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.

Aspirin-exacerbated respiratory disease (AERD) is the triad of asthma, nasal polyposis, and respiratory reactions to COX-1 inhibitors. Overproduction of cysteinyl leukotrienes and underproduction of prostaglandin E2 (PGE2) are hallmarks of AERD. A mouse model predicted a key role for the thromboxane-prostanoid (TP) receptor in AERD.
Our aim was to determine whether ifetroban, a TP receptor antagonist, attenuates aspirin-induced respiratory symptoms in patients with AERD.
A total of 35 patients with AERD completed a 4-week double-blinded, placebo-controlled trial of ifetroban and underwent an oral aspirin challenge. The primary outcome was change in the provocative dose of aspirin that caused a 2-point increase in Total Nasal Symptom Score. Changes in lung function, eicosanoid levels, and platelet and mast cell activation were assessed. Cultured human nasal fibroblasts were stimulated with or without the TP agonist U46619 and assayed for prostanoid production.
Ifetroban was well tolerated in AERD and did not change the mean 2-point increase in Total Nasal Symptom Score (P = .763). Participants taking ifetroban had greater aspirin-induced nasal symptoms and a greater decline in FEV1 value than did participants receiving placebo (-18.8% ± 3.6% with ifetroban vs -8.4% ± 2.1% with placebo [P = .017]). Four weeks of ifetroban significantly increased urinary leukotriene E4 levels and decreased nasal PGE2 levels compared with placebo. Peak aspirin-induced urinary thromboxane levels correlated with peak urinary leukotriene E4 and prostaglandin D2 metabolite levels in participants taking ifetroban. U46119 significantly potentiated the production of PGE2 by cultured nasal fibroblasts from subjects with AERD but not by cultured nasal fibroblasts from controls without polypoid sinusitis.
Contrary to our hypothesis, TP receptor blockade worsened aspirin-induced reactions in AERD, possibly by exacerbating dysregulation of the eicosanoid system. TP signaling on stromal cells may be critical to maintaining PGE2 production when COX-2 function is low.

Aspirin exacerbated respiratory disease (AERD) is a condition caused by increased bronchoconstriction in people with asthma after taking aspirin or another NSAID. Molecular analysis of the human genome has opened up new perspectives on human polymorphisms and disease. This study was conducted to identify the genetic factors that influence this disease due to its unknown genetic factors. We evaluated research studies, letters, comments, editorials, eBooks, and reviews. PubMed/MEDLINE, Web of Sciences, Cochrane Library, and Scopus were searched for information. We used the keywords polymorphisms, aspirin-exacerbated respiratory disease, asthma, allergy as search terms. This study included 38 studies. AERD complications were associated with polymorphisms in ALOX15, EP2, ADRB2, SLC6A12, CCR3, CRTH2, CysLTs, DPCR1, DPP10, FPR2, HSP70, IL8, IL1B, IL5RA, IL-13, IL17RA, ILVBL, TBXA2R, TLR3, HLA-DRB and HLA-DQ, HLA-DR7, HLA-DP. AERD was associated with heterogeneity in gene polymorphisms, making it difficult to pinpoint specific gene changes. Therefore, diagnosing and treating AERD may be facilitated by examining common variants involving the disease.

Dupilumab has been shown to be safe and effective in treating chronic rhinosinusitis with polyposis (CRSwNP). There is to this date no published data whether subgroups like patients with aspirin exacerbated respiratory disease (AERD), increased histologic eosinophilia or elevated blood eosinophil or IgE-levels benefit greater from dupilumab therapy. Moreover, there is no data comparing the efficacy of functional endoscopic sinus surgery (FESS) with dupilumab therapy. We conducted a retrospective chart review of all patients that were treated at a tertiary referral center for CRswNP with dupilumab. We also contacted the patients with a questionnaire to evaluate the efficacy of previous surgeries and dupilumab therapy by visual analogue scale (VAS) and the glasgow benefit inventory (GBI) as well as report on side effects. Overall, 75 patients were included in the study at hand that reported back 138 times. While dupilumab treatment was efficient, we found no systematic evidence of greater efficacy of dupilumab in patients with AERD, histologic eosinophilia or increased blood eosinophil or IgE-levels. All patients showed a considerable decrease in subjective burden of disease, objective smell tests and endoscopic findings. From the patients point of view, dupilumab therapy showed greater efficacy both in the VAS and the GBI overall and all subcategories but \"social support.\" Dupilumab is efficient in treating CRSwNP; this effect is independent from disease characteristics like AERD, histologic eosinophilia, serum IgE-levels or eosinophil counts. There seems to be a group of patients that benefit greater from dupilumab therapy compared to FESS.

BACKGROUND: In France, data regarding epidemiology and management of severe asthma are scarce. The objective of this study was to describe asthma phenotypes using a cluster analysis in severe asthmatics recruited in a real world setting.
METHODS: The study design was prospective, observational and multicentric. The patients included were adults with severe asthma (GINA 4-5) followed-up in French Non Academic Hospital between May 2016 and June 2017. One hundred and seven physicians included 1502 patients. Both sociodemographic and clinical variables were collected. Hierarchical cluster analysis was performed by the Ward method followed by k-means cluster analysis on a population of 1424 patients.
RESULTS: Five clusters were identified: cluster 1 (n = 690, 47%) called early onset allergic asthma (47.5% with asthma before 12 years), cluster 2 (n = 153, 10.5%): obese asthma (63.5% with BMI > 30 kg/m2), cluster 3 (n = 299, 20.4%): late-onset asthma with severe obstructive syndrome (89% without atopy), cluster 4 (n = 143, 9.8%): eosinophilic asthma (51.7% had more than 500 eosinophils/mm3), and cluster 5 (n = 139, 9.5%): aspirin sensitivity asthma (63% had severe asthma attacks).
CONCLUSIONS: In our population of adults with severe asthma followed by pulmonologists, five distinct phenotypes were identified and are quite different from those mentioned in previous studies.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by eosinophilic rhinosinusitis, nasal polyposis, and bronchial asthma, along with the onset of respiratory reactions after the ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA). In addition to the therapeutic routines and surgical options available, a low dietary intake of food salicylate has been suggested as adjunctive therapy for this condition. This study aimed to assess the influence of a short-term low salicylate diet on inflammatory markers in patients with AERD and whether that would result in symptomatic improvement.
METHODS: Prospective study with randomization to either a high or low salicylate diet for 1 week, followed by cross-over to the other study arm. Participants were asked to record their dietary salicylate for each week of the study. Urinary creatinine, salicylate and leukotriene levels were measured at the time of recruitment, end of week one and end of week two and the SNOT-22 questionnaire was filled out at the same time points.
RESULTS: A total of seven participants completed the study. There was no statistical difference in the urinary salicylate and leukotriene levels between the two diets; nevertheless, participants on low salicylate diet reported improved SNOT-22 symptoms scores (p = 0.04), mainly in the rhinologic, ear/facial, and sleep dysfunction symptom domains. In addition, these last two domains outcomes were more significant than the minimal clinically important difference.
CONCLUSIONS: A short-term low salicylate diet may not result in biochemical outcomes changes but seems to provide significant symptomatic relief for patients with AERD.
BACKGROUND: NCT01778465 ( www.clinicaltrials.gov ).

AERD (aspirin-exacerbated respiratory disease) is a severe form of an inflammatory disease of the upper airway system. Therapy remains challenging due to a complex underlying pathophysiology.
To evaluate the efficacy of postoperative antileukotriene therapy concerning recurrence of nasal polyposis in patients with AERD and to compare it with AD (aspirin desensitization) over time.
In this retrospective study we analyzed AERD patients (N = 61) after functional endoscopic sinus surgery (FESS). Patients were treated at our institution postoperatively with topical mometasone (control group, N = 22), leukotriene-receptor-antagonists (montelukast [MT], N = 18) or underwent an aspirin desensitization (N = 21). Subjective parameters as assessed by SNOT (sinonasal outcome test) questionnaire and endoscopic endonasal examination (polyposis grading) were evaluated throughout a follow-up period of 6-9 and >12 (long-term) months after surgery.
Endoscopic endonasal examinations 6-9 months after sinus surgery showed a good disease control in all 3 groups with significant reduction in polyp grading in the AD group. After a follow-up period of more than 12 months, MT and AD patients had significantly less polyp recurrences as compared to the topical treatment group. Subjective sinonasal symptoms revealed that hyposmia and nasal obstruction were prominent factors in all 3 groups throughout the follow-up period. MT group showed significant improvement in sinonasal symptoms over time.
Postoperative treatment with leukotriene-receptor-antagonists and aspirin desensitization both significantly reduce nasal polyp recurrence. MT has a positive effect on subjective sinonasal outcomes and patients\' quality of life over time.

BACKGROUND: Benralizumab, an anti-interleukin-5 (IL-5) receptor α monoclonal antibody, significantly reduces the number of annual exacerbations and oral corticosteroid (OCS) maintenance doses for patients with severe eosinophilic asthma (SEA). However, few studies on the efficacy of this biologic in real life are available. The aim was to elucidate the efficacy of benralizumab by evaluating changes in clinical parameters after benralizumab treatment in patients with SEA.
METHODS: From July 2018 to December 2019, 24 Japanese patients with SEA received benralizumab at Jikei University Hospital. We retrospectively evaluated the patients\' characteristics, parameters, numbers of exacerbations and maintenance OCS doses.
RESULTS: Among the 24 patients, eleven patients had received mepolizumab treatment and were directly switched to benralizumab. The peripheral blood eosinophil and basophil counts significantly decreased after benralizumab treatment regardless of previous mepolizumab treatment. Pulmonary function, Asthma Control Test scores, the numbers of annual exacerbations and maintenance OCS doses in patients without previous mepolizumab treatment tended to improve without significant differences. Fourteen patients (58%) were responders according to the Global Evaluation of Treatment Effectiveness (GETE) score. The proportion of GETE responders among patients with aspirin-exacerbated respiratory disease (AERD) tended to be lower than that among patients without AERD (p = 0.085). After benralizumab treatment, the change in the forced expiratory volume in 1 s from baseline was 200 ml or greater in eight patients (33%), including three patients who were switched from mepolizumab.
CONCLUSIONS: Benralizumab treatment improved and controlled asthma symptoms based on the GETE score.

Rationale: Aspirin-exacerbated respiratory disease is characterized by severe asthma, nonsteroidal antiinflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic corticosteroid therapy does not completely suppress lifelong aspirin hypersensitivity. Omalizumab efficacy against aspirin-exacerbated respiratory disease has not been investigated in a randomized manner.Objectives: To evaluate omalizumab efficacy against aspirin hypersensitivity, leukotriene E4 overproduction, and symptoms during an oral aspirin challenge in patients with aspirin-exacerbated respiratory disease using a randomized design.Methods: We performed a double-blind, randomized, crossover, placebo-controlled, single-center study at Sagamihara National Hospital between August 2015 and December 2016. Atopic patients (20-79 yr old) with aspirin-exacerbated respiratory disease diagnosed by systemic aspirin challenge were randomized (1:1) to a 3-month treatment with omalizumab or placebo, followed by a >18-week washout period (crossover design). The primary endpoint was the difference in area under logarithm level of urinary leukotriene E4 concentration versus time curve in the intent-to-treat population during an oral aspirin challenge.Measurements and Main Results: Sixteen patients completed the study and were included in the analysis. The area under the logarithm level of urinary leukotriene E4 concentration versus time curve during an oral aspirin challenge was significantly lower in the omalizumab phase (median [interquartile range], 51.1 [44.5-59.8]) than in the placebo phase (80.8 [interquartile range, 65.4-87.8]) (P < 0.001). Ten of 16 patients (62.5%) developed oral aspirin tolerance up to cumulative doses of 930 mg in the omalizumab phase (P < 0.001).Conclusions: Omalizumab treatment inhibited urinary leukotriene E4 overproduction and upper/lower respiratory tract symptoms during an oral aspirin challenge, resulting in aspirin tolerance in 62.5% of the patients with aspirin-exacerbated respiratory disease.

Rationale: Daily high-dose aspirin therapy benefits many patients with aspirin-exacerbated respiratory disease but provides no benefit for aspirin-tolerant patients with asthma. Type 2 inflammation characterizes aspirin-exacerbated respiratory disease.Objectives: To determine whether high-dose aspirin therapy changes biomarkers of type 2 inflammation in aspirin-exacerbated respiratory disease.Methods: Forty-two subjects with aspirin-exacerbated respiratory disease underwent an aspirin desensitization and were placed on high-dose aspirin (1,300 mg daily). Fifteen aspirin-tolerant subjects with asthma were also placed on high-dose aspirin. Biologic specimens and clinical parameters were collected at baseline and after 8 weeks on aspirin. Urinary eicosanoids, plasma tryptase and cytokine levels, platelet-leukocyte aggregates, and granulocyte transcripts were assessed.Measurements and Main Results: Eight weeks of high-dose aspirin decreased nasal symptoms and urinary prostaglandin E metabolite (P < 0.05) and increased urinary leukotriene E4 (P < 0.01) levels in subjects with aspirin-exacerbated respiratory disease, but not in those with aspirin-tolerant asthma. Urinary prostaglandin D2 and thromboxane metabolites decreased in both groups. Only in subjects with aspirin-exacerbated respiratory disease, exhaled nitric oxide (P < 0.05), plasma tryptase (P < 0.01), and blood eosinophil (P < 0.01) and basophil (P < 0.01) counts increased and plasma tryptase correlated with eosinophil counts (Pearson r = 0.514; P < 0.01) on aspirin. After correction for eosinophil counts, aspirin-induced changes in blood granulocyte transcripts did not differ between groups. Aspirin had no effect on platelet-leukocyte aggregates, platelet activation markers, or plasma cytokines in either group.Conclusions: High-dose aspirin therapy for 8 weeks paradoxically increases markers of type 2 inflammation in subjects with aspirin-exacerbated respiratory disease, despite reducing nasal symptoms. This effect of aspirin is unique to aspirin-exacerbated respiratory disease and not observed in subjects with aspirin-tolerant asthma.