Upper and lower airway cultures in children with cystic fibrosis: Do not neglect the upper airways

AbstractBackgroundAirways of cystic fibrosis (CF) patients are colonised with bacteria early in life. We aimed to analyse differences between results of simultaneously taken upper airway (UAW) and lower airway (LAW) cultures, to describe clinical characteristics of patients with positive versus negative cultures and to follow up the patients with P. aeruginosa positive UAW cultures.MethodsBacteriological and clinical data from 157 children were collected during annual check up. The number of positive UAW and LAW cultures and correspondence between these results and clinical characteristics were analysed.ResultsPositive LAW and UAW cultures were found in 79.6% and 43.9% of patients respectively (p<0.001). Patients with positive LAW cultures were significantly older (11.9 vs. 9.8years, p<0.05) and had more LAW symptoms (73.6% vs. 46.7%, p<0.05), especially when P. aeruginosa was found. Patients with positive UAW cultures (especially S. aureus) had more nasal discharge (50.7% vs. 25.0%, p<0.001). In 65% of patients with positive UAW and negative LAW culture for P. aeruginosa the next LAW became P. aeruginosa positive.ConclusionUAW cultures and LAW cultures differ in children with CF and there are differences in clinical characteristics between patients with positive versus negative culture results. P. aeruginosa positive UAW cultures appeared to precede positive LAW cultures in a substantial part of patients, suggesting some kind of cross-infection between the UAW and LAW

T helper cell subsets specific for pseudomonas aeruginosa in healthy individuals and patients with cystic fibrosis

Background: We set out to determine the magnitude of antigen-specific memory T helper cell responses to Pseudomonas aeruginosa in healthy humans and patients with cystic fibrosis. Methods: Peripheral blood human memory CD4+ T cells were co-cultured with dendritic cells that had been infected with different strains of Pseudomonas aeruginosa. The T helper response was determined by measuring proliferation, immunoassay of cytokine output, and immunostaining of intracellular cytokines. Results: Healthy individuals and patients with cystic fibrosis had robust antigen-specific memory CD4+ T cell responses to Pseudomonas aeruginosa that not only contained a Th1 and Th17 component but also Th22 cells. In contrast to previous descriptions of human Th22 cells, these Pseudomonal-specific Th22 cells lacked the skin homing markers CCR4 or CCR10, although were CCR6+. Healthy individuals and patients with cystic fibrosis had similar levels of Th22 cells, but the patient group had significantly fewer Th17 cells in peripheral blood. Conclusions: Th22 cells specific to Pseudomonas aeruginosa are induced in both healthy individuals and patients with cystic fibrosis. Along with Th17 cells, they may play an important role in the pulmonary response to this microbe in patients with cystic fibrosis and other conditions

paediatric respiratory disease past present and future

Paediatric respiratory disease has changed in the past 20 yrs; we could fill a whole issue of the journal paying tribute to our famous forebears. We are posing new challenges to our colleagues in the field of adult respiratory disease. They have to learn to deal with conditions that 20 yrs ago were rare in the adult chest clinic, such as cystic fibrosis (CF) and the long-term consequences of premature birth and congenital malformations of the respiratory tract. Furthermore, studies in childhood are challenging pathophysiological concepts throughout life. The many great prospective birth cohort studies have shed light on the different patterns of wheezing, their risk factors and their evolution through childhood. Who would have thought it was good to be born in a barn! It is becoming increasingly clear that even for "adult" diseases, such as chronic obstructive pulmonary disease (COPD), antenatal and early life events are at least as important as smoking in adulthood 1. CF has become a disease also of adults 2. Although many factors have contributed, the main reason has been the development of expert special CF centres, a model increasingly adopted by adult teams. This can serve as a model for other diseases; how a well-structured multidisciplinary approach to treatment can translate into benefits for patients. Perhaps numerically the most important achievement is in the field of public health. The benefit of the decrease in invasive bacterial infections, due to vaccination programmes for infants, is among the most important achievements of the past. Other areas of change include the survival of ever smaller preterm neonates. These children are reaching adult life with impaired lung function and abnormal computed tomography scans. What will happen to their ageing lungs? Interstitial lung disease (ILD) is becoming increasingly well understood, with new genetic entities, such as

Multiple breath washout in bronchiectasis clinical trials: is it feasible?

BACKDGROUND: Evaluation of multiple breath washout (MBW) set-up including staff training, certification and central “over-reading” for data quality control is essential to determine the feasibility of MBW in future bronchiectasis studies. AIMS: To assess the outcomes of a MBW training, certification and central over-reading programme. METHODS: MBW training and certification was conducted in European sites collecting lung clearance index (LCI) data in the BronchUK Clinimetrics and/or i-BEST-1 studies. The blended training programme included the use of an eLearning tool and a 1-day face-to-face session. Sites submitted MBW data to trained central over-readers who determined validity and quality. RESULTS: Thirteen training days were delivered to 56 participants from 22 sites. Of 22 sites, 18 (82%) were MBW naïve. Participant knowledge and confidence increased significantly (p<0.001). By the end of the study recruitment, 15 of 22 sites (68%) had completed certification with a mean (range) time since training of 6.2 (3–14) months. In the BronchUK Clinimetrics study, 468 of 589 (79%) tests met the quality criteria following central over-reading, compared with 137 of 236 (58%) tests in the i-BEST-1 study. CONCLUSIONS: LCI is feasible in a bronchiectasis multicentre clinical trial setting; however, consideration of site experience in terms of training as well as assessment of skill drift and the need for re-training may be important to reduce time to certification and optimise data quality. Longer times to certification, a higher percentage of naïve sites and patients with worse lung function may have contributed to the lower success rate in the i-BEST-1 study

Psychosocial Response to Uncertain Newborn Screening Results for Cystic Fibrosis

Objective To explore the psychosocial implications of diagnostic uncertainty that result from inconclusive results generated by newborn bloodspot screening (NBS) for cystic fibrosis (CF). Study design Using a mixed methods prospective cohort study of children who received NBS for CF, we compared psychosocial outcomes of parents whose children who received persistently inconclusive results with those whose children received true positive or screen-negative results. Results Mothers of infants who received inconclusive results (n = 17), diagnoses of CF (n = 15), and screen-negative results (n = 411) were surveyed; 23 parent interviews were completed. Compared with mothers of infants with true positive/screen-negative results, mothers of infants with inconclusive results reported greater perceived uncertainty (P .05). Qualitatively, parents valued being connected to experts but struggled with the meaning of an uncertain diagnosis, worried about their infant's health-related vulnerability, and had mixed views about surveillance. Conclusion Inconclusive CF NBS results were not associated with anxiety or vulnerability but led to health-related uncertainty and qualitative concerns. Findings should be considered alongside efforts to optimize protocols for CF screening and surveillance. Educational and psychosocial supports are warranted for these families.Peer reviewe

Parent experience with false-positive newborn screening results for cystic fibrosis

BACKGROUND: The risk of psychosocial harm in families of infants with false-positive (FP) newborn bloodspot screening (NBS) results for cystic fibrosis (CF) is a longstanding concern. Whether well designed retrieval and confirmatory testing systems can mitigate risks remains unknown. METHODS: Using a mixed-methods cohort design, we obtained prospective self-report data from mothers of infants with FP CF NBS results 2 to 3 months after confirmatory testing at Ontario\u27s largest follow-up center, and from a randomly selected control sample of mothers of screen negative infants from the same region. Mothers completed a questionnaire assessing experience and psychosocial response. A sample of mothers of FP infants completed qualitative interviews. RESULTS: One hundred thirty-four mothers of FP infants (response rate, 55%) and 411 controls (response rate, 47%) completed questionnaires; 54 mothers of FP infants were interviewed. Selected psychosocial response measures did not detect psychosocial distress in newborns or 1 year later (P \u3e .05). Mothers recalled distress during notification of the positive result and in the follow-up testing period related to fear of chronic illness, but valued the screening system of care in mitigating concerns. CONCLUSIONS: Although immediate distress was reported among mothers of FP infants, selected psychometric tools did not detect these concerns. The NBS center from which mothers were recruited minimizes delay between notification and confirmatory testing and ensures trained professionals are communicating results and facilitating follow-up. These factors may explain the presence of minimal psychosocial burden. The screening system reflected herein may be a model for NBS programs working to minimize FP-related psychosocial harm

Neutrophil Elastase Enhances Sputum Solubilization in Cystic Fibrosis Patients Receiving DNase Therapy

Cystic fibrosis patients suffer from chronic lung infection and inflammation due to the secretion of viscous sputum. Sputum viscosity is caused by extracellular DNA, some of which originates from the release of neutrophil extracellular traps (NETs). During NET formation neutrophil elastase (NE) partially processes histones to decondense chromatin. NE is abundant in CF sputum and is thought to contribute to tissue damage. Exogenous nucleases are a palliative treatment in CF as they promote sputum solubilization. We show that in a process reminiscent of NET formation, NE enhances sputum solubilization by cleaving histones to enhance the access of exogenous nucleases to DNA. In addition, we find that in Cf sputum NE is predominantly bound to DNA, which is known to downregulate its proteolytic activity and may restrict host tissue damage. The beneficial role of NE in CF sputum solubilization may have important implications for the development of CF therapies targeting NE

Assessment of pulmonary antibodies with induced sputum and bronchoalveolar lavage induced by nasal vaccination against Pseudomonas aeruginosa: a clinical phase I/II study

<p>Abstract</p> <p>Background</p> <p>Vaccination against <it>Pseudomonas aeruginosa </it>is a desirable albeit challenging strategy for prevention of airway infection in patients with cystic fibrosis. We assessed the immunogenicity of a nasal vaccine based on the outer membrane proteins F and I from <it>Pseudomonas aeruginosa </it>in the lower airways in a phase I/II clinical trial.</p> <p>Methods</p> <p>N = 12 healthy volunteers received 2 nasal vaccinations with an OprF-OprI gel as a primary and a systemic (n = 6) or a nasal booster vaccination (n = 6). Antibodies were assessed in induced sputum (IS), bronchoalveolar lavage (BAL), and in serum.</p> <p>Results</p> <p>OprF-OprI-specific IgG and IgA antibodies were found in both BAL and IS at comparable rates, but differed in the predominant isotype. IgA antibodies in IS did not correlate to the respective serum levels. Pulmonary antibodies were detectable in all vaccinees even 1 year after the vaccination. The systemic booster group had higher IgG levels in serum. However, the nasal booster group had the better long-term response with bronchial antibodies of both isotypes.</p> <p>Conclusion</p> <p>The nasal OprF-OprI-vaccine induces a lasting antibody response at both, systemic and airway mucosal site. IS is a feasible method to non-invasively assess bronchial antibodies. A further optimization of the vaccination schedule is warranted.</p

Non-invasive MR imaging techniques for measuring femoral arterial flow in a pediatric and adolescent cohort

This is the final version. Available on open access from Wiley via the DOI in this recordMagnetic Resonance Imaging (MRI) is well-suited for imaging peripheral blood flow due to its non-invasive nature and excellent spatial resolution. Although MRI is routinely used in adults to assess physiological changes in chronic diseases, there are currently no MRI-based data quantifying arterial flow in pediatric or adolescent populations during exercise. Therefore the current research sought to document femoral arterial blood flow at rest and following exercise in a pediatric-adolescent population using phase contrast MRI, and to present test-retest reliability data for this method. Ten healthy children and adolescents (4 male; mean age 14.8 ± 2.4 years) completed bloodwork and resting and exercise MRI. Baseline images consisted of PC-MRI of the femoral artery at rest and following a 5 × 30 s of in-magnet exercise. To evaluate test-retest reliability, five participants returned for repeat testing. All participants successfully completed exercise testing in the MRI. Baseline flow demonstrated excellent reliability (ICC = 0.93, p = 0.006), and peak exercise and delta rest-peak flow demonstrated good reliability (peak exercise ICC = 0.89, p = 0.002, delta rest-peak ICC = 0.87, p = 0.003) between-visits. All three flow measurements demonstrated excellent reliability when assessed with coefficients of variance (CV's) (rest: CV = 6.2%; peak exercise: CV = 7.3%; delta rest-peak: CV = 7.1%). The mean bias was small for femoral arterial flow. There was no significant mean bias between femoral artery flow visits 1 and 2 at peak exercise. There were no correlations between age or height and any of the flow measurements. There were no significant differences between male and female participants for any of the flow measurements. The current study determined that peripheral arterial blood flow in children and adolescents can be evaluated using non-invasive phase contrast MRI. The MRI-based techniques that were used in the current study for measuring arterial flow in pediatric and adolescent patients demonstrated acceptable test-retest reliability both at rest and immediately post-exercise.Cystic Fibrosis TrustExercise Medicine Fund at the Hospital for Sick Children (Canada

Sequential analysis of surfactant, lung function and inflammation in cystic fibrosis patients

BACKGROUND: In a cross-sectional analysis of cystic fibrosis (CF) patients with mild lung disease, reduced surfactant activity was correlated to increased neutrophilic airway inflammation, but not to lung function. So far, longitudinal measurements of surfactant function in CF patients are lacking and it remains unclear how these alterations relate to the progression of airway inflammation as well as decline in pulmonary function over time. METHODS: As part of the BEAT trial, a longitudinal study to assess the course of airway inflammation in CF, we studied lung function, surfactant function and endobronchial inflammation using bronchoalveolar lavage fluid from 20 CF patients with normal pulmonary function (median FEV(1 )94% of predicted) at three times over a three year period. RESULTS: There was a progressive loss of surfactant function, assessed as minimal surface tension. The decline in surfactant function was negatively correlated to an increase in neutrophilic inflammation and a decrease in lung function, assessed by FEV(1), MEF(75/25%VC), and MEF(25%VC). The concentrations of the surfactant specific proteins A, C and D did not change, whereas SP-B increased during this time period. CONCLUSION: Our findings suggest a link between loss of surfactant function driven by progressive airway inflammation and loss of small airway function in CF patients with limited lung disease