Cell distribution and cytokine levels in induced sputum from healthy subjects and patients with asthma after using different nebulizer techniques.

BACKGROUND: Sputum induction is an important noninvasive method for analyzing bronchial inflammation in patients with asthma and other respiratory diseases. Most frequently, ultrasonic nebulizers are used for sputum induction, but breath-controlled nebulizers may target the small airways more efficiently. This treatment may produce a cell distribution similar to bronchoalveolar lavage (less neutrophils and more macrophages) and provide deeper insights into the underlying lung pathology. The goal of the study was to compare both types of nebulizer devices and their efficacy in inducing sputum to measure bronchial inflammation, i.e., cell composition and cytokines, in patients with mild allergic asthma and healthy controls. METHODS: The population of this study consisted of 20 healthy control subjects with a median age of 17 years, range: 8-25 years, and 20 patients with a median age of 12 years, range: 8-24 years, presenting with mild, controlled allergic asthma who were not administered an inhaled steroid treatment. We induced sputum in every individual using both devices on two separate days. The sputum weight, the cell composition and cytokine levels were analyzed using a cytometric bead assay (CBA) and by real-time quantitative PCR (qRT-PCR). RESULTS: We did not observe significant differences in the weight, cell distribution or cytokine levels in the sputum samples induced by both devices. In addition, the Bland-Altman correlation revealed good concordance of the cell distribution. As expected, eosinophils and IL-5 levels were significantly elevated in patients with asthma. CONCLUSIONS: The hypothesis that sputum induction with a breath-controlled "smart" nebulizer is more efficient and different from an ultrasonic nebulizer was not confirmed. The Bland-Altman correlations showed good concordance when comparing the two devices. TRIAL REGISTRATION: NCT01543516 Retrospective registration date: March 5, 2012.

Short-Term Variation of Lung Function and Airway Inflammation in Children and Adolescents with Bronchiolitis Obliterans.

PURPOSE: Bronchiolitis obliterans (BO) is an inadequately researched disease in terms of lung function as well as inflammatory profile. The short-term variation of these parameters has not been investigated. Therefore, the objective of this study was the investigation of lung function, sputum cells and cytokine profiles in BO at two visits within of four to six weeks. METHODS: Twenty patients with BO (median age = 14.6, range 8.3-24.3) performed lung function tests, airway reversibility testing and induction of sputum within four to six weeks. The cell composition in the sputum was analysed and cytokine levels of IL-1ß, IL-6 and IL-8 were determined by cytometric bead array analysis. The short-term variation was then statistically quantified and compared to that of twenty-two healthy controls. Furthermore, we compared data on short-term variation of lung function and airway inflammation with a previous investigation in these patients 10-15 months earlier. RESULTS: Patients with BO showed minimal variation of lung function (VCmax, FVC, FEV1, FEV1/VC, MEF25 and RV/TLC) and the inflammatory cell profile. The lung function data were significantly lower for FVC, FEV1, the Tiffeneau index and MEF25 compared to the control group, whereas RV/TLC was significantly increased. Analysis of the BO sputum cells showed a consistent neutrophil inflammation. The levels of inflammatory cytokines IL-1ß, IL-6 and IL-8 had a great variability. CONCLUSIONS: The short-term variability of sputum neutrophilia and lung function is low in BO patients. This finding should be considered to identify successful treatment in the individual patient and could be used as endpoints for future BO-related studies.

Airway inflammation in children and adolescents with bronchiolitis obliterans.

BACKGROUND: Airway inflammation plays a major role in the progression of chronic lung diseases. The features of airway inflammation are not well defined among patients with cases of bronchiolitis obliterans (BO) that began in childhood. OBJECTIVES: To investigate the sputum cell and cytokine profiles of stable cases of BO regarding lung function and the involvement of small airway disease (SAD). METHODS: Twenty patients with BO (median age=14.5, range=7-23years) and 22 healthy controls (median age=16.5years, range=7-24years) were investigated. Lung function parameters and bronchial reversibility testing as well as sputum cell and cytokine profiles (IL-1ß, IL-6, IL-8, TNF-α, IL-5, IFN-γ, and NFκB regulation) were analysed using quantitative RT-PCR and cytometric bead assay (CBA) in induced sputum. RESULTS: Patients with BO had significantly lower lung function values, including FVC, forced expiratory volume (FEV1), the Tiffeneau index (FEV1/VC), and MEF25, but increased functional residual capacity (RV/TLC) values. Bronchial reversibility was found in five patients (25%). Moreover, airway inflammation (as indicated by total cells, neutrophils, IL-1ß, IL-6, IL-8, TNF-α, and NFκB) was significantly increased among patients with BO compared with controls. CONCLUSIONS: BO is predominantly a neutrophilic disease of the small bronchioles featuring elevated levels of pro-inflammatory cytokines leading to tissue remodelling and fibrosis of the small airways. Future therapies for patients with BO should more efficiently target the small airways.

Bronchial allergen challenges in children - safety and predictors.

BACKGROUND: In allergic asthma, the diagnosis of house dust mite (HDM) allergy is mainly based on the patient's history, allergy testing by the skin prick test (SPT) or the levels of allergen-specific IgE. We retrospectively analysed data from 350 bronchial provocations with HDM and related it to the following parameters: specific IgE, bronchial hyperresponsiveness (BHR) to methacholine testing (MCT) and exhaled NO (eNO). METHODS: Approximately 350 patients (5-18 yr of age) with allergic asthma and a positive SPT to HDMs were included. To define the sensitivity and specificity for the detection method of an early asthmatic response (EAR), a receiver-operating characteristic (ROC) curve was plotted. The accuracy was measured by the area under the ROC curve (AUC). A logistic regression model was used to predict the individual probability of a positive challenge. The results of the regression model were validated in a prospective group of n = 75 patients. RESULTS: The following cut-off values showed the best combination of sensitivity and specificity: specific IgE Dermatophagoides farinae 19.6 kU/l (AUC, 0.88), PD(20) FEV(1) 0.13 mg methacholine (AUC, 0.73) and eNO 20.1 ppb (AUC, 0.71). The following equation predicted the individual probability of a positive challenge in the retrospective and prospective group: p = 1(.) [1 + exp[-(-1.78 + 2.46.(10) log D. far - 1.25(.10) logPD(20) metha)]](-1) , (AUC = 0.88). CONCLUSIONS: The value of using the specific IgE and MCT as predictors was confirmed in a large number of patients. We also showed, for the first time, that the eNO predicted the EAR. The logistic regression model is repeatable with a good accuracy.

Bronchial allergen provocation: a useful method to assess the efficacy of specific immunotherapy in children.

BACKGROUND: The clinical efficacy of subcutaneous allergen-specific immunotherapy (SCIT) varies between patients. New preparations are under development, and an objective tool with which to evaluate their efficacies in individual patients has become necessary. Our primary research question is whether bronchial allergen provocation (BAP) can be used to assess the efficacy of SCIT. METHODS: In 42 house dust mite (HDM) allergic children (average age: 8.6 yr) with asthma, we analysed the clinical and objective improvements of a standardised HDM allergoid. All patients underwent two BAPs, one before SCIT and another 1 yr after SCIT. Fourteen patients who were recommended but chose not to undergo SCIT represented the control group. The total and specific IgE were analysed before SCIT; in addition, after SCIT, specific IgG and IgG4 were analysed. RESULTS: After SCIT, the patients' allergen-specific bronchial hyper-reactivity (BHR) was significantly improved; specifically, their PD(20) FEV(1) was 34.4 AU before and 63.3 AU after SCIT (p < 0.01). The PD(20) FEV(1) of the control group remained unchanged. Although BHR improved significantly in the treatment group, we were able to differentiate between the responders (n = 17, 60.7%) and non-responders (n = 11, no improvement in BAP). The patients in both groups stated that SCIT had led to a subjective improvement in their symptoms, in contrast to the untreated control group, but only the responders required less medication after SCIT (p < 0.01). CONCLUSIONS: After 1 yr of SCIT against HDM, 60.7% of the patients observed in this study exhibited significant improvements, as defined by BAP. However, BAP was also able to identify the non-responders to treatment. Thus, BAP is a useful and objective method of estimating the effectiveness of SCIT and is not influenced by a placebo effect.

Bronchial allergen challenge using the Medicaid dosimeter.

BACKGROUND: Bronchial allergen provocations are well established in asthma research. We evaluated the reproducibility of single-concentration, single-step allergen challenges in volunteers with grass pollen allergy. METHODS: Forty-seven subjects underwent bronchial challenges using the aerosol provocation system nebulizer (Medicaid Sidestream) with incremental doses of grass pollen to define the individual allergen dose that causes a 20% drop in FEV(1) (PD(20)FEV(1)). In 39 subjects this procedure was followed by single-step challenges. Early and late asthmatic responses were monitored, and increases in exhaled nitric oxide were measured before and 24 h after single-step challenges. RESULTS: After the first single-step challenge, the maximum drop in FEV(1) was 21.3% ± 8.0. A comparison of the drop in FEV(1) to the initial incremental challenge (29.7% ± 7.5) revealed an intraclass correlation of -0.30 (p < 0.05). In the second single-step challenge, the mean drop in FEV(1) was 20.9% ± 7.2. Compared with the first single-step challenge, the intraclass correlation was 0.37 (p < 0.05) and the 95% limits of agreement according to Bland and Altman were -17.5 to 18.1%. The increases in exhaled nitric oxide revealed substantial agreement in repeated single-step challenges (26.8 ppb ± 27.8 and 21.8 ppb ± 21.9, ICC 0.62, p < 0.001). CONCLUSIONS: The use of aerosol provocation system to calculate the PD(20)FEV(1) allergen is a timesaving procedure and is less prone to errors because only one dilution of the allergen is used. The repeatability in well-defined subjects is excellent to study the mechanisms of allergen-induced airway inflammation and the development of new treatments for allergic diseases.

Epigenetic regulation of inflammation by microRNAs in post-infectious bronchiolitis obliterans.

OBJECTIVES: Post-infectious bronchiolitis obliterans (PiBO) is a rare, chronic disease initiated by severe infection and followed by perpetuating inflammation and obliteration of the small airways. MicroRNAs (miRNAs) have been proposed to play a central role as epigenetic regulators, which control resolution and prevent the uncontrolled progress of inflammation. The aim of this study was to define biomarkers on the level of post-transcriptional gene regulation in order to characterise PiBO. METHODS: A total of 39 patients with well-defined PiBO and 31 controls from two centres, Barcelona, Spain, and Frankfurt, Germany, were analysed by next-generation sequencing (NGS). The evaluation of the biological targets of the miRNAs was performed by pathway enrichment analysis and protein-protein interaction network analysis respectively. RESULTS: Patients with PiBO had significantly lower lung function values and increased airway inflammation in induced sputum as indicated by total cell counts, neutrophils, IL-1ß, IL-6, IL-8 and TGF-ß compared to controls.Next-generation sequencing analysis revealed a total of 22 dysregulated miRNAs, which passed significance threshold for Padj ≤ 0.001 with 17 being upregulated and 5 being downregulated. Of these dysregulated miRNAs, miR-335-5p, miR-186-5p, miR-30b-5p and miR-30c-5p were further validated using qRT-PCR. Interestingly, these miRNAs are functionally implicated in cytokine-cytokine receptor interaction, TGF-ß signalling and FoxO signalling pathway and significantly correlated with lung function values (FEV1). CONCLUSION: Our results demonstrate an aberrant miRNA expression profile in PiBO, which impacts pathways responsible for the regulation of inflammation and fibrosis. The defined miRNAs are useful biomarkers and should be assessed as potential target in the field of miRNA therapeutics.

Hypersensitivity pneumonitis: Lessons from a randomized controlled trial in children.

INTRODUCTION: Hypersensitivity pneumonitis (HP) in children is a severe interstitial lung disease and potentially, a chronic condition, if not treated appropriately. No evidence-based guidelines are available; in particular, the role of systemic glucocorticoid therapy is unclear. METHODS: The aim of this randomized, double-blind, placebo-controlled, parallel-group, multi-center, phase II trial in pediatric HP was to assess the outcome of HP in children after 6 months of treatment and to compare 3 months of treatment with oral prednisolone or placebo. RESULTS: After 1.5 years and the inclusion of only four children, we terminated the study prematurely. Two of the children randomized to prednisolone did not achieve the predefined response of FVC to normal. One child treated with placebo recovered to normal, similar to another child treated with prednisolone. All children treated with steroids developed drug-related side effects. DISCUSSION: This uncompleted study illustrates the urgent medical need for evidence-based treatment protocols for this condition. We discuss the hurdles which were specific for completion of this trial in a rare condition. Among other options, we suggest the inclusion of children into an all-age study of HP, as in adults the same questions are unanswered.

Sputum biomarker profiles in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) and association between pulmonary function.

Lung diseases like cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are associated with chronic airway inflammation. The aim of our study was to compare a complex biomarker profile in order to characterize specific inflammatory patterns in sputum of patients with CF and COPD. Induced sputum samples of 19 CF-, 26 COPD patients and 21 healthy controls were analyzed for concentrations of IL-1beta, IL-2, IL-6, IL-8, IL-13, IP-10, MCP-1, IFN-gamma and TNF-alpha using the new cytometric bead array (CBA) technology. Significant differences in airway biomarker profiles of CF and COPD were detected. Patients with CF showed a significant increase in IL-1beta, IL-6, IL-8, IL-13, TNF-alpha, IFN-gamma and MCP-1. COPD patients showed an increase in IL-6, IL-8, IL-13 and MCP-1 compared to healthy controls. CF and COPD compared to each other exhibited differences in IL-1beta, IL-2, IL-8, TNF-alpha, IFN-gamma and MCP-1 levels. Significant correlations between the parameters of lung function and sputum biomarker levels were found. Analyzing induced sputum allows characterization of specific airway biomarker profiles in CF and COPD and can be related to the clinical status of the patient. CBA of induced sputum seems to be a pivotal tool to characterize pulmonary inflammation.

Ultra-short course immunotherapy in children and adolescents during a 3-yrs post-marketing surveillance study.

Ultra-short course immunotherapy (uSCIT) has shown good efficacy and tolerability in children and adolescents with seasonal allergic rhinitis (SAR), conjunctivitis and/or asthma in clinical studies. Here, we investigate the efficacy of uSCIT in the juvenile subpopulation of a 3-year post-marketing surveillance (PMS) study. To assess the differences in the efficacy of uSCIT between adults and children respectively adolescents enrolled in a PMS study. In a prospective open study 422 patients aged 6-18 years with SAR, conjunctivitis and/or asthma received four pre-seasonal injections with pollen allergoids formulated with monophosphoryl lipid A (MPL, Pollinex Quattro) over a minimum of 3 weeks. Efficacy was evaluated by response to therapy and consumption of anti-allergic medication during the pollen season. Tolerability was evaluated by patients' acceptance of therapy. These results were compared with the adult subpopulation of this study. Response to treatment was assessed as good or very good in 94% of patients, mirroring findings for the entire cohort. Further improvements were noted in patients receiving subsequent courses of therapy. Anti-allergic medication use decreased from 83% to 24% of patients after the first treatment course (p < 0.0001). Therapy was well accepted by children/adolescents and considered 'very good' or 'good' by 93% of juveniles. No serious adverse events or cases of anaphylaxis were reported. This subanalysis indicated that uSCIT with Pollinex Quattro had similar efficacy and tolerability in children/adolescents and adults. The convenient dosing regimen and favourable safety profile of uSCIT may support a wider uptake of uSCIT in this patient population.

Postinfectious Bronchiolitis Obliterans in Children: Diagnostic Workup and Therapeutic Options: A Workshop Report.

Bronchiolitis obliterans (BO) is a rare, chronic form of obstructive lung disease, often initiated with injury of the bronchiolar epithelium followed by an inflammatory response and progressive fibrosis of small airways resulting in nonuniform luminal obliteration or narrowing. The term BO comprises a group of diseases with different underlying etiologies, courses, and characteristics. Among the better recognized inciting stimuli leading to BO are airway pathogens such as adenovirus and mycoplasma, which, in a small percentage of infected children, will result in progressive fixed airflow obstruction, an entity referred to as postinfectious bronchiolitis obliterans (PIBO). The present knowledge on BO in general is reasonably well developed, in part because of the relatively high incidence in patients who have undergone lung transplantation or bone marrow transplant recipients who have had graft-versus-host disease in the posttransplant period. The cellular and molecular pathways involved in PIBO, while assumed to be similar, have not been adequately elucidated. Since 2016, an international consortium of experts with an interest in PIBO assembles on a regular basis in Geisenheim, Germany, to discuss key areas in PIBO which include diagnostic workup, treatment strategies, and research fields.

Year-round treatment initiation for a 6-grasses pollen allergoid in specific immunotherapy of allergic rhinoconjunctivitis and asthma.

Aim: Allergen immunotherapy (AIT) is an effective treatment for allergic diseases. We investigate whether treatment-initiation during the pollen season is safe. Methods: RCT-IIIb-trial of 6-grass-pollen-allergoid (Allergovit®) in grass pollen-allergic patients (18-65 years) with moderate-severe rhinitis/rhinoconjunctivitis (± controlled asthma), randomized 2:1 to treatment-initiation during (Group-A) versus outside the pollen season (Group-B). Results: Of 240 patients (32.8 ± 9.9 years, 19.5% asthma) treated, 84.9% (Group-A) and 86.6% (Group-B) reached maintenance dose without delay. Treatment-emergent adverse events occurred in 108 (68.4%/Group-A) and 41 patients (56.2%/Group-B) leading to premature trial-termination in 11 patients (7%/A) versus 3 (4.1%/B). Across groups, physicians (for 190 patients; 85.2%) and patients (192; 86.1%) rated the tolerability as 'very good'-'good'. Phleum pratense-specific IgG4 increased in both groups (p < 0.0001). Conclusion: Year-round allergen immunotherapy-initiation with this preparation is safe.

Fast up-dosing with a birch allergoid is safe and well tolerated in allergic rhinitis patients with or without asthma.

AIM: Subcutaneous immunotherapy is effective in treating allergic rhinoconjunctivitis and asthma, but is still inconvenient when heavy schedules are used. A faster dose escalation is desirable. MATERIALS & METHODS: In this open-label, Phase II trial, 130 adults were randomized 1:1 to receive a birch pollen allergoid subcutaneous immunotherapy. Group I with four weekly injections and Group II with seven weekly injections. Safety, tolerability and immunogenicity were assessed. RESULTS: Mild-to-moderate treatment-related adverse events were reported for 57.7% of the patients (Group I: 36, Group II: 39). Tolerability was assessed by physicians and rated as 'good' or 'very good' for 55 patients in Group I (87.3%) and for 63 patients in Group II (94.0%). Levels of IgG and IgG4 increased before and after treatment significantly (p < 0.0001) in both groups. CONCLUSION: Standard versus fast dose escalation is comparable in terms of safety and tolerability.

Long-term effect of monophosphoryl lipid A adjuvanted specific immunotherapy in patients with grass pollen allergy.

BACKGROUND: Ultra-short course pollen immunotherapy adjuvanted with monophosphoryl lipid A (MPL) is attractive to conventional allergen-specific immunotherapy (AIT). Long term efficacy of MPL-AIT has not been evaluated. METHODS: 68 patients (age 16.75 ± 5.3 years) with allergic rhinitis to grass pollen were investigated. Group 1: 21 controls; Group 2: 19 after complete AIT, and Group 3: 28 with AIT and treatment cessation: 4 years range 3-6 years ago. RESULTS: The clinical symptoms (running nose, sneezing, conjunctivitis and the weekly overall score) were significantly reduced in patients group 2 and 3 compared with controls without AIT p < 0.0001. T-regulatory cells and TH1/TH2 cytokine pattern did not differ between patient groups. CONCLUSION: The patients in our trial with grass pollen allergy exhibited significant and long-lasting improvements after MPL-AIT, however larger trials are needed to support this finding.

Recurrent somatic mutations are rare in patients with cryptic dyskeratosis congenita.

Dyskeratosis congenita (DKC) is a paradigmatic telomere disorder characterized by substantial and premature telomere shortening, bone marrow failure, and a dramatically increased risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). DKC can occur as a late-onset, so-called cryptic form, with first manifestation in adults. Somatic MDS-related mutations are found in up to 35% of patients with acquired aplastic anemia (AA), especially in patients with short telomeres. The aim of our study was to investigate whether cryptic DKC is associated with an increased incidence of MDS-related somatic mutations, thereby linking the accelerated telomere shortening with the increased risk of MDS/AML. Samples from 15 adult patients (median age: 42 years, range: 23-60 years) with molecularly confirmed cryptic DKC were screened using next-generation gene panel sequencing to detect MDS-related somatic variants. Only one of the 15 patients (7%) demonstrated a clinically relevant MDS-related somatic variant. This incidence was dramatically lower than formerly described in acquired AA. Based on our data, we conclude that clonal evolution of subclones carrying MDS-related mutations is not the predominant mechanism for MDS/AML initiation in adult cryptic DKC patients.

Comparison of two different assays and the predictive value of allergen components in house dust mite allergy.

AIM: In house dust mite (HDM) allergy diagnostics, the IMMULITE, ImmunoCAP and assays for allergen components (nDer p 1 and rDer p 2) are available. METHODS: Serum sIgE levels were compared and the predictive values for the detection of an early asthmatic response (EAR) were calculated with receiver operating characteristics and a log-logistic regression model. RESULTS: sIgE levels of IMMULITE and ImmunoCAP were similar (Dermatophagoides pteronyssinus [D. pter.] 47.3 ± 35.7 and 42.9 ± 34.4 kU.l-1; p = 0.23). ImmunoCAP slgEs exhibited similar accuracy in detecting an EAR, area under the curves (AUCs): D. pter. (0.76); Dermatophagoides farinae (0.79); nDer p 1 (0.69); and rDer p 2 (0.72). At low sIgE concentrations (3.5 kU.l-1), rDer p 2 was more specific and better predicted an EAR (probability rDer p 2: 62%; D. pter.: 19%).

Mucolytic Effectiveness of Tyloxapol in Chronic Obstructive Pulmonary Disease - A Double-Blind, Randomized Controlled Trial.

OBJECTIVE: Mucoactive drugs should increase the ability to expectorate sputum and, ideally, have anti-inflammatory properties. The aim of the study was to evaluate the mucolytic activity of Tyloxapol compared to saline (0.9%) in COPD. DESIGN: A randomized, placebo-controlled, double-blinded crossover, clinical trial was carried out. Patients were randomly assigned to either inhale 5 ml Tyloxapol 1% or saline 0.9% solution three times daily for 3 weeks and vice versa for another 3 weeks. 28 patients (18 male, 10 female, 47 to 73 years old, median age 63.50) were screened, 21 were treated and 19 patients completed the study per protocol. RESULTS: A comparison of the two treatment phases showed that the primary endpoint sputum weight was statistically significant higher when patients inhaled Tyloxapol (mean 4.03 g, 95% CI: 2.34-5.73 g at week 3) compared to saline (mean 2.63 g, 95% CI: 1.73-3.53 g at week 3). The p-value at three weeks of treatment was 0.041 between treatment arms. Sputum cells decreased during the Tyloxapol treatment after 3 weeks, indicating that Tyloxapol might have some anti-neutrophilic properties. Lung function parameters (FVC, FEV1, RV, and RV/TLC) remained stable during the study, and no treatment effect was shown. Interestingly, there was a mean increase in all inflammatory cytokines (IL-1ß, IL-6, and IL-8) during the saline treatment from day 1 to week 3, whereas during the Tyloxapol treatment, all cytokines decreased. Due to the small sample size and the large individual variation in sputum cytokines, these differences were not significant. However, analyses confirmed that Tyloxapol has significant anti-inflammatory properties in vitro. Despite the high number of inhalations (more than 1000), only 27 adverse events (20 during the Tyloxapol and seven during saline) were recorded. Eleven patients experienced AEs under Tyloxapol and six under saline treatment, which indicates that inhalation of saline or Tyloxapol is a very safe procedure. CONCLUSION: Our study demonstrated that inhalation of Tyloxapol by patients with COPD is safe and superior to saline and has some anti-inflammatory effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT02515799.

Induction of Bronchial Tolerance After 1 Cycle of Monophosphoryl-A-Adjuvanted Specific Immunotherapy in Children With Grass Pollen Allergies.

PURPOSE: Subcutaneous allergen-specific immunotherapy (SCIT) is a well-established and clinically effective method to treat allergic diseases, such as rhinitis and asthma. It remains unclear how soon after initiation of an ultra-short course of grass pollen immunotherapy adjuvanted with monophosphoryl lipid A (MPL)-specific bronchial tolerance can be induced. METHODS: In a prospective study of 69 children double-sensitized to birch and grass pollens (51 males, average age 11.1 years), development of bronchial tolerance after 1 cycle of SCIT for grass was evaluated. In all the patients, the bronchial allergen provocation test (BAP) was performed before and after treatment. According to the results of the first BAP, the patients were divided into 2 groups: those showing a negative BAP with a decrease in FEV1 of <20% (seasonal allergic rhinitis [SAR] group, n=47); and those showing a positive BAP with a decrease in FEV1 of ≥20% (SAR with allergic asthma [SAR and Asthma] group, n=22). All the patients received MPL-adjuvanted, ultra-short course immunotherapy for birch, but only those with a positive BAP to grass received MPL-SCIT for grass. RESULTS: After the pollen season, the BAP in the SAR group remained unchanged, while it was improved in the SAR and Asthma group (decrease in FEV1 of 28.8% vs 12.5%, P<0.01). The IgG4 levels increased after SCIT (median before SCIT 0.34 to 11.4 after SCIT), whereas the total and specific IgE levels remained unchanged. CONCLUSIONS: After 1 cycle of MPL-SCIT, specific bronchial tolerance may be significantly induced, whereas in patients without SCIT, bronchial hyperactivity may remain unchanged.

Pollinex Quattro: an innovative four injections immunotherapy in allergic rhinitis.

The prevalence of seasonal allergic rhinitis in the western world is high and increasing. Besides considerably affecting physical and psychosocial aspects of patients' lives, allergic rhinitis is often associated with allergic asthma and may aggravate this condition over time. Specific immunotherapy is currently the only approved therapy that can modify the underlying disease process and induce long-term tolerance to allergens. Pollinex Quattro is a subcutaneous four injections immunotherapy consisting of tyrosine-absorbed specific allergoids and enhanced with the adjuvant monophosphoryl lipid A (MPL(®)). MPL(®) induces a significant Th 1-type immune response, characterized by an increase of allergen-specific IgG antibody levels and dampening of the IgE response during allergen exposure. Due to this dual action of stimulating the immune system, Pollinex Quattro is clinically effective after only four injections given pre-seasonally. A large clinical program has demonstrated efficacy and tolerability of Pollinex Quattro in children, adolescents and adults with grass and tree pollen allergy. A health economics study concluded that an immunotherapy with only 4 injections might be more cost-beneficial than other application forms of immunotherapy.