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.

Characterisation of severe obliterative bronchiolitis in rheumatoid arthritis.

The characteristics of patients with rheumatoid arthritis (RA) who develop obliterative bronchiolitis characterised by severe airflow obstruction have been hitherto poorly investigated. A retrospective study of 25 patients with RA and functional evidence of obliterative bronchiolitis (forced expiratory volume in one second (FEV(1))/forced vital capacity (FVC) <50% and/or residual volume (RV)/total lung capacity (TLC) >140% predicted) was conducted. Patients (mean+/-SD age 64+/-11 yrs) included 17 never-smokers and eight ex-smokers (10.5+/-5.4 pack-yrs). The diagnosis of RA preceded respiratory symptoms in 88% of cases. Dyspnoea on exertion was present in all patients and bronchorrhea in 44%. High-resolution computed tomography findings included: bronchial wall thickening (96%), bronchiectasis (40%), mosaic pattern (40%), centrilobular emphysema (56%), and reticular and/or ground-glass opacities (32%). Pulmonary function tests showed: FEV(1) 41+/-12% pred, FEV(1)/FVC 49+/-14%, FVC 70+/-20% pred, RV 148+/-68% pred and RV/TLC 142+/-34% pred. Lung biopsy, available in nine patients, demonstrated constrictive, follicular and mixed bronchiolitis. Patients were followed for 48.2+/-49 months. Treatment was poorly effective. Chronic respiratory failure occurred in 40% of patients, and four patients died. Obliterative bronchiolitis associated with rheumatoid arthritis is a severe and under-recognised condition leading to respiratory failure and death in a high proportion of patients.

Homozygous variant rs2076530 of BTNL2 and familial sarcoidosis.

RATIONALE: Despite extensive studies, the pathogenesis of sarcoidosis is largely unknown. Although multiple environmental and putative infectious agents have been proposed, none was retained as a major contributor to the disease occurrence. Genetic predisposition to sarcoidosis was considered as a significant factor and numerous candidate genes have been reviewed. This last point was reinforced since the discovery of a pathogenic polymorphism (rs2076530 or G > A) of the BTNL2 gene, leading to an early truncation of the protein, which increases the relative risk of the disease. BTNL2 is known to act as a co-stimulatory molecule, inducing a negative signal to T-lymphocyte activation and the mutated gene is responsible for a truncated protein and disruption of membrane localization. OBJECTIVES: Our work attempted to confirm this observation in a highly penetrant familial form of sarcoidosis. RESULTS: In this family, the disease was diagnosed in 5 members through 3 generations. Despite individual clinical specificities, all displayed severe forms of the disease. Peripheral blood samples were collected from 3 patients and 2 additional healthy children of the fourth generation. Analysis of the BTNL2 gene confirmed the presence of the pathogenic variant of BTNL2 on both alleles (A/A homozygous genotype) in all subjects tested. CONCLUSIONS: Our data suggest that the absence of a membrane anchored BTNL2 protein may increase genetic susceptibility to sarcoidosis and familial occurrence of the disease. This observation assessed the putative pathogenic involvement of the rs2076530 variant of BTNL2 in the development of this granulomatosis disease.

[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.

[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.

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.

Galectin-10 mRNA is overexpressed in peripheral blood of aspirin-induced asthma.

BACKGROUND: In sensitive patients, aspirin is associated with nasal and bronchial inflammation, eliciting local symptoms. Although the disease is clinically well characterized, its physiopathology is incompletely understood and noninvasive procedures, allowing an effective distinction between aspirin-induced asthma (AIA) and aspirin-tolerant asthma (ATA) are missing. OBJECTIVES: The aims of the study were to compare AIA and ATA cohorts for clinical characteristics and to screen peripheral blood for differential mRNA expression. METHODS: Patients experiencing symptoms following aspirin ingestion were considered as aspirin sensitive. Peripheral blood was collected to quantify mRNA expression, using microarray technology and quantitative RT-PCR. RESULTS: Data indicated that AIA and ATA share large number of similarities for clinical phenotype. Screening of mRNA expression using microarray showed an overexpression of galectin-10 mRNA in AIA (AIA/ATA ratio = 1.9, P < 0.05). Results were confirmed using qRT-PCR. A positive correlation was established between microarray and qRT-PCR results for galectin-10 mRNA expression (r = 0.92, P < 0.0001). Finally, qRT-PCR results were validated on a subset of asthmatics and controls, showing an increased expression of galectin-10 mRNA in AIA vs ATA (P < 0.001) and vs controls (P < 0.01). CONCLUSIONS: Our results demonstrate that AIA and ATA remain difficult to distinguish using clinical criteria. Employing two molecular biological methods, we demonstrate that galectin-10 mRNA is overexpressed in AIA, suggesting a novel candidate gene and a potentially innovative pathway for mucosal inflammation in aspirin intolerance.

[The Whim syndrome: a rare cause of diffuse bronchiectasis. Immune defect of CXCR4 and chronic bronchial suppuration]. / Le syndrome de Whim: une cause exceptionnelle de bronchiectasies diffuses.

Whim syndrome, an association of warts, hypogammaglobulinemia, recurrent bacterial infections and the retention of mature polymorphonuclear cells within the bone marrow is an orphan disease. It occurs due to a complex immune defect, mutation and/ or dysfunction of CXCR4, the natural receptor of stromal cell-derived factor 1 [SDF-1 or CXCL12], which is implicated in the control of bone marrow homing of precursor cells and lymphocyte trafficking. Recently described, this poorly recognized immune defect is often inherited as an autosomal dominant trait and is responsible for multiple respiratory infectious events and the development of extensive HPV-induced warts. We report the case of a 36 year old man, who had been under follow up for many years because of diffuse bronchiectasis, with frequent pulmonary infections and progressive lung function deterioration. Late identification of a CXCR4 gene mutation led to a better understanding of the pathophysiology of his condition, allowing the discussion of future therapeutic strategies and finally to test relatives for similar mutations.

[Late respiratory function complications following burns]. / Séquelles fonctionnelles respiratoires tardives compliquant une immolation.

INTRODUCTION: Twenty five per cent of thermal injuries are associated with secondary respiratory events linked to several mechanisms. In the acute phase of the accident oedema of the airways, the fume inhalation syndrome and ARDS are the most common causes responsible for death in 60% of cases. Late respiratory complications are little known and neglected. They comprise obstructive ventilatory defects due to the inhalation syndrome and restrictive defects secondary to ARDS or to dermal injury. CASE REPORT: We report the case of a female patient, extensively burnt 2 years previously, admitted to hospital with severe acute respiratory failure complicating COPD. The presence of both restrictive and obstructive defects led to the suggestion of alternative underlying mechanisms such as the pulmonary consequences of ARDS and extensive dermal scars. The latter were responsible for an armour like thickening of the skin of the thorax compatible with the restrictive defect. CONCLUSIONS: These functional abnormalities and the potential severity of acute respiratory failure are indications for regular pulmonary follow-up of patients with severe circumferential scarring of the thorax who are at high risk for respiratory complications.

[Pneumomediastinum, giant subcutaneous emphysema and pneumoperitoneum revealed by jaw pain. Uncommon physiopathology of pneumomediastinum]. / Pneumomédiastin, emphysème sous-cutané géant et pneumopéritoine d'origine dentaire Physiopathologie inhabituelle d'un pneumomédiastin.

INTRODUCTION: Spontaneous pneumomediastinum is a rare entity, predominantly described in young man. The association of acute dyspnea, chest pains and subcutaneous emphysema is usually reported. CASE REPORT: We report the observation of a pneumomediastinum, fortuitously discovered in front of an isolated giant subcutaneous emphysema in a 59 year old man. The recent clinical history was only marked by the presence of intense and acute dental pains. Associated with a pneumoperitoneum, a retro-pneumoperitoneum, this clinical presentation is uncommon and differs from previous published case reports. Despite a complete evaluation of classical risk factors, its origin remains uncertain. However, the presence of huge dental injuries led to consider such local origin, facilitating air diffusion. CONCLUSION: This case report allows to reconsider spontaneous pneumomediastinum entity and to propose additional physiopathological mechanisms. This original description underlines the interest to systematically perform dental examination in the presence of unexplained pneumomediastinum.

[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.

Patient-reported adverse events under asthma therapy: a community pharmacy-based survey.

The characteristics of patients who report adverse events (AEs) attributed to asthma therapy have been little investigated. Asthma patients aged 18-50 years were surveyed in pharmacies. Patients completed a questionnaire linked to computerized records of dispensed medications. Patients reported all AEs that they attributed to asthma therapy. The correlates of reporting 2+ AEs were identified. Almost 59% of the 1,351 patients (mean age: 37, 56% females) attributed AEs to asthma therapy, and 35% at least two. Most common AEs included tiredness (21.8%) and palpitations (21.1%). Poor asthma control and perception of asthma as a handicap were the major correlates of reporting 2+ AEs (odds ratio (OR)=2.5, 95% confidence interval (CI)=[1.7-3.7] and OR=1.9, 95% CI=[1.4-2.5]). Other significant correlates included age >30 years, female gender, and receiving psychotropic therapy. Inadequate control may partly account for AEs attributed by patients to asthma therapy. Improving patients' education may help to improve acceptability of asthma therapy.

[Pulmonary metastases from Abrikossoff's tumour. Transformation capability of a benign granular cell tumour]. / Métastases pulmonaires d'une tumeur d'Abrikossoff. Transformation ou potentiel évolutif d'une tumeur bénigne à cellules granuleuses.

INTRODUCTION: Abrikossoff's tumour or granular cell tumour is usually benign involving multiple anatomical sites, most frequently the head, neck and airways. Occasional observations of aggressive malignant tumours have been reported, associated with a poor prognosis. CASE REPORT: We report the case of a mammary Abrikossoff's tumour, initially considered benign and treated solely by local surgery. Seven years later the tumour was responsible for the development of sub-cutaneous and pulmonary metastases. Local surgery was again the only treatment given in the absence of evidence for the effectiveness of alternative treatment with chemotherapy or radiotherapy. CONCLUSION: This original observation reports the case of a benign granular cell tumour that underwent malignant transformation after an interval of 7 years as indicated by the clinical progress and the cellular proliferation index Ki-67.

[Sweet's syndrome associated with squamous cell bronchial carcinoma. Neutrophilic dermatosis and non-small cell lung cancer]. / Syndrome de Sweet révélant un carcinome bronchique épidermoïde. Cancer bronchique et dermatose neutrophilique.

INTRODUCTION: Sweet's syndrome, one of the neutrophilic dermatoses, is idiopathic in most cases. In 10-20% of cases it is paraneoplastic, associated with a solid tumour or haematological malignancy. An association with carcinoma of the bronchus has been only rarely described. CASE REPORT: We report the case of a 56 year old man who presented with Sweet's syndrome two months before the diagnosis of a squamous cell carcinoma of the bronchus. The dermatosis responded well to corticosteroids. The progress of the tumour was favourable, with stabilisation following 3 courses of chemotherapy and local radiotherapy. DISCUSSION: This case report updates this rare association and underlines the importance of undertaking appropriate thoracic investigations in the presence of this dermatosis. A paraneoplastic secretion of interleukin-8, GM-CSF and/or G-CSF by the bronchial tumour cells facilitating the recruitment of neutrophils, particularly in the skin, may account for the pathophysiology of this condition.

[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.

[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.