H.M. Janssens

Medication adherence and the risk of severe asthma exacerbations: a systematic review

The benefits of drug therapy for asthma have been well established, but adherence to treatment is poor, and this might be associated with an increased risk of asthma exacerbations. The aim of this study was to review the literature on the association between adherence to asthma controller treatment and risk of severe asthma exacerbations in children and adults. A systematic literature search was performed in PubMed, Embase and Web of Science, from inception until January 2014. Studies were included if data on the association between medication adherence and severe asthma exacerbations were presented. Quality was assessed using a modified version of the Newcastle–Ottawa Scale. The search yielded 2319 unique publications, of which 23 met the inclusion criteria and underwent data extraction and quality scoring. High levels of heterogeneity across studies with regard to adherence and exacerbation measurements, designs and analysis precluded a formal meta-analysis. Although effect measures varied widely, good adherence was associated with fewer severe asthma exacerbations in high-quality studies. Good adherence tended to be associated with lower risk of severe asthma exacerbations. Future studies should use standardised methodology to assess adherence and exacerbations, and should consider inhaler competence. High-quality studies indicated that better adherence is associated with fewer severe asthma exacerbations http://ow.ly/BU6ro

Inhaled antibiotics: dry or wet?

Dry powder inhalers (DPIs) delivering antibiotics for the suppressive treatment of Pseudomonas aeruginosa in cystic fibrosis patients were developed recently and are now increasingly replacing time-consuming nebuliser therapy. Noninferiority studies have shown that the efficacy of inhaled tobramycin delivered by DPI was similar to that of wet nebulisation. However, there are many differences between inhaled antibiotic therapy delivered by DPI and by nebuliser. The question is whether and to what extent inhalation technique and other patient-related factors affect the efficacy of antibiotics delivered by DPI compared with nebulisers. Health professionals should be aware of the differences between dry and wet aerosols, and of patient-related factors that can influence efficacy, in order to personalise treatment, to give appropriate instructions to patients and to better understand the response to the treatment after switching. In this review, key issues of aerosol therapy are discussed in relation to inhaled antibiotic therapy with the aim of optimising the use of both nebulised and DPI antibiotics by patients. An example of these issues is the relationship between airway generation, structural lung changes and local concentrations of the inhaled antibiotics. The pros and cons of dry and wet modes of delivery for inhaled antibiotics are discussed. Concentrations of inhaled antibiotics depend on airway generation, mode of delivery, disease severity and competence http://ow.ly/AJLs9

Prescription patterns, adherence and characteristics of non-adherence in children with asthma in primary care.

Adherence to treatment remains important for successful asthma management. Knowledge about asthma medication use and adherence in real‐life offers opportunities to improve asthma treatment in children.

Potentiator synergy in rectal organoids carrying S1251N, G551D, or F508del CFTR mutations

The potentiator VX-770 (ivacaftor/KALYDECO™) targets defective gating of CFTR and has been approved for treatment of cystic fibrosis (CF) subjects carrying G551D, S1251N or one of 8 other mutations. Still, the current potentiator treatment does not normalize CFTR-dependent biomarkers, indicating the need for development of more effective potentiator strategies. We have recently pioneered a functional CFTR assay in primary rectal organoids and used this model to characterize interactions between VX-770, genistein and curcumin, the latter 2 being natural food components with established CFTR potentiation capacities. Results indicated that all possible combinations of VX-770, genistein and curcumin synergistically repaired CFTR-dependent forskolin-induced swelling of organoids with CFTR-S1251N or CFTR-G551D, even under suboptimal CFTR activation and compounds concentrations, conditions that may predominate in vivo. Genistein and curcumin also enhanced forskolin-induced swelling of F508del homozygous organoids that were treated with VX-770 and the prototypical CFTR corrector VX-809. These results indicate that VX-770, genistein and curcumin in double or triple combinations can synergize in restoring CFTR-dependent fluid secretion in primary CF cells and support the use of multiple potentiators for treatment of CF.

Concordance between upper and lower airway microbiota in infants with cystic fibrosis

Nasopharyngeal and oropharyngeal samples are commonly used to direct therapy for lower respiratory tract infections in non-expectorating infants with cystic fibrosis (CF). We aimed to investigate the concordance between the bacterial community compositions of 25 sets of nasopharyngeal, oropharyngeal and bronchoalveolar lavage (BAL) samples from 17 infants with CF aged ∼5u2005months (n=13) and ∼12u2005months (n=12) using conventional culturing and 16S-rRNA sequencing. Clustering analyses demonstrated that BAL microbiota profiles were in general characterised by a mixture of oral and nasopharyngeal bacteria, including commensals like Streptococcus, Neisseria, Veillonella and Rothia spp. and potential pathogens like Staphylococcus aureus, Haemophilus influenzae and Moraxella spp. Within each individual, however, the degree of concordance differed between microbiota of both upper respiratory tract niches and the corresponding BAL. The inconsistent intra-individual concordance between microbiota of the upper and lower respiratory niches suggests that the lungs of infants with CF may have their own microbiome that seems seeded by, but is not identical to, the upper respiratory tract microbiome. Lungs of CF infants have a microbiome that seems seeded by, but is not identical to, the URT microbiome http://ow.ly/1NlA306DuPv

Time trends in the incidence, prevalence and age at diagnosis of asthma in children

Current knowledge on the prevalence of asthma is mainly based on cross‐sectional questionnaire data. Current population‐based data on the incidence of asthma in children are scarce.

Real life data on incidence and risk factors of severe asthma exacerbations in children in primary care

Real-life data on the incidence rates (IR) and risk factors of severe asthma exacerbations in children are sparse. We aimed to assess IR and risk factors of severe asthma exacerbations in children in real life. We conducted a population-based cohort study using a Dutch GP database containing complete medical records of >1 million patients. All records of children with physician-diagnosed asthma aged 5-18 years between 2000 and 2012 were examined for exacerbations, defined as either hospitalization, emergency department visit or need of systemic steroids for asthma. IR was expressed as number of exacerbations per person year (PY). We identified 14,303 asthmatic children with 35,118 PY of follow-up and 732 exacerbations. The overall IR was 2.1/100PY (95% CI 1.9-2.2), 4.1/100PY (3.8-4.4) for children on asthma treatment. Re-exacerbation occurred in 2% (1.3-4.3) of patients within 1 month, in 25% (20.6-28.8) within 1 year. Predictors for (frequent) exacerbations were age, medication use and prior exacerbations (all pxa0<xa00.001). The overall IR of severe asthma exacerbations was 4/100PY in children on asthma treatment, highest in spring and fall. 25% of the patients with an exacerbation will experience a next exacerbation within 1 year. More severe asthma is a predictor of subsequent and future exacerbations.

196 Airway surface liquid concentrations of aztreonam lysine for inhalation in children with cystic fibrosis: A modelling study

Introduction nnThe mechanics of inhaled antibiotics in obstructed airways are not well known. It is possible that local areas with concentration below the minimal inhibitory concentration (10xMIC90, 128µg/ml for P. Aeruginosa) exist, causing undertreated parts of the lung. To optimize inhaled therapy, knowledge about antibiotic concentrations throughout the lung should be known. Local deposition characteristics of inhaled Aztreonam lysine (AZLI) were simulated using Functional Respiratory Imaging.nnMethods nnAirways and lungs were segmented from a retrospective dataset of 40 in- and expiratory CT-scans of children with cystic fibrosis (CF) between 5 and 17 years. FRI simulations were performed that simulated the nebulisation of 75mg AZLI through PARI eFlow® with minimal/median/maximal reported aerodynamic diameters (MMAD) and different thicknesses of airway surface liquid (ASL). Figure 1 shows local concentrations in the central airways and lung.nn![Figure][1] nnnnResults nnIn Figure 2, it is shown how many lobes are being undertreated.nn![Figure][1] nnnnConclusion nnParts of the CF-lung receive concentrations < 10xMIC90 with inhaled antibiotics, such as AZLI.nn [1]: pending:yes

81 The concordance between the microbiome of the upper and lower respiratory tract is investigated in infants with cystic fibrosis

Background Nasopharyngeal (NP) and oropharyngeal samples (OP) are commonly used to direct therapy for lower respiratory tract (LRT) infections in non-expectorating infants with Cystic Fibrosis (CF). The level of concordance between microbiota of the upper respiratory tract (URT) and LRT in young children is, however, largely unknown. Objective To examine the concordance between URT and LRT microbiota in infants with CF. Methods Paired bronchoalveolar lavage fluid (BAL), NP and OP samples were longitudinally collected from 17 CF patients at the age of 3 and 12 months. We studied the concordance between the URT and LRT microbial communities by 16S-rRNA-based sequencing. Results Bacterial diversity is lower in NP compared to the OP and BAL samples. On group level, OP microbiota profiles showed more similarity with BAL microbiota compared to NP microbiota. However, potential pathogens like staphylococci , Moraxella and Haemophilus influenzae were almost exclusively observed in the NP but not in OP. Moreover, intraindividual concordance between both NP and OP microbiota profiles and paired BAL microbiota was limited. Conclusion At a population level, OP microbiota profiles resemble lung microbiota more closely than NP microbiota, however, potential respiratory pathogens are often detected in NP but not in OP samples. More importantly, within-individual concordance between the URT and LRT microbiome in CF patients is limited, restricting the diagnostic value of URT sampling during LRT infections in infancy. Whether microbiota profiling of BAL samples will indeed more reliably guide treatment of infections in CF infants compared to conventional culture remains to be studied.

ePS04.7 Tobramycin nebulization with I-neb® in children with cystic fibrosis (TONI study): Pharmacokinetics and safety

Objectives Usage of the efficient, small, silent and rapid I-neb® nebulizer can reduce treatment burden in patients with cystic fibrosis (CF). Limited information is available for use in children, especially regarding the correct dosage and safety of potentially toxic antibiotics. We aimed to determine pharmacokinetics (PK) and safety of tobramycin inhalation solution (TIS) with the I-neb® compared to the standard PARI-LC® Plus nebulizer in children with CF. Methods In two separate study visits (cross-over) blood samples of 22 children aged 6–18 years were collected for PK analysis following TIS nebulization with the I-neb® (75 mg) and PARI-LC® Plus (300 mg) nebulizer. Study visits were separated by one month, in which one of the study nebulizers was used twice daily (randomized). Renal and hearing tests were performed on both study visits to test for aminoglycoside toxicity. Adverse events were monitored. Results (preliminary results of 16 patients): Safe serum levels were reached with no significant differences in PK parameters between nebulizers. Maximum serum level (mg/L), time to maximum serum level (h), trough serum level 12 h (mg/L) and area under the curve 0–24 h (h·mg/L) were 1.96±1.41, 1.02±0.48, 0.20±0.08 and 12.78±7.33 for the I-neb® and 1.44±0.99, 1.05±0.51, 0.18±0.11 and 10.28±5.16 for the PARI-LC® Plus, respectively. There was no impairment in renal or hearing function and inhalations were well tolerated. Conclusion Nebulization of 75 mg TIS with the I-neb® in children with CF was safe and resulted in comparable systemic exposure to 300 mg TIS with the PARI-LC® Plus. Funding: The study was partly funded by the Dutch CF foundation.