Relevance of TH2 Markers in the Assessment and Therapeutic Management of Severe Allergic Asthma: A Real-Life Perspective.

BACKGROUND: Although blood eosinophils are currently recognized as the main clinical marker of TH2-type inflammation, their relevance in identifying asthma severity remains a matter of debate. METHODS: Our retrospective real-life study on severe asthmatics included in the NEONet Italian database aimed to investigate the relevance of blood eosinophil count and fractional exhaled nitric oxide (FeNO) in the clinical assessment of severe asthma and their role as potential predictors of responsiveness to anti-IgE therapy. The cut-off values chosen were 300 eosinophils/mm3 and FeNO of 30 ppm. RESULTS: We evaluated 132 adult patients. No significant differences were observed between the groups (high and low baseline eosinophil counts) in terms of demographic data, total IgE, lung function, patient-reported outcomes, or nasal comorbidities. The Asthma Control Test score and Asthma Quality of Life Questionnaire scores were poorer in patients with FeNO ≥30 ppb than in patients with FeNO <30 ppb. In the high FeNO subgroup, more frequent hospital admissions and a higher number of working days lost in the previous year were registered. A combined score including both eosinophils and FeNO did not improve the accuracy of the individual parameters. In the high-eosinophil subgroup, the proportion of responders to omalizumab was greater and increased at each follow-up time point. CONCLUSIONS: Our findings show that blood eosinophil count is not an unequivocal marker of asthma severity, whereas a higher FeNO level is associated with more frequent hospital admissions and more working days lost. Blood eosinophils seem to act as a predictor of response to omalizumab.

Relevance of TH2 markers in the assessment and therapeutic management of severe allergic asthma: a real-life perspective

BACKGROUND: Although blood eosinophils are currently recognized as the main clinical marker of TH2-type inflammation, their relevance in identifying asthma severity remains a matter of debate. METHODS: Our retrospective real-life study on severe asthmatics included in the NEONet Italian database aimed to investigate the relevance of blood eosinophil count and fractional exhaled nitric oxide (FeNO) in the clinical assessment of severe asthma and their role as potential predictors of responsiveness to anti-IgE therapy. The cut-off values chosen were 300 eosinophils/mm3 and FeNO of 30 ppm. RESULTS: We evaluated 132 adult patients. No significant differences were observed between the groups (high and low baseline eosinophil counts) in terms of demographic data, total IgE, lung function, patient-reported outcomes, or nasal comorbidities. The Asthma Control Test score and Asthma Quality of Life Questionnaire scores were poorer in patients with FeNO ≥30 ppb than in patients with FeNO <30 ppb. In the high FeNO subgroup, more frequent hospital admissions and a higher number of working days lost in the previous year were registered. A combined score including both eosinophils and FeNO did not improve the accuracy of the individual parameters. In the high-eosinophil subgroup, the proportion of responders to omalizumab was greater and increased at each follow-up time point. CONCLUSIONS: Our findings show that blood eosinophil count is not an unequivocal marker of asthma severity, whereas a higher FeNO level is associated with more frequent hospital admissions and more working days lost. Blood eosinophils seem to act as a predictor of response to omalizumab

ANTECEDENTES: Aunque los eosinófilos en la sangre actualmente son reconocidos como el principal marcador clínico de la inflamación Th2, su relevancia en la identificación de la gravedad del asma sigue siendo un tema de debate. MÉTODOS: Nuestro estudio retrospectivo de la vida real sobre asmáticos graves, incluido en la base de datos italiana de NEONet, tuvo como objetivo investigar la relevancia del recuento de eosinófilos en sangre y el FeNO en la evaluación clínica del asma grave y su función como posible factor predictivo de la capacidad de respuesta al tratamiento con anti-IgE. Como valores de corte se eligieron 300 eosinófilos/mm3en sangre y 30 ppm para FeNO. RESULTADOS: En total se evaluaron 132 pacientes adultos. No se pudieron observar diferencias significativas entre los grupos de eosinófilos basales altos y bajos, en términos de datos demográficos, IgE total, función pulmonar, resultados informados por el paciente (PRO) o comorbilidades nasales. Los pacientes con ≥ FeNO 30 ppb mostraron una puntuación de ACT peor y una puntuación AQLQ más baja en comparación con los de FeNO <30 ppb. En el subgrupo de FeNO alto, se registraron ingresos hospitalarios con más frecuencia y un mayor número de días de trabajo perdidos en el último año. Una puntuación combinada que incluye tanto a los eosinófilos como el FeNO no mejoró la precisión de los parámetros individuales. En el subgrupo de eosinófilos altos, la proporción de pacientes que respondieron al tratamiento con omalizumab fue mayor y aumentó significativamente en cada punto de tiempo de seguimiento. CONCLUSIONES: De acuerdo con nuestros hallazgos, los eosinófilos en sangre no representan un marcador unívoco de la gravedad del asma, mientras que un nivel más alto de FeNO se asocia con más ingresos hospitalarios y más días de trabajo perdidos. Los eosinófilos de la sangre parecen actuar como predictores de la respuesta del tratamiento al omalizumab

Drop-out rate among patients treated with omalizumab for severe asthma: Literature review and real-life experience.

BACKGROUND: In patients with asthma, particularly severe asthma, poor adherence to inhaled drugs negatively affects the achievement of disease control. A better adherence rate is expected in the case of injected drugs, such as omalizumab, as they are administered only in a hospital setting. However, adherence to omalizumab has never been systematically investigated. The aim of this study was to review the omalizumab drop-out rate in randomized controlled trials (RCTs) and real-life studies. A comparative analysis was performed between published data and the Italian North East Omalizumab Network (NEONet) database. RESULTS: In RCTs the drop-out rate ranged from 7.1 to 19.4 %. Although the reasons for withdrawal were only occasionally reported, patient decision and adverse events were the most frequently reported causes. In real-life studies the drop-out rate ranged from 0 to 45.5 %. In most cases lack of efficacy was responsible for treatment discontinuation. According to NEONet data, 32 % of treated patients dropped out, with an increasing number of drop outs observed over time. Patient decision and lack of efficacy accounted for most treatment withdrawals. CONCLUSIONS: Treatment adherence is particularly crucial in patients with severe asthma considering the clinical impact of the disease and the cost of non-adherence. The risk of treatment discontinuation has to be carefully considered both in the experimental and real-life settings. Increased knowledge regarding the main reasons for patient withdrawal is important to improve adherence in clinical practice.

Long term results of surgery and chemotherapy in small cell lung cancer.

OBJECTIVE: The aim of the study is to analyse long-term results of patients with small cell lung cancer (SCLC) treated at the same institution according to a prospective study including surgery, chemotherapy, and radiotherapy. METHODS: From 1981 to 1995, 104 patients with a proven histology of SCLC underwent surgery, chemotherapy, and radiotherapy. Fifty-one patients with operable stage I or II lesion received surgical resection followed by adjuvant chemotherapy and radiotherapy. Fifty-three patients with proved SCLC and clinical stage III received induction chemotherapy followed by surgery and radiotherapy. All patients received from four to six courses of chemotherapy and 36 had prophylactic cranial irradiation (PCI). All patients had follow-up for at least 1 year, and survival time was calculated from the date of the diagnosis until death or most recent follow-up. RESULTS: Ninety-six patients were male and eight female. We performed 29 pneumonectomies, eight bilobectomies, 66 lobectomies and one no resection. Regarding the clinical stage, 35 patients (33.6%) had stage I, 16 patients (15.4%) had stage II and 53 (51%) had stage III. Post-operative pathologic staging revealed stage I in 37 patients (35.6%), stage II in nine patients (8.6%), stage III in 45 patients (43.3%), and in 13 patients (12.5%) there was no more tumor. The 30-day mortality was 2% (two patients). Fourteen patients (13.4%) had post-operative complications. Fifty-one patients (49%) had a relapse. The median follow-up was 55 months. Twenty-six patients remain alive and 78 patients have died. The overall 5-year survival rate was 32%, with an estimate median survival time of 28 months; according to the pathologic stage, the survival data were 52.2%, 30% and 15.3% for stage I, II and III, respectively (P < 0.001). The 5-year survival was 41% in patients without SCLC after chemotherapy. CONCLUSION: As with non-small cell lung cancer, survival following surgery and chemotherapy clearly correlates with the stage. At present, it is not clear whether surgery is truly effective for patients with SCLC. In our experience, the complete elimination of small cell lung cancer is associated with an improvement in survival (41% at 5 years).

Mitomycin C, vinblastine, and carboplatin regimen in patients with nonsmall cell lung cancer. A phase II trial.

BACKGROUND: The mitomycin C, vinblastine, and cisplatin (MVP) combination is one of the most frequently used in the palliative setting, but it produces considerable toxicity. Carboplatin and cisplatin have different patterns of toxicity. The goal of this study was to evaluate a combination similar to MVP, using carboplatin instead of cisplatin to render it more feasible in an outpatient setting. METHODS: Inclusion criteria for this study included: inoperable patients or patients relapsing after previous surgery, with nonsmall cell lung carcinoma (NSCLC), a performance status (PS) > 50%, and no previous chemotherapy. The chemotherapy regimen included carboplatin, 300 mg/m2 on Day 1; mitomycin, 8 mg/m2 on Day 1; and vinblastine, 4 mg/m2 on Days 1, 8, and 15 (on Day 15 vinblastine was delivered only in the first cycle) (MVC) every 3 weeks for at least 3 cycles. RESULTS: From August 1991 until August 1994, 70 patients entered the trial. All were evaluable for toxicity and response. The median age was 62 years (range, 40-73 years). The male/female ratio was 60:10 (86%:14%); the ratio of Stage III to Stage IV disease was 26:44 (37%:63%); and the ratio of PS > 70 to < or = 70 was 49:21. A total of 296 cycles (median, 4 [range, 1-6 cycles] per patient) were delivered, 280 of 296 (95%) in an outpatient setting with only 4 patients requiring hospitalization for treatment delivery. Overall response rate (RR) was 38.6% (95% confidence interval [CI], 27-51%) (1 complete response, 1.5%; 26 partial responses, 37.1%). Median duration of response was 9.8 months (range, 2-27 months). In Stage III patients the RR was 42% and in Stage IV patients it was 34%. Overall median survival was 9.5 months (95% CI, 6.8-15.3 months). Survival at 1 year was 39% (standard error [SE] 3.6%) and was 11% at 2 years (SE 3.6%). In Stage III patients median survival was 13 months and the 1-year survival rate was 54% (SE 10%); Stage IV patients had a median survival of 7.4 months and a 1-year survival rate of 28% (SE 7%). Delivered dose intensity was: carboplatin, 71%; vinblastine, 60%; and mitomycin C, 77% of the planned dose intensity. The back calculation of carboplatin area under the curve (AUC) with Calvert's formula and with the Cockcroft-Gault glomerular filtration rate estimation, showed a median AUC value of 4 (range, 2-8). Using the more precise Chatelut formula, AUC was again 4 (range, 2-7). Hematologic toxicity was the major side effect; Grades 3 and 4 leukopenia were observed in 34% and 6% of patients, respectively, and Grades 3 and 4 thrombocytopenia in 25% and 4% of patients, respectively. Grade 2 infection occurred in 10% of patients, with only 1 case of sepsis; severe constipation and Grade 2 alopecia occurred in only 1 patient; and no case of higher than Grade 1 nephrotoxicity was observed. No pulmonary toxicity was observed. Compliance with treatment was good with only one patient refusal after the first cycle. CONCLUSIONS: Chemotherapy for advanced NSCLS is still controversial, because effectiveness in terms of RR and symptom control must be weighed against treatment toxicity and costs. From our study it appears that MVC is easy to deliver in an outpatient setting, and has good patient compliance, low toxicity profile, and promising RR and response duration. The substitution of carboplatin for cisplatin in regimens for advanced NSCLC should be considered.

Pleural effusion in sarcoidosis: a case report.

Pleural effusion is a well-recognized clinical entity that can be associated with sarcoidosis. Nevertheless, the real prevalence of this phenomenon remains to be established. This study describes the case of a 57-year-old male sarcoid patient who presented with right exudative pleural effusion, dyspnea on exertion, and bilateral pulmonary interstitial infiltrates. Sarcoidosis was diagnosed more than 2 years prior to the onset of pleural involvement. Pleural biopsy revealed the presence of typical sarcoid non caseating granulomas. Sarcoid involvement of the pleura resolved following a 1-month course of high doses of steroids and did not recur during a 18-month follow up. When we retrospectively analyzed clinical data obtained from 624 consecutive sarcoid patients who were referred to our hospital between January 1980 and June 1993 and examined for the presence of pleural involvement, the only patient who showed pleural effusion and histologically proven sarcoidosis of the pleura was the case here described. The frequency of the phenomenon in our series is 0.16%. We conclude that pleural effusion represents a rare event in sarcoidosis.

CD8 alveolitis in sarcoidosis: incidence, phenotypic characteristics, and clinical features.

PURPOSE: Although the accumulation of CD4 cells in the lung and other involved tissues is regarded as the distinctive immunologic feature of sarcoidosis, a few sarcoid patients can present with CD8 alveolitis. This study evaluates the incidence as well as the clinical and immunologic features of sarcoidosis presenting with CD8 alveolitis. PATIENTS AND METHODS: A total of 2,214 consecutive bronchoalveolar lavage (BAL) specimens obtained from 481 patients with sarcoidosis between January 1985 and December 1991 were retrospectively analyzed. Subjects who entered the study had the following characteristics: (1) lymphocyte alveolitis and (2) lung CD4/CD8 ratio less than 1.0. Only data obtained from patients with a first episode of pulmonary involvement were included in the analysis (394 patients). RESULTS: Fifteen of the 394 patients studied at the time of diagnosis showed CD8 alveolitis as the presenting manifestation; the incidence of this phenomenon was 3.8%. A follow-up study of BAL T-cell subsets demonstrated that patients who showed high-intensity CD8 alveolitis at the onset of the disease maintained the CD8 pattern of alveolitis during relapses. Phenotypic analysis of lung T cells revealed that the accumulation of CD8 lymphocytes was due to the discrete local increase of CD45RO+ "memory" cells equipped with a number of accessory structures, including adhesion molecules and class II major histocompatibility complex-related HLA-DR antigen. CONCLUSIONS: The accumulation of CD8 cells in the sarcoid lung is likely to reflect a homing of memory cells due to the ongoing immunologic response against the unknown antigen causing the disease. Although CD8 alveolitis can be considered a relatively rare event in sarcoidosis, the possibility that an increase of CD8 cells in the BAL fluid might be sustained by an underlying sarcoid inflammatory process should never be dismissed on clinical grounds in patients with interstitial lung disease.

[Methacholine test in the study of non-specific bronchial reactivity in a group of patients allergic to pollen]. / Il test alla metacolina nello studio della reattività bronchiale aspecifica in un gruppo di pollinosici.

We have studied thirty subjects sensitive to pollens suffering from seasonal rhinitis and/or mild seasonal asthma. The patients were submitted to a preseasonal and to a seasonal evaluation of their bronchial reactivity by means of a metacholine provocation test in order to measure possible variations of their responsiveness. Our data shown that the metacholine provocation test is not substantially influenced by seasonal pollen stimulation; it is likely that in patients sensitive to pollens, aspecific bronchial reactivity is intermittent, so explaining the inconstant behaviour of responsiveness observed in our allergic patients.

Cisplatin, etoposide, and ifosfamide in non-small cell lung carcinoma. A phase II randomized study with cisplatin and etoposide as the control arm.

A Phase II randomized study testing the combination of cisplatin, etoposide, and ifosfamide (PEI) in non-small cell lung cancer (NSCLC) was performed. The standard combination of cisplatin and etoposide (PE) was used as the control arm. Since January 1987, 78 patients were enrolled and then stratified for previous treatments and performance status (PS). The response rate (RR) of PEI was 26% (95% confidence limits [95 CL], 12% to 40%), with one complete response (CR). The RR of PE was 26% (95 CL, 13% to 39%), with no CR. The median response duration was 5 months (range, 2 to 13 months) for PEI and 4 months (range, 2 to 6 months) for PE. The median survival time was 6 months (range, 1 to 22+ months) for PEI and 7 months (range, 1 to 21+ months) for PE. Leukopenia at recycling was similar in both arms (25% for PEI and 29% of PE). The median leukocyte nadir was 2100/microliters (range, 430 to 4870/microliters) for PEI patients and 3150/microliters (range, 500 to 5000/microliters) for PE patients. Three patients had a drug-related death secondary to infections. This Phase II randomized study suggested that the combination of cisplatin plus etoposide and ifosfamide produces results similar to those obtainable with cisplatin and etoposide.

Pulmonary alveolar macrophages from patients with active sarcoidosis express type IV collagenolytic proteinase. An enzymatic mechanism for influx of mononuclear phagocytes at sites of disease activity.

Alveolar macrophages (AMs) recovered from the bronchoalveolar lavage (BAL) of 44 patients with sarcoidosis were evaluated for their ability to release type IV collagenolytic metalloproteinase (IV-Case). This enzyme, which is produced by peripheral blood monocytes (PBMs) but not by tissue macrophages, degrades type IV collagen, the major structural component of vessel wall basement membranes, and helps to promote the migration of PBMs from the blood compartment to peripheral tissues. Our results demonstrated that AMs from patients with active sarcoidosis released significantly increased levels of IV-Case with respect to patients with inactive disease and control subjects. After in vitro culture, sarcoid AMs secreted IV-Case during the first 24 h of collection; after that time, AMs progressively lost their ability to release IV-Case. Exposition of both sarcoid and normal AMs to recombinant IL 2 or gamma IFN did not influence their property to release IV-Case. The immunoblot analysis of IV-Case demonstrated complete identity between IV-Case released by AMs and the degradative enzyme obtained from PBMs. The increased property to release IV-Case was significantly related to the increase of the absolute number of AMs and, in particular, of AMs bearing two determinants that are usually expressed by most PBMs (CD11b and CD14). Selective depletion of CD11b+/CD14+ AMs from the entire macrophagic population was associated with the recovery of the IV-Case activity to normal values. A positive correlation was also found between the increase in the absolute number of lung T cells and the enhanced CD4/CD8 pulmonary ratio. A 6-mo follow-up study indicated a significant association between the positivity for the 67Gallium scan and the increased property of AMs to release IV-Case. Our data are consistent with the hypothesis that a IV-Case mediated influx of peripheral monocytes takes place in the lung of sarcoid patients. Furthermore, the correlation found between the IV-Case release and disease activity suggests that this assay could represent a useful tool in sarcoidosis disease staging.