Lung parenchyma and structure visualisation in paediatric chest MRI: a comparison of different short and ultra-short echo time protocols.

AIM: To evaluate image quality acquired at lung imaging using magnetic resonance imaging (MRI) sequences using short and ultra-short (UTE) echo times (TEs) with different acquisition strategies (breath-hold, prospective, and retrospective gating) in paediatric patients and in healthy volunteers. MATERIALS AND METHODS: End-inspiratory and end-expiratory three-dimensional (3D) spoiled gradient (SPGR3D) and 3D zero echo-time (ZTE3D), and 3D UTE free-breathing (UTE3D), prospective projection navigated radial ZTE3D (ZTE3D vnav), and four-dimensional ZTE (ZTE4D) were performed using a 1.5 T MRI system. For quantitative assessment, the contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) values were calculated. To evaluate image quality, qualitative scoring was undertaken on all sequences to evaluate depiction of intrapulmonary vessels, fissures, bronchi, imaging noise, artefacts, and overall acceptability. RESULTS: Eight cystic fibrosis (CF) patients (median age 14 years, range 13-17 years), seven children with history of prematurity with or without bronchopulmonary dysplasia (BPD; median 10 years, range 10-11 years), and 10 healthy volunteers (median 32 years, range 20-52 years) were included in the study. ZTE3D vnav provided the most reliable output in terms of image quality, although scan time was highly dependent on navigator triggering efficiency and respiratory pattern. CONCLUSIONS: Best image quality was achieved with prospective ZTE3D and UTE3D readouts both in children and volunteers. The current implementation of retrospective ZTE3D readout (ZTE4D) did not provide diagnostic image quality but rather introduced artefacts over the entire imaging volume mimicking lung pathology.

Model of mucociliary clearance in cystic fibrosis lungs.

Mucus clearance is a primary innate defense mechanism in the human airways. Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CF is characterized by dehydration of airway surface liquid and impaired mucociliary clearance. As a result, microorganisms are not efficiently removed from the airways, and patients experience chronic pulmonary infections and inflammation. We propose a new physiologically based mathematical model of muco-ciliary transport consisting of the two major components of the mucociliary clearance system: (i) periciliary liquid layer (PCL) and (ii) mucus layer. We study mucus clearance under normal conditions and in CF patients. Restoring impaired clearance of airway secretions in one of the major goals of therapy in patients with CF. We consider the action of the aerosolized and inhaled medication dornase alfa, which reduces the viscosity of cystic fibrosis mucus, by selectively cleaving the long DNA strands it contains. The results of the model simulations stress the potential relevance of the location of the drug deposition in the central or peripheral airways. Mucus clearance was increased in case the drug was primarily deposited peripherally, i.e. in the small airways.

Improved treatment response to dornase alfa in cystic fibrosis patients using controlled inhalation.

Better treatment of obstructed small airways is needed in cystic fibrosis. This study investigated whether efficient deposition of dornase alfa in the small airways improves small airway obstruction. In a multicentre, double-blind, randomised controlled clinical trial, cystic fibrosis patients on maintenance treatment with 2.5 mL dornase alfa once daily were switched to a smart nebuliser and randomised to small airway deposition (n = 24) or large airway deposition (n = 25) for 4 weeks. The primary outcome parameter was forced expiratory flow at 75% of forced vital capacity (FEF(75%)). FEF(75%) increased significantly by 0.7 sd (5.2% predicted) in the large airways group and 1.2 sd (8.8% pred) in the small airways group. Intention-to-treat analysis did not show a significant difference in treatment effect between groups. Per-protocol analysis, excluding patients not completing the trial or with adherence <70%, showed a trend (p = 0.06) in FEF(75%) Z-score and a significant difference (p = 0.04) between groups in absolute FEF(75%) (L · s(-1)) favouring small airway deposition. Improved delivery of dornase alfa using a smart nebuliser that aids patients in correct inhalation technique resulted in significant improvement of FEF(75%) in children with stable cystic fibrosis. Adherent children showed a larger treatment response for small airway deposition.

The spectrum of structural abnormalities on CT scans from patients with CF with severe advanced lung disease.

RATIONALE: In cystic fibrosis (CF), lung disease is the predominant cause of morbidity and mortality. Little is known about the spectrum of structural abnormalities on CT scans from patients with CF with severe advanced lung disease (SALD). No specific CT scoring system for SALD is available. OBJECTIVES: To design a quantitative CT scoring system for SALD, to determine the spectrum of structural abnormalities in patients with SALD and to correlate the SALD system with an existing scoring system for mild CF lung disease and pulmonary function tests (PFTs). METHODS: 57 patients with CF contributed one CT made during screening for lung transplantation. For the SALD system, lung tissue was divided into four components: infection/inflammation (including bronchiectasis, airway wall thickening, mucus and consolidations), air trapping/hypoperfusion, bulla/cysts and normal/hyperperfused tissue. The volume proportion of the components was estimated on a 0-100% scale; mean volumes for the whole lung were computed. Scores were correlated with Brody-II scores and PFTs. RESULTS: The SALD system identified a wide spectrum of structural abnormalities ranging from predominantly infection/inflammation to predominantly air trapping/hypoperfusion. SALD infection/inflammation scores correlated with Brody-II scores (r(s) = 0.36-0.64) and SALD normal/hyperperfusion scores correlated with forced expiratory volume in 1 s (FEV(1); r(s) = 0.37). Reproducibility for both systems was good. CONCLUSIONS: A CT scoring system was developed to characterise the structural abnormalities in patients with SALD. A wide spectrum was observed in SALD, ranging from predominantly air trapping to predominantly infection/inflammation-related changes. This spectrum may have clinical implications for patients with SALD.

Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis.

BACKGROUND: A sensitive and valid non-invasive marker of early cystic fibrosis (CF) lung disease is sought. The lung clearance index (LCI) from multiple-breath washout (MBW) is known to detect abnormal lung function more readily than spirometry in children and teenagers with CF, but its relationship to structural lung abnormalities is unknown. A study was undertaken to determine the agreements between LCI and spirometry, respectively, with structural lung disease as measured by high-resolution computed tomography (HRCT) in children and teenagers with CF. METHODS: A retrospective study was performed in 44 consecutive patients with CF aged 5-19 years (mean 12 years). At an annual check-up inspiratory and expiratory HRCT scans, LCI and spirometric parameters (forced expiratory volume in 1 s (FEV1) and maximal expiratory flow when 75% of forced vital capacity was expired (FEF75)) were recorded. Abnormal structure was defined as a composite HRCT score of >5%, the presence of bronchiectasis or air trapping >30%. Abnormal lung function was defined as LCI above the predicted mean +1.96 residual standard deviations (RSD), or FEV1 or FEF75 below the predicted mean -1.96 RSD. Sensitivity/specificity assessments and correlation analyses were done. RESULTS: The sensitivity to detect abnormal lung structure was 85-94% for LCI, 19-26% for FEV1 and 62-75% for FEF75. Specificity was 43-65% for LCI, 89-100% for FEV1 and 75-88% for FEF75. LCI correlated better with HRCT scores (Rs +0.85) than FEV1 (-0.62) or FEF75 (-0.66). CONCLUSIONS: LCI is a more sensitive indicator than FEV1 or FEF75 for detecting structural lung disease in CF, and a normal LCI almost excludes HRCT abnormalities. The finding of an abnormal LCI in some patients with normal HRCT scans suggests that LCI may be even more sensitive than HRCT scanning for detecting lung involvement in CF.

Imaging of respiratory muscles in neuromuscular disease: A review.

Respiratory muscle weakness frequently occurs in patients with neuromuscular disease. Measuring respiratory function with standard pulmonary function tests provides information about the contribution of all respiratory muscles, the lungs and airways. Imaging potentially enables the study of different respiratory muscles, including the diaphragm, separately. In this review, we provide an overview of imaging techniques used to study respiratory muscles in neuromuscular disease. We identified 26 studies which included a total of 573 patients with neuromuscular disease. Imaging of respiratory muscles was divided into static and dynamic techniques. Static techniques comprise chest radiography, B-mode (brightness mode) ultrasound, CT and MRI, and are used to assess the position and thickness of the diaphragm and the other respiratory muscles. Dynamic techniques include fluoroscopy, M-mode (motion mode) ultrasound and MRI, used to assess diaphragm motion in one or more directions. We discuss how these imaging techniques relate with spirometric values and whether these can be used to study the contribution of the different respiratory muscles in patients with neuromuscular disease.

Facemasks and aerosol delivery by metered dose inhaler-valved holding chamber in young children: a tight seal makes the difference.

A facemask on a valved holding chamber (VHC) facilitates the inhalation of aerosols from metered dose inhalers (MDI) for young children. Only recently the facemask has been recognized as a vital part for efficient aerosol delivery. Several in vitro and in vivo studies show that a tight seal of the facemask is crucial for optimal aerosol deposition to the lungs. Even a small leak can reduce the dose delivered to the lungs considerably. However, a tight seal is difficult to obtain when a child is not cooperative. Depending on the design of the facemask, it is easier to obtain a good seal. Factors such as dead space, shape, and material should be considered when designing a facemask. However, when a child is upset and not cooperative during the administration, aerosol deposition will be minimal, even with the best-designed facemask.

Inhaled dry powder mannitol in children with cystic fibrosis: A randomised efficacy and safety trial.

INTRODUCTION: Inhaled mannitol has beneficial effects on lung function, mucociliary clearance, quality of life and sputum properties. This trial examined the efficacy of inhaled mannitol in children with cystic fibrosis (CF). METHODS: The efficacy of inhaled mannitol in children with CF aged 6-17years was assessed in a phase 2, randomised, placebo-controlled crossover study. Subjects were randomly assigned to mannitol 400mg every 12h or matching placebo for 8weeks, followed by an 8week washout and an 8week period with the alternate treatment. The primary endpoint was the absolute change from baseline in ppFEV1 (percent predicted FEV1). RESULTS: A total of 92 subjects were studied, with a mean age of 12years and mean baseline ppFEV1 of 72.2%. During mannitol treatment ppFEV1 was 3.42% (p=0.004) higher compared to placebo or a 4.97% (p=0.005) relative difference; relative change from baseline FEF25-75 was 10.52% (p=0.013). During mannitol treatment, acute post-treatment sputum weight was higher (p=0.012). In pre-specified subgroups (rhDNase use, age, and disease severity), the treatment differences consistently favoured mannitol. The most common AEs were cough and pulmonary exacerbations. Pulmonary exacerbation AEs were approximately 30% lower in the mannitol group. CONCLUSIONS: In children with CF, inhaled mannitol was associated with significant improvements in lung function and sputum weight, irrespective of rhDNase use, age or disease severity. Inhaled mannitol was well tolerated and was associated with a reduced incidence of pulmonary exacerbation AEs. (Clinical Trials.Gov: NCT 01883531).

Effect of dry powder inhaler resistance on the inspiratory flow rates and volumes of cystic fibrosis patients of six years and older.

Several inhaled drugs for use by cystic fibrosis (CF) patients are formulated for nebulizer use only. This therapy is time consuming and includes the risk of contamination of the nebulizers. Dry powder inhalers (DPI) can be an attractive alternative for CF drugs. Inhaled flow rate and volume, and the device resistance are important determinants for optimal dispersion of drug from a DPI. It is important to understand how these variables interact in the CF population in order to properly design a new DPI formulation targeted for these patients. The objective of this study was to assess the inspiratory variables of a representative population of CF subjects 6 years and older with varying degrees of lung disease while inhaling through resistances that simulate DPI devices. Ninety-six stable CF patients were enrolled, ages 6-54 years, FEV(1) 19-126% predicted. Subjects inhaled forcefully through four different resistances (0.019, 0.024, 0.038, and 0.048 kP(0.5)/LPM, respectively), while inspiratory time (IT(DPI)), peak inspiratory flow (PIF(DPI)), and volumes (V(DPI)) were measured. For any resistance, inspired V(DPI) increased with the older age groups; PIF(DPI) was similar between adults and adolescents but lower in the children. Subjects with lower FEV(1) had lower V(DPI) and PIF(DPI). As resistance increased, PIF(DPI) decreased, IT(DPI) increased, with no significant change in V(DPI). At the lowest resistance mean PIF(DPI) was 105 LPM (range 45-163) for all patients; 112 LPM (range 75-163) in adults; and 89 LPM (45-126) in children. Mean inspired V(DPI) was 1.75 L for all patients; 2.2 L (0.8-3.7) in adults; and 1.2 L (0.5-1.8) in children. At the lowest resistance a minimal flow rate of 30, 45, and 60 LPM was attained in 100%, 99%, and 96% of all patients. Volumes of 1.0, 1.5, and 2.0 L were attained by 85%, 57%, and 30% of the patients. At the highest resistance mean PIF(DPI) was 52 LPM (range 26-70) for all patients; 55 LPM (40-70) in adults; and 47 LPM (26-62) in children. Mean inspired V(DPI) was 1.5 L in all patients; 1.9 L (0.9-3.5) in adults and 1.1 L (0.5-2.3) in children. At the highest resistance, a minimal flow rate of 30, 45, and 60 LPM was attained in 99%, 80%, and 22% of all patients. Volumes of 1, 1.5, and 2 L were attained in 84%, 45%, and 23% of the patients. We defined ranges for inspiratory variables in a diverse CF population for a range of device resistances that bracket those of current DPIs. The recorded inspiratory patterns can be used on the bench to design and test new dry powder formulations and devices to target the largest proportion of the CF population.

[Airway malacia: not uncommon in children with atypical respiratory symptoms]. / Luchtwegmalacie: niet zeldzaam bij kinderen met atypische luchtwegsymptomen.

OBJECTIVE: To estimate the prevalence of primary airway malacia at birth, determine the predictive value of a clinical diagnosis of airway malacia compared with bronchoscopy results and describe the presenting symptoms. DESIGN: Retrospective descriptive study. METHOD: We reviewed the results of all bronchoscopies performed in the period 1997-2004 at the Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands, and the standardised status assessment of children diagnosed with primary airway malacia. RESULTS: A total of 512 bronchoscopies were performed. Primary airway malacia was diagnosed in 136 children (80 boys) with a median age of 4.3 years (range: 0-17). The prevalence of primary airway malacia at birth was estimated at approximately 1 in 2100. A diagnosis of probable airway malacia based on symptoms, patient history and targeted assessment of pulmonary function proved to be correct in 74% of patients. However, airway malacia was not suspected before bronchoscopy in 52% of patients. The symptoms were atypical and included: cough, recurrent airway infections, dyspnoea, wheezing and reduced exertional tolerance. The peak expiratory flow was more affected than the forced expiratory volume in 1 second value. CONCLUSION: Primary airway malacia occurs in an estimated 1 out of 2100 children and is difficult to recognise based on patient history and symptoms. Bronchoscopy should be considered to rule out airway malacia in patients with unexplained exertional intolerance, recurrent lower airway infections, or with 'atypical' or 'treatment-resistant' asthma.

[Fatal asthma in childhod preventable by recognizing risk factors and presenting features]. / Fataal astma op de kinderleeftijd te voorkomen door herkenning van risicofactoren en presentatiewijze.

A 6-year-old child known with asthma died from an asthma attack after having had severe dyspnoea which lasted for 1 day. She had been having an average of 40 salbutamol 'puffs' each day for 1 month. For the preceding 8 months she had been having just over half this number as well as fluticasone. A 13-year-old girl died of an asthma attack. Three weeks previously she had been dyspnoeic and had taken salbutamol and prednisone as well as amoxicillin at a later stage. Each year between 8 and 10 children die of an acute exacerbation of asthma in the Netherlands. There are 2 different types of acute fatal asthma: a slow type (I) and a rapidly progressing type (II). In type I there is progressive obstruction of the airways due to oedema, mucous and spasm. Type II predominantly consists of bronchoconstriction. The main risk factors are previous hospital admission with asthma and inadequate maintenance medication. Effective maintenance therapywith the correct dosage ofinhalational corticosteroids administered correctly can probably stop the potentially fatal asthma type II from developing.

Pharmacokinetics and Tolerability of Once Daily Double Dose Tobramycin Inhalation in Cystic Fibrosis Using Controlled and Conventional Nebulization.

BACKGROUND: Better treatment outcomes in cystic fibrosis (CF) may be expected by changing standard twice daily (BID) tobramycin inhalation with the conventional nebulizer to once daily (OD) inhalation at double the standard BID dose with a controlled-inhalation nebulizer. We aimed to determine the pharmacokinetics and tolerability of inhaled double-dose tobramycin with the controlled-inhalation AKITA(®) and conventional PARI-LC(®) Plus nebulizer in patients with CF. METHODS: Randomized, open label, crossover study. Pharmacokinetics were assessed in 10 adult CF patients following inhalation of tobramycin (Bramitob(®)) at double the recommended BID dose with the AKITA (300 mg fill dose) and PARI-LC Plus (600 mg fill dose). RESULTS: No significant differences were found in pharmacokinetic parameters between the two nebulizers. Median maximum serum levels were 3.44 (2.25-5.49) and 2.84 (0.82-6.63) mg/L for AKITA and PARI-LC Plus, respectively. Trough serum levels were very low for both nebulizers: 0.03 (0.00-0.09) and 0.02 (0.00-0.06) mg/L for AKITA and PARI-LC Plus, respectively. Time to maximum level was comparable: 0.44 (0.08-0.96) and 0.40 (0.08-0.96) hours for AKITA and PARI-LC Plus, respectively. Serum levels were well below the toxic limit. Inhalations were well tolerated and no serious adverse events occurred. Nebulization time was 33% shorter with the AKITA. CONCLUSIONS: OD tobramycin inhalation of the double standard BID dose with a controlled-inhalation and conventional nebulizer resulted in similar pharmacokinetics in the doses given, with serum levels below the toxic limit. Further research demonstrating clinical efficacy and safety of this treatment approach is required. Dutch trial register number NTR4525.

Open label study of inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: The ALPINE study.

BACKGROUND: Consensus guidelines recommend early treatment to eradicate newly acquired Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients although there is no single preferred regimen. Aztreonam for inhalation solution (AZLI) significantly reduces sputum Pa density in CF patients with chronic Pa infection and has been well tolerated in the pediatric population. This single-arm, open-label Aztreonam Lysine for Pseudomonas Infection Eradication (ALPINE) study was conducted to evaluate the safety and efficacy of a 28-day treatment course of AZLI to eradicate newly acquired Pa infection in pediatric CF patients. METHODS: CF patients (3 months to <18 years) with new onset Pa infection were treated with AZLI 75 mg 3 times daily for 28 days. New onset Pa infection was defined as first lifetime Pa-positive respiratory tract culture (throat swab, sputum) or Pa-positive culture after a ≥2-year history of Pa-negative cultures (≥ 2 cultures/year). Sputum or throat swab cultures were collected at study entry (baseline) and at weeks 4 (end of treatment), 8, 16, and 28. Primary endpoint was the percentage of patients with cultures negative for Pa at all post-treatment time points. RESULTS: A total of 105 pediatric CF patients enrolled (3 months to <2 years, n=24; 2 to <6 years, n=25; 6 to <18 years, n=56). Of the 101 patients who completed treatment, 89.1% (n=90) were free of Pa at the end of treatment and 75.2% (n=76) were free of Pa 4 weeks after the end of treatment. Of the 79 patients evaluable for the primary endpoint, 58.2% were free of Pa at all post-treatment time points. CONCLUSIONS: AZLI was effective and well tolerated in eradicating Pa from newly infected pediatric patients with CF. These eradication rates are consistent with success rates reported in the literature for various antibiotic regimens, including other inhaled antibiotics studied for eradication. ClinicalTrials.gov: NCT01375049.

The micro-plethysmograph: a new device to measure small volume displacements by isolated human airway segments.

For the study of airway responsiveness in vitro, airway segments have important advances over strip or spiral preparations. The method to study isobaric contraction of segments is not well established. The aim of this work was to develop a model to assess the smooth muscle responses in isolated airway segments under isobaric conditions. We developed a microplethysmograph with a volume measurement range of 10 to 700 microL, a resolution of 0.02-0.4 microL, and a drift of 2.6-0.7% of measurement range min(-1) for its most and least sensitive setting, respectively. The plethysmograph is able to compensate for the pressure changes induced by the volume changes, enabling for true isobaric measurements. We show examples of the isobaric contraction and relaxation of isolated human airway segments after stimulation of an airway segment by methacholine, isoprenaline, or electrical field stimulation. Apart from studying airway responses, the micro-plethysmograph is potentially useful to study the contractile properties of watertight and hollow structures like blood vessels, gut, and ureter. In addition, this device can be used to measure leak or diffusion at any transmural pressure.

Pulmonary diffusing capacity at reduced alveolar volumes in children.

The diffusing capacity, when normalized per liter of alveolar volume (DL,CO/VA) decreases in normal adults, whereas their total diffusing capacity (DL,CO) increases as alveolar volume (VA) increases. We studied these relationships in a group of normal children below 20 years of age. Diffusion variables were determined using the single breath technique. The effects of sex, age, and height on these relationships were estimated. DL,CO increased and DL,CO/VA decreased as alveolar volume increased. DL,CO and DL,CO/VA reference values at total lung capacity (TLC) appeared to be comparable to reference values at TLC in the literature. Reference values of DL,CO and DL,CO/VA derived from measurements at various alveolar volumes also predict similar values at TLC. The advantage of our reference equations is their applicability to patients with restrictive lung disease. Actual DL,CO/VA can be compared with reference DL,CO/VA at actual (restrictive) TLC instead of reference DL,CO/VA at reference TLC. This comparison extends the evaluation of a diffusion disorder.

Aerosol therapy in cystic fibrosis: a survey of 54 CF centers.

Aerosol therapy has become increasingly important in the treatment of lung disease of patients with cystic fibrosis (CF). Still, many questions concerning this therapy remain unanswered. It is unclear at what age aerosol therapy should be started; which aerosolized drugs are essential in the treatment of CF lung disease; which delivery system(s) should be used; and how aerosol therapy should be timed in relation to physiotherapy. We hypothesized that large differences in aerosol treatment practices between CF centers would be present. To investigate this, we performed an observational survey to evaluate different aspects of aerosol therapy. A questionnaire was sent to 102 CF centers in 28 different countries. A completed questionnaire was returned by 54 out of 94 centers (57%). In these 54 centers, 7,324 CF patients were treated. Substantial differences were found in aerosol therapy between centers. Patients below age 1 year were not treated with any form of aerosol therapy in 10% of the centers, while 37.5% of the centers treated all of these patients. The timing of nebulization and physiotherapy varied substantially for many important and expensive drugs. We conclude that many aspects of aerosol therapy in cystic fibrosis need to be executed in a more rational and evidence-based manner than is currently the case.

Staphylococcal pneumonia in childhood: will early surgical intervention lower mortality?

Staphylococcus aureus pneumonia (SAP) continues to be a serious bacterial infection which is associated with a high incidence of complications. We retrospectively reviewed the case records of 36 infants and children admitted with SAP to the Sophia Children's Hospital between 1970 and 1992 to analyse changes over time in the clinical presentation, diagnostic work-up, management and complications. Fifteen of these 36 children (42%) were less than 1 year old. Fever (97%) and respiratory distress (83%) were the most common symptoms at the initial presentation. Chest X-ray findings on admission or during hospitalisation included pleural effusion (75%), pneumothorax (47%), and abscess and/or pneumatocele (39%). Diagnostic and/or therapeutic thoracentesis of pleural fluid was performed in 17 of the 36 patients (47%). Twenty-one patients (58%) needed chest tube drainage. Twelve had a thoracotomy (33%). Artificial ventilation was needed in 13 of the patients (36%). Extrapulmonary complications included convulsions in 6 patients (17%) and osteomyelitis in 2 children (6%). The mean duration of hospitalization was 36 days. Two of the 36 children died (6%). The low mortality rate in this study may be the result of the relatively high rate of thoracotomy and of improvements in supportive treatment.

Altered immunoglobulin concentrations and light chain ratios in juvenile onset mixed connective tissue disease.

Immunological disturbances may result in altered immunoglobulin concentrations and kappa/lambda light chain (kappa/lambda) ratios. We measured the kappa/lambda ratios of total serum immunoglobulins and of polyclonal IgG, A, and M separately as well as concentrations of these immunoglobulins in fourteen patients with juvenile onset mixed connective tissue disease. When comparing the patient group with a reference group the mean serum IgG and IgA concentrations were respectively 2.98 G/L (p = 0.0012) and 0.79 G/L (p = 0.0114) higher in the group of patients with juvenile onset mixed connective tissue disease. The mean IgM concentration was 0.39 G/L (p = 0.0002) lower. The mean kappa/lambda ratios of total serum immunoglobulins, serum IgG, and serum IgA were respectively 0.20 (p = 0.0226), 0.28 (p = 0.0016) and 0.10 (p = 0.0732), higher in the group of patients with mixed connective tissue disease as compared with the reference group. Mean serum IgM kappa/lambda ratio, however, was 0.21 (p = 0.0046) lower. The alterations of the serum immunoglobulin concentrations and of the kappa/lambda ratios reflect immunological disturbances in patients with juvenile onset mixed connective tissue disease. The increased concentration of serum IgG and raised IgG kappa/lambda ratio and decreased concentration of serum IgM with decreased IgM kappa/lambda ratio indicate that the synthesis of kappa-bearing immunoglobulins mainly is affected.

Effect of a facemask leak on aerosol delivery from a pMDI-spacer system.

The objective of this investigation was to study the relation between size and position of a mask leak on spacer output and lung dose. An upper-airway model (SAINT model, Erasmus MC) was connected to a breathing simulator. Facemasks with leaks ranging between 0 and 1.5 cm(2) were examined. Leaks were located close to the nose or close to the chin. During simulated breathing, 200 microg budesonide (Pulmicort, AstraZeneca) was delivered to the model via NebuChamber (AstraZeneca) with facemask. Spacer output and lung dose were measured by placing a filter between spacer and facemask or between model and breathing simulator, respectively. Budesonide trapped on the filter was quantified by means of HPLC, and expressed as percentage of the nominal dose. Mean spacer output doses for the nose position were 50, 38, 28, 12, 10, 6, and 0%, and for the chin position were 50, 40, 31, 11, 9, 4, and 0% for leaks of 0, 0.05, 0.1, 0.16, 0.2, 0.3, and larger than 0.4 cm(2), respectively. Mean lung doses for the nose position were 10, 8, 6, 3, 3, 1, 0, 0, 0, and 0%, and for the chin position were 10, 9, 8, 6, 6, 5, 1, 1, 0, and 0% for leaks of 0, 0.05, 0.1, 0.16, 0.2, 0.3, 0.4, 0.5, 1, and 1.5 cm(2). Efficiency of a pMDI-spacer facemask strongly depends on the size of a facemask leak. Spacer output did not depend on the position of the leak. Lung dose was higher for leaks near the chin than for leaks near the nose.

The Sophia Anatomical Infant Nose-Throat (Saint) model: a valuable tool to study aerosol deposition in infants.

Relatively little is known about the variables that influence lung deposition of inhaled aerosols in children. A model of the upper airways of an infant could be a useful tool to study these variables in vitro. The objective of this study was to construct an anatomically correct model of the upper airways of a young child. A routine three-dimensional (3D) CT scan of the skull and neck of a child was selected that included the airway from the nasal cavity down to the subglottic region. The CT scan was edited to obtain an anatomically correct distinction between air and mucosa. Next, a model was constructed with a stereolithographic technique using a UV-sensitive resin. To validate the model, a 3D CT scan of the model was made and compared to the anatomy of the original image. To study aerosol deposition, the model was connected to a breathing simulator. Medical aerosols were delivered to the model by MDI/spacer during stimulated breathing. An upper airway model was made of a 9-month-old child that needed reconstructive surgery for a skull deformity and with normal anatomy of the upper airways. The nasal airway of the model was open for air passage and the oral airway was closed. The CT scan of the model matched the original in vivo CT scan closely. Aerosol deposition measurements showed that dose passing the model, or lung dose, was comparable with in vivo lung deposition data. We have constructed an anatomically correct model of the upper airways of a child, using a stereolithographic method for in vitro studies of aerosol deposition in young children. This model will be used to obtain insight in aerosol treatment that cannot be obtained in vivo.