Eosinophil granulocytes in chronic inflammatory respiratory diseases and CRSwNP: Function, immunological basis, and clinical significance.

INTRODUCTION: Eosinophils play an important regulatory and immunomodulatory role in airway mucosa and have antiparasitic and antiviral properties as well as pro-inflammatory effects that may also cause persistence of inflammation with tissue remodeling. The number of eosinophils and the detection of specific mediators in biological samples from, e.g., blood, nasal secretions, and bronchial fluid can serve as biomarkers that reflect the underlying pathophysiology of certain diseases, predict treatment success, and detect therapy effects. MATERIALS AND METHODS: A literature search was conducted to determine the immunologic basis, mode of action, clinical significance, and available evidence for therapeutic approaches using eosinophil-targeted monoclonal antibodies by searching Medline, Pubmed, and the national and international trial database (ClinicalTrials.gov) and guideline registries as well as the Cochrane Library. Human studies published on the topic in the period up to and including 10/2023 were considered. RESULTS: Based on the international literature and previous experience, the results are summarized, and recommendations are given. CONCLUSION: The important role of eosinophils in immunological processes in the airway mucosa is comprehensively analyzed and can serve as a basis for current and future treatment approaches.

EGPA: Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) as a special presentation of chronic rhinosinusitis with nasal polyps (CRSwNP).

INTRODUCTION: Eosinophilic granulomatosis with polyangiitis (EGPA) was formerly known as Churg-Strauss syndrome. The condition is characterized by disseminated necrotizing vasculitis with extravascular granulomas associated with hypereosinophilia. The vasculitides affect small vessels and are associated with antineutrophil cytoplasmic antibodies (ANCAs) detectable in the blood. Distinguishing between type 2-mediated chronic airway inflammation such as chronic rhinosinusitis with nasal polyps (CRSwNP) without vasculitis can be clinically challenging and should be considered. MATERIALS AND METHODS: Immunological background, diagnosis, and therapy of EGPA were identified through literature searches in Medline, PubMed, as well as national and international studies (ClinicalTrials.gov) and the Cochrane Library. Human studies published up to and including 10/2023 on the topic were considered. RESULTS: In cases of deteriorating general health with previously known eosinophilic inflammation of the upper and lower airways, EGPA and its interdisciplinary investigation should be considered. Various types of eosinophilic inflammation and syndromes must be considered differentially. CONCLUSION: Characterization of mucosal airway inflammation through biomarker determination is meaningful and occasionally makes the difference for targeted therapy.

Monitoring mepolizumab treatment in chronic rhinosinusitis with nasal polyps (CRSwNP): Discontinue, change, continue therapy?

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the mucous membranes of the nose and sinuses. Eosinophilic inflammation is described as a common endotype. The anti-IL-5 antibody mepolizumab was approved in November 2021 as an add-on therapy to intranasal glucocorticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps when systemic glucocorticosteroids or surgery do not provide adequate disease control. While national and international recommendations exist for the use of mepolizumab in CRSwNP, it has not yet been adequately specified how this therapy should be monitored, what follow-up documentation is necessary, and when it should be discontinued if necessary. MATERIALS AND METHODS: A literature search was performed to analyze previous data on the treatment of CRSwNP with mepolizumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries, and the Cochrane Library. Human studies published in the period up to and including 10/2022 were considered. RESULTS: Based on the international literature and previous experience by an expert panel, recommendations for follow-up, adherence to therapy intervals, and possible therapy breaks as well as discontinuation of therapy when using mepolizumab for the indication CRSwNP in the German healthcare system are given on the basis of a documentation sheet. CONCLUSION: Understanding the immunological basis of CRSwNP opens up new non-surgical therapeutic approaches with biologics for patients with severe, uncontrolled courses. Here, we provide recommendations for follow-up, adherence to therapy intervals, possible therapy pauses, or discontinuation of therapy when mepolizumab is used as add-on therapy with intranasal glucocorticosteroids to treat adult patients with severe CRSwNP that cannot be adequately controlled with systemic glucocorticosteroids and/or surgical intervention.

The pharmacotherapeutic management of allergic rhinitis in people with asthma.

INTRODUCTION: Up to 90% of asthmatic patients have comorbid allergic rhinitis (AR). Although appropriate therapy of AR can improve asthma symptoms and management, AR is often underdiagnosed and under-treated in asthmatics.A non-systematic literature research was conducted on AR as a comorbidity and risk factor of asthma. Latest international publications in medical databases, international guidelines, and the Internet were reviewed. AREAS COVERED: Based on the conducted literature research there is proved evidence of the necessity of diagnosis and treatment of AR in patients with asthma because it affects health care utilization. Therefore, it is recommended in national and global guidelines. EXPERT OPINION: AR increases the risk of asthma development and contributes to the severity of an existing asthma. Early treatment of AR with drugs as intranasal steroids, antihistamines, leukotriene receptor antagonists, and especially allergen-specific immunotherapy can reduce the risk of asthma development and the concomitant medication use in addition to severity of symptoms in AR and asthma.

Epithelial immune regulation of inflammatory airway diseases: Chronic rhinosinusitis with nasal polyps (CRSwNP).

BACKGROUND: The epithelial immune regulation is an essential and protective feature of the barrier function of the mucous membranes of the airways. Damage to the epithelial barrier can result in chronic inflammatory diseases, such as chronic rhinosinusitis (CRS) or bronchial asthma. Thymic stromal lymphopoietin (TSLP) is a central regulator in the epithelial barrier function and is associated with type 2 (T2) and non-T2 inflammation. MATERIALS AND METHODS: The immunology of chronic rhinosinusitis with polyposis nasi (CRSwNP) was analyzed in a literature search, and the existing evidence was determined through searches in Medline, Pubmed as well as the national and international study and guideline registers and the Cochrane Library. Human studies or studies on human cells that were published between 2010 and 2020 and in which the immune mechanisms of TSLP in T2 and non-T2 inflammation were examined were considered. RESULTS: TSLP is an epithelial cytokine (alarmin) and a central regulator of the immune reaction, especially in the case of chronic airway inflammation. Induction of TSLP is implicated in the pathogenesis of many diseases like CRS and triggers a cascade of subsequent inflammatory reactions. CONCLUSION: Treatment with TSLP-blocking monoclonal antibodies could therefore open up interesting therapeutic options. The long-term safety and effectiveness of TSLP blockade has yet to be investigated.

Use of telemedicine by practising allergists before and during the SARS-CoV-2 pandemic: A survey among members of the Association of German Allergists (AeDA).

BACKGROUND: The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic presented unprecedented challenges to both inpatient and outpatient care. In order to maintain good care under necessary contact restrictions, especially in the outpatient sector, the use of telemedical applications was demanded and promoted. The exploratory survey among members of the Association of German Allergists (AeDA) was intended to show how these were received among allergists in private practice. METHODS: The survey was restricted to actively practising members of the AeDA who had previously given their consent to receive such surveys (n = 437). They were invited by email to participate in a survey on the topic of "Telemedicine in everyday clinical practice in allergology". The survey included quantitative and qualitative questions on the use of telemedicine services before and during the pandemic and was conducted anonymously on the SoSci Survey platform. Participation was possible in the period from June to August 2020. RESULTS: In all, 76 specialists with additional qualification in allergology took part in the survey. Of these, 71 completed the full questionnaire. Before the start of the pandemic-related contact restrictions, 46.5% (33/71) stated that they had used telemedicine in their clinical practice. This number increased to 73.2% (52/71) after 31 January 2020. The largest increase (4.3% vs. 15.6%) was seen in the area of video consultations. Furthermore, 43/76 participants can imagine integrating telemedicine services into their daily clinical routine in the future. CONCLUSION: The use of telemedical services, especially video consultations, increased significantly during the SARS-CoV­2 pandemic in Germany. The majority of respondents perceive the implementation as positive and can imagine continuing to use telemedical methods after the end of the pandemic.

Telemedicine in allergology: practical aspects: A position paper of the Association of German Allergists (AeDA).

Since spring 2020, the wide-ranging contact restriction measures in the context of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic have also led to a reduction in physician-patient contacts in the ambulatory care setting. Telemedicine applications will increasingly provide a way to efficiently deliver patient care under infection control measures. In allergology, telemedical as well as digital applications can also significantly facilitate everyday clinical practice. However, the technical and legal hurdles associated with the implementation of digital strategies must be overcome for this to happen. The aim of this article is to provide an intuitive overview of the aspects to be considered in the implementation of telemedicine consultations and to highlight the current state of the framework as well as optimization possibilities and perspectives in allergology. If a structured use is guaranteed, digital and telemedical applications can improve patient care-also in allergology. There is potential to be exploited in many areas, from the remote collection of clinical history, and video consultations, to the discussion of diagnostic findings, disease monitoring, and therapy support. The use of telemedical applications, especially video consultations, has experienced a remarkable acceleration in the context of the coronavirus disease 2019 (COVID-19) pandemic. The present overview of the legal, technical and professional framework is intended to support the anchoring of digital and telemedical technologies in everyday allergology. However, in order to consolidate these in the future, an agreement is needed regarding professional standards of action as well as a remuneration structure that is permanently defined beyond the current pandemic.

Use of biologicals in allergic and type-2 inflammatory diseases during the current COVID-19 pandemic: Position paper of Ärzteverband Deutscher Allergologen (AeDA)A, Deutsche Gesellschaft für Allergologie und Klinische Immunologie (DGAKI)B, Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA)C, Österreichische Gesellschaft für Allergologie und Immunologie (ÖGAI)D, Luxemburgische Gesellschaft für Allergologie und Immunologie (LGAI)E, Österreichische Gesellschaft für Pneumologie (ÖGP)F in co-operation with the German, Austrian, and Swiss ARIA groupsG, and the European Academy of Allergy and Clinical Immunology (EAACI)H.

BACKGROUND: Since the beginning of the COVID-19 pandemic, the treatment of patients with allergic and atopy-associated diseases has faced major challenges. Recommendations for "social distancing" and the fear of patients becoming infected during a visit to a medical facility have led to a drastic decrease in personal doctor-patient contacts. This affects both acute care and treatment of the chronically ill. The immune response after SARS-CoV-2 infection is so far only insufficiently understood and could be altered in a favorable or unfavorable way by therapy with monoclonal antibodies. There is currently no evidence for an increased risk of a severe COVID-19 course in allergic patients. Many patients are under ongoing therapy with biologicals that inhibit type 2 immune responses via various mechanisms. There is uncertainty about possible immunological interactions and potential risks of these biologicals in the case of an infection with SARS-CoV-2. MATERIALS AND METHODS: A selective literature search was carried out in PubMed, Livivo, and the internet to cover the past 10 years (May 2010 - April 2020). Additionally, the current German-language publications were analyzed. Based on these data, the present position paper provides recommendations for the biological treatment of patients with allergic and atopy-associated diseases during the COVID-19 pandemic. RESULTS: In order to maintain in-office consultation services, a safe treatment environment must be created that is adapted to the pandemic situation. To date, there is a lack of reliable study data on the care for patients with complex respiratory, atopic, and allergic diseases in times of an imminent infection risk from SARS-CoV-2. Type-2-dominant immune reactions, as they are frequently seen in allergic patients, could influence various phases of COVID-19, e.g., by slowing down the immune reactions. Theoretically, this could have an unfavorable effect in the early phase of a SARS-Cov-2 infection, but also a positive effect during a cytokine storm in the later phase of severe courses. However, since there is currently no evidence for this, all data from patients treated with a biological directed against type 2 immune reactions who develop COVID-19 should be collected in registries, and their disease courses documented in order to be able to provide experience-based instructions in the future. CONCLUSION: The use of biologicals for the treatment of bronchial asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, and spontaneous urticaria should be continued as usual in patients without suspected infection or proven SARS-CoV-2 infection. If available, it is recommended to prefer a formulation for self-application and to offer telemedical monitoring. Treatment should aim at the best possible control of difficult-to-control allergic and atopic diseases using adequate rescue and add-on therapy and should avoid the need for systemic glucocorticosteroids. If SARS-CoV-2 infection is proven or reasonably suspected, the therapy should be determined by weighing the benefits and risks individually for the patient in question, and the patient should be involved in the decision-making. It should be kept in mind that the potential effects of biologicals on the immune response in COVID-19 are currently not known. Telemedical offers are particularly desirable for the acute consultation needs of suitable patients.

[Therapy of Allergies and Allergy Immunotherapy in Children]. / Allergietherapie und Allergie-Immuntherapie im Kindesalter.

Adequate diagnostical workup for respiratory allergies and consequent therapy in children determine the individual course of disease. Therapy consists first of symptomatic treatment and includes in the next step the important option of allergy immunotherapy (AIT) as a causative treatment of disease. Children are an important target group for AIT, since AIT offers a proven longterm effect including secondary preventive properties with not only transiently reduced symptoms but moreover longstanding and beneficial disease modification.New strategies with AIT as primary and secondary preventive interventions are being evaluated with the aim to reduce clinical appearance and the amount and extent of sensitizations to allergens in high-risk children. Until implementation of such potentially preventive strategies the currently more attractive early intervention is the early adoption of AIT within the first 12 to 24 months of onset of symptoms as a first-line treatment of allergic rhinitis.Simplified treatment protocols can improve the willingness to perform an AIT and the adherence and compliance of children and their parents. The overall goal is to make AIT as the most important treatment modality available to more affected children.

ARIA guideline 2019: treatment of allergic rhinitis in the German health system.

BACKGROUND: The number of patients affected by allergies is increasing worldwide. The resulting allergic diseases are leading to significant costs for health care and social systems. Integrated care pathways are needed to enable comprehensive care within the national health systems. The ARIA (Allergic Rhinitis and its Impact on Asthma) initiative develops internationally applicable guidelines for allergic respiratory diseases. METHODS: ARIA serves to improve the care of patients with allergies and chronic respiratory diseases. In collaboration with other international initiatives, national associations and patient organizations in the field of allergies and respiratory diseases, real-life integrated care pathways have been developed for a digitally assisted, integrative, individualized treatment of allergic rhinitis (AR) with comorbid asthma. In the present work, these integrated care pathways have been adapted to the German situation and health system. RESULTS: The present ICP (integrated care pathway) guideline covers key areas of the care of AR patients with and without asthma. It includes the views of patients and other healthcare providers. DISCUSSION: A comprehensive ICP guideline can reflect real-life care better than traditional guideline models.

Post-transcriptional regulation of the human inducible nitric oxide synthase (iNOS) expression by the cytosolic poly(A)-binding protein (PABP).

Affinity purification using the 3'-untranslated region (3'-UTR) of the human inducible nitric oxide synthase (iNOS) mRNA identified the cytosolic poly(A)-binding protein (PABP) as a protein interacting with the human iNOS 3'-UTR. Downregulation of PABP expression by RNA interference resulted in a marked reduction of cytokine-induced iNOS mRNA expression without changes in the expression of mRNAs coding for the major subunit of the RNA polymerase II (Pol 2A) or ß2-microglobuline (ß2M). Along with the mRNA also iNOS protein expression was reduced by siPABP-treatment, whereas in the same cells protein expression of STAT-1α, NF-κB p65, or GAPDH was not altered. Reporter gene analyses showed no change of the inducibility of the human 16kb iNOS promoter in siPABP cells. In contrast, the siPABP-mediated decline of iNOS expression correlated with a reduction in the stability of the iNOS mRNA. As the stability of the Pol 2A and ß2M mRNA was not changed, siPABP-treatment seems to have a specific effect on iNOS mRNA decay. UV-crosslinking experiments revealed that PABP interacts with one binding site in the 5'-UTR and two different binding sites in the 3'-UTR of the human iNOS mRNA. Mutation or deletion of the binding site in the 5'-UTR but not in the 3'-UTR reduced luciferase expression in DLD-1 cells transfected with iNOS-5'-UTR or iNOS-3'-UTR luciferase reporter constructs. In summary, our data demonstrate that PABP by binding to specific sequence elements in the 5'-UTR post-transcriptionally enhances human iNOS mRNA stability and thereby iNOS expression.