Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

Prospective evaluation of azole resistance in Aspergillus fumigatus clinical isolates in France.

OBJECTIVES: Several studies, especially in Europe, have recently reported the emerging phenomenon of azole resistance in Aspergillus fumigatus, but very few data are available in France. Our study aimed to determine the resistance prevalence in A. fumigatus isolates recovered from clinical samples over a 1-year period in two university hospital centers. METHODS: All A. fumigatus isolates were screened for azole resistance using RPMI agar plates supplemented with itraconazole and voriconazole. Resistance was then confirmed by the EUCAST method. A part of the beta-tubulin gene was amplified for resistant isolates to confirm the A. fumigatus species, and the Cyp51A gene and its promoter were afterward sequenced to detect mutations potentially responsible for this resistance. RESULTS: One hundred sixty-five A. fumigatus isolates were recovered from 134 patients. Three isolates recovered from three patients were found resistant with MICs of >8 mg/l, 4 mg/l, and 1 mg/l for itraconazole, voriconazole, and posaconazole, respectively. The TR34/L98H mutation, previously and largely described in other countries, was detected in the three isolates. CONCLUSION: Our study demonstrated the occurrence of azole resistance among unselected A. fumigatus clinical isolates, with an overall prevalence of 1.8%.

Routine use of granulocyte colony-stimulating factor is not cost-effective and does not increase patient comfort in the treatment of small-cell lung cancer: an analysis using a Markov model.

PURPOSE: The clinical indications and economic consequences of human granulocyte colony-stimulating factor (G-CSF) prescription during small-cell lung cancer (SCLC) chemotherapy remain controversial. The aim of this study, based on a Markov model, was to assess the impact of routine G-CSF use in the treatment of SCLC on costs and patient comfort. Markov models allow the modeling SCLC chemotherapy, in which the risk of febrile neutropenia (FN) is continuous over time and may occur more than once. PATIENTS AND METHODS: We used a Markov model to compare three strategies: a chemotherapy dose reduction after FN and nonuse of G-CSF ("never" strategy), secondary use of G-CSF ("CSF if FN" strategy) and primary use of G-CSF ("systematic CSF" strategy). Model baseline probabilities were based on a review of medical records for all patients (n = 39) treated for SCLC in our unit during 1993 (when G-CSF was not used) and on published reductions in the incidence of FN obtained by using G-CSF. Two different types of rewards were used: a cost-utility scale that took into account the costs of FN (CFN) episodes and G-CSF (CCSF) courses; and a comfort-utility scale that took into account the discomfort of FN and G-CSF therapy. Costs were analyzed from the health care payer's perspective and utilities were assessed prospectively in standardized interviews with treated SCLC patients. RESULTS: The never strategy was the least costly ($4,875 [United States] versus $5,816 and $7,690 for CSF if FN and systematic CSF) and gave the highest comfort value (378 U v 365 and 327 for CSF if FN and systematic CSF). Sensitivity analyses showed that the never strategy remains the less costly when the probability of a first FN episode was less than 49%, the probability of FN recurrence was less than 60%, or the CFN was less than $6,077, or the CCSF was greater than $863. In terms of patient comfort, the never strategy was the best choice, except for patients who considered that a course of G-CSF caused little or no discomfort, whether or not it prevented FN. CONCLUSION: Routine use of G-CSF during SCLC chemotherapy is not justified by clinical benefits, improved patient comfort, or economic considerations.

Vaccine coverage in CF children: A French multicenter study.

BACKGROUNDS: Recent reports have pointed the low vaccine coverage in patients with chronic diseases. Data are lacking in patients with cystic fibrosis (CF). Gaining more information on coverage both for mandatory vaccines and those more specifically recommended would help to optimize care of these patients. METHODS: Data were extracted from the "MucoFlu" study, which was a prospective study performed in 2009 in the 5 cystic fibrosis centers of the Paris metropolitan area. Data on mandatory and recommended vaccines in CF were collected in the health booklet and compared to the coverage of the general population. RESULTS: A total of 134 CF children were included. Vaccination coverage for mandatory vaccines was insufficient (DTPCaHi, conjugate pneumococcal, BCG, MMR and hepatitis B) at 1year of age with no catching-up with age in contrast to the general population. Approximately 66% of the children had immunization for seasonal influenza and 91% for 2009 pandemic flu. Coverage for vaccines specifically recommended in CF was low for hepatitis A, non conjugate pneumococcal and varicella. CONCLUSION: This study shows a defect in vaccine coverage for both routine immunization and vaccines more specifically recommended in CF.

[Primary pleural lymphoma: a rare complication of tuberculosis pleural sequelae]. / Lymphome pleural primitif: une complication rare des séquelles pleurales de tuberculose.

We report two cases of malignant lymphoma of B phenotype occurring after therapeutic pneumothorax for tuberculosis. In both cases, outcome was fatal without time for specific treatment. Mainly reported in Japan, this pathology seems to be less frequent in western countries. As for B phenotype lymphoma associated with immunodeficiency, association with Epstein Barr virus is reported. Definite diagnosis is difficult and requires surgical biopsy. Prognosis remains poor with a survival ranging from 3 to 6 month.

[Evaluation of occupational exposures in lung cancer]. / Evaluation des expositions professionnelles et cancer bronchopulmonaire.

Occupational lung cancers are underestimated by the number of cases compensated in the French National Insurance System. Rules of compensation of occupational diseases were recently modified in France. Therefore a study was conducted on incident cases of lung cancer in a general hospital in the Paris area. The aim was to evaluate the exposure to carcinogens using data of a detailed specific occupational questionnaire, and to determine the number of cases who could receive compensation. Two hundred and seven subjects (171 males, 36 females, mean age = 64.5 years) were eligible in 1996, and 122 had an occupational questionnaire. Definite exposure to one or more occupational carcinogens in at least one job was identified in 50 subjects, the most frequent agent was asbestos (42 subjects). Claim for compensation was done in 32 subjects, mainly for asbestos (30 subjects). This study emphasizes the frequency of occupational exposure to carcinogens, and the usefulness of systematic occupational questionnaire in subjects having lung cancer. Social and financial consequences are important for these subjects. Further studies are needed, with recruitement of control subjects to allow calculation of the attributable risk to occupational factors in lung cancer.

[Inhaled treatments in cystic fibrosis: what's new in 2013?]. / Mucoviscidose et traitements inhalés: quoi de neuf en 2013?

In the past few years some new inhaled drugs and inhalation devices have been proposed for the treatment of cystic fibrosis. Breath-controlled nebulizers allow increased pulmonary deposition, with a lower variability and a shorter delivery time. The new dry powder formulations of tobramycin, colistine and mannitol require a change in the inhalation technique which must be slow and deep. In the field of the inhaled mucolytic drugs, hypertonic saline and mannitol have an indication in some patients. With regard to antibiotics, dry-powder tobramycin and colistine can be substituted for the same drug delivered by nebulization. Nebulized aztreonam needs more studies to determine its place. These new treatments represent a definite advance for cystic fibrosis patients and need to be known by all practitioners. Their position in our therapeutic arsenal remains to be accurately defined.

[Cavitating pulmonary infarcts revealing thromboembolic pulmonary hypertension]. / Infarctus pulmonaires excavés révélant une hypertension pulmonaire post-embolique.

Several etiologies are involved in the pathogenesis of cavitating pulmonary disease including neoplastic, infectious or inflammatory processes. Another is pulmonary infarction associated with venous thromboembolism. The lung cavities tend to be located peripherally and are the result of pulmonary embolism. We report the case of a woman with chronic thromboembolic pulmonary hypertension (CTEPH), associated with familial thrombophilia, revealed by cavitating pulmonary infarcts. CTEPH is sometimes diagnosed during an episode of recurrent pulmonary embolism following previously unnoticed lesions. Thrombophilias such as isolated elevated factor VIII are risk factors for CTEPH.

[Pleuropneumonia due to Mycobacterium chelonae]. / Pleuropneumonie à Mycobacterium chelonae.

Mycobacterium chelonae (M. chelonae) is rarely responsible for respiratory infection. This report concerns the case of an 81-year-old man with previously asymptomatic bronchiectasis, colonised by M. chelonae for 3 years. He was hospitalised for acute dyspnoea and fever due to a right hydro-pneumothorax with cavitated alveolar opacities of the right lung. Pleural fluid and bronchial aspiration were positive for M. chelonae and no other microorganisms were detected. The effusion was drained and the patient treated with clarythromycin and amikacin. The radiological abnormalities improved but the patient's general condition remained poor. Treatment was continued for 11 months. Because of the absence of any other bacteria, clinical deterioration following broad-spectrum antibiotics and stabilisation of the lesions after anti-mycobacterial treatment, our diagnosis was severe M. chelonae pleuro-pneumonia in an immunocompetent patient.

Role of adhesins and toxins in invasion of human tracheal epithelial cells by Bordetella pertussis.

Bordetella pertussis, the agent of whooping cough, can invade and survive in several types of eukaryotic cell, including CHO, HeLa 229, and HEp-2 cells and macrophages. In this study, we analyzed bacterial invasiveness in nonrespiratory human HeLa epithelial cells and human HTE and HAE0 tracheal epithelial cells. Invasion assays and transmission electron microscopy analysis showed that B. pertussis strains invaded and survived, without multiplying, in HTE or HAE0 cells. This phenomenon was bvg regulated, but invasive properties differed between B. pertussis strains and isolates and the B. pertussis reference strain. Studies with B. pertussis mutant strains demonstrated that filamentous hemagglutinin, the major adhesin, was involved in the invasion of human tracheal epithelial cells by bacteria but not in that of HeLa cells. Fimbriae and pertussis toxin were not found to be involved. However, we found that the production of adenylate cyclase-hemolysin prevents the invasion of HeLa and HTE cells by B. pertussis because an adenylate cyclase-hemolysin-deficient mutant was found to be more invasive than the parental strain. The effect of adenylate cyclase-hemolysin was mediated by an increase in the cyclic AMP concentration in the cells. Pertactin (PRN), an adhesin, significantly inhibited the invasion of HTE cells by bacteria, probably via its interaction with adenylate cyclase-hemolysin. Isolates producing different PRNs were taken up similarly, indicating that the differences in the sequences of the PRNs produced by these isolates do not affect invasion. We concluded that filamentous hemagglutinin production favored invasion of human tracheal cells but that adenylate cyclase-hemolysin and PRN production significantly inhibited this process.

Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models.

BACKGROUND: Apolipoprotein (apo) A-I is the major component of HDL, and it displays antiatherogenic properties. METHODS AND RESULTS: The human apoA-I gene has been transferred into different mouse models by use of a recombinant adenovirus under the control of an RSV-LTR promoter (AV RSV apoA-I). Administration of AV RSV apoA-I to C57BL/6 mice resulted in moderate expression of human apoA-I for 3 weeks, leading to a transient elevation (40% at day 11 after injection) of HDL cholesterol concentration. In contrast, administration of AV RSV apoA-I to human apoA-I-transgenic mice induced a large increase of human apoA-I and HDL cholesterol concentrations (300% and 360%, respectively, at day 14 after injection) for 10 weeks, indicating that an immune response to the transgene was one major hurdle for long-term duration of expression. Recombinant adenovirus expressing human apolipoprotein A-I (AV RSV apoA-I) was also injected into human apoA-I-transgenic/apoE-deficient mice, which are prone to develop atherosclerosis. Over a 6-week period, overexpression of human apoA-I inhibited fatty streak lesion formation by 56% in comparison with control. CONCLUSIONS: Somatic gene transfer of human apoA-I prevents the development of atherosclerosis in the mouse model.