NSAIDs)-exacerbated Respiratory Disease Research Articles

Importance of aspirin challenges in patients with NSAID-exacerbated respiratory disease

Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is often characterized by asevere 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 aplausible positive history of NSAID hypersensitivity and CRSwNP with asthma. The following review describes the performance of ASA challenges and their sensitivity and specificity. It also examines the extent to which apositive history of NSAID hypersensitivity correlates with ASA challenge results in clinical trials and when ASA challenges should be performed. ASA challenges have high sensitivity and specificity. In clinical ASA challenge studies, there is ahigh concordance between apositive 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.

Real-Life Study of Patient Preference for Dupilumab or Revision Surgery for Recurrent Chronic Rhinosinusitis with Nasal Polyps.

(1) Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) has a high rate of recurrence in patients, despite therapy with local corticosteroids and functional endoscopic sinus surgery. Dupilumab, a recombinant monoclonal human IgG4 antibody directed against the IL-4 receptor α that inhibits both IL-4 and IL-13 signal transduction, is available for symptomatic therapy. Patient preference between repeated surgery and injection therapy with Dupilumab is not known. (2) Methods: Patients who had experienced at least one surgical intervention for nasal polyps and were treated with Dupilumab for at least 3 months completed a retrospective patient questionnaire. (3) Results: In a cohort of 75 previously operated CRSwNP patients, 91.5% preferred therapy with Dupilumab to repeated surgery for nasal polyps. Preference for Dupilumab in the subgroups of patients with concomitant Non-steroidal Anti-inflammatory Drugs Exacerbated Respiratory Disease (N-ERD) (n = 32), patients with concomitant asthma (n = 25), and patients without concomitant disease (n = 18) was 100%, 96%, and 72%, respectively. (4) Conclusions: Patient preference for Dupilumab over repeat surgery is strongest in previously operated CRSwNP patients with concomitant asthma or N-ERD, but remains very high in patients without concomitant disease.

Difficult-to-treat chronic rhinosinusitis-when thestandard treatment is not effective and biologics are not available

In recent years, significant improvements have been made in the treatment options for uncontrolled chronic rhinosinusitis (CRS) refractory to standard medical and surgical therapy. This is the result of abetter understanding of the pathophysiology and the resulting development of biologicals for CRS with nasal polyps (CRSwNP). However, biologics are not (yet) available for all patients in Europe. Based on the session "Difficult-to-treat CRS, when biologics are not available" at the 29thCongress of the European Rhinologic Society (ERS) 2023 in Sofia, Bulgaria, the treatment options for uncontrolled CRS with the exclusion of biologics will be discussed. The content of the presentations "Is there aplace for antibiotics?" "Indications for revision surgery," "Novel systemic treatment options," "Novel local treatment options," and "Phototherapy for nasal polyps" are outlined and supported by areview of the literature. Various treatment options are available for managing uncontrolled CRS, even if biologic treatments are unavailable. Treatment options for type‑2 (T2)CRS include steroid rinses, repeated short-term oral steroids, steroid-eluting stents, and extended sinus surgery. In the case of nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD), acetylsalicylic acid (ASA) desensitization can be considered. Non-T2 endotypes or CRS without nasal polyps (CRSsNP) may benefit from several weeks of macrolides and xylitol rinses. To accurately assess the efficacy of second-line therapies for treatment of difficult-to-treat CRS within an endotype-specific framework, additional controlled clinical trials are needed that take into account the heterogeneity of CRS endotypes.

Correlation between inflammatory biomarkers and disease control in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) may have a heterogeneous response to medical/surgical treatments based on endotypes. Data correlating biomarkers and severity of the disease are lacking. We aimed to determine if IL-5 and calprotectin may be useful in defining severity of disease and identifying uncontrolled patients. This was a case-control study including 81 patients with diffuse CRSwNP who underwent at least one previous surgery and treated with intranasal steroids. We enrolled 39 uncontrolled patients (SNOT-22≥40 and two or more cycles of systemic corticosteroids in last year) (Group A) and 42 controlled one (SNOT-22<40 and less than two cycles of systemic corticosteroids in last year) (Group B). We analyzed IL-5 and calprotectin in both nasal secretions and nasal polyp tissue. Calprotectin and IL-5 were significantly higher in Group A in both secretions and tissue, and the higher the number of previous surgeries, the higher the levels detected in nasal secretions. At univariate analyses, smoking, asthma, non-steroidal anti-inflammatory drugs-exacerbated respiratory disease (NSAID-ERD), blood eosinophilia, neutrophils, and eosinophils at nasal cytology were significantly associated with uncontrolled disease. Multivariate analyses showed that asthma, NSAID-ERD, and IL-5 in nasal secretion/polyp tissue were significantly related to the risk of uncontrolled disease. Our data suggest that asthma, NSAID-ERD, and IL-5 in nasal secretions/tissue may be helpful to identify more severe patients, as they are related to the risk of uncontrolled disease. Nonetheless, high levels of calprotectin and neutrophilia were also observed in uncontrolled patients, especially after multiple surgeries.

Eosinophilia, asthma, NERD and the use of oral corticosteroids predict uncontrolled chronic rhinosinusitis with nasal polyps after surgery.

Severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) is a challenging condition to treat. The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 (EPOS2020) has the following criteria when considering biological therapy for severe uncontrolled CRSwNP: eosinophilia, need for oral corticosteroids (OCS), symptom score, loss of sense of smell and co-morbid asthma. This study aimed at finding associations of baseline factors with uncontrolled CRSwNP after endoscopic sinus surgery (ESS). Electronic health record data of CRSwNP patients (N = 137) undergoing ESS in 2002-17 were used. Endpoints of uncontrolled CRSwNP were revision ESS, purchased OCS and antibiotic courses during follow up. Baseline factors were chosen based on EPOS2020 and the data available: nasal polyp (NP) eosinophilia, peripheral blood eosinophilia, co-existing asthma and/or non-steroidal anti-inflammatory drug exacerbated respiratory disease (NERD), need for OCS during the previous year, previous ESS, endoscopic NP score, and Lund-Mackay score of sinus computed tomography scans. During the follow-up of 10.1 ± 3.1 (mean ± standard deviation) years, 35 (25.5%) individuals underwent revision ESS. The best predictive model was obtained by a sum of baseline (1) blood eosinophilia ≥ 250 cells/≥l and/or NP eosinophilia ≥ 30% (Eos), (2) asthma/NERD, and (3) ≥ 1 OCS/year. It was significantly associated with revision ESS, purchased doctor-prescribed OCS and antibiotic courses during follow-up. We identified similar predictive variables for uncontrolled CRSwNP that are used in the EPOS2020 indications of biological therapy, thus suggesting that these estimates are usable in clinical practice.

Hypersensitivity to intravenous succinate corticosteroids in patients with nonsteroidal anti-inflammatory drug-exacerbated respiratory disease.

Although there are many case reports of asthma exacerbations with intravenous corticosteroids, especially hydrocortisone succinate, in nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD), the frequency and mechanism remain unclear. We hypothesized that N-ERD patients are potentially hypersensitive to succinates, especially succinate corticosteroids, based on the results of previous provocation studies and considered specific mechanisms. The objective of this study was to determine the frequency and mechanism of succinate corticosteroids hypersensitivity in patients with N-ERD. Eleven patients with stable, moderate to severe N-ERD were tested with hydrocortisone sodium succinate (HCs), hydrocortisone sodium phosphate (HCp), methylprednisolone sodium succinate (MPSLs), prednisolone sodium succinate (PSLs), and chloramphenicol sodium succinate (CPs, without a steroidal chemical structure) at doses below the normal dose through intravenous administration using a single-blind test. As a comparison, seven patients with aspirin-tolerant asthma (ATA) also underwent an intravenous provocation test of HCs. The positive intravenous provocation test rates of HCs 100-500 mg, HCp 500 mg, MPSLs 80 mg, PSLs 20 mg, and CPs 500 mg in N-ERD patients were 82% (9/11), 9% (1/11), 50% (5/10), 33% (1/3), and 86% (6/7), respectively. Most positive reactions began with a severe cough within 5 min of intravenous injection. The course of these hypersensitivity symptoms differed from those seen with the usual aspirin challenge test. The HCs 100-500 mg intravenous test was negative in all seven patients with ATA. In conclusion, patients with N-ERD have high rates of potential hypersensitivity to the succinate ester structure, which is not linked to the corticosteroid structure, but to the succinate ester structure. We hypothesized that the mechanism of hypersensitivity observed during rapid intravenous administration of succinate corticosteroids is mast cell activation via succinate receptor stimulation, rather than due to the corticosteroid itself.

Addressing the unmet needs in patients with type 2 inflammatory diseases: when quality of life can make a difference.

Patients with asthma (AS), atopic dermatitis (AD), allergic rhinitis (AR), eosinophilic esophagitis (EoE), chronic rhinosinusitis with nasal polyps (CRSwNP), chronic urticaria (CU), non-steroidal anti-inflammatory drugs-exacerbated respiratory disease (N-ERD), and certain phenotypes of chronic obstructive pulmonary disease (COPD), among others, have a common underlying pathogenesis known as Type 2 inflammation (T2i). These diseases often coexist with other T2i conditions and have a substantial impact on the quality of life (QoL) of patients. However, limited data on patients' experiences, perspectives, and current management of T2i diseases have been published thus far. This survey, promoted by the patient-driven T2i Network Project, aimed at identifying the common drivers and challenges related to the QoL of patients with T2i diseases by putting the patient's perspective at the force and including it in the design of new care strategies. An anonymous online survey was carried out through convenience sampling between May and June 2023. The survey was codesigned by members of different patient associations, healthcare professionals and healthcare quality experts, and implemented using EUSurvey and distributed through eight patient associations from Spain. The survey consisted of 29 questions related to the participant's sociodemographic features, a series of self-reported multiple choice or rating scale questions, including diagnosis, QoL measures, disease severity, healthcare resource utilization, and quality of care. The survey included 404 participants, members from eight patient associations, the majority of whom had moderate-to-severe self-reported disease severity (93%) and one or more coexisting pathologies related to T2i (59%). Patients with more than one pathology had a significantly greater impact on QoL than those with only one pathology (p < .001). Participants with self-reported severe symptoms reported significantly worse QoL than those with mild-to-moderate severity (p < .001). More than half of the patients (56%) felt constantly bothered by the unpredictability of their illness caused by potential exposure to known or unknown disease triggers. The lack of coordination between specialists and primary care was also expressed as an area of dissatisfaction by participants, with 52% indicating a complete lack of coordination and 21% indicating an average coordination. This article reports the initial findings of a patient-led initiative, which highlights the common QoL challenges faced by individuals with type 2 inflammation-related diseases and emphasizes the importance of further clinical research to improve the management of this patient group. Considering the significant impact on QoL, a multidisciplinary approach integrated into new healthcare protocols has the potential to improve patient management and QoL, shorten the time to diagnosis and reduce healthcare resource utilization.

Non-steroidal anti-inflammatory drug exacerbated respiratory disease (N-ERD) in the pediatric population

Non-steroidal anti-inflammatory drug exacerbated respiratory disease (N-ERD) is predominantly encountered in adults and rarely documented and less well-defined clinically and epidemiologically in children. The cause remains unclear, with the main pathogenic mechanism being represented by a decrease in prostaglandin E2 production, increased production of cysteinyl-leukotrienes, and eosinophilic inflammation. N-ERD symptoms in the pediatric population are similar to those in adults: chronic eosinophilic rhinosinusitis with nasal polyps, asthma and respiratory symptoms upon aspirin/NSAID administration, but they can initially present with gastrointestinal or cutaneous symptoms or be more subtle, making early diagnosis difficult and requiring rigorous differential diagnosis. Pediatric onset of N-ERD should be considered by specialists when faced with cases of asthma associated with chronic rhinosinusitis and nasal polyps. Studies involving a larger number of patients are needed to determine the frequency of non-steroidal anti-inflammatory drug hypersensitivity in children with asthma and to establish the evolutionary and therapeutic characteristics of this patient category.

The unified airway hypothesis: evidence from specific intervention with anti-interleukin-5 biologic therapy.

The unified airway hypothesis proposes that upper and lower airway diseases reflect a single pathological process manifesting in different locations within the airway. Functional, epidemiological and pathological evidence has supported this well-established hypothesis for some time. However, literature on the pathobiologic roles/therapeutic targeting of eosinophils and interleukin (IL)-5 in upper and lower airway diseases (including asthma, chronic rhinosinusitis with nasal polyps [CRSwNP] and non-steroidal anti-inflammatory drug exacerbated respiratory disease) has recently emerged. This narrative review revisits the unified airway hypothesis by searching the scientific literature for recent learnings and clinical trial/real-world data that provide a novel perspective on its relevance for clinicians. According to the available literature, eosinophils and IL-5 have important pathophysiological roles in both the upper and lower airways, although the impact of eosinophils and IL-5 may vary in asthma and CRSwNP. Some differential effects of anti-IL-5 and anti-IL-5-receptor therapies in CRSwNP have been observed, requiring further investigation. However, pharmaceutical targeting of eosinophils and IL-5 in patients with upper, lower, and comorbid upper and lower airway inflammation has led to clinical benefit, supporting the hypothesis that these are linked conditions manifesting in different locations. Consideration of this approach may improve patient care and aid clinical decision-making.

Can we apply biomarkers in the management of non-steroidal anti-inflammatory drug exacerbated respiratory disease?

Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is characterized by adult-onset asthma, chronic rhinosinusitis with nasal polyps (CRSwNPs), and aspirin/NSAID hypersensitivity, presenting recurrent asthma exacerbation and poor clinical outcomes. Patients with NERD have heterogeneous clinical phenotypes/endotypes, and the management of NERD remains challenging. Dysregulation of arachidonic acid (AA) metabolism and persistent eosinophilic airway inflammation are the major pathogenic mechanisms in the upper and lower airways of NERD. To date, increased levels of urinary leukotriene E4 (uLTE4) [a terminal metabolite of the lipoxygenase (LOX) pathway] have been the most relevant biomarker for NERD. It is demonstrated that mast cells, platelets, and epithelial cells can amplify upper and lower airway inflammation in NERD, and several potential biomarkers based on these complicated and heterogeneous mechanisms have been suggested. This review summarizes potential biomarkers for application in the management of NERD.

The value of aspirin challenge tests in the diagnosis of non-steroidal anti-inflammatory drugs-exacerbated respiratory disease

Objective: To investigate the value of aspirin challenge tests in the diagnosis of non-steroidal anti-inflammatory drugs-exacerbated respiratory disease (NERD). Methods: Fifty patients (28 females; age, 16-61 years) who were diagnosed with chronic rhinosinusitis with nasal polyps (CRSwNP) with/without asthma, and underwent NERD standardized diagnosis in the Allergy Centre of West China Hospital, Sichuan University from December 2021 to November 2022 were included in the study. The first step was asking about the history of exacerbation respiratory symptoms after intake of any non-steroidal anti-inflammatory drug, including aspirin; the second step was performing intranasal aspirin challenge (IAC); the third step was performing oral aspirin challenge (OAC). The diagnosis of NERD was made if any of the above steps was positive, and the subsequent steps were not performed, otherwise the diagnosis was made to OAC. If OAC was negative, the diagnosis was non-NERD. All patients completed the sino-nasal outcome test 22 (SNOT 22) score, Lund-Kennedy score by nasal endoscopic, allergen skin prick test, blood routine and serum total IgE test. SPSS version 20.0 was used for statistical analysis. Results: The diagnosis of NRED was confirmed in 27 patients (27/50, 54%). Seven (7/50, 14%) of them were diagnosed by clinical history and 20 (20/50, 40%) were diagnosed by aspirin challenge tests, of which 17 (17/20, 85%) were positive to IAC and 3 (3/20, 15%) to OAC. Of the 43 patients who underwent IAC testing, only 2 (2/43, 5%) developed asthma attacks during challenge. Comparing the clinical characteristics of patients in NERD and non-NERD group, there were significant differences between the two groups in gender (P=0.001), hyposmia (P=0.003), history of repeated CRSwNP surgeries (P=0.028), comorbid asthma (P=0.013), SNOT-22 score (P=0.004) and the percentage of peripheral blood eosinophil (P=0.043). Conclusions: Patients may be underdiagnosed if the diagnosis of NERD is made only by medical history, and it is necessary to carry out aspirin challenge tests. IAC is an important means to diagnose NERD with high accuracy and good safety. However, If IAC is negative, further OAC is required.

Toxic retrobulbar neuritis due to recurrent nonsteroidal antiinflammatory drug-exacerbated respiratory disease-based chronic sinusitis in the left sphenoid sinus: a case report

BackgroundAbrupt visual impairment constitutes a medical urgency, necessitating an interdisciplinary diagnostic and therapeutic approach owing to the broad spectrum of potential etiologies, thereby engaging numerous medical specialties.Case presentationA 21-year-old Mixed White and Asian female patient, with medical history of nonsteroidal antiinflammatory drug-exacerbated respiratory disease necessitating previous sinus surgery, reported sudden monocular vision loss. Unremarkable ophthalmological examination of the fellow eye and hematological parameters, save for a slight elevation in lymphocytes and eosinophils, were observed. Imaging studies indicated recurrence of bilateral chronic rhinosinusitis with nasal polyps and a mucocele in the left sphenoid sinus, accompanied by bony structural deficits. Emergency revision sinus surgery, guided by navigation, was promptly performed. The patient received treatment with methylprednisolone, ceftriaxone, cyanocobalamin, pyridoxine, thiamine, and acetylsalicylic acid. During the hospital stay, she developed steroid-induced glaucoma, which was subsequently managed successfully. Negative microbiological swabs, along with pathohistological evidence of increased tissue eosinophilia and the patient’s clinical history, led to the diagnosis of toxic retrobulbar neuritis secondary to recurrent nonsteroidal antiinflammatory drug-exacerbated respiratory disease-associated chronic rhinosinusitis of the left sphenoid sinus.ConclusionsIn cases of acute unilateral vision loss, optic neuritis is a highly probable differential diagnosis and may be induced by pathologies of the paranasal sinuses. Nonsteroidal antiinflammatory drug-exacerbated respiratory disease, a subtype of chronic rhinosinusitis, is associated with type 2 inflammation, which is increasingly recognized for its role in the pathogenesis of bronchial asthma, eosinophilic esophagitis, and atopic eczema. Clinicians should consider chronic rhinosinusitis as a potential differential diagnosis in unilateral visual loss and be cognizant of the rising significance of type 2 inflammations, which are relevant to a variety of diseases.

Sex, Ethnicity, Body Mass Index, and Environmental Exposures Associated With NSAID-Exacerbated Respiratory Disease Symptom Sequence

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has a triad of symptoms: nasal polyposis, asthma, and NSAID hypersensitivity. Little is known about symptom timing and disease progression. The aim of this study is to characterize disease progression in N-ERD. Patients with N-ERD were prospectively interviewed and classified into 4 groups based on their first symptom at initial N-ERD onset (asthma, nasal polyps, NSAID hypersensitivity, or all concurrently). Associations of patient characteristics with the 4 groups were examined, along with associations within the "asthma first" group. Patients (N= 240) were mostly female (68%) and self-identified as non-White (77%). Half (N= 119) reported asthma as the earliest symptom in the N-ERD triad. Compared with other groups, "asthma first" was associated with younger age of onset (25 years, standard error ±1.3, P < .001) and higher body mass index (BMI) (odds ratio [OR]= 1.3, 95% confidence interval [CI]: 1.06-1.7, P= .02). In this group, age of onset <20 years was associated with female sex, Latino ethnicity, and higher BMI (all P < .05). The "NSAID sensitivity first" group was significantly associated with male sex (OR= 3.3, 95% CI: 1.5-7.4, P= .004) and pollution exposure (OR= 4.4, 95% CI: 1.6-11.9, P= .003). At the initial presentation, 27% of patients were unaware of their N-ERD diagnosis. Black and Latino patients were more likely to be unaware of their N-ERD diagnosis compared with White (P= .003). The median diagnostic delay was 3 years (interquartile range: 0-5 years). In this cohort, N-ERD is highly variable in onset and progression, with sex, BMI, race and ethnicity, and environmental exposures significantly associated with disease patterns and diagnostic delay.

Efficacy and safety of switching between biologics in chronic rhinosinusitis with nasal polyps or N-ERD.

The effectiveness of biologics in chronic rhinosinusitis with nasal polyps (CRSwNP) is well-established. However, real-world experience on the effectiveness of transitioning between two monoclonal antibodies is scarce. Therefore, we aimed to analyze the safety and efficacy of antibody switching in treatment of chronic rhinosinusitis. All patients with CRSwNP or nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease (N-ERD) requiring a switch between biologics were retrospectively studied. Analysis included changes in polyp size, quality of life parameters, asthma control, and side effects. Out of 195 patients treated with biologics for CRSwNP or N-ERD in our center, 23 (11.8%) required transition to a different monoclonal antibody. The majority switched from omalizumab to dupilumab (17/23, 73.9%), mostly due to inadequate symptom control. Nine out of these 17 patients (52.9%) were switched without a washout period. All patients showed significant improvement in nasal polyp score, asthma control test and sino-nasal outcome test-22 after changing to dupilumab. Keratoconjunctivitis sicca was the side-effect (4.3%) reported after the switch from omalizumab to dupilumab, which lead to termination of therapy in one patient. Due to limited sample size, other antibody transitions were reported in a descriptive manner. The transition to dupilumab is an effective option in patients with inadequate treatment response or side-effects of omalizumab in nasal polyposis. Our preliminary results indicate that a wash-out period may not be necessary when switching between biologics, however, these findings require further investigations. Other monoclonal antibody transitions also show promising results, but warrant validations in larger cohorts due to small patient samples in our study.

Aspirin challenge tests in non-steroidal anti-inflammatory drugs-exacerbated respiratory disease: clinical application and current research

Aspirin challenge tests in non-steroidal anti-inflammatory drugs-exacerbated respiratory disease: clinical application and current research

Evaluation of disease control after SARS-CoV-2 infection or vaccination in patients with NSAID-exacerbated airway disease.

Background: There are insufficient data on changes in disease control after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection or vaccination in patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease (N-ERD). Objective: This study aimed to investigate the history of coronavirus disease 2019 (COVID-19) in patients with N-ERD, determine whether they experienced exacerbations of asthma or rhinitis after COVID-19, and evaluate their postvaccination asthma and rhinitis control data. Methods: The demographic characteristics of patients with N-ERD and whether they had had symptoms of asthma, changes in nasal symptom scores Sino-nasal outcome test (SNOT-22), Asthma Control Test (ACT) within 1 month after SARS-CoV-2 vaccination or infection were recorded. The prevalence of COVID-19 in patients with N-ERD and in healthy controls was estimated. Results: A total of 103 patients with N-ERD and 100 healthy controls were included in the study. Thirty seven of the patients (35.9%) and 65 of the controls (65%) had a history of COVID-19. There were no significant differences in changes in the ACT and SNOT-22 scores after SARS-CoV-2 vaccination (p = 0.999). Although, the change in ACT score after infection was significant (p = 0.017; r = 0.39), there was no significant change in level of asthma control (p < 0.001). Conclusion: The history of COVID-19 was less frequent in the N-ERD group. There was no deterioration in asthma and rhinitis controls after SARS-CoV-2 vaccination. Although a significant decrease was observed in the ACT scores after COVID-19, there was no deterioration in the level of asthma control.

Effect of Dupilumab on Type 2 Biomarkers in Chronic Rhinosinusitis With Nasal Polyps: SINUS-52 Study Results.

Chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) are frequent coexisting conditions and share type 2 inflammatory pathophysiology, with interleukin (IL)-4 and IL-13 as key cytokines. Dupilumab is a monoclonal antibody that blocks the shared receptor for IL-4 and IL-13. The objective of this analysis was to evaluate dupilumab's effect on type 2 inflammation biomarkers in patients with CRSwNP with/without coexisting asthma or NSAID-ERD from the SINUS-52 (NCT02898454) study. Patients received treatment with dupilumab or placebo for 52 weeks. Blood and urinary biomarkers were evaluated through 52 weeks, and nasal secretions and mucosa brushings through 24 weeks. Of 447 patients, 60% had coexisting asthma and 27% had coexisting NSAID-ERD. At baseline, blood eotaxin-3, eosinophils, and periostin, nasal secretion eotaxin-3, and urinary leukotriene E4 were significantly higher in patients with coexisting NSAID-ERD than without. Dupilumab reduced eotaxin-3, thymus and activation-regulated chemokine, periostin, and total immunoglobulin E in blood, eotaxin-3, periostin, IL-5, and eosinophil cationic protein in nasal secretions, and leukotriene E4 in urine. Reductions were generally similar or greater in the subgroups with asthma and NSAID-ERD than without. Dupilumab also reduced MUC5AC and mast cell counts in nasal mucosa brushings. Dupilumab reduced local and systemic type 2 inflammatory biomarkers in patients with CRSwNP, including mast cells in nasal mucosa and cysteinyl leukotrienes in urine. These findings provide insight into the processes driving CRSwNP and the mechanisms of dupilumab's therapeutic effects. SINUS-52 https://www.clinicaltrials.gov/ct2/show/NCT02898454. NCT02898454.

Co-treatment of non-steroidal anti-inflammatory drug-exacerbated respiratory disease with dupilumab and aspirin therapy after desensitization.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

The nasal microbiome in patients suffering from non-steroidal anti-inflammatory drugs-exacerbated respiratory disease in absence of corticosteroids.

Chronic rhinosinusitis (CRS) is a chronic inflammatory disease phenotypically classified by the absence (CRSsNP) or presence of nasal polyps (CRSwNP). The latter may also be associated with asthma and hypersensitivity towards non-steroidal anti-inflammatory drugs (NSAID) as a triad termed NSAID-exacerbated respiratory disease (N-ERD). The role of the microbiome in these different disease entities with regard to the underlying inflammatory process and disease burden is yet not fully understood. To address this question, we measured clinical parameters and collected nasal samples (nasal mucosal fluids, microbiome swabs from middle meatus and anterior naris) of patients suffering from CRSsNP (n=20), CRSwNP (n=20) or N-ERD (n=20) as well as from patients without CRS (=disease controls, n=20). Importantly, all subjects refrained from taking local or systemic corticosteroids or immunosuppressants for at least two weeks prior to sampling. The nasal microbiome was analyzed using 16S rRNA gene amplicon sequencing, and levels of 33 inflammatory cytokines were determined in nasal mucosal fluids using the MSD platform. Patients suffering from N-ERD and CRSwNP showed significantly worse smell perception and significantly higher levels of type 2 associated cytokines IL-5, IL-9, Eotaxin and CCL17. Across all 4 patient groups, Corynebacteria and Staphylococci showed the highest relative abundances. Although no significant difference in alpha and beta diversity was observed between the control and the CRS groups, pairwise testing revealed a higher relative abundance of Staphylococci in the middle meatus in N-ERD patients as compared to CRSwNP (p<0.001), CRSsNP (p<0.01) and disease controls (p<0.05) and of Lawsonella in patients suffering from CRSwNP in middle meatus and anterior naris in comparison to CRSsNP (p<0.0001 for both locations) and disease controls (p<0.01 and p<0.0001). Furthermore, we observed a positive correlation of Staphylococci with IL-5 (Pearson r=0.548) and a negative correlation for Corynebacteria and Eotaxin-3 (r=-0.540). Thus, in patients refraining from oral and nasal corticosteroid therapy for at least two weeks known to alter microbiome composition, we did not observe differences in microbiome alpha or beta diversity between various CRS entities and disease controls. However, our data suggest a close association between increased bacterial colonization with Staphylococci and decreased colonization by Corynebacteria as well as increased type 2 inflammation.

Bronchial epithelial cell transcriptome shows endotype heterogeneity of asthma in patients with NSAID-exacerbated respiratory disease

Nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease (N-ERD) is currently classified as a type-2 (T2) immune-mediated disease characterized by asthma, chronic rhinosinusitis, and hypersensitivity to cyclooxygenase-1 inhibitors. The aim of this study was to characterize immunological endotypes of N-ERD based on the gene expression profile in the bronchial epithelium. mRNA transcriptome (mRNA-sequencing) was analyzed in bronchial brushings from patients with N-ERD (n=22), those with nonsteroidal anti-inflammatory drug-tolerant asthma (NTA, n= 21), and control subjects (n=11). Additionally, lipid and protein mediators were measured in bronchoalveolar lavage fluid (BALF). Initial analysis of the entire asthma group revealed 2 distinct gene expression signatures: "T2-high" with increased expression of T2-related genes (eg, CLCA1, CST1), and "proinflammatory" characterized by the expression of innate immunity (eg, FOSB, EGR3) and IL-17A response genes. These endotypes showed similar prevalence in N-ERD and NTA (eg, T2-high: 33% and 32%, respectively). T2-high asthma was characterized by increased expression of mast cell and eosinophil markers, goblet cell hyperplasia, and elevated LTE4 and PGD2 in BALF. Patients with a proinflammatory endotype showed mainly neutrophilic inflammation and increased innate immunity mediators in BALF. Furthermore, the proinflammatory signature was associated with a more severe course of asthma and marked airway obstruction. These signatures could be recreated invitro by exposure of bronchial epithelial cells to IL-13 (T2-high) and IL-17A (proinflammatory). T2-high signature was found only in one-third of patients with N-ERD, which was similar to what was found in patients with NTA. The proinflammatory endotype, which also occurred in N-ERD, suggests a novel mechanism of severe disease developing on a non-T2 background.