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Background: Chronic rhinosinusitis with nasal polyps affects approximately 2–4% of the general population, and long-term use of systemic corticosteroids is associated with adverse effects. The aim of this study was to assess the efficacy and safety of mepolizumab in adults with recurrent, refractory severe bilateral chronic rhinosinusitis with nasal polyps. Methods: SYNAPSE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done at 93 centres, mainly hospitals, in 11 countries. Eligible patients were aged 18 years or older with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. Patients were randomly assigned (1:1), using permuted block design, to receive either 100 mg mepolizumab subcutaneously or placebo once every 4 weeks, in addition to standard of care (mometasone furoate intranasal spray for at least 8 weeks before screening and during the study, saline nasal irrigations, systemic corticosteroids or antibiotics, or both), as required, for 52 weeks. Site staff, the central study team, and patients were masked to study treatment and absolute blood eosinophil counts. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49–52, assessed in the intention-to-treat population (ITT). This study is registered with ClinicalTrials.gov, NCT03085797. Findings: From May 25, 2017, to Dec 12, 2018, 854 patients were screened for eligibility. 414 patients were randomly assigned with 407 included in the ITT population; 206 received mepolizumab and 201 received placebo. Total endoscopic nasal polyp score significantly improved at week 52 from baseline with mepolizumab versus placebo (adjusted difference in medians −0·73, 95% CI −1·11 to −0·34; p

Hintergrund Die chronische Rhinosinusitis (CRS) betrifft weltweit ca. 5–12 % der Allgemeinbevolkerung und wird traditionell eingeteilt in einen Phanotyp ohne (CRSsNP) und einen mit Ausbildung von Nasenpolypen (CRSwNP). Wurden Nasenpolypen bis vor kurzem eher als mechanisches Hindernis mit der Notwendigkeit einer operativen Beseitigung betrachtet, wird die CRSwNP heute als eine multifaktorielle entzundliche Erkrankung der nasalen und paranasalen Schleimhaute angesehen, der als Endotyp haufig eine T2-Inflammation zugrunde liegt. Biologika, die mit diesen Entzundungsmechanismen interferieren, stellen interessante neue Therapiemoglichkeiten dar. Methoden Das aktuelle Wissen zur Immunologie der CRSwNP und Wirkung von Biologika wurde mittels einer Literaturanalyse durch Recherchen in Medline, PubMed sowie den nationalen und internationalen Studien- und Leitlinienregistern und der Cochrane Library zusammengestellt. Ergebnisse Basierend auf der internationalen Literatur und bisherigen Erfahrungen werden von einem Expertengremium Empfehlungen fur die Anwendung von Biologika bei CRSwNP im deutschen Gesundheitssystem auf der Grundlage eines Dokumentationsbogens gegeben. Schlussfolgerung Das Verstandnis uber die immunologischen Grundlagen der CRSwNP eroffnet neue nichtoperative Therapieansatze mit Biologika fur Patienten mit schweren Verlaufsformen.

ZusammenfassungHintergrund Die chronische Rhinosinusitis mit Nasenpolypen (CRSwNP) ist eine multifaktorielle entzündliche Erkrankung, oftmals auf der Grundlage einer Typ-2-Inflammation. Für die Behandlung von Patienten mit einer schweren Ausprägung ohne ausreichendes Ansprechen auf die Standardtherapie mit topischen nasalen Steroiden und/oder Zustand nach endonasaler Operation sind als Biologika aktuell Dupilumab und Omalizumab für die Therapie zugelassen. Nachdem wir in einer früheren Publikation für Dupilumab bereits entsprechende Hinweise gegeben haben, ist das Ziel der vorliegenden Arbeit die Standardisierung von Patienteninformation und -aufklärung vor einer Therapie mit Omalizumab.Methoden Auf Grundlage des aktuellen Wissensstandes zur Immunologie der CRSwNP und zu den erwünschten und möglichen unerwünschten Wirkungen von Omalizumab werden Empfehlungen für die Patienteninformation entwickelt.Ergebnisse Basierend auf der internationalen Literatur, der aktuellen Fachinformation und Erfahrungen aus der praktischen Anwendung und den derzeitigen Pharmakovigilanz-Daten hat ein Expertengremium Empfehlungen für die Patienteninformation und -aufklärung zur Anwendung von Omalizumab bei CRSwNP entwickelt und auf dieser Grundlage einen Patienteninformations- und Aufklärungsbogen erstellt.Schlussfolgerung Die Information und Einwilligung des Patienten wird vor der Verordnung bzw. Verabreichung von allen Biologika, damit auch Omalizumab, empfohlen. Das vorliegende Positionspapier enthält wichtige Informationen zur praktischen Umsetzung und einen Vorschlag für eine Patienteninformation.

The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review. ispartof: EUROPEAN RESPIRATORY JOURNAL vol:60 issue:2 ispartof: location:England status: published

Background Native allergen extracts or chemically modified allergoids are routinely used to induce allergen tolerance in allergen-specific immunotherapy (AIT), although mechanistic side-by-side studies are rare. It is paramount to balance optimal dose and allergenicity to achieve efficacy warranting safety. AIT safety and efficacy could be addressed by allergen dose reduction and/or use of allergoids and immunostimulatory adjuvants, respectively. In this study, immunological effects of experimental house dust mite (HDM) AIT were investigated applying high-dose HDM extract and low-dose HDM allergoids with and without the adjuvants microcrystalline tyrosine (MCT) and monophosphoryl lipid A (MPL) in a murine model of HDM allergy. Methods Cellular, humoral, and clinical effects of the different AIT strategies were assessed applying a new experimental AIT model of murine allergic asthma based on physiological, adjuvant-free intranasal sensitization followed by subcutaneous AIT. Results While low-dose allergoid and high-dose extract AIT demonstrated comparable potency to suppress allergic airway inflammation and Th2-type cytokine secretion of lung-resident lymphocytes and draining lymph node cells, low-dose allergoid AIT was less effective in inducing a potentially protective IgG1 response. Combining low-dose allergoid AIT with MCT or MCT and dose-adjusted MPL promoted Th1-inducing mechanisms and robust B-cell activation counterbalancing the allergic Th2 immune response. Conclusion Low allergen doses induce cellular and humoral mechanisms counteracting Th2-driven inflammation by using allergoids and dose-adjusted adjuvants. In light of safety and efficacy improvement, future therapeutic approaches may use low-dose allergoid strategies to drive cellular tolerance and adjuvants to modulate humoral responses.

ZusammenfassungInnovative und wirksame Impfstrategien entwickeln sich zum wichtigsten Hebel zur Bekämpfung der durch SARS-COV-2 ausgelösten globalen Pandemie. Innerhalb weniger Monate wurden durch Wissenschaftler weltweit vielversprechende neue Vakzine entwickelt; hierbei nutzen mehrere Impfstoffe das Prinzip adenoviraler Vektoren zum Einbringen der eigentlich immunogenen Moleküle des SARS-Coronavirus zum Auslösen einer Immunantwort. Die vom russischen Gamaleya-Institut entwickelte COVID-19-Vakzine Sputnik V (Gam-COVID-Vac) nutzt die adenoviralen Vektoren 26 und 5, um das vollständige SARS-Spike-Protein zur Impfung einzubringen, wobei die unterschiedlichen adenoviralen Vektoren mögliche neutralisierende Effekte gegen Adenoviren umgehen und dadurch eine ausreichende Immunogenität auch bei der Zweitimpfung (booster) gewährleisten. Die bisher veröffentlichten Studien werden teils kontrovers diskutiert, u. a. wegen kleiner Fallzahlen in Phase II und früher klinischer Endpunkte in der Phase III. Auch die bisher fehlende Verfügbarkeit der vollständigen Studienprotokolle und Datensätze wurde in der wissenschaftlichen Gemeinschaft zur Kenntnis genommen. Vulnerable Patientengruppen könnten durch eine wie in Brasilien beschriebene erhaltene Vermehrungsfähigkeit der Ad5-Adenoviren oder wie in der Slowakei beobachtete fehlende Chargenreproduzierbarkeit gefährdet werden, ein Wirksamkeitsverlust der Impfung bei Gesunden ist möglich. Die finale Bewertung in einem geordneten Zulassungsverfahren (z. B. EMA) bleibt daher abzuwarten.

BACKGROUND Studies show that proallergic TH 2 cells decrease after successful allergen-specific immunotherapy (AIT). It is likely that iatrogenic administration of allergens drives these cells to exhaustion due to chronic T-cell receptor stimulation. This study aimed to investigate the exhaustion of T cells in connection with allergen exposure during AIT in mice and two independent patient cohorts. METHODS OVA-sensitized C57BL/6J mice were challenged and treated with OVA, and the development of exhaustion in local and systemic TH 2 cells was analyzed. In patients, the expression of exhaustion-associated surface markers on TH 2 cells was evaluated using flow cytometry in a cross-sectional grass pollen allergy cohort with and without AIT. The treatment effect was further studied in PBMC collected from a prospective long-term AIT cohort. RESULTS The exhaustion-associated surface markers CTLA-4 and PD-1 were significantly upregulated on TH 2 cells upon OVA aerosol exposure in OVA-allergic compared to non-allergic mice. CTLA-4 and PD-1 decreased after AIT, in particular on the surface of local lung TH 2 cells. Similarly, CTLA-4 and PD-1 expression was enhanced on TH 2 cells from patients with allergic rhinitis with an even stronger effect in those with concomitant asthma. Using an unbiased Louvain clustering analysis, we discovered a late-differentiated TH 2 population expressing both markers that decreased during up-dosing but persisted long term during the maintenance phase. CONCLUSIONS This study shows that allergen exposure promotes CTLA-4 and PD-1 expression on TH 2 cells and that the dynamic change in frequencies of exhausted TH 2 cells exhibits a differential pattern during the up-dosing versus the maintenance phases of AIT.

ZusammenfassungObwohl allergische Reaktionen auf mRNA-COVID-19-Impfstoffe selten sind, ist durch die hohe Zahl der durchzuführenden Impfungen mit Anaphylaxien bei Personen zu rechnen, die zuvor auf Impfstoffkomponenten sensibilisiert wurden. Dargelegt werden hier praktische Aspekte zu diagnostischen Möglichkeiten, zur Prävention, zum Erkennen und zur Therapie einer anaphylaktischen Reaktion. Risikopopulationen, die nicht geimpft werden sollten oder die eine allergologische Abklärung vor Impfung benötigen, werden besprochen. Patienten mit Allergien des atopischen Formenkreises sowie Insektengiftallergiker zeigen aus allergologischer Sicht kein erhöhtes Risiko für eine Anaphylaxie durch eine COVID-Impfung.

BackgroundChronic rhinosinusitis is regarded as a chronic airway disease. According to WHO recommendations, it may be a risk factor for COVID-19 patients. In most CRSwNP cases, the inflammatory changes affecting the nasal and paranasal mucous membranes are type-2 (T2) inflammation endotypes. MethodsThe current knowledge on COVID-19 and on treatment options for CRS was analyzed by a literature search in Medline, Pubmed, international guidelines, the Cochrane Library and the Internet. ResultsBased on international literature, on current recommendations by WHO and other international organizations as well as on previous experience, a panel of experts from EAACI and ARIA provided recommendations for the treatment of CRS during the COVID-19 pandemic. ConclusionIntranasal corticosteroids remain the standard treatment for CRS in patients with SARS-CoV-2 infection. Surgical treatments should be reduced to a minimum and surgery preserved for patients with local complications and for those with no other treatment options. Systemic corticosteroids should be avoided. Treatment with biologics can be continued with careful monitoring in noninfected patients and should be temporarily interrupted during the course of the COVID-19 infection.

Zwei Mitarbeiter des National Health Service (NHS) in England entwickelten nach der Verabreichung des BNT162b2-Impfstoffs von BionNTech gegen COVID-19 schwere allergische Reaktionen. Die britische Fachinformation fur den BNT162b2-Impfstoff enthalt bereits Hinweise auf eine Kontraindikation zur Anwendung bei Personen, die allergisch auf den Impfstoff oder einen seiner Bestandteile reagiert haben. Als Vorsichtsmasnahme hat die englische Regulationsbehorde fur Arzneimittel und Gesundheitsprodukte (MHRA) eine vorlaufige Anleitung herausgegeben, "Patienten mit schweren Allergien" grundsatzlich nicht zu impfen. Allergische Reaktionen auf Impfstoffe sind sehr selten, aber Impfstoffkomponenten verursachen bekanntermasen allergische Reaktionen. BNT162b2 ist ein Impfstoff, der auf einer in Lipidnanopartikel eingebetteten mRNA basiert und mit weiteren Substanzen angereichert wird, um den Transport in die Zellen zu ermoglichen. In der zentralen klinischen Phase-III-Studie wurde der BNT162b2-Impfstoff im Allgemeinen gut vertragen. Impfstoffe gelten als eine der wirksamsten Masnahmen im Bereich der offentlichen Gesundheit. Schwere allergische Reaktionen auf Impfstoffe sind selten, konnen jedoch lebensbedrohlich sein. Es ist ratsam, die Impfteams auf diese Gefahr aufmerksam zu machen und angemessene Vorsichtsmasnahmen zu treffen, wahrend mehr Erfahrungen mit dem neuen Impfstoff gesammelt werden.

Background Nonsteroidal anti-inflammatory drug–exacerbated respiratory disease (N-ERD) is a chronic inflammatory condition, which is driven by an aberrant arachidonic acid metabolism. Macrophages are major producers of arachidonic acid metabolites and subject to metabolic reprogramming, but they have been neglected in N-ERD. Objective This study sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD. Methods Transcriptional, metabolic, and lipid mediator profiles in macrophages from patients with N-ERD and healthy controls were assessed by RNA sequencing, Seahorse assays, and LC-MS/MS. Metabolites in nasal lining fluid, sputum, and plasma from patients with N-ERD (n = 15) and healthy individuals (n = 10) were quantified by targeted metabolomics analyses. Genome-wide methylomics were deployed to define epigenetic mechanisms of macrophage reprogramming in N-ERD. Results This study shows that N-ERD monocytes/macrophages exhibit an overall reduction in DNA methylation, aberrant metabolic profiles, and an increased expression of chemokines, indicative of a persistent proinflammatory activation. Differentially methylated regions in N-ERD macrophages included genes involved in chemokine signaling and acylcarnitine metabolism. Acylcarnitines were increased in macrophages, sputum, nasal lining fluid, and plasma of patients with N-ERD. On inflammatory challenge, N-ERD macrophages produced increased levels of acylcarnitines, proinflammatory arachidonic acid metabolites, cytokines, and chemokines as compared to healthy macrophages. Conclusions Together, these findings decipher a proinflammatory metabolic and epigenetic reprogramming of macrophages in N-ERD.

ZusammenfassungImpfungen sind der Goldstandard zur Prophylaxe gefährlicher Infektionserkrankungen. Innerhalb weniger als 12 Monaten seit Entschlüsselung der kodierenden RNA-Sequenzen von SARS-CoV-2 wurden bereits 2 RNA-Impfstoffe gegen COVID-19 in wesentlichen Teilen der Welt zugelassen und seit Dezember 2020 eingesetzt. Der Herausforderung durch eine beispiellose globale Pandemie folgte in bisherig einmaliger Art und Weise der Zusammenarbeit und koordinierten Antwort die Entwicklung verschiedener Impfstoffe basierend auf unterschiedlichen Technologieplattformen. In diesem Artikel werden die verschiedenen Charakteristiken der in Prüfung befindlichen sowie bereits zugelassenen Impfstoffe dargestellt und erklärt, z. B. Subunit-Impfstoffe, inaktivierte Vollimpfstoffe, abgeschwächte Lebendimpfstoffe und Virus-like-Particle (VLP) -Impfstoffe. Die neuartigen rekombinanten Impfstoffstrategien basierend auf adenoviralen Vektoren sowie die durch die schnelle Entwicklung und erstmalige Zulassung in den Fokus gerückten RNA-Impfstoffe sowie ihre Biologie und Pharmakologie werden erläutert. Allergische Reaktionen gegen diese Impfstoffe und Bestandteile existieren, sind aber selten. Immunreaktionen sowie Nebenwirkungen sollten gut dokumentiert werden. In seltenen Fällen einer vermuteten Allergie gegen Impfstoffbestandteile, vor allem gegen PEGs, ist eine präemptive Hauttestung möglich. Die Entwicklung innovativer Impfstofftechnologien und antiviraler Medikamente ist von strategischer Bedeutung im Sinne einer zukünftigen „pandemic preparedness“.

Biologicals have transformed the management of severe disease phenotypes in asthma, atopic dermatitis, and chronic spontaneous urticaria. As a result, the number of approved biologicals for the treatment of atopic diseases is continuously increasing. Although atopic diseases are among the most common diseases in the reproductive age, investigations, and information on half-life, pharmacokinetics defining the neonatal Fc receptors (FcRn) and most important safety of biologicals in pregnancy are lacking. Given the complex sequence of immunological events that regulate conception, fetal development, and the intrauterine and postnatal maturation of the immune system, this information is of utmost importance. We conducted a systematic review on biologicals in pregnancy for indications of atopic diseases. Evidence in this field is scare and mainly reserved to reports on the usage of omalizumab. This lack of evidence demands the establishment of a multidisciplinary approach for the management of pregnant women who receive biologicals and multicenter registries for long-term follow-up, drug trial designs suitable for women in the reproductive age, and better experimental models that represent the human situation. Due to the very long half-life of biologicals, pre-conception counseling, and health care provider education is crucial to offer the best care for mother and fetus. This position paper integrates available data on safety of biologicals during pregnancy in atopic diseases via a systematic review with a detailed review on immunological considerations how inhibition of different pathways may impact pregnancy.

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Specific IgE measurements obtained from patients suffering from respiratory allergy (n = 952) show that, despite similar climatic conditions, there are clear regional differences in pollen sensitization between North Rhine-Westphalia and Bavaria. The data on sensitization levels and pollen concentration was taken from the research and development project Ufoplan 3710 61 228 of the German Environment Agency for North Rhine-Westphalia and Bavaria (2011 - 2014). Most poly-sensitized patients have already shown sensitization, both in the form of cross-reactivity and species-specific sensitization, to "new" pollen allergens, such as Bermuda grass and olive tree. These plants are currently not common in Germany, but may become considerably more widespread due to the increase in average yearly temperatures caused by the global warming. The other "new" aeroallergens discussed here are plants that can be found throughout Germany, such as nettle, cypress, and pine. Their current sensitization levels are higher than 8%; however, their clinical impact appears to be underestimated. For clinical practice it is important to identify when patients' symptoms are typically severe and which regional plants might be responsible for the patients' complaints in this period of time, as this affects further diagnostic strategy. Allergens having an immune effect can then be targeted by specific immunotherapies. The information on complaints of the patients should be regularly recorded in symptom diaries. Recording this information for at least 1 year may allow to discover a correlation between specific types of pollen and allergy symptoms.

Die Anzahl der von Allergien betroffenen Patienten nimmt weltweit zu. Hiermit gehen erhebliche Kosten fur die Gesundheits- und Sozialsysteme durch allergische Erkrankungen einher. Integrierte Versorgungskonzepte sind erforderlich, die innerhalb der nationalen Gesundheitssysteme eine umfassende Versorgung ermoglichen. Die ARIA-Initiative entwickelt international gultige Leitlinien fur allergische Atemwegserkrankungen. ARIA dient der verbesserten Versorgung von Patienten mit Allergien und chronischen Atemwegserkrankungen. In Zusammenarbeit mit anderen internationalen Initiativen, nationalen Fachgesellschaften und Patientenorganisationen im Bereich Allergien und Atemwegserkrankungen wurde eine realitatsnahe, integrative Versorgungsleitlinie („integrated care pathways“, ICPs) fur eine digital unterstutzte, integrative, individualisierte Behandlung von allergischer Rhinitis (AR) mit komorbidem Asthma entwickelt, die in der vorliegenden Arbeit auf das deutsche Gesundheitssystem ubertragen wird. Die vorliegende ICP-Versorgungsleitlinie umfasst wesentliche Bereiche der Versorgung von Patienten mit AR mit und ohne Asthma einschlieslich der Sicht von Patienten und weiterer versorgungsnaher Gesundheitsdienstleister. Eine umfassende ICP-Leitlinie kann die Versorgungsrealitat wesentlich besser abbilden als herkommliche Leitlinienmodelle.

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.

ZusammenfassungInhalationsallergien bei Kindern erfordern eine umfassende Diagnostik und konsequente Therapie. Das Behandlungsspektrum umfasst neben der Allergenkarenz die symptomatische Pharmakotherapie und die kausale Allergie-Immuntherapie (AIT). Kinder sind eine wichtige Zielgruppe für eine AIT, da sie aufgrund ihrer Langzeiteffekte und sekundär-präventiven Eigenschaften den Verlauf der Erkrankung nachhaltig beeinflussen kann.

Sensing of the intestinal microbiota by the host immune system is important to induce protective immune responses. Hence, modification of the gut microbiota might be able to prevent or treat allergies, mediated by proinflammatory Th2 immune responses. The aim was to investigate the ex vivo immunomodulatory effects of the synbiotics Pollagen® and Kallergen®, containing the probiotic bacterial strains Lactobacillus, Lacticaseibacillus and Bifidobacterium, in the context of grass pollen allergy. Peripheral blood mononuclear cells (PBMCs) from grass pollen-allergic patients and healthy controls were stimulated with grass pollen extract (GPE) and synbiotics and Gata3 expression and cytokine secretion analyzed. Monocyte-derived dendritic cells (MoDCs) cells were matured in the presence of GPE and synbiotics, co-cultured with autologous naïve T cells and maturation markers and cytokine secretion analyzed. GPE stimulation of PBMCs from grass pollen-allergic patients resulted in a significant higher production of the Th2 cytokines IL-4, IL-5, IL-9 and IL-13 compared to healthy controls. Gata3

Sensing of the intestinal microbiota by the host immune system is important to induce protective immune responses. Hence, modification of the gut microbiota might be able to prevent or treat allergies, mediated by proinflammatory Th2 immune responses. The aim was to investigate the ex vivo immunomodulatory effects of the synbiotics Pollagen® and Kallergen®, containing the probiotic bacterial strains Lactobacillus, Lacticaseibacillus and Bifidobacterium, in the context of grass pollen allergy. Peripheral blood mononuclear cells (PBMCs) from grass pollen–allergic patients and healthy controls were stimulated with grass pollen extract (GPE) and synbiotics and Gata3 expression and cytokine secretion analyzed. Monocyte-derived dendritic cells (MoDCs) cells were matured in the presence of GPE and synbiotics, co-cultured with autologous naïve T cells and maturation markers and cytokine secretion analyzed. GPE stimulation of PBMCs from grass pollen–allergic patients resulted in a significant higher production of the Th2 cytokines IL-4, IL-5, IL-9 and IL-13 compared to healthy controls. Gata3+CD4+ T cell induction was independent of the allergic status. The synbiotics promoted IL-10 and IFN-γ secretion and downregulated the GPE-induced Th2-like phenotype. Co-culturing naïve T cells with MoDCs, matured in the presence of GPE and synbiotics, shifted the GPE-induced Th2 cytokine release towards Th1-Th17-promoting conditions in allergic subjects. The investigated synbiotics are effective in downregulating the GPE-induced Th2 immune response in PBMCs from grass pollen–allergic patients as well as in autologous MoDC-T cell stimulation assays. In addition to increased IL-10 release, the data indicates a shift from a Th2- to a more Th1- and Th17-like phenotype.

BACKGROUND: The persistently high prevalence of allergic diseases in Western industrial nations and the limited possibilities of causal therapy make evidence-based recommendations for primary prevention necessary.; METHODS: The recommendations of the S3 guideline Allergy Prevention, published in its last version in 2014, were revised and consulted on the basis of a current systematic literature search. The evidence search was conducted for the period 06/2013 - 11/2020 in the electronic databases Cochrane and MEDLINE, as well as in the reference lists of current reviews and through references from experts. The literature found was screened in two filtering processes, first by title and abstract, and the remaining papers were screened in the full text for relevance. The studies included after this were sorted by level of evidence, and the study quality was indicated in terms of potential bias (low/high). The revised recommendations were formally agreed and consented upon with the participation of representatives of the relevant professional societies and (self-help) organizations (nominal group process). Of 5,681 hits, 286 studies were included and assessed.; RESULTS: Recommendations on maternal nutrition during pregnancy and breastfeeding as well as on infant nutrition in the first months of life again play an important role in the updated guideline: Many of the previous recommendations were confirmed by the current data. It was specified that breastfeeding should be exclusive for the first 4 - 6 months after birth, if possible, and that breastfeeding should continue with the introduction of complementary foods. A new recommendation is that supplementary feeding of cow's milk-based formula should be avoided in the first days of life if the mother wishes to breastfeed. Furthermore, it was determined that the evidence for a clear recommendation for hydrolyzed infant formula in non-breastfed infants at risk is currently no longer sufficient. It is therefore currently recommended to check whether an infant formula with proven efficacy in allergy prevention studies is available until the introduction of complementary feeding. Finally, based on the EAACI guideline, recommendations were made for the prevention of chicken egg allergy by introducing and regularly giving thoroughly heated (e.g., baked or hard-boiled) but not "raw" chicken egg (also no scrambled egg) with the complementary food. The recommendation to introduce peanut in complementary feeding was formulated cautiously for the German-speaking countries: In families who usually consume peanut, the regular administration of peanut-containing foods in age-appropriate form (e.g., peanut butter) with the complementary diet can be considered for the primary prevention of peanut allergy in infants with atopic dermatitis (AD). Before introduction, a clinically relevant peanut allergy must be ruled out, especially in infants with moderate to severe AD. There is still insufficient evidence for an allergy-preventive efficacy of prebiotics or probiotics, vitamin D, or other vitamins in the form of supplements so that recommendations against their supplementation were adopted for the first time in the current guideline. Biodiversity plays an important role in the development of immunological tolerance to environmental and food allergens: there is clear evidence that growing up on a farm is associated with a lower risk of developing asthma and allergic diseases. This is associated with early non-specific immune stimulation due to, among other things, the greater microbial biodiversity of house dust in this habitat. This aspect is also reflected in the recommendations on animal husbandry, on which a differentiated statement was made: In families without a recognizable increased allergy risk, pet keeping with cats or dogs should not generally be restricted. Families with an increased allergy risk or with children with already existing AD should not acquire a new cat - in contrast, however, dog ownership should not be discouraged. Interventions to reduce exposure to dust mite allergens in the home, such as the use of mite allergen-proof mattress covers ("encasings"), should be restricted to patients with already proven specific sensitization against house dust mite allergen. Children born by caesarean section have a slightly increased risk of asthma - this should be taken into account when advising on mode of delivery outside of emergency situations. Recent work also supports the recommendations on air pollutants: Active and passive exposure to tobacco smoke increase the risk of allergies, especially asthma, and should therefore be avoided. Exposure to nitrogen oxides, ozone, and small particles (PM 2.5) is associated with an increased risk, especially for asthma. Therefore, exposure to emissions of nitrogen oxides, ozone, and small particles (PM 2.5) should be kept low. The authors of this guideline are unanimously in favor of enacting appropriate regulations to minimize these air pollutants. There is no evidence that vaccinations increase the risk of allergies, but conversely there is evidence that vaccinations can reduce the risk of allergies. All children, including children at risk, should be vaccinated according to the current recommendations of the national public health institutes, also for reasons of allergy prevention.; CONCLUSION: The consensus of recommendations in this guideline is based on an extensive evidence base. The update of the guideline enables evidence-based and up-to-date recommendations for the prevention of allergic diseases including asthma and atopic dermatitis. © Dustri-Verlag Dr. K. Feistle.

Background Children with asthma have impaired production of interleukin (IL) 37; in mice, IL-37 reduces hallmarks of experimental allergic asthma (EAA). However, it remains unclear how IL-37 exerts its inhibitory properties in asthma. This study aimed to identify the mechanism(s) by which IL-37 controls allergic inflammation. Methods IL-37 target cells were identified by single-cell RNA-seq of IL-1R5 and IL-1R8. Airway tissues were isolated by laser-capture microdissection and examined by microarray-based gene expression analysis. Mononuclear cells (MNC) and airway epithelial cells (AECs) were isolated and stimulated with allergen, IL-1β, or IL-33 together with recombinant human (rh) IL-37. Wild-type, IL-1R1- and IL-33-deficient mice with EAA were treated with rhIL-37. IL-1β, IL-33, and IL-37 levels were determined in sputum and nasal secretions from adult asthma patients without glucocorticoid therapy. Results IL-37 target cells included AECs, T cells, and dendritic cells. In mice with EAA, rhIL-37 led to differential expression of >90 genes induced by IL-1β and IL-33. rhIL-37 reduced production of Th2 cytokines in allergen-activated MNCs from wild-type but not from IL-1R1-deficient mice and inhibited IL-33-induced Th2 cytokine release. Furthermore, rhIL-37 attenuated IL-1β- and IL-33-induced pro-inflammatory mediator expression in murine AEC cultures. In contrast to wild-type mice, hIL-37 had no effect on EAA in IL-1R1- or IL-33-deficient mice. We also observed that expression/production ratios of both IL-1β and IL-33 to IL-37 were dramatically increased in asthma patients compared to healthy controls. Conclusion IL-37 downregulates allergic airway inflammation by counterbalancing the disease-amplifying effects of IL-1β and IL-33.

Die Anzahl der von Allergien betroffenen Patienten nimmt weltweit zu. Hiermit gehen erhebliche Kosten fur die Gesundheits- und Sozialsysteme durch allergische Erkrankungen einher. Integrierte Versorgungskonzepte sind erforderlich, die innerhalb der nationalen Gesundheitssysteme eine umfassende Versorgung ermoglichen. Die ARIA-Initiative entwickelt international gultige Leitlinien fur allergische Atemwegserkrankungen. ARIA dient der verbesserten Versorgung von Patienten mit Allergien und chronischen Atemwegserkrankungen. In Zusammenarbeit mit anderen internationalen Initiativen, nationalen Fachgesellschaften und Patientenorganisationen im Bereich Allergien und Atemwegserkrankungen wurde eine realitatsnahe, integrative Versorgungsleitlinie („integrated care pathways“, ICPs) fur eine digital unterstutzte, integrative, individualisierte Behandlung von allergischer Rhinitis (AR) mit komorbidem Asthma entwickelt, die in der vorliegenden Arbeit auf das deutsche Gesundheitssystem ubertragen wird. Die vorliegende ICP-Versorgungsleitlinie umfasst wesentliche Bereiche der Versorgung von Patienten mit AR mit und ohne Asthma einschlieslich der Sicht von Patienten und weiterer versorgungsnaher Gesundheitsdienstleister. Eine umfassende ICP-Leitlinie kann die Versorgungsrealitat wesentlich besser abbilden als herkommliche Leitlinienmodelle.

Background The COVID‐19 pandemic has affected health care systems unexpectedly. However, data focusing on practical considerations experienced by health care professionals (HCPs) providing care to allergic patients is scarce. Methods Under the framework of the European Academy of Allergy and Clinical Immunology (EAACI), a panel of experts in the field of immunotherapy developed a 42‐question online survey, to evaluate real‐life consequences of the COVID‐19 pandemic in allergy practice. Results The respondents in the survey were 618. About 80% of HCPs indicated being significantly affected in their allergy practice. A face‐to‐face visit reduction was reported by 93% of HCPs and about a quarter completely interrupted diagnostic challenges. Patients with severe uncontrolled asthma (59%) and anaphylaxis (47%) were prioritized for in‐person care. About 81% maintained an unaltered prescription of inhaled corticosteroids (ICS) in asthmatics. About 90% did not modify intranasal corticosteroids (INCS) in patients with allergic rhinitis. Nearly half of respondents kept biological prescriptions unmodified for asthma. About 50% of respondents kept their allergen immunotherapy (AIT) prescription patterns unchanged for respiratory allergies; 60% for insect venom allergies. Oral immunotherapy (OIT) for food allergies was initiated by 27%. About 20% kept carrying out up‐dosing without modifications and 14% changed to more prolonged intervals. Telemedicine practice was increased. Conclusions HCPs providing care to allergic patients were affected during the pandemic in diagnostic, management, and therapeutic approaches, including AIT for respiratory, insect‐venom, and food allergies. Most HCPs maintained controller treatments for both asthma, and allergic rhinitis consistent with international recommendations, as well as biological agents in asthma. Remote tools are valuable in delivering allergy care.

Clinical and translational allergy : CTA 11(8), e12058 (2021). doi:10.1002/clt2.12058, Published by BioMed Central, London

TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β acts in AAI by driving effector T cells into Th9 cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the TGFβ-receptor 2 (TGFBR2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of Th9 cell frequencies, but increased Treg cells. To translate these findings into a human clinically relevant context, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9 cell and reduced Tregs, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs.

Abstract SARS-CoV-2 has evolved to enter the host via the ACE2 receptor which is part of the kinin-kallikrein pathway. This complex pathway is only poorly understood in context of immune regulation but critical to control infection. This study examines SARS-CoV-2-infection and epithelial mechanisms of the kinin-kallikrein-system at the kinin B2 receptor level in SARS-CoV-2-infection that is of direct translational relevance. From acute SARS-CoV-2-positive study participants and -negative controls, transcriptomes of nasal curettages were analyzed. Primary airway epithelial cells (NHBEs) were infected with SARS-CoV-2 and treated with the approved B2R-antagonist icatibant. SARS-CoV-2 RNA RT-qPCR, cytotoxicity assays, plaque assays, and transcriptome analyses were performed. The treatment effect was further studied in a murine airway inflammation model in vivo. Here, we report a broad and strong upregulation of kallikreins and the kinin B2 receptor (B2R) in the nasal mucosa of acutely symptomatic SARS-CoV-2-positive study participants. A B2R-antagonist impeded SARS-CoV-2 replication and spread in NHBEs, as determined in plaque assays on Vero-E6 cells. B2R-antagonism reduced the expression of SARS-CoV-2 entry receptor ACE2, G protein–coupled receptor signaling, and ion transport in vitro and in a murine airway inflammation in vivo model. In summary, this study provides evidence that treatment with B2R-antagonists protects airway epithelial cells from SARS-CoV-2 by inhibiting its replication and spread, through the reduction of ACE2 levels and the interference with several cellular signaling processes. Future clinical studies need to shed light on the airway protection potential of approved B2R-antagonists, like icatibant, in the treatment of early-stage COVID-19. Graphical Abstract Key messages Induction of kinin B2 receptor in the nose of SARS-CoV-2-positive patients. Treatment with B2R-antagonist protects airway epithelial cells from SARS-CoV-2. B2R-antagonist reduces ACE2 levels in vivo and ex vivo. Protection by B2R-antagonist is mediated by inhibiting viral replication and spread.

Correction to: Allergo J Int 2019 https://doi.org/10.1007/s40629-019-00110-9 Affiliation and disclaimer have been misrepresented and are hereby corrected: Vera Mahler: Affiliation: Med. Faculty, Friedrich-Alexander-University (FAU) Erlangen-Nurnberg, Germany. Disclaimer: The views expressed in this …

Background Chronic rhinosinusitis (CRS) is one of the most frequent chronic diseases. Among these patients the prevalence of immune defects is higher than in the healthy general population. Methods A selective review of the literature was carried out in PubMed and Medline covering the period between 2008 and 2019. Additionally, recent German publications in journals not listed in the abovementioned databases were analyzed. Results The diagnostic workflow with respect to the immunodeficiency consists of a detailed anamnesis and physical examination, laboratory tests and the antibody reaction to polysaccharide vaccines and antigens. Beside antibiotic treatment, vaccinations and immunoglobulin replacement are available. Notwithstanding the above, functional endoscopic surgery of the paranasal sinuses should be performed according to guideline recommendations. Conclusion Patients with CRS who do not sufficiently respond to conservative and surgical treatment should be checked for underlying immunodeficiencies.

ispartof: ALLERGY vol:74 issue:4 pages:837-840 ispartof: location:Denmark status: published

ZusammenfassungMit BNT162b2 (zugelassen am 27.12.2020) und mRNA-1273 (zugelassen am 06.01.2021) wurden erstmalig RNA-Impfstoffe zur breiten Anwendung in einem beschleunigten Verfahren in der EU bedingt zugelassen und stehen nun zur effektiven Bekämpfung der durch SARS-CoV-2 verursachten Pandemie in der EU zur Verfügung. Einzelne Berichte über Anaphylaxien nach Impfung zunächst in Großbritannien sowie die Identifikation von PEGs (Polyethylenglykole) als mögliche Auslöser der Reaktionen als bisher wenig im allergologischen Fokus stehende Gruppe von Zusatzstoffen führten zur Verunsicherung von Ärzten und Patienten. Ziel dieser Artikelserie ist die Zusammenfassung bisher bekannter pathophysiologischer und klinischer Erkenntnisse (Teil 1), der Charakteristiken der Impfstoffe (Teil 2) sowie praktische Aspekte zur Erkennung und Therapie möglicher Allergien gegen Bestandteile der mRNA-COVID-19-Impfstoffe (Teil 3).

Peanuts are Leguminosae, commonly known as the legume or pea family, and peanut allergy is among the most common food allergies and the most common cause of fatal food reactions and anaphylaxis.The prevalence of peanut allergy increased 3.5-fold over the past two decades reaching 1.4–2% in Europe and the United States. The reasons for this increase in prevalence are likely multifaceted. Sensitization via the skin appears to be associated with the development of peanut allergy and atopic eczema in infancy is associated with a high risk of developing peanut allergy.Until recently, the only possible management strategy for peanut allergy was strict allergen avoidance and emergency treatment including adrenaline auto-injector in cases of accidental exposure and reaction.This paper discusses the various factors that impact the risks of peanut allergy and the burden of self-management on peanut-allergic children and their caregivers.

Due to the drastically rising coronavirus disease (COVID-19) incidence since March 2020, social life was shut down across the globe, and most opera houses were closed. As a result, there are limited data on SARS-CoV-2 infections among artists. The Bavarian State Opera has been reopened in September 2020. This study aimed to identify the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among employees in the Bavarian State Opera. In addition, the various hygiene strategies for the work groups within the institution are described. During the study period from September 1, 2020 to July 31, 2021, 10,061 nasopharyngeal swabs were obtained from 1,460 artistic staff members in a rolling system. During the entire study period, 61 individuals tested positive for SARS-CoV-2. None of the patients had a severe disease course. Compared to the seven-day-incidence per 100,000 German inhabitants, the estimated corresponding incidence among employees was lower at 37 weeks and higher or equal at 9 weeks. Among the infected individuals, 58.3% were symptomatic, 23.3% were presymptomatic, and 18.3% were asymptomatic. Forty-five percent of employees reported that they had been infected in their private environment, 41.7% suspected that their colleagues were the main contact, and 13.3% were unsure about the origin of their infection. Twenty-four diseased employees were ballet dancers, eight from the orchestra, seven from the administration, seven from the choir singers, six from the costume department, 10 from technical support, and one guest solo singer. In the 2020/2021 theater season, increased SARS-CoV-2 infections and large disease outbreaks were avoided at the Bavarian State Opera. Hygiene strategies, that existed since the beginning, was specifically designed for various work areas in the opera. Regular, mandatory PCR testing and follow-up of positive cases with the issuance of quarantine were performed. Using this disease management approach, artistic work at and reopening of the Bavarian State Opera was feasible with a well-controlled risk.

For patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) which cannot be controlled by continuous therapy with intranasal corticosteroids (INCS) and systemic corticosteroids and/or surgical treatment, there were no approved curative options for a long time. For CRSwNP treatment with T2-addressing biologics is possible. On October 24, 2019, the European Commission granted extended approval for dupilumab as the first biological agent for treatment of insufficiently controlled severe CRSwNP. The Federal Joint Committee (G‑BA) evaluates the benefits of reimbursable drugs with new active ingredients. This includes assessment of the additional benefit and its therapeutic relevance.A meta-analysis was performed using individual patient data based on two phase III studies. Both studies examined the safety and efficacy of dupilumab as an add-on therapy to INCS for treatment of CRSwNP in adults inadequately controlled with systemic corticosteroids and/or surgery compared to INCS alone.Based on the present data, the G‑BA decided that there is an indication of a considerable additional benefit of dupilumab compared to mometasone furoate.For patients with severe CRSwNP inadequately controlled with INCS and systemic corticosteroids and/or surgery, there is an indication of a considerable additional benefit for the administration of dupilumab as an add-on therapy to INCS compared to mometasone furoate alone.HINTERGRUND: Für Patienten mit schwerer chronischer Rhinosinusitis mit Nasenpolypen (CRSwNP), die durch eine Dauertherapie mit intranasalen Kortikosteroiden (INCS) und Gabe von systemischen Kortikosteroiden und/oder eine chirurgische Behandlung nicht ausreichend kontrolliert werden konnten, gab es für lange Zeit keine zugelassenen kurativen Therapieoptionen. Bei der CRSwNP ist eine Behandlung mit T2-adressierenden Biologika möglich. Am 24.10.2019 hat die Europäische Kommission für Dupilumab als erstes Biologikum eine Zulassungserweiterung zur Therapie von unzureichend kontrollierter, schwerer CRSwNP ausgesprochen. Der Gemeinsame Bundesausschuss (G‑BA) bewertet den Nutzen von erstattungsfähigen Arzneimitteln mit neuen Wirkstoffen. Hierzu gehört insbesondere die Bewertung des Zusatznutzens und seiner therapeutischen Bedeutung.Auf der Grundlage zweier Phase-III-Studien wurde eine Metaanalyse anhand von individuellen Patientendaten durchgeführt. In beiden Studien wurde die Wirksamkeit und Sicherheit von Dupilumab als Add-on-Therapie zu INCS zur Behandlung von Erwachsenen mit schwerer CRSwNP, die mit systemischen Kortikosteroiden und/oder chirurgischem Eingriff nicht ausreichend kontrolliert werden kann, im Vergleich zu INCS untersucht.Basierend auf den Studiendaten hat der G‑BA entschieden, dass für Dupilumab als Add-On zu INCS ein Hinweis auf einen beträchtlichen Zusatznutzen gegenüber Mometasonfuroat vorliegt.Für Patienten mit schwerer CRSwNP, die durch eine Erhaltungstherapie mit INCS und Gabe von systemischen Kortikosteroiden und/oder eine chirurgische Behandlung nicht ausreichend kontrolliert werden, besteht für die Gabe von Dupilumab als Add-On zu INCS ein Hinweis auf einen beträchtlichen Zusatznutzen gegenüber Mometasonfuroat allein.