Lung function in Birt-Hogg-Dubé syndrome: a retrospective analysis of 96 patients.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the FLCN gene coding for folliculin. Its clinical expression includes cutaneous fibrofolliculomas, renal tumors, multiple pulmonary cysts, and recurrent spontaneous pneumothoraces. Data on lung function in BHD are scarce and it is not known whether lung function declines over time. We retrospectively assessed lung function at baseline and during follow-up in 96 patients with BHD. RESULTS: Ninety-five percent of BHD patients had multiple pulmonary cysts on computed tomography and 59% had experienced at least one pneumothorax. Mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and total lung capacity were normal at baseline. Mean (standard deviation) residual volume (RV) was moderately increased to 116 (36) %pred at baseline, and RV was elevated > 120%pred in 41% of cases. Mean (standard deviation) carbon monoxide transfer factor (DLco) was moderately decreased to 85 (18) %pred at baseline, and DLco was decreased < 80%pred in 33% of cases. When adjusted for age, gender, smoking and history of pleurodesis, lung function parameters did not significantly decline over a follow-up period of 6 years. CONCLUSIONS: Cystic lung disease in BHD does not affect respiratory function at baseline except for slightly increased RV and reduced DLco. No significant deterioration of lung function occurs in BHD over a follow-up period of 6 years.

Clinical ACO phenotypes: Description of a heterogeneous entity.

BACKGROUND: Because ACO (Asthma-COPD-Overlap) does not fill out asthma or COPD (Chronic Obstructive Pulmonary Disease) criteria, such patients are poorly evaluated. The aim of this study was to screen asthma and COPD for an alternative diagnosis of ACO, then to determine subgroups of patients, using cluster analysis. MATERIAL AND METHODS: Using GINA-GOLD stepwise approach, asthmatics and COPD were screened for ACO. Clusterization was then performed employing Multiple Correspondent Analysis (MCA) model, encompassing 9 variables (age, symptoms onset, sex, BMI (Body Mass Index), smoking, FEV-1, dyspnea, exacerbation, comorbidity). Finally, clusters were compared to determine phenotypes. RESULTS: MCA analysis was performed on 172 ACO subjects. To better distinguish clusters, the analysis was then focused on 55 subjects, having at least one cosine squared >0.3. Six clusters were identified, allowing the description of 4 phenotypes. Phenotype A represented overweighed heavy smokers, with an early onset and a severe disease (27% of ACO patients). Phenotype B gathered similar patients, with a late onset (29%). Patients from Phenotypes C-D were slighter smokers, presenting a moderate disease, with early and late onset respectively (respectively 13% and 31%). CONCLUSIONS: By providing evidences for clusters within ACO, our study confirms its heterogeneity, allowing the identification of 4 phenotypes. Further prospective studies are mandatory to confirm these data, to determine both specific management requirements and prognostic value.

[Diffuse infiltrative lung disease, pericarditis, pleural effusion and ceritinib hypersensitivity]. / Pneumopathie infiltrative diffuse, péricardite et pleurésie d'hypersensibilité compliquant un traitement par ceritinib.

Tyrosine kinase inhibitors are now major actors for the treatment of non-small-cell metastatic lung cancers where ROS 1 gene rearrangement is present. Because of the rapid development of these new therapies, developing information about their monitoring and knowledge about their potential toxicities is essential. We describe the case of a patient who was treated with ceritinib as a third line approach for a metastatic lung adenocarcinoma with ROS1 rearrangement. After two months, the patient developed acute respiratory distress with pericarditis and pleurisy. A hypersensitivity reaction was suggested and supported by favorable clinical and radiological outcomes within three days following ceritinib discontinuation and systemic corticosteroid introduction. Pleural effusion, pericarditis and diffuse pulmonary infiltration associated to ceritinib have not often been described previously. Despite few data of pulmonary toxicity related to ceritinib, the current observation highlights the need for caution and regular monitoring when using these inhibitors.

[Patients in the IDEAL cohort: A snapshot of severe asthma in France]. / Les patients de la cohorte IDEAL : une photographie de l'asthme sévère en France.

INTRODUCTION: This paper reports the French data from a post-hoc analysis of the international IDEAL study, which aimed to describe a recent cohort of patients with severe asthma, the impact of the disease on quality of life, as well as the population of patients eligible for treatment with omalizumab, mepolizumab and reslizumab. METHODS: Eligible patients were≥12 years of age, with severe asthma (GINA steps 4 and 5). RESULTS: A total of 129 patients were included in this post-hoc analysis. Their mean age was 53 years, the majority were overweight, they were mainly women (64%) and had at least one medical comorbidity (85%). More than half had suffered from asthma for more than 25 years and were non-smokers. Lung function was moderately impaired. Blood eosinophil count was≥150 cells/µL in 66% of patients,≥300 cells/µL in 34% of patients, and≥500 cells/µL in 12% of patients. One out of three patients was currently treated with omalizumab and 24% had maintenance oral corticosteroids. Asthma was poorly controlled with a negative impact on quality of life (ACQ≥1.5) in 67% of patients. In this population 40% of patients were eligible for omalizumab, 27% for mepolizumab and 2% for reslizumab. CONCLUSIONS: These findings show that a considerable proportion of patients with severe asthma remain uncontrolled and are not eligible for any of the available biological treatments. This underlines the need for therapeutic innovations in this disease.

[Acquired hemophilia A revealing lung cancer]. / Une hémophilie A acquise ayant révélé un cancer du poumon.

Acquired hemophilia A (AHA) is a rare disease, defined by the production of anti-factor VIII antibodies causing disordered hemostasis. It is idiopathic in 50% of cases, but sometimes associated with solid tumors. We report a case where AHA led to the diagnosis of lung cancer. CASE REPORT: An 82-year-old man with spontaneous hematomas on his trunk and extremities, and isolated prolongation of activated partial thromboplastin time was admitted to the emergency room. A severely reduced factor VIII level and a high factor VIII inhibitor title confirmed the diagnosis of AHA. Thoracic computed tomography scan found a suspect lung nodule and biopsy was consistent with a primary lung adenocarcinoma. The patient received recombinant factor VIII, immunosuppressive therapies, and finally lung stereotactic radiotherapy. Thirty months after diagnosis, the patient is in complete remission both from AHA and from his lung cancer. CONCLUSIONS: Acquired hemophilia A is a rare but potentially severe disease, which may be idiopathic or linked to a solid tumor. The severity of AHA depends on both the volume of hemorrhage and the presence of associated diseases.

[Pulmonary embolism as a presentation of nephrotic syndrome]. / Embolie pulmonaire révélant un syndrome néphrotique.

BACKGROUND: Nephrotic syndrome (NS) in adults is defined by proteinuria>3g/24h or 50mg/kg/d, hypoproteinemia<60g/24h and hypoalbuminemia<30g/L. The final diagnosis is guided by the histopathology evidence when a renal biopsy is possible. The consequences of NS are multiple: high blood pressure, undernutrition, infections and a hypercoagulable state. OBSERVATION: We report the case of a patient presenting with thromboembolic disease, occurring in the absence of other thromboembolic risk factors, which revealed NS with spontaneously favorable evolution. CONCLUSION: Thromboembolic disease in NS is frequent but underestimated and may remain underdiagnosed. Thorough investigation - including serum protein levels and testing for proteinuria - are essential in thromboembolism, as is excluding cancer or another cause. The treatment of thromboembolic disease in NS is based on anticoagulation for as long as the NS persists. There is no consensus about primary prophylaxis but an albumin level below 20g/L should be considered as a risk factor of thrombosis and prophylactic anticoagulation should be started.

[Therapeutic adherence in asthma in France: A general review]. / L'adhésion thérapeutique dans l'asthme en France : revue générale.

INTRODUCTION: Adherence in asthma is a paramount issue of disease management. A general review of the French publications on this topic has been conducted. METHODS: Research equations used for bibliographic databases (MEDLINE, Science Direct, Banque de données en santé publique, Cochrane and Cairn.info) comprised the following keywords: "asthma", "therapeutic adherence" and "France". These publications unrelated to asthma, focused on asthma management without exploring adherence, or those conducted in populations without French patients were excluded. RESULTS: A total of 82 articles have been selected (36 surveys, 4 randomized trials and 42 reviews/syntheses). Whatever the methodology used and publication year, the inadequate therapeutic adherence in asthma was steadily reported, notably for controllers and the quality of use of inhaled devices. CONCLUSION: The present review highlights the sustainability of adherence-related issues in asthma and the need to improve patients' knowledge on asthma and the finality of therapy. It also highlights the need of an improved communication between patients and physicians is also advocated. Further studies with more recent data are desirable to assess changes in disease management of asthma and the impact of potential future corrective interventions.

[Effects of fine particulate matter from on bronchial epithelial cells]. / Effets des particules fines sur les cellules épithéliales bronchiques.

INTRODUCTION: Ambient air contains a variety of pollutants including solid particles. Human bronchial epithelial cells (HBEC) play a key role following inhalation of these toxic particles. In a cell culture system of HBEC, we investigated the effects of several fractions of Lyons air-derived particles on cell viability/proliferation and production of the inflammatory mediators IL-8 and TGF-ß. METHODS: Air particles were collected in Lyon (France) by filtration of the air and impaction on filters located on a tapered element oscillating microbalance. Several diameter-based fractions of particles were prepared. HBEC were then exposed to different concentrations of these fractions. RESULTS: HBEC survival was not altered after 48hours of culture in the presence of particles regardless of their diameter and concentration. A dose-dependent inhibitory effect on cell growth was observed for all fractions. The particles caused an increase of both TGF-ß and Il-8 protein levels as a function of their diameters and/or concentrations. CONCLUSION: Air-derived particle fractions exhibit both an inhibitory effect on cell proliferation and a pro-inflammatory activity on HBEC.

[Severe uncontrolled asthma in patients over 75 years old: Treatment with omalizumab]. / Asthme sévère mal contrôlé de sujets de plus de 75 ans : traitement par omalizumab.

INTRODUCTION: With an aging population and an increase in the prevalence of asthma, this disease is becoming more common in the elderly. Nevertheless, the management of severe asthma can be complex, due to an increased risk of uncontrolled disease in patients over 65 years old and partly to the inherent characteristics of old age: comorbidities, underestimation of the role of allergies, poor adherence, difficulties with inhalation devices, etc. CASE REPORTS: We report two cases of women over 75 with severe persistent allergic asthma not controlled by high doses of inhaled corticosteroids and long-acting beta-2-agonists in whom treatment with omalizumab was initiated. Following treatment with omalizumab a decrease in the number and severity of exacerbations, improved asthma control and dose reduction or discontinuation of systemic corticosteroids were observed. The tolerance of omalizumab was good in both cases. CONCLUSIONS: Omalizumab is to be considered an effective and well-tolerated therapeutic option for elderly patients with inadequately controlled severe allergic asthma.

[COPD: An early disease]. / La BPCO : une maladie qui commence précocement.

This general review deals with the mechanisms which underlie the genetic factors in COPD. Many cellular and biochemical mechanisms occur in bronchial inflammation. We present the experimental models of COPD, insisting on the importance of oxydative stress, and on recent knowledge about the lung microbiome. Starting from this pathophysiology basis, we show how various genetic targets are able to interfere with the disease model. Thanks to these genetic targets, new markers in exhaled breath condensates and new drug targets are rising.

[Aspirin hypersensitivity: characteristics and diagnostic approach]. / Intolérance à l'aspirine : caractéristiques et éléments diagnostiques.

INTRODUCTION: In routine medical practice, the diagnosis of aspirin hypersensitivity (AH) remains difficult. No clinical feature or biomarker is available to reliably confirm this diagnosis and oral provocation tests (OPT) are rarely performed. AIM: To compare asthmatics with and without AH. METHOD: The clinical characteristics of 21 asthmatics with and 24 without AH respectively were determined. AH was defined by a positive OPT. A full blood count was done before and 24 hours after the OPT. RESULTS: The medical history was associated with a weak sensitivity (52%) and a good specificity (96%) for assessing the diagnosis of AH. There was a higher prevalence of AH in women, and a higher frequency of allergic rhinitis in AH, but no characteristic was useful to facilitate the diagnosis of AH in asthmatic patients. Our results demonstrate higher values of platelets in AH patients. Following OPT, in AH patients only, a decrease in blood eosinophils and an increase in neutrophils was observed. CONCLUSIONS: These results confirm that the diagnosis of AH is challenging, with the history having only weak sensitivity. The observation that fluctuations in eosinophils and neutrophils occur following OPT in AH patients only warrants further investigations and suggests a rapid pro-inflammatory role for aspirin.

[Deliberate interruptions and changes of dose of inhaled corticosteroids by asthma patients: "a community pharmacy study"]. / Interruptions et changements de posologie des corticoïdes inhalés par les patients asthmatiques: "enquête en pharmacie ".

BACKGROUND: Adherence to inhaled corticosteroids (ICS) remains a major issue for asthma management, even among patients receiving a regular prescription from their doctor. The frequency of deliberate interruption of ICS, and of spontaneous changes of dose, were studied in a population of asthma patients recruited in community pharmacies. METHODS: Asthma patients (aged 18-50) recruited in community pharmacies reported in self-administered questionnaires their spontaneous interruptions and changes of doses of ICS during the past 3 months. The characteristics of patients who interrupted their therapy or who modified the dose were compared with other patients. RESULTS: The studied population included 252 patients (mean age 35 year-old, females: 59%), of whom 62% had inadequately controlled asthma. Among these patients, 25% had interrupted ICS therapy during the past 3 months, while 21% spontaneously changed the dose. The most reported reason for interrupting ICS was the cessation of symptoms (50%). In multivariate analysis, interrupting ICS was mainly associated with inadequate asthma control (OR=3.1, 95% CI 1.5-6.4), while the strongest association with changing ICS doses was the patients' perception of asthma as a concern in their lives (OR=3.2, 95% CI 1.2-8.4). CONCLUSION: These results underline a poor understanding of the purpose of ICS therapy by patients. They also highlight the need of therapeutic education to improve the management of the disease.

[Physiopathology of aspirin intolerant asthma]. / Physiopathologie de l'asthme avec intolérance à l'aspirine. Concepts classiques et nouvelles voies métaboliques d'intérêt.

Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in individuals with asthma following the ingestion of aspirin. AERD affects up to 20 % of adults with asthma. At present, no reliable in vitro test is available to confirm the diagnosis. The confirmation of the diagnosis of AERD therefore depends on the response to challenge testing with aspirin. The pathogenesis of AERD is linked to abnormalities in arachidonic acid metabolism. Prior to exposure to aspirin, respiratory mucosal inflammation is the result of a cell infiltration, an overproduction of leukotrienes, prostaglandins D2, 5-oxo-eicosatetraenoic acid and an underproduction of lipoxins. After aspirin ingestion, patients with AERD synthesize excessive amounts of cysteinyl leukotrienes and prostaglandin metabolites involved in bronchoconstriction. New hypotheses concerning AERD pathogenesis have been added to the initial cyclooxygenase theory. These propose that AERD may be linked to the complement system, adenosine metabolism or angiotensin converting enzyme gene and IgE receptor gene polymorphisms.

[Montelukast in the treatment of mild to moderate persistent asthma]. / Place du montelukast dans le traitement de l'asthme persistant léger à modéré

INTRODUCTION: Anti-inflammatory preventive treatment is recommended in cases of persistent asthma. Besides inhaled corticosteroids (ICS), which represent the mainstay of treatment, other therapeutic options are available, of which only antileukotrienes are approved for all age groups. BACKGROUND: Given as a substitute of low-dose ICS, montelukast prevents exacerbations as efficiently and for a longer period than long-acting ß2-agonists. Montelukast is as efficient as doubling the dose of ICS on asthma symptoms in cases of inadequate control with low-dose ICS. Combined with ICS, it can lead to better control of asthma and potentially to ICS sparing. CONCLUSIONS: Given the efficacy, tolerance and long-term treatment compliance of montelukast in mild persistent asthma in adults and children, montelukast, given as a substitute or combined with ICS, could contribute to enhanced control of asthma, especially in children.

[Multiple spontaneous pneumothoraces revealing Birt-Hogg-Dube syndrome]. / Pneumothorax itératifs et spontanés révélant un syndrome de Birt-Hogg-Dubé.

The Birt-Hogg-Dubé (BHD) syndrome is associated with cutaneous disorders including fibrofolliculomas and trichodiscomas, and also lung pneumatocysts and kidney tumours. The BHD syndrome occurs as a consequence of an autosomal dominantly inherited genodermatosis, linked to multiple germline mutations in the 14 exons of the BHD gene, mapped on 17p11.2 and encoding for folliculin (FLCN). The size and number of lung pneumatocysts are extremely variable and the cysts are surrounded by normal pulmonary tissue. In the absence of smoking lung function is usually unimpaired. The lung cysts are frequently complicated by the development of recurrent pneumothoraces. Treatment of pneumothorax in patients with the BHD syndrome is similar to the approach taken for patients with spontaneous pneumothorax. Lung cysts in the BHD syndrome are a rare cause of cystic pulmonary lesions. However, they must be systematically evaluated since kidney tumours occur in one third of patients. We report a case of classical BHD syndrome with specific cutaneous involvement, recurrent pneumothoraces complicating lung cysts, an exon 12 germline mutation on BHD gene and a familial history suggesting other related cases. This observation allows us to update this orphan disease, to consider BHD in the differential diagnosis of lung cysts and, above all, to highlight the high frequency and the prognostic significance of associated kidney tumours.

[Assessment of prognostic factors of thoracic synovial sarcoma]. / Evaluation des facteurs pronostiques du synovialosarcome thoracique.

INTRODUCTION: Synovial sarcoma is an uncommon tumour and thoracic involvement is rare and of varying location. Clinical characteristics are dominated by pain, with a slow progression over years. Pathological and immuno-histochemical characteristics are helpful in the diagnosis but a specific translocation between chromosomes X and 18 is crucial for confirmation. Extensive surgical resection is required for cure, combined with adjuvant radiotherapy in the presence of adverse prognostic factors. CASE REPORT: We report a case of synovial sarcoma of the chest wall, responsible for chronic local pain for several years, presenting as an acute pleuropneumonitis in a 21-year-old patient. In view of the large size of the tumour, associated with a high proliferation index (Ki-67), a surgical resection was performed, together with local adjuvant radiotherapy. CONCLUSION: This case report reviews synovial sarcoma and underlines the difficulties and requirements of both diagnostic strategy and therapeutic management. Among them, an initial systematic review of prognostic factors (tumour size, mitotic activity, proliferation index, SYT-SSX type fusion, histological grade) is crucial to determine the therapeutic options.

[Lung abscess due to community acquired Klebsiella pneumonia]. / Pneumopathie communautaire abcédée à Klebsiella pneumoniae.

INTRODUCTION: In western countries, community-acquired pneumonias due to Klebsiella pneumoniae (Kp) are rare and associated with a poor prognosis and a high mortality. The severity is in part linked to the virulence of Kp. Immuno-depression, sepsis and visceral abscesses are frequently found, constituting other classical risk factors for severity and contributing to the poor prognosis. The therapeutic strategy is based on third generation cephalosporins, aminoglycosides and quinolones. CASE REPORT: We report the case of a young adult, with undiagnosed diabetes, hospitalized as an emergency for septic shock complicating a community-acquired pneumonia due to Kp and associated with multiple brain and lung abscesses. After several weeks of treatment, initially with empirical then specific antibiotics, a favourable outcome was obtained. CONCLUSION: This case report underlines the particular severity of infections due to Kp and their main pathophysiological mechanisms. It is also an opportunity to highlight the potential responsibility of Kp in the presence of a pneumonia with lung abscesses and finally to update the principles of antibiotic therapy.