Neonatal screening of cystic fibrosis: diagnostic problems with CFTR mild mutations.

Newborn screening (NBS) of cystic fibrosis (CF) was implemented throughout the whole of France in 2002, but it had been established earlier in three western French regions. It can reveal atypical CF with one or two known CFTR mild mutations, with an uncertain evolution. The sweat test can be normal or borderline. In Brittany, from 1989 to 2004, 196 CF cases were diagnosed (1/2885 births). The incidence of atypical CF diagnosed by NBS is 9.7% (19 from 196). The outcome of 17 (2 lost of view) has been studied, with 9 other atypical CF cases diagnosed by NBS in two other regions. The follow-up period extends from 0.25 to 19.8 years (NBS implemented in Normandy in 1980) with mean age 4.6 years. The most frequent mild mutation is R117H ISV8-7T (50%). At the time of the last visit, nutritional status is normal. All these CF patients are pancreatic sufficient. Only one patient exhibits respiratory infections, whereas 7 others have them intermittently. Two of them had intermittent Pseudomonas aeruginosa colonization at 2.8 and 6.5 years. Mean Shwachman score is 96.7, mean Brasfield score is 22.8. Eight children have had lung function tests (mean follow-up of 10 years): mean FVC was 99% of predicted, mean FEV1 101%, but one of them has FEV1 of 48%. Predicting the phenotype of these atypical CF patients remains difficult, thus complicating any genetic counselling. A regular clinical evaluation is necessary, if possible by a CF unit, because CF symptoms may appear later.

[Longitudinal evaluation of pulmonary function tests in children with newborn screening for cystic fibrosis. Relationships with pulmonary infection. Study of 40 children undergoing 744 pulmonary function tests]. / Evolution des épreuves fonctionnelles respiratoires (EFR) chez des enfants atteints de mucoviscidose et dépistés à la naissance. Lien avec l'infection pulmonaire. Etude sur 40 enfants et 744 EFR.

OBJECTIVES: To report longitudinal assessment of pulmonary function in children with neonatal screening for cystic fibrosis and its relationships with Pseudomonas aeruginosa (PA) chronic infection, nutritional status, sex, age and genotype. POPULATION AND METHODS: Children benefited systematically of 3 visits a year with pulmonary function tests (PFT) and bacteriological examination. Forty children and 744 PFTs were analysed, with 38 children during at least 4 years. RESULTS: We reported a decrease of pulmonary function tests with chronic PA infection and the genotype DeltaF508/DeltaF508. The decline was gradual and not different between not infected and recently infected children. The PFTs of children infected for a long times were very deteriorate, probably due to the fact that they were infected with multiresistant strains of PA. CONCLUSION: We think that it is important to survey pulmonary function before 5 years old in these early infected children. We should determinate if the important decrease of PFT in these early infected children is due to infection by PA mucoid.

[Management of infants whose diagnosis is inconclusive at neonatal screening for cystic fibrosis]. / Recommandations pour la prise en charge et le suivi des nourrissons pour lesquels un diagnostic de mucoviscidose n'a pu être conclu après dépistage néonatal.

Neonatal screening for cystic fibrosis (CF) may detect infants with elevated immunoreactive trypsinogen (IRT) levels but with inconclusive sweat tests and/or DNA results. This includes cases associating (1) either the presence of at most one CF-causing mutation and sweat chloride values between 30 and 59mmol/L or (2) two CFTR mutations with at least one of unknown pathogenicity and a sweat chloride below 60mmol/L. This encompasses different clinical situations whose progression cannot be predicted. These cases require redoing the sweat test at 12 months and if possible at 6 and 24 months of life. This must be associated with extended genotyping. CFTR functional explorations can also help by investigating CFTR dysfunction. These infants must be initially evaluated in dedicated CF centers including bacteriological sputum analysis, chest radiology and fecal elastase dosage. A home practitioner must be informed of the specificity of follow-up. These infants will be reviewed in the CF center at 3, 6 and 12 months and every year. Any CF-related symptom requires reevaluation of the diagnosis. These guidelines were established by the "neonatal screening and difficult diagnoses" working group of the French CF Society. They aim to standardize management of infants with unclear diagnosis in French CF centers.

Guidelines for the clinical management and follow-up of infants with inconclusive cystic fibrosis diagnosis through newborn screening.

Neonatal screening for cystic fibrosis (CF) can detect infants with elevated immunoreactive trypsinogen (IRT) levels and inconclusive sweat tests and/or CFTR DNA results. These cases of uncertain diagnosis are defined by (1) either the presence of at most one CF-associated cystic fibrosis transmembrane conductance regulator (CFTR) mutation with sweat chloride values between 30 and 59mmol/L or (2) two CFTR mutations with at least one of unknown pathogenic potential and a sweat chloride concentration below 60mmol/L. This encompasses various clinical situations whose progression cannot be predicted. In these cases, a sweat chloride test has to be repeated at 12 months, and if possible at 6 and 24 months of life along with extended CFTR sequencing to detect rare mutations. When the diagnosis is not definite, CFTR functional explorations may provide a better understanding of CFTR dysfunction. The initial evaluation of these infants must be conducted in dedicated CF reference centers and should include bacteriological sputum analysis, chest radiology, and fecal elastase assay. The primary care physicians in charge of these patients should be familiar with the current management of CF and should work in collaboration with CF centers. A follow-up should be performed in a CF reference center at 3, 6, and 12 months of life and every year thereafter. Any symptom indicative of CF requires immediate reevaluation of the diagnosis. These guidelines were established by the "neonatal screening and difficult diagnoses" working group of the French CF society. Their objective is to standardize the management of infants with unclear diagnosis.

[Severe asthma due to an esophageal foreign body in a child]. / Un asthme rebelle en rapport avec un corps étranger oesophagien méconnu.

A 4-year-old boy had infantile bronchial asthma resistant to treatment. He was referred for a febrile respiratory distress which led to the diagnosis of periesophagus mediastinis mass with erosion of both contiguous vertebral discs. The oesophagogram showed a foreign body in an esophageal diverticulum. After its extraction, all pulmonary symptoms disappeared.

[Respiratory outcome of bronchopulmonary dysplasia in school-age children]. / Devenir respiratoire à l'âge scolaire de la dysplasie bronchopulmonaire.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy. The influence of its initial severity on long-term respiratory outcome remains uncertain. OBJECTIVES: The purpose of this study was to examine the impact of "new BPD" on respiratory morbidity as well as respiratory function at rest and during exercise in school-age children. METHODS: The 93 preterm newborns (<33 weeks gestation) presenting with BPD between 1997 and 2004 at the Rennes University Hospital had been proposed for a specific follow-up program. The children included in this cohort and presenting without severe handicap or motor deficit were eligible for this observational retrospective study. Their standardized clinical evaluation and the results of the pulmonary function tests and cardiopulmonary exercise tests performed between the ages of 7 and 14 years were studied. BPD was considered to be moderate when respiratory or oxygen support continued at 36 weeks gestation with an FiO2 less than 30% and severe when FiO2 was greater than 30%. RESULTS: Among the 36 children assessed, the initial severity of the BPD was mild in 12 cases, moderate in 12 cases, and severe in 12 cases. The mean age at the time of the pulmonary function test (PFT) was 9.9 (±1.9) years, 19 children (53%) had respiratory symptoms during the year before the test, and six (17%) underwent long-term treatment. The PFT was abnormal for 32 children (89%): 23 showed airway obstruction, 16 hyperinflation, three increases in bronchial reactivity, and two restrictions. The residual volume/total lung capacity ratio was the only parameter related to the severity of BPD (P<0.05). The cardiopulmonary exercise test was given to 35 children: 15 of them had normal exercise ability but with a limited ventilatory reserve. CONCLUSIONS: Half of the children included in this "new-BPD" follow-up cohort had clinical respiratory morbidity and most of the children followed presented with persistent alterations in pulmonary function tests at school age, which were not associated with significant alterations in the maximum aerobic performance.

[Indoor fungal exposure: What impact on clinical and biological status regarding Aspergillus during cystic fibrosis]. / Exposition domiciliaire aux moisissures : quel impact sur le statut aspergillaire du patient atteint de mucoviscidose ?

The sources of exposure during diseases due to Aspergillus fungi in cystic fibrosis patients are still poorly explored. We assessed home fungal exposure in patients suffering from cystic fibrosis and analysed its impact on the presence of Aspergillus biological markers, the colonisation of airways, as well as the sensitization and Aspergillus serology. Between March 2012 and August 2012, 34 patients benefited from a visit performed by a home environment medical adviser including sampling for mycological analysis. The number of colonies of Aspergillus was not significantly different in the various sampling sites (P=0.251), but the number of non-Aspergillus colonies was much higher in the kitchen (P=0.0045). Subsequently, home fungal exposure was compared between the groups "absence of Aspergillus-related markers" and "presence of Aspergillus-related markers". Home exposure to Aspergillus (P=0.453) and non-Aspergillus (P=0.972) flora was not significant between the 2 groups. Within this series of 34 patients that should be expanded, we note an absence of clear relationship between home exposure and the Aspergillus-linked markers in patients suffering from cystic fibrosis. This result should be taken into account regarding too restrictive hygiene advices provided to families, given the fact that fungal exposure can also results from activities performed away from home.

[Influence of surfactants on hemodynamics during neonatal respiratory distress syndrome]. / Influence du surfactant sur l'hémodynamique du syndrome de détresse respiratoire néonatal.

The neonatal respiratory distress syndrome tends to delay the circulatory adaptation to extra-uterine life and leads to systematic hypotension. Haemodynamic changes following the instillation of surfactant are not stereotyped. They depend on the type of surfactant, the time of the instillation, the degree of prematurity, the severity of the respiratory disease and the mode of instillation. They are characterized by a transient haemodynamic instability with variable consequences on arterial pressure and systemic blood flow. The use of surfactant tends to decrease pulmonary arterial resistances and pulmonary arterial pressures but this effect is variable and is not obviously accompanied by long-term deleterious effect on the arterial duct. Haemodynamics and blood gases changes due to surfactant instillation have a variable effect on cerebral blood flow. The potential role of blood gas and haemodynamics changes on the occurrence of pulmonary haemorrhage or cerebral damage following instillation of surfactant remains poorly established but has to be taken into account.

[Diffusing capacity for carbon monoxide (T(LCO)) and oxygen saturation during exercise in patients with cystic fibrosis]. / Capacité de transfert du monoxyde de carbone (TLCO) et saturation artérielle à l'exercice chez les patients atteints de mucoviscidose.

OBJECTIVES: To estimate the value of diffusing capacity for carbon monoxide (T(LCO)) in patients with cystic fibrosis and to evaluate its ability to predict arterial desaturation during exercise. METHOD: Fourty-four patients (9-30 years) with cystic fibrosis performed pulmonary function tests with measure of T(LCO) and a bicycle incremental exercise test. They represent a wide variation in disease severity: mean Shwachman score: 77.8 (range: 40-100), mean FEV1%: 72.8 (range: 17-131). This study investigated the relationship between T(LCO), lung volumes and exercise data. RESULTS: T(LCO) remained normal for a long time in patients with cystic fibrosis: 82% of them show a normal T(LCO) (mean value: 91.3% of predicted). T(LCO) was significantly correlated with FEV(1), residual volume, maximal work load and maximum oxygen uptake. A fall in arterial oxygen saturation was uncommon in our study (five patients) and not significantly correlated with T(LCO). CONCLUSIONS: T(LCO) is a good criter of severity of cystic fibrosis but remains unreliable to predict values above which physical activity is safe, without arterial desaturation. Exercise tests should be proposed in order to evaluate exercise adaptation of each patient and determine which factor limits maximal performance.

[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.

Characteristics of endobronchial primitive tumors in children.

Primary endobronchial tumors are rare in children and they include a broad spectrum of lesions. The aim of this study was to determine the characteristic features, treatments and outcomes of these tumors. We report a retrospective analysis of all patients treated for endobronchial tumor in nine French hospitals between 1990 and 2010 and a comparison of the results with those reported in the medical literature. Twelve tumors were reported: five low grade muco epidermoid carcinomas, two inflammatory myofibroblastic tumors, two hemangiomas, one anaplastic large cell lymphoma, one carcinoid tumor, and one juvenile xanthogranuloma. The mean age of the patients was 7.5 ± 3.5 years. The most common sign revealing the disease was persistent atelectasis or recurrent pneumonia (eight cases). The other revealing signs were a persistent bronchospasm (three cases) and hemoptysis (one case). The clinical presentation, biology, serum tumor markers, and chest X-ray abnormalities were not specific to a particular histological diagnosis. Chest CT scan revealed the presence of an endobronchial tumor in 11 cases. Nine tumors could be diagnosed from a biopsy obtained by video endoscopy. Complete surgical resection was performed in seven patients. Bronchoscopic removal was performed in five cases and was successful in three. There were no deaths. Endobronchial tumors are rare in childhood and their histology is diverse. Chest CT scan and per-endoscopic endobronchial biopsies are required for diagnosis, when possible. Surgical or endoscopic treatment should be discussed by a multidisciplinary team. Despite the multiple etiologies, the prognosis of these tumors is good if diagnosis is early and if resection is complete. Long-term recurrences have been described, so long-term follow-up of these children is recommended.

Long-term evaluation of respiratory status after esophageal atresia repair.

RATIONALE: Esophageal atresia (EA) is a congenital malformation. Nowadays, its initial prognosis is excellent thanks to improvements in neonatal and surgical management. However, the assessment of long-term respiratory outcome has become necessary in affected children and was thus performed in this study. The benefits of cardiopulmonary function testing were also examined. METHODS: The medical records of 77 children operated on for EA between 1990 and 2004 were reviewed. The results of respiratory function testing and cardiopulmonary response to effort were collected, together with neonatal and anthropometric data. RESULTS: Acceptable measurements were obtained in 31 children with EA. These children were comparable to the ones lost during follow-up. The results of pulmonary function tests (PFTs) were abnormal in 21 cases (68%). A poor ventilatory response was detected in 14 children (45%) by cardiopulmonary function testing. Ten children who had abnormal results on PFTs were not under any anti-asthmatic treatment. CONCLUSIONS: Impaired lung function was noted in children with repaired EA. Indeed, cardiopulmonary function tests results correlated with standard spirometric parameters and revealed minimal clinical symptoms. Moreover, many children with EA had a limited ventilatory reserve (VR). These results indicate that respiratory symptoms are often neglected in children with repaired EA and reinforce the need to provide adequate treatment.

[Primary ciliary dyskinesia: a retrospective review of clinical and paraclinical data]. / Dyskinésie ciliaire primitive : revue rétrospective clinique et paraclinique.

INTRODUCTION: Primary ciliary dyskinesia (PCD) is an inherited disease responsible for a disruption of normal ciliary function. Its clinical presentation is usually in early childhood with pulmonary and otorhinolaryngologic symptoms. Early diagnosis is essential to avoid the development of bronchiectasis. The aim of the study was to retrospectively review the clinical features of children suspected to have PCD. RESULTS: A total of 89 children had a bronchoscopy to perform a biopsy analyzed by transmission electron microscopy (TEM) in the childrens' hospital of Rennes between 2000 and 2009. PCD was diagnosed in 17 children, excluded in 51 and results were uncertain in 21 children. Mean age at diagnosis was 6.5 years. In the PCD group, a history of neonatal respiratory distress was found in 40% of cases, 82% had had bronchopneumonia, 37% sinusitis, 82% recurrent otitis and 23% situs inversus. These subjects had defects in ciliary structure, 59% in the dynein arms, 35% in the central complex and 6% having both. Nasal nitric oxide production was consistent with the results of TEM in 16 cases: five PCD, 11 without PCD. In two cases, the results were discordant. CONCLUSION: This case series highlights the key clinical features of recurrent otitis, sinusitis, and situs inversus, especially when occurring in combination with bronchitic symptoms. Measures of nasal nitric oxide are useful for the diagnosis of PCD and in the case of high levels of NO, PCD is unlikely. Results may not be definitive and TEM analysis of biopsies is still indispensable to ensure the diagnosis and guide genetic counselling.

[Nocardia farcinica infection in a patient with cystic fibrosis]. / Infection à Nocardia farcinica chez un patient porteur d'une mucoviscidose.

Infections by Nocardia species are uncommon and generally affect immunocompromised patients. This bacteria has rarely been isolated from cystic fibrosis patients (CF), especially those who are not taking oral corticosteroids. We report a case of a patient with CF harbouring Nocardia farcinica. An 18-year-old male diagnosed with CF at the age of eight (F508 del/G85E) had been treated for allergic bronchopulmonary aspergillosis in 1998 with itraconazole, and a first colonization with Pseudomonas aeruginosa was eradicated in 2003. From May 2006, he presented with recurrent left- and right-sided pneumothorax. In June 2006, he presented with dyspnoea, fever, and nodular eruption on his ankles. Chest X-ray and CT scan revealed a right pneumothorax, severe bronchiectasis and bilateral alveolar consolidation. N. farcinica was idolated from his sputum without any other pathogens. Treatment with intravenous cotrimoxazole associated with imipenem and amikacin was initiated for three weeks followed by oral cotrimoxazole for a further nine months. The patient's symptoms and alveolar consolidation on CT scan improved. During 2007, his respiratory condition worsened and his FEV(1) declined from 50 to 26 % predicted. His pneumothorax recurred. He had chronic colonization with P. aeruginosa and was on the list for lung transplantation. Nocardia, a Gram positive bacillus, causes mainly pulmonary infection, usually in the context of immune suppression. The most frequent species is N. asteroides. In CF, very few cases have been reported; almost always N. asteroides, but exceptionally N. farcinica. In CF patients with worsening pulmonary condition, Nocardia should be considered, as well as other unusual pathogens.

Dose-dependent in vitro effect of recombinant human DNase on rheological and transport properties of cystic fibrosis respiratory mucus.

Recombinant human deoxyribonuclease (rhDNase) has been demonstrated to reduce the viscosity of purulent cystic fibrosis (CF) respiratory mucus, to improve pulmonary function and to reduce the risk of respiratory tract infectious exacerbations, but its effect on mucus transportability has not so far been investigated. The dose-dependent effect of rhDNase was analysed in vitro on mucus transport rate (tr) by ciliary activity and by simulated cough (cough transport (ct)), as well as on mucus viscosity and surface properties. Purulent CF sputa (n = 15) were incubated for 30 min at 37 degrees C with either rhDNase at three different concentrations (final concentrations 0.2, 2 or 20 micrograms.ml-1 of mucus) or placebo. No significant dose-dependent effect of rhDNase on the mucociliary transport rate was observed when the samples wer statistically analysed together. However, in the larger group of mucus samples (n = 11) with a low initial mucociliary transport rate, the latter was improved at each rhDNase concentration (tr0.2 = 0.69, tr2 = 0.88 and tr20 = 0.87) as compared to placebo (trp = 0.58). In the smaller group of mucus samples (n = 4) with high initial transport rate, a decrease in mucociliary transport rate was observed, particularly at the highest concentration rhDNase assayed, i.e. 20 micrograms.ml-1 of mucus (tr20 = 0.58) as compared to placebo (trp = 0.86). The mucus cough transport was increased by rhDNase (ct0.2 = 25 mm, ct2 = 27.5 mm and ct20 = 31 mm) as compared to placebo (ctp = 23.5 mm).(ABSTRACT TRUNCATED AT 250 WORDS)

Revisited physicochemical and transport properties of respiratory mucus in genotyped cystic fibrosis patients.

We investigated the physicochemical and transport properties of sputum samples collected in physiotherapy from a well-documented group of 27 cystic fibrosis (CF) patients with identified CF genotypes. Sputum samples were characterized ex vivo for their water content, surface properties (surface tension and contact angle), rheologic properties (viscosity and elastic modulus), and transport properties (mucociliary and cough transport). These data were analyzed in relation to the clinical status of the patients (FEV1, FVC, Shwachman score, Brasfield score, nutritional status), their genotype, and the degree of infection of their sputa (leukocyte and Pseudomonas aeruginosa counts). We observed negative and significant correlations between mucociliary transport and elastic modulus of the patients' sputum (r = -0.63, p < 0.01), and between the cough transport and contact angle of the sputum (r = -0.81, p < 0.0001), respectively. The P. aeruginosa count was also significantly correlated with the sputum water content (r = -0.53, p < 0.02) as well as with the cough transport of the sputum (r = -0.62, p < 0.01). In CF patients with a sputum leukocyte count > 2,000/mm3, the sputum water content (p < 0.02), FEV1 (p < 0.05) and FVC (p < 0.02) were significantly lower than those of CF patients with a leukocyte count < or = 2,000/mm3. CF patients with a homozygous delta F 508 genotype had significantly greater values of sputum water content (p < 0.05), and cough-transport capacity (p < 0.05) than did heterozygous patients. No correlation was observed between the sputum properties and any of the clinical data. These results suggest that the control of infection should be emphasized in CF, since it can directly or indirectly modulate the degree of hydration, and therefore the physicochemical and transport properties, of airway secretions.