Vaccine coverage in CF children: A French multicenter study.

BACKGROUNDS: Recent reports have pointed the low vaccine coverage in patients with chronic diseases. Data are lacking in patients with cystic fibrosis (CF). Gaining more information on coverage both for mandatory vaccines and those more specifically recommended would help to optimize care of these patients. METHODS: Data were extracted from the "MucoFlu" study, which was a prospective study performed in 2009 in the 5 cystic fibrosis centers of the Paris metropolitan area. Data on mandatory and recommended vaccines in CF were collected in the health booklet and compared to the coverage of the general population. RESULTS: A total of 134 CF children were included. Vaccination coverage for mandatory vaccines was insufficient (DTPCaHi, conjugate pneumococcal, BCG, MMR and hepatitis B) at 1year of age with no catching-up with age in contrast to the general population. Approximately 66% of the children had immunization for seasonal influenza and 91% for 2009 pandemic flu. Coverage for vaccines specifically recommended in CF was low for hepatitis A, non conjugate pneumococcal and varicella. CONCLUSION: This study shows a defect in vaccine coverage for both routine immunization and vaccines more specifically recommended in CF.

[Inhaled treatments in cystic fibrosis: what's new in 2013?]. / Mucoviscidose et traitements inhalés: quoi de neuf en 2013?

In the past few years some new inhaled drugs and inhalation devices have been proposed for the treatment of cystic fibrosis. Breath-controlled nebulizers allow increased pulmonary deposition, with a lower variability and a shorter delivery time. The new dry powder formulations of tobramycin, colistine and mannitol require a change in the inhalation technique which must be slow and deep. In the field of the inhaled mucolytic drugs, hypertonic saline and mannitol have an indication in some patients. With regard to antibiotics, dry-powder tobramycin and colistine can be substituted for the same drug delivered by nebulization. Nebulized aztreonam needs more studies to determine its place. These new treatments represent a definite advance for cystic fibrosis patients and need to be known by all practitioners. Their position in our therapeutic arsenal remains to be accurately defined.

[News in cystic fibrosis]. / Actualités dans la mucoviscidose.

The improvement over the last two decades in the treatment of cystic fibrosis led to an increase in life expectancy approaching 40 years at birth. Logically, the population of adult patients has been increasing and is currently 50% of patients followed in France. These therapeutic advances have justified the establishment in 2003 of a generalized neonatal screening for cystic fibrosis. The latest data of this screening show an incidence of CF of 1/5359 live births, far below the incidence of 1/2500 which was widely accepted twenty years ago. The performance of this screening is currently based on the dosage of trypsin immuno reactive, followed in case of exceeding the threshold of a search of the 30 most common mutations, can detect around 96% of 150 to 200 CF cases every year. Therefore, the possibility of a false negative of the screening cannot be excluded and evocative symptoms of cystic fibrosis, even for children born after 2003, will lead to prescribe a sweat test. While treatments available so far goal consequences of cystic fibrosis, a new therapeutic class to correct the functional defect of the mutated protein, called CFTR modulators, is emerging. Ivacaftor, leader of this new class, belonging to the category of "CFTR potentiator" got its access on the market in September 2012 for patients carrying the G551D mutation. New other molecules, named "CFTR correctors" which can have synergistic effect with ivacaftor and concern patients carrying the most common mutation--DF 508--are under development.

[Intricated asthma tracheomalacia: diagnosis and therapeutic aspects]. / 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.

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.

[Aspergillosis in cystic fibrosis patients]. / Aspergillose et mucoviscidose.

Allergic bronchopulmonary aspergillosis (ABPA) should be suspected in any CF patient whose pulmonary disease deteriorates precipitously, suddenly or unexpectedly, and has to be correlated to fungal hypersensitivity biological tests. The standard therapeutic approach is based upon systemic corticosteroids. Invasive pulmonary aspergillosis (IPA) may occur mainly but not exclusively in immunosuppressed patients undergoing lung transplantation. New antifungal compounds (Triazoles, Itraconazole, Voriconazole), Echinochandins (Caspofungin) are effective, synergistic, well tolerated, should their contraindications and side effects be carefully respected and monitored.

[International registry on mucoviscidosis: comparison of the French data with the European data for 1995]. / Registre international sur la mucoviscidose: comparaison des données françaises avec données européennes pour 1995.

BACKGROUND: The Epidemiologic Registry of Cystic Fibrosis (ERCF) is an international registry, sponsored by Roche Laboratories, collecting data about CF patients in Europe. The aim of the our study is to compare the French data with the European data collected during the year 1995. RESULTS: By December 31st 1995, 8,831 patients have been enrolled in Europe, including 1,457 patients in France. French CF patients are younger (mean age = 12.6 years) than European CF patients (mean age = 14.6 years). Genotype is better characterised in France (89 vs 75% for European patients), but only 49% of CF patients are homozygote for the DF508 deletion in France versus 77% in Denmark. Two clinical features of French CF patients are interesting: 1) presence of Staphylococcus aureus and Haemophilus influenzae (52%) is more frequent in France than in Europe (65 vs 48% and 52 vs 29%, respectively), 2) lung function tests (forced vital capacity [FVC]), forced expiratory volume per second [FEV1] are worse in France (P < 0.001) particularly in the older patients (> 18 years): 39% of these patients in France have a FEV1 < 40% of predicted value compared to only 29% in Europe. Similarly there are fewer patients in this age group in France (22 vs 31% in Europe) having a FVC > 90% of the predicted value in France. With regard to the treatment, three differences emerge: 1) dornase alfa is more used in France (55 vs only 34% in Europe); 2) use of prophylactic inhaled and oral antibiotics is less common in France than in all age groups; 3) the use of inhaled corticosteroids and bronchodilators is also less common in France despite the same incidence of asthma-like symptoms. Finally we notice that the mean age at death in 1995 is 18.2 years (+/- 2.38) in France and 20.6 years (+/- 0.85) in Europe. CONCLUSION: These results are preliminary because 1995 is the first year for ERCF in France and a low percentage of French CF patients are included for this year. Therefore they must be interpreted with caution. Nevertheless, we can hypothesise about a relationship between these results and a less aggressive treatment regimen. The impact of dornase alfa use on prognosis seems interesting to analyse in future years.

Expression of insulin-like growth factors and their binding proteins by bronchoalveolar cells from children with and without interstitial lung disease.

The involvement of the insulin-like growth factor (IGF) system in lung growth and repair following injury is sustained by a number of studies. Based on this knowledge, the aim of the present work was to document the expression of the IGFs and their binding proteins by alveolar cells obtained by bronchoalveolar lavage (BAL). Two groups were investigated: a control group of five children and a group of 11 children referred to the department for exploration of interstitial lung disease (ILD). Components of the IGF system studied included IGF-I, IGF-II and IGF-binding proteins (IGFBP). Expression of these factors was analysed at the level of messenger ribonucleic acid (mRNA) (by semi-quantitative reverse transcription polymerase chain reaction techniques), and of protein for the IGFBPs. In addition, expression of two major cytokines associated with the inflammatory process, tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), was also documented. In children without parenchymal disease, the growth factor expressed was IGF-I, in association with the presence of mRNA for IGFBP-2 in all cases. In children with ILD, expression of IGF-I was observed in nine patients and of IGF-II in three patients, and the presence of IGFBP-2 was found in all extracts analysed (mRNA and proteins). Evaluation of IGFBP-2 expression indicated an increase in the group of children with ILD. Interestingly, a significant association was observed between the increase in IGFBP-2 expression and TGF-beta expression. The present data emphasize the presence on insulin-like growth factor-binding protein-2 in the BAL of all patients, and suggest that this protein may be an important factor of the injury/repair processes during the progression of alveolar inflammation.

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.

[Tuberculous pneumopathy in the course of cystic fibrosis]. / Pneumopathie tuberculeuse au cours d'une mucoviscidose.

BACKGROUND: Tuberculosis is rarely seen in patients with cystic fibrosis. CASE REPORT: A 14-year old female adolescent, regularly followed for a well-tolerated form of cystic fibrosis, developed an acute respiratory infection with consolidation of the left inferior lobe, and no response to the usual antibiotic treatment of cystic fibrosis. Mycobacterium tuberculosis was found in aspirate by fibroscopy, on Loewenstein medium. No familial or social infection contact were identified. Antituberculous chemotherapy with three drugs brought about a prompt improvement of sytemic signs, weight gain, resolution of pulmonary foci and sedation of biological findings referable to inflammation. CONCLUSION: This case report reminds us that tuberculosis may occur in cystic fibrosis patients. Loewenstein cultures should routinely be made when faced with an unexplainable worsening of the condition.

[Diagnosis of acute bronchopulmonary infections in children]. / Diagnostic des infections bronchopulmonaires aiguës de l'enfant.

Positive diagnosis of acute bronchopneumopathy in the child is relatively easy, but defining its aetiology is another matter. Criteria to distinguish between pneumopathy of viral or of bacterial origin should be known but are often on the wrong track. Some clinical and radiological pictures, associated with epidemiological data, can also orient toward an infectious agent and should be taken into account. When clinical severity or the background requires precise diagnosis in order to better adapt the treatment, a choice will need to be made among the numerous techniques now available to detect the responsible infectious agent.

[Bronchial mucoepidermoid carcinoma: apropos of 3 cases]. / Carcinomes mucoépidermoïdes bronchiques: à propos de trois observations.

BACKGROUND: Mucoepidermoïd 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.

[New pharmacological approaches: rhDNase]. / Nouvelles approches pharmacologiques: la rhDNase.

rhDNase (Pulmozyme) is a new agent in the therapeutic strategy for patients with cystic fibrosis. It is one of the first specific treatments aimed at the respiratory tract. It affects the extracellular DNA which is present in abundant quantities in the bronchial secretions of these patients. rhDNase significantly reduces the incidence of infections and improves respiratory function. It should be used as a major treatment in combination with all other treatments in patients over 5 years of age with a vital capacity of at least 40% the theoretical value. It is important to schedule the respiratory exercises as a function of rhDNase intake. The long-term therapeutic benefit remains to be evaluated.

Insulin responses to intravenous glucose and the hyperglycemic clamp in cystic fibrosis patients with different degrees of glucose tolerance.

The relationship between altered insulin secretion and impaired glucose tolerance was studied in 32 cystic fibrosis patients, 16 men and 16 women, aged 8-26 y, using oral and i.v. glucose tolerance tests and a hyperglycemic glucose clamp (10 mmol/L). Seven of these subjects were already being treated with insulin; seven had fasting blood glucose levels below 7.2 mmol/L but satisfied diabetic criteria at the oral glucose tolerance test; glucose tolerance was impaired in 13 subjects and normal in five. The insulin responses to the two i.v. glucose stimuli were inversely correlated with the plasma glucose levels (60 and 120 min) and the area under the curve of the oral glucose tolerance test. However, the acute insulin response to i.v. glucose was severely altered in patients with impaired glucose tolerance, whereas plasma insulin levels during the hyperglycemic clamp did not differ from those of healthy subjects. The responses to the two stimuli were dramatically low in the diabetic patients. These results suggest that cystic fibrosis patients with normal or impaired glucose tolerance retain their capacity to secrete insulin. Alterations in the acute phase of glucose-stimulated insulin secretion seem to be principally responsible for the early impairment in glucose tolerance.