Outcome measures to assess therapeutic interventions in cystic fibrosis (CF) patients with mild lung disease are lacking. Our aim was to determine if the lung clearance index (LCI) can detect a ...treatment response to dornase alfa in paediatric CF patients with normal spirometry. CF patients between 6-18 yrs of age with FEV(1 )≥ 80% pred were eligible. In a crossover design, 17 patients received 4 weeks of dornase alfa and placebo in a randomised sequence separated by a 4-week washout period. The primary end-point was the change in LCI from dornase alfa versus placebo. A mixed model approach incorporating period-dependent baselines was used. The mean ± sd age was 10.32 ± 3.35 yrs. Dornase alfa improved LCI versus placebo (0.90 ± 1.44; p = 0.022). Forced expiratory flow at 25-75% expired volume measured by % pred and z-scores also improved in subjects on dornase alfa (6.1% ± 10.34%; p = 0.03 and 0.28 ± 0.46 z-score; p = 0.03). Dornase alfa significantly improved LCI. Therefore the LCI may be a suitable tool to assess early intervention strategies in this patient population.
The atopic march describes the progression from atopic dermatitis during infancy to asthma and allergic rhinitis in later childhood. In a Canadian birth cohort we investigated whether concomitant ...allergic sensitization enhances subsequent development of these allergic diseases at age 3 years.
Children completed skin prick testing at age 1 year. Children were considered sensitized if they produced a wheal 2 mm or larger than that elicited by the negative control to any of 10 inhalant or food allergens. Children were also assessed for atopic dermatitis by using the diagnostic criteria of the UK Working Party. At age 3 years, children were assessed for asthma, allergic rhinitis, food allergy, and atopic dermatitis. Data from 2311 children were available.
Atopic dermatitis without allergic sensitization was not associated with an increased risk of asthma at age 3 years after adjusting for common confounders (relative risk RR, 0.46; 95% CI, 0.11-1.93). Conversely, atopic dermatitis with allergic sensitization increased the risk of asthma more than 7-fold (RR, 7.04; 95% CI, 4.13-11.99). Atopic dermatitis and allergic sensitization had significant interactions on both the additive (relative excess risk due to interaction, 5.06; 95% CI, 1.33-11.04) and multiplicative (ratio of RRs, 5.80; 95% CI, 1.20-27.83) scales in association with asthma risk. There was also a positive additive interaction between atopic dermatitis and allergic sensitization in their effects on food allergy risk (relative excess risk due to interaction, 15.11; 95% CI, 4.19-35.36).
Atopic dermatitis without concomitant allergic sensitization was not associated with an increased risk of asthma. In combination, atopic dermatitis and allergic sensitization had strong interactive effects on both asthma and food allergy risk at age 3 years.
•This study was completed in children.•Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) can be quantified in airway secretions of people with cystic fibrosis (CF).•Significant changes occur ...in SPLUNC1 sputum levels with treatment for CF pulmonary exacerbations.•The present study suggests that SPLUNC1 has potential as a sensitive biomarker for mild pulmonary exacerbations and for assessing treatment responses.
Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) is an innate defence protein that acts as an anti-microbial agent and regulates airway surface liquid volume through inhibition of the epithelial sodium channel (ENaC). SPLUNC1 levels were found to be reduced in airway secretions of adults with cystic fibrosis (CF). The potential of SPLUNC1 as a biomarker in children with CF is unknown.
We quantified SPLUNC1, interleukin-8 (IL-8) and neutrophil elastase (NE) in sputum of CF children treated with either intravenous antibiotics or oral antibiotics for a pulmonary exacerbation (PEx)s, and in participants of a prospective cohort of CF children with preserved lung function on spirometry, followed over a period of two years.
Sputum SPLUNC1 levels were significantly lower before compared to after intravenous and oral antibiotic therapy for PEx. In the longitudinal cohort, SPLUNC1 levels were found to be decreased at PEx visits compared to both previous and subsequent stable visits. Higher SPLUNC1 levels at stable visits were associated with longer PEx-free time (hazard ratio 0.85, p = 0.04). SPLUNC1 at PEx visits did not correlate with IL-8 or NE levels in sputum or forced expiratory volume in one second (FEV1) but did correlate with the lung clearance index (LCI) (r=-0.53, p < 0.001).
SPLUNC1 demonstrates promising clinometric properties as a biomarker of PEx in children with CF.
Objectives: Inhaled colistin is commonly used in patients with cystic fibrosis (CF), but only limited data are available to define its pharmacokinetic profile. Patients and methods: We performed a ...multicentre study in 30 CF patients to assess sputum, serum and urine concentrations after a single dose of 2 million units of colistin administered by inhalation. In a subgroup of patients we also compared the efficacy of two different nebulizers for administration of inhaled colistin. Results: Serum concentrations of colistin reached their maximum 1.5 h after inhalation and decreased thereafter. Serum concentrations were well below those previously reported for systemic application in all patients. A mean 4.3 ± 1.3% of the inhaled dose was detected in urine. Elimination characteristics did not differ significantly from those previously reported for systemic application. A positive correlation was found between forced expiratory volume in 1 s (FEV1) in per cent predicted and both AUC and maximal colistin concentrations in serum (Cmax). Maximum sputum concentrations were at least 10 times higher than the MIC breakpoint for Pseudomonas aeruginosa proposed by the British Society for Antimicrobial Chemotherapy. Although sputum drug concentrations decreased after a peak at 1 h, the mean colistin concentrations were still above 4 mg/L after 12 h. No differences were seen in polymyxin E sputum concentrations, for CF patients between the two nebulizer systems. Conclusions: The low systemic and high local concentrations of colistin support the use of inhaled colistin in CF patients infected with P. aeruginosa.
Infant pulmonary function testing using the raised volume rapid thoracoabdominal compression (RVRTC) technique requires sedation and is time consuming. Many cystic fibrosis (CF) centers do not have ...access to equipment and the utility of routine testing remains to be determined. We aimed to assess whether RVRTC tests performed during infancy predict spirometry at early school age.
The RVRTC-based forced expiratory flow measures in infants were compared to the first adequately performed spirometry at school age. All tests were carried out during routine clinic visits and expressed as age related z-scores; only test occasions where patients were considered stable were included in the analysis.
47 patients had useable infant RVRTC as well as matching school age spirometry data. There was weak correlation between infant FEV0.5 and early school age FEV1 (R = 0.29, p = 0.05). Four infants had significantly low zFEV0.5 (zFEV0.5 < -1.96), of which one of those remained under that limit at childhood. Changes in spirometry between infancy and early childhood were negatively correlated to baseline FEV0.5 (R = 0.61 p<0.001) reflecting that the change was driven by where individuals started off with. There was no difference in clinical characteristics between those improving, those with stable or deteriorating in lung function.
Infant RVRTC measures were not predictive of pulmonary function in early school age, likely due to the high proportion of measures of forced expiratory flows within the normal range at both time points.
Abstract Background Cystic fibrosis (CF) airways are nitric oxide (NO) deficient. We studied safety and efficacy of repeated inhalations of nebulized l -arginine, the substrate for NO synthase (NOS), ...in patients with CF. Methods Double-blind, randomized, placebo-controlled crossover treatment trial of twice daily inhalation of 500 mg l -arginine for two weeks compared to inhalation of saline in 19 CF patients (ClinicalTrials.gov Identifier: NCT00405665 ). Results l -Arginine inhalation was well tolerated and resulted in a significant increase in exhaled NO. FEV1 increased by an average of 56 ml compared to − 8 ml after saline solution; but this difference did not reach statistical significance. Sputum concentrations of l -ornithine, the product of arginase activity, increased significantly while the l -ornithine derived polyamines did not. There was no change in inflammatory markers in sputum. Conclusion Repeated inhalation of l -arginine in CF patients was safe and well tolerated. Inhaled l -arginine increased NO production without evidence for changes in airway inflammation.
Summary Considerable advances in cystic fibrosis (CF) research have translated into improved patient care, reflected by a continuing trend of improving life expectancy in CF patients. This review ...summarises some of the major findings of CF research that have occurred in the past year. The review specifically focuses on those developments that have direct implications for patient care or those in which clinical trials suggest benefits that may impact on the treatment of CF patients in the near future.
Summary
Background
While allergic sensitization and atopic dermatitis (AD) are known to increase the risk for allergic diseases, the impact of different temporal and clinical patterns of ...sensitization and AD is less well defined.
Objective
We investigated patterns of sensitization and AD from early infancy to age 3, and the differential risk of developing allergic diseases within each pattern in a general cohort.
Methods
Children (n = 2629) from the Canadian Healthy Infant Longitudinal Development (CHILD) Study underwent skin prick tests and were assessed clinically for AD at ages 1 and 3 years. We applied an unsupervised latent class analysis (LCA) to the following 5 factors at these ages: AD, food sensitization, inhalant sensitization, poly‐sensitization to foods and poly‐sensitization to inhalants. The risks for developing asthma, allergic rhinitis and food allergy at 3 years were evaluated for each identified group.
Results
Five distinct classes were revealed by LCA: healthy (81.8%), atopic dermatitis (7.6%), inhalant sensitization (3.5%), transient sensitization (4.1%) and persistent sensitization (3.2%). Using healthy children as the baseline, children in the “atopic dermatitis” group had the next lowest risk for all allergic outcomes at 3 years; those in the “inhalant sensitization” group had the highest risk for allergic rhinitis; children in the “transient sensitization” group were at an increased risk for food allergy; while children in the “persistent sensitization” group had the highest risk for all allergic diseases.
Conclusion and Clinical Relevance
There is substantial heterogeneity among allergen‐sensitized children. Researchers and clinicians need to be aware of the non‐specificity associated with labelling children simply as “atopic” and “non‐atopic” without considering the timing of their atopic history, type of sensitization and AD status. Children with AD who were poly‐sensitized to foods at an early age appear to be at greatest risk of developing other allergic diseases.
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