Ludger Klimek’s research while affiliated with Universitätsmedizin der Johannes Gutenberg-Universität Mainz and other places

The transitioning of named patient products (NPPs) of therapy allergens is regulated under the German therapy allergen ordinance (TAO) since 2008. The establishment of a sound dose–response relationship constitutes a pivotal aspect in clinical development programs of drugs in general. Up to now, there are only few comprehensive studies dedicated to the determination of a dose–response relationship in allergen immunotherapy (AIT) because of various challenges. Among these aggravating factors are high placebo effects, variability of trial endpoints and especially for native allergens a narrow therapeutic window and safety profile. The phase II trials of the modified allergen tyrosine associated—monophosphoryl lipid A (MATA MPL) platform for birch and grasses established convincing and significant dose–response relationships decisive for AIT product optimization. The significant dose–response relationship for birch and grass allergoids reached an efficacy plateau and allowed the definition of critical milestones in drug development such as the median effective dose (ED50) for the MATA MPL platform combining modified allergens (allergoids) with microcrystalline tyrosine (MCT) and MPL in an adjuvant system. This marked a pivotal milestone in AIT drug development allowing the definition of the “optimal dose” (optimal risk–benefit ratio) to be taken forward to phase III trial. The MATA MPL platform is characterized by a scientifically sound dose–response relationship across allergens which underlines the pivotal role of a well-defined optimal dose as a success factor for phase III.

Chronic rhinosinusitis (CRS) is a clinical syndrome defined by typical sinonasal symptoms persisting for at least 12 weeks. CRS is divided into two distinct phenotypes, CRS with nasal polyps (CRSwNP) and without (CRSsNP). The aim of the review is to provide an update on the current knowledge in CRS endotypes. The prevailing hypothesis regarding the pathogenesis of CRS suggests that dysfunctional interactions between the host and environmental stressors at the mucosal surface drive the diverse inflammatory mechanisms. Genetic and epigenetic variations in the mucosal immune system are believed to play a significant role in the pathomechanisms of CRS. Various environmental agents (such as microbes and irritants) have been implicated in CRS. In a healthy state, the sinonasal mucosa acts as a barrier, modulating environmental stimulation and mounting appropriate immune responses against pathogens with minimal tissue damage. Different endotypes may exist based on the specific mechanistic pathways driving the chronic tissue inflammation of CRS. There is a need to understand endotypes in order to better predict, diagnose, and treat CRS. This literature review provides an update on the role of the endotypes in CRS and the limitations of endotyping CRS in clinical practice. Understanding of the pathogenesis and optimal management of CRS has progressed significantly in the last decades; however, there still are several unmet needs in endotype research.

Introduction: Antimicrobial resistance poses a significant global health threat, partly due to the overprescription of antibiotics. Understanding prescribers’ behaviors and identifying knowledge gaps and misconceptions are essential for addressing antibiotic misuse and inappropriate use. Methods: Through online questionnaires, this study surveyed key stakeholders in outpatient antibiotic use in Germany (DE) and Poland (PL), including patients, physicians, and pharmacists. Results: Despite generally good knowledge about antibiotics, discrepancies exist between physicians’ perceptions and patients’ actual expectations regarding antibiotic prescriptions. Physicians often misjudge patients’ attitudes toward antibiotics, with many patients having a neutral stance. This study found a strong physician interest in non-antibiotic treatments and patient willingness to engage with information about antibiotics. Conclusions: Improved communication between healthcare providers and patients was identified as a potential measure for enhancing antimicrobial stewardship, with education on effective alternative treatments, such as symptomatic therapies, as a likely strategy to reduce antibiotic reliance.

Purpose of the Review Thymic stromal lymphopoietin (TSLP) is increasingly recognized for its pivotal role in the pathogenesis of various epithelial-driven chronic inflammatory diseases. This review navigates the existing evidence on TSLP, with a particular focus on asthma, before delving into the current understanding of its role in chronic rhinosinusitis with nasal polyps (CRSwNP). We explore the role of TSLP in the pathogenesis of asthma and CRSwNP, two conditions often interconnected and collectively referred to as”Global Airway Disease”. Additionally, this review assesses the therapeutic potential of TSLP inhibition as a treatment option for both CRSwNP and asthma. A systematic literature search was conducted; selected publications were used to describe the biology of TSLP, including its expression and diverse effects on inflammation. Recent Findings The role of TSLP in asthma is well established and supported by the efficacy of tezepelumab, the first anti-TSLP monoclonal antibody approved for both type 2 (T2)-high and T2-low severe asthma. TSLP may be a key contributor to CRSwNP pathogenesis as evidenced by genetic and mechanistic studies in which TSLP has been shown to regulate T2 inflammation and influence non-T2 responses. Preliminary data from the NAVIGATOR trial indicate that tezepelumab may reduce CRSwNP symptoms in patients with comorbid asthma. Summary While further research is required to clarify the extent of TSLP contribution in CRSwNP, this review highlights the potential of anti-TSLP therapies as a novel approach for managing severe, uncontrolled CRSwNP. If these preliminary findings are confirmed, targeting TSLP could become a promising strategy to treat CRSwNP with or without comorbid asthma.

Background Allergic rhinitis (AR) is a highly prevalent disease. We aimed to assess the symptoms that physicians who see patients with AR perceive as the most bothersome in their patients. Methods We performed a cross-sectional study based on an online questionnaire sent to all members of the Allergic Rhinitis and its Impact on Asthma (ARIA) initiative. The survey included questions on the physicians' perceptions of patients’ AR symptoms as well as of their own AR symptoms. Results Among 401 respondents, 155 (38.7%) reported having AR. ARIA members reported nasal symptoms to be the most frequent (89.7%) and bothersome (80.0%) symptoms experienced by themselves. Likewise, nasal symptoms were reported by ARIA members as the most frequent (94.8% in members with AR vs 96.0% in members without AR) and bothersome (57.0% in members with AR vs 67.9% in members without AR) in their patients. We found a significant association (p = 0.001) between physicians’ own symptoms and those perceived as the most bothersome in their patients. Conclusion Physicians perceive nasal symptoms to be the most frequent and the most bothersome symptoms in AR patients. The physicians' personal experiences with AR may influence their perception of patients’ symptoms.