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Background: Real‐world evidence is sparse on the benefits of allergen immunotherapy [AIT; subcutaneous/sublingual immunotherapy (SCIT/SLIT)], the only disease‐modifying intervention for allergic rhinitis (AR) with long‐term efficacy. This real‐life study evaluated the effect of six AITs (native pollen SLIT/SCIT, four allergoid SCITs) vs symptomatic medication use, on AR symptoms and asthma symptoms/onset, in patients with birch pollen‐associated AR and/or asthma.
Methods: In this retrospective cohort analysis of a German longitudinal prescription database, AIT patients received ≥2 successive seasonal treatment cycles; non‐AIT patients had ≥3 AR prescriptions in three seasons or previous month. Patients were matched for: index year, age, gender, main indication at index, number of seasonal cycles within treatment period, baseline AR/asthma treatment prescriptions. Multiple regression analysis compared prescription data in AIT and non‐AIT groups as proxy for clinical status/disease progression.
Results: Up to 6 years of follow‐up, significantly more AIT (65.4%) vs non‐AIT (47.4%) patients were AR medication‐free; odds ratio (OR) [95% confidence interval (CI)]: 0.51 [(0.48‐0.54); P < 0.001] (28.6% covariate‐adjusted reduction vs non‐AIT; P < 0.001), and significantly more AIT (49.1%) vs non‐AIT (35.1%) patients were asthma medication‐free [OR (95% CI): 0.59 (0.55‐0.65); P < 0.001] (32% reduction vs non‐AIT; P < 0.001), or reduced existing asthma medication use (32% covariate‐adjusted reduction vs non‐AIT; P < 0.001). During treatment, new‐onset asthma risk was significantly reduced in the AIT vs non‐AIT group (OR: 0.83; P = 0.001).
Conclusions: Birch pollen AIT demonstrated real‐world benefits up to 6 years post‐treatment cessation through significantly reduced AR and asthma medication intake, and significantly decreased risk of new‐onset asthma medication use on‐treatment.
Objective: Ligelizumab is a humanised IgG1 anti-IgE antibody that binds IgE with higher affinity than omalizumab. Ligelizumab had greater efficacy than omalizumab on inhaled and skin allergen provocation responses in mild allergic asthma. This multi-centre, randomised, double-blind study was designed to test ligelizumab in severe asthma patients not adequately controlled with high-dose inhaled corticoids plus long-acting β2-agonist.
Methods: Patients received 16 weeks ligelizumab (240 mg q2w), omalizumab or placebo subcutaneously, and ACQ-7 was measured as primary outcome at Week 16. In addition, the study generated dose-ranging data of ligelizumab and safety data.
Results: A total of 471 patients, age 47.4 ± 13.36 years, were included in the study. Treatment with ligelizumab did not significantly improve asthma control (ACQ-7) and exacerbation rates compared to omalizumab and placebo. Therefore, primary and secondary objectives of the study were not met. The compound was well tolerated, and the safety profile showed no new safety findings. Pharmacokinetic data demonstrated faster clearance and lower serum concentrations of ligelizumab than historical omalizumab data, and exploratory in vitro data showed differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds.
Conclusion: Ligelizumab failed to demonstrate superiority over placebo or omalizumab. Although ligelizumab is more potent than omalizumab at inhibiting IgE binding to the high-affinity FcεRI, there is differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds. Therefore, the data suggest that different anti-IgE antibodies might be selectively efficacious for different IgE-mediated diseases.
Background: Both standard and low-dose allergen provocations are an established tool in asthma research to improve our understanding of the pathophysiological mechanism of allergic asthma. However, clinical symptoms are less likely to be induced. Therefore, we designed a protocol for repetitive high-dose bronchial allergen challenges to generate clinical symptoms and airway inflammation.
Methods: A total of 27 patients aged 18 to 40 years with positive skin-prick tests and mild asthma underwent repetitive high-dose allergen challenges with household dust mites for four consecutive days. Pulmonary function and exhaled NO were measured at every visit. Induced sputum was analysed before and after the allergen challenges for cell counts, ECP, IL-5, INF-γ, IL-8, and the transcription factor Foxp3.
Results: We found a significant decrease in pulmonary function, an increased use of salbutamol and the development of a late asthmatic response and bronchial hyperresponsiveness, as well as a significant induction of eNO, eosinophils, and Th-2 cytokines. Repeated provocation was feasible in the majority of patients. Two subjects had severe adverse events requiring prednisolone to cope with nocturnal asthma symptoms.
Conclusions: Repeated high-dose bronchial allergen challenges resulted in severe asthma symptoms and marked Th-2-mediated allergic airway inflammation. The high-dose challenge model is suitable only in an attenuated form in diseased volunteers for proof-of-concept studies and in clinical settings to reduce the risk of severe asthma exacerbations.
Trial registration: ClinicalTrials.govNCT00677209
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.
Background: Asthma is increasing worldwide and results from a complex immunological interaction between genetic susceptibility and environmental factors. Autovaccination with E. coli induces a strong TH-1 immune response, thus offering an option for the treatment of allergic diseases. Methods: Prospective open trial on safety, tolerability, and impact on allergic inflammation of an autologous E.coli autovaccine in intermittent or mild persistent house dust mite asthma. Determination of exhaled nitric monoxide (eNO) before and after bronchial mite challenge initially and after nine months of autovaccination. Results: Median eNO increase after autovaccination was significantly smaller (from 27.3 to 33.8 ppb; p=0.334) compared to initial values (from 32.6 to 42.2 ppb; p=0.046) (p=0.034). In nine subjects and a total of 306 injections, we observed 101 episodes of local erythema (33.3%; median of maximal diameter 2.5 cm), 95 episodes of local swelling (31.1%; median of maximal diameter 3 cm), and 27 episodes of local pain (8.8%). Four subjects reported itching at the injection site with a total of 30 episodes (9.8%). We observed no serious adverse events. All organ functions (inclusive electrocardiogramm) and laboratory testing of the blood (clinical chemistry, hematology) and the urine (screening test, B-microglobuline) were within normal limits. Vital signs undulated within the physiological variability. Conclusion: The administration of autologous autovacine for the treatment of house dust mite asthma resulted in a reduction of the eNO increase upon bronchial mite challenge. In nine subjects and 306 injections, only a few mild local reactions and no systemic severe adverse events were observed. EudraCT Nr. 2005-005534-12 ClinicalTrials.gov ID NCT00677209
BACKGROUND: In two clinical trials, low-grade fever was observed more frequently after coadministration than after separate administration of two recommended routine pediatric vaccines. Since fever is an important issue with vaccine tolerability, we performed this open-label study on the efficacy and safety of prophylactic use of paracetamol (acetaminophen, Benuron(R)) in children administered routine 7-valent pneumococcal conjugate vaccine (PCV-7) coadministered with hexavalent vaccine (diphtheria-tetanus-acellular pertussis-hepatitis B, polio, Haemophilus influenzae type b vaccine [DTPa-HBV-IPV/Hib]) in Germany.
METHODS: Healthy infants (N = 301) who received a 3-dose infant series of PCV-7 and DTPa-HBV-IPV/Hib plus a toddler dose were randomly assigned 1:1 to prophylactic paracetamol (125 mg or 250 mg suppositories, based on body weight) at vaccination, and at 6--8 hour intervals thereafter, or a control group that received no paracetamol. Rectal temperature and local and other systemic reactions were measured for 4 days post vaccination; adverse events were collected throughout the study.
RESULTS: In the intent-to-treat population, paracetamol reduced the incidence of fever >=38[degree sign]C, but this reduction was only significant for the infant series, with computed efficacy of 43.0% (95% confidence interval [CI]: 17.4, 61.2), and not significant after the toddler dose (efficacy 15.9%; 95% CI: -19.9, 41.3); results were similar in the per protocol (PP) population. Fever >39[degree sign]C was rare during the infant series, such that there were too few cases for assessment. After the toddler dose, paracetamol effectively reduced fever >39[degree sign]C, reaching statistical significance in the PP population only (efficacy 79%; 95% CI: 3.9, 97.7). Paracetamol also reduced reactogenicity, but there were few significant differences between groups after any dose. No vaccine-related serious adverse events were reported.
CONCLUSIONS: Paracetamol effectively prevented fever and other reactions, mainly during the infant series. However, as events were generally mild and of no concern in either group our data support current recommendations to administer paracetamol to treat symptoms only and not for routine prophylaxis.Trial registration: NCT00294294.
Ataxia telangiectasia (A-T) is a progressive and life-limiting disease associated with cerebellar ataxia due to progressive cerebellar degeneration. In addition to ataxia, which is described in detail, the presence of chorea, dystonia, oculomotor apraxia, athetosis, parkinsonism, and myoclonia are typical manifestations of the disease. The study aimed to evaluate the specificity and sensitivity of neurofilament light chain (NfL) as a biomarker of neurodegeneration in relation to SARA score. In this prospective trial, one visit of 42 A-T patients aged 1.3–25.6 years (mean 11.6 ± 7.3 years) was performed, in which NfL was determined from serum by ELISA. Additionally, a neurological examination of the patients was performed. Blood was collected from 19 healthy volunteers ≥ 12 years of age. We found significantly increased levels of NfL in patients with A-T compared to healthy controls (21.5 ± 3.6 pg/mL vs. 9.3 ± 0.49 pg/mL, p ≤ 0.01). There was a significant correlation of NfL with age, AFP, and SARA. NfL is a new potential progression biomarker in blood for neurodegeneration in A-T which increases with age.
Aims: We have provided evidence in former studies that cytokines (IL-8, TNF alpha, LBP, TGFß) measured in blood correlate negatively with lung function in deltaF508 homozygous patients. GAP junction proteins might be of importance for the influx of blood cells into the lung. Our aim was to assess the relationship between connexin genotypes and cytokines (IL-8, TNF-alpha, LBP, TGFß) in induced sputum and serum, and lung disease.
Methods: 36 patients homozygous for deltaF508 (median age 18 y, m/f 16/20, FEV1(%) 77) were examined. Sequence analysis was performed for genes encoding GAP junction protein alpha 1 (GJA1/connexin 43) and gap junction protein alpha 4 (GJA4/connexin 37). Cytokines were assessed in serum and induced sputum (IS) by chemiluminescence (DPC Biermann, Bad Homburg, Germany) as well as leukocyte counts.
Results: DNA analysis was performed in 35 patients. Whereas GJA1 showed only one rare heterozygous synonymous SNP (rs138386744) in one patient, four common SNPs were detected in GJA4. Two were synonymous changes, but the third variant (rs41266431) predicts an amino acid substitution (GTA → valine, ATA → isoleucine) as well as the fourth SNP (rs1764391: CCC→proline, TCC→serine). For rs41266431 patients with homozygosity for the G variant had higher IL-8 levels (median: 13.3/8.0 pg/ml, p=0.07) in serum as well as leukocytes in sputum (median: 2050/421 /µl p=0.041) than those showing heterozygosity (G/A). In individuals > 30 years lung function (FEV1 41.3/84.83 % predicted, p=0.07) was worse.
Conclusion: SNP rs41266431 seems a promising candidate for further investigations, suggesting GJA4 a potential disease modifying gene.
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.
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-1β, 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.