Invariant natural killer T cells in bronchial asthma.
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Asthma↗
Biomedical subjects
Jacques de Blic
Publications and source records attributed to Jacques de Blic.
Nitric oxide in children with persistent asthma.
OBJECTIVE: To assess the difference in exhaled nitric oxide levels in atopic and nonatopic asthmatic patients treated with anti-inflammatory drugs, and to compare exhaled nitric oxide measurement with lung function tests. METHODS: Cross-sectional study with 45 consecutively selected patients with moderate and severe persistent asthma, aged between 6 and 17 years, and treated with anti-inflammatory drugs for at least 1 year. The patients were split into two groups: atopic ones (with positive skin tests) and nonatopic ones. The clinical and functional assessments and the measurement of exhaled nitric oxide were carried out concomitantly. RESULTS: There was a male predominance (62.5%), with an age range between 6 and 13 years (mean of 10.4 years) in 85% of the patients. Neither the symptoms associated with asthma (p = 0.07), allergic rhinitis (p = 0.17), food allergy (p = 0.09), necessity of systemic corticosteroids (p = 0.10), antileukotrienes (p = 0.20) and antihistamines (p = 0.70), nor the three parameters used to assess lung function (FEV(1), FEV(1)/FVC and FEF(25-75%), p > or = 0.14) were statistically significant. The frequency of eczema (p < 0.005) and exhaled nitric oxide levels (p < 0.001) were higher among atopic patients. CONCLUSION: Results suggest that clinical and functional stability of asthma among atopic patients does not necessarily reflect an efficient control over the inflammatory process and a higher probability for recurrence after discontinuation of anti-inflammatory therapy.
Administration, Inhalation↗
Impairment of nitric oxide output of conducting airways in primary ciliary dyskinesia.
Nasal nitric oxide (NO) concentration is dramatically reduced in primary ciliary dyskinesia (PCD). The aims of this study were to apply a multiple-flow NO analysis to investigate whether NO output from the bronchial tree was affected in a similar way to nasal NO output, and to search for a relationship between flow-independent exchange parameters and airflow limitation. Multiple flow rate analysis of exhaled NO, allowing the calculation of maximum airway wall flux and alveolar NO concentration, was performed in 17 PCD patients (median age, 25-75th percentiles: 13.5, 12.1-17.6) with documented ultrastructural cilia abnormalities and 28 healthy subjects (16.0, 11.0-21.0). Median maximum airway wall flux and median alveolar NO concentration were significantly reduced in PCD patients compared to healthy subjects: 16.0, 7.5-29.5, vs. 25.0, 15.0-32.5 nl/min (P<0.05) and 2.5, 1.6-3.3, vs. 5.0, 3.6-6.5 ppb (P<0.01), respectively. Significant correlations between maximum airway wall flux and airflow limitation were found, i.e., resistance of respiratory system (rho=0.74, P<0.005), forced expiratory volume in one second (FEV(1))/VC (rho= -0.61, P<0.05), FEV(1) (rho=-0.52, P< 0.05), mid expiratory flow between 25 and 75% of forced vital capacity (MEF(25-75)) (rho=-0.54, P<0.05), and maximal instantaneous expiratory flow at 50% of the vital capacity (MEF(50)) (rho=-0.55, P<0.05). In conclusion, the impairment of NO output is less pronounced in the lower than in the upper (nasal) respiratory tract in PCD. A decrease in maximal NO output from conducting airways is associated with limited airflow impairment.
Adolescent↗
Enhanced frequency of immunoregulatory invariant natural killer T cells in the airways of children with asthma.
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Asthma↗
DC-SIGN induction in alveolar macrophages defines privileged target host cells for mycobacteria in patients with tuberculosis.
BACKGROUND: Interplays between Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB) in human and host professional phagocytes, namely macrophages (Mphis) and dendritic cells (DCs), are central to immune protection against TB and to TB pathogenesis. We and others have recently shown that the C-type lectin dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN; CD209) mediates important interactions between mycobacteria and human monocyte-derived DCs (MoDCs) in vitro. METHODS AND FINDINGS: In order to explore the possible role of DC-SIGN in M. tuberculosis infection in vivo, we have analysed DC-SIGN expression in broncho-alveolar lavage (BAL) cells from patients with TB (n = 40) or with other non-mycobacterial lung pathologies, namely asthma (n = 14) and sarcoidosis (n = 11), as well as from control individuals (n = 9). We show that in patients with TB, up to 70% of alveolar Mphis express DC-SIGN. By contrast, the lectin is barely detected in alveolar Mphis from all other individuals. Flow cytometry, RT-PCR, and enzyme-linked immunosorbent assay analyses of BAL-derived fluids and cells indicated that M. tuberculosis infection induces DC-SIGN expression in alveolar Mphis by a mechanism that is independent of Toll-like receptor-4, interleukin (IL)-4, and IL-13. This mechanism most likely relies on the secretion of soluble host and/or mycobacterial factors that have yet to be identified, as both infected and uninfected bystander Mphis were found to express DC-SIGN in the presence of M. tuberculosis. Immunohistochemical examination of lung biopsy samples from patients with TB showed that the bacilli concentrate in pulmonary regions enriched in DC-SIGN-expressing alveolar Mphis in vivo. Ex vivo binding and inhibition of binding experiments further revealed that DC-SIGN-expressing alveolar Mphis constitute preferential target cells for M. tuberculosis, as compared to their DC-SIGN- counterparts. In contrast with what has been reported previously in MoDCs in vitro, ex vivo DC-SIGN ligation by mycobacterial products failed to induce IL-10 secretion by alveolar Mphis, and IL-10 was not detected in BALs from patients with TB. CONCLUSION: Altogether, our results provide further evidence for an important role of DC-SIGN during TB in humans. DC-SIGN induction in alveolar Mphis may have important consequences on lung colonization by the tubercle bacillus, and on pulmonary inflammatory and immune responses in the infected host.
Case-Control Studies↗
Foreign body aspiration: clinical, radiological findings and factors associated with its late removal.
OBJECTIVE: The study was carried out to assess the clinical and radiological findings and factors related to delay in definite diagnosis of foreign body aspiration and its removal. METHODS: Medical charts of 280 bronchoscopic-proven foreign body (FB) inhalators were reviewed. To analyze factors related to late removal, the population studied was divided into two groups according to time elapsed between injury and care-seeking (up to 24h and longer than 24h) followed by FB removal. RESULTS: Most children (69.5%) were under three, most were males (63.1%) and in 47.5%, rigid bronchoscopy was performed 24h after the accident. Organic foreign bodies were found in 63.4% of cases, most frequently peanuts (20.5%). Mortality related to FB aspiration reached 0.7%. In comparison with endoscopic diagnosis, clinical and radiological abnormalities were found in 99.3 and 84.3% (95% CI, 79.5-88.4%) of studied patients, respectively. The number of health services sought until definite diagnosis was the only factor associated with late removal (OR=23.0, 95% CI, 10.7-49.3%, p<0.001). CONCLUSION: The population studied presented a long delay in FB removal, thus demanding actions enhancing parent, physician and health services awareness, aiming at an earlier referral for diagnostic and therapeutic bronchoscopy.
Age Distribution↗
French experience of silicone tracheobronchial stenting in children.
Silicone stents were inserted into the trachea or left main-stem bronchus in 14 children aged 2-69 months (median, 7 months). Indications were as follows: tracheomalacia or airway kinking (7 cases), vascular compression (5 cases), and surgically corrected congenital tracheal stenoses (2 cases). The best results were obtained in tracheomalacia. Overall, 6 cases out of 14 (43%) were considered successful, with a stent placement duration of 3-15 months (median, 7 months). Two cases were considered a technical success, although they were clinical failures. Five cases were considered failures primarily due to stent migration. A retrospective analysis of failures suggests that most of these could have been avoided by the use of larger stents. One patient died of stent obstruction. No wall erosion was observed, and the development of granulation tissue was infrequent. Endoscopic removal of the prostheses was uneventful. The biocompatibility of silicone stents appears to be better than what is reported for metal ones, although the stability of the former is less satisfactory. The present study shows the feasibility of silicone stent placement in infants. These stents should be considered as a possible therapeutic option in certain types of childhood airway disorders, although further studies are required.
Airway Obstruction↗
High-resolution computed tomography scan and airway remodeling in children with severe asthma.
BACKGROUND: Children with severe asthma have a significantly higher bronchial wall thickness (BWT) on high-resolution computed tomography scan than control children. OBJECTIVE: We sought to determine whether a BWT score correlates with markers of airway remodeling and inflammation. METHODS: In 37 children with severe asthma, we determined reticular basement membrane thickness; number of intraepithelial neutrophils and eosinophils on bronchial biopsy; IFN-gamma, IL-4, IL-5, and eosinophil cationic protein levels and IFN-gamma/IL-4 ratio on bronchoalveolar lavage specimen; and alveolar nitric oxide (NO) concentration and the maximum airway wall NO flux. RESULTS: The BWT score significantly correlated with reticular basement membrane thickening (r = 0.34; P = .04) and NO production by the airway wall (r = 0.45; P = .02). The correlation with the eosinophil cationic protein level was just significant (r = 0.40; P = .05), whereas there was no correlation with IFN-gamma/IL-4 ratio (r = -0.31; P = .08). The BWT score did not correlate with FEV(1) or forced expiratory flow at 25% to 75% of forced vital capacity. CONCLUSION: High-resolution computed tomography scan is a noninvasive technique that might be valuable for quantifying airway remodeling in children with severe asthma. The new generations of multislice computed tomography scanners will allow higher definition and lower radiation exposure and probably give a better assessment of airway remodeling and efficacy of treatment in children with asthma.
Adolescent↗
Levocetirizine in children: evidenced efficacy and safety in a 6-week randomized seasonal allergic rhinitis trial.
Studies evaluating newer antihistamines in children are few. Levocetirizine is a potent and highly selective H1-antihistamine with a proven efficacy in adults. Primary objective was to assess the efficacy of levocetirizine 5 mg once-daily in reducing seasonal allergic rhinitis (SAR) symptoms, as measured by Total Four Symptom Score (T4SS = sum of sneezing, rhinorrhea, nasal and ocular pruritus), over the first 2 wk of treatment. Efficacy over 4 and 6 wk of treatment, effect on nasal congestion and on health-related quality of life as measured by PRQLQ (Paediatric Rhinoconjunctivitis Quality of Life Questionnaire) were among the major secondary objectives. A double-blind, randomized, placebo-controlled study including 177 children with a documented SAR (to grass and/or weed) for at least a year and having a mean baseline T4SS > or = 6 (out of 12). Children evaluated daily the severity of T4SS and nasal congestion on a scale from 0 (absent) to 3 (severe). PRQLQ responses were assessed on a scale from 0 (not bothered) to 6 (extremely bothered) and analysed descriptively. Global evaluation of disease evolution judged by investigators, parents and children was made on a scale from 1 (marked worsening) to 7 (marked improvement). For the primary objective, levocetirizine was statistically highly superior to placebo with a difference in adjusted means of 1.29 (95% CI: 0.66-1.92) in favour of levocetirizine (p < 0.001). The effect of levocetirizine was almost twice that of placebo (94.1% relative improvement over placebo). Nasal congestion was improved with levocetirizine reaching maximum difference to placebo of 0.31 (p < 0.05), a relative improvement over placebo of 77.5%. PRQLQ scores at week 2 improved with levocetirizine more than with placebo (0.85 vs. 0.51, respectively) remaining larger after 4 and 6 wk of treatment. In the study, 84.3%, 80.9%, 80.9% of children had their disease evolution rated as slightly-to-markedly improved by, respectively, the investigators, the parents and children themselves. Incidence of treatment-emergent adverse events was similar in both groups (33.7% with levocetirizine; 30.7% with placebo). No child in the levocetirizine group discontinued treatment because of adverse events. The 6-wk duration of this study was longer than the usual 2-4-wk duration for similar studies and shows that levocetirizine controls SAR symptoms in children over the entire pollen season.
Adolescent↗
Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease.
Pulmonary surfactant protein C (SP-C) is a highly hydrophobic peptide produced by type-II alveolar cells through the processing of a high-molecular weight precursor (pro-SP-C), that enhances surface tension and facilitates the recycling of pulmonary surfactant in vitro. Recently, two seemingly dominant-negative mutations of the pro-SP-C-encoding gene (SFTPC, MIM 178620), were reported in families with vertically-inherited interstitial lung disease (Nogee et al. [2001: N Engl J Med 344:573-579]; Thomas et al. [2002: Am J Respir Crit Care Med 165:1322-1328]). We have examined the SP-C protein and its precursor as well as the encoding gene, in a cohort of 34 sporadic or familial cases with unexplained respiratory distress (URD) in which surfactant protein B (SP-B) deficiency related to SFTPB mutation had been ruled out. One patient with complete SP-C deficiency had no detectable mutation of SFTPC. Of the 10 patients with abnormal pro-SP-C processing, as suggested from analysis of broncho-alveolar lavage (BAL) fluid, two distinct heterozygous SFTPC missense mutations were identified. The first, g.1286T > C (p.I73T), was de novo and resulted in progressive respiratory failure with intra-alveolar storage of a granular, protein- and lipid-rich, periodic acid Schiff (PAS)-positive material (pulmonary alveolar proteinosis (PAP)), and interstitial lung disease. The second, g.2125G > A (p.R167Q), was found in two PAP patients from the endogamous white settler population of Réunion Island in which URD has an unexpectedly high prevalence. Since this mutation was diagnosed in subjects from this subpopulation who did not have evidence for lung disease, we propose environmental exposures or modifier genes to play a role in the phenotype, as suggested from murine models lacking the SP-C protein, although we cannot rule out a rare polymorphism, hitherto restricted to that subpopulation. Most remarkably, these observations extend the phenotypic spectrum related to SFTPC mutation from interstitial lung disease to PAP. Notably, the reported mutations do not appear to be dominant negatives. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html.
Bronchoalveolar Lavage Fluid↗
Airway inflammation and asthma treatment modalities.
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Acetates↗
Both inflammation and remodeling influence nitric oxide output in children with refractory asthma.
BACKGROUND: Exhaled nitric oxide can be used to monitor airway inflammation in asthma. We hypothesized that the strong link between nitric oxide and inflammation may obscure a weaker link with airway remodeling. OBJECTIVE: The aim of this study was to determine whether airway remodeling influenced exhaled nitric oxide in 28 asthmatic children (median age [25th-75th], 11 [10-14] years old) with refractory asthma defined as airflow limitation and/or exacerbations despite high-dose inhaled steroids. METHODS: Multiple-flow analysis of exhaled nitric oxide was used to correlate alveolar nitric oxide concentration and maximal conducting airway nitric oxide output to pulmonary function tests, bronchoalveolar lavage, and bronchial biopsy findings. RESULTS: Nitric oxide measurements were related to inflammation and T(H)1/T(H)2 balance, that is, subepithelial eosinophilic infiltration and eosinophilic cationic protein and IFN-gamma/IL-4 ratio in bronchoalveolar lavage fluids. Nitric oxide measurements were also correlated with several parameters of airway remodeling: alveolar nitric oxide concentration with TGF-beta in bronchoalveolar lavage fluid (r = 0.42, P =.03) and maximal conducting airway nitric oxide output with reticular basement membrane thickness (r = 0.61, P =.0007) and tissue inhibitor of matrix metalloproteinases 1/matrix metalloproteinase 9 ratio in bronchoalveolar lavage fluid (r = 0.43, P =.04). Moreover, alveolar nitric oxide concentration was correlated with MEF(25-75) (r = 0.60, P =.02). CONCLUSIONS: These findings suggest that both subacute inflammation and remodeling influence nitric oxide output in refractory asthma.
Adolescent↗
Difficult asthma in children: an analysis of airway inflammation.
BACKGROUND: Difficult asthma in children displays distinct clinical patterns, and its physiopathology remains poorly understood. OBJECTIVE: To determine the characteristics of the bronchial inflammatory profile in children with difficult asthma. METHODS: We performed endobronchial biopsy and bronchoalveolar lavage in 28 children with persistent bronchial obstruction despite high doses of inhaled corticosteroids and regular treatment with long-acting beta(2)-agonists: 13 had persistent symptoms and 15 had few or no symptoms. RESULTS: The number of eosinophils (P =.03) and neutrophils (P =.04) in the epithelium was significantly higher in symptomatic children than in children with few symptoms. Reticular basement membrane thicknening was similar in both groups. IFNgamma levels (P =.03) and IFNgamma/IL-4 ratio (P =.01) were significantly higher in children with few symptoms. CONCLUSIONS: In symptomatic children, T(H)2-type inflammation was associated with the presence of activated eosinophils in the epithelium, whereas asthma in children with few symptoms was associated with an increase in T(H)1 cytokine levels. The high levels of IFNgamma suggest that this T(H)1 cytokine may modulate the local inflammatory response.
Asthma↗
Pulmonary alveolar proteinosis in children.
Pulmonary alveolar proteinosis (PAP) is a rare cause of chronic interstitial lung disease in children characterised by accumulation of a lipoproteinaceous material in the alveoli. Bronchoalveolar lavage is the key diagnostic tool, revealing a milky appearance of the return fluid and a periodic acid-Schiff staining material in the alveolar macrophages. PAP is a heterogeneous disease. Immediate-onset forms leading to early and fatal respiratory failure may be related to SP-B deficiency. Postnatal-onset PAP may be associated with various diseases or may be primary. The latter has a polymorphic progression from asymptomatic to uncontrollable respiratory failure. Recent studies have implicated GM-CSF and/or its receptor but the exact underlying mechanisms are still unknown. Therapeutic lung lavages are the only effective treatment for severe cases.
Age of Onset↗
Pulmonary alveolar proteinosis.
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Bronchoalveolar Lavage↗
Analysis of 40 sporadic or familial neonatal and pediatric cases with severe unexplained respiratory distress: relationship to SFTPB.
We have analyzed surfactant protein B (SP-B) and its encoding gene (SFTPB, MIM 178640) in 40 unrelated pediatric patients with unexplained respiratory distress (URD). There was high consanguinity (eight kindreds) and an underlying autosomal recessive trait could be inferred in most cases, with overall high sex ratio (32/17) suggesting proband's gender to impact on penetrance. The clinical/biological presentations fitted into three major nosologic frameworks. I: SP-B deficiency (nine probands), complete or incomplete, with homozygous/compoundly heterozygous mutations identified (six probands), including one from the population isolate of Réunion Island (496delG). In addition, there was a consanguineous kindred in which incomplete deficiency was unambiguously unlinked to SFTPB. II: pulmonary alveolar proteinosis (PAP, 19 probands), with typical storage of PAS-positive material within the alveoli with foamy macrophages and variable interstitial reaction, which was diagnosed in most patients from Réunion Island. In contrast to previously published findings, mutation and/or segregation analyses excluded SFTPB as a disease locus, although slight metabolic derangement related to SP-B and/or mild SFTPB changes could somehow contribute to disease. III: URD without evidence for SP-B deficiency or PAP (12 probands), equally unlinked to SFTPB, although a single patient had a possibly causal, maternally-derived, heterozygous genetic change (G4521A). The population frequency of five known and four novel SNPs was studied, providing as many potential markers for pulmonary disease related to SFTPB. Overall, URD was found to be heterogeneous, both phenotypically and genetically, even in population isolates where a founder effect might have been expected. When disease loci are identified, patient genotyping will be crucial as a diagnostic aid, for devising proper treatment, and as a basis for genetic counseling.
Amino Acid Sequence↗