[New therapies for cystic fibrosis targeting the CFTR gene or the CFTR protein]. / Nouvelles thérapeutiques de la mucoviscidose ciblant le gène ou la protéine CFTR.

BACKGROUND: The treatment of cystic fibrosis has been symptom-based for a number of years. New therapies that aim to improve CFTR protein function are now emerging. CURRENT SCIENTIFIC KNOWLEDGE: The results of gene therapy has been modest but a recent clinical trial shows a positive effect on FEV1. Recent research has focused primarily on CFTR protein function. Significant respiratory improvement (an average 10% FEV1 increase and a decrease in the frequency of exacerbations) has been achieved with ivacaftor, a CFTR potentiator, in patients with gating mutations, resulting in its marketing authorization (in 2012 for the G551D mutation and in 2015 for rarer mutations). In phe508del homozygous patients, the combination of ivacaftor with a CFTR corrector (lumacaftor) has also led to respiratory improvement, albeit less impressive. The effectiveness of ataluren in patients with nonsense mutations is being evaluated. OUTLOOK: New CFTR correctors and potentiators are being developed. CFTR protein therapy could change the course of the disease but cost/effectiveness issues should not be overlooked. CONCLUSION: Ivacaftor can be prescribed in CF patients with a class 3 mutation from the age of 6 years. The Orkambi® will soon be available for homozygous phe508del patients from the age of 12 years.

[Infections in cystic fibrosis: Up-to-date]. / Actualités en infectiologie dans la mucoviscidose.

This review focused on the news in CF airways infection. International guidelines were provided for the care of non tuberculous mycobacteria, and recent studies stressed on the benefit effect of azithromycin or combined antibiotics. The identification of multiresistant environmental bacteria in airways made to account for little-known consequences. Early diagnosis and eradication of Pseudomonas aeruginosa and Staphylococcus aureus methi-R were still a concern, and reports were proposed. However, the studies on staphylococcus methi-R should be interpreted as regards the European or American continent. Thus, levofloxacine has demonstrated its efficacy without enhancing the efficiency. This drug will increase the choice for treating the patient, but no study were provided on the expected modification of the patient microbiota and the known risk of emergent resistance to antibiotics. Lastly, this review underlined that the CF practitioner was encouraged to search and not underestimate the presence of fungus, of which the not so well studied Aspergillus fumigatus.

[New therapeutic developments in cystic fibrosis]. / Nouvelles thérapeutiques ciblant le canal chlorure dans la mucoviscidose.

Since the discovery of chloride secretion by the Cystic Fibrosis Transport regulator CFTR in 1983, and CFTR gene in 1989, knowledge about CFTR synthesis, maturation, intracellular transfer and function has dramatically expanded. These discoveries have led to the distribution of CF mutations into 6 classes with different pathophysiological mechanisms. In this article we will explore the state of art on CFTR synthesis and its chloride secretion function. We will then explore the consequences of the 6 classes of mutations on CFTR protein function and we will describe the new therapeutic developments aiming at correcting these defects.

[What methods can we use to measure inflammation in the asthmatic child?]. / Quels outils en 2007 pour mesurer l'inflammation dans l'asthme de l'enfant ?

Pulmonary function tests remain the best method to assess underlying bronchial inflammation, particularly distal airway flow. However, these tests are limited in their ability to differentiate treatment-reversible small airway obstruction from definitive remodeling related to a viral infection. The increased availability of the exhaled fraction of nitric oxide (FeNO) measurement means that this method is accessible and attractive. In spite of a number of studies, mainly in adults, its use in the management of asthma needs more investigation. Threshold values that permit optimum management are poorly defined, and strategies based on variations of FeNO do not result in reduction of the number of exacerbations, although they do permit better control of drug use and better control of inflammation. Sputum eosinophil counts are of interest for the prevention of exacerbations, although while not well validated they may be useful in some asthmatic children. Also, they require an experienced cytology laboratory. Finally, recent data on bronchial biopsies in children with difficult-to-treat asthma will be summarized.

Advances in the surgical management of nephrolithiasis.

The surgical management of urinary calculus disease has undergone a dramatic evolution over the past 2 decades. Twenty years ago, open surgical procedures for urinary calculi were some of the most frequently performed urologic procedures. Since then, however, stone management has been at the forefront of "minimally invasive" intervention. Specifically, the initiation and refinement of percutaneous and ureteroscopic access to the upper tracts, along with the rapid and nearly simultaneous development of both extracorporeal and intracorporeal lithotripsy techniques, has limited the role of open surgery to less than 1% of patients undergoing intervention for their stone disease. This manuscript will review the current indications for the surgical management of urinary calculi, the basic physics of the most frequently utilized vehicles for both extracorporeal and intracorporeal lithotripsy, and the respective roles of extracorporeal and intracorporeal lithotripsy with percutaneous or ureteroscopic access and open surgery. In addition, the results and complications associated with each of these forms of intervention will be reviewed. Finally, a discussion of specific clinical challenges to the urologist will be presented.

[Flexible bronchoscopy in children. Experience at French centers of pediatric pneumology]. / La fibroscopie bronchique chez l'enfant. Expertise des centres français de pneumologie pédiatrique.

INTRODUCTION: Fibreoptic bronchoscopy (FB) is an important diagnostic examination in paediatric pulmonology. In 2002 the Paediatric Pulmonology and Allergy Club undertook a retrospective study to establish the current status of fibreoptic bronchoscopy among its members. METHODS: In 2001 sixty five paediatric pulmonologists carried out an average of 116 examinations (+/- 111) in 35 paediatric centres. FB was performed either in an operating theatre (15 centres), a dedicated bronchoscopy suite (6 centres) or an endoscopy suite shared with gastro-enterologists (7 centres). Other examinations were performed in areas dedicated to, or associated with intensive care. General anaesthesia was routinely used in 18 centres. The others used sedation including an equimolar mixture of oxygen and nitrous oxide in 14 centres. Ten centres performed less than 50 examinations, 12 between 51 and 100, 4 between 101 and 200 and 8 centres more than 200 in the year. Seventy two per cent of the children were less than 6 years old. The washing and disinfection procedures were manual in 20 centres and automatic in 15. RESULTS: Three principal indications were reported: persistent wheezing, suspicion of a foreign body and ventilatory difficulties. Cough, desaturation and fever were the most frequently reported side effects. CONCLUSIONS: This is the first survey in paediatric pulmonology in France. It shows a wide variation in the practice of fibreoptic bronchoscopy in children.

[Inflammatory markers in infant asthma]. / Marqueurs de l'inflammation dans l'asthme du nourrisson.

After a brief review of airway inflammation mechanisms, the main results concerning the studies on airways inflammation in wheezing infants are commented. Infantile asthma differed from adult asthma by a predominance of neutrophils in airways, but less eosinophils or mastocytes. However, the presence of eosinophil or mastocyte markers does not allow to exclude a contribution of eosinophils in infantile wheeze. Studies on macrophages at cell level showed that a potent inflammation from macrophages exists in asymptomatic asthmatic infants. Lymphocyte subsets studies demonstrated a modulation of CD8 in these infants, suggesting the role of lymphocytes and the contribution of viruses in the pathophysiology of the disease. Lastly, the measurement of various mediators in airways confirmed that airway inflammation is present in infantile wheeze.

[Chronic cough, asthma and allergy]. / Toux chronique, asthme et allergie.

The medical approach of chronic cough suffers from the lack of a standardised definition. The most frequently encountered criterion is a recurrent cough observed during several consecutive months, each episode lasting at least 1 week. The link between recurrent cough and asthma is still discussed. Cough-related asthma diagnosis is facilitated when wheezing is clearly confirmed, or may be reminded by a nonproductive middle night cough, or an exercise-triggered cough, or the presence of personal or familial atopy. Conversely, an early morning and productive cough associated with tobacco exposure do not suggest asthma.

Eosinophil cationic protein and interleukin-8 levels in bronchial lavage fluid from children with asthma and infantile wheeze.

It has been shown previously that airway eosinophils characterize childhood asthma and neutrophils contribute to the pathophysiology of both infantile wheezing and asthma. Therefore, eosinophil cationic protein (ECP) and interleukin-8 (IL-8) levels in bronchoalveolar lavage fluid (BALF) from asthmatics (n = 16) and infantile wheezers (n = 30) were analyzed as markers of eosinophil- and neutrophil-mediated inflammation. To aid the interpretation, a control group of children (n = 10) with no lower airway pathology were included. Disease severity was assessed by using a symptom score. Surprisingly, no significant difference was found in IL-8 or ECP levels among asthma, infantile wheeze, and control groups. Asthma was characterized by: a correlation between ECP levels and eosinophil counts (r = 0.618, p = 0.014); a correlation between neutrophil number and IL-8 levels (r = 0.747, p = 0.002); and increasing IL-8 levels with symptom score (p = 0.03). In infantile wheezers, IL-8 levels were poorly related to neutrophil number but were significantly increased when neutrophils were > 10%. Although detectable levels were found in all but one symptomatic infant, IL-8 concentrations did not reflect the symptom score in infantile wheeze. ECP was unexpectedly correlated to neutrophil percentages (Rho = 0.832, p = 0.001), and a threshold of ECP>20 ng/ml was associated with persistent symptoms in these infantile wheezers. Hence, in accordance with BALF cellularity, activation of eosinophils was suggested by raised levels of ECP in childhood asthma, but not in infantile wheeze. Neutrophil-mediated inflammation appeared to better reflect the severity of asthma than that of infantile wheeze. Although its meaning remains to be elucidated, ECP was suggested to be a helpful indicator of persistent infantile wheeze. However, its utility as a marker predicting ongoing asthma remains to be established.

[Lyme disease in Upper Normandy: report of a hospital survey]. / Maladie de Lyme chez l'enfant en Haute-Normandie: à propos d'une enquête hospitalière.

This study presents the results of a hospital survey on Lyme disease in children living in upper Normandy, a region that is quite densely wooded (with 18% forest areas and woods). The aim of this survey was to assess the prevalence of this disease in children from the Seine-Maritime and L'Eure, hospitalized in pediatric wards in the Seine-Maritime department, which includes Rouen, Dieppe, Fécamp, Elbeuf, and Le Havre. Fifteen cases of Lyme disease were diagnosed between September 1988 and June 1997. The children (6 girls and 9 boys) were aged between 5 and 14 years old. Only 7 subjects showed primary symptoms, while secondary symptoms were observed in 12 children. In the study population, a high prevalence (11 out of the 15 children) of neurological disorders was found. The following secondary symptoms were noted: 5 cases of erythema migrans, 2 cases of non-malignant cutaneous lymphocytoma, and 4 cases which in fact had previously displayed primary clinical signs (3 subjects with erythema migrans and 1 subject with non-malignant cutaneous lymphocytoma); 7 cases of uni- or bilateral facial paralysis, the most frequent neurological manifestation with or without lymphocytic meningitis; 1 case of central vestibular syndrome with a hyperalgesic meningoradicular reaction in the vicinity of the tick bite; 1 case of peripheral radicular involvement and intense pain in the left lower limb; 4 cases of ocular disorders (3 diplopias, 1 bilateral conjunctivitis complicated by kerato-uveitis, 1 bilateral complete cecitis). Only 10 child had rheumatological symptoms, i.e., Lyme arthritis of the right knee. Treatment consisted of amoxicillin (10 children) administered at a dosage of 50 to 100 mg/kg/d over a period ranging from 10 days to 1 month, or ceftriaxone (7 children) at a dosage of 50 to 100 mg/kg/d administered intravenously over a period ranging from 8 days to 3 weeks. Two of the children received combined antibiotic therapy, and 5 subjects had adjunct corticotherapy.

Issues in understanding childhood asthma.

Asthma and related allergic disorders in childhood have increased considerably in prevalence over the last few decades. During the same period of increasing morbidity from childhood asthma in the community, there have been dramatic advances in understanding of the basic immunopathologic features of the disease and consequently the development of a far more rational approach to its treatment. The immunopathologic condition of eosinophil-mediated airway inflammation is established very early in the evolution of asthma in childhood. It may even antedate the onset of symptoms. The present state of the art dictates that early intervention with potent therapies cannot be justified on the basis of symptoms alone and may in any case have no influence on the natural history of the condition. This means that current cautious therapeutic guidelines should continue to be followed. However, with the development of more accurate markers predicting ongoing disease, it will be possible to evaluate a whole range of early interventions in the future. Much evidence, though indirect, points to the possibility that the only true prophylaxis that will affect the natural history of asthma will need to be commenced before clinical features are manifest.

Bronchoalveolar cell profiles in children with asthma, infantile wheeze, chronic cough, or cystic fibrosis.

Differential cell counts of bronchoalveolar lavage (BAL) have been reported in normal children but few data on cellular profiles in bronchial diseases in childhood are available. We determined the BAL cell profiles of 72 children divided into 5 groups: asthma (n = 14), chronic cough (n = 12), infantile wheeze (n = 26), cystic fibrosis (n = 10), and control (n = 10). The highest total cell, eosinophil, and neutrophil counts were found in children with cystic fibrosis. The cell profile of children with chronic cough was similar to that of control children. Asthma and infantile wheeze were characterized by a high median ratio of eosinophils (3%) and neutrophils (12%), respectively. In both diseases, epithelial shedding was suggested by an elevated epithelial cell count, 13.5 and 12%, respectively. Lymphocyte subset analysis showed a higher proportion of CD8 cells (58 versus 40%) and therefore a lower CD4/CD8 ratio (0.266 versus 0. 455) in children with asthma compared with infantile wheezers (p = 0. 02). Irrespective of the presence or absence of radiological abnormalities, a proportion of neutrophils > 10%, was found in one-third of the children with asthma and in half of the infantile wheezers, and was related to symptom severity. We suggest that neutrophil-mediated inflammation, with or without bacterial infection, may contribute to symptoms of asthma in childhood. Chronic cough, however, is not associated with the cell profiles suggestive of asthma and in isolation should not be treated with prophylactic antiasthma drugs.

Inflammatory mechanisms in childhood asthma.

There is now a reasonable body of data that would suggest that the immunopathology of asthma is similar, if not identical, in childhood asthmatics compared with adult asthmatics. Indeed, we now have evidence that much of the immunopathology is established within the airways of asthmatics very early after the onset of symptoms and, given the lack of correlation with duration of symptoms, may even antedate the first manifestations. There are, however, some differences with neutrophil recruitment being somewhat more prominent than has been recorded from adult observations. The utility of any inflammation parameter in identifying the real future asthmatics has yet to be studied in sufficient detail to define sensitivity, specificity and predictive value. Such studies will be an essential prerequisite to establishing very early intervention strategies, particularly if these involve the use of inhaled and/or oral corticosteroid.

Rational use of CT in acute pyelonephritis: findings and relationships with reflux.

Enhanced renal CT scanners were performed in 38 children (82% girls) to rule out acute pyelonephritis. Patients were divided in 2 groups on the basis of clinical presentation and bacteriology data. In patients of group A (n = 16, preliminary study), upper urinary tract infection (UTI) was certain. CT confirmed the diagnosis in all but 3 patients (a 2-year-old child and 2 patients with UTI developed on prior obstruction). In subsequently studied patients of group B (n = 22), clinical findings or bacteriology data were negative or questionable. CT made the diagnosis of acute pyelonephritis in 11 patients. As well as DMSA scintigraphy, CT scanner can help to diagnose or to rule out upper UTIs in difficult cases. In all boys of both groups, ipsilateral vesico-ureteric reflux (VUR) was found by subsequent voiding cystourethrography (VCUG) on the side of pyelonephritis. In girls, this correlation was shown in only 7 of the 25 kidneys with pyelonephritis. This result supports the hypothesis of a gender-dependent contamination. We believe that absence of radiologic reflux cannot exclude the possibility of bacterial crossings of ureteric meatus capable to lead to genuine upper UTIs.