Non-classic cystic fibrosis associated with D1152H CFTR mutation.

BACKGROUND: Limited knowledge exists on phenotypes associated with the D1152H cystic fibrosis transmembrane conductance regulator (CFTR) mutation. METHODS: Subjects with a D1152H allele in trans with another CFTR mutation were identified using the French Cystic Fibrosis Registry. Phenotypic characteristics were compared with those of pancreatic insufficient (PI) and pancreatic sufficient (PS) cystic fibrosis (CF) subjects in the Registry (CF cohort). RESULTS: Forty-two subjects with D1152H alleles were identified. Features leading to diagnosis included chronic sinopulmonary disease (n = 25), congenital absence of the vas deferens (n = 11), systematic neonatal screening (n = 4), and genetic counseling (n = 2). Median age at diagnosis was 33 [interquartile range (IQR, 24-41)] years in D1152H subjects. Median sweat chloride concentrations were 43.5 (39-63) mmol/l in D1152H subjects and were markedly lower than in PI and PS CF subjects (p < 0.05). Bronchiectasis was present in 67% of D1152H subjects, but Pseudomonas aeruginosa colonization and pancreatic insufficiency were present in <30% of subjects. Estimated rates of decline in forced expiratory volume in 1 s (FEV(1)) were lower in D1152H subjects vs PI CF subjects (p < 0.05). None of the D1152H subjects identified since 1999 had died or required lung transplantation. CONCLUSIONS: When present in trans with a CF-causing mutation, D1152H causes significant pulmonary disease, but all subjects had prolonged survival.

[Neuromuscular function in patients with cystic fibrosis]. / Etude de la fonction neuromusculaire chez des patients atteints de mucoviscidose.

INTRODUCTION: In patients with cystic fibrosis impaired exercise tolerance and the reasons for this dysfunction are now well documented. This decrease in performance is mainly related to respiratory and nutritional problems but also to impaired muscle function. The aim of this study was to determine whether there is a specific neuromuscular disorder in this population that could explain the decreased muscular performance. METHODS: Nine male subjects with forced expiratory volume (FEV1) values ranging from 40% to 80% of predicted values and taking regular nutritional supplements were included in this study. Ten untrained healthy subjects were used as a control group. The neuromuscular properties of the quadriceps were evaluated by voluntary maximal isometric force (VMIF) and EMG values (spectral analysis) before, and immediately after, maximal incremental cycling exercise to exhaustion. RESULTS: At rest the subjects with cystic fibrosis had, significantly lower values of VMIF than the control group (-26%; p<0.05), with no difference in EMG. After fatigue a similar decrease in VMIF was observed in the two groups (cystic fibrosis -20%; controls -19.4%). Furthermore no significant difference in the decrease of EMG values (mean power frequency) was observed between the two groups. CONCLUSION: An identical decrease in maximal isometric force and EMG parameters was observed in both populations after exhausting exercise. Therefore, no specific alteration of muscular function seems to exist in subjects with cystic fibrosis with FEV1 values above 40% of maximal predicted values and taking adapted nutritional supplementation.

Absence of calf muscle metabolism alterations in active cystic fibrosis adults with mild to moderate lung disease.

BACKGROUND: Specific alterations in skeletal muscle related to genetic defects may be present in adults with cystic fibrosis (CF). Limb muscle dysfunction may contribute to physical impairment in CF. AIMS AND OBJECTIVES: We hypothesized that adults with CF would have altered calf muscle metabolism during exercise. METHODS: Fifteen adults with CF and fifteen healthy controls matched for age, gender and physical activity performed a maximal cycling test and an evaluation of calf muscle energetics by 31P magnetic resonance spectroscopy before, during and after plantar flexions to exhaustion. RESULTS: Maximal cycling test revealed lower exercise capacities in CF (VO2peak 2.44±0.11 vs. 3.44±0.23L·Min-1, P=0.03). At rest, calf muscle phosphorus metabolites and pHi were similar in CF and controls (P>0.05). Maximal power output during plantar flexions was significantly lower in CF compared to controls (7.8±1.2 vs. 6.6±2.4W; P=0.013). At exhaustion, PCr concentration was similarly reduced in both groups (CF -33±7%, controls -34±6%, P=0.44), while PCr degradation at identical absolute workload was greater in CF patients (P=0.04). These differences disappeared when power output was normalized for differences in calf size (maximal power output: 0.10±0.02 vs. 0.10±0.03W/cm2; P=0.87). Pi/PCr ratio and pHi during exercise as well as PCr recovery after exercise were similar between groups. CONCLUSION: Similar metabolic calf muscle responses during exercise and recovery were found in CF adults and controls. Overall, muscle anabolism rather than specific metabolic dysfunction may be critical regarding muscle function in CF.

[Cystic intrathoracic hemolymphangioma: a rare differential diagnosis of acute bronchiolitis in an infant]. / Hémolymphangiome kystique intrathoracique: un diagnostic différentiel rare de bronchiolite aiguë chez un nourrisson.

Hemolymphangioma is a benign malformation of the lymphatic vessels. Cervical localisation is the most frequent. Mediastinal localisation is rare, but may be life-threatening because of airway compression. We report on a four-month-old boy who presented, in a context of epidemics, with clinical signs of acute bronchiolitis requiring mechanical ventilation for several days. Chest X-rays showed an important mediastinal mass with airways compression. Diagnosis was evoked on CT-scan aspects and confirmed by histology. Surgery allowed complete resolution, but dysphonia and oropharyngeal disorders persisted for several months. This rare congenital malformation is reviewed.

[The beta-2-agonists in asthma in infants and young children]. / Les beta 2-mimétiques dans l'asthme du nourrisson et du jeune enfant.

beta 2-agonists, by inducing a fast and long relaxation of the bronchial smooth muscle, are considered as the more potent bronchodilators. beta 2-receptors are present from the 16th gestational week, explaining a possible bronchial response in the youngest children. beta 2-agonists do not induce any bronchodilator response in healthy children. Short-acting beta 2-agonists (salbutamol or albuterol, terbutaline) are indicated for asthma attacks, as needed in chronic asthma, and for prevention of symptoms during effort. They are safe and secure. The more efficient route of administration in preschool children is pressurized metered-dose inhaler used with a spacer device. Therefore, whatever the route of inhalation chosen (inhalation, injection, or continuous nebulization in acute asthma attack), more specified indications and doses are needed in young children. Long-acting beta 2-agonists (formoterol, salmeterol) are not authorized in France in children under 4 to 5 years of age depending on the drug used. Because of new oral formulations and recent considerations about their use in asthma attack, instead of short-acting beta 2-agonists, their indication in preschool asthmatic children might be reconsidered.

[Inhalers and nebulizers in the children]. / Inhalation et nébulisation chez l'enfant.

Inhaled way is the most efficient method to deliver drugs for the treatment of respiratory diseases. Pulmonary deposition depends upon the inhalation system and technique. The evaluation of the drug deposition is difficult, particularly in children. Because of irradiation, scintigraphic studies which permit the best approach of the pulmonary deposition are rare in children. Various inhalation systems are available: nebuliser, metered-dose inhaler with or without spacer device, dry powder inhaler. Whatever the system used, the control of asthma will be only possible with the regular evaluation of the child inhalatory technique.

[Isolated agenesia of pulmonary artery]. / Agénésie isolée de l'artère pulmonaire. A propos de huit observations.

Unilateral primitive agenesia of pulmonary artery is a rare congenital disorder. Experience of three hospital-based pulmonology pediatric units including eight children (three boys and five girls) with such anomaly is reported (11 years median follow-up, range 6 months to 10 years). Median age at diagnosis was 4 years. Clinical features included recurrent respiratory tract infections (75%), effort dyspnea (50%) and, curiously, asthmatic symptoms (75%). Diagnosis was evoked on chest X rays and confirmed by angiography in all cases. Agenesis of the right pulmonary artery was more frequent (five cases). Abnormal vascular ring was associated in two cases of agenesis of the left pulmonary artery. Pulmonary function tests were performed in six children, with bronchial obstruction in two. Regular clinical follow-up, up to adult age in four cases, showed no complication, such as hemoptysis or pulmonary hypertension in our patients.

[Acute asthmatic crisis in children]. / La crise d'asthme aigu grave de l'enfant.

Acute asthma attack in children is an attack responsible for life-threatening acute respiratory distress with partial or no response to bronchodilator drugs. The severity of the episode needs to be quickly evaluated. This presupposes a perfect knowledge of the clinical signs of severity. Treatment is urgent and first based on the administration of high doses of inhaled short-acting beta 2-agonists. In the more obstructed children, anti-cholinergic drugs can be added to nebulized beta 2-agonists. Because of their delayed effect, systemic steroids require an early prescription. Symptomatic treatments are: urgent hospitalization, oxygen if needed, proper hydratation. Continuous nebulization or intravenous perfusion of beta 2-agonists are prescribed with cardiac monitoring when no objective improvement is noted. Admission into the pediatric intensive care unit when bronchial obstruction continues will permit the association of bronchodilator drugs and the proposal of mechanical ventilation if needed. When the episode is resolved, a prophylactic treatment using inhaled corticosteroids must be prescribed. Clinical and spirometric follow-up has to be organized, and the patient and his/her family have to be educated.

[Influence of the inhaler device on bronchodilatation in the asthmatic child]. / Influence de la chambre d'inhalation sur la bronchodilatation chez l'enfant asthmatique.

The use of spacer devices is recommended in asthmatic children for inhaled therapeutics. Therefore, in vitro studies prove the dependent-device delivery of the drug. The aim of this study was to compare, in vivo, the effect of 200 micrograms of albuterol, delivered via one of the five spacer devices currently marketed in France (Aerochamber, Aeroscopic, Babyhaler with a face mask, Nebuhaler or Volumatic) and assessed by the induced peak expiratory flow (PEF) change. One hundred asthmatic children were recruited and randomized in 5 groups. The mean age was 8.9 +/- 3.3 years. Each group was comparable regardless of gender, height, weight, characteristics of asthma and baseline PEF. The maximal change in PEF was obtained with Babyhaler (14.9 +/- 12.8%; p = 0.009). The increase in PEF elicited with Aeroscopic was 9.7 +/- 10.2%. The others spacer devices did not offer a change greater than the variation of PEF in the studied population. Further studies, concerned with a measurement of drug deposition or with an assessment of its use in obstructive episodes of asthma, are required, but Babyhaler with a face mask, usually reserved to infants, deserves to be advised to older children for salbutamol intake.

[Modes of administration of inhaled corticosteroids in mild to moderate persistent asthma]. / Modalités d'administration des corticoïdes inhalés dans l'asthme persistant léger à modéré.

Inhaled corticosteroids are the treatment of choice for asthma. However, poor compliance by patients is one of the principal difficulties forced by clinicians. Thus, it seems important to propose the minimal daily number of doses. This study has compared the various modes of administration of inhaler corticosteroids and was carried out in patients with mild to moderate persistent asthma. Thus, comparing two to four doses per day shows an identical efficacy if the dose is less than 800 micrograms per day. At higher doses only two studies have been carried out and there are discordant results. The studies compare two doses versus one single dose per day and equally disagree with numerous works in favor of a single daily dose. In the single study carried out for at least twelve months the twice daily dose was the most effective. Thus it seems reasonable to suggest a single dose for mild persistent asthmatics. For moderate persistent asthmatics the choice between a single or twice daily dose would depend on the therapeutic compliance of the patient.

[Virus and respiratory allergy in children]. / Virus et allergie respiratoire de l'enfant.

Links between viruses and respiratory allergy are not easy to understand in children. For example, the risk of atopy or asthma is increased after an infection with syncytial respiratory virus. In some studies, more the child suffers from viral infections, more the risk of atopy increases. On the other hand, other studies state that the development of allergy is reduced if a child enters day nursery before 12 months, and consequently if he is exposed early in life to viruses. Measles and hepatitis A viruses could also protect from allergy. In fact, viruses seem modulate the expression of a preexisting atopic status. Depending on their nature and their circumstances of occurrence, they could induce some sensitizations or inversely protect from atopy by facilitating the lymphocyte Th2 or Th1 response.

Pandoraea pulmonicola chronic colonization in a cystic fibrosis patient, France.

Pandoraea are considered emerging multidrug resistant pathogens in the context of cystic fibrosis. We report herein for the first time the case of a 30-year-old woman with cystic fibrosis, living in France, who was chronically infected with Pandoraea pulmonicola and who died of Pseudomonas aeruginosa sepsis 3 weeks after bilateral lung transplantation.

Neuromuscular fatigue after maximal exercise in patients with cystic fibrosis.

The aim of this study was to determine whether patients with cystic fibrosis (CF), despite their ventilatory limitation, would develop neuromuscular fatigue of quadriceps muscles following a maximal cycling exercise. Eleven adults with CF (age=26.8±6.9years; forced expiratory volume in 1s=54.1±12.8% predicted) and 11 age-matched healthy subjects performed a maximal incremental cycle test with respiratory gas exchange measurements. Maximal voluntary contraction (MVC) and electromyographic (EMG) activity of the vastus medialis muscle were recorded before and after exercise. Neural and contractile properties of the quadriceps were also investigated using femoral nerve electrical stimulation. Patients had lower exercise capacity, peak oxygen uptake and MVC than controls. MVC fell significantly postexercise in both groups (CF: -20±10%, controls: -19±6%; p<0.01). EMG root mean square values, M-wave amplitude and duration were unchanged in both groups. Peak twitch (-46.9±13.8%), maximal rate of twitch torque development (-50.3±13.8%) and relaxation (-35.2±19.5%) were all reduced after exercise in CF patients. The control group followed the same pattern (-38.4±14.4%, -42.1±14.7% and -15±20.4%) but the statistical significance was not reached for the maximal rate of twitch torque relaxation. In conclusion, CF patients demonstrated lower limb fatigue following symptom-limited cycle exercise, which was comparable to that exhibited by healthy controls. This fatigue may be due to contractile impairments and not to transmission failure. Further studies should be conducted in a larger sample to confirm these preliminary results.

Clinical utility of the oxygen uptake efficiency slope in cystic fibrosis patients.

BACKGROUND: The present study investigated the validity and the reliability of the oxygen uptake efficiency slope (OUES) as a determinant of exercise tolerance in adults with cystic fibrosis (CF). METHODS: 31 CF patients and 34 healthy controls performed a maximal incremental cycle test with respiratory gas-exchange measurements. OUES was calculated from data taken from different percentages of the entire exercise duration, including 80% (OUES(80)) and 100% (OUES(100)). Peak oxygen uptake (VO(2peak)) and gas exchange threshold (GET) were also determined. The agreement between submaximal parameters and VO(2peak) was assessed using Bland Altman plots. Test retest reliability was evaluated in CF patients using absolute (SEM) and relative indices (ICC). RESULTS: On the contrary to the GET, which was undetectable in 16% of the CF patients, the OUES was easily determined in all patients. Among all the submaximal variables, OUES(80) had the best reliability (ICC=0.94, SEM=7.3%) and agreement with VO(2peak) (r(2)=0.83, P<0.01; limits of agreement: ±365mL min(-1)) and did not differ from OUES(100). CONCLUSIONS: OUES(80) is a reliable and more useful submaximal parameter than the GET and may find use in the interpretation of exercise studies in CF patients who are unable to perform maximal exercise.

Long term reliability of EMG measurements in adults with cystic fibrosis.

The aim of this study was to investigate the long term reliability of surface electromyography (sEMG) measurements in adults with cystic fibrosis (CF). Eighteen healthy subjects (CO) and sixteen adults with CF were tested on two occasions, six weeks apart. sEMG was recorded from the rectus femoris, vastus lateralis and vastus medialis obliquus muscles during maximal voluntary contraction (MVC) and 50% MVC until exhaustion. Quadriceps muscle activity during 50% MVC was described using four measures (initial, final, normalized and slope values) for both frequency and time domain. Relative (ICC) and absolute (SEM) reliabilities were applied to asses test-retest reliability. In CF group, median frequency (MDF) values for 100% MVC and initial, final and normalized final MDF for 50% MVC demonstrated moderate to very high relative reliability (ICC = 0.60-0.91) and low variability (SEM = 5.5-13%). MDF slope showed large variability in both groups. Root mean square (RMS) values were not reproducible in both groups whatever the intensity of exercise and can not be recommended as outcomes parameters. In conclusion, sEMG measurements during maximal and submaximal isometric contractions could be valid and reliable tools for clinical applications in cystic fibrosis patients but mainly in the frequency domain and from rectus femoris.

Association of three different congenital malformations in a same pulmonary lobe in a 5-year-old girl.

We report the case of a 5-year-old girl with persistent chest X-ray abnormalities following an episode of pneumonia who has a complex congenital pulmonary malformation comprising of a congenital pulmonary airway malformation, an intralobar sequestration and two bronchogenic cysts, all present within the same lobe. The observation suggests a common embryological origin of these malformations.

[Physical activity and exercise training for patients with cystic fibrosis]. / Activité physique et réentraînement à l'effort du patient atteint de mucoviscidose.

In France patients with cystic fibrosis benefit from a multidisciplinary follow-up in Cystic Fibrosis Centres. In this follow-up, despite the numerous therapeutic benefits of exercise in this disease, little emphasis is placed on the promotion of physical activity. The aim of this article is to improve this aspect of management, giving advice from a working group of experts, based on the medical literature and clinical experience. These proposals include quantification of physical activity, evaluation of exercise, training and rehabilitation programs and finally, modification of behaviour to include physical activity in the overall cystic fibrosis treatment strategy. It is intended to set up multicentre studies to evaluate the impact of these proposals.

Acute presentation of congenital diaphragmatic hernia past the neonatal period: a life threatening emergency.

PURPOSE: Major gastric distension in the left hemithorax can threaten life in patients with congenital diaphragmatic hernia (CDH) presenting after the neonatal period. After presentation of two pediatric cases, guidelines for the optimal care of these patients are given. CLINICAL FEATURES: Both children had respiratory and cardio-circulatory compromise on arrival. The diagnosis of late presenting CDH was made and the severity of symptoms was related to a voluminous distension of an intrathoracic stomach. Successful placement of an naso-gastric tube in the first patient, lead to a rapid clinical improvement, allowing surgical repair. In the second patient, oro- or naso-gastric decompression was not possible, and while the lungs were mechanically ventilated and the patient was prepared for surgery, a sudden cardiocirculatory arrest was managed by external chest compressions and rescuscitation drugs. Transthoracic percutaneous decompression of the stomach was the sole treatment allowing spontaneous cardiac activity to reappear, and haemodynamic condition to normalize. However, the child died from brain death after this episode. CONCLUSION: Gastric decompression is the key for the treatment of patients with CDH who present respiratory and/or cardiocirculatory distress due to the intrathoracic distension of the stomach. If an oro- or naso-gastric decompression is not possible, then radiologically directed percutaneous decompression under local anesthesia is required. After decompression, the patient is prepared for surgery, with particular emphasis on fluids infusion, in order to correct the frequently associated hypovolaemia.

Cytokines, from atopy to asthma: the Th2 dogma revisited.

Asthma is a spreading condition in Western countries, in most cases in relationship with atopy. Atopy is defined by an individual predisposition to develop allergic diseases in response to environmental allergens. The atopic immune system is characterized by a Th2 deviation determined by genetic and environmental factors. Among these factors, the role of allergen exposure, dietary behavior, air pollution and early exposure to microbes is discussed. In asthma, a Th2 cell activation is evident, but is accompanied by a Tc1 cell activation. These Tc1 cells probably down-regulate Th2 cells, but are also relevant to the bronchial hyperresponsiveness characterizing asthma. We propose that Tc1 activation in asthma could be the link between allergy and bronchial hyperresponsiveness.