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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.
COPD and asthma are two distinct but sometimes overlapping diseases exhibiting varying degrees and types of inflammation on different stages of the disease. Although several biomarkers are defined to estimate the inflammatory endotype and stages in these diseases, there is still a need for new markers and potential therapeutic targets. We investigated the levels of a phytohormone, abscisic acid (ABA) and its receptor, LANCL2, in COPD patients and asthmatics. In addition, PPAR-γ that is activated by ABA in a ligand-binding domain-independent manner was also included in the study. In this study, we correlated ABA with COPD-propagating factors to define the possible role of ABA, in terms of immune regulation, inflammation, and disease stages. We collected blood from 101 COPD patients, 52 asthmatics, and 57 controls. Bronchoscopy was performed on five COPD patients and 29 controls. We employed (i) liquid chromatography–tandem mass spectrometry and HPLC to determine the ABA and indoleamine 2,3-dioxygenase levels, respectively; (ii) real-time PCR to quantify the gene expression of LANCL2 and PPAR-γ; (iii) Flow cytometry to quantify adipocytokines; and (iv) immunoturbidimetry and ELISA to measure CRP and cytokines, respectively. Finally, a multinomial regression model was used to predict the probability of using ABA as a biomarker. Blood ABA levels were significantly reduced in COPD patients and asthmatics compared to age- and gender-matched normal controls. However, PPAR-γ was elevated in COPD patients. Intriguingly, ABA was positively correlated with immune-regulatory factors and was negatively correlated with inflammatory markers, in COPD. Of note, ABA was increased in advanced COPD stages. We thereby conclude that ABA might be involved in regulation of COPD pathogenesis and might be regarded as a potential biomarker for COPD stages.
Children are commonly exposed to second-hand smoke (SHS) in the domestic environment or inside vehicles of smokers. Unfortunately, prenatal tobacco smoke (PTS) exposure is still common, too. SHS is hazardous to the health of smokers and non-smokers, but especially to that of children. SHS and PTS increase the risk for children to develop cancers and can trigger or worsen asthma and allergies, modulate the immune status, and is harmful to lung, heart and blood vessels. Smoking during pregnancy can cause pregnancy complications and poor birth outcomes as well as changes in the development of the foetus. Lately, some of the molecular and genetic mechanisms that cause adverse health effects in children have been identified. In this review, some of the current insights are discussed. In this regard, it has been found in children that SHS and PTS exposure is associated with changes in levels of enzymes, hormones, and expression of genes, micro RNAs, and proteins. PTS and SHS exposure are major elicitors of mechanisms of oxidative stress. Genetic predisposition can compound the health effects of PTS and SHS exposure. Epigenetic effects might influence in utero gene expression and disease susceptibility. Hence, the limitation of domestic and public exposure to SHS as well as PTS exposure has to be in the focus of policymakers and the public in order to save the health of children at an early age. Global substantial smoke-free policies, health communication campaigns, and behavioural interventions are useful and should be mandatory.
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.
Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations.
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
Asthma bronchiale ist eine obstruktive Lungenerkrankung, die mit einer Hyperreagibilität der Atemwege verbunden ist, ausgelöst durch eine Vielzahl von Stimuli. Es stellt die häufigste chronische Erkrankung im Kindesalter dar, ist jedoch bei Säuglingen und Kleinkindern nur schwer zu diagnostizieren. In diesem Alter stellen sehr häufig rezidivierende, teilweise durch (Virus-) Infekte ausgelöste obstruktive Bronchitiden die ersten Symptome eines Asthma bronchiale dar. In der vorliegenden Arbeit wurde an einem Patientenkollektiv von 172 Säuglingen und Kleinkindern (m:w = 115:57; Alter in Monaten = 13,1+/-11) mittels Bodyplethysmographie und Metacholin-Provokation untersucht, wie häufig einer rezidivierend obstruktiven Symptomatik eine bronchiale Hyperreagibilität (BHR) zugrunde liegt, und ob Kinder mit Risikofaktoren für ein Asthma bronchiale Unterschiede in der Lungenfunktion oder in der Reaktion auf eine Metacholin-Provokation zeigen im Vergleich zu Kindern ohne vorbestehende Risikofaktoren. Als Risikofaktoren galten Atopie, Allergie (erhöhte eosinophile Leukozyten, erhöhte IgE-Werte, positiver RAST) sowie eine Passivrauch-Exposition durch Tabakrauch der Eltern, die anhand eines Fragebogens ermittelt wurden. Insgesamt reagierten 26 der 108 Kinder mit RAST (24,1%) leicht- bis hochgradig, aber nur 14 der 108 Kinder (13,0%) mittel- bis hochgradig hyperreagibel, wobei ein Anstieg des Atemwegswiderstandes von mindestens 80% des Ausgangswertes, ein Abfall der Sauerstoffsättigung unter 95% sO2 oder eine klinische Symptomatik in Form von Husten und / oder Giemen, bzw. die Erfüllung mehrerer Kriterien als positive Reaktion gewertet wurde, gemäß den PD20-Leitlinien abhängig von der verabreichten Metacholin-Dosis. Hierbei zeigten Kinder mit atopischer Dermatitis tendenziell häufiger eine mittel- bis hochgradige BHR als das Vergleichskollektiv (mittel- bis hochgradige BHR: Kinder ohne Risikofaktoren= 14,1%; Kinder mit Atopie= 20,8%). Weitere Zusammenhänge zwischen Risikofaktoren für ein Asthma bronchiale und eine BHR konnten nicht festgestellt werden. Auch fand sich zwischen Tabakrauch-Exposition (exponierte Kinder: n=36; nicht exponierte Kinder: n=102) und der BHR keine Beziehung. Unsere Untersuchungen belegen, dass eine mittel- bis hochgradige Hyperreagibilität im Sinne eines Asthmasyndroms nur bei einem geringen Anteil (13,0%) der Kinder mit obstruktiven Bronchitiden nachweisbar ist. Entsprechend kritisch sollte der Einsatz von inhalativen Steroiden bei Kindern mit obstruktiven Zeichen gestellt werden.