Remodelling and inflammation in preschoolers with severe recurrent wheeze and asthma outcome at school age.

BACKGROUND: The influence of airway remodelling and inflammation in preschoolers with severe recurrent wheeze on asthma outcomes is poorly understood. OBJECTIVE: To assess their association with asthma symptoms and lung function at school age. METHODS: Preschoolers (38.4 months) initially investigated with bronchial biopsies were re-assessed for asthma symptoms and lung function at school age. RESULTS: Thirty-six of 49 preschoolers (73.5%) were assessed at 10.9 years. Twenty-six (72.2%) had persistent asthma. Submucosal eosinophil counts were higher in children with severe exacerbations at school age than in those without (16/0.1 mm2 [11.2-30.4] vs 8/0.1 mm2 [2.4-17.6], P = .02), and correlated with the number of severe exacerbations (P = .04, r = .35). Submucosal neutrophil counts correlated with FEV1/FVC (P < .01, r = .47) and FEF25-75% predicted (P = .02, r = .43). Airway smooth muscle (ASM) area correlated with FEV1/FVC (P < .01, r = .51). Vessel numbers negatively correlated with FEV1% predicted and FEV1/FVC (P = .03, r = -.42; P = .04, r = -.41; respectively) and FEF25-75% predicted (P = .02, r = -.46). CONCLUSION: Eosinophilic inflammation in preschoolers with severe recurrent wheeze might be predictive of future severe exacerbations, neutrophilia might be associated with better lung function. Changes in ASM and vascularity might affect lung function at school age.

Contribution of exhaled nitric oxide measurement in airway inflammation assessment in asthma. A position paper from the French Speaking Respiratory Society.

Nitric oxide (NO) is both a gas and a ubiquitous inter- and intracellular messenger with numerous physiological functions. As its synthesis is markedly increased during inflammatory processes, NO can be used as a surrogate marker of acute and/or chronic inflammation. It is possible to quantify fractional concentration of NO in exhaled breath (FENO) to detect airway inflammation, and thus improve the diagnosis of asthma by better characterizing asthmatic patients with eosinophilic bronchial inflammation, and eventually improve the management of targeted asthmatic patients. FENO measurement can therefore be viewed as a new, reproducible and easy to perform pulmonary function test. Measuring FENO is the only non-invasive pulmonary function test allowing (1) detecting, (2) quantifying and (3) monitoring changes in inflammatory processes during the course of various respiratory disorders, including corticosensitive asthma.

[Physiological characteristics associated with previous control in asthmatic children]. / Caractéristiques fonctionnelles associées au contrôle antérieur chez l'enfant asthmatique.

OBJECTIVE: To analyze MEF(50%) (central airways), RV/TLC (distal airways), reversibility of FEV(1) (bronchial tone, REV(FEV1)) and FE(NO) (inflammation) in relation to clinical events in asthmatic children on the assumption that mild symptoms and severe exacerbations in the previous 3 months could be associated with distinct functional characteristics. PATIENTS AND METHODS: A retrospective, single center, out-patient hospital study including all asthmatic children who had complete lung function testing (without and with bronchodilation) during a period of clinical stability, without treatment on the day of the test. RESULTS: Two hundred and forty-five children (11.4±2.4 years) were included: 114 (46%) were asymptomatic, 87 (36%) had minor symptoms and 44 (18%) had had a severe exacerbation in the past 3 months. FEV(1), FEV(1)/FVC and MEF(50%) were not different in these three groups. REV(FEV1) was higher in the symptomatic than in the asymptomatic group (P=0.019), RV/TLC was greater in the exacerbation group than in the asymptomatic group (P=0.019), and FE(NO) was higher in the symptomatic group than in the asymptomatic and exacerbation groups (P=0.006). CONCLUSIONS: In asthmatic children, minor symptoms and severe exacerbation in the previous 3 months are associated with distinct functional characteristics that are not detected by single baseline spirometry without treatment on the day of testing.

Multicentre trial evaluating alveolar NO fraction as a marker of asthma control and severity.

BACKGROUND: Exhaled NO can be partitioned in its bronchial and alveolar sources, and the latter may increase in the presence of recent asthmatic symptoms and in refractory asthma. The aim of this multicentre prospective study was to assess whether alveolar NO fraction and FE(NO) could be associated with the level of asthma control and severity both at the time of measurement and in the subsequent 3 months. METHODS: Asthma patients older than 10 years, nonsmokers, without recent exacerbation and under regular treatment, underwent exhaled NO measurement at multiple constant flows allowing its partition in alveolar (with correction for back-diffusion) and bronchial origins based on a two-compartment model of NO exchange; exhaled NO fraction at 50 ml/s (FE(NO,0.05)) was also recorded. On inclusion, severity was assessed using the four Global initiative for asthma (GINA) classes and control using Asthma Control Questionnaire (ACQ). Participants were followed-up for 12 weeks, control being assessed by short-ACQ on 1st, 4th, 8th and 12th week. RESULTS: Two-hundred patients [107 children and 93 adults, median age (25th; 75th percentile) 16 years (12; 38)], 165 receiving inhaled corticosteroid, were included in five centres. The two-compartment model was valid in 175/200 patients (87.5%). Alveolar NO and FE(NO,0.05) did not correlate to control on inclusion or follow-up (either with ACQ /short-ACQ values or their changes), nor was influenced by severity classes. Alveolar NO negatively correlated to MEF(25-75%) (rho = -0.22, P < 0.01). CONCLUSION: Alveolar and exhaled NO fractions are not indexes of control or severity in asthmatic children and adults under treatment.

[Lung function testing and assessment of distal airways in asthma]. / Epreuves fonctionnelles respiratoires et évaluation des voies aériennes distales dans l'asthme.

INTRODUCTION: Small airways are defined (in humans) as those<2mm in diameter. BACKGROUND: They were originally described as the "quiet zone" of the lungs contributing less than 10% of the total resistance to airflow. Pulmonary function tests remain the most used method to assess distal airway flow limitation. VIEWPOINTS: However, these tests are limited in adults and also in children because MEF25-75% and FEF50% are highly variable spirometric indices and they depend on vital capacity, which increases with expiratory time in obstructed subjects. There is a need for promising non invasive new tools like the forced oscillation technique to measure resistance. The increased availability of the exhaled fraction of nitric oxide (FeNO) measurement means that this method is accessible and attractive. CONCLUSION: The production of nitric oxide (NO) can be assessed by measuring the fraction of NO during a prolonged expiration (FENO) or by estimating other parameters of NO exchange including the alveolar NO concentration (CalvNO) and may provide information about small airway inflammation and assist the optimal control of the disease.

Exhaled nitric oxide in cystic fibrosis: relationships with airway and lung vascular impairments.

A reduction of exhaled nitric oxide (NO) fraction and endothelial-mediated dysfunction have been reported in cystic fibrosis (CF). The aims of the present study were to search for relationships between flow-independent NO exchange parameters (bronchial NO flux (J'(aw,NO)) and alveolar NO concentration (C(A,NO))) and lung function tests characterising airflow limitation and pulmonary vascular bed (capillary blood volume and physiological dead space/tidal volume (V(D)/V(T)) ratio on exercise). In total, 34 patients (16 children, 18 adults) with CF, without resting pulmonary hypertension, underwent spirometry, exhaled NO measurement (multiple constant flow analytical method), gas transfer assessment (carbon monoxide and NO, allowing the calculation of capillary volume and membrane conductance) and a graded exercise test with oxygen uptake (V'(O(2))), carbon dioxide production (V'(CO(2))) and arterial blood gas evaluations. Both J'(aw,NO) and C(A,NO )correlated positively with airflow limitation. C(A,NO) correlated positively with capillary/alveolar volume. During exercise, criteria of mild pulmonary vascular disease were evidenced in some patients that participated in exercise limitation (negative correlation between physiological V(D)/V(T) and peak V'(O(2))). C(A,NO )at rest correlated positively with these parameters of wasted ventilation during exercise (physiological V(D)/V(T), minute ventilation (V'(E))/V'(CO(2)) at ventilatory threshold and V'(E)/V'(CO(2)) slope). Flow-independent exhaled NO parameters are linked to airway and early vascular diseases in patients with CF.

Update on the roles of distal airways in asthma.

The present review is the summary of an expert workshop that took place in Vence (France) in 2007 on the role of distal airways in asthma. The evidence showing inflammation and remodelling in distal airways, and their possible involvement in asthma control and natural history, was reviewed. The usefulness and limitations of various techniques used for assessing distal airways were also evaluated, including pulmonary function tests and imaging. Finally, the available data studying the benefit of treatment better targeting distal airways in asthma was examined. It was concluded that both proximal and distal airways were involved in asthma and that distal airways were the major determinant of airflow obstruction. Inflammation in distal airways appeared more intense in severe and uncontrolled asthma. Distal airways were poorly attained by conventional aerosol of asthma medications owing to their granulometry, being composed of 3-5 µm particles. Both proximal and distal airways might be targeted either by delivering medications systemically or by aerosol of extra-fine particles. Extra-fine aerosols of long-acting ß-agonists, inhaled corticosteroids or inhaled corticosteroid/long-acting ß-agonist combinations have been shown in short-term studies to be not inferior to non-extra-fine aerosols of comparators. However, available studies have not yet demonstrated that extra-fine inhaled medications offer increased benefit compared with usual aerosols in asthmatic patients.

Nitric oxide evaluation in upper and lower respiratory tracts in nasal polyposis.

BACKGROUND: A decrease in nasal nitric oxide (NO) and an increase in exhaled NO have been demonstrated in patients with nasal polyposis (NP). OBJECTIVES: The aims were to evaluate the flux of NO from the three compartments of the respiratory tract, namely, upper nasal, lower conducting and distal airways, and to search for relationships between NO parameters and indexes of upper and lower disease activity (bronchial reactivity and obstruction). The effect of medical treatment of polyposis was also evaluated. METHODS: Seventy patients with polyposis were recruited. At baseline, pulmonary function tests (spirometry, plethysmography, bronchomotor response to deep inspiration using forced oscillation measurement of resistance of respiratory system, methacholine challenge, multiple flow rates of exhaled NO and nasal NO measurements) were performed together with an assessment of polyposis [clinical, endoscopic and computed tomography (CT) scores]. RESULTS: Statistical relationships were demonstrated between nasal NO flux and severity scores (clinical: rho=-0.31, P=0.015; endoscopic: rho=-0.57, P<0.0001; CT: rho=-0.46, P=0.0005), and between alveolar NO concentration and distal airflow limitation (FEF(25-75), rho=-0.32, P=0.011). Thirty-six patients were assessed after 11 [7-13] (median [interquartile]) months of medical treatment, demonstrating an improvement in clinical and endoscopic scores, an increase in nasal NO flux, a decrease in NO flux from conducting airways, an improvement in the mild airflow limitation (forced expiratory volume in 1 s, FEF(25-75), even in non-asthmatic patients) and a decrease in the bronchoconstrictor effect of deep inspiration. CONCLUSIONS: The medical treatment of NP improves both airway reactivity and obstruction, whatever the presence of asthma, suggesting a functional link between upper and lower airway functions.

[Measurement of exhaled nitric oxide: methodology]. / Mesure du NO expiré: méthodologie.

INTRODUCTION: The singular relationship between the exhaled nitric oxide (NO) fraction and the expiratory flow rate has both technical (subject of international guidelines) and theoretical (modelling of pulmonary NO exchange) implications. STATE OF THE ART: Guidelines recommend the measurement of exhaled NO at a single, defined, expiratory flow rate (V') against a positive expiratory pressure to ensure velum closure, providing a fraction of exhaled NO, FE(NO,V'). With some oversimplifications concerning the relationship between FENO and V', NO exchange parameters independent of the expiratory flow rate can be calculated based on a two-compartment model: maximum conducting airway NO flux (J'awNO), alveolar NO concentration (CalvNO), and in some conditions, airway NO diffusing capacity (DawNO) and epithelial NO concentration of conducting airways (CawNO). PERSPECTIVES: Technical progress has provided the pulmonologist with simple equipment to allow the determination of the NO output from the respiratory tract. The two-compartment model provides the physiologist with a non-invasive technique for evaluating the contribution of alveolar space and conducting airways. CONCLUSION: The measurement of exhaled NO allows the non-invasive evaluation of a key mediator involved in the regulation of biological processes.

[The place of expired nitric oxide measurements in asthma]. / Place de la mesure du NO expiré dans l'asthme.

INTRODUCTION: The production of nitric oxide (NO) can be assessed by measuring the fraction of NO during a prolonged expiration (FENO) or by estimating other parameters of NO exchange including the alveolar NO concentration (CalvNO). STATE OF THE ART: Changes in the production of NO are seen in association with clinical events (allergen exposure, minor symptoms, acute crises, changes of treatment) and functional (bronchial hyper-reactivity) or pathological (eosinophilia, remodeling markers) features characterising asthmatic phenotypes. PERSPECTIVE: Measurement of NO is a non-invasive tool for the evaluation of atopy, particularly in the course of allergic asthma. The interpretation of a single measurement is limited by the variability of the values associated with a stable state in the allergic population: the use in practice (risk of exacerbation, follow up, adjustment of steroid treatment) depends on analysis of sequential variations in FENO. Calculation of CalvNO may provide information about small airway inflammation and assist the optimal control of the disease. CONCLUSION: Ambulatory measurement of expired NO and the estimation of parameters describing NO exchange, independently of expiratory flow, could become the key evaluations in the monitoring of allergic asthma.

[Off-line exhaled nitric oxide measurement in children]. / Mesure de la fraction expirée de NO chez l'enfant par une analyse extemporanée.

INTRODUCTION: The objective is to test the validity of a tool allowing an offline measurement of the fraction of expired nitric oxide (FENO). The device is a T-tube on which a pressure gauge allows the control of the expiratory flow and whose two side branches have a gauge such as the bags assembled on each one of them fill successively. METHODS: The first phase aims to check that the sample collected in the second bag answers the criteria of analysis of NO during a single expiration and that this measurement can be delayed. The second phase aims to test the feasibility and the repeatability of the offline analysis in children. RESULTS: The device makes it possible to stabilize the expiratory flow at 100 ml/s. The NO concentration in the second bag is stable during 6 hours. The intra measurement coefficient of variation of delayed FENO 0.1 is 7% (N = 19). CONCLUSION: A off line measurement of the exhaled nitric oxide is reliable in asthmatic children.

Bronchial casts in children with cardiopathies: the role of pulmonary lymphatic abnormalities.

Expectoration of bronchial casts, a condition also called plastic bronchitis, is very rare in children. Bronchial casts may be associated with bronchopulmonary diseases associated with mucus hypersecretion, bronchopulmonary bacterial infections, congenital and acquired cardiopathies, or pulmonary lymphatic abnormalities. A classification based on anatomy and pathology has been proposed which identifies an "acellular" group associated with congenital cardiopathies and palliative surgery. We report on 3 cases with bronchial casts associated with cardiopathy. Observations suggest that the formation of bronchial casts may result from lymphatic leakage into the bronchi. The 3 cases on which we report were immunodeficient and had pulmonary lymphatic abnormalities. The bronchial casts contained lymphocytes and lipids, as determined by histologic examination. In the absence of congenital pulmonary or diffuse lymphatic dysplasia associated with cardiopathy, the principal factors resulting in the formation of bronchial casts appear to be surgical trauma to the lymphatic channels surrounding the bronchi, pleural adhesions, and high systemic venous blood pressure. The prognosis for these patients is poor, and possibilities for treatment are limited.

[Acute viral respiratory infections and asthma]. / Infections respiratoires aiguës virales et asthme.

Respiratory viral infections are very important triggers of asthma exacerbation. Recent epidemiologic studies support the hypothesis that they are associated with 80 to 85% of acute attacks of asthma in children. The respiratory syncytial and parainfluenza viruses are predominantly detected in infants, while rhinovirus and mycoplasma are the commonest in children. In practice for an asthmatic child, it is necessary: 1. to vaccinate against influenza; 2. resume or increase the inhaled antiinflammatory therapeutics in moderate to severe asthma, before the viral epidemic season; 3. teach the child and his family on the attitude to have during an upper respiratory infection and when to visit a physician.

Efficacy of nebulized budesonide in treatment of severe infantile asthma: a double-blind study.

BACKGROUND AND OBJECTIVE: Treatments with inhaled corticosteroids yielded conflicting results in infants with severe asthma. The purpose of this study was to assess the efficacy of nebulized budesonide on the control of asthma in this age group. METHODS: In a double-blind, placebo-controlled study, 40 infants with severe asthma received either nebulized budesonide (1 mg) or placebo twice daily for 12 weeks, followed by a follow-up period of up to 12 weeks. A jet nebulizer driven by an air compressor was used to administer budesonide and placebo. RESULTS: Fewer patients in the budesonide group had an exacerbation during the treatment period (40%) compared with the placebo group (83%, p < 0.01). The duration of oral steroid therapy was shorter in the budesonide group than in the placebo group (median number of days of exacerbation as a proportion of the total treatment time, 0% vs 14.5%; p < 0.05). The incidence of daytime (p < 0.05) and nighttime wheezing (p < 0.01) was lower in the budesonide group than in the placebo group during the treatment period. The proportion of patients without an exacerbation of asthma during the entire 24 weeks was 28% for those patients who had received budesonide and 0% for those patients who had received placebo. Asthma improved in more patients in the budesonide group (17 and 19, 89%) than in the placebo group (7 of 16, 44%; p < 0.005). These results should improve and modify the treatment of infants with severe asthma. CONCLUSION: Nebulized budesonide (1 mg twice daily) is a well-tolerated and efficient treatment for severe infantile asthma.

Pulmonary alveolar proteinosis: experience with eight pediatric cases and a review.

We report eight pediatric cases of pulmonary alveolar proteinosis (PAP) that illustrate the polymorphic nature of this disease: two cases with severe neonatal onset, three cases with progressive respiratory distress in patients under 1 year old, and three cases in older children with mild symptoms. Consanguineous parents or affected siblings were identified or suspected in four families. Three patients suffered from associated immune or blood disorders (severe combined immune deficiency, myelodysplasia). The respective roles of a macrophagic dysfunction and of an anomaly of the surfactant are discussed according to the various clinical presentations of pediatric PAP. We performed eight unilateral pulmonary lavages under endoscopy and selective ventilation for two patients under 7 kg in weight. These interventions led to progressive discontinuation of oxygen therapy in one case, and temporarily stabilized the disease for the second. Subsequent recurrence in this second patient was treated by massive lavage under extracorporeal oxygenation. A third infant was successfully transplanted with no recurrence within 3 years. Ambroxol was administered in one case. The three oldest children of our series remained asymptomatic, whereas three of the younger patients died. In the light of this experience, we propose that the treatment administered should be determined according to the age of the patient, the degree of respiratory deficiency, and the nature of any associated pathology.

Use of polymerase chain reaction for improved diagnosis of tuberculosis in children.

OBJECTIVE: To study the value of a rapid diagnostic method based on the amplification by polymerase chain reaction (PCR) of a fragment of the IS6110 insertion element for the detection of Mycobacterium tuberculosis in children. DESIGN: We tested 199 specimens obtained from 68 children referred for evaluation of suspected tuberculosis. RESULTS: In 83.3% of children with active disease and 38.9% with tuberculous infection but no evidence of disease, at least one positive PCR result was observed. No child without tuberculosis had positive PCR results (100% specificity). The sensitivity of the PCR was increased by testing of multiple samples from the same child and use of Chelex particles (Bio-Rad Laboratories, Ivry, France) rather than guanidine isothiocyanate-silica particles for DNA extraction. Bronchoalveolar lavage samples were no more useful than gastric aspirates. CONCLUSIONS: If appropriate laboratory methods are used, DNA amplification is a reliable method for the early diagnosis of tuberculosis in children and appears to be very helpful in clinical pediatric practice when the diagnosis of active tuberculosis is difficult or needs to be rapidly confirmed.

Cerebrospinal fluid penetration of amikacin in children with community-acquired bacterial meningitis.

The penetration of amikacin into the cerebrospinal fluid (CSF) was studied with 16 children (mean age, 1 year and 9 months; range, 4 months to 8 years) with community-acquired bacterial meningitis. Amikacin was given intravenously at a dose of 7.5 mg/kg of body weight twice daily. CSF was collected on day 1, at the expected peak concentration of amikacin in CSF. The mean (standard deviation) concentration of amikacin in CSF was 1.65 (1.6) mg/liter. Concentrations of amikacin in CSF correlated significantly with CSF glucose levels on admission. The mean concentrations of amikacin in CSF were 2.9, 1.1, and 0.20 mg/liter in patients with CSF glucose levels of < 1, 1 to 2, and > 2 mmol/liter, respectively. Thus, amikacin penetrates the blood-brain barrier substantially in children with bacterial meningitis and achieves particularly high concentrations when CSF glucose level is < 1 mmol/liter on admission.