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BACKGROUND: For 7 years we gained experience of how asthma and chronic rhinosinusitis with nasal polyposis respond to biologics. In contrast, it is much less known, how ASA/NSAID intolerance (Widal\'s disease) behaves under biologicals. We therefore describe the case of a patient with both clinical conditions who reacted with a severe intolerance reaction under perioperative metamizole administration.
UNASSIGNED: Neumanifestation einer Typ-2-Inflammation im Bereich der oberen Atemwege mit Polyposis nasi unter einem Asthmabiologikum.
UNASSIGNED: Seit 7 Jahren verfügen wir über Erfahrungen, wie Asthma und chronische Rhinosinusitis mit Polyposis nasi auf Biologika ansprechen. Viel weniger ist dagegen bekannt, wie sich eine ASS/NSAR-Intoleranz (M. Widal) unter Biologika verhält. Wir schildern deshalb den Fall eines Patienten mit beiden Krankheitsbildern, der unter perioperativer Metamizol-Gabe mit einer schweren Intoleranzreaktion reagiert hat. Schlüsselwörter: M. Widal, AERD, Asthma-Biologika, Metamizol-Intoleranz.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a severe disease involving dysregulated type 2 inflammation. However, the role other inflammatory pathways play in AERD is poorly understood.
OBJECTIVE: We sought to broadly define the inflammatory milieu of the upper respiratory tract in AERD and to determine the effects of IL-4Rα inhibition on mediators of nasal inflammation.
METHODS: Twenty-two AERD patients treated with dupilumab for 3 months were followed over 3 visits and compared to 10 healthy controls. Nasal fluid was assessed for 45 cytokines and chemokines using Olink Target 48. Blood neutrophils and cultured human mast cells, monocytes/macrophages, and nasal fibroblasts were assessed for response to IL-4/13 stimulation in vitro.
RESULTS: Of the nasal fluid cytokines measured, nearly one third were higher in AERD patients compared to healthy controls, including IL-6 and the IL-6 family-related cytokine oncostatin M (OSM), both of which correlated with nasal albumin levels, a marker of epithelial barrier dysregulation. Dupilumab significantly decreased many nasal mediators, including OSM and IL-6. IL-4 stimulation induced OSM production from mast cells and macrophages but not from neutrophils, and OSM and IL-13 stimulation induced IL-6 production from nasal fibroblasts.
CONCLUSIONS: In addition to type 2 inflammation, innate and IL-6-related cytokines are also elevated in the respiratory tract in AERD. Both OSM and IL-6 are locally produced in nasal polyps and likely promote pathology by negatively affecting epithelial barrier function. IL-4Rα blockade, although seemingly directed at type 2 inflammation, also decreases mediators of innate inflammation and epithelial dysregulation, which may contribute to dupilumab\'s therapeutic efficacy in AERD.

BACKGROUND: Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is often characterized by a severe course of chronic rhinosinusitis with nasal polyps (CRSwNP), comorbid asthma, and NSAID hypersensitivity. The gold standard for N-ERD diagnosis is challenge with acetylsalicylic acid (ASA). In expert recommendations, the diagnosis of N-ERD is established based on a plausible positive history of NSAID hypersensitivity and CRSwNP with asthma.
OBJECTIVE: The following review describes the performance of ASA challenges and their sensitivity and specificity. It also examines the extent to which a positive history of NSAID hypersensitivity correlates with ASA challenge results in clinical trials and when ASA challenges should be performed.
CONCLUSIONS: ASA challenges have high sensitivity and specificity. In clinical ASA challenge studies, there is a high concordance between a positive history of NSAID hypersensitivity obtained by rhinologists and the measured data of ASA challenge in patients with CRSwNP and comorbid asthma. Therefore, ASA challenge is primarily indicated in patients with an unclear history of NSAID hypersensitivity.
UNASSIGNED: HINTERGRUND: Das Analgetika-Intoleranz-Syndrom (AIS) ist häufig durch schwere Verläufe der chronischen Rhinosinusitis mit nasaler Polyposis (CRSwNP) mit komorbidem Asthma und einer Acetylsalicylsäure(ASS)-Intoleranz gekennzeichnet. Bei Intoleranzreaktionen stellen ASS-Provokationen den Goldstandard der Diagnostik dar. Expertenempfehlungen zufolge liegt ein AIS bei plausibler positiver Anamnese von Intoleranz gegenüber nichtsteroidalen Antirheumatika (NSAR) und einer CRSwNP mit Asthma vor.
UNASSIGNED: Im vorliegenden Review wird die Durchführung von ASS-Provokationen sowie deren Sensitivität und Spezifität dargestellt. Des Weiteren wird untersucht, inwieweit eine positive NSAR-Intoleranz-Anamnese mit Ergebnissen von ASS-Provokationen in klinischen Studien übereinstimmt und wann ASS-Provokationen erfolgen sollten.
UNASSIGNED: ASS-Provokationen weisen eine hohe Sensitivität und Spezifität auf. In klinischen ASS-Provokationsstudien zeigt sich eine hohe Übereinstimmung zwischen einer von Rhinologen erhobenen positiven NSAR-Intoleranz-Anamnese und den Messdaten von ASS-Provokationen bei Patienten mit einer CRSwNP und einem komorbiden Asthma. Somit sind ASS-Provokationen vorrangig bei unklarer NSAR-Intoleranz-Anamnese indiziert.

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BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type‑2 inflammatory disease of the upper airways, with severe impairment of quality of life. Persons affected by NSAID-exacerbated respiratory disease (NERD) usually present with highly dynamic recurrence of polyps and disease despite prior treatment with sinus surgeries, oral corticosteroids, and aspirin desensitization (ATAD). Biologic therapy has fundamentally changed the choice of therapeutic concept; however, limited data exist on subgroups such as NERD patients. The aim of the current article is to report on a multicenter retrospective study on add-on therapy with dupilumab, omalizumab, and mepolizumab in patients with NERD.
METHODS: This is a retrospective cohort study of patients (NERD+, status after ATAD) in three reference centers in Germany (Munich, Mainz, Berlin). Subjective and objective parameters were collected at 4, 8, and 12 months after biologic therapy initiation in accordance with current EPOS/EUFOREA (European Position Paper on Rhinosinusitis and Nasal Polyps/European Forum for Research and Education in Allergy and Airway Diseases) guidelines. Biologic agents were chosen depending on availability and patient characteristics.
RESULTS: Treatment was commenced in 122 patients meeting the criteria for CRSwNP and NERD. The endoscopic polyp score, SNOT-22 questionnaire score, visual analogue scoring of total symptoms/severity of disease, and sense of smell (psychophysical testing with Sniffin\'Sticks/Brief Smell Identification Test, B‑SIT; Sensonics, Inc., Haddon Heights, NJ, USA) improved significantly after 4 and 12 months of add-on therapy (p < 0.0001). All three biologic agents significantly improved one or more disease parameter. Adverse events were not life threatening but led to change of biologic agent in 4 cases. Patients rated biologic therapy significantly better than ATAD, with improved long-term disease control.
CONCLUSIONS: Add-on biologic therapy is effective, safe, and widely accepted among CRSwNP + NERD patients. Future studies might allow for personalized algorithms with sequential surgery, ATAD, and/or biologic therapy.
UNASSIGNED: HINTERGRUND: Die chronische Rhinosinusitis mit Nasenpolypen (CRSwNP) ist eine chronisch-entzündliche Erkrankung der oberen Atemwege mit starker Beeinträchtigung der Lebensqualität. Die von „NSAID-exacerbated respiratory disease“ (NERD) betroffenen Patienten weisen i. d. R. ein hochdynamisches Wiederauftreten der Beschwerden nach Operation, oraler Kortikosteroidgabe und Acetylsalicylsäuredesensibilisierung (ATAD) auf. Die Add-on-Biologikatherapie hat die Wahl des therapeutischen Konzepts grundlegend verändert, Subgruppen wie der der NERD sind jedoch unzureichend untersucht. Ziel der vorliegenden Arbeit ist, es eine multizentrische retrospektive Studie über die Add-on-Therapie mit Dupilumab, Omalizumab und Mepolizumab bei Patienten mit gesichertem NERD vorzustellen.
METHODS: Es handelt sich um eine retrospektive Kohortenstudie von Patienten (NERD+, Status nach ATAD) dreier Referenzzentren in Deutschland (München, Mainz, Berlin). Subjektive und objektive Parameter wurden nach 4/8/12 Monaten in Übereinstimmung mit EPOS/EUFOREA-Richtlinien (European Position Paper on Rhinosinusitis and Nasal Polyps/European Forum for Research and Education in Allergy and Airway Diseases) erhoben. Die Auswahl der Biologika erfolgte je nach Verfügbarkeit und Patientencharakteristik.
UNASSIGNED: Behandlungen wurden bei n = 122 Patienten mit CRSwNP und NERD begonnen. Der endoskopische Polypenscore, der SNOT-22-Fragebogen-Score (Sino-Nasal Outcome Test), der visuelle Analogskala-Score für die Gesamtsymptome/Schwere der Erkrankung und der Geruchssinn (psychophysische Tests mit Sniffin’Sticks/Brief Smell Identification Test, B‑SIT, Fa. Sensonics, Inc., Haddon Heights, NJ, USA) verbesserten sich signifikant nach 4 bzw. 12 Monaten Zusatztherapie (p < 0,0001). Alle 3 Biologika führten zu einer signifikanten Verbesserung eines oder mehrerer Krankheitsparameter. Unerwünschte Ereignisse waren nicht lebensbedrohlich, führten aber in 4 Fällen zu einem Wechsel des Biologikums. Die Patienten bewerteten die Biologikatherapie signifikant besser als ATAD, mit einer besseren langfristigen Kontrolle der Krankheit.
UNASSIGNED: Die Add-on Biologikatherapie ist wirksam, sicher und wird in der Gruppe der CRSwNP + NERD-Patienten weitgehend akzeptiert. Künftige Studien könnten personalisierte Algorithmen mit sequenzieller Chirurgie, ATAD und/oder Biologikatherapie ermöglichen.

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Genetic variation and epigenetic factors are thought to contribute to the development of hypersensitivity to aspirin. DNA methylation fluctuates dynamically throughout the day. To discover new CpG methylation in lymphocytes associated with aspirin-exacerbated respiratory disease (AERD), we evaluated changes in global CpG methylation profiles from before to after an oral aspirin challenge in patients with AERD and aspirin-tolerant asthma (ATA). Whole-genome CpG methylation levels of peripheral blood mononuclear cells were quantified with an Illumina 860K Infinium Methylation EPIC BeadChip array and then adjusted for inferred lymphocyte fraction (ILF) with GLINT and Tensor Composition Analysis. Among the 866,091 CpGs in the array, differentially methylated CpGs (DMCs) were found in 6 CpGs in samples from all 12 patients with asthma included in the study (AERD, n = 6; ATA, n = 6). DMCs were found in 3 CpGs in the 6 ATA samples and in 615 CpGs in the 6 AERD samples. A total of 663 DMCs in 415 genes and 214 intergenic regions differed significantly in the AERD compared with the ATA. In promoters, 126 CpG loci were predicted to bind to 38 transcription factors (TFs), many of which were factors already known to be involved in the pathogenesis of asthma and immune responses. In conclusion, we identified 615 new CpGs methylated in peripheral blood lymphocytes by oral aspirin challenge in AERD but not in ATA. These findings indicate that oral aspirin challenge induces epigenetic changes in ILFs, specifically in AERD patients, possibly via changes in TF binding, which may have epigenetic effects on the development of AERD.