adherence to human tracheal cells.

This study evaluated, in vitro, the role of different Pseudomonas aeruginosa exopolysaccharides (EPS) in mediating adherence to human respiratory epithelial cells. Two mucoid and non-mucoid isogenic pairs of P aeruginosa strains isolated from patients with cystic fibrosis (CF) and bronchiectasis were used. Adherence was tested with human tracheal epithelial cell lines from CF and normal fetuses. The CF cells bound significantly more bacteria than the normal cells. The strain from the bronchiectasis patient was significantly more adherent than that from the CF patient and this difference was consistently most marked with the non-mucoid variant and with normal epithelial cells. The differing behaviour of mucoid CF and non-mucoid bronchiectasis strains reflected the chemical composition of their EPS: mainly alginate in the former and neutral polysaccharides in the latter. Additive inhibition experiments with chemically characterised EPS indicated that neutral polysaccharides associated with alginate may act as ligands for the adherence of P. aeruginosa to CF epithelial cells.

A comparison of spirometric variables in cystic fibrosis and bronchiectasis over 4 years

Bronchiectasis, which is a sequel to childhood infection, is characterized by lung function decline akin to that in the general population (1,2). Bronchiectasis in cystic fibrosis is a consequence of altered mucus rheology, which predisposes the airway to mucoid impaction and recurrent lower respiratory infection. The pathology in cystic fibrosis is widespread and constantly active compared to bronchiectasis. This can cause a faster decline of lung function in cystic fibrosis. The goal of this report was to compare lung function decline in cystic fibrosis and bronchiectasis.

Pulmonary Resection for Localized Bronchiectasis in Cystic Fibrosis

Three children with cystic fibrosis and localized bronchiectasis were treated by surgical removal of the affected lobe, after attempts to clear the obstructed bronchus by medical therapy and bronchoscopy with suction and lavage had been unsuccessful. Three to six years after surgery, the results are excellent. Pulmonary disease is mild in all patients, shown by chest radiographs and pulmonary function tests. A review of 102 cases reported in the literature demonstrates that pulmonary surgery is effective and can be performed safely in selected patients.

SELF-ADMINISTERED HOME INTRAVENOUS ANTIBIOTIC THERAPY IN BRONCHIECTASIS AND ADULT CYSTIC FIBROSIS

10 patients (mean age 23·1, range 17·1-40·5 years), 8 with cystic fibrosis (CF), and 2 with advanced bronchiectasis without CF, were taught, while being treated in hospital for exacerbations of pseudomonas infection, how to continue to give themselves intravenous antibiotics at home. They were discharged after satisfactory antibiotic levels had been achieved, and 22 courses were given at home over a total of 116 patient-days. In 14 of these, the greater part of the course was given at home (mean duration 6·6, range 5-10 days); 2 of these were given without admission to hospital. In the 8 patients with two or more infective exacerbations within a 12-month period there was no difference between home and hospital treatments in clinical improvement or in relapse time, defined as the interval between completion of treatment and subsequent antibiotic therapy. Self-administration of antibiotics intravenously at home for selected adults with cystic fibrosis and severe bronchiectasis reduces hospital stay and does not seem to be associated with an increased rate of recurrent infection.

MUCOID IMPACTION OF THE BRONCHI IN CYSTIC FIBROSIS

Mucoid impaction of the bronchi (MIB) is an unusual complication of adult asthma. In a review of 675 serial chest radiographs of 68 children and 2 adults with cystic fibrosis (CF), opacifications consistent with the diagnosis of MIB have been noted in 22 children and 1 adult, an overall incidence of 33%. The lesion of MIB in CF is a bronchusrelated complex of branched finger-like or nodular densities due to progressive distention of bronchi with tenacious mucopus. It is most commonly observed in the right upper lobe. Although it may spontaneously disappear, it tends to recur. Persistence of MIB for periods longer than 1 month can be related to subsequent bronchiectasis in the same segment. Clinical diagnosis is totally dependent on radiographic recognition, since symptoms and signs are characteristically lacking or non-specific. Atelectasis does not occur, probably because of collateral ventilation from adjacent uninvolved lung. Certain apparent differences have been noted between the adult (asthma) and childhood (CF) forms of MIB. Planigraphic and bronchographic studies in selected patients confirm the intrabronchial location of this process. Bronchial lavage is effective in washing out some impactions that have not responded to more conventional mucolytic and physical therapy. Recognition of MIB in a roentgenogram of a child should be considered presumptive evidence of CF, since similar opacifications are very rarely seen in children with other diseases. We believe that (1) progressive MIB at a subsegmental level is the major cause of bronchiectasis in CF and (2) secondary collateral ventilation may be the major cause of obstructive overinflation of the lungs in CF.