J. Christian Virchow

Dendritic cell subsets in human bronchoalveolar lavage fluid after segmental allergen challenge

Background: Dendritic cells control pulmonary immune reactions. Characteristics of dendritic cells in human bronchoalveolar lavage fluid (BALF) after allergen challenge are unknown. Methods: 7 patients with allergic asthma (median 23 years, range 19–25 years) underwent segmental challenge and were lavaged 10 min and 24 h after challenge. Dendritic cell subsets and surface markers in BALF and in peripheral blood were analysed using four-colour flow cytometry. Results: Plasmacytoid dendritic cells (pDCs, median 0.06%, range 0.01–0.08%) and myeloid dendritic cells (mDCs, median 0.47%, range 0.27–0.87%) were detectable in BALF from control segments. CD1a-positive dendritic cells in BALF were identified as a subpopulation of mDCs. Both pDCs (median 0.56%, range 0.09–1.83%) and mDCs (median 1.82%, range 0.95–2.29%) increased significantly in BALF 24 h (p = 0.018 compared with the control segments for pDCs and mDCs), but not 10 min, after allergen challenge. The percentage increase in pDCs was higher than that of mDCs after allergen challenge, as reflected by an enhanced pDC:mDC ratio after allergen challenge. In peripheral blood, there was a significant decrease in mDCs (p = 0.038) and a trend to a decrease in pDCs (p = 0.068) 24 h after allergen challenge. Analysis of dendritic cell surface molecules showed that after allergen challenge, BALF dendritic cells have a less mature phenotype compared with BALF dendritic cells from control segments. Conclusion: Using a comprehensive strategy to analyse dendritic cell subsets in human BALF, we have shown for the first time that both myeloid and plasmacytoid dendritic cells accumulate in the airway lumen after allergen challenge in patients with asthma.

Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults With Allergic Asthma: A Randomized Clinical Trial

IMPORTANCE The house dust mite (HDM) sublingual allergen immunotherapy (SLIT) tablet is a potential novel treatment option for HDM allergy-related asthma. OBJECTIVES To evaluate the efficacy and adverse events of the HDM SLIT tablet vs placebo for asthma exacerbations during an inhaled corticosteroid (ICS) reduction period. DESIGN, SETTINGS, AND PARTICIPANTS Double-blind, randomized, placebo-controlled trial conducted between August 2011 and April 2013 in 109 European trial sites. The trial included 834 adults with HDM allergy-related asthma not well controlled by ICS or combination products, and with HDM allergy-related rhinitis. Key exclusion criteria were FEV1 less than 70% of predicted value or hospitalization due to asthma within 3 months before randomization. Efficacy was assessed during the last 6 months of the trial when ICS was reduced by 50% for 3 months and then completely withdrawn for 3 months. INTERVENTIONS 1:1:1 randomization to once-daily treatment with placebo (n = 277) or HDM SLIT tablet (dosage groups: 6 SQ-HDM [n = 275] or 12 SQ-HDM [n = 282]) in addition to ICS and the short-acting β2-agonist salbutamol. MAIN OUTCOMES AND MEASURES Primary outcome was time to first moderate or severe asthma exacerbation during the ICS reduction period. Secondary outcomes were deterioration in asthma symptoms, change in allergen-specific immunoglobulin G4 (IgG4), change in asthma control or asthma quality-of-life questionnaires, and adverse events. RESULTS Among 834 randomized patients (mean age, 33 years [range, 17-83]; women, 48%), 693 completed the study. The 6 SQ-HDM and 12 SQ-HDM doses both significantly reduced the risk of a moderate or severe asthma exacerbation compared with placebo (hazard ratio [HR]: 0.72 [95% CI, 0.52-0.99] for the 6 SQ-HDM group, P = .045, and 0.69 [95% CI, 0.50-0.96] for the 12 SQ-HDM group, P = .03). The absolute risk differences based on the observed data (full analysis set) in the active groups vs the placebo group were 0.09 (95% CI, 0.01-0.15) for the 6 SQ-HDM group and 0.10 (95% CI, 0.02-0.16) for the 12 SQ-HDM group. There was no significant difference between the 2 active groups. Compared with placebo, there was a reduced risk of an exacerbation with deterioration in asthma symptoms (HR, 0.72 [95% CI, 0.49-1.02] for the 6 SQ-HDM group, P = .11, and 0.64 [95% CI, 0.42-0.96] for the 12 SQ-HDM group, P = .03) and a significant increase in allergen-specific IgG4. However, there was no significant difference for change in asthma control questionnaire or asthma quality-of-life questionnaire for either dose. There were no reports of severe systemic allergic reactions. The most frequent adverse events were mild to moderate oral pruritus (13% for the 6 SQ-HDM group, 20% for the 12 SQ-HDM group, and 3% for the placebo group), mouth edema, and throat irritation. CONCLUSIONS AND RELEVANCE Among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate or severe asthma exacerbation during ICS reduction, with an estimated absolute reduction at 6 months of 9 to 10 percentage points; the reduction was primarily due to an effect on moderate exacerbations. Treatment-related adverse events were common at both active doses. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION clinicaltrialsregister.eu Identifier: 2010-018621-19.

Choosing inhaler devices for people with asthma: Current knowledge and outstanding research needs

Recommendations in asthma guidelines presuppose that practitioners have the evidence, information, knowledge, and tools to select inhaler devices appropriate for individual patients. Randomised controlled trials usually exclude patients with suboptimal inhaler technique. There is therefore little evidence on which to base inhaler selection in the real world, where patients often use their inhalers incorrectly. The lung deposition of inhaled drug varies according to inhaler device, drug particle size, inhalation technique, and pattern of inspiratory flow. Even with training, not all patients can use their inhalers correctly and maintain inhaler technique; patients may have inability to handle the inhaler, strong negative preferences, or natural breathing patterns that do not match their prescribed inhaler. Therefore, matching device to the patient may be a better course of action than increasing therapy or training and retraining a patient to use a specific inhaler device. Several research questions require answers to meet the goal of helping prescribers make a more informed choice of inhaler type. Is the level of drug deposition in the lungs a key determinant of clinical short- and long-term outcomes? What should be measured by a clinical tool designed to check inhaler technique and therefore help with device selection? If we have a tool to help in individualising inhaler choice, will we achieve better asthma outcomes? Do we have to refine inhaler device choice for each individual, or will we get better outcomes if we select our current best option in light of current knowledge and apply this on a population level?

Maternal serum concentrations of BDNF and depression in the perinatal period

There is accumulating evidence that a deficiency in brain-derived neurotrophic factor (BDNF) plays a critical role in the pathophysiology of depression. This is in line with the postulate that low BDNF levels in serum are associated with depression. However, the regulation of maternal BDNF serum levels in the perinatal period, and its relationship to maternal depression is unknown. In this study, serum BDNF concentrations were measured in 40 pregnant (follow-up: 30th and 37th week of gestation, 1 week and 8 weeks after childbirth) and 40 non-pregnant women (20-40 years old). The Edinburgh Postnatal Depression Scale (EPDS) was assessed in all subjects at all time points. Maternal serum levels of BDNF were markedly decreased, both before and after childbirth (median: <30% of non-pregnant controls). BDNF correlated with decreased Serotonin (5-HT) levels in serum (r>0.6 and p<0.001 at all time points). In contrast, there was no association with altered estrogen, progesterone, dehydroepiandrosterone or cortisol concentrations in serum. There were significantly higher cortisol levels in cases of maternal depression (EPDS scores>9 points) than in cases without depression. There was a trend to a decrease of BDNF and 5-HT levels in cases of maternal depression (as compared to cases without depression), but this was not significant. In conclusion, we demonstrate that women display markedly decreased BDNF serum levels before and after childbirth. This phenomenon might reflect an increased risk for the development of mood disorders in the perinatal period. However, the individual serum concentration of BDNF alone did not predict maternal depression in our study.

Inflammatory determinants of asthma severity: Mediator and cellular changes in bronchoalveolar lavage fluid of patients with severe asthma

Cellular and mediator profiles in bronchoalveolar lavage have not been compared systematically between patients with asthma of different severities, mainly because the patients with more severe asthma have an increased need for antiinflammatory medication. Information is limited to comparisons of allergic and intrinsic asthma, which can be distinguished clinically. When patients from these two groups with similar degrees of bronchial hyperresponsiveness were compared, both groups showed increased numbers of activated T-helper lymphocytes; those in the allergic group expressed the IL-2 receptor (CD25+), whereas in patients with intrinsic asthma there was also an increased number of T-suppressor cells with the activation markers CD25, class II histocompatibility antigen, and very late activation antigen-I, as well as T-helper cells class II histocompatibility antigen and very late activation antigen-I. This pattern is compatible with a more chronic T-cell activation in patients with intrinsic asthma. In patients with allergic asthma the cytokine pattern is compatible with a pure TH2 response (elevated IL-4 and IL-5); however, intrinsic asthma is characterized by elevated IL-5 and IL-2 but not IL-4. Our own findings show similar concentrations of IL-1, IL-8, and granulocyte-macrophage colony-stimulating factor in bronchoalveolar lavage fluid of patients with allergic and intrinsic asthma, whereas IL-6 and interferon-gamma tended to be higher in patients with intrinsic asthma. There are probably fundamental differences in the pathogenesis of allergic and intrinsic asthma. These findings suggest that asthma does not depend on the presence of IgE or IL-4, although both may contribute to the pathogenesis of atopic asthma. The only common pathway in the different presentations of asthma that has been related to clinical symptoms appears to be IL-5-mediated activation of eosinophils; therapies aimed at this mechanism may be promising.

Clinically relevant effect of a new intranasal therapy (MP29-02) in allergic rhinitis assessed by responder analysis.

Background: It is unclear what constitutes a clinically meaningful response for allergic rhinitis (AR) outcomes. The objectives of these post hoc analyses were (1) to define a clinically meaningful response using novel efficacy analyses (including a responder analysis), and (2) to compare the efficacy of MP29-02 [a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP)] with commercially available FP, AZE and placebo in seasonal AR (SAR) patients, using these novel analyses. Methods: 610 moderate-to-severe SAR patients (≥12 years old) were randomized into a double-blind, placebo-controlled, 14-day, parallel-group trial. Change from baseline in the reflective total nasal symptom score (rTNSS) over 14 days was the primary outcome. Post hoc endpoints included the sum of nasal and ocular symptoms (rT7SS), efficacy by disease severity and by predominant nasal symptom, and a set of responder analyses. Results: MP29-02 most effectively reduced rT7SS (relative greater improvement: 52% to FP; 56% to AZE) and both nasal and ocular symptoms irrespective of severity. More MP29-02 patients achieved a ≥30, ≥50, ≥60, ≥75 and ≥90% rTNSS reduction, which occurred days faster than with either active comparator; MP29-02 alone was superior to placebo at the ≥60% (or higher) threshold. One in 2 MP29-02 patients achieved a ≥50% rTNSS reduction and 1 in 6 achieved complete/near-to-complete response. Only MP29-02 was consistently superior to placebo for all patients, whatever their predominant symptom. Conclusions: MP29-02 provided faster and more complete symptom control than first-line therapies. It was consistently superior irrespective of severity, response criteria or patient-type, and may be considered the drug of choice for moderate-to-severe AR. These measures define a new standard for assessing relevance in AR.

Add-on montelukast in inadequately controlled asthma patients in a 6-month open-label study: The MONtelukast In Chronic Asthma (MONICA) study

Bronchial asthma often remains uncontrolled despite treatment with inhaled corticosteroids (ICS), long-acting beta(2)-agonists (LABA) or both, necessitating additional treatment. Patients >or=18 years (n=1681) with mild-to-moderate asthma received oral montelukast 10mg added to ICS or ICS+LABAs, and were followed for 6 months in a prospective, open-label observational study. The primary endpoint was change in Asthma Control Test (ACT) score. Secondary endpoints included mini-Asthma Quality-of-Life Questionnaire (mini-AQLQ) and FEV(1)/PEF. Mean ACT scores improved from 14.6+/-4.6 (baseline) to 19.4+/-4.4 (month 6; p<0.0001). Using ACT score categories, the percentage of patients with uncontrolled (57.5%) or poorly controlled (25.0%) asthma at baseline decreased at month 6 (17.6 and 21.7%, respectively); the percentage of patients with well controlled (13.9%) or completely controlled (1.2%) asthma at baseline increased at month 6 (47.5 and 11.4%, respectively). The mini-AQLQ score (mean+/-SD) improved from 4.0+/-1.1 to 5.3+/-1.1 (p<0.0001); FEV(1) increased from 2.46+/-0.89 to 2.60+/-0.92L (p<0.0001). Treatment with montelukast was generally well tolerated. In patients insufficiently controlled with ICS or ICS+LABAs, daily add-on montelukast improved both asthma control and asthma-related quality of life. Clinicaltrials.gov registry number NCT00802789.

Impact of immunotherapy on blood dendritic cells in patients with Hymenoptera venom allergy

BACKGROUND Modulation of T-cell differentiation, which is controlled by dendritic cells (DCs), plays a crucial role in specific immunotherapy (SIT). However, the number and the characteristics of blood DCs before and during immunotherapy are unknown. OBJECTIVE To analyze the number and the characteristics of blood DC subsets in patients with Hymenoptera venom allergy before and after initiation of SIT. METHODS In this clinical trial (NCT00947908), blood myeloid and plasmacytoid DCs were analyzed in 20 patients with Hymenoptera venom allergy (bee or wasp venom) by using 4-color flow cytometry at 3 time points: directly before SIT, and 52 hours and 12 months after initiation of SIT. In addition, 20 age-matched and sex-matched controls were examined. RESULTS In patients with Hymenoptera venom allergy, the number of plasmacytoid DCs before SIT was comparable to that of controls. Plasmacytoid DCs decreased markedly 52 hours after initiation of SIT and returned to control levels after 12 months of treatment. Myeloid DCs were elevated in patients with Hymenoptera venom allergy before, during, and after the first 12 months of SIT. In addition, there were changes in the expression of function-associated surface molecules on myeloid DCs (such as Fc γ receptor 2 and Toll-like receptor 2) during SIT. CONCLUSION Numbers of blood myeloid DCs are elevated in patients with Hymenoptera venom allergy, and there are specific changes in the expression of function-associated surface molecules on these cells during SIT. Numbers of plasmacytoid DCs in blood are profoundly but are only transiently decreased after initiation of SIT.

Differential effect of clopidogrel and aspirin on the release of BDNF from platelets.

Anti-platelet treatment is a key therapeutic intervention in patients with cerebrovascular diseases. However, there is no information on its impact on the release of Brain-derived neurotrophic factor (BDNF), which is stored in large amounts in human platelets and essential for neuronal protection and repair. Here, we show that a single oral dose of clopidogrel, but not aspirin, significantly reduced the release of BDNF from platelets in healthy volunteers. These data point, for the first time, to possible differential effects of anti-platelet regimens on neuronal function in patients with cerebrovascular disorders.

Differential development of plasmacytoid dendritic cells in Th1- and Th2-like cytokine milieus

To cite this article: Bratke K, Klein C, Kuepper M, Lommatzsch M, Christian Virchow J. Differential development of plasmacytoid dendritic cells in Th1‐ and Th2‐like cytokine milieus. Allergy 2011; 66: 386–395.