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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

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.

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.

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.

International audience

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.

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 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.

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).

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.

Background While several systemic immunomodulatory effects of allergen-specific immunotherapy (AIT) have been discovered, local anti-inflammatory mechanisms in the respiratory tract are largely unknown. We sought to elucidate local and epithelial mechanisms underlying allergen-specific immunotherapy in a genome-wide approach. Methods We induced sputum in hay fever patients and healthy controls during the pollen peak season and stratified patients by effective allergen immunotherapy or as untreated. Sputum was directly processed after induction and subjected to whole transcriptome RNA microarray analysis. Nasal secretions were analyzed for Secretoglobin1A1 (SCGB1A1) and IL-24 protein levels in an additional validation cohort at three defined time points during the 3-year course of AIT. Subsequently, RNA was extracted and subjected to an array-based whole transcriptome analysis. Results Allergen-specific immunotherapy inhibited pro-inflammatory CXCL8, IL24, and CCL26mRNA expression, while SCGB1A1, IL7, CCL5, CCL23, and WNT5BmRNAs were induced independently of the asthma status and allergen season. In our validation cohort, local increase of SCGB1A1 occurred concomitantly with the reduction of local IL-24 in upper airways during the course of AIT. Additionally, SCGB1A1 was identified as a suppressor of epithelial gene expression. Conclusions Allergen-specific immunotherapy induces a yet unknown local gene expression footprint in the lower airways that on one hand appears to be a result of multiple regulatory pathways and on the other hand reveals SCGB1A1 as novel anti-inflammatory mediator of long-term allergen-specific therapeutic intervention in the local environment.

Background: As in many fields of medical care, the coronavirus disease 2019 (COVID-19) resulted in an increased uncertainty regarding the safety of allergen immunotherapy (AIT). Therefore, the European Academy of Allergy and Clinical Immunology (EAACI) aimed to analyze the situation in different countries and systematically collect all information available regarding tolerability and possible amendments in daily practice of sublingual AIT (SLIT), subcutaneous AIT (SCIT) for inhalant allergies and venom AIT.Method: Under the framework of the EAACI, a panel of experts in the field of AIT coordinated by the Immunotherapy Interest Group (IT IG) set-up a web-based retrospective survey (SurveyMonkey®) including 27 standardized questions on practical and safety aspects on AIT in worldwide clinical routine. Results: 417 respondents providing AIT to their patients in daily routine answered the survey. For patients (without any current symptoms to suspect COVID-19), 60% of the respondents informed of not having initiated SCIT (40% venom AIT, 35% SLIT) whereas for the maintenance phase of AIT, SCIT was performed by 75% of the respondents (74% venom AIT, 89% SLIT). No tolerability concern arises from this preliminary analysis. 16 physicians reported having performed AIT despite (early) symptoms of COVID-19 and/or a positive test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Conclusions: This first international retrospective survey in atopic diseases investigated practical aspects and tolerability of AIT during the COVID-19 pandemic and gave no concerns regarding reduced tolerability under real-life circumstances. However, the data indicate an undertreatment of AIT, which may be temporary, but could have a long-lasting negative impact on the clinical care of allergic patients. Keywords: COVID-19, allergen immunotherapy (AIT), SARS-CoV-2, practicability, survey, safety, pandemic

International audience; The outbreak of the SARS-CoV-2-induced coronavirus disease 2019 (COVID-19) pandemic re-shaped doctor-patient interaction and challenged capacities of healthcare systems. It created many issues around the optimal and safest way to treat complex patients with severe allergic disease. A significant number of the patients are on treatment with biologicals, and clinicians face the challenge to provide optimal care during the pandemic. Uncertainty of the potential risks for these patients is related to the fact that the exact sequence of immunological events during SARS-CoV-2 is not known. Severe COVID-19 patients may experience a "cytokine storm" and associated organ damage characterized by an exaggerated release of pro-inflammatory type 1 and type 3 cytokines. These inflammatory responses are potentially counteracted by anti-inflammatory cytokines and type 2 responses. This expert-based EAACI statement aims to provide guidance on the application of biologicals targeting type 2 inflammation in patients with allergic disease. Currently, there is very little evidence for an enhanced risk of patients with allergic diseases to develop severe COVID-19. Studies focusing on severe allergic phenotypes are lacking. At present, noninfected patients on biologicals for the treatment of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, or chronic spontaneous urticaria should continue their biologicals targeting type 2 inflammation via self-application. In case of an active SARS-CoV-2 infection, biological treatment needs to be stopped until clinical recovery and SARS-CoV-2 negativity is established and treatment with biologicals should be re-initiated. Maintenance of add-on therapy and a constant assessment of disease control, apart from acute management, are demanded.

Background Allergic rhinitis (AR) continues to increase in incidence and is the most common allergic disease. If abstention of the allergen triggering substances is not possible, allergen-specific immunotherapy (AIT) as causal treatment or a drug therapy with mast cell stabilizers, antihistamines (AHs), glucocorticoids (GCs), leukotriene (LT) receptor antagonists and decongestants is indicated. Despite these diverse therapeutic options, studies on the real-life care situation of patients with AR regularly show that a considerable proportion of patients do not feel adequately treated with monotherapy of the usual drugs and therefore use several preparations with different active ingredients simultaneously and in various combinations. However, such parallel applications of several active ingredients are normally not tested in approval studies and therefore carry a potential risk of side effects or lack of efficacy. Methods For the present publication, a focused literature search in PubMed, Livivo and on the World Wide Web for the previous 20 years (period 01/1999 to 01/2020) was carried out. This literature search included original and review articles in German or English. A further analysis of current publications was also conducted for German-language journals that are not available in international literature databases. Results AHs and nasal GCs represent the therapeutic standard in AR. Their efficacy is well documented for several preparations. The evidence for combination therapies is documented very well for a fixed combination of azelastine and fluticasone (MP29-02). For the simultaneous use of non-fixed combined monopreparations, only a few efficacy and safety studies based on modern evidence criteria exist. Conclusion The free combination therapies of mast cell stabilizers, decongestants, AHs and nasal GCs, frequently used in the routine care of patients with AR, cannot be recommended because they are not evidence-based. Due to the fact that over-the-counter antiallergic drugs are not reimbursable in Germany, there is no medical supervision of the therapy. In addition, there are doubts about appropriate treatment, especially of patients with persistent rhinitis with severe symptoms, as these patients often use several preparations at the same time to alleviate their symptoms.

Background Pollen exposure induces local and systemic allergic immune responses in sensitized individuals, but nonsensitized individuals also are exposed to pollen. The kinetics of symptom expression under natural pollen exposure have never been systematically studied, especially in subjects without allergy. Objective We monitored the humoral immune response under natural pollen exposure to potentially uncover nasal biomarkers for in-season symptom severity and identify protective factors. Methods We compared humoral immune response kinetics in a panel study of subjects with seasonal allergic rhinitis (SAR) and subjects without allergy and tested for cross-sectional and interseasonal differences in levels of serum and nasal, total, and Betula verrucosa 1–specific immunoglobulin isotypes; immunoglobulin free light chains; cytokines; and chemokines. Nonsupervised principal component analysis was performed for all nasal immune variables, and single immune variables were correlated with in-season symptom severity by Spearman test. Results Symptoms followed airborne pollen concentrations in subjects with SAR, with a time lag between 0 and 13 days depending on the pollen type. Of the 7 subjects with nonallergy, 4 also exhibited in-season symptoms whereas 3 did not. Cumulative symptoms in those without allergy were lower than in those with SAR but followed the pollen exposure with similar kinetics. Nasal eotaxin-2, CCL22/MDC, and monocyte chemoattactant protein-1 (MCP-1) levels were higher in subjects with SAR, whereas IL-8 levels were higher in subjects without allergy. Principal component analysis and Spearman correlations identified nasal levels of IL-8, IL-33, and Betula verrucosa 1–specific IgG4 (sIgG4) and Betula verrucosa 1–specific IgE (sIgE) antibodies as predictive for seasonal symptom severity. Conclusions Nasal pollen–specific IgA and IgG isotypes are potentially protective within the humoral compartment. Nasal levels of IL-8, IL-33, sIgG4 and sIgE could be predictive biomarkers for pollen-specific symptom expression, irrespective of atopy.

Eicosanoids are key mediators of type-2 inflammation, e.g., in allergy and asthma. Helminth products have been suggested as remedies against inflammatory diseases, but their effects on eicosanoids are unknown. Here, we show that larval products of the helminth Heligmosomoides polygyrus bakeri (HpbE), known to modulate type-2 responses, trigger a broad anti-inflammatory eicosanoid shift by suppressing the 5-lipoxygenase pathway, but inducing the cyclooxygenase (COX) pathway. In human macrophages and granulocytes, the HpbE-driven induction of the COX pathway resulted in the production of anti-inflammatory mediators [e.g., prostaglandin E-2 (PGE(2)) and IL-10] and suppressed chemotaxis. HpbE also abrogated the chemotaxis of granulocytes from patients suffering from aspirin-exacerbated respiratory disease (AERD), a severe type-2 inflammatory condition. Intranasal treatment with HpbE extract attenuated allergic airway inflammation in mice, and intranasal transfer of HpbE-conditioned macrophages led to reduced airway eosinophilia in a COX/PGE(2)-dependent fashion. The induction of regulatory mediators in macrophages depended on p38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1 alpha (HIF-1 alpha), and Hpb glutamate dehydrogenase (GDH), which we identify as a major immunoregulatory protein in HpbE. Hpb GDH activity was required for anti-inflammatory effects of HpbE in macrophages, and local administration of recombinant Hpb GDH to the airways abrogated allergic airway inflammation in mice. Thus, a metabolic enzyme present in helminth larvae can suppress type-2 inflammation by inducing an anti-inflammatory eicosanoid switch, which has important implications for the therapy of allergy and asthma.

ZusammenfassungHintergrund Die chronische Rhinosinusitis mit Nasenpolypen (CRSwNP) ist eine multifaktorielle entzündliche Erkrankung der nasalen und paranasalen Schleimhaut, der oftmals eine Typ-2-Inflammation zugrunde liegt. Durch die Entwicklung von Biologika, die in diese Entzündungsmechanismen eingreifen können, steht eine neuartige Therapiemöglichkeit zur Verfügung.Methoden Auf Grundlage des aktuellen Wissensstandes zur Immunologie der CRSwNP und der Wirkung von Biologika sowie deren mögliche unerwünschte Wirkungen werden Empfehlungen für die Patienteninformation entwickelt.Ergebnisse Basierend auf der internationalen Literatur und bisherigen Erfahrungen hat ein Expertengremium Empfehlungen für die Patienteninformation und -aufklärung zur Anwendung von Biologika bei CRSwNP entwickelt und auf dieser Grundlage einen Aufklärungsbogen erstellt.Schlussfolgerung Die Information und Einwilligung des Patienten ist vor der Verordnung bzw. Verabreichung von Biologika erforderlich. Das vorliegende Positionspapier enthält wichtige Informationen hierzu und einen Vorschlag für eine Patienteninformation.

Exposures to occupationally relevant ultrafine, zinc- and copper-containing welding fumes cause inflammatory responses involving systemic IL-6, C-reactive protein (CRP) and serum amyloid A (SAA), all associated with elevated risk of cardiovascular events. We investigated whether the systemic response is preceded by nasal inflammatory reactions. Fifteen nonsmoking male subjects were exposed for 6 h under controlled conditions to zinc-/copper-containing welding fumes (at 2.5 mg/m

The burden of allergic diseases is of particular relevance for the economy and the social welfare and health insurance framework. Allergic rhinitis (AR) has a life-time prevalence of approximately 30% and is one of the most common chronic diseases with considerable socioeconomic impact thus leading to substantial direct, indirect and intangible costs. This article explores the common hypothesis that allergen-specific immunotherapy (ASIT) saves national economic expenses in the long term in comparison to other standard symptomatic treatment or no therapy.We conducted a selective search and analysis of the literature in PubMed and Medline including otherwise listed publications in German. Using a predefined model and data extrapolation over 9 years for data from different sources and short-term clinical studies we further discuss the problems and difficulties in analyzing heterogeneous datasets.Using a health-economic model with currently available and accepted variables ASIT proves to be cost-effective in comparison to symptomatic treatment in allergic rhinitis; however, numerous parameters from other models have to be controlled, such as adherence to therapy and therapy discontinuation, heterogeneous costs for different treatment modalities, effect sizes with respect to symptoms including cross-influences with symptomatic rescue medication, duration of efficacy after treatment discontinuation and asthma protection.The personal appraisal of the authors demonstrates not only the current knowledge but also the problems in health economical evaluation of ASIT in allergic diseases.

Manifestationen von Autoimmunerkrankungen stellen eine diagnostische Herausforderung dar. Es existieren jedoch verschiedene Erkrankungen dieser Genese, die sich mit typischen Symptomen im Hals-Nasen-Ohren-Bereich manifestieren und daher bei der Differenzialdiagnose berucksichtigt werden sollten. Das Sjogren-Syndrom, verschiedene Vaskulitiden und die Sarkoidose reprasentieren die haufigsten Autoimmunerkrankungen der Hals-Nasen-Ohren-Heilkunde, es werden jedoch auch IgG4-assoziierte Erkrankungen, die rezidivierende Polychondritis und autoimmune Erkrankungen der Schleimhaute beobachtet. Autoimmunerkrankungen konnen zu Schallempfindungsdefiziten fuhren. Im Bereich der Schilddruse konnen sowohl Hypo- als auch Hyperthyreosen durch Autoimmunerkrankungen verursacht werden. Haufig orientiert sich die Diagnose an entsprechenden Klassifikationskriterien, deren korrekte Anwendung die Abklarung dieser Erkrankungen erleichtern kann.

Ze339, an herbal extract from Petasites hybridus leaves is effective in treatment of allergic rhinitis by inhibition of a local production of IL-8 and eicosanoid LTB4 in allergen-challenged patients. However, the mechanism of action and anti-inflammatory potential in virally induced exacerbation of the upper airways is unknown. This study investigates the anti-inflammatory mechanisms of Ze339 on primary human nasal epithelial cells (HNECs) upon viral, bacterial and pro-inflammatory triggers. To investigate the influence of viral and bacterial infections on the airways, HNECs were stimulated with viral mimics, bacterial toll-like-receptor (TLR)-ligands or cytokines, in presence or absence of Ze339. The study uncovers Ze339 modulated changes in pro-inflammatory mediators and decreased neutrophil chemotaxis as well as a reduction of the nuclear translocation and phosphorylation of STAT molecules. Taken together, this study suggests that phyto drug Ze339 specifically targets STAT-signalling pathways in HNECs and has high potential as a broad anti-inflammatory drug that exceeds current indication. © 2016 BioFactors, 43(3):388-399, 2017.

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 pathways) 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.

The combination of cervical spondylodiscitis and esophageal fistula is rare but life-threatening. Due to both the rarity of these conditions’ coincidence and the complexity and heterogeneity of individual cases, there is no optimal treatment or management approach. The aims of this study are to obtain an overview of patients’ outcomes and to discuss treatment options. This study is a retrospective analysis of patients who presented with cervical spondylodiscitis and associated esophageal fistula between January 2010 and November 2018. We examined reports of 59 patients who suffered from cervical spondylodiscitis and included nine patients (15.25%) who had an esophageal fistula as the underlying cause. We assessed clinical findings, treatment, and outcome. Three of the nine patients were female, and the mean age of the sample was 64.56 years. Six of the patients had a history of esophagopharyngeal cancer and had undergone tumor resection followed by radiotherapy. Two of the remaining patients’ fistulas were caused by an iatrogenic injury during cervical spine surgery and a swallowed toothpick; in the final case, the origin remained unclear. Five patients presented with tetraparesis or tetraplegia, and the other four patients were neurologically intact. In seven cases, dorsal instrumentation was initially performed. Three patients secondarily received a ventral approach for debridement, and one received explantation of the ventral implants. Two patients died during the hospital stay, and three were transferred to a palliative care unit. Thus, the spondylodiscitis and esophageal fistula were cured in only four patients. At discharge, two patients were neurologically intact, two others remained in tetraparesis. Cervical spondylodiscitis in association with an esophageal fistula carries high morbidity and high mortality. Because patients whose infections are not cured have high morbidity, we recommend using interdisciplinary and individual management, including definite surgical treatment of the discitis and fistula, in every case.

The seventh "Future of the Allergists and Specific Immunotherapy (FASIT)" workshop held in 2019 provided a platform for global experts from academia, allergy clinics, regulatory authorities and industry to review current developments in the field of allergen immunotherapy (AIT). Key domains of the meeting included the following: (a) Biomarkers for AIT and allergic asthma; (b) visions for the future of AIT; (c) progress and data for AIT in asthma and the updates of GINA and EAACI Asthma Guidelines (separated for house dust mite SCIT, SLIT tablets and SLIT drops; patient populations) including a review of clinically relevant endpoints in AIT studies in asthma; (d) regulatory prerequisites such as the "Therapy Allergen Ordinance" in Germany; (e) optimization of trial design in AIT clinical research; (f) challenges planning and conducting phase III (field) studies and the future role of Allergen Exposure Chambers (AEC) in AIT product development from the regulatory point of view. We report a summary of panel discussions of all six domains and highlight unmet needs and possible solutions for the future. ispartof: ALLERGY vol:74 pages:3-25 ispartof: location:Denmark status: published

BACKGROUND: Besides allergens, pollen release bioactive, low molecular weight compounds that modulate and stimulate allergic reactions. Clinical relevance of these substances hasn't been investigated to date. OBJECTIVE: To elucidate the effect of a non-allergenic, low molecular weight factors from aqueous birch pollen extracts (Bet-APE

Eine Vielzahl von lokalen oder systemischen Erkrankungen kann zu Schwellungen einer oder mehrerer Kopfspeicheldrusen fuhren. Neben kongenitalen zystischen oder vaskularen Fehlbildungen konnen sowohl entzundliche als auch tumorose Prozesse differenzialdiagnostisch abgegrenzt werden. Auch Obstruktionen der Ausfuhrungsgange, verursacht durch Konkremente oder Stenosen, konnen zu Schwellungen der Speicheldrusen fuhren. Verschiedene Systemerkrankungen konnen sich im Bereich der Ohr- oder Unterkieferspeicheldrusen manifestieren. Da sich die Therapie je nach Ursache erheblich unterscheidet, ist die Kenntnis der unterschiedlichen Differenzialdiagnosen fur den Hals-Nasen-Ohren-Arzt von groser Bedeutung.

Comprehensive analysis of biomarkers in upper and lower airways revealed greatest relation to lower airway biomarker specifically IL-24. All other biomarker candidates showed weak to moderate correlation between upper and lower airways (r < 0.5).

Background Allergen-specific immunotherapy (AIT) is a causative treatment in allergic airway disease, comprising long-term allergen administration and requiring three years of treatment. Mechanisms and biomarkers that translate into clinical efficacy remain urgently needed. Methods In an exploratory observational allergy cohort we phenotyped 32 grass-pollen allergic patients with hayfever undergoing AIT for over three years and controls using local and systemic samples for ex vivo FACS, nasal transcriptomes and in vitro phleum-stimulation at critical time windows six hours after therapeutic allergen administration and during peak-season responses. Findings The up-dosing phase is marked by increased IL-10+ B-cells with allergen-specific PD-L1 up-regulation, while effector Th1/Th17 cells and CCR6+IL-17+FoxP3+T-cells decrease. The conversion phase exhibits Th17 recovery in the absence of Th2 cells. The tolerance-mounting phase after three years of treatment is characterized by induction of Tregs while Th2 and phleum-specific Th17 responses decrease. Notably, high ratios of circulating Breg/Th17 following initial AIT correlate significantly with clinical improvement after three years. Interpretation Our exploratory data hypothezise differential shifts in the hierarchy of tolerance in three distinct phases of AIT characterized by conversion of regulatory against pro-inflammatory mechanisms, of which the Breg/Th17 ratio after initial treatment emerges as potential early prediction of AIT efficacy. Fund This study was partially funded by Allergopharma GmbH & Co. KG, intramural funding and the German Center for Lung Research (DZL).

Background: Allergic upper airway disease involves pro-inflammatory type-2 cytokines such as IL-5 and regulatory tissue repair mediators, in particular transforming growth factor (TGF)-β1. The TGF-β-superfamily member activin-A displays multiple biological functions and shares certain signalling pathways with TGF-β1. We aimed to examine the coregulation of mucosal activin-A and TGF-β1 in acute allergic and chronic Th2-driven upper airway disease. Methods: We investigated mucosal cytokine expression profiles and kinetics using RT-PCR after nasal allergen challenges in patients with seasonal allergic rhinitis. Furthermore, we analysed mucosal specimens from patients with chronic upper airway disease with nasal polyps using ELISPOTs and confocal microscopy. In addition, we stimulated nasal mucosa ex vivo from patients with nasal polyps as well as primary nasal cell cultures from healthy donors. Results: Mucosal activin-A expression revealed increasing correlation with IL-5 and TGF-β1 at 0.25, 6, and 24 h, respectively, and was significantly upregulated at 6 h after allergen challenge. The correlated expression was found to be more pronounced in chronic disease with nasal polyps, showing substantially (48-fold) increased activin-A-producing cells in nasal polyps by ELISPOT, while submucosal downstream signalling as determined by confocal microscopy was decreased. Ex vivo stimulations of nasal tissue suggested that activin-A and TGF-β1 mutually regulate each other’s expression at the mRNA level and, when combined, enhance IL-5 expression. Conclusion: Activin-A in allergic upper airway disease acts as a pro-inflammatory mediator and TGF-β1 modifier. Our data in the upper airways oppose the view of potentially anti-inflammatory properties in contrast to lymphatic compartments.

Clinical diagnoses of allergic airway disease need confirmation of a relevant sensitization to allergens. Serum-based component-resolved diagnosis has become increasingly popular and allows the precise assessment of specific IgE to molecular allergens. Molecular allergen diagnosis has improved our understanding of disease phenotypes in allergic patients, including cross-reactive patterns and food allergy. Beyond sensitization profiles, characterization of the (endo-)type and severity of a local allergic disease is useful for targeted therapy with biologics in advanced allergic airway disease. Surrogate markers of treatment efficacy are increasingly under validation. Prognostic and predictive biomarkers will represent a promising option for stratified prevention strategies.

Chronic rhinosinusitis is an umbrella term for several phenotypes and mechanistically distinct inflammatory diseases of the nose and the paranasal sinuses affecting around 11% of the population in Europe and the USA. Approximately 20% of the patients present with uncontrolled disease despite adequate treatment, and revision surgery is common. While a clinical characterization alone does not improve treatment results, novel but expensive biologics have increasingly become available, but they require a better understanding of the mechanism. Mechanistic markers of disease may help to allocate the optimal drug to a patient, thus reducing undesirable side effects and avoiding unnecessary treatment and costs with respect to potential non-responders, thereby increasing responder rates and compliance.

Background Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers. Method The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG-subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE-FAB and IgE-BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?). Results All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed. Conclusions It is recommended to explore the use of allergen-specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE-FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed.

Diagnosis early in life, sensitization, asthma endotypes, monitoring of disease and treatment progression are key motivations for the exploration of biomarkers for allergic rhinitis and allergic asthma. The number of genes related to allergic rhinitis and allergic asthma increases steadily; however, prognostic genes have not yet entered clinical application. We hypothesize that the combination of multiple genes may generate biomarkers with prognostic potential. The current review attempts to group more than 161 different potential biomarkers involved in respiratory inflammation to pave the way for future classifiers. The potential biomarkers are categorized into either epithelial or infiltrate-derived or mixed origin, epithelial biomarkers. Furthermore, surface markers were grouped into cell-type-specific categories. The current literature provides multiple biomarkers for potential asthma endotypes that are related to T-cell phenotypes such as Th1, Th2, Th9, Th17, Th22 and Tregs and their lead cytokines. Eosinophilic and neutrophilic asthma endotypes are also classified by epithelium-derived CCL-26 and osteopontin, respectively. There are currently about 20 epithelium-derived biomarkers exclusively derived from epithelium, which are likely to innovate biomarker panels as they are easy to sample. This article systematically reviews and categorizes genes and collects current evidence that may promote these biomarkers to become part of allergic rhinitis or allergic asthma classifiers with high prognostic value.

Background Allergic rhinitis is an inflammatory disease characterized by local overproduction of type 2 cytokines and tissue eosinophilia. Recent research suggests the involvement of additional cytokines such as IL-17, chemokine (C-C motif) ligand (CCL) 26/eotaxin-3, and CCL13/monocyte chemoattractant protein-4 (MCP-4) in its pathophysiology. Furthermore, bronchial epithelial cells treated with IL-17 and type 2 cytokines distinctively up-regulated eotaxin-3 gene expression. In this study we investigated the kinetics of IL-4, IL-10, IL-17, eotaxin-3, and MCP-4 in seasonal allergic rhinitis volunteers after nasal allergen challenge (NAC) and their release during natural pollen exposure. Methods The nasal lavages of 15 symptomatic allergic and 14 nonallergic subjects were collected during the pollination season. Additionally, six allergic subjects underwent a single unilateral nasal allergen and control challenge out of season, and nasal secretions were collected. Levels of IL-4, IL-10, IL-17, eotaxin-3, and MCP-4 in nasal lavages and secretions were measured using an electrochemiluminescent assay. Results After NAC, allergic subjects had a significant immediate response of nasal symptoms as well as a significant increase at 5 hours of IL-4, IL-10, and IL-17 and at 2, 5, and 24 hours significantly raising levels of eotaxin-3. IL-17 and eotaxin-3 concentrations at 5 hours were correlated (r = 0.94; p = 0.005). During natural pollen exposure, barely detectable levels of IL-17 in allergic subjects were also correlated with eotaxin-3 (r = 0.62; p = 0.01). Eotaxin-3 and MCP-4 levels were significantly elevated 9- or 3.7-fold, respectively, and IL-10 and, unexpectedly, IL-4 were significantly lower in allergic subjects compared with nonallergic subjects. Conclusion Nasal IL-17, MCP-4, and, possibly, eotaxin-3 may aggravate and IL-10 may alleviate nasal mucosal allergy.

International journal of hygiene and environmental health 219(3), 252-260 (2016). doi:10.1016/j.ijheh.2016.01.007, Published by Elsevier, München