[Allergic Broncho-Pulmonary Aspergillosis (ABPA) in cystic fibrosis: Mechanisms, diagnosis and therapeutic options]. / Aspergillose bronchopulmonaire allergique (ABPA) et mucoviscidose : mécanismes, diagnostic et alternatives thérapeutiques.

INTRODUCTION: Fungal aspergillosis colonization and allergic bronchopulmonary aspergillosis (ABPA) can have a strong impact on the prognosis in cystic fibrosis (CF). We conducted round table discussions involving French experts from pediatric and adult centers caring for patients with CF, microbiologists, radiologists and pharmacists. The aim was to explore the current state of knowledge on: the pathophysiological mechanisms of Aspergillus and other micromycetes infections in CF (such as Scedosporium sp.), and on the clinico-biological diagnosis of ABPA. In perspective, the experts explored the role of imaging in the diagnosis of APBA, specifically CT and MRI; as well as the role of bronchoscopy in the management. We also reviewed the therapeutic management, including different corticosteroid regimens, antifungals and anti-IgE antibodies. CONCLUSION: The diagnosis of ABPA in CF should be based on more standardized biological assays and imaging to optimize treatment and follow-up.

Population pharmacokinetics of ceftazidime in critically ill children: impact of cystic fibrosis.

BACKGROUND: Pharmacokinetics data on ceftazidime are sparse for the paediatric population, particularly for children with cystic fibrosis (CF) or severe infections. OBJECTIVES: To characterize the population pharmacokinetics of ceftazidime in critically ill children, identify covariates that affect drug disposition and evaluate the current dosing regimens. METHODS: The study was registered with Clinicaltrials.gov (NCT01344512). Children receiving ceftazidime were selected in 13 French hospitals. Plasma concentrations were determined by UPLC-MS/MS. Population pharmacokinetic analyses were performed using NONMEN software. RESULTS: One hundred and eight patients, aged 28 days to 12 years, with CF (n = 32), haematology and/or oncology disorders (n = 47) or severe infection (n = 29) were included. Ceftazidime was administered by continuous or intermittent infusions; 271 samples were available for analysis. A two-compartment model with first-order elimination and allometric scaling was developed and covariate analysis showed that ceftazidime pharmacokinetics were also significantly affected by CLCR and CF. Ceftazidime clearance was 82% higher in CF than in non-CF patients. Monte Carlo simulations showed that the percentage of target attainment (PTA) for the target of T>MIC = 65% was (i) lower in CF than in non-CF children with intermittent infusions and (ii) higher with continuous than intermittent infusion in all children. CONCLUSIONS: The population pharmacokinetics model for ceftazidime in children was influenced by body weight, CLCR and CF. A higher PTA was obtained with continuous versus intermittent infusions. Further studies should explore the benefits of continuous versus intermittent infusion of ceftazidime, including current versus increased doses in CF children.

Variability of ciprofloxacin pharmacokinetics in children: impact on dose range in sickle cell patients.

Objectives: To determine the ciprofloxacin population pharmacokinetics in paediatric patients and the impact of underlying disease and evaluate the appropriateness of current dosage regimens. Patients and methods: Plasma concentrations of ciprofloxacin from children treated with ciprofloxacin were measured by HPLC. The pharmacokinetic population analysis was performed using NONMEM v7.2 (Icon Development Solutions, USA). Results: Two datasets were combined and 128 plasma concentrations in 60 patients aged 5.6 years (range 0.3-18.9), treated with a median daily dose of 30.0 mg/kg (range 6.5-52.0) presenting with sickle cell disease (SCD; n = 20, 33%), haemopathy (n = 15, 25%), cystic fibrosis (CF; n = 3, 5%) and other diseases (n  =  22, 37%) were analysed. Data were best described by a two-compartment model with first-order elimination. Ciprofloxacin clearance (mean ±â€Šâ€ŠSD) was 0.81 ±â€Š0.30 L/h/kg, increased allometrically with weight, decreased with increasing creatinine concentration, was 89% higher in SCD compared with non-SCD patients and increased by 0.95 L/h/kg per year of age. The volume of distribution was 6.9 L/kg and depended only on the weight. Monte Carlo simulations were performed separately in SCD and non-SCD patients to target an AUC/MIC ratio >125 at steady-state, required for antibacterial efficacy, and recommendations of dosing regimens were proposed. Conclusions: In addition to known covariates, ciprofloxacin clearance is greater in SCD children compared with non-SCD patients. The dosing of this agent needs to be adapted to this subgroup of patients.

[Early lung disease in infants with cystic fibrosis. Diagnostic tools and possible therapeutic pathways]. / Atteinte respiratoire précoce chez les nourrissons atteints de mucoviscidose. Outils de diagnostic et pistes pour la prise en charge.

The lungs of infants with cystic fibrosis (CF) have been considered to be normal at birth. However, recent data indicates that this is unlikely to be true in most cases. Animal CF-models developed in the early 2000s have shown that constitutional airway narrowing may be present at birth, and is associated with both functional and structural abnormalities. Longitudinal birth cohort studies have shown that 25 % of CF infants followed in specialized centers, while being asymptomatic, showed decreased lung function at 3months of age. Air trapping was present in 68 % and bronchiectasis in 28 % of patients at the same age. The presence of neutrophil elastase in the bronchoalveolar lavage at 3months of age tripled the risk of bronchiectasis at the age of 3years. Currently available tools such as infant pulmonary function tests (both the jacket and multiple breath washout) as well as high-resolution volume controlled chest-computed tomography or functional magnetic resonance imaging will facilitate early intervention trials in the very near future. The role of such tools for the routine follow-up of patients, and the ability of early therapeutic interventions to alter the natural history of CF-lung disease should soon be established.

[New tools in cystic fibrosis]. / Nouvelles techniques d'évaluation dans la mucoviscidose.

The use of 3 novel tools available for the diagnosis and treatment in cystic fibrosis are described here. 1) The lung clearance index is a sensitive method which can detect functional impairment in the first months after birth. 2) Detailed morphological analyses of the lung can be performed with the new MRI sequences, without any contrast medium or risk of radiation. The analysis of functional MRI data (perfusion, diffusion, ventilation, inflammation) will be possible, and these data will be correlated to morphological data. The exploration of other organs such as the sinuses, liver and abdomen during the same examination represents another definite advantage. 3) Organoïds are a good example of personalized medicine. This tool explores CFTR function and treatment response in each of the 2000 or so known CFTR mutations. These tests are limited to specialized centers, mostly within a research context. However, their generalization after standardization is expected in the near future.

[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.

[Early lung disease in cystic fibrosis]. / Atteinte respiratoire précoce dans la mucoviscidose.

Recent data has shown that lung inflammation and infection subvene very early in very young infants with Cystic Fibrosis (CF). This leads to impaired lung function and structural damage, even in asymptomatic children. In the CF-pig model constitutional airway narrowing is present at birth, and is associated with defective mucus migration, and impaired bacterial clearance. At the age of 3 months, 25% of screened CF infants show decreased lung function. Air trapping is also present in 68% and bronchiectasis in 28% of patients. At the same age, the presence of neutrophil elastase in the bronchoalveolar lavage is an ominous sign since it triples the risk of bronchiectasis at the age of 3 years. Since only very few drug therapies have been validated in the preschool children, adapted clinical trials are warranted in this age group. Early interventions may have a huge impact on the natural history of CF, on the condition of not interfering with normal lung growth.

Exploring the expression of Pseudomonas aeruginosa genes directly from sputa of cystic fibrosis patients.

UNLABELLED: Acquisition of Pseudomonas aeruginosa is known as a negative prognostic factor in patients with cystic fibrosis. We started a pilot study to evaluate Ps. aeruginosa gene expression directly from the sputum of infected patients. Total RNA was purified from 15 sputum samples collected from 10 patients, and the expression levels of five genes from Ps. aeruginosa were measured by RT-qPCR. Expression of algD, algR, antB, lasB and pqsA genes was determined in sputa that contained Ps. aeruginosa cells. The resultant data provided an overview of the expression of these genes in CF patients. Except for the correlation between algD expression and the mucoid phenotype, the gene expression profile could not be associated with the clinical status of patients. However, beyond the heterogeneity of the Ps. aeruginosa phenotype in sputum, we observed a correlation between the expression of antB and pqsA and a low level of lasB transcripts. SIGNIFICANCE AND IMPACT OF THE STUDY: Pseudomonas aeruginosa infection leads to high morbidity and mortality in cystic fibrosis patients. The identification of Ps. aeruginosa-assigned factors is important to eradicate the colonization. We started a pilot study to evaluate the gene expression of Ps. aeruginosa directly from the sputum of infected patients. Preliminary results suggest that beyond the heterogeneity of the Ps. aeruginosa phenotype in sputum, we observe a correlation between the expression of antB and pqsA and a low level of lasB transcripts. This approach could shed some light on the behaviour of Ps. aeruginosa during pulmonary infection and may reveal some important elements for optimizing therapy.

[National consensus regarding azithromycin use in cystic fibrosis]. / Consensus national sur la prescription de l'azithromycine dans la mucoviscidose.

AIM: To propose a formalized consensus agreement regarding the prescription of azithromycin in cystic fibrosis (CF). MATERIAL AND METHODS: Application of the Delphi method in 5 thematic fields: indications, contra-indications, dosage, precautions for use and treatment follow-up. RESULTS: Thirty identified French CF centers participated in the process on 49 (61%), which comprised 3 rounds. Experts validated azithromycin as a long-term anti-inflammatory agent in children aged over 6 years, presenting with the classical form of CF, irrespective of the bacteriological status of the patient (except for non-tuberculous mycobacteria). Azithromycin administration should not be routine in the milder forms of the disease, and avoided in the presence of severe hepatic or renal involvement. In children whose weight is below 40 kg, a strong consensus recommended a single daily oral dose, administered three times weekly. However, in adults, the level of agreement was weaker. Minimal duration of treatment is 6 months, after which the drug should be discontinued if no observable effect is noted on clinical parameters, exacerbation rate and/or FEV1. Clinical monitoring of treatment tolerance is recommended (nausea, diarrhea, skin rash, tinnitus, deafness, arthropathy), without increasing the frequency of surveillance of sputum bacteria. However, it is essential to monitor sputum for fungi (expectoration, Aspergillus, broncho-pulmonary allergic aspergillosis). CONCLUSION: This consensus statement defines an area for the prescription of azithromycin in CF, with the aim of better harmonization of its use.

Open label study of inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: The ALPINE study.

BACKGROUND: Consensus guidelines recommend early treatment to eradicate newly acquired Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients although there is no single preferred regimen. Aztreonam for inhalation solution (AZLI) significantly reduces sputum Pa density in CF patients with chronic Pa infection and has been well tolerated in the pediatric population. This single-arm, open-label Aztreonam Lysine for Pseudomonas Infection Eradication (ALPINE) study was conducted to evaluate the safety and efficacy of a 28-day treatment course of AZLI to eradicate newly acquired Pa infection in pediatric CF patients. METHODS: CF patients (3 months to <18 years) with new onset Pa infection were treated with AZLI 75 mg 3 times daily for 28 days. New onset Pa infection was defined as first lifetime Pa-positive respiratory tract culture (throat swab, sputum) or Pa-positive culture after a ≥2-year history of Pa-negative cultures (≥ 2 cultures/year). Sputum or throat swab cultures were collected at study entry (baseline) and at weeks 4 (end of treatment), 8, 16, and 28. Primary endpoint was the percentage of patients with cultures negative for Pa at all post-treatment time points. RESULTS: A total of 105 pediatric CF patients enrolled (3 months to <2 years, n=24; 2 to <6 years, n=25; 6 to <18 years, n=56). Of the 101 patients who completed treatment, 89.1% (n=90) were free of Pa at the end of treatment and 75.2% (n=76) were free of Pa 4 weeks after the end of treatment. Of the 79 patients evaluable for the primary endpoint, 58.2% were free of Pa at all post-treatment time points. CONCLUSIONS: AZLI was effective and well tolerated in eradicating Pa from newly infected pediatric patients with CF. These eradication rates are consistent with success rates reported in the literature for various antibiotic regimens, including other inhaled antibiotics studied for eradication. ClinicalTrials.gov: NCT01375049.

[Viral epidemiology and clinical severity during the peak of the influenza A(H1N1) variant epidemic in febrile respiratory diseases of children]. / Epidémiologie virale et sévérité clinique pendant le pic d'épidémie grippale A(H1N1) variant dans les atteintes respiratoires fébriles de l'enfant.

UNLABELLED: In 2009, a new emerging flu virus, A(H1N1), was identified. Its true medical impact on children's health remains widely debated. AIM: To define the prevalence of respiratory disease in children hospitalized with fever during the influenza A(H1N1) epidemic and to determine the clinical, paraclinical, and outcome characteristics according to the viruses identified. MATERIAL AND METHODS: Children hospitalized for a febrile respiratory disease were included in this prospective cohort study conducted at Bordeaux University's Children's Hospital (France) during the influenza epidemic from 2009/11/23 to 2009/12/20. RESULTS: Seventy-three children were included in the study. Viruses were identified by PCR in 52% (38/73) of cases, including 23% (17/73) A(H1N1) virus and 29% (21/73) other viruses, 22% (16/73) of which were syncytial respiratory viruses. There was only one case of co-infection between A(H1N1) virus and another virus from the para-influenza virus or adenovirus or bocavirus pool. No significant difference regarding age, sex, or risk factors in the different viral groups was noted. Regarding the A(H1N1) virus, the most frequent symptoms were deterioration of the overall health status, cough, ENT disease, and rapid breathing, with significantly less increased breathing effort and auscultatory abnormality albeit with more seizures. There was no significant difference between groups regarding laboratory data. Management and outcome were similar. CONCLUSION: The prevalence of A(H1N1) virus during the 2009 epidemic in Aquitaine was low among febrile hospitalized children with breathing symptoms. Clinical and paraclinical signs were non-specific. The tolerance and prognosis of influenza A(H1N1) infection in children was satisfactory.

[National consensus regarding the prescription of inhaled corticosteroids in cystic fibrosis]. / Consensus national sur les modalités de prescription des corticoïdes inhalés dans la mucoviscidose.

UNLABELLED: The conditions for the prescription of inhaled steroids (ISs) in cystic fibrosis (CF) are not well established. AIM: To propose a formalized consensus agreement regarding the prescription of ISs in this disease. MATERIAL AND METHODS: Application of the Delphi method in five thematic fields: indications, non-indications, dosage, precautions for use, and treatment follow-up. RESULTS: Thirty of forty-nine (61 %) reference CF centers in France participated in the process, which comprised three rounds. Experts strongly agreed that ISs are indicated in the presence of pulmonary manifestations with wheezing, personal history of atopy, and/or bronchial hyper-responsiveness. In contrast, ISs are not indicated as first-line therapy for allergic bronchopulmonary aspergillosis. Strong agreement was reached regarding the daily dose of ISs, which should be similar to what is given in asthma and adapted to control symptoms so as to prescribe the smallest possible dose. Increasing the frequency of bacterial and fungal sputum analyses and eye (cataract) assessments was not deemed necessary. However, in case of prolonged (>6months) use of high-dose ISs, monitoring bone mineral density and the hypothalamic-pituitary-adrenal axis, in particular if itraconazole is concomitantly prescribed, was recommended. CONCLUSION: This consensus statement defines a perimeter for the prescription of ISs in CF, with the aim of limiting their prescription (until new data are available).

[Pulmonary inflammation in cystic fibrosis]. / L'inflammation pulmonaire dans la mucoviscidose.

Inflammation in Cystic Fibrosis is higher than bacterial clearance needs and contributes significantly to the deterioration of lung tissue and vital prognosis. Its physiology remains controversial and is more complex than the cycle infection-obstruction-inflammation previously described with many interactions and potentiating of the responsible different mechanisms (Mechanical factors, cells, protease/anti-protease, oxidative stress, leukotriens...). This perpetual inflammatory spiral is an important therapeutic target due to its crucial prognosis.

[The use of postnatal corticosteroid therapy in premature infants to prevent or treat bronchopulmonary dysplasia: current situation and recommendations]. / Utilisation de la corticothérapie postnatale chez le nouveau-né prématuré dans la prévention et le traitement de la dysplasie bronchopulmonaire : état des lieux et conduite à tenir.

In the last few years, several studies related to the benefit/risk balance of postnatal corticosteroids administered to premature neonates for prevention or treatment of bronchopulmonary dysplasia (BPD) have been published. These data encourage caution, given the risk of long-term adverse neurodevelopmental outcomes. In the meantime, the clinical profile of BPD has been altered based on the progress made in the pre- and postnatal care of premature infants. In 2006, a survey conducted in France in neonatal centers showed that corticosteroids were still frequently used (57% of the centers) following various protocols in very preterm-born infants for respiratory impairment. To promote safer practices and rational use of corticosteroids in the prevention and treatment of BPD in preterm-born neonates, we reviewed the available data in order to establish recommendations. Systemic administration of corticosteroids for prevention or treatment of BPD: (i) should not be used during the first 4 days of life; (ii) is not indicated in the first 3 weeks of life nor (iii) in extubated infants (nasal ventilation or oxygen therapy). The systemic administration of steroids can only be considered after the first 3 weeks of life in very preterm-born ventilator-dependent infants to facilitate extubation (or prevent reintubation related to the severity of BPD). Postnatal dexamethasone administration studied in several randomized clinical trials was shown to have an unfavorable benefit/risk profile, mainly because of the long-term adverse neurocognitive outcomes. Very few studies have been conducted with betamethasone in the postnatal period. According to sparse data, this drug might be as efficacious as dexamethasone, but its long-term risk profile is unknown. It should be noted that following prenatal administration, the benefit/risk profile of betamethasone is better than that of dexamethasone, especially with regard to neurocognitive development. Intravenous hydrocortisone administered at an early stage for the prevention of BPD is being evaluated and should not be administered in this indication, except within clinical trials approved by the ethics committee. No other corticosteroids have been evaluated in the postnatal period in respiratory indications. In conclusion, in the situations described above for which systemic corticosteroids could be justified, the use of betamethasone (or hydrocortisone) appears to be better. As usual, the lowest possible dose of corticosteroids should be administered for the shortest possible duration. The betamethasone-equivalent dose of 0.125 mg/kg/day for 3 days is deemed adequate. If inhaled, corticosteroid therapy may facilitate extubation. Neither its efficacy in respiratory diseases nor its long-term risk profile has been so far established.

[Tracheomalacia (TM) or bronchomalacia (BM) in children: conservative or invasive therapy]. / Trachéobronchomalacie de l'enfant : de l'abstention à l'interventionnel.

Tracheomalacia (TM) or bronchomalacia (BM) refers to softness or weakness of the trachea or the bronchi. Its management is not evidenced-based. Conservative therapy is preferred in milder cases, since the outcome is usually favourable within the first 2 years of life. The clinical utility of non-specific treatments (anti-inflammatory agents, bronchodilators, antibiotics, physiotherapy) has not been proven by clinical trials. Treatment of symptomatic cases should be discussed on an individual basis. Airway surgery should be avoided, and non-invasive ventilation may be proposed as a temporary measure. In case of very severe cases, aortopexy, trachostomy or stent placement are the preferred treatments. Regular respiratory monitoring until remission is mandatory.

Intravenous peripherally-inserted central catheters for antibiotic therapy in children with cystic fibrosis.

BACKGROUND: We aimed to evaluate the use of central catheters introduced by a peripheral vein (PICC) in children with CF. METHODS: A descriptive study in patients in whom a PICC (Beckton Dickinson) was inserted. RESULTS: 24 children aged (median (range) 10.2 years (0.3-17.3) undergoing 44 procedures were included. PICC was successfully inserted in 93.2% (41/44) of cases. Total procedure duration was (median (range)) 32.5 (10-105) minutes. The operators encountered few difficulties, median (range) 2 (1-10) (1 (absence) to 10 (maximal)); median (range) 1 (1 to 5) attempt per child). No major side effects or infections were observed. PICC obstruction in 5 (12%) cases was successfully unblocked in 4 cases (urokinase). The catheter was functional throughout the antibiotic course in 40/41 cases. A final Doppler scan (30 cases) showed total permeability of the central veins in all cases. Satisfaction index of the operators and the patients were high: median (range) 9.5 (1-10) and 8.0 (6-10) (scale: 1 (worse) to 10 (best)), respectively. CONCLUSION: PICCs are simple to use, and may be safely inserted in the ward. Such catheters are well tolerated, may increase the well-being of children with CF and prove an effective means by which to deliver IV therapy in this population.

[Measurement of pulmonary inflammation in cystic fibrosis]. / Mesure de l'inflammation pulmonaire dans la mucoviscidose.

Lung inflammation is a pivotal phenomenon in the pathogenesis of cystic fibrosis. Inflammation can be measured and quantified within a research perspective, as well as in daily clinical practice. In this review paper, the "Inflammation Task Force" of the "Société Française de Mucoviscidose" has reviewed the literature regarding the various techniques currently available (bronchoalveolar lavage, sputum analysis, nasal wash and brushing, exhaled breath condensates, carbon monoxide and nitric oxide, and systemic measurements (plasma and urine)). The interpretation of all these determinations in children and adults is also discussed.

Epicutaneous aeroallergen sensitization in atopic dermatitis infants - determining the role of epidermal barrier impairment.

BACKGROUND: Sensitization to atopens is an early phenomenon that overlaps with the onset of atopic dermatitis (AD) in infancy. Early epidermal barrier impairment may facilitate the epicutaneous penetration of atopens. OBJECTIVE: To correlate transepidermal water loss (TEWL) and aeroallergen sensitization in infants with AD. METHODS: In this cross-sectional study we enrolled 59 AD children and 30 controls aged 3-12 months. Transepidermal water loss in uninvolved skin, specific immunoglobulin E, atopy patch test (APT) and skin prick tests were performed with respect to seven aeroallergens, i.e., Dermatophagoides pteronyssinus, D. farinae, cat, dog, birch pollen, ambrosia, and cockroach. Environmental conditions were assessed by a questionnaire, and the house dust mite (HDM) concentration was determined in dust samples. RESULTS: Eighty-nine percent of AD infants had a positive APT vs one out of eleven controls. AD infants had a significantly higher mean TEWL than controls (27.4 vs 11.1 g/m(2)/h, P < 0001). Children with two or more positive APT had higher TEWL than the others (31.1 vs 19.0 g/m(2)/h, P < 0.025). No correlation was found between indoor APT results and exposure to HDM, cats, and dogs at home. CONCLUSIONS: This study confirms the high prevalence of delayed sensitization to indoor and outdoor aeroallergens in AD infants, and shows that the higher the TEWL, the higher the prevalence of sensitization to aeroallergens. These data are in favor of a major role of a constitutive epidermal barrier impairment in determining early atopen sensitization in infants with AD.

CF-Emerging therapies: Modulation inflammation.

Persistent and dysregulated inflammation, combined with an exaggerated host response is a major contributor to CF lung disease. As lung disease progresses, neutrophil accumulation in the airways ensues. Modulation of CF airway inflammation may result in either beneficial or deleterious side effects, resulting in more harm than good. Antibiotics, in particular, macrolides which act as a long-term anti-inflammatory agent with an excellent safety profile, and dornase alpha, are very interesting agents; steroids are not indicated in CF except in very special situations, and other promising agents such as leukotriene modifiers, high-dose N-acetylcysteine, anti-elastase and anti-cytokines require further research. Research should focus on early treatment, before lung damage has occurred.