Cluster analysis of sputum cytokine-high profiles reveals diversity in T(h)2-high asthma patients.

BACKGROUND: Asthma is characterized by a heterogeneous inflammatory profile and can be subdivided into T(h)2-high and T(h)2-low airway inflammation. Profiling of a broader panel of airway cytokines in large unselected patient cohorts is lacking. METHODS: Patients (n = 205) were defined as being "cytokine-low/high" if sputum mRNA expression of a particular cytokine was outside the respective 10th/90th percentile range of the control group (n = 80). Unsupervised hierarchical clustering was used to determine clusters based on sputum cytokine profiles. RESULTS: Half of patients (n = 108; 52.6%) had a classical T(h)2-high ("IL-4-, IL-5- and/or IL-13-high") sputum cytokine profile. Unsupervised cluster analysis revealed 5 clusters. Patients with an "IL-4- and/or IL-13-high" pattern surprisingly did not cluster but were equally distributed among the 5 clusters. Patients with an "IL-5-, IL-17A-/F- and IL-25- high" profile were restricted to cluster 1 (n = 24) with increased sputum eosinophil as well as neutrophil counts and poor lung function parameters at baseline and 2 years later. Four other clusters were identified: "IL-5-high or IL-10-high" (n = 16), "IL-6-high" (n = 8), "IL-22-high" (n = 25). Cluster 5 (n = 132) consists of patients without "cytokine-high" pattern or patients with only high IL-4 and/or IL-13. CONCLUSION: We identified 5 unique asthma molecular phenotypes by biological clustering. Type 2 cytokines cluster with non-type 2 cytokines in 4 out of 5 clusters. Unsupervised analysis thus not supports a priori type 2 versus non-type 2 molecular phenotypes. www.clinicaltrials.gov NCT01224938. Registered 18 October 2010.

Real-life effectiveness of extrafine beclometasone dipropionate/formoterol in adults with persistent asthma according to smoking status.

BACKGROUND: The efficacy and safety of extrafine beclomethasone dipropionate 100 µg/formoterol 6 µg (BDP/F HFA) pressurized metered dose inhaler (pMDI) in patients with moderate-to-severe persistent asthma, has been demonstrated in randomised controlled trials (RCTs). The aim of this prospective observational study was to assess real-life effectiveness in terms of asthma control in smoking (most of the time excluded from RCTs) and non-smoking asthmatics. METHODS: Adult patients with persistent asthma, in whom treatment with an inhaled corticosteroid/long-acting ß(2)-agonist (ICS/LABA) combination is indicated, were included. Pulmonary function (FEV1%pred or PEF absolute value), Asthma Control Questionnaire (ACQ) and asthma control according to GINA criteria were measured at baseline as well as 2-8 months and >8-14 months after treatment initiation with BDP/F HFA. RESULTS: Overall, 619 patients were enrolled by 97 investigators. In the effectiveness cohort (N = 568), at baseline, smoking asthmatics (N = 123) had higher ACQ6 (p < 0.0001) and lower asthma control (p = 0.021) than non-smoking asthmatics. Treatment with BDP/F HFA pMDI was associated with significant (p < 0.0001) improvements in pulmonary function (+7.1% in FEV1% pred), ACQ6 (-1.32) and GINA asthma control (improvement of control in 49.8% of patients). Importantly, the same treatment benefits were observed in former or current smokers compared with non-smoking asthmatics. There was a reduction in the dose of ICS from 489 ± 192 µg BDP extrafine equivalents at baseline to 265 ± 125 µg after one year. The drug was well-tolerated. CONCLUSION: This prospective cohort study demonstrates the real-life effectiveness and safety of BDP/F HFA in adult asthma patients, including smokers, in normal clinical practice.

Efficacy of add-on montelukast in patients with non-controlled asthma: a Belgian open-label study.

OBJECTIVE: To evaluate the efficacy of add-on montelukast on asthma control and allergic rhinitis symptoms in asthmatic patients still symptomatic with chronic treatment with inhaled corticosteroid and long-acting beta(2) agonist (ICS/LABA), irrespective of the dose. RESEARCH DESIGN AND METHODS: This 2-month, open-label, real-life, multicentre, observational study was undertaken by 499 general practitioners in Belgium. Patients (>or= 4 years old) with uncontrolled asthma despite fluticasone/salmeterol or budesonide/formoterol therapy had oral montelukast 4, 5, or 10 mg daily added to their therapy, depending on the registered dose for their age. Asthma control, assessed by the 6-item Juniper Asthma Control Questionnaire (ACQ) was recorded at baseline and after 2 months of treatment with montelukast and the patients' global evaluation of asthma was also recorded at the end of the study. Concomitant allergic rhinitis symptoms were evaluated according to the patients' perception. RESULTS: A total of 5769 patients were eligible for analysis. Addition of montelukast was associated with significant decrease in mean (SD) ACQ score (from 1.97 [0.77] at baseline to 1.05 [0.69] after add-on treatment, p < 0.001). There was also a significant improvement in all individual symptoms of the ACQ score (p < 0.001). After 2 months, 89% of the patients reported global improvement of their asthma, with a good correlation between patients' global evaluation and change in ACQ scores. Of the 2442 patients who reported allergic rhinitis symptoms at baseline, 91% showed a global improvement of their asthma symptoms and 82% in their rhinitis symptoms after adding montelukast. CONCLUSION: This open-label observational study showed an improvement, after 2 months of add-on therapy with montelukast, in both asthma and allergic rhinitis symptoms in patients not adequately controlled on a fixed association of ICS/LABA.

Revised guidelines for the diagnosis and control of tuberculosis: impact on management in the elderly.

Despite major progress in the development of new strategies for diagnosing and treating tuberculosis, the disease still remains a major challenge for healthcare workers throughout the world. A number of causes are responsible for this threat but, unfortunately, many of these cannot be resolved easily because of cultural and social factors. Furthermore, not all countries throughout the world have enough financial resources to support educational and therapeutic programmes. The major challenges with tuberculosis are 2-fold: (i) to deal with the growing epidemic around the world (and especially in 'low-income' [developing] countries), and; (ii) to ensure correct use of antituberculosis medications in order to protect these drugs for future use. In 'high-income' countries, a major decline in the incidence of tuberculosis has been observed. Nevertheless, tuberculosis remains an important challenge in some risk groups, particularly the elderly patient, in these countries. The clinical and radiological presentations are often nonspecific, leading to delayed diagnosis and appropriate treatment, which often results in a large proportion of cases being discovered at autopsy only. Considering tuberculosis in the differential diagnosis remains the cornerstone of a fast and accurate diagnosis of this condition. Management of active tuberculosis in the elderly does not differ fundamentally from that in younger patients with respect to outcomes or adverse effects of treatment. However, empirical treatment perhaps may be considered more readily in the elderly patient. Elderly persons infected with tuberculosis at the beginning of the 20th century constitute a large reservoir of latent tuberculosis infection. Furthermore, these individuals are at increased risk of reactivation of this remote infection as their immunological status declines with aging. Compared with the past, modern guidelines are less reluctant to recommend use of tuberculin skin testing, treatment of latent tuberculosis infection in elderly persons, and prevention of transmission of tuberculosis in nursing homes.

The value of tuberculin skin testing in haemodialysis patients.

BACKGROUND: Chronic haemodialysis patients are at increased risk for developing tuberculosis (TB). Appropriate screening methods to detect latent Mycobacterium tuberculosis infection are required. The aim of this prospective multi-centre study was to evaluate the tuberculin skin test (TST) as a screening method for detection of M.tuberculosis infection in haemodialysis patients. METHODS: A total of 224 patients in two haemodialysis centres were prospectively tested, using 2 units of tuberculin PPD RT23. Up to three booster injections were given with a 7 day interval to patients not responding to the previous test. The results were compared with clinical and radiological data. RESULTS: The cumulative prevalence of a positive TST was 14.7% for the first test, 27.8% for the second test and 32.6% for the fourth test. There was no influence of age, gender, haemodialysis centre, dialysis efficiency, nutritional state, levels of zinc, vitamin D therapy, primary renal disease, (previous or active) immunosuppressive therapy or response to hepatitis B vaccination. There was a significant, but weak, correlation between TST positivity and a history of positive TST or TB. Chest radiography and positive TST were not correlated, yet a positive chest X-ray increased the detection of patients with latent M.tuberculosis infection up to 47.8%. CONCLUSIONS: In haemodialysis patients, a positive response of >30% to repeated TST was obtained. Two consecutive TSTs were sufficient to recruit most of the booster reactions. Since only a weak correlation was found with anamnestic data, regular TST evaluation in combination with a chest X-ray, is a useful tool to detect infection with M.tuberculosis in haemodialysis patients.

Influence of cisplatin-use, age, performance status and duration of chemotherapy on symptom control in advanced non-small cell lung cancer: detailed symptom analysis of a randomised study comparing cisplatin-vindesine to gemcitabine.

BACKGROUND: We previously reported that treatment of patients with symptomatic advanced non-small cell lung cancer with single agent Gemcitabine (GEM) resulted in a superior clinical-benefit response rate (RR) compared to cisplatin-based combination chemotherapy. We now report the detailed individual symptom control analysis, and the influence of cisplatin-use, age, performance status (PS) and duration of treatment. PATIENTS AND METHODS: Patients received either GEM (1000 mg/m(2), days 1, 8 and 15) or cisplatin (100 mg/m(2), day 1) plus Vindesine (3 mg/m(2), days 1 and 15) (PV), both every 4 weeks. Scores of 9 symptoms were listed weekly by the patient on visual analogue scales. Improvement of a symptom was defined as 2 consecutive cycles of improvement over baseline. RESULTS: Baseline symptoms in the 169 patients were well balanced between the 2 arms (84 GEM, 85 PV). Both patients with objective response and disease stabilisation had clearly better symptom control than those with disease progression. Symptom control in both arms was similar for 'disease-specific' symptoms such as cough, dyspnea, pain or haemoptysis. Compared to PV, a significantly larger number of GEM-patients had better scores for 'constitutional' items such as anorexia (P=0.007), ability to carry on with daily activities (P=0.04) and overall impression of quality-of-life (P=0.008). Symptom control was very similar in younger (<65 years) versus older (>/=65 years) patients, and only slightly better in those with a Karnofsky PS >/=80% compared to those <80%. Most of the symptom improvement occurred in the first 3 cycles, with some further symptom improvement in the following cycles in the GEM-arm only. CONCLUSIONS: Both GEM and PV yield a symptom control rate much higher than expected by the objective tumour RR. GEM is equally effective in controlling 'disease-specific' symptoms, but superior in controlling 'constitutional' symptoms. Most of the symptom control was achieved during the first 3 cycles of treatment, with some further improvement thereafter in the GEM-arm only.

Dose-intensified accelerated vindesine-ifosfamide-cisplatin (VIP) chemotherapy followed by high-dose accelerated hyperfractionated radiotherapy in patients with pathologically proven stage IIIB non-small cell lung cancer: a feasibility study.

This study shows the feasibility of accelerated vindesine-ifosfamide-cisplatin chemotherapy, immediately followed by intensive radiotherapy to the residual tumour in responding patients, in 16 patients with pathologically proven stage IIIB non-small lung cancer. All toxicities were reversible, with only two of ten patients experiencing grade 3 oesophagitis, no treatment-related deaths and no serious late effects.

Impact of montelukast on symptoms in mild-to-moderate persistent asthma and exercise-induced asthma: results of the ASTHMA survey. Adding Singulair Treatment to Handle symptoms in Mild to moderate Asthmatics.

A nation-wide survey was undertaken in Belgium among general practitioners (GPs) to evaluate the impact of the leukotriene receptor antagonist (LTRA) montelukast on the control of asthma symptoms, after at least 4 weeks of treatment. Patients from 6 years of age were eligible if they were suffering from mild-to-moderate persistent asthma which was still symptomatic despite inhaled corticosteroids (ICS) treatment, or from exercise-induced asthma. Patient general satisfaction was evaluated by recording the willingness to continue the treatment. A total of 1360 GPs took part in the study and more than 11000 patients were included in the survey. Of the included patients, 85% were receiving inhaled corticosteroids, 60% of whom were also on long-acting beta2-agonists (LABA). However, despite the use of daily controller medication, 92% of the patients still reported limitation of activities, 49% difficulties with sleep and 45% early morning awakening due to asthma. Moreover, 78% of the patients used rescue medication more than twice a week. At the end of the survey, 90% of the patients expressed their willingness to continue montelukast therapy. Of the patients having symptoms at the start of the study, 87% reported amelioration in sleep while on montelukast therapy, 80% less frequent early morning awakening, 85% better ability to perform daily activities and 77% decreased need for rescue medication.