Gilles Devouassoux

Combined pulmonary fibrosis and emphysema: A distinct underrecognised entity

The syndrome resulting from combined pulmonary fibrosis and emphysema has not been comprehensively described. The current authors conducted a retrospective study of 61 patients with both emphysema of the upper zones and diffuse parenchymal lung disease with fibrosis of the lower zones of the lungs on chest computed tomography. Patients (all smokers) included 60 males and one female, with a mean age of 65 yrs. Dyspnoea on exertion was present in all patients. Basal crackles were found in 87% and finger clubbing in 43%. Pulmonary function tests were as follows (mean±sd): total lung capacity 88%±17, forced vital capacity (FVC) 88%±18, forced expiratory volume in one second (FEV1) 80%±21 (% predicted), FEV1/FVC 69%±13, carbon monoxide diffusion capacity of the lung 37%±16 (% predicted), carbon monoxide transfer coefficient 46%±19. Pulmonary hypertension was present in 47% of patients at diagnosis, and 55% during follow-up. Patients were followed for a mean of 2.1±2.8 yrs from diagnosis. Survival was 87.5% at 2 yrs and 54.6% at 5 yrs, with a median of 6.1 yrs. The presence of pulmonary hypertension at diagnosis was a critical determinant of prognosis. The authors hereby individualise the computer tomography-defined syndrome of combined pulmonary fibrosis and emphysema characterised by subnormal spirometry, severe impairment of gas exchange, high prevalence of pulmonary hypertension, and poor survival.

Transcriptional blood signatures distinguish pulmonary tuberculosis, pulmonary sarcoidosis, pneumonias and lung cancers.

Rationale New approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations. Objectives To determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases. Methods We compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations. Measurements and Main Results An Interferon-inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls. Conclusions Tuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the heterogeneity of their profiles and their transcriptional response to treatment.

A Proof-of-Concept, Randomized, Controlled Trial of Omalizumab in Patients With Severe, Difficult-to-Control, Nonatopic Asthma

BACKGROUND While up to 50% of patients with severe asthma have no evidence of allergy, IgE has been linked to asthma, irrespective of atopic status. Omalizumab, an anti-IgE monoclonal antibody, is reported to significantly benefit a subset of patients with severe, persistent, allergic asthma. Therefore, we investigated whether omalizumab has biologic and clinical effects in patients with refractory nonatopic asthma. METHODS Forty-one adult patients who, despite daily treatment with or without maintenance oral corticosteroids, had severe, nonatopic, refractory asthma according to GINA (Global Initiative for Asthma) step 4, were randomized to receive omalizumab or placebo in a 1:1 ratio. The primary end point was the change in expression of high-affinity IgE receptor (FcεRI) on blood basophils and plasmacytoid dendritic cells (pDC2) after 16 weeks. The impact of omalizumab on lung function and clinical variables was also examined. RESULTS Compared with placebo, omalizumab resulted in a statistically significant reduction in FcεRI expression on basophils and pDC2 (P < .001). The omalizumab group also showed an overall increase in FEV1 compared with baseline (+250 mL, P = .032; +9.9%, P = .029). A trend toward improvement in global evaluation of treatment effectiveness and asthma exacerbation rate was also observed. CONCLUSIONS Omalizumab negatively regulates FcεRI expression in patients with severe nonatopic asthma, as it does in severe atopic asthma. Omalizumab may have a therapeutic role in severe nonatopic asthma. Nonetheless, our preliminary findings support further investigation to better assess the clinical efficacy of omalizumab. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01007149; URL: www.clinicaltrials.gov and European Clinical Trials Database, EudraCT; No.: 2009-010937-38; URL: https://www.clinicaltrialsregister.eu.

Sarcoidosis complicating anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody biotherapy

To the Editor: In August 2009, a 57-yr-old male smoker (30 pack-yrs) without medical history was diagnosed as having a melanoma of the left shoulder. A complete surgical excision was performed. The lesion was ulcerated. Breslow’s thickness was 1.034 mm and Clark’s level was III. As the axillary sentinel lymph node was positive for tumour cells, an additional lymphadenectomy was performed. The disease was finally staged at IIIb (pT2b N2a M0), in agreement with the American Joint Committee on Cancer Classification. In December 2009, the patient was included in a placebo-controlled trial to evaluate ipilimumab (a monoclonal antibody anti-cytotoxic T-lymphocyte-associated antigen (CTLA)-4 antibody), after complete resection of a high-risk stage III melanoma. Ipilimumab was administered by intravenously at 10 mg·kg−1, every 3 weeks for four doses (induction) followed by 10 mg·kg−1 every 12 weeks (maintenance). After two infusions of the maintenance phase, in July 2010, subcutaneous nodules appeared on his left arm and elbow. A concomitant computed tomography (CT) scan showed multiple micronodular, reticulonodular lesions of the lung and bilateral hilar lymph nodes. Positron emission tomography–CT showed an intense fluorodeoxyglucose binding of lung nodules and mediastinal lymph nodes (fig. 1). The skin lesions were biopsied and a pathological study revealed the presence of noncaseating granulomas. Bronchoalveolar lavage showed a mild lymphocytic alveolitis (11%, with a predominance of …

Asthma drug ratios and exacerbations: claims data from universal health coverage systems

In claims data, controller-to-total asthma drug ratios may reflect adequacy of disease management. We verified whether asthma patients with high ratios (≥50%) experienced fewer asthma-related outcomes. Two ratios were studied: that of the inhaled corticosteroids to total asthma drug (ICS/R03) and that of the inhaled corticosteroids plus leukotriene antagonist receptors-to-total asthma drug (ICS+LTRA/R03). Patients aged 13–40 years, with ≥3 respiratory drugs dispensed prescriptions in 2005 were selected from the French national claims data. After excluding null ratios, two groups were defined according to ratio values in 2007: low-ratio group (0%<ratio<50%) and high-ratio group (ratio ≥50%). For both ratios, asthma-related outcomes and medical-resource utilisation were compared between groups. Of 2162 patients (mean age 27 years and 52% female), patients with non-null ratios were 81% and 85% for ICS/R03 and ICS+LTRA/R03 ratios, respectively. Patients with high ratios were less likely to receive oral corticosteroids than those in the low-ratio group (relative risk 0.79, 95% CI 0.72–0.88, and 0.80, 95% CI 0.72–0.88, for ICS/R03 and ICS+LTRA/R03, respectively). High ratio groups also presented fewer asthma-related hospitalisations. Significant negative correlations were also observed for both ratios, when studied quantitatively, according to patients’ dispensed level of oral corticosteroids in 2007. In claims data, both ICS/R03 and ICS+LTRA/R03 ≥50% were related to fewer asthma-related outcomes. Ratios should be explored to identify asthma patients at risk of exacerbations. Low ratios can be considered as risk factors of exacerbation whatever the underlying cause. Asthma patients with therapeutic ratios ≥50% had fewer asthma exacerbation markers, suggesting better control http://ow.ly/tHa59

Influence of sociodemographic factors on quality of life during pollen season in seasonal allergic rhinitis patients

BACKGROUND Quality of life (QOL) is an important outcome in asthma and seasonal allergic rhinitis (SAR), and its determinants are imperfectly understood. More specifically, the influence of sociodemographic factors on QOL in patients with SAR has been so far little investigated. OBJECTIVE To examine the changes of QOL during the pollen season in patients with isolated SAR or SAR associated with asthma. METHODS A prospective cohort study was conducted in southern France. Outpatients aged 18 to 60 years and regularly treated by respiratory physicians for SAR (with or without associated asthma) were identified. Patients were recruited before the grass or ragweed pollination period. At peak pollination, patients completed the French versions of the Mini Rhino-conjunctivitis Quality of Life Questionnaire (mini-RQLQ) and the 12-item Short-Form Health Survey (SF-12) physical component summary (PCS) and mental component summary (MCS). RESULTS A total of 135 patients was included, 83 with isolated SAR and 52 with associated asthma (mean age, 35.4 years; SD, 10.6 years; 56% female). At pollen peak, QOL scores were lower in women for all instruments, with significant effects on SF-12 MCS and PCS scores in multivariate analyses. Likewise, a university-level education was an independent predictor of higher SF-12 PCS and MCS scores. Patients who lived in rural areas had significantly poorer QOL at pollen peak, as measured by the mini-RQLQ (P = .002) and SF-12 PCS (P = .008). No influence of age, presence of an animal at home, or smoking status could be identified on any QOL scores. CONCLUSIONS Being a woman, living in the countryside, and having a lower education level were all independent predictors of poorer QOL of SAR patients. These factors must be taken into account when interpreting QOL of patients with SAR. Further studies are needed to confirm these results.

Prescribed therapy for asthma: therapeutic ratios and outcomes

BackgroundInhaled corticosteroids (ICS) are the cornerstone of asthma therapy. The ICS-to-total-asthma-medication ratios, calculated from claims data, indicate potentially risky disease management in asthma. Our aim was to assess the utility of ICS-to-total-asthma-medication ratios from primary care electronic medical records (EMRs) in detecting patients at risk of asthma exacerbation, as approached by prescription of oral corticosteroids and/or antibiotics.MethodsRetrospective cohort studies were identified, using the Health Improvement Network general practice database (THIN, United Kingdom) and the Cegedim Longitudinal Patient Data (France). We selected asthma patients aged 16–40 years, with ≥ 4 prescriptions for asthma medications in 2007 and ≥ 1 prescription in 2008. For each country, three groups were defined according to ratio value in 2008: 0% (non-ICS users), <50% (low-ICS-ratio group) and ≥50% (high-ICS-ratio group). Outcomes were marker of asthma exacerbations: systemic corticosteroids and antibiotics. They were compared between groups in each country.ResultsAmong 38,637 British and 4,587 French patients, higher numbers of prescriptions per patient of systemic corticosteroids, antibiotics and total asthma medications were observed in the low-ICS-ratio groups compared to other groups (p < 0.0001 for each outcome in both countries). Likewise, low-ICS-ratio patients had more medical contacts (p < 0.0001 in both countries), suggesting poorly controlled asthma. ICS-treated patients had lower risks of receiving systemic corticosteroids in 2008 in the high-ICS-ratio group, compared to the low-ICS-ratio group: RR = 0.54, 95%CI = [0.50-0.57] and RR = 0.78, 95%CI = [0.67-0.91] in the UK and France, respectively.ConclusionsPatients with high ICS-to-total-asthma-medication ratios presented fewer asthma-related outcomes. The low ICS-to-total-asthma-medication ratio calculated with EMRs data reflects insufficient prescribing of ICS relative to all asthma medications, which may lead to deteriorated asthma control.

Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort

BackgroundThe occurrence of familial forms of sarcoidosis (OMIM 181100) suggests a genetic predisposition. The involvement of butyrophilin-like 2 (BTNL2) gene (rs2076530 variant) has to be investigated.ResultsThe study performed independent analyses of BTNL2 polymorphism, clinical phenotypes, and outcomes in familial vs. sporadic presentations in 256 sporadic and 207 familial cases from 140 families. The logistic multivariate model showed that a young age at diagnosis and the combination of lung and skin involvement at diagnosis may distinguish sporadic from familial sarcoidosis (p = 0.016 and p = 0.041). We observed also that Sarcoid Clinical Activity Classification (SCAC) profiles were significantly different between familial and sporadic cases (p = 0.0497).Variant rs2076530 was more frequent in patients than in controls (OR = 2.02; 95% CI: [1.32–3.09]) but showed no difference between sporadic and familial cases and no difference according to the clinical phenotype or the outcome.ConclusionDespite a significant difference in BTNL2 polymorphism between sarcoid patients and controls, there was no such difference between familial and sporadic sarcoidosis cases and no correlation between BTNL2 polymorphism and disease severity or outcome. Thus, BTNL2 difference cannot be considered as a key marker for disease classification or patient management.

Impact of montelukast on asthma associated with rhinitis, and other triggers and co-morbidities.

Abstract Introduction: Rhinitis and other specific triggers or co-morbidities (tobacco exposure, excess weight, aspirin sensitivity or heredity factors) are frequently associated with uncontrolled asthma. Asthma associated with these exacerbating factors appears to be related to an increase in leukotriene-mediated inflammation. Methods: We reviewed the role of montelukast, a leukotriene receptor antagonist, in the treatment of asthma associated with these factors by using the PubMed database to search the English and French biomedical literature for articles describing randomized-controlled trials, large observational studies and reviews (published up to May 2012, inclusive). Results: Montelukast, either alone or in combination with other drugs, is an effective treatment against rhinitis-associated asthma. Montelukast also offers therapeutic benefits against exercise-induced asthma or in cases of asthma linked to tobacco exposure, excess weight or aspirin hypersensitivity. Thus, for some patients, montelukast may constitute an alternative to the gold-standard treatment of inhaled corticosteroids. Polymorphisms in several genes encoding proteins of the leukotriene signaling pathway may contribute to the variability in response to montelukast. Conclusions: In conclusion, we have shown that montelukast treatment could be of particular benefit to subgroups of patients with asthma associated with rhinitis, exercise, tobacco exposure, being overweight or aspirin hypersensitivity.

Un cas d’aspergillome associé à une bronchite aspergillaire traités par voriconazole

INTRODUCTION Aspergillus fumigatus is a ubiquitous soil-dwelling organism, which can cause both aspergillomas which develop in a preformed lung cavity, and aspergillus bronchitis. The two pathologies can occasionally co-exist, notably in patients with of cystic fibrosis. CASE REPORT We describe a 57 year old patient, with diffuse bronchiectasis, who developed aspergillus bronchitis as well as an aspergilloma complicating a cavity caused by an atypical mycobacterial infection. After one month of therapy with voriconazole the aspergilloma had decreased in size and the endobronchial changes had resolved. CONCLUSION This case report illustrates that in addition to its established role for the treatment of invasive aspergillosis, voriconazole is a promising new therapy for the treatment of aspergilloma and aspergillus bronchitis.Resume Introduction Aspergillus fumigatus est un champignon ubiquitaire pouvant etre responsable d’aspergillome sur des cavites preexistantes, ou de bronchite aspergillaire. Ces 2 pathologies peuvent parfois coexister, notamment chez des patients atteints de mucoviscidose. Observation Ce cas clinique rapporte l’association peu commune d’une bronchite aspergillaire et d’un aspergillome chez un patient immunodeprime atteint de dilatations des bronches diffuses, d’evolution rapidement favorable sous voriconazole. Apres un mois d’utilisation, une detersion de l’aspergillome et une negativation des prelevements endo-bronchiques ont ete obtenus. Conclusion Cette observation suggere une indication nouvelle du voriconazole dans la pathologie aspergillaire, a cote de son utilisation deja classique dans l’aspergillose invasive.