Pulmonary function testing: tools and applications in young children with asthma

Many (pre-)school children with acute or chronic respiratory problems are seen every day by physicians, both in primary care and in hospitals. Although in many children these respiratory symptoms are self-limiting, it is important to recognise early in the course of the disease those children that are at risk to suffer from persistent respiratory diseases and to develop pulmonary function abnormalities and chronic airway remodelling. In most children diagnosis and treatment of respiratory disease are mainly based on medical history and physical examination. However, the evaluation of objective disease markers, e.g. pulmonary function could be helpful for the assessment of functional abnormalities. Especially in pre-school children respiratory function parameters are rarely available. Although recently several alternative methods have been developed, most have and can not be implemented for use in daily clinical practice and are currently only available in specialised centres. Many of these tests require difficult technical procedures, anaesthetic care or are even invasive. Clinical application of new or alternative pulmonary function tests in young children is only possible for techniques that are easily performed in children of all ages, do not require much time or sedation and show results quickly. They should be reproducible, cheap, able to distinguish healthy from diseased children, not invasive, applicable during spontaneous breathing, responsive to intervention and useful for follow up. Promising techniques that might fulfil (most of these) requirements are tidal breathing analysis, interrupter resistance measurement and impulse oscillometry. Adaptation of traditional techniques (MEFV) or standardisation of these newer techniques and availability of reference values might enable more widespread use of these techniques in daily practice. The studies described in this thesis addressed several aspects of pulmonary function testing in pre-school and school children

No positive effect of rhdnase on the pulmonary colonization in children with cystic fibrosis

Background. Long-term clinical trials have shown that daily treatment with recombinant human deoxyribonuclease (rhDNAse) in patients with mild to moderate cystic fibrosis (CF) improves lung function and decreases the number of respiratory exacerbations. The aim of this study was to analyze the effect of rhDNAse on the bacterial colonization of the airways in children with CF. Methods. This was a retrospective cohort study. From the database of the CF Center Utrecht, we selected two groups, an rhDNAse group (daily 2.5 mg rhDNAse) and a control group (no rhDNAse). Primary outcome parameter was the difference in change in bacterial colonization between the treatment and control group during 1.5-year. Secondary outcome parameters were changes in lung function (FEV1) and pulmonary exacerbations. Results. Children treated with rhDNAse showed no significant changes in bacterial colonization during the treatment period, apart from an increase of P. aeruginosa positive cultures, both compared to baseline (53.1% versus 25%, p<0.05) and control group (no change during study period, 37% versus 37%). The change in FEV1 after one year of treatment was +4.0% in the treatment group versus -0.3% in the control group (p=0.22). There were no significant changes in number of pulmonary exacerbations. Conclusions. This study showed no significant beneficial decrease in bacterial airway colonization during 1.5-year of treatment with rhDNAse. The positive effects of rhDNAse on the lung function can therefore not be explained by a change in airway colonization

Позиционирование изображений фотошаблонов в системах автоматизированного оптического контроля

Разработана система автоматизированного оптического позиционирования фотошаблонов интегральных схем, которая имеет высокие показатели помехоустойчивости и точности

Bordetella species in children with cystic fibrosis: What do we know? The role in acute exacerbations and chronic course

AbstractDespite vaccination, pertussis is still endemic in the Netherlands. A literature search was performed to verify what is known about the role of Bordetella species in children with cystic fibrosis, with regard to the incidence of Bordetella infections, the involvement in pulmonary exacerbations and the influence on chronic course.Little is known about the frequency of Bordetella infections and the involvement of Bordetella species both in relation to the chronic course of cystic fibrosis and to pulmonary exacerbations. Since it is difficult to detect Bordetella species in cultures and few sputum cultures investigated have been obtained during an exacerbation, it is likely that the frequency of Bordetella species in CF patients is underestimated. Identification of Bordetella species in these patients may have serious consequences for the treatment of exacerbations in CF.Future research investigating the role of Bordetella species in cystic fibrosis should use specific techniques to detect Bordetella in cultures

Pharmacokinetics and safety of tobramycin nebulization with the I-neb and PARI-LC Plus in children with cystic fibrosis: A randomized, crossover study

Aims: We aimed to compare the pharmacokinetics (PK) and safety profile of tobramycin inhalation solution (TIS) using the I-neb device to the standard PARI-LC Plus nebulizer in children with cystic fibrosis. Methods: A randomized, open-label, crossover study was performed. In 2 separate study visits, blood samples from 22 children were collected following TIS nebulization with I-neb (75 mg) and PARI-LC Plus (300 mg). Study visits were separated by 1 month, in which 1 of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian PK modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard estimated glomerular filtration rate values, biomarkers for tubular injury (KIM-1 and NAG) were measured. Patient and nebulizer satisfaction were assessed. Results: Inhalations were well tolerated and serum trough concentrations below the predefined toxic limit were reached with no significant differences in PK parameters between nebulizers. Results of audiometry and estimated glomerular filtration rate revealed no abnormalities. However, increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest TIS-induced subclinical tubular kidney injury. Nebulization time was 50% shorter and patient satisfaction was significantly higher with the I-neb. Conclusions: Nebulization of 75 mg TIS with the I-neb in children with cystic fibrosis resulted in comparable systemic exposure to 300 mg TIS with the PARI-LC Plus and was well tolerated and preferred over the PARI-LC Plus. Long-term safety of TIS nebulization should be monitored clinically, especially regarding the effects on tubular kidney injury

Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis

In vitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that in vitro drug responses in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two in vivo therapeutic endpoints. We measured individual in vitro efficaciousness using a functional assay in rectum-derived organoids based on forskolininduced swelling and studied the correlation with in vivo effects. The in vitro organoid responses correlated with both change in pulmonary response and change in sweat chloride concentration. Receiver operating characteristic curves indicated good-toexcellent accuracy of the organoid-based test for defining clinical responses. This study indicates that an in vitro assay using stem cell cultures can prospectively select efficacious treatments for patients and suggests that biobanked stem cell resources can be used to tailor individual treatments in a cost-effective and patient-friendly manner

Pharmacogenomics of inhaled corticosteroids and leukotriene modifiers : a systematic review

BACKGROUND Pharmacogenetics studies of anti-inflammatory medication of asthma have expanded rapidly in recent decades, but the clinical value of their findings remains limited. OBJECTIVE To perform a systematic review of pharmacogenomics and pharmacogenetics of inhaled corticosteroids (ICS) and leukotriene modifiers (LTMs) in patients with asthma. METHODS Articles published between 1999 and June 2015 were searched using PubMed and EMBASE. Pharmacogenomics/genetics studies of patients with asthma using ICS or LTMs were included if ≥1 of the following outcomes were studied: lung function, exacerbation rates or asthma symptoms. The studies of Single Nucleotide Polymorphisms (SNPs) that had been replicated at least once were assessed in more detail. RESULTS In total, 59 publications were included in the systematic review: 26 addressed LTMs (including two genomewide Genome-Wide association studies [GWAS]) and 33 addressed ICS (including four GWAS). None of the GWAS reported similar results. Furthermore, none of the SNPs assessed in candidate gene studies were identified in a GWAS. No consistent reports were found for candidate gene studies of LTMs. In candidate gene studies of ICS, the most consistent results were found for rs28364072 in FCER2. This SNP was associated with all three outcomes of poor response, and the largest effect was reported with the risk of exacerbations (hazard ratio, 3.95; 95% CI, 1.64–9.51). CONCLUSION AND CLINICAL RELEVANCE There is a lack of replication of genetic variants associated with poor ICS or LTM response. The most consistent results were found for the FCER2 gene [encoding for a low-affinity IgE receptor (CD23)] and poor ICS response. Larger studies with well-phenotyped patients are needed to assess the clinical applicability of ICS and LTM pharmacogenomics/genetics