No drug-drug interaction between tezacaftor-ivacaftor and clofazimine: A case report.

In this case report the potential drug-drug interaction between cytochrome P450 (CYP) 3A4 substrates tezacaftor-ivacaftor and CYP3A4/5 inhibitor clofazimine is investigated in a patient with cystic fibrosis. Exposure to tezacaftor, ivacaftor and its metabolites was assessed by determination of the area under the plasma concentration versus time curve (AUC0-24 h for tezacaftor and AUC0-12 h for ivacaftor and its metabolite) before start of clofazimine and 8 and 115 days after start of clofazimine. The AUC-ratio at day 115 and pre-start was 1.09, 1.45 and 0.747 for ivacaftor, hydroxymethyl ivacaftor and tezacaftor, respectively. This case suggests that clofazimine exhibits no clinically relevant increase in exposure to tezacaftor and ivacaftor.

Airway and interstitial lung disease are distinct entities in paediatric common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a common primary immune deficiency, caused by undefined defects in lymphocyte function, and is treated routinely by immunoglobulin substitution. CVID complications include airway disease (AD) and interstitial lung disease (ILD). It was not known if AD and ILD in CVID have a common immunological aetiology and should be considered separate features of the same disease, or as distinct syndromes that require specialized monitoring and treatment. We used high-resolution computed tomography (CT) to diagnose AD or ILD in paediatric CVID patients. Spirometry and body plethysmography did not differentiate between ILD and AD. Patients with AD (n = 11, 20%) developed more pneumonias while children with ILD (n = 8, 15%) showed immune dysregulation characterized by autoimmune complications, more severe memory B cell reduction and expansion of non-naive cytotoxic T cells. In conclusion, ILD and AD in CVID have dissimilar clinical and immunological characteristics, suggesting distinct aetiology requiring tailored monitoring and treatment of these patient subgroups.

High-resolution computed tomography and pulmonary function in children with common variable immunodeficiency.

High-resolution computed tomography (HRCT) may be useful to monitor lung disease in children with common variable immunodeficiency disorder (CVID). We evaluated interobserver agreement and correlation with pulmonary function tests (PFTs) for automated quantification and visual scoring of air trapping and airway wall thickening on HRCT in paediatric CVID patients. In a cohort of 51 children with CVID, HRCT was analysed visually and automated for presence of air trapping and airway wall thickening. PFTs were expressed as % predicted. Disease duration, physician-diagnosed pneumonias and antibiotic prophylaxis were recorded. Interobserver agreement for automated airway wall thickening was good with an intra-class correlation coefficient of 0.88, compared with 0.51 for visual scoring. Presence of air trapping on HRCT correlated significantly with PFTs and disease duration, but was not associated with previous pneumonias. Airway wall thickening did not correlate significantly with PFTs or disease duration and was not associated with previous pneumonias or prophylactic antibiotic use. In children with CVID disorders, HRCT air trapping measurements are significantly correlated with PFTs and disease duration. Quantitative air trapping is a feasible and promising technique for small airway disease quantification that may be applied to monitor (silent) disease progression in CVID.

Modified Chrispin-Norman chest radiography score for cystic fibrosis: observer agreement and correlation with lung function.

OBJECTIVE: To test observer agreement and two strategies for possible improvement (consensus meeting and reference images) for the modified Chrispin-Norman score for children with cystic fibrosis (CF). METHODS: Before and after a consensus meeting and after developing reference images three observers scored sets of 25 chest radiographs from children with CF. Observer agreement was tested for line, ring, mottled and large soft shadows, for overinflation and for the composite modified Chrispin-Norman score. Correlation with lung function was assessed. RESULTS: Before the consensus meeting agreement between observers 1 and 2 was moderate-good, but with observer 3 agreement was poor-fair. Scores correlated significantly with spirometry for observers 1 and 2 (-0.72

Radiological and functional changes over 3 years in young children with cystic fibrosis.

The aim of the present study was to evaluate airway disease progression assessed by chest radiology, expiratory interrupter resistance (Rint,exp) and spirometry in young children with cystic fibrosis (CF) over a 3-yr period. Two chest radiographs combined with two R(int,exp) measurements were performed with a 3-yr interval in 21 preschool children (age (mean+/-sd) 3.2+/-0.9 yrs) and 30 schoolchildren with CF (age 7.2+/-1.9 yrs). Chest radiographs were scored using five different CF scoring systems and Rint,exp measurements were expressed as height-adjusted Z-scores. Spirometry was assessed in schoolchildren and the results were expressed as a percentage of predicted values. Chest radiograph scores worsened significantly over the 3-yr period and a tendency towards more pronounced changes was observed, especially for the Wisconsin score, in preschool children. Most preschool and schoolchildren had Rint,exp Z-scores within the normal range at start and follow-up, and the annual change in Rint,exp Z-score was not significant. In schoolchildren, only the forced expiratory volume in one second as a percentage of forced vital capacity declined significantly during the study period. In summary, in young children with cystic fibrosis, chest radiograph scores worsen significantly over time even while lung function remains stable.

Diagnostic value of serological tests against Pseudomonas aeruginosa in a large cystic fibrosis population.

BACKGROUND: Serological methods to monitor Pseudomonas aeruginosa colonisation in patients with cystic fibrosis (CF) are advocated but the diagnostic value of a commercially available P aeruginosa antibody test to detect early and chronic P aeruginosa colonisation in a non-research setting has not been assessed. METHODS: Colonisation with P aeruginosa was estimated by regular culture of sputum or oropharyngeal swabs during three consecutive years in 220 patients with CF aged 0-65 years. Commercially available ELISA tests with three P aeruginosa antigens (elastase, exotoxin A, alkaline protease) were performed at the end of the study period. In a subgroup of 57 patients (aged 4-14 years) serological tests were performed annually. RESULTS: Using culture as the reference standard, the ELISA tests using the advised cut off values had a sensitivity of 79% and a specificity of 89% for chronic colonisation. Receiver-operator characteristic curves were created to optimise cut off values. Applying these new cut off values resulted in a sensitivity of 96% and a specificity of 79%. All three individual serological tests discriminated well between the absence and presence of chronic P aeruginosa colonisation. The sensitivity of the individual antibody test was 87% for elastase, 79% for exotoxin A, and 76% for alkaline protease. First colonisation was preceded by positive serological results in only five of 13 patients (38%). CONCLUSION: In patients with CF, serological tests using specific antigens are sensitive for diagnosing chronic P aeruginosa colonisation. However, the failure of serological tests to detect early colonisation in young patients emphasises the need for continued reliance on cultures.

The role of airway epithelium and blood neutrophils in the inflammatory response in cystic fibrosis.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which accounts for the cAMP-modulated chloride conductance of airway epithelial cells. CFTR also regulates other membrane proteins like the negative regulation of the amiloride-sensitive epithelial sodium channel (ENaC). Mutations in the CFTR gene lead to hyperabsorption of sodium chloride and a reduction in the periciliary salt and water content which leads to impaired mucociliary clearance. It seems that a lack of functional CFTR leads to abnormal function of the NF-kappaB pathway in submucosal gland cells, causing an increased production of pro-inflammatory cytokines and the chemokine IL-8, and a pro-inflammatory environment. CFTR is also expressed in neutrophils and several neutrophil functions like cytokine production, migration, phagocytosis and apoptosis seem altered in CF. In this review we describe the role of airway epithelium and blood neutrophils in the viscious circle of inflammation and infection seen in CF.

[Acute hemorrhagic edema in children: excellent prognosis]. / Acuut hemorragisch oedeem bij kinderen: uitstekende prognose.

In 2 young children, boys aged 8 and 14 months, who were referred with fever and typical concentric skin lesions and oedema (except for on the trunk), acute haemorrhagic oedema was diagnosed. This is a benign leucocytoclastic vasculitis of the skin accompanied by oedema, which affects children between birth and 36 months of age. It is often preceded by an infection or vaccination. As a rule, recovery is complete.

No effect of nadroparin prophylaxis in the prevention of central venous catheter (CVC)-associated thrombosis in bone marrow transplant recipients.

Complications of CVCs in 382 consecutive patients receiving a stem cell transplantation (SCT) were analysed. Early complications were pneumothorax (3.6%), haematothorax (0.5%), dislocation (3%) and dysfunction (3.6%). Eighty-seven-associated infections (22%) were observed, leading to removal of the CVC in 26 patients. More bacteraemias were associated with double- or triple-lumen CVCs, 19% vs 5% in single lumen CVCs (P < 0.0001). Coagulase-negative staphylococci were the predominant microorganisms in 72%. A special point of investigation was CVC-associated thrombosis and the prophylactic value of nadroparin. Two consecutive regimens with nadroparin were used and compared; 7 days 2850 IE nadroparin and 10 days 5700 IE nadroparin. The incidence of CVC-associated thrombosis was 6.9% in 382 patients with 390 catheters. The incidence was 8% in patients receiving one of the prophylactic nadroparin regimens compared to 6% in a comparable control group without prophylaxis. A short course of nadroparin was unable to prevent thrombotic complications after discontinuation.

The psychological and social functioning of 14 children and 12 adolescents after Ilizarov leg lengthening.

We studied the psychological and social impact of the Ilizarov leg lengthening procedure in 26 patients (aged 6-17 years), who had completed the treatment at least 2 months previously. Measurements of depression and anxiety were performed preoperatively and at follow-up. Questions about functioning at school, daily life activities and treatment-related experiences were answered by the patient and his/her parents. The school or work results showed no significant decline during the lengthening procedure. Serious sleeping problems occurred during the procedure. There was no subjective improvement in physical skill after the procedure and almost one-fourth of the children still had complaints about their leg. We conclude that the Ilizarov procedure caused no serious psychological disturbances.