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.

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.

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.

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.

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.

[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.

[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.

[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.

Local side-effects of inhaled corticosteroids in asthmatic children: influence of drug, dose, age, and device.

BACKGROUND: The objective was to investigate the local side-effects of inhaled corticosteroids (ICS) in daily life in asthmatic children, particularly the younger ones, by an observational prospective cross-sectional cohort study. METHODS: Asthmatic children (n=639, 75.9+/-48.9 months, 61.3% boys), treated with beclomethasone dipropionate (BDP) (721.0+/-287.3 microg per day) or budesonide (BUD) (835.5+/-684.9 microg per day) for at least 1 month, were recruited at the time of a scheduled visit. Local side-effects were researched by questionnaire (cough during inhalation, hoarseness, dysphonia, and thirsty feeling) and clinical examination (perioral dermatitis, oral candidiasis, and tongue hypertrophy). RESULTS: Exactly 63.3% of the children aged under 6 years and 59.5% of the older ones reported one local side-effect. Cough (39.7%) was dependent on young age, use of BDP, and mainly use of spacer device, with an OR of 4.7 (95% CI: 2.7-8.2). Thirsty feeling (21.9%) and hoarseness (14.1%) occurred in children using ICS and long-acting beta2-agonists. Dysphonia (11.1%) was favored by high doses of BDP and BUD, and by inhalation from spacer devices or nebulizers. No factor favored oral candidiasis (10.7%). Perioral dermatitis (2.9%) and tongue hypertrophy (0.1%) were associated with nebulization. CONCLUSION: Local side-effects of ICS are common in asthmatic children of all ages, and the device used constitutes the most influential factor.

Venom immunotherapy induces monocyte activation.

BACKGROUND: Venom immunotherapy (VIT) is an efficient treatment of hymenoptera venom allergy. The mechanism of VIT is based on the induction of tolerance of allergen-specific Th2 cells. The mechanisms of this T cell modulation are unknown, and could depend on cytokines produced by other cell types such as interleukin (IL)-12, tumour necrosis factor (TNF)-alpha and IL-10 by monocytes. OBJECTIVE: To assess if VIT modifies the monocyte production of IL-12, TNF-alpha and IL-10 during the 45 first days of treatment. METHODS: Fourteen patients and seven controls were included. Blood samples were taken once in controls and at day (D)1, D30 and D45 of VIT in patients. Monocytes were isolated, cultured with and without lipopolysaccharide (LPS), and the culture supernatant was harvested. IL-10, IL-12 and TNF-alpha were assayed in supernatants by ELISA. RESULTS: Baseline cytokine levels were not statistically different between patients and controls. During treatment, an increase of spontaneous monocyte production of IL-12 and TNF-alpha was observed at D15 and D45. The production of IL-10 increased at D15 and D45 but not significantly. After LPS-stimulation, IL-12, TNF-alpha and IL-10 monocyte production was not modified by VIT. CONCLUSION: VIT induces a monocyte activation characterized by a delayed overproduction of IL-12 and TNF-alpha. These cytokines could be relevant to the inhibition of Th2 cells during VIT. Therefore, VIT-induced tolerance could depend not only on the specific action of venom antigens on T cells, but also on a secondary non-specific action of monocytes.

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.

Flow cytometric microsphere-based immunoassay: analysis of secreted cytokines in whole-blood samples from asthmatics.

The ability of flow cytometry to resolve multiple parameters was used in a microsphere-based flow cytometric assay for the simultaneous determination of several cytokines in a sample. The flow cytometer microsphere-based assay (FMBA) for cytokines consists of reagents and dedicated software, specifically designed for the quantitative determination of cytokines. We have made several improvements in the multiplex assay: (i) dedicated software specific for the quantitative multiplex assay that processes data automatically, (ii) a stored master calibration curve with a two-point recalibration to adjust the stored curve periodically, and (iii) an internal standard to normalize the detection step in each sample. Overall analytical performance, including sensitivity, reproducibility, and dynamic range, was investigated for interleukin-4 (IL-4), IL-6, IL-10, IL-12, gamma interferon (IFN-gamma), and tumor necrosis factor alpha. These assays were found to be reproducible and accurate, with a sensitivity in the picograms-per-milliliter range. Results obtained with FMBA correlate well with commercial enzyme-linked immunosorbent assay data (r > 0.98) for all cytokines assayed. This multiplex assay was applied to the determination of cytokine profiles in whole blood from atopic and nonatopic patients. Our results show that atopic subjects' blood produces more IL-4 (P = 0.003) and less IFN-gamma (P = 0.04) than the blood of nonatopic subjects. However, atopic asthmatic subjects' blood produces significantly more IFN-gamma than that of atopic nonasthmatic subjects (P = 0.03). The results obtained indicate that the FMBA technology constitutes a powerful system for the quantitative, simultaneous determination of secreted cytokines in immune diseases.

[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.

Assessment of the Th1/Th2 paradigm in whole blood in atopy and asthma. Increased IFN-gamma-producing CD8(+) T cells in asthma.

Atopy is characterized by an immune system that is biased to T helper cell, type 2 (Th2) activation. This condition predisposes to asthma, a disease in which a Th2 activation was found in blood and lungs. However, most blood studies have considered purified cells, which might give an incomplete view of immune reactions. In this study, we assessed in whole blood cultures the Th1/Th2 paradigm in atopy and asthma. Sixty-nine subjects (31 atopic asthmatics, six nonatopic asthmatics, 13 atopic nonasthmatics, and 19 control subjects) were included in this study. Interleukin-4 (IL-4), interferon gamma (IFN-gamma), and IL-12 were assayed in stimulated whole blood culture supernatants by using a flow cytometer microsphere-based assay. Intracellular IL-4 and IFN-gamma were detected in T cells and CD8(+) T cells by flow cytometry. Atopy was characterized by a higher production of IL-4, which was correlated to total IgE levels, and by an impairment of the T-cell capacity to produce IFN-gamma. This impairment was correlated to the number of positive skin tests. In asthma, the overproduction of IL-4 was still found if atopy was present. Unexpectedly, an overproduction of IFN-gamma was found, which was related to an increased capacity of CD8(+) T cells to produce IFN-gamma. The number of IFN-gamma-producing CD8(+) T cells was related to asthma severity, to bronchial hyperresponsiveness, and to blood eosinophilia. In addition, this number was correlated to IL-12 production. These results show that in addition to the well-known Th2 inflammation in asthma, there are IFN-gamma-producing CD8(+) T cells in the blood, possibly controlled by IL-12.