Reported Exercise-Related Respiratory Symptoms and Exercise-Induced Bronchoconstriction in Asthmatic Children.

BACKGROUND: Unlimited physical activity is one of the key issues of asthma control and management. We investigated how reliable reported exercise-related respiratory symptoms (ERRS) are in predicting exercise-induced bronchoconstriction (EIB) in asthmatic children. METHODS: In this prospective study, 179 asthmatic children aged 7 - 15 years were asked for specific questions on respiratory symptoms related to exercise and allocated into two groups according to whether they complained about symptoms. Group I (n = 134) consisted of children answering "yes" to one or more of the questions and group II (n = 45) consisted of children answering "no" to all of the questions. RESULTS: Sixty-four of 179 children showed a positive exercise challenge test (ECT). There was no difference in the frequency of a positive test between children in group I (n = 48) and group II (n = 12) (P = 0.47). The sensitivity of a positive report for ERRS to predict a positive ECT was only 37%, with a specificity of 0.72. CONCLUSION: According to current guidelines, the report or lack of ERRS has direct consequences on treatment decisions. However, the history of ERRS did not predict EIB and one-third of asthmatic children without complaints of ERRS developed EIB during the ECT. This raises the question of the need for objective measures of bronchial hyperresponsiveness (BHR) in pediatric asthma management.

Effects of a short-term rehabilitation program on airway inflammation in children with cystic fibrosis.

BACKGROUND: Respiratory therapy in cystic fibrosis (CF) consists of airway clearance, infection control, and reduction of airway inflammation. It is well recognized that physical activity as well as daily chest physiotherapy, enhance airway clearance. We investigated the effects of pulmonary rehabilitation, including physical activity and chest physiotherapy, on airway inflammation in children with CF. METHODS: Eighteen children with stable CF (six females), aged 8.2-16.2 years, participating in a 3-week multidisciplinary inpatient rehabilitation program were recruited. Assessment at the beginning and the end of the program included clinical score, pulmonary function test, exhaled breath condensate (EBC) and sputum analysis. Sputum supernatant and EBC were analyzed for interleukin (IL)-1b, 6, 8, 10, 12, tumor necrosis factor-alpha (TNF-alpha) and LTB4. RESULTS: Median (IQR) symptom scores decreased from 19 [23] to 16 [21], P = 0.005. Vital capacity and FVC increased significantly (P < 0.05). However no difference was found for the total sputum cells and sputum as well as EBC cytokines between the two visits. Significant correlations were found for sputum IL-1 (+), IL-6 (-), and IL-8 (+) to total sputum cell count and neutrophils and for IL-8 to TNF-alpha. CONCLUSIONS: We have shown that a short-term inpatient rehabilitation for children with stable CF with intensive physical activity mainly improve subjective clinical symptoms and measures of lung function such as VC and FVC but does not influence airflow obstruction and airway inflammation as assessed by sputum and EBC analysis.

Aerosol delivery of nebulised budesonide in young children with asthma.

BACKGROUND: Lung deposition of inhaled steroids, likely to be of benefit in the anti-inflammatory treatment of asthma in young children, is low. This is explained by age specific anatomical and physiological characteristics as well as poor cooperation with aerosol therapy. However, total lung deposition and the ratio of lung deposition to oropharyngeal deposition are key determinants of clinical efficacy and of systemic side effects of aerosolized drugs. OBJECTIVES: The aim of this study was to determine lung deposition and ratio of lung deposition to oropharyngeal deposition using a modified vibrating membrane nebuliser to deliver budesonide with a small particle size, taking into account the needs of young children. PATIENTS AND METHODS: Ten asthmatic children (5 males), mean age 20.3 months (range 6-41 months) inhaled radiolabelled budesonide (MMD 2.6microm) through a modified vibrating membrane nebuliser (modified PARI e-Flow). Lung deposition expressed as a percentage of the emitted dose was measured using scintigraphy and the ratio of lung deposition to oropharyngeal deposition was calculated. RESULTS: Mean lung deposition (SD) expressed as percentage of emitted dose and mean lung to oropharyngeal deposition ratio (SD) in quietly breathing children (n=5) and in children crying during inhalation were 48.6% (10.5) versus 20.0% (10.9), and 1.0 (0.3) versus 0.3 (0.2), respectively. CONCLUSIONS: We have shown that by using an improved age-adjusted complementary combination of delivery device and drug formulation to deliver small particles, lung deposition and ratio of lung deposition to oropharyngeal deposition in young asthmatic children is highly improved. But the main factor limiting aerosol delivery in this age group remains cooperation.

Respiratory flow phenomena and gravitational deposition in a three-dimensional space-filling model of the pulmonary acinar tree.

The inhalation of micron-sized aerosols into the lung's acinar region may be recognized as a possible health risk or a therapeutic tool. In an effort to develop a deeper understanding of the mechanisms responsible for acinar deposition, we have numerically simulated the transport of nondiffusing fine inhaled particles (1 mum and 3 microm in diameter) in two acinar models of varying complexity: (i) a simple alveolated duct and (ii) a space-filling asymmetrical acinar branching tree following the description of lung structure by Fung (1988, "A Model of the Lung Structure and Its Validation," J. Appl. Physiol., 64, pp. 2132-2141). Detailed particle trajectories and deposition efficiencies, as well as acinar flow structures, were investigated under different orientations of gravity, for tidal breathing motion in an average human adult. Trajectories and deposition efficiencies inside the alveolated duct are strongly related to gravity orientation. While the motion of larger particles (3 microm) is relatively insensitive to convective flows compared with the role of gravitational sedimentation, finer 1 microm aerosols may exhibit, in contrast, complex kinematics influenced by the coupling between (i) flow reversal due to oscillatory breathing, (ii) local alveolar flow structure, and (iii) streamline crossing due to gravity. These combined mechanisms may lead to twisting and undulating trajectories in the alveolus over multiple breathing cycles. The extension of our study to a space-filling acinar tree was well suited to investigate the influence of bulk kinematic interaction on aerosol transport between ductal and alveolar flows. We found the existence of intricate trajectories of fine 1 microm aerosols spanning over the entire acinar airway network, which cannot be captured by simple alveolar models. In contrast, heavier 3 microm aerosols yield trajectories characteristic of gravitational sedimentation, analogous to those observed in the simple alveolated duct. For both particle sizes, however, particle inhalation yields highly nonuniform deposition. While larger particles deposit within a single inhalation phase, finer 1 microm particles exhibit much longer residence times spanning multiple breathing cycles. With the ongoing development of more realistic models of the pulmonary acinus, we aim to capture some of the complex mechanisms leading to deposition of inhaled aerosols. Such models may lead to a better understanding toward the optimization of pulmonary drug delivery to target specific regions of the lung.

Eicosanoids in exhaled breath condensates in the assessment of childhood asthma.

The value of measurements of eicosanoids in exhaled breath condensate (EBC) for the evaluation of childhood asthma is still inconclusive most likely because of the limited value of the methods used. In this case-control study in 48 asthmatic and 20 healthy children, we aimed to characterize the baseline profile of the inflammatory mediators cysteinyl leukotrienes (cysLTs), 9(alpha)11(beta)PGF(2), PGE(2), PGF(2alpha), 8-isoprostane (8-iso-PGF(2alpha)) within EBC in asthmatic compared with healthy children using new methods. In addition, we investigated their relation to other inflammatory markers. The assessment included collection of EBC, measurement of fractional exhaled nitric oxide (FE(NO)) and evaluation of urinary excretion of leukotriene E(4.) cysLTs were measured directly in EBC by radioimmunoassay and prostanoids were measured using gas chromatography negative-ion chemical ionization mass spectrometry. Only cysLT levels were significantly higher in asthmatic compared with healthy children (p = 0.002). No significant differences in cysLTs were found between steroid naïve and patients receiving inhaled corticosteroids. In contrast, FE(NO) was significantly higher in steroid naïve compared with steroid-treated asthmatic and healthy children (p = 0.04 and 0.024, respectively). The diagnostic accuracy of cysLTs in EBC for asthma was 73.6% for the whole group and 78.2% for steroid-naïve asthmatic children. The accuracy to classify asthmatic for FE(NO) was poor (62.9%) for the whole group, but improved to 79.9% when only steroid-naïve asthmatic children were taken into consideration. cysLTs in EBC is an inflammatory marker which distinguishes asthmatics, as a whole group, from healthy children.

Exhaled nitric oxide distinguishes between subgroups of preschool children with respiratory symptoms.

BACKGROUND: Respiratory symptoms are common in early childhood. The clinical characterization of disease presentation and hence its likely disease progression has so far been proven difficult. OBJECTIVE: To investigate whether exhaled nitric oxide (NO) could be helpful to distinguish between subgroups of nonwheezy and wheezy young children less than 4 years of age. METHODS: Exhaled NO was measured in 391 children (age 3-47 months) with nonwheezy and wheezy respiratory symptoms. Children were divided into 3 groups: children with recurrent cough but no history of wheeze (group 1), with early recurrent wheeze and a loose index for the prediction of asthma at school age (group 2), and with frequent recurrent wheeze and a stringent index for the prediction of asthma at school age (group 3). RESULTS: Children from group 3 showed significantly higher median (interquartile range) fractional exhaled NO (FeNO) levels (11.7 [11.85]) than children from groups 1 (6.5 [5.5]; P < .001) and 2 (6.4 [6.5]; P < .001). No difference in FeNO levels was found between children from groups 1 and 2 (P = .91). CONCLUSION: Wheezy young children less than 4 years of age with a stringent index for the prediction of asthma at school age have elevated levels of FeNO compared with children with recurrent wheeze and a loose index for the prediction of asthma at school age or children with recurrent cough.

Correlation of spirometry and symptom scores in childhood asthma and the usefulness of curvature assessment in expiratory flow-volume curves.

BACKGROUND: Spirometry, and in particular forced expiratory volume in the first second (FEV(1)), are standard tools for objective evaluation of asthma. However, FEV(1) does not correlate with symptom scores, and hence its value in the assessment of childhood asthma may be limited. Therefore, some clinicians subjectively assess the presence of curvature in the maximum expiratory flow-volume (MEFV) curves obtained from spirometry, where concave patterns are observable despite normal FEV(1) values. OBJECTIVE: To evaluate the usefulness of subjective and objective measures of the curvature in the descending phase of the MEFV curve for the assessment of asthma. METHODS: We obtained symptom scores and performed spirometry in 48 patients with asthma (21 females, mean +/- SD age 10.8 +/- 2.4 y). We measured FEV(1), the ratio of FEV(1) to forced vital capacity (FEV(1)/FVC), maximum expiratory flow at one quarter of the way, and at halfway, through the forced expiratory maneuver (MEF(25) and MEF(50), respectively), and maximum expiratory flow in the middle half of the forced expiratory maneuver (MEF(25-75)). Expiratory obstruction was ranked independently by 3 pediatric pulmonologists, by subjective assessment of the MEFV curve. In addition, the curvature of the descending limb of the MEFV curve was quantitatively estimated by introducing an "average curvature index." RESULTS: No significant correlations were found between FEV(1), MEF(50), MEF(25), and MEF(25-75,) respectively, and symptom score (r = -0.22, p = 0.14; r = -0.23, p = 0.11; r = -0.28, p = 0.057; r = -0.27, p = 0.06). A weak correlation was found for FEV(1)/FVC and symptom score (r = -0.33, p = 0.021). However, quantitatively determined average curvature index (ACI) correlated significantly better with measured symptom scores (r = 0.53, p < 0.001) and were in good agreement with the assessment of expiratory obstruction from subjective curvature assessment. CONCLUSIONS: Our general findings show that individual lung function variables do not correlate well with symptoms, whereas subjective curvature assessment is thought to be helpful. With the average curvature index we have illustrated a potential clinical usefulness of quantifying the curvatures of MEFV curves.

Facemasks and aerosol delivery in vivo.

It has been shown in vitro that even a small air leak in the facemask can drastically reduce the efficiency of drug delivery. In addition, it has been shown that drug deposition on the face does significantly add to overall drug loss and has the potential of local side effects. The aim of this study is therefore to verify these findings in vivo. Eight asymptomatic recurrently wheezy children, aged 18-36 months, inhaled a radiolabeled salbutamol formulation either from a pressurized metered-dose inhaler through a spacer with attached facemask or from a nebulizer with attached facemask. Drug deposition of radiolabeled salbutamol was assessed with a gamma camera and expressed as a percentage of the total dose. Lung deposition expressed as a percentage of the total dose (metered dose and nebulizer fill, respectively) was 0.2% and 0.3% in children who inhaled with a non-tightly fitted facemask. Lung deposition was 0.6% and 1.4% in screaming children with a tightly fitted facemask and between 4.8% and 8.2% in patients breathing normally. Overall mask deposition was between 0.8% and 5.2%. Overall face deposition was between 2.6% and 8.4%. The results from this pilot study support the results found in in vitro studies, where a facemask leak greatly reduces drug delivery to the patient.

Sleep and respiration in children: time to wake up!

The interest in paediatric sleep disorders over the last few decades has had its main focus on the sudden infant death syndrome (SIDS) - healthy infants who go to sleep and never wake up again. Overall, this is the most dramatic form of paediatric sleep disordered breathing. By contrast, classical presentations of sleep disordered breathing in children, such as snoring and obstructive sleep apnoea as well as their clinical implications have been greatly neglected and underestimated in the past. In contrast to snoring in adults, snoring in children has so far generally been regarded as noisy breathing with no significant impact on the general health of children. This is also to a lesser extent true for obstructive sleep apnoea syndrome (OSAS). The sometimes dramatic complications of OSAS, such as cor pulmonale and developmental retardation have at least indicated that OSAS in children is important and may have a great impact on the general health of children. This has led to an increased interest from a clinical as well as a scientific point of view with some important findings, mainly that sleep disordered breathing in childhood varies from sleep disordered breathing in adulthood and that even mild to moderate disease has a huge impact on the general health of children, mainly on neurocognitive development.

Asthma control in Switzerland: a general practitioner based survey.

BACKGROUND: Achievement of optimal asthma control is the goal of the Global Initiative for Asthma (GINA) guidelines. METHODS: In a survey involving 281 physicians, asthma control was assessed using the Juniper asthma control questionnaire (ACQ); physicians were also asked to judge patients' asthma control subjectively. RESULTS: In total, 2127 patients were included. Follow-up was available in 1893 (89%) patients (885 females). The mean time between visits was 62 +/- 29.3 days; mean age was 45 years (+/- 19 years) and 30% were smokers. Well-controlled asthma was found in 298 patients (16%). Smokers were less likely to have well-controlled asthma (smokers 12% vs. non-smokers 18%). Physicians assessed asthma control to be good in 292 patients (15%), sufficient in 504 (27%), insufficient in 954 (50%) and poor in 137 (7%) patients. Of the 292 patients assessed by their physicians as 'good asthma control', only 142 (49%) were confirmed as 'well-controlled' by the ACQ. At the first visit, 1308 (69%) patients were pre-treated with any inhaled corticosteroids (ICS). Pretreatment with leukotriene receptor antagonists (LTRAs) was reported in 127 patients (7%). Add-on therapy with the LTRA montelukast was the most frequent treatment adjustment at the first visit. Out of 1893 patients who had a follow-up visit, 298 (16%) were well controlled at the first visit and 1170 (62%) at the follow-up visit. CONCLUSION: Asthma control is insufficient in the majority of patients. Improvement of asthma control can be achieved by using objective measures such as the ACQ in regular clinical practice and adapting therapy.

Free 3-nitrotyrosine in exhaled breath condensates of children fails as a marker for oxidative stress in stable cystic fibrosis and asthma.

3-Nitrotyrosine (3-NT) is considered as a marker of oxidative stress, which occurs during inflammation. Since 3-NT levels in exhaled breath condensate (EBC) are very low, we applied a specific and sensitive gas chromatography-negative ion chemical ionization-mass spectrometry (GC-NICI-MS) method and high performance liquid chromatography (HPLC) with electrochemical detection for the analysis of free 3-NT in EBC. A total of 42 children (aged 5-17 years) were enrolled in this study, including children with asthma (n=12), cystic fibrosis (n=12), and healthy controls (n=18). Additionally, 14 healthy non-smoking adults (aged 18-59 years) were included. An EcoScreen system was used for the collection of EBC samples. Free 3-NT levels in EBC ranged from 0.54-6.8 nM. Median (interquartile range) concentrations (nM) were similar in all groups: 1.46 (0.97-2.49) in healthy adults, 2.51 (1.22-3.51) in healthy children, 1.46 (0.88-2.02) in children with asthma, and 1.97 (1.37-2.35) in CF children, respectively (p=0.24, Kruskall-Walis test). No difference was found between the children with airway disease and age-matched healthy controls. In healthy subjects, there was no effect of age on 3-NT concentrations. HPLC analyses provided similar concentration ranges for EBC 3-NT when compared with GC-NICI-MS. Our study has clearly demonstrated that free 3-NT in EBC fails as a marker for oxidative stress in children with stable CF and asthma.

Disease control in asthmatic children seen in private practice in Switzerland.

BACKGROUND: Asthma is the most common chronic childhood disease in Switzerland with a prevalence of 10%. Asthma has a high economic burden accounting for high medical costs. Assessment of disease control is likely to be of help in the implementation of strategies to improve asthma. Therefore, we aimed to evaluate asthma control and therapy regimens among children in private practice. METHODS: We assessed asthma control as well as therapy regimens in 575 asthmatic children in an experience programme in Switzerland by using an abbreviated questionnaire based on the asthma control questionnaire and the child health questionnaire on Visit 1 and Visit 2. RESULTS: Good asthma control at Visit 1 was only present in 25.7% of asthmatic children. Occasional asthma symptoms, limitation of physical activity, nocturnal awakening and anxiety of the parent was present in 80.5%, 41.2%, 46.8% and 57% of the children, respectively. After adjustment of therapy regimens at Visit 1, mainly by adding a leukotriene receptor antagonist, asthma control was reported to be much better in 53.4% of the children at Visit 2. CONCLUSIONS: As asthma control is inadequately achieved within a major portion of asthmatic children, it is imperative to find measures to improve asthma control and hence, to reduce the burden of disease.

Novel molecular therapy.

Anti-inflammatory treatment, mainly with inhaled corticosteroids, is the cornerstone of asthma therapy. There are a number of new more specific therapies based on a molecular approach. Despite some promising results from some novel molecular therapies there are also some studies which have shown no effect of these treatments.

Aerosols: the environmental harmful effect.

Aerosols as end products of ambient indoor and outdoor pollution have some potential harmful effect. Children are especially at risk due to their developing organ systems. This is mainly true for the lungs, but may also be true for other organ systems, such as the immune system.

Measuring exhaled breath condensates in infants.

There is growing interest in investigating compounds of exhaled breath condensates (EBC) as potential noninvasive markers of airways disease processes. Some of these markers have the potential to provide information on the early stages of disease. In this paper, we present a method for collecting EBC during both oral and nasal breathing in infants. Fifty-four infants (mean age, 13.3 months; range, 1-30 months) undergoing infant lung-function testing were recruited for this study. Breath condensates were collected during sedated sleep, using a custom-made collection device. Collections were made for 10 min during normal tidal breathing. Nasal measurements were attempted in all children by placing a face-mask over the nose and mouth and keeping the mouth closed. In 14 infants, oral measurements were made by placing a face-mask over the mouth only and occluding the nose. Condensates were collected successfully in all but one child. The collected volume ranged from 50-550 microl (mean +/- SD, 281.8 +/- 145.8 microl). The volume of EBC collected was correlated to age, length, weight, and minute ventilation. Significantly more EBC was collected during oral compared to nasal breathing (354.3 vs. 277.5 microl, P=0.03). There were no significant changes in heart rate, respiratory rate, or oxygen saturation during collection. The collection of EBC in young children and infants is feasible and safe, and the method used here allows the successful collection of reasonable amounts of exhaled condensate.

In vitro determination of the optimal particle size for nebulized aerosol delivery to infants.

We investigated the in vitro influence of breathing patterns on lung dose (LD) and particle size distribution in an infant upper airway cast model in order to determine the optimal particle size for nebulized aerosol delivery to infants. Budesol (nebulizer solution of budesonide) delivery from a perforated vibrating membrane nebulizer (eFlow Baby functional prototype) through an upper airway cast of a nine month old infant (SAINT-model) was measured at a fixed respiratory rate (RR) of 30 breaths per minute (bpm) and a tidal volume (Vt) of 50, 100, and 200 mL, respectively, and at a fixed Vt of 100 mL and a RR of 30, 60, and 78 bpm, respectively. LD expressed as a percentage of the nominal dose (ND; range, 5.8-30.3%) decreased with increasing Vt (p < 0.001) and with increasing RR (p < 0.001). Median mass aerodynamic diameter (MMAD) after passage (range, 2.4-3.4 microm) through the upper airway cast showed a negative correlation with increasing Vt (p < 0.001) and with increasing RR (p = 0.015). Particles available as LD for all simulated breathing pattern showed a particle size distribution with a MMAD of 2.4 microm and a geometric standard deviation (GSD) of 1.56. From our in vitro study, we conclude that the optimal particle size for nebulized aerosols for inhalation therapy for infants should have a MMAD of <2.4 microm.

Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia.

RATIONALE: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by recurrent infections of the airways and situs inversus in half of the affected offspring. The most frequent genetic defects comprise recessive mutations of DNAH5 and DNAI1, which encode outer dynein arm (ODA) components. Diagnosis of PCD usually relies on electron microscopy, which is technically demanding and sometimes difficult to interpret. METHODS: Using specific antibodies, we determined the subcellular localization of the ODA heavy chains DNAH5 and DNAH9 in human respiratory epithelial and sperm cells of patients with PCD and control subjects by high-resolution immunofluorescence imaging. We also assessed cilia and sperm tail function by high-speed video microscopy. RESULTS: In normal ciliated airway epithelium, DNAH5 and DNAH9 show a specific regional distribution along the ciliary axoneme, indicating the existence of at least two distinct ODA types. DNAH5 was completely or only distally absent from the respiratory ciliary axoneme in patients with PCD with DNAH5- (n = 3) or DNAI1- (n = 1) mutations, respectively, and instead accumulated at the microtubule-organizing centers. In contrast to respiratory cilia, sperm tails from a patient with DNAH5 mutations had normal ODA heavy chain distribution, suggesting different modes of ODA generation in these cell types. Blinded investigation of a large cohort of patients with PCD and control subjects identified DNAH5 mislocalization in all patients diagnosed with ODA defects by electron microscopy (n = 16). Cilia with complete axonemal DNAH5 deficiency were immotile, whereas cilia with distal DNAH5 deficiency showed residual motility. CONCLUSIONS: Immunofluorescence staining can detect ODA defects, which will possibly aid PCD diagnosis.

The effect of montelukast on exhaled nitric oxide and lung function in asthmatic children 2 to 5 years old.

OBJECTIVE: The study was undertaken to investigate the influence of once-daily treatment with montelukast (Singulair; MSD; Glattbrugg, Switzerland) on levels of exhaled nitric oxide (eNO) and lung function in preschool children with asthma. METHODS: A total of 30 children (19 girls), 2 to 5 years of age, in whom asthma had been newly diagnosed, who had a positive first-degree family history of asthma and a positive allergy test result, were allocated to undergo a 1-week run-in period of montelukast treatment. eNO and airway resistance were measured in all patients before (visit 1) and after the run-in period (visit 2), and after treatment with montelukast (4 mg once daily) for 4 weeks (visit 3). RESULTS: There were no significant differences in all parameters before and after the run-in period. However, the mean (SD) levels of eNO and the mean (SD) levels of airway resistance after treatment at visit 3 were 11.6 parts per billion (ppb) [9.5 ppb] and 1.15 kPa/L/s (0.26 kPa/L/s), respectively, and were significantly lower compared to values of 33.1 ppb (12.0 ppb) and 1.28 kPa/L/s (0.23 kPa/L/s), respectively, before treatment (p < 0.001) and at visit 2 (p = 0.01). There was no significant change in mean bronchodilator responsiveness between visit 3 (13.2%; SD, 6.8%) and visit 1/visit 2 (13.3%; SD, 7.0%; p = 0.47). CONCLUSION: We have shown that montelukast has a positive effect on lung function and airway inflammation as measured by nitric oxide level in preschool children with allergic asthma.