[Severe adult asthma and treatment adherence: Results of the FASE-CPHG study]. / Asthme sévère de l'adulte et observance : résultats de l'étude FASE-CPHG.

INTRODUCTION: Data on severe asthma in France are scarce. The aim of this study was to evaluate adherence to asthma treatments and its determinants in a population of severe asthmatics. METHODS: From May 2016 to June 2017, the French Collège des Pneumologues des Hôpitaux Généraux organized a large-scale prospective, cross-sectional, multicenter study on this topic; 1502 patients with severe asthma were included. RESULTS: The average number of substantive treatments was 2.5±1.1. Assessed by self-questionnaire in 1289 patients, overall adherence was 64.8%, in good agreement with the findings of the pneumologist in charge (p<0.0001). Control of asthma according to the GINA criteria was more successful in compliant patients (p<0.01). In univariate analysis, the most compliant participants were frequent exacerbator patients (p=0.02), those with nasal polyposis (p=0.01) and those receiving an anticholinergic agent (p<0.01), anti-IgE biotherapy (p<0.0001) or oral corticosteroids (p<0.01). The least compliant participants were younger (p<0.0001), active smokers (p<0.001), with shorter average disease duration (24.2±15.7 vs 29.1±18.7 years, p<0.0001) and a lower number of substantive asthma treatments (2.2±1 vs 2.6±1, p<0.0001). In multivariate analysis, age, length of disease and anti-IgE treatment were the only factors affecting therapeutic compliance. CONCLUSION: In this large-scale study of severe asthmatic patients, 64.8% were compliant according to the MMAS-4© self-administered questionnaire and appeared to be better monitored according to the criteria defined in our study. Overall, adherence was more satisfactory among older patients and those whose disease had been evolving over a long period of time or were receiving anti-IgE biotherapy.

Effectiveness of Omalizumab in Severe Allergic Asthma and Nasal Polyposis: A Real-Life Study.

BACKGROUND AND OBJECTIVE: Omalizumab is a human anti-IgE antibody approved for the treatment of severe allergic asthma (SAA). However, its effectiveness in SAA associated with chronic rhinosinusitis with nasal polyposis (CRSNP+) is less well documented. Objective: The aim of this study was to evaluate the real-life effectiveness of omalizumab in patients with SAA and CRSNP+ who tolerated and did not tolerate aspirin. METHODS: We performed a retrospective, observational, multicenter, real-life study of patients with SAA and CRSNP+ treated with omalizumab for 6 months. Asthma outcome parameters (symptoms, number of salbutamol rescues/wk, number of moderate/severe exacerbations, Asthma Control Test score, and lung function), sinonasal outcome parameters (symptoms, number of episodes of acute rhinosinusitis, sinus computed tomography images, nasal polyps endoscopy score), and serum eosinophil levels were analyzed 6 months before and after treatment with omalizumab. RESULTS: Twenty-four adult patients were included (9 with documented aspirin intolerance). All respiratory parameters were significantly improved by the treatment. In parallel, a significant improvement was observed in sinonasal clinical outcomes and sinus computed tomography images, with no major effect on the nasal polyps endoscopy score. The serum eosinophil count decreased significantly after 6 months of treatment with omalizumab. CONCLUSION: Treatment of SAA with omalizumab improves the outcome of associated CRSNP+, thus supporting the concept of a "one airway disease".

[Therapeutic strategies in patients undergoing surgery for non-small cell lung cancer. Results of the ESCAP-2011-CPHG study, promoted by the French College of General Hospital Respiratory Physicians (CPHG)]. / Stratégies thérapeutiques chez les patients opérés pour un carcinome bronchique non à petites cellules. Résultats de l'étude ESCAP-2011-CPHG réalisée par le Collège des pneumologues des hôpitaux généraux (CPHG).

BACKGROUND: The aim of ESCAP-2011-CPHG, promoted by the French College of General Hospital Respiratory Physicians, was to describe therapeutic strategies in lung cancer in the first 2 years after diagnosis, in a real-life setting. This article focuses on patients undergoing surgical management of a non-small cell lung cancer (NSCLC). METHODS: A prospective multicentre study was conducted in 53 French general hospitals. For each patient with lung cancer diagnosed in 2010, a standardised form was completed following each change in treatment strategy up to 2 years after diagnosis. RESULTS: Overall, 3418 of the 3943 included patients had NSCLC. 741 patients (21.7%) underwent curative surgery (stage 0-II, IIIA, IIIB, and IV: 65%, 27%, 3% and 5%, respectively). The therapeutic strategy changed less often in surgical than non-surgical patients and average follow-up time was longer: 23.3 months (SD: 9.3) versus 10.4 months (SD: 9.5) for non-surgical patients. Among patients with a surgical first strategy (92.6% of surgical patients as a whole), 56.9% did not receive any other treatment, 34.7% received chemotherapy, 5.9% radio-chemotherapy, 2.6% radiotherapy. At the end of follow-up, 55.8% were still alive without any other strategy, 13.1% had died, and 31.1% had received at least one more strategy. Among patients with a surgical second strategy, 63% had received chemotherapy alone during the first strategy. CONCLUSIONS: ESCAP -2011- CPHG assessed everyday professional practice in the surgical management of NSCLC in general hospitals. It pointed out the discrepancies between current guidelines and the therapeutic strategies applied in real life conditions.

Randomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: results from the IFCT-0802 trial†.

BACKGROUND: This randomized phase II-III trial sought to evaluate the efficacy and safety of adding bevacizumab (Bev) following induction chemotherapy (CT) in extensive small-cell lung cancer (SCLC). PATIENTS AND METHODS: Enrolled SCLC patients received two induction cycles of CT. Responders were randomly assigned 1:1 to receive four additional cycles of CT alone or CT plus Bev (7.5 mg/kg), followed by single-agent Bev until progression or unacceptable toxicity. The primary end point was the percentage of patients for whom disease remained controlled (still in response) at the fourth cycle. RESULTS: In total, 147 patients were enrolled. Partial response was observed in 103 patients, 74 of whom were eligible for Bev and randomly assigned to the CT alone group (n = 37) or the CT plus Bev group (n = 37). Response assessment at the end of the fourth cycle showed that disease control did not differ between the two groups (89.2% versus 91.9% of patients remaining responders in CT alone versus CT plus Bev, respectively; Fisher's exact test: P = 1.00). Progression-free survival (PFS) since randomization did not significantly differ, with a median PFS of 5.5 months [95% confidence interval (CI) 4.9% to 6.0%] versus 5.3 months (95% CI 4.8% to 5.8%) in the CT alone and CT plus Bev groups, respectively [hazard ratio (HR) for CT alone: 1.1; 95% CI 0.7% to 1.7%; unadjusted P = 0.82]. Grade ≥2 hypertension and grade ≥3 thrombotic events were observed in 40% and 11% of patients, respectively, in the CT plus Bev group. Serum vascular endothelial growth factor (VEGF) and soluble VEGF receptor titrations failed to identify predictive biomarkers. CONCLUSION: Administering 7.5 mg/kg Bev after induction did not improve outcome in extensive SCLC patients.

Nerve growth factor levels and localisation in human asthmatic bronchi.

Nerve growth factor (NGF) has recently been suggested to be an important mediator of inflammation. In support of this, serum levels of NGF have been shown to be enhanced in asthmatics. However, it has not yet been shown whether the levels of NGF are also altered locally in asthmatic airways, when compared with healthy subjects, and the localisation of potential sources of NGF in the human bronchus have not yet been described. The aim of the present study was to assess NGF levels in bronchoalveolar lavage fluid (BALF) from asthmatics and to compare them to those of control subjects. Furthermore, the authors wanted to localise potential sources of NGF in bronchial tissue, and to number NGF-immunopositive infiltrating cells in the bronchial submucosa. BALF and bronchial biopsies were obtained from seven control subjects and seven asthmatic patients by fibreoptic bronchoscopy. NGF protein levels were quantified by enzyme-linked immunosorbent assay in BALF. NGF localisation was examined by immunohistochemistry on bronchial biopsy sections. The asthmatics exhibited significantly enhanced NGF levels in BALF. Intense NGF-immunoreactivity was observed in bronchial epithelium, smooth muscle cells and infiltrating inflammatory cells in the submucosa, and to a lesser extent in the connective tissue. The asthmatics exhibited a higher number of NGF-immunoreactive infiltrating cells in the bronchial submucosa than control subjects. This study provides evidence that nerve growth factor is locally produced in the airways, and shows that this production is enhanced in asthmatics. These findings suggest that nerve growth factor is produced by both structural cells and infiltrating inflammatory cells in human bronchus in vivo, and the authors suggest that the increase in nerve growth factor protein in bronchoalveolar lavage fluid observed in asthmatic patients may originate both from structural cells, producing increased nerve growth factor levels in inflammatory conditons, and from the increase in nerve growth factor-immunopositive cells determined in the bronchial submucosa.

The allergen profile of ash (Fraxinus excelsior) pollen: cross-reactivity with allergens from various plant species.

BACKGROUND: Ash, a wind-pollinated tree belonging to the family Oleaceae, is distributed world-wide and has been suggested as a potent allergen source in spring time. OBJECTIVE: The aim of this study was to determine the profile of allergen components in ash pollen in order to refine diagnosis and therapy for patients with sensitivity to ash pollen METHODS: The IgE reactivity profile of 40 ash pollen-allergic patients was determined by immunoblotting. Antibodies raised to purified pollen allergens from tree and grass pollens were used to identify cross-reactive structures in ash pollen extract. IgE immunoblot inhibition studies were performed with recombinant and natural pollen allergens to characterize ash pollen allergens and to determine the degree of cross-reactivity between pollen allergens from ash, olive, birch, grasses and weeds. RESULTS: The allergen profile of ash pollen comprises Fra e 1, a major allergen related to the major olive allergen, Ole e 1, and to group 11 grass pollen allergens, the panallergen profilin, a two EF-hand calcium-binding protein, a pectinesterase-like molecule and an allergen sharing epitopes with group 4 grass pollen allergens. Thus, the relevant allergens of ash are primarily allergens that share epitopes with pollen allergens from other tree, grass and weed species. CONCLUSIONS: Allergic symptoms to ash pollen can be the consequence of sensitization to cross-reactive allergens from other sources. The fact that ash pollen-allergic patients can be discriminated on the basis of their specific IgE reactivity profile to highly or moderately cross-reactive allergens has implications for the selection of appropriate forms of treatment.

[Nasosinusal sarcoidosis: 13 cases]. / La sarcoïdose nasosinusienne. A propos de 13 cas.

We report 13 cases of nasosinusal sarcoidosis. Sarcoidosis is a chronic, non caseating granulomatous disease. Nasosinusal involment is rare or exceptional and may be isolated (1 case in our series) or associated (12 cases in our series) with other lesions of the chest, skin, liver, spleen, bone, eyes, salivary glands, peripheral lymph nodes or with neurosarcoidosis. The clinical and CT features are various and often non specific. Nasal biopsy guided by physical examination is easy and constitute the main diagnostic criterion. The course of nasosinusal sarcoidosis is variable and no standard treatment has been established. Response to local or systemic corticosteroid therapy is also variable. The recurrence is frequent after tapering off or interrupting corticosteroids that also have important side effects.

Comparative prognostic value of lactate dehydrogenase and neuron-specific enolase in small-cell lung cancer patients treated with platinum-based chemotherapy.

The influence of pretreatment serum levels of lactate dehydrogenase (LDH) and neuron-specific enolase (NSE) on survival was investigated in a series of 263 consecutive patients with small-cell lung cancer. LDH was elevated in one-half of the patients, NSE in 79%. Both were significantly higher when the disease was considered extensive than when it was limited. The markers were significantly correlated (r= 0.54, P=1.03 x 10(-20)), and both had a significant impact on survival in the univariate analysis. The multivariate survival analysis of the entire population showed that LDH, along with performance status, extent of disease, and albumin, was a more important prognostic factor than NSE. Only when LDH was removed from the model did NSE become an independent prognostic factor. In the separate multivariate survival analyses of limited and extensive disease, LDH remained an independent prognostic factor. For extensive disease, NSE did not even appear in the model when LDH was excluded; for limited stage disease, NSE did become a weak independent prognostic factor when LDH was excluded. In conclusion, LDH, which is less expensive to assay than NSE, is also a stronger independent prognostic factor for small-cell lung cancer and should be part of the initial work-up. In clinical trials, stratification for LDH levels should be considered because of its prognostic weight.

Comparison of genetically engineered hypoallergenic rBet v 1 derivatives with rBet v 1 wild-type by skin prick and intradermal testing: results obtained in a French population.

BACKGROUND: Bet v 1, the major allergen in birch pollen, is recognized by more than 90% of patients allergic to birch in northern and central Europe. Immunotherapy is commonly performed with birch pollen extracts. Recently, hypoallergenic derivatives of Bet v 1 (rBet v 1 fragments, rBet v 1 dimer and trimer) were constructed and purified. OBJECTIVE: Our aim was to compare the allergenic activity of wild-type rBet v 1 with recombinant Bet v 1 derivatives (rBet v 1 fragments, dimer and trimer) with potentially reduced anaphylactic activity by skin testing in a French population. METHODS: Among the 36 birch pollen allergic patients included in the study, 29 were tested by skin prick testing and 30 by intradermal injections with purified monosubstances: rBet v 1 fragments (F1: aa1-74 and F2: aa75-160), Bet v 1 dimer and trimer. Intradermal tests were performed by the end-point intradermal titration method. Eight of the intradermally-tested patients were previously hyposensitized. Tests were performed over a period of 6 months (before, during and after birch pollen season); Bet v 1-specific IgE and IgG4 subclass responses were measured by immunoblotting and ELISA. RESULTS: All patients showed lower reactivity with the modified rBet v 1 allergens, both in skin prick and intradermal tests. In 25 and 23 out of 29 patients the lowest concentration of fragment 1 and 2, respectively, resulting in a positive prick test was 100-fold higher than the lowest concentration of monomer resulting in a positive prick test. For dimer it was 100-fold or more in 25 out of 29 patients, and for trimer it was 100-fold or superior in 26 out of 29 patients. By intradermal testing, the end-point concentration was 160-fold higher for trimer than for monomer in 24 patients and 40-fold higher in five patients. For the two fragments the end-point concentration was 160-fold higher in 20 out of 22 patients. CONCLUSION: Genetically modified hypoallergenic derivatives of the major birch pollen allergen, Bet v 1 showed reduced capacity to induce immediate type skin reactions. They may represent candidate molecules for immunotherapy of birch pollen allergy with reduced risk of anaphylactic side-effects.

Genetics and specific immune response in allergy to birch pollen and food: evidence of a strong, positive association between atopy and the HLA class II allele HLA-DR7.

BACKGROUND: In some geographic areas birch pollen represents the most prominent cause for airborne allergic diseases. Up to 70% of patients allergic to birch pollen are hypersensitive to fruits, especially apples. Associations have been found, in some instances, with a sensitivity to aeroallergens and HLA class II genes. OBJECTIVES: We investigated whether susceptibility or resistance to birch pollen allergy with and without food allergy was associated with HLA class II genes. METHODS: Blood samples were obtained from 2 groups of unrelated European-born white adults: 42 atopic patients (31 of them with asthma) and 42 healthy control subjects with no personal or familial history of asthma or atopy. Their antibody responses to birch pollen, apples, grass, and weed pollens were evaluated by skin tests, RASTs, and immunoprints. Genomic DNA was extracted from PBLs. The exons of DQA1, DQB1, DRB1, and DPB1 genes were selectively amplified by using the PCR method. Genotyping was carried out by digestion of the amplified DNA products with allele-specific endonucleases (PCR-RFLP), which recognize allelic variations in the polymorphic exon. RESULTS: We found no significant differences in the frequency of DPB1 alleles between patients and control subjects. HLA class II DR4 and/or DR7 alleles were present in 42.6% of the patients and in only 2.4% of the healthy subjects. These results confirm a previous study of a group of polysensitized atopic patients, which showed that DR4 and DR7 alleles were rare in healthy control subjects and frequently observed in atopic subjects with or without concomitant asthma. CONCLUSION: We conclude that the allele HLA-DR7 is significantly involved in the presentation of apple and pollen allergens. However, we suggest that this susceptibility is more related to atopy than to specific responses to allergens.

Skin testing with wild-type recombinant birch pollen allergens and hypoallergenic modified molecules.

UNLABELLED: Our aim was to compare the allergenic activity of wild type rBet v 1 with recombinant Bet v 1 derivatives (rBet v 1 fragments, dimer and trimer) with potentially reduced anaphylactic activity by skin testing in a French population. METHODS: Among the 36 birch pollen allergic patients included in the study, 29 were tested by skin prick testing and 30 by intradermal injections with purified monosubstances: rBet v 1 fragments (F1: aa1-74 and F2: aa75-160), Bet v 1 dimer and trimer. Intradermal tests were performed by the endpoint intradermal titration method. Tests were performed over a period of 6 months (before, during and after birch pollen season). RESULTS: All patients showed lower reactivity with the modified rBet v 1 allergens, both in skin prick- and intradermal tests. In 25 and 23 out of 29 patients the lowest concentration of fragment 1 and 2 respectively, resulting in a positive prick test was 100 fold higher than the lowest concentration of monomer resulting in a positive prick test. For dimer it was 100 fold or more in 25 out of 29 patients, and for trimer it was 100 fold or superior in 26 out of 29 patients. By intradermal testing, the end point concentration was 160 fold higher for trimer than for monomer in 24 patients and 40 fold higher in 5 patients. For the 2 fragments the end point concentration was 160 fold higher in 20 out of 22 patients. CONCLUSION: rBet v 1 fragments and trimer may represent candidate molecules for immunotherapy of birch pollen allergy with reduced risk of anaphylactic side effects.

[Radiochemotherapy and radiosensitization for locally advanced non-small-cell bronchial cancer]. / Radiochimiothérapie optimisée pour le cancer bronchique non à petites cellules localement évolué.

Combined chemotherapy and radiotherapy can improve the survival of patients with locally advanced non-small cell lung cancer, when compared to irradiation alone. This survival benefit is essentially due to an increased control of distant micrometastases, whereas local control remains poor. In order to improve local control, new radiotherapy modalities such as 3D conformal treatment, hyperfractionation or accelerated hyperfractionation, are under development. Cytotoxic drugs given at low doses concomitantly to radiotherapy may act as radiosensitizers on the primary tumor. Concomitant chemotherapy at cytotoxic doses and radiotherapy would also allow better control on micrometastases and better local control due to radiosensitization by chemotherapy. However, the concomitant use of chemotherapy and radiotherapy is limited by increased toxicity on normal tissues, more particularly on the esophagus. Randomized comparisons of these modalities versus induction chemotherapy followed by radiotherapy are needed to determine the optimal treatment sequence.

Skin testing with recombinant allergens rBet v 1 and birch profilin, rBet v 2: diagnostic value for birch pollen and associated allergies.

OBJECTIVE: This study assesses the value of two recombinant birch allergens for diagnosis of patients sensitized to birch pollen with or without associated food allergy. METHODS: Fifty-one patients with positive skin test responses to Betulaceae and seven nonallergic control subjects were investigated; specific IgE antibodies were evaluated by specific immunoassay and blot immunodetection. RESULTS: Among 51 patients, 47 reacted to rBet v 1 and 10 to rBet v 2. Seven patients reacted to both recombinant allergens. In skin prick tests we found a correlation between the wheal produced by the commercial birch extract and the wheal produced by rBet v 1. Among 47 patients with positive test responses to rBet v 1, 83% had IgE binding to the Bet v 1 protein as determined by immunoblotting. Among 10 patients sensitized to rBet v 2, six had IgE binding to Bet v 2. Eleven patients with negative results, as determined by immunoblotting, had low levels of birch IgE in the sera (less than 10 kU/L) and low concentrations of IgE to rBet v 1 or rBet v 2 in ELISA. The nonallergic control subjects (n = 7) did not react to rBet v 1 or rBet v 2 in skin prick tests, nor did they have detectable amounts of specific IgE to rBet v 1 or rBet v 2. Histamine release tests confirmed sensitization to Bet v 1 in two patients with discordant results; for Bet v 2, one patient had positive results only at a high concentration, and one had results that remained negative. Thirty-four patients had birch pollinosis, and all reacted to rBet v 1. Patients who were monosensitized to birch never reacted to rBet v 2. Sensitization to rBet v 2 was only found in patients who reacted to other pollens (mainly grass). Twenty-nine patients demonstrated allergy to apples, cherries, or hazelnuts; and all reacted to rBet v 1. Among 11 patients with allergy to Umbelliferae, only three reacted to rBet v 2. CONCLUSIONS: Use of the two recombinant allergens (rBet v 1 and rBet v 2) always permits the diagnosis of birch sensitization. Sensitization to rBet v 1 is specific for birch and Rosaceae allergies, whereas sensitization to birch profilin, Bet v 2, is encountered in multisensitized subjects and is not always related to Umbelliferae allergy.