Human leukocyte antigen-G and regulatory T cells during specific immunotherapy for pollen allergy.

BACKGROUND: TH2-biased immune responses are important in allergy pathogenesis. Mechanisms of allergen-specific immunotherapy (SIT) might include the induction of regulatory T cells (Tregs) and immunoglobulin (Ig) G4 blocking antibodies, a reduction in the number of effector cells, and skewing of the cytokine profile towards a TH1-polarized immune response. We investigated the effects of SIT on T cells, on immunomodulation of human leukocyte antigen (HLA)-G, which has been associated with allergy, on regulatory cytokine expression, and on serum allergen-specific antibody subclasses (IgE and IgG4). METHODS: Eleven birch and/or grass pollen-allergic patients and 10 healthy nonatopic controls were studied before and during SIT. Tregs, chemokine receptors, soluble HLA-G (sHLA-G), Ig-like transcript (ILT) 2, specific IgE, and IgG4 were studied. Peripheral blood mononuclear cells (PBMCs) were stimulated with pollen extract in vitro and immune factors were evaluated. RESULTS: During SIT, the main changes in the peripheral blood were an increase in CXCR3(+)CD4(+)CD25(+)CD127(low/-) Tregs and a decrease in CCR4(+)CD4(+)CD25(+)CD127(low/-) Tregs, an increase in allergen-specific IgG4, and a decrease in sHLA-G during the first half of the treatment period. In the PBMC in vitro experiments, the following changes were observed upon allergen-stimulation: an increase in CD4(+)CD25(+)CD127(low/-) Tregs and ILT2(+)CD4(+)CD25(+)CD127(low/-) Tregs, an increase in IL-10 and IL-2 levels, and an increase in sHLA-G that was most pronounced at the start of SIT. CONCLUSIONS: The changes in CXCR3(+)CD4(+)CD25(+)CD127(low/-) Treg, IgG4, and sHLA-G levels in the peripheral blood and in ILT2(+) Treg, IL-10, IL-2, and sHLA-G levels upon in vitro allergen stimulation suggest an upregulation in immunomodulatory factors and, to some degree, a shift towards TH1 during SIT.

Budesonide/formoterol maintenance and reliever therapy versus conventional best standard treatment in asthma in an attempted 'real life' setting.

AIMS: The purpose of this study was to compare the efficacy of budesonide/formoterol maintenance and reliever therapy (Symbicort® SMART®, AstraZeneca AB, Södertälje, Sweden) with conventional best standard treatment (CBST) in patients with persistent asthma in an attempted 'real life' setting. METHODS: In total, 1835 patients from Denmark, Finland and Norway were randomized to 26 weeks treatment with budesonide/formoterol 160/4,5 µg twice daily plus budesonide/formoterol 160/4,5 µg for symptom relief or CBST according to the Global Initiative for Asthma guidelines. The study was randomized, open-label and designed to reflect 'real life' asthma management. Efficacy variables were time to first severe asthma exacerbation, rate of severe asthma exacerbations, asthma control (Asthma Control Questionnaire-5) and use of inhaled glucocorticosteroids (IGCS). RESULTS: Treatment with budesonide/formoterol maintenance and reliever therapy led to a 21% reduction in time to first severe asthma exacerbation compared with CBST, although not statistically significant (hazard ratio 0.794, P = 0.189). A trend towards a reduction in the rate of severe exacerbations in the budesonide/formoterol maintenance and reliever therapy group was observed (16 vs 22 events/100 patient years; P = 0.058). The percentage of patients with well-controlled asthma increased significantly among those treated with budesonide/formoterol maintenance and reliever therapy compared with CBST (45% vs 40%; odds ratio 1.39; P < 0.01), in spite of a significant 31% reduction in total mean daily IGCS dose (P < 0.0001). No difference in mean as-needed medication use was seen (P = 0.98). All treatments were well tolerated. CONCLUSION: Budesonide/formoterol maintenance and reliever therapy resulted in a better overall asthma control with a significant lower daily IGCS dose compared with CBST.

Budesonide/formoterol maintenance and reliever therapy versus conventional best practice.

Budesonide/formoterol maintenance and reliever therapy (Symbicort SMART) reduces asthma exacerbations and symptoms versus fixed-dose regimens plus short-acting beta(2)-agonists (SABA) in double-blind trials. Information is lacking regarding its effectiveness versus conventional best practice (CBP). This pooled analysis of six 6-month, randomized, open-label studies examined asthma control and exacerbation risk in asthmatics (aged> or =12 years). Patients (N=7855) symptomatic on inhaled corticosteroids (ICS) or stable/symptomatic on ICS/long-acting beta(2)-agonists (LABA) received budesonide/formoterol maintenance and reliever therapy (160/4.5microg bid and as needed) or CBP (ICS or ICS/LABA+/-other agents at an approved dose plus as-needed SABA). Overall asthma control was assessed comparing the incidence of exacerbations and levels of asthma control using the asthma control questionnaire (ACQ). Budesonide/formoterol maintenance and reliever therapy did not significantly reduce time to first severe exacerbation (primary variable) versus CBP (P=0.062). However, patients in this group experienced 15% fewer exacerbations (0.20 versus 0.24/patient/year; P=0.021) and used 27% less ICS (P<0.0001). Odds of remaining well controlled (ACQ< or =0.75) over 6 months were higher with budesonide/formoterol maintenance and reliever therapy versus CBP (45% versus 41%, odds ratio [OR] 1.29; P<0.01) while risk of remaining uncontrolled decreased (25% versus 29%, OR 0.81; P<0.01). Budesonide/formoterol maintenance and reliever therapy improves key aspects of asthma control versus physicians' choice of CBP.

Disease variability in asthma: how do the patients respond?--and why?

BACKGROUND AND AIM: Asthma is a variable disease, and therapy should be tailored accordingly. The aim of this study was to explore patterns of self-management in response to disease variability in adult asthmatics. METHODS: Adult asthmatics (n = 509), recruited through a web-based panel, answered a questionnaire concerning asthma knowledge, compliance, and treatment, including specified treatment options, through the Internet. RESULTS: Two-thirds of the patients on inhaled corticosteroids (ICS) stepped-up and down their daily dose without prior contact to their doctor, and more than 50% took less ICS than prescribed during periods with fewer symptoms. In case of deterioration, 57% of the patients would only increase their reliever medication, whereas 23% would also increase their controller medication, although 59% were instructed by their doctor to do so. The self-perceived severity of asthma (graded as mild, moderate or severe) was not associated with the patients' response pattern. The preferred treatment strategy, differing primarily with regard to dosing and timing of controller medication, was associated with feeling safe about self-adjustment of controller medication (p < 0.001), but not with self-reported knowledge of asthma (p > 0.5). CONCLUSION: In case of deterioration, the majority of adult asthmatics only increase their reliever medication, although instructed by their doctors also to increase their controller medication. Furthermore, the patients' preferred strategy for management of disease variability seems not to be driven by their knowledge of the disease.

[The quality of asthma treatment in Denmark. How far are we--and how far are our patients?]. / Kvaliteten af astmabehandling i Danmark. Hvor langt er vi--og hvor langt er patienterne?

INTRODUCTION: Despite the availability of safe and effective therapies for asthma, many patients have sub-optimal asthma control. AIM: To assess the current status with regard to the treatment and monitoring of adult asthmatics and to identify factors of importance for compliance with controller therapy. MATERIALS AND METHODS: Based on information from focus group interviews, we developed a questionnaire focusing on knowledge of asthma, compliance and therapy. The participants (n = 509) answered the questionnaire over the Internet. RESULTS: Approximately 70% of patients were treated with inhaled corticosteroids (ICS), whereas 25% were only treated with a short-acting beta2-agonist, 20% of whom had severe asthma. In the preceding year, 46% of patients had their lung function measured. Up to 25% of patients stated that they forgot or deliberately decided not to take their ICS at least twice a week. The most frequent reason for non-compliance was lack of asthma symptoms. Non-compliance was associated with disagreement with the statement that ICS is an essential part of asthma therapy (p<0.002). Self-assessed asthma severity was positively associated with regular scheduled doctor visits (p<0.001) and good compliance (p<0.001). CONCLUSION: The treatment and monitoring of asthma in Denmark is not in accordance with guidelines, e.g. with regard to patient education and the use of spirometry. Non-compliance with controller therapy is frequent, and the reasons seem to be accessible through education of both patients and doctors.

Treatment and evaluation of patients with acute exacerbation of asthma before and during a visit to the ER in Denmark.

BACKGROUND: Acute exacerbation of asthma may be life-threatening and quite often results in a visit to the emergency room (ER) or admission to a hospital. The aim was to evaluate the treatment and the quality of clinical management of asthma exacerbations, and finally, to identify the factors leading to admission. MATERIAL AND METHODS: In a retrospective design, we audited the hospital records of all patients aged 18-40 years admitted to five Danish university hospitals with an acute exacerbation of asthma in 2004. RESULTS: We found records covering 323 asthmatic patients (186 women). Before admission, the mean (standard deviation) duration of the exacerbation was 5.2 (7.5) days. Of those admitted, 14% did not use any medication, 39% used inhaled corticosteroids (ICS) either with a beta(2)-agonist or alone, systemic steroids, and 34% used a beta(2)-agonist alone. Lung function (peak flow or forced expiratory volume in first second) was measured in 60% on admission, in 58% on discharge and in 47% on both occasions (P < 0.01). Temperature, heart rate and oxygen saturation were measured in 231 of the patients (72%), but the respiratory frequency rate was measured in only 16% of the patients, with some differences between the five hospitals. On discharge, 50% were treated with systemic steroids, and a further 20% had ICS prescribed (P < 0.01, admission vs discharge). In 21% of the cases, inadequate treatment was identified as the most likely reason for their ER visit/admission to a hospital. CONCLUSIONS: The assessment and treatment of patients admitted with acute asthma exacerbation was often suboptimal. Under-treatment with the anti-asthmatic medication was the main reason for admission.

Management of asthma in adults: do the patients get what they need--and want?

Suboptimal asthma control may be caused by a combination of factors, such as nonadherence to guidelines, lack of compliance, and poor asthma education. The aim was to assess patients' knowledge of asthma and different management strategies, including patients' attitudes toward involvement in treatment decisions. The participants (n=509) were recruited from all parts of Denmark through a web-based panel (Zapera Danmarkspanel). A questionnaire concerning asthma knowledge, compliance, and treatment was fulfilled through the Internet. Among the participating adult asthmatic patients, signs of uncontrolled disease with night asthma (16%), daily symptoms (18%), or exercise-induced asthma (11%) were found. Of 285 participants with persistent asthma, 70% used inhaled corticosteroids. Lung function was measured within the preceding 6 months in 24% of patients, whereas 7% had never had their lung function measured and peak flow monitoring was reported by 5%. Written action plans were provided for 12% of patients and 50% had had their inhaler technique checked. Although 59% of patients were instructed to adjust their controller therapy if needed, only 23% reported that they had done so. In conclusion, this study of adult asthmatic patients revealed an important deficit in patient education, little use of lung function measurements, and poor compliance with guidelines for asthma management. Furthermore, asthmatic patients want more education, although they do not use it when provided by their doctor, indicating that change in educational strategy is needed.

The patient's perspective: adherence or non-adherence to asthma controller therapy?

STUDY OBJECTIVE: Adherence with controller therapy poses a major challenge to the effective management of persistent asthma. The aim of this study was to explore the patient-related aspects of adherence among adult asthmatics. DESIGN AND PARTICIPANTS: The participants (n = 509 adult asthmatics), recruited from all parts of Denmark, answered the questionnaire concerning asthma knowledge, attitudes, adherence, and treatment through the Internet. RESULTS: A total of 67% of the patients were prescribed inhaled corticosteroids (ICS). However, according to Global Initiative for Asthma (GINA)-guidelines' symptom severity classification, 85% should have been on ICS. Accidental and intentional non-adherence with ICS at least twice a week was reported by 27% and 24%, respectively. In case of deterioration, 60% of the patients preferred to take more reliever medication, instead of increasing the ICS dose. Having a fixed daily routine with regard to medication and following the advice given by their doctor were the main reasons for adherence, whereas lack of perceived symptoms was the main reason for non-adherence. Non-adherence was associated with increasing disagreement with the statements that controller therapy is effective (p < 0.04), as well as an essential part of asthma therapy (p < 0.002). CONCLUSIONS: Both accidental and intentional non-adherence with controller therapy is common among adult asthmatics. The reasons for suboptimal adherence seem to be accessible through education of both patients and caregivers.

A multicenter, randomized, double-blind, placebo-controlled, 6-month trial of bupropion hydrochloride sustained-release tablets as an aid to smoking cessation in hospital employees.

Despite changes in smoking behavior, one-third of the Danish population continues to smoke. Many of these smokers are hospital employees. This 6-month, multicenter, parallel group, randomized, double-blind, placebo-controlled study evaluated treatment with bupropion hydrochloride sustained release (Zyban) compared with placebo as an aid to smoking cessation in health care workers. A total of 336 hospital employees who smoked at least 10 cigarettes daily were randomized (2:1) to 7 weeks of treatment with bupropion (n=222) or placebo (n=114). All participants were motivated to quit smoking and received behavioral counseling. Continuous smoking abstinence during weeks 4-7 was the primary endpoint, and long-term smoking abstinence was among the secondary endpoints. Of the original participants, 212 completed the 6-month trial. Continuous smoking abstinence at week 7 was achieved by 43% in the bupropion group and 18% in the placebo group, p<.001. After 26 weeks, 18% and 7%, respectively, were continuously abstinent, p=.008. Side-effects were frequent but simple and reversible in both groups, and generally consistent with the findings of previous studies. Dizziness, insomnia, and pruritus appeared more frequently in the bupropion group than in the placebo group. Bupropion was effective as an aid to smoking cessation in a broad group of hospital employees in Denmark.