[Tuberculosis and healthcare workers: Risk reduction and disease prevention in health care settings]. / Tuberculose et personnel soignant : prévention du risque en milieu de soins.

Tuberculosis is a human disease caused by Mycobacteriumtuberculosis, and transmitted by airborne pathway. Documented cases of tuberculosis infection in healthcare workers have been reported in both developed and developing countries. Early recognition of potentially infectious cases, immediate implementation of airborne precautions and prompt medical treatment of cases, are required to lower the risk of disease transmission. Molecular biology techniques allow earlier diagnosis. In the event of non-compliance with airborne precautions, the investigation will further have to establish exhaustive lists of potentially exposed healthcare workers and patients, looking for cases of latent tuberculosis infections whose treatment should help avoid active tuberculosis disease.

Score for pulmonary tuberculosis in patients with clinical presumption of tuberculosis in a low-prevalence area.

OBJECTIVES: To develop a diagnostic predictive model for the identification of patients with presumptive pulmonary tuberculosis (PTB) at high risk for active disease and those requiring nucleic acid amplification (NAAT) testing and/or preventive respiratory isolation in low-incidence, high-income countries. DESIGN: A 1:1 case-control study was conducted in consecutive immunocompetent patients with presumed PTB hospitalised between 2009 and 2012 in Paris, France. Cases were defined as individuals with culture-confirmed PTB, regardless of smear result. Those with presumed PTB and three smear- and culture-negative samples were selected as controls. A score was derived using conditional logistic regression. Internal validity of the score was assessed using the bootstrap method. RESULTS: A total of 354 patients were included in the analysis (177 cases, 177 controls). Among the 177 cases, 74 (42%) were smear-negative but culture-positive. Factors independently associated with PTB were age <50 years (adjusted OR [aOR] 4.7, 95%CI 1.8-12), diabetes (aOR 3.2, 95%CI 1.1-9.8), absence of cough with or without sputum (aOR 3.7, 95%CI 1.7-8.3), fever >15 days (aOR 3.5, 95%CI 1.3-9.5), apical infiltration without cavity (aOR 3.4, 95%CI 1.4-8.5) and cavitation or miliary pattern (aOR 19.7, 95%CI 7.6-51.1). Score C-index was 0.84 (95%CI 0.79-0.88). Calibration for the overall population (P = 0.770) and in smear-negative patients (P = 0.980) was appropriate. A score of 3.3 had 90% sensitivity, 50% specificity and 79% (IQR 28-95) median probability of PTB. CONCLUSIONS: This score could be used to build an algorithm to determine the need for respiratory isolation and/or NAAT use in PTB disease.

[Omalizumab: What have we learned after ten years of prescription?]. / Omalizumab : qu'avons-nous appris après 10ans d'utilisation ?

INTRODUCTION: Omalizumab, an anti-immunoglobulin E monoclonal antibody, has now been used for ten years as an add-on therapy for severe adult atopic asthma, poorly controlled by high-doses inhaled steroids and long-acting beta-agonists. BACKGROUND: This innovative therapy has been the first biotherapy used on a large scale in severe asthma. It has shown clinical benefits, especially in the prevention of severe exacerbation, with a satisfactory safety profile. Despite its cost, it is an interesting alternative to continuous oral steroids, which cause more long-term side effects. PERSPECTIVES: After ten-years of prescription of omalizumab, we review here the mechanism of action, the benefits, the main side effects, the cost-effectiveness and also the alternative indications of this interesting molecule. We also consider the practicalities of using omalizumab, particularly the importance a rigorous assessment of its efficacy after 16 weeks of treatment, and possible future therapeutic indications. CONCLUSION: Omalizumab has proven its efficacy in large randomized studies but also in real life practice in severe allergic asthma.

Roflumilast for asthma: Efficacy findings in non-placebo-controlled comparator and dosing studies.

BACKGROUND: Roflumilast, a phosphodiesterase-4 inhibitor, has an established place in the treatment of chronic obstructive pulmonary disease. Its potential role as a treatment for asthma is unclear. AIM: We report the results from seven double-blind, parallel group, phase II or III studies designed to compare roflumilast with two anti-inflammatory treatments, beclomethasone dipropionate (BDP) and montelukast, in patients with asthma. METHODS: The studies of 6-12 week duration were conducted at 309 sites in Europe, North America, South Africa and Australia from 1998 to 2005. Data from 3802 patients, aged 12-70 years who received either roflumilast 100 µg, 250 µg or 500 µg once daily, BDP 400 µg or 500 µg twice daily, or 10 mg montelukast once daily was analyzed. Primary endpoints were mean change and time averaged excess area under the curve in forced expiratory volume in one second (FEV1) over the duration of the study. Secondary endpoints included change in forced vital capacity and peak expiratory flow, asthma symptoms and the concomitant use of rescue medication. RESULTS: Roflumilast was non-inferior to BDP and montelukast and consistently increased FEV1. Use of rescue medication and all asthma symptom scores decreased significantly with all treatments, but no statistically significant between-group differences were observed. Secondary lung function endpoints generally supported the conclusions of the primary outcome measure. CONCLUSIONS: Roflumilast improves FEV1 and asthma symptoms in patients with mild to moderate asthma, and is non-inferior compared with both BDP and montelukast. It deserves further study as a potentially effective anti-inflammatory treatment for asthma.

[Mediastinal fat necrosis]. / Nécrose de la graisse médiastinale.

Epicardial fat necrosis is a rare cause of benign chest pain. Its physiopathological mechanism is unknown. Diagnosis is easily performed through radiological investigations that show a round opacity of fat density limited by a dense pseudo-capsule in the anterior mediastinum, close to the heart.

Anaphylactic bronchospasm during general anesthesia is not related to asthma.

In the general population, a history of asthma (HA) is associated with a higher risk of mortality of anaphylactic shock (AS), but it is unknown whether this association remains valid for intra-operative AS. The goal of this retrospective study was to investigate whether a HA was associated with a higher risk of bronchospasm during intra-operative AS. We analyzed 106 patients (January 2009-December 2012) with intra-operative AS: 57% of them had a confirmed IgE-mediated reaction and 27% had a HA. On logistic regression, the only factor statistically associated with bronchospasm was a neuromuscular blocking drug, with both IgE- or non-IgE-mediated reactions. These results suggest that the mechanisms of bronchospasm in AS may be different from those of asthma and that, in the presence of bronchospasm during anesthesia, AS should be considered to be the most likely cause.

[Bronchial thermoplasty in the treatment of severe adult asthma]. / La thermoplastie bronchique dans le traitement de l'asthme sévère de l'adulte.

Bronchial thermoplasty is a recent endoscopic technique for the treatment of severe asthma. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. Since this is a device-based treatment, the evaluation procedure of risks and benefits is different that for pharmaceutical products; safety aspects, regulatory requirements, study design and the assessment of the magnitude of effects may all be different. The mechanism of action and optimal patient selection need to be assessed further in rigorous clinical and scientific studies. This technique is in harmony with the development of personalised medicine in the 21st century. It should be developed further in response to the numerous challenges and needs not yet met in the management of severe asthma.

Beyond corticosteroids: future prospects in the management of inflammation in COPD.

Inflammation plays a central role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Exposure to cigarette smoke induces the recruitment of inflammatory cells in the airways and stimulates innate and adaptive immune mechanisms. Airway inflammation is involved in increased bronchial wall thickness, increased bronchial smooth muscle tone, mucus hypersecretion and loss of parenchymal elastic structures. Oxidative stress impairs tissue integrity, accelerates lung ageing and reduces the efficacy of corticosteroids by decreasing levels of histone deacetylase-2. Protease-antiprotease imbalance impairs tissues and is involved in inflammatory processes. Inflammation is also present in the pulmonary artery wall and at the systemic level in COPD patients, and may be involved in COPD-associated comorbidities. Proximal airways inflammation contributes to symptoms of chronic bronchitis while distal and parenchymal inflammation relates to airflow obstruction, emphysema and hyperinflation. Basal levels of airways and systemic inflammation are increased in frequent exacerbators. Inhaled corticosteroids are much less effective in COPD than in asthma, which relates to the intrinsically poor reversibility of COPD-related airflow obstruction and to molecular mechanisms of resistance relating to oxidative stress. Ongoing research aims at developing new drugs targeting more intimately COPD-specific mechanisms of inflammation, hypersecretion and tissue destruction and repair. Among new anti-inflammatory agents, phosphodiesterase-4 inhibitors have been the first to emerge.

Pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterised by alveolar accumulation of surfactant. It may result from mutations in surfactant proteins or granulocyte macrophage-colony stimulating factor (GM-CSF) receptor genes, it may be secondary to toxic inhalation or haematological disorders, or it may be auto-immune, with anti-GM-CSF antibodies blocking activation of alveolar macrophages. Auto-immune alveolar proteinosis is the most frequent form of PAP, representing 90% of cases. Although not specific, high-resolution computed tomography shows a characteristic "crazy paving" pattern. In most cases, bronchoalveolar lavage findings establish the diagnosis. Whole lung lavage is the most effective therapy, especially for auto-immune disease. Novel therapies targeting alveolar macrophages (recombinant GM-CSF therapy) or anti-GM-CSF antibodies (rituximab and plasmapheresis) are being investigated. Our knowledge of the pathophysiology of PAP has improved in the past 20 yrs, but therapy for PAP still needs improvement.

[COPD and inflammation: Statement from a French expert group. How to treat inflammation?]. / BPCO et inflammation : mise au point d'un groupe d'experts. Comment traiter l'inflammation ?

INTRODUCTION: Management of chronic obstructive pulmonary disease (COPD) has made considerable progress over the last 15 years, with the development of pulmonary rehabilitation, new molecules to facilitate smoking cessation, and several medical treatments. Many therapeutic needs, however, remain to be met. STATE OF THE ART: Several lines of research on inflammation and COPD are promising, and some will probably result in new treatments. These may target specific populations, identified by clinical phenotype or by biomarkers. The forthcoming arrival of iPDE-4s on the market illustrates how knowledge of inflammation and remodeling and of some of the underlying mechanisms finally, after many years' development, has broadened the range of treatments available to help improve patients' daily life and outcomes. PERSPECTIVES AND CONCLUSIONS: The availability of such treatments, however, does not mean that knowledge of the disease in the general population and among healthcare workers can be neglected. Early detection (at a stage when treatment can already be effective) and patient education which promotes therapeutic compliance and lasting lifestyle change need to be developed further.

Comparing asthma treatment in elderly versus younger patients.

A randomised 6-month study compared two maintenance doses of budesonide/formoterol (Symbicort® Turbuhaler® (h) maintenance and reliever therapy (Symbicort SMART®), 160/4.5 µg 1 × 2 and 2 × 2, in 8053 asthmatics with symptoms despite treatment with inhaled corticosteroids ± inhaled long-acting ß2-agonists. This analysis compared response to the two treatments in elderly patients, ≥ 65 years, with that in younger patients. Elderly patients with early- or late-onset asthma were also compared. Elderly patients had lower post-bronchodilator FEV1 percentage predicted normal at baseline than younger patients (85.6% vs. 91.0%, respectively). The elderly had more exacerbations and risk of first severe exacerbation was increased by 55.3% (hazard ratio 1.553; 95% confidence interval: 1.249-1.931, p < 0.0001). However, no differences in exacerbations were seen between 1 × 2 or 2 × 2 budesonide/formoterol maintenance and reliever therapy treatment in the elderly. Five-item Asthma Control Questionnaire (ACQ-5) scores improved equally in the two age groups. Changes in mean ACQ-5 scores between 1 × 2 and 2 × 2 were significant in both age groups but not clinically relevant (≥ 65 years, 0.12; p = 0.018; <65 years, 0.09; p < 0.0001). Elderly patients with early- and late-onset asthma responded equally well to treatment. Budesonide/formoterol maintenance and reliever therapy (1 × 2 or 2 × 2) is an effective, well-tolerated and practical treatment concept in elderly and younger asthmatic patients.

[COPD and inflammation: statement from a French expert group. Phenotypes related to inflammation]. / BPCO et inflammation: mise au point d'un groupe d'experts. Les phénotypes en lien avec l'inflammation.

INTRODUCTION: The objective of the present article is to review available data on possible links between phenotypes and inflammatory profiles in patients with chronic obstructive pulmonary disease (COPD). BACKGROUND: Chronic bronchitis is associated with proximal bronchial inflammation and small airway inflammation with remodeling at the site of obstruction. CT scanning enables patients to be phenotyped according to the predominantly bronchial or emphysematous nature of the morphological abnormality. Exacerbations, in a context of persistently elevated baseline inflammation, are associated with increased inflammation and a poor prognosis. Long-term studies have correlated inflammatory markers (and anti-inflammatory drug effects) with dynamic hyperinflation, possibly confirming that inflammation promotes hyperinflation. The inflammatory cell count in the pulmonary arterial walls correlates with the severity of endothelial dysfunction. The risk of developing pulmonary hypertension would seem to increase with low-grade systemic inflammation. The role of low-grade systemic inflammation in COPD co-morbidities, and in nutritional and muscular involvement in particular, remains a matter of debate. Regular physical exercise may help reduce this inflammation. CONCLUSIONS: In COPD, many aspects of the clinical phenotype are related to inflammation. Better knowledge of these relationships could help optimize current and future treatments.

[Pneumocystis pneumonia in a patient treated with pemetrexed for non small cell lung cancer]. / Pneumocystose chez un patient traité par pemetrexed pour adénocarcinome pulmonaire.

INTRODUCTION: Pneumocystis pneumonia is a life-threatening infection in patients undergoing chemotherapy for solid malignancies. CASE REPORT: A 49-year-old man developed gradually increasing dyspnoea while receiving pemetrexed as a third line treatment for an adenocarcinoma of the lung. The diagnosis of pneumocystis pneumonia was based on ground-glass opacities on the thoracic CT scan and alveolar lavage revealing occasional cysts of Pneumocystis jiroveci in the context of recent lymphopenia developing during chemotherapy. Treatment with cotrimoxazole for three weeks was only partially successful due to progression of the tumour. CONCLUSIONS: Pneumocystis pneumonia should be considered in cancer patients receiving antifolate drugs and presenting with increasing dyspnoea. It is important to identify a high-risk population among patients undergoing chemotherapy because of the significant morbidity and mortality and in order to administer effective prophylactic agents.

[COPD and inflammation: statement from a French expert group: inflammation and remodelling mechanisms]. / BPCO et inflammation: mise au point d'un groupe d'experts. Les mécanismes de l'inflammation et du remodelage.

The present study reviews the literature on inflammation and remodelling mechanisms in chronic obstructive pulmonary disease (COPD). The development of COPD is associated with chronic pulmonary inflammation. Immunity (innate or adaptive) plays a role in its onset and continuation. Airways inflammation alters bronchial structure/function relations: increased bronchial wall thickness, increased bronchial smooth muscle tone, seromucosal gland hypersecretion and loss of elastic structures. Circulating markers of pulmonary inflammation indicate its systemic dissemination. Oxidative stress plays a major role in the onset and persistence of tissue abnormalities. The determinants of extra- and intra-cellular redox control are only partially known. Susceptibility genes, antioxidant system insufficiency and reduced levels of anti-age molecules and of histone deacetylation are also involved. The molecular and cellular targets of inflammation and remodelling are numerous and complex. Currently, tools exist to limit inflammation in COPD but not to act on structural remodelling.

Comparison of two twice-daily doses of budesonide/formoterol maintenance and reliever therapy.

The aim of this study was to compare two budesonide/formoterol maintenance doses within the budesonide/formoterol maintenance and reliever therapy concept and to identify possible patient characteristics at baseline which would predict a better response to a higher than standard maintenance dose. A total of 8,424 patients with symptomatic asthma when using an inhaled corticosteroid (ICS) with or without a long-acting ß(2)-agonist were randomised to budesonide/formoterol 160/4.5 µg, one (1 × 2) or two (2 × 2) inhalations b.i.d. Patients used the same inhaler as needed for symptom relief. The primary outcome variable was time to first severe asthma exacerbation. In the total study population, the time to first severe asthma exacerbation was prolonged by 18% with 2 × 2 versus 1 × 2 (hazard ratio 0.82; p = 0.03). Lung function (peak expiratory flow) was the only statistically significant predictor of a better response to 2 × 2. The mean daily ICS doses were 737 and 463 µg in the 2 × 2 and 1 × 2 groups, respectively. In a real-life setting, budesonide/formoterol maintenance and reliever therapy at the 2 × 2 maintenance dose did prolong time to first severe exacerbation but at a higher medication load. Patients with low lung function benefited most from the higher maintenance dose.

Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics.

BACKGROUND: Masitinib is a tyrosine kinase inhibitor targeting stem cell factor receptor (c-kit) and platelet-derived growth factor (PDGF) receptor, which are expressed on several cell types including mast cells and bronchial structural cells, respectively. We hypothesized that c-kit and PDGF receptor inhibition may decrease bronchial inflammation and interfere with airway remodeling, which are crucial features of severe asthma. OBJECTIVES: The primary endpoint was the percent change from baseline in oral corticosteroids after 16 weeks of treatment. Change in asthma control (asthma control questionnaire), exacerbation rate, pulmonary function tests, rescue medication requirement and safety were secondary endpoints. METHODS: A 16-week randomized, dose-ranging (3, 4.5, and 6 mg/kg/day), placebo-controlled study was undertaken in 44 patients with severe corticosteroid-dependent asthma who remained poorly controlled despite optimal asthma management. RESULTS: At 16 weeks of treatment, a comparable reduction in oral corticosteroids was achieved with masitinib and placebo (median reduction of -78% and -57% in the masitinib and placebo arms, respectively). Despite this similar reduction, the Asthma Control Questionnaire score was significantly better in the masitinib arm as compared to placebo with a reduction by 0.99 unit at week 16 (P < 0.001) vs 0.43 unit in the placebo arm. Masitinib therapy was associated with more transient skin rash and edema. CONCLUSIONS: Masitinib, a c-kit and PDGF-receptor tyrosine kinase inhibitor, may represent an innovative avenue of treatment in corticosteroid-dependent asthma. These preliminary results warrant further long-term clinical studies in severe asthma