Bertrand Delaisi

RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa.

Introduction: Primary ciliary dyskinesia (PCD) is a rare disease classically transmitted as an autosomal recessive trait and characterised by recurrent airway infections due to abnormal ciliary structure and function. To date, only two autosomal genes, DNAI1 and DNAH5 encoding axonemal dynein chains, have been shown to cause PCD with defective outer dynein arms. Here, we investigated one non-consanguineous family in which a woman with retinitis pigmentosa (RP) gave birth to two boys with a complex phenotype combining PCD, discovered in early childhood and characterised by partial dynein arm defects, and RP that occurred secondarily. The family history prompted us to search for an X linked gene that could account for both conditions. Results: We found perfect segregation of the disease phenotype with RP3 associated markers (Xp21.1). Analysis of the retinitis pigmentosa GTPase regulator gene (RPGR) located at this locus revealed a mutation (631_IVS6+9del) in the two boys and their mother. As shown by study of RPGR transcripts expressed in nasal epithelial cells, this intragenic deletion, which leads to activation of a cryptic donor splice site, predicts a severely truncated protein. Conclusion: These data provide the first clear demonstration of X linked transmission of PCD. This unusual mode of inheritance of PCD in patients with particular phenotypic features (that is, partial dynein arm defects and association with RP), which should modify the current management of families affected by PCD or RP, unveils the importance of RPGR in the proper development of both respiratory ciliary structures and connecting cilia of photoreceptors.

Mycobacterial lung disease in cystic fibrosis: a prospective study.

BACKGROUND Patients with cystic fibrosis (CF) may be predisposed to airway infections with unusual organisms, such as mycobacteria. The aim of the study was to determine the incidence and clinical picture of mycobacterial infection in CF children. METHODS At least 2 acid-fast bacillus (AFB) smears and mycobacterial cultures were performed on a prospective basis on 682 sputum specimens from 106 patients during a 1-year period. RESULTS Thirty-three percent of the cultures were contaminated with other bacteria. Seven children had at least one sputum culture positive for one mycobacterium. Five children had only one positive AFB culture. Their clinical status and lung function remained stable during follow-up. Two teenagers with severe lung disease had several positive AFB smears and cultures for Mycobacterium chelonae and Mycobacterium abscessus. The isolation of M. chelonae and M. abscessus was associated with a clinical and functional decline. Clarithromycin treatment resulted in temporary improvement with the disappearance of the mycobacteria after 6 months of treatment. This prospective study shows an incidence of 2.3% for positive cultures. The prevalence was 6.6% for mycobacterial colonization but only 1.9% for mycobacterial lung disease in our pediatric population. CONCLUSIONS We recommend performing AFB smears and cultures in CF children with severe lung disease and/or during a lung exacerbation. In these patients persistence of M. chelonae or M. abscessus in sputum should lead to consideration of treatment with clarithromycin.

Influence of Interleukin-10 on Aspergillus fumigatus Infection in Patients with Cystic Fibrosis

Recent evidence suggests that genetic polymorphisms that affect the production of interleukin (IL)-10 may play a role in the response to pathogens in cystic fibrosis (CF). The present study was designed to investigate a possible association between alleles carried at position -1082 in the promoter region of the IL-10 gene and clinical data on 378 patients with CF. After adjustment for potential confounding variables, a significant relationship was found between the -1082GG genotype and both colonization with Aspergillus fumigatus and allergic bronchopulmonary aspergillosis. In addition, higher serum levels of IL-10 were observed in patients colonized with A. fumigatus. These results suggest that polymorphisms in the promoter region of the IL-10 gene may influence the host response to A. fumigatus in the context of CF.

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 probands 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.

Pharmacokinetics and safety of tobramycin administered by the PARI eFlow ® rapid nebulizer in cystic fibrosis ☆

BACKGROUND Nebulization times have been identified as an issue in patient compliance with tobramycin solution for inhalation (TSI) therapy in cystic fibrosis (CF). METHODS In this randomized, open-label, multicentre, two-period, crossover study, patients (n=25) with CF and chronic pulmonary pseudomonal infection received TSI for 15 days via eFlow rapid or LC PLUS nebulizer. Nebulization times and sputum/serum tobramycin concentrations were determined, and safety evaluated. RESULTS Nebulization times were significantly shorter for eFlow rapid versus LC PLUS on Day 1 (least squares mean estimate of the difference -10.5 min, 95% confidence intervals [CI] -12.6, -8.3, p<0.0001) and Day 15 (difference -7.7 min, 95% CI -9.0, -6.5, p<0.0001). Broadly comparable sputum/systemic exposure to tobramycin was observed and the incidence of adverse events was similar for both nebulizers. CONCLUSION Use of the eFlow rapid nebulizer reduced TSI nebulization time. The systemic exposure to tobramycin appeared to be broadly similar in this exploratory study.

Glutathione-S-transferase M1, M3, P1 and T1 polymorphisms and severity of lung disease in children with cystic fibrosis

OBJECTIVES Progression and severity of lung disease differs markedly and early between patients with cystic fibrosis (CF). We investigated the hypothesis that polymorphisms in the detoxifying enzymes glutathione-S-transferase (GST) could influence phenotypic presentation of lung disease in CF. METHODS Genotypes for GSTM1, GSTM3, GSTP1 and GSTT1 were determined in a cohort of 146 children with CF by PCR-based methods. Pulmonary function, assessed by spirometric measures of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), was analysed in children at the age of 9. RESULTS No association between spirometric measurements, and GSTM1, GSTP1 or GSTT1 genotypes was found. As compared with patients homozygous for GSTM3*A allele, CF children carrying the GSTM3*B allele displayed a significant better lung function, assessed by both mean values of FEV1 and of FVC (respectively P = 0.01 and P = 0.002). These correlations remained significant after adjustment for potential confounding factors (respectively adjusted P = 0.008 and P = 0.002) and also in subgroups of CF patients who carry the deltaF508 CFTR mutation. Haplotype analysis of GSTM3 in combination with GSTM1 indicated that the positive impact of GSTM3*B allele on pulmonary performances was barely influenced by the GSTM1 genotypes of CF children. CONCLUSIONS These data provide the first evidence suggesting that polymorphism of the GSTM3 gene contributes to clinical severity in CF, which may have prognostic significance and could prompt to start a more targeted therapy in young patients with CF.

Carcinomes mucoépidermoïdes bronchiques: à propos de trois observations

BACKGROUND: Mucoepidermoid carcinomas (MEC) are very rare (less than 20 cases reported in the literature) and potentially malignant bronchial gland carcinomas. PATIENTS: Three children, two boys (11 and 7 years old) and one girl (5 years old) suffered from respiratory symptoms such as cough, recurrent pneumonia and/or hemoptysis for 2 to 12 months. Bronchial endoscopy showed a mass into the left (two cases), or the right main bronchus (one case). Chest CT scan identified local extension, and lung-associated lesions. Histopathological study concluded to MEC in the three cases. The patients were treated by segmental bronchial resection, completed with left upper lobectomy (two cases), bronchotomy (one case). All the tumor could be removed; there was no metastasis. The outcome was uneventful with a 8 to 24 months follow-up. CONCLUSION: Bronchial tumors of children must be considered in patients with chronic cough, recurrent pneumonia and/or hemoptysis and require bronchial endoscopy for their diagnosis.

142 Immunisation coverage in children with cystic fibrosis: a French multicenter survey

Objectives: To determine platelet aggregation capability for various variants of antigene system AB0 in patients with cystic fibrosis (CF). Methods: 55 CF children (homozygous and heterozygous on F508 del mutation) were enrolled. 46% girls and 54% boys had mild form of CF, 54% girls and 46% boys had severe form. We investigated the function of platelet aggregation with: thrombin, adenosinediphosphate (ADP) and arachidonic acid (AA). Results: Patients with severe form of CF most frequently (29%) had 0 (I); B (III) have not been revealed in this group, meanwhile 22.2% patients with mild form of CF had A (II) and AB (IV) have been revealed. Platelet aggregation with ADP has significant differences between blood groups A (II) and 0 (I), (p = 0.019). Values were ranged 2.5–97.5 percentile in patients with 0 (I) and 2.5−25 percentile in A (II). Data of aggregation with AA did not show significant differences between groups. Significant difference between homozygous F508 del and heterozygous F508 del patients was shown in aggregation with trombin (p = 0.03). There is a tendency to hyperaggregation in heterozygous patients meanwhile homozygous had both hypoaggregation and hyperaggregation. Difference on other tests between homozygous and heterozygous patients is not significant. Conclusion: First results of this study should be interpreted according to system ABO, severity of disease and genotype in patients with CF. These aspects play an important role for individual treatment.

Asthme et trachéomalacie associés : aspects diagnostiques et thérapeutiques

An asthmatic girl was first hospitalized at age 2(9/12) years because of dyspnoea, lung consolidations and/or atelectasis, and rattling. Between ages 2(9/12) and 6(2/12) years, she required three hospitalizations in ICU out of nine hospitalizations for the same symptoms. Differential diagnosis of this difficult to treat asthma disclosed severe tracheomalacia and persistent asthma. Treatments given according to the clinical, radiological and functional findings failed to decrease frequency and severity of acute respiratory episodes. Eventually, positive pressure ventilation delivered at airway opening (via a mouthpiece) associated to active respiratory physiotherapy succeeded in removing atelectasis and quickly cured the five following acute episodes without any further hospitalization. This case report is about diagnosis procedure, intricate asthma and tracheomalacia, and open mind to unusual therapeutics that may disclose potential help.