ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension.

Germline mutations in genes encoding members of the transforming growth factor-ß (TGF-ß)/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II-like kinase-1 (ACVRL1) gene mutations are usually identified. We report a remarkable ACVRL1 germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non-mutant ACVRL1 allele in a woman diagnosed with PAH at the age 40. She also met the Curaçao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of ACVRL1 identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation-associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele-specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non-mutant ACVRL1 allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure-mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability.

[Nasopharyngeal carriage of SARS-CoV-2 among health personnel with symptoms suggestive of COVID-19 in a University Hospital in the Paris suburbs]. / Évaluation par RT-PCR du portage nasopharyngé du SARS-Cov-2 chez les personnels de santé symptomatiques suspects de COVID-19 dans un CHU de la banlieue parisienne.

INTRODUCTION: A consultation dedicated to symptomatic health professionals was opened at the beginning of the COVID-19 epidemic in order to meet the specific needs of this population. The objective of this work was to estimate the frequency of SARS-Cov-2 nasopharyngeal carriage in symptomatic healthcare workers suspected of having COVID-19 and to determine the factors associated with this carriage. METHODS: Of the 522 consultants, 308 worked in the Hospital and 214 outside. They had mild forms of COVID-19 and non-specific clinical signs with the exception of agueusia/anosmia, which was significantly more common in those with positive RT-PCR. The rate of RT-PCR positivity was 38% overall, without significant difference according to profession. It was higher among external consultants (47% versus 31%). In the hospital, this rate was significantly lower for symptomatic staff in the care sectors, compared to staff in the technical platforms and laboratories (24%, versus 45%, p = 0.006 and 54%, respectively, p < 0.001), but did not differ between staff in COVID units and other care sectors (30% versus 28%). Among the external consultants, the positivity rates of nursing home and private practices staff (53% and 55% respectively) were more than double that of acute care hospital staff (24%, p < 0.001). CONCLUSIONS: These data confirm the strong impact of COVID-19 on health professionals. The higher positivity rates among symptomatic professionals working outside the hospital compared to those working in hospital may be explained in part by a shortage of protective equipment and by difficulties in accessing virological diagnosis, which were greater outside the hospital when the epidemic began.

[Cushing's syndrome induced by combined treatment with inhaled fluticasone and oral ritonavir]. / Syndrome de Cushing induit par la prise concomitante de fluticasone et de ritonavir.

INTRODUCTION: Fluticasone is a corticosteroid drug which is used in inhaled and nasal formulations for the treatment of asthma and allergic rhinitis. It is metabolized in the liver by the cytochrome P450. Ritonavir, an inhibitor of the HIV protease, also acts as an inhibitor of several isoenzymes of the P450 cytochrome. This property explains the many drug interactions observed with this agent. CASE REPORT: We report two cases of Cushing's syndrome with adrenal insufficiency associated with the combined administration of oral low dose ritonavir and moderate to high dose inhaled fluticasone. CONCLUSION: These observations highlight the fact that the combined administration of fluticasone and ritonavir must be avoided as well as the combined administration of fluticasone and other inhibitors of the cytochrome P450.

[Screening of occupational exposure to asbestos and silica by job-exposure matrix among patients with lung cancer and mesothelioma]. / Dépistage des expositions professionnelles à l'amiante et à la silice par matrice emplois-expositions auprès de patients atteints de cancer bronchopulmonaire et de mésothéliome.

INTRODUCTION: In the context of underreporting of occupational diseases, the aim was to study the validity of silica and asbestos job-exposure matrices in screening occupational exposure in the field of thoracic oncology. METHODS: Fifty patients hospitalized with primitive lung cancer or mesothelioma in a university hospital center in the Hauts-de-Seine department of France were included between November 2016 and September 2017. For each patient 1/the job history was collected, from which data was entered single-blindly into the job-exposure matrices by a resident in occupational medicine, 2/a questionnaire (Q-SPLF) was completed similarly, and 3/the patients also had a consultation with a chief resident in occupational medicine, considered the gold standard. The main outcome was the diagnostic performance of the matrices. The Q-SPLF diagnostic performance was also studied. RESULTS: The asbestos and silica matrices had sensitivities of 100%, specificities of respectively 76.1% and 87.8%, the positive likelihood ratios were at 4.19 [2.5-6] and 8.17 [3.8-10], and the negative likelihood ratios were at 0. The Q-SPLF diagnostic performance was comparable to that of the matrices. CONCLUSIONS: The matrices and the questionnaire have a great diagnostic performance which seems interesting for a use as a screening tool for occupational exposures. These results have yet to be confirmed by large-scale studies.

[Bronchial involvement in an immunocompetent adult with varicella pneumonia]. / Atteinte bronchique au cours d'une pneumonie varicelleuse chez un adulte immunocompétent.

INTRODUCTION: Pneumonitis caused by varicella infection is a serious and potentially life-threatening complication of the disease when it occurs in adults. The incidence of this complication has increased in the last 10 years. OBSERVATION: We report the case of a non-immunocompromised patient admitted to hospital because of varicella pneumonia not requiring intensive care. Bronchoscopy revealed vesicular lesions on the bronchial mucosa. The patient made a full recovery with anti-viral therapy. CONCLUSION: Vesicular lesions can be observed on the bronchial mucosa of adult patients with varicella zoster infection.

Endothelin-1 is synthesized and inhibits cyclic adenosine monophosphate- dependent anion secretion by an autocrine/paracrine mechanism in gallbladder epithelial cells.

Ion and fluid transport across the biliary epithelium contributes to bile secretion. Since endothelin (ET)-1 affects ion transport activities and is released by human gallbladder- derived biliary epithelial cells in primary culture, we examined the expression of ET peptides and ET receptors and the influence of ET-1 on ion transport in this epithelium ex vivo. In freshly isolated gallbladder epithelial cells, preproET-1, -2, and -3 mRNAs were detected by reverse transcription PCR and ET-1 isopeptide was identified by chromatography. The cells also displayed ET receptor mRNAs and high-affinity binding sites for ET-1, mostly of the ETB type. Electrogenic anion secretion across intact gallbladder mucosa was stimulated by forskolin, secretin, and exogenous ATP, as assessed by short-circuit current (Isc) increases in Ussing-type chambers. ET-1 inhibited forskolin- and secretin-induced changes in Isc, without affecting baseline Isc or ATP-induced changes. Accordingly, ET-1 significantly reduced the accumulation of intracellular cAMP elicited by forskolin and secretin in the epithelial cells, and this effect was abolished by pertussis toxin. This is the first evidence that ET-1 is synthesized and inhibits, via a Gi protein-coupled receptor, cAMP-dependent anion secretion in human gallbladder epithelium, indicating a role in the control of bile secretion by an autocrine/paracrine mechanism.

[Embolization of localized pulmonary arteriovenous malformations in adults]. / Embolisation des malformations artérioveineuses pulmonaires localisées de l'adulte.

OBJECTIVES: To report our experience using embolization in managing localized pulmonary arteriovenous malformations in adults. MATERIAL: and methods. All patients presenting with localized pulmonary arteriovenous malformations treated with embolization were included in the study. Clinical presentation (respiratory symptoms and previous history of paradoxical embolism) and the characteristics of pulmonary arteriovenous malformations (single or multiple, location, diameter of the afferent artery and simple or complex angioarchitecture) before embolization were analyzed. The details of the procedure, including the number of pulmonary arteriovenous malformations embolized, the number of coils used, and the type of intraoperative complications were recorded. Postembolization clinical and imaging follow-up were described. RESULTS: Forty-two patients (26 women, 16 men; mean age, 45 years), including 36 with hereditary hemorrhagic telangiectasia were treated with embolization. Twenty-two patients (53%) were dyspneic and 12 (29%) had a previous history of paradoxical embolism prior to embolization. Forty-seven procedures were carried out on a total of 99 pulmonary arteriovenous malformations (mean, 2.3 per patient), using 530 coils (12.6 per patient). The pulmonary arteriovenous malformations were located in the lower lobes in 60% of cases and a simple architecture was reported in 81% of cases. The average diameter of the afferent artery was 6mm. No preoperative complications were reported. After embolization, two patients (5%) presented with a paradoxical embolism and five patients out of 22 (23%) remained dyspneic. The rate of complete occlusion of treated arteriovenous malformations was 92% using computer tomography. CONCLUSION: Embolization is a highly effective and safe technique for treating pulmonary arteriovenous malformations. Improvement in dyspnea and prevention of paradoxical embolism can be expected. A high technical success rate can be obtained by experienced interventional radiologists.

[The effects of inhaled steroids withdrawal in COPD]. / Impact du sevrage des corticostéroïdes inhalés dans la BPCO.

The key pathophysiological feature of chronic obstructive pulmonary disease (COPD) is an abnormal inflammatory bronchial reaction after inhalation of toxic substances. The priority is the avoidance of such toxic inhalations, but the use of anti-inflammatory drugs also seems appropriate, especially corticosteroids that are the sole anti-inflammatory drug available for this purpose in France. The risks associated with the prolonged use of these parenteral drugs are well known. Inhalation is therefore the optimal route, but inhaled drugs may also lead to adverse consequences. In COPD, there is an inhaled corticosteroids overuse, and a non-satisfactory respect of the guidelines. Consequently, their withdrawal should be considered. We reviewed seven clinical studies dealing with inhaled corticosteroids withdrawal in patients with COPD and found that included populations were heterogenous with different concomitant treatments. In non-frequent exacerbators receiving inhaled corticosteroids outside the recommendations, withdrawal appears to be safe under a well-managed bronchodilator treatment. In patients with severe COPD and frequent exacerbations, the risk of acute respiratory event is low when they receive concomitant optimal inhaled bronchodilators. However, other risks may be observed (declining lung function, quality of life) and a discussion of each case should be performed, especially in case of COPD and asthma overlap.

[Is the severity of occupational asthma related to the molecular weight of the allergen?]. / La sévérité de l'asthme professionnel est-elle liée au poids moléculaire de l'allergène?

INTRODUCTION: The aim of the study was to compare the characteristics of occupational asthma (OA) resulting from sensitisation to allergens of high (HMW) or low (LMW) molecular weight. METHODS: All new cases of allergic OA seen in an occupational health department between January 2001 and March 2004 were included. The patients underwent a standardised assessment including a questionnaire, skin tests, spirometry and measurement of non-specific bronchial reactivity. They were divided into 2 groups depending on the molecular weight of the causal agent (groups HMW and LMW). RESULTS: 77 patients were included, 30 in the HMW group and 47 in the LMW group. No significant difference in severity at the time of diagnosis was found between the two groups (symptoms, spirometry, PD20 methacholine) but the time between the first symptoms and diagnosis was longer in the HMW group (7.1 +/- 7.8 years against 3.2 +/- 4.1 years, p = 0.01). Atopy was more common in the HMW group (57% vs. 27%, p = 0.01). CONCLUSION: The severity of OA at the time of diagnosis does not appear to be influenced by the molecular weight of the causal agent.

[Miliary cerebral carcinomatosis secondary to EGFR mutation-positive lung adenocarcinoma]. / Miliaire cérébrale carcinomateuse secondaire a un adénocarcinome pulmonaire muté EGFR.

INTRODUCTION: Miliary brain metastases are a rare form of brain metastatic lesions. CASE REPORT: We report the case of a 58-year-old patient with lung adenocarcinoma and an EGFR mutation, who had metastatic lesions in the bones, pleura and pericardia at the time of diagnosis. The patient was treated with tyrosine kinase inhibitor. A few months later, he presented with progressive neuropsychiatric symptoms, which were attributed to miliary brain metastases based on the radiological pattern (micronodules, some of which were calcified) and the elimination of alternative possible diagnoses. Despite tumour stability in the thorax and metastatic sites other than the brain, his neurological condition deteriorated, even after cerebral radiotherapy, leading to his death eight months after the diagnosis of lung cancer. CONCLUSION: Miliary brain metastases are a rare form of brain metastases with unusual clinical presentation. The diagnosis is based on the radiological pattern of cerebral miliary dissemination, with sometimes calcified tumor nodules. Despite its rarity, several cases have been reported in lung adenocarcinoma in the presence of EGFR mutations.

[Validation of an evaluation questionnaire for COPD acute exacerbations (Exascore)]. / Validation d'un questionnaire d'évaluation de l'exacerbation dans la BPCO : l'Exascore.

BACKGROUND: Early identification of acute exacerbations of COPD facilitates better care. This study was designed to validate a short questionnaire (Exascore) developed to help patients, relatives and carers to diagnose acute exacerbations. METHOD: We first addressed content validity that allowed the elaboration of two questionnaires, one assessing the current status and the other stable status (transition). The second step tested their construction validity, reproducibility and concomitant validity among 126 COPD patients aged 64.4±9.9 years. They included 56 presenting with an exacerbation and 70 in stable state, of whom 57 completed the questionnaire a second time after 7 days. The diagnosis of exacerbation and assessment of severity (gold standard) were established by the treating respiratory physician and confirmed by two independent experts. RESULTS: Factorial analyses established a "current status" questionnaire comprising 8 items and 2 dimensions. Cronbach's alpha coefficients were satisfactory, 0.867 for "respiratory impact", 0.886 for "psychosocial impact" and 0.886 for the total score. Concomitant validity and reproducibility were also adequate. The transition questionnaire did not obtain convincing psychometric results. CONCLUSIONS: The "current status" Exascore questionnaire satisfies psychometric quality criteria while being usable in clinical practice. It helps in diagnosing acute exacerbations and assessing their intensity. Further studies will need to test the adequacy of proposed thresholds, the factorial structure of the score in healthcare professionals and patients' relatives, and its predictive power.

[The place of inhaled corticosteroids in COPD]. / Place des corticostéroïdes inhalés dans la BPCO.

INTRODUCTION: Clinical trials have provided some evidence of a favorable effect of inhaled corticosteroids on the frequency of exacerbations and on the quality of life of patients with chronic obstructive pulmonary disease (COPD). In contrast, ICS have little or no impact on lung function decline and on mortality. STATE OF THE ART: Inhaled corticosteroids are recommended only in a minority of COPD patients, those with severe disease and repeated exacerbations and probably those with the COPD and asthma overlap syndrome. However, surveys indicate that these drugs are inappropriately prescribed in a large population of patients with COPD. Overtreatment with inhaled corticosteroids exposes these patients to an increased risk of potentially severe side-effects such as pneumonia, osteoporosis, and oropharyngeal candidiasis. Moreover, it represents a major waste of health-care spending. CONCLUSION: Primary care physicians as well as pulmonologists should be better aware of the benefits as well as the side-effects and costs of inhaled corticosteroids.

Contribution of exhaled nitric oxide measurement in airway inflammation assessment in asthma. A position paper from the French Speaking Respiratory Society.

Nitric oxide (NO) is both a gas and a ubiquitous inter- and intracellular messenger with numerous physiological functions. As its synthesis is markedly increased during inflammatory processes, NO can be used as a surrogate marker of acute and/or chronic inflammation. It is possible to quantify fractional concentration of NO in exhaled breath (FENO) to detect airway inflammation, and thus improve the diagnosis of asthma by better characterizing asthmatic patients with eosinophilic bronchial inflammation, and eventually improve the management of targeted asthmatic patients. FENO measurement can therefore be viewed as a new, reproducible and easy to perform pulmonary function test. Measuring FENO is the only non-invasive pulmonary function test allowing (1) detecting, (2) quantifying and (3) monitoring changes in inflammatory processes during the course of various respiratory disorders, including corticosensitive asthma.

Induction of a cAMP-stimulated chloride secretion in regenerating poorly differentiated airway epithelial cells by adenovirus-mediated CFTR gene transfer.

In cystic fibrosis (CF), the airway epithelium is in the process of injury and regeneration. In the context of the CF gene therapy, we previously reported that regenerating poorly differentiated (PD) cells of human airway epithelium represent preferential cell targets for recombinant adenoviral gene vectors. To define whether PD non-CF and CF epithelial cells possess a functional cystic fibrosis transmembrane conductance regulator protein (CFTR) chloride channel, we analyzed the CFTR expression and the regulation of chloride secretion under cyclic (c)AMP stimulation in these regenerating PD epithelial cells of non-CF and CF airway tissue. Moreover, we studied the effects of CFTR gene transfer mediated by a replication-defective adenovirus containing the wild-type CFTR gene (AdCFTR) on CFTR expression and on cAMP-stimulated chloride secretion. Distribution of the CFTR protein was evaluated in regenerating PD airway cells by light fluorescence microscopy and scanning laser confocal microscopy. The cAMP-mediated regulation of cell membrane chloride secretion was investigated using the whole-cell patch clamp and SPQ (6-methoxy-N-[3-sulfopropyl]quinolinium) techniques. Compared with the absence of CFTR expression and cAMP-regulated chloride secretion in nontransduced regenerating PD cells of either non-CF or CF origin, transduction with AdCFTR induces a CFTR expression and a cAMP-regulated stimulation of the cell membrane chloride secretion in the regenerating PD cells. These results suggest that, out of the context of CF, remodeled and poorly differentiated airway epithelium may present abnormalities in ion transport. Moreover, our data suggest that, in the context of CF gene therapy, adenoviral vectors can be efficient in correcting, at least partially, the chloride secretion defect in the remodeled CF airway epithelium.

CFTR gene mutations in adults with disseminated bronchiectasis.

The severity and type of clinical manifestations are variable in patients with cystic fibrosis (CF). The respiratory syndromes in these patients consist of lung infections associated with disseminated bronchiectasis (DB), asthma, and chronic obstructive pulmonary disease. To investigate the possible involvement of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in chronic pulmonary disease in adults, we studied 32 DB patients with a clinically isolated respiratory syndrome. Careful analysis of all the CFTR gene exons and their flanking regions revealed a significantly increased frequency of CFTR gene mutations in these patients. Thirteen CFTR gene mutations were identified in sixteen different alleles. Six of these mutations, which have previously been reported as CF defects, were found on nine alleles. A further four, two of which had not previously been described (D192N and 406-2 AdeltaC), are potentially disease-causing mutations. We also identified three rare substitutions (R31C, L997F, T1220I), which could be involved in mild CFTR gene disease. Four patients were compound heterozygotes, one carried two CFTR gene mutations (possibly allelic) and six were heterozygous for a mutation. These results indicate that CFTR gene mutations may play a role in bronchiectatic lung disease, possibly in a multifactorial context. These findings have implications for genetic counselling of DB patients and their families.

Effects of smoking on bronchial clearance of technetium-99m-DTPA and indium-113m-DTPA.

UNLABELLED: In asymptomatic smokers, epithelial permeability in the distal lung regions is increased. To date, the effect of smoking on the epithelial permeability in proximal lung regions is still debated. The measurement of bronchial clearance of inhaled radiolabeled diethylene-triaminepentaacetic acid (BC-DTPA) can be used to assess epithelial permeability of proximal bronchi, but there are two potential limitations to this method: in vivo breakdown of 99mTc-DTPA in smokers and mucociliary transport of DTPA. METHODS: Eight nonsmokers and eight asymptomatic smokers were studied. We used a spinning disk system to generate an aerosol of large particles of 99mTc-DTPA or 113mIn-DTPA (MMAD 6.3 microns). To measure the bronchial clearance of 99mTc-DTPA and 113mIn-DTPA, we analyzed the perihilar regions of the lung. To determine the contribution of mucociliary transport, we measured the activity over a tracheal region of interest (ROI) in eight nonsmokers. RESULTS: Technetium-99m-DTPA bronchial clearance did not differ in smokers (1.16 +/- 0.54%/min; mean +/- s.d.) or nonsmokers (1.29 +/- 0.51%/min; ns). The 113mIn-DTPA bronchial clearances in nonsmokers (1.24 +/- 0.51%/min) and in smokers (1.01 +/- 0.66%/min) were similar to the 99mTc-DTPA bronchial clearances (ns). In the tracheal ROI, we found no increase in activity. CONCLUSION: In smokers, BC-DTPA was not increased compared to nonsmokers. In contrast to distal lung regions, there was no evidence of breakdown of the 99mTc-DTPA complex in the proximal regions of smokers' lungs. Mucociliary clearance does not significantly contribute to BC-DTPA.

Metered-dose inhaler to deliver methacholine in bronchial provocation testing: a pilot study.

BACKGROUND: Nonspecific bronchial provocation tests may be simplified by the use of hand-held devices to deliver methacholine. OBJECTIVE: To study the feasibility of using a metered-dose inhaler (MDI) to administer methacholine in bronchial provocation tests, and the ability of such a device to diagnose bronchial hyperresponsiveness (BHR) accurately. METHODS: In an open randomized crossover pilot study, we compared the provocative dose that induces a 20% fall in FEV1 (PD20 FEV1) obtained with the methacholine MDI with that obtained using a conventional nebulizer in 20 hyperresponsive and 20 nonhyperresponsive subjects. The MDI delivers 400 doses of 100 microg of methacholine, and was used via a spacer. Bronchial hyperresponsiveness (BHR) was defined as a PD20 FEV1 <2,000 microg with the conventional test using the nebulizer. The tests were performed in each subject in a randomized order, 1 to 7 days apart. RESULTS: Of the subjects who had a nebulizer PD20 FEV1 <2,000 microg, all but one had an MDI PD20 FEV1 <800 microg. When 800 microg was taken as the threshold for the diagnosis of BHR with the MDI test, the accuracy of this test to diagnose BHR was 97.5%, and the two tests were highly concordant for the diagnosis of BHR (Pearson chi2, 36.19; p<0.0001). CONCLUSION: A hand-held device may be suitable for delivery of methacholine during bronchial provocation tests, if these results are confirmed in large samples.

Inhaled therapy in asthma: metered-dose inhaler experience.

Metered-dose inhalers are the most widely-used mode of administration of bronchodilators and anti-inflammatory agents in the treatment of asthma. However, their use is complex and about 50% of the patients do not use their metered-dose inhaler(s) properly. The most frequent errors include inadequate coordination between actuation and inspiration, rapid inspiration, absence of breathhold, and actuation of the aerosol on more than one occasion during the same inspiration. The misuse of metered-dose inhalers results in a loss of efficacy of the drug. It is, therefore, recommended that the patient be carefully trained in the proper use of metered-dose inhalers at the time of prescription. If a patient is unable to use a metered-dose inhaler properly, despite education, it may be advisable to employ a different inhalation system.

[Changes in metered dose inhaler propellants]. / Modifications des gaz propulseurs dans les aérosols-doseurs pressurisés.

The understanding of the damaging effect of chlorofluorocarbons (CFCs) on the stratospheric ozone has led to international agreements calling for the total phase-out of CFC production. The banning of CFCs in pressurized metered dose inhalers used in airways disorders has been postponed on a temporary basis until replacement propellants have been identified. Hydrofluoroalkanes HFA-134a and HFA-227 have been shown to have no ozone damaging potential and to be safe. However, HFAs cannot simply be substituted for CFCs in inhalers of identical design. Their use has required changes in many aspects of the drug formulation, inhaler design and manufacture. This, in turn, has provided at least to some pharmaceutical companies an opportunity to assess and enhance the performances of new inhalers. The new products are neither technically nor pharmacologically identical to their CFC-based counterparts. Some of them have now completed clinical trials and the transition has already started: by the end of 1998, 2 short acting beta-agonist HFA-based inhalers and a corticosteroid HFA-based inhaler have reached the marketplace in France.