NSAID-exacerbated Respiratory Disease Research Articles

A retrospective study on long-term efficacy of intranasal lysine-aspirin in controlling NSAID-exacerbated respiratory disease

PurposeAspirin treatment after desensitization (ATAD) represents an effective therapeutic option suitable for NSAID-exacerbated respiratory disease (N-ERD) patients with recalcitrant disease. Intranasal administration of lysine-aspirin (LAS) has been suggested as a safer and faster route than oral ATAD but evidence for its use is less strong. We investigated nasal LAS therapy long-term efficacy based on objective outcomes, smell function, polyp recurrence and need for surgery or rescue therapy. Clinical biomarkers predicting response to intranasal LAS, long-term side effects and consequences of discontinuing treatment have been evaluated.MethodsA retrospective analysis of a database of 60 N-ERD patients seen between 2012 and 2020 was performed in March 2021. They were followed up at 3-months, 1-, 2- and 3-years with upper and lower airway functions assessed at each follow-up.ResultsHigher nasal airflow and smell scores were found at each follow-up in patients taking LAS (p < 0.001 and p = 0.048 respectively). No influence of LAS on pulmonary function measurements was observed. Patient on intranasal LAS showed a lower rate of revision sinus surgery when compared to those who discontinued the treatment (p < 0.001). None of the variables studied was found to influence LAS treatment response.ConclusionOur study demonstrates the clinical effectiveness of long-term intranasal LAS in the management of N-ERD in terms of improved nasal airflow and olfaction and a reduced need for revision sinus surgery. Intranasal LAS is safe, being associated with a lower rate of side effects when compared to oral ATAD. However, discontinuation of the treatment at any stage is associated with a loss of clinical benefit.

Contribution of dipeptidyl peptidase 10 to airway dysfunction in patients with NSAID-exacerbated respiratory disease.

Genetic variants of dipeptidyl peptidase 10 (DPP10) have been suggested to contribute to the development of NSAID-exacerbated respiratory disease (NERD). However, the mechanisms of how DPP10 contributes to NERD phenotypes remain unclear. To demonstrate the exact role of DPP10 in the pathogenesis of NERD. Patients with NERD (n=110), those with aspirin-tolerant asthma (ATA, n=130) and healthy control subjects (HCs, n=80) were enrolled. Clinical characteristics were analysed according to the serum DPP10levels in both NERD and ATA groups. The function of DPP10 in airway inflammation and remodelling was investigated with in vitro, ex vivo and in vivo experiments. NERD patients had higher levels of serum DPP10 and TGF-β1 with lower FEV1 than ATA patients or HCs (p<.05 for each). NERD patients with higher DPP10levels had higher TGF-β1, but lower FEV1 (p<.05 for all), whilst no differences were noted in ATA patients. Moreover, the seum DPP10levels had a positive correlation with TGF-β1 (r=0.384, p<.001), but a negative correlation with FEV1 (r=-0.230, p=.016) in NERD patients. In in vitro studies, expression of DPP10 in airway epithelial cells was enhanced by TGF-β1 treatments. Furthermore, DPP10 was found to be produced from immune cells and this molecule induced the ERK phosphorylation in airway epithelial cells, which was suppressed by anti-DPP10 treatment. In asthmatic mouse models, increased levels of DPP10 in the serum and TGF-β1 in the bronchoalveolar lavage fluid were noted, which were suppressed by anti-DPP10 treatment. Moreover, anti-DPP10 treatment inhibited the ERK phosphorylation and extracellular matrix deposition in the lungs. These findings suggest that increased production of DPP10may contribute to TGF-β1-mediated airway dysfunction in NERD patients, where blockade of DPP10may have potential benefits.

Evaluating the Safety of Non-Steroidal Anti-inflammatory Drugs use in Asthmatic Patients: A Systematic, Critical Review of Literature

Background: Evidence suggest avoidance of Non-steroidal anti-inflammatory drugs (NSAID) in aspirinintolerantasthmatics due to the risk of triggering exacerbation attack; however, evidence around avoidingNSAIDs in all other asthmatic patients are unclear. This study aimed to evaluate the evidence surroundingthe safety of using NSAIDs, including selective COX-2 inhibitors, among asthmatic patients.Methods: A systematic review used Medline (OVID), Scopus and Embasefrom January-2008 toJanuary-2019. Inclusion criteria includedEnglish, and human studies that evaluated the use of NSAID inasthmatics. Data was screened/extracted using a pre-designed data extraction form using Covidence®,thenwere critically appraised.Conclusion: Of the 49 identified studies,eight were eligible. Prevalence of NSAID-induced asthmaexacerbation was 9%(95%CI:6.0–12.0%)-9.9% (95%CI:9.4-10.5%). Asthmatics who were aspirin/NSAIDintolerant had 37% higher risk of hospitalisation compared to tolerant patients (RR:1.37; 95%CI:1.12–1.67).Use of COX-2 inhibitors showed non-significant associations with worsening respiratory symptoms/exacerbation. Only low-quality evidence was found for the safety of topical NSAID. NSAIDs-inducedrespiratory reactions/symptoms is relatively uncommon with the majority of asthmatic patients couldtolerate NSAIDs therapy. Asthmatic patients who suffer from aspirin-induced asthma or NSAIDsexacerbatedrespiratory disease (NSAIDs intolerant) should be avoided NSAIDs prescribing but could besafely prescribed selective COX-2 inhibitors as an alternative.

Polymorphisms in eicosanoid-related biosynthesis enzymes associated with acute urticaria/angioedema induced by nonsteroidal anti-inflammatory drug hypersensitivity.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity, with NSAID-induced acute urticaria/angioedema (NIUA) the most frequent phenotype. NSAID hypersensitivity is caused by cyclooxygenase 1 inhibition, which leads to an imbalance in prostaglandin (PG) and cysteinyl leukotriene (CysLT) synthesis. As only susceptible individuals develop NSAID hypersensitivity, genetic factors are believed to be involved; however, no study has assessed the overall genetic variability of key enzymes in PG and CysLT synthesis in NSAID hypersensitivity. To evaluate simultaneously variants in the main genes involved in PG and CysLT biosynthesis in NIUA. Two independent cohorts of patients were recruited in Spain, alongside NSAID-tolerant controls. The discovery cohort included only patients with NIUA; the replication cohort included patients with NSAID-exacerbated respiratory disease (NERD). A set of tagging single-nucleotide polymorphisms (tagSNPs) in PTGS1, PTGS2, ALOX5 and LTC4S was genotyped using mass spectrometry coupled with endpoint polymerase chain reaction. The study included 1272 individuals. Thirty-five tagSNPs were successfully genotyped in the discovery cohort, with three being significantly associated after Bonferroni correction (rs10306194 and rs1330344 in PTGS1; rs28395868 in ALOX5). These polymorphisms were genotyped in the replication cohort: rs10306194 and rs28395868 remained associated with NIUA, and rs28395868 was marginally associated with NERD. Odds ratios (ORs) in the combined analysis (discovery and replication NIUA populations) were 1·7 for rs10306194 [95% confidence interval (CI) 1·34-2·14; Pcorrected = 2·83 × 10-4 ) and 2·19 for rs28395868 (95% CI 1·43-3·36; Pcorrected = 0·002). Variants of PTGS1 and ALOX5 may play a role in NIUA and NERD, supporting the proposed mechanisms of NSAID-hypersensitivity and shedding light on their genetic basis.

Aspirin Actions in Treatment of NSAID-Exacerbated Respiratory Disease.

Non-steroidal Anti-inflammatory drugs (NSAID)-exacerbated respiratory disease (N-ERD) is characterized by nasal polyposis, chronic rhinosinusitis, adult-onset asthma and hypersensitive reactions to cyclooxygenase-1 (COX-1) inhibitors. Among the available treatments for this disease, a combination of endoscopic sinus surgery followed by aspirin desensitization and aspirin maintenance therapy has been an effective approach. Studies have shown that long-term aspirin maintenance therapy can reduce the rate of nasal polyp recurrence in patients with N-ERD. However, the exact mechanism by which aspirin can both trigger and suppress airway disease in N-ERD remains poorly understood. In this review, we summarize current knowledge of aspirin effects in N-ERD, cardiovascular disease, and cancer, and consider potential mechanistic pathways accounting for the effects of aspirin in N-ERD.

Baseline Conservative and Surgical Management in the Treatment of NSAID-Exacerbated Respiratory Disease.

Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) is a chronic medical condition that includes asthma, chronic rhinosinusitis with nasal polyposis, and hypersensitivity to aspirin and other NSAIDs. Eosinophilic inflammation in the upper and lower airways is treated with local corticosteroids, repeated antibiotics, oral corticosteroid courses, endoscopic sinus surgery, and in some cases aspirin treatment after desensitization (ATAD). Nevertheless, the disease may be uncontrolled and it has a great impact on quality of life. A better understanding of the pathomechanisms of the disease and the development of medications that target type 2 inflammation mediators may have a crucial role in achieving better disease control in patients with N-ERD.

Genetic Variants in Cytosolic Phospholipase A2 Associated With Nonsteroidal Anti-Inflammatory Drug-Induced Acute Urticaria/Angioedema.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main triggers of drug hypersensitivity reactions, probably due to their high consumption worldwide. The most frequent type of NSAID hypersensitivity is NSAID cross-hypersensitivity, in which patients react to NSAIDs from different chemical groups in the absence of a specific immunological response. The underlying mechanism of NSAID cross-hypersensitivity has been linked to cyclooxygenase (COX)-1 inhibition causing an imbalance in the arachidonic acid pathway. Despite NSAID-induced acute urticaria/angioedema (NIUA) being the most frequent clinical phenotype, most studies have focused on NSAID-exacerbated respiratory disease. As NSAID cross-hypersensitivity reactions are idiosyncratic, only appearing in some subjects, it is believed that individual susceptibility is under the influence of genetic factors. Although associations with polymorphisms in genes from the AA pathway have been described, no previous study has evaluated the potential role of cytosolic phospholipase A2 (cPLA2) variants. This enzyme catalyzes the initial hydrolysis of membrane phospholipids to release AA, which can be subsequently metabolized into eicosanoids. Here, we analyzed for the first time the overall genetic variation in the cPLA2 gene (PLA2G4A) in NIUA patients. For this purpose, a set of tagging single nucleotide polymorphisms (tagSNPs) in PLA2G4A were selected using data from Europeans subjects in the 1,000 Genomes Project, and genotyped with the iPlex Sequenom MassArray technology. Two independent populations, each comprising NIUA patients and NSAID-tolerant controls, were recruited in Spain, for the purposes of discovery and replication, comprising a total of 1,128 individuals. Fifty-eight tagSNPs were successfully genotyped in the discovery cohort, of which four were significantly associated with NIUA after Bonferroni correction (rs2049963, rs2064471, rs12088010, and rs12746200). These polymorphisms were then genotyped in the replication cohort: rs2049963 was associated with increased risk for NIUA after Bonferroni correction under the dominant and additive models, whereas rs12088010 and rs12746200 were protective under these two inheritance models. Our results suggest a role for PLA2G4A polymorphisms in NIUA. However, further studies are required to replicate our findings, elucidate the mechanistic role, and evaluate the participation of PLA2G4A variants in other phenotypes induced by NSAID cross-hypersensitivity.

Aspirin desensitization in NSAID-exacerbated respiratory disease and its outcomes in the clinical course of asthma: A systematic review of the literature and meta-analysis

Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NERD) might benefit from aspirin desensitization (AD) as an alternative treatment to standard care. However, there is conflicting evidence regarding its role in bronchial symptoms and asthma exacerbations. To analyze the clinical effects of AD in terms of lung function, systemic and inhaled steroid use, the frequency of acute asthma exacerbations, and adverse effects in patients with NERD and asthma. We identified randomized clinical trials (RCTs) from PubMed, EMBASE, SCOPUS, and EBSCO. We also searched the RCT references for additional studies. Studies comparing AD to placebo in patients with a previous history of pulmonary symptoms triggered by ASA or other NSAIDs or with a positive provocation test to ASA were included. Five studies with 210 participants with NERD were included in this review. The study duration ranged from 3 to 6 months. Overall, the risk of bias across the included RCTs was low. We identified 3 studies evaluating lung function, 2 of which reported a significant improvement in FEV1 in the AD group after 6 months, while the other reported no difference among the treatments. Due to high heterogeneity, we did not pool the results. The remaining primary outcomes were reported only in a single study each, hindering their interpretation. Secondary outcomes revealed reduced symptom and medication scores in patients with AD. Due to the small number of studies included in this systematic review, conclusions should be made with caution. AD shows a trend towards improving lung function (FEV1) following 6 months of treatment, although no conclusions can be made regarding the use of corticosteroids or the frequency of acute exacerbations. AD appears to reduce both symptom and medication scores. Additional RCTs are needed to fully assess the efficacy of AD in reducing bronchial symptoms in patients with NERD.

NSAID-Exacerbated Respiratory Disease in Patients with Nasosinusal Polyposis in the Othorhynolaringology service at Hospital de Clinicas, Paraguay, from January, 2016 to June, 2020.

NSAID-Exacerbated Respiratory Disease in Patients with Nasosinusal Polyposis in the Othorhynolaringology service at Hospital de Clinicas, Paraguay, from January, 2016 to June, 2020.

Cytosolic Phospholipase A2 (PLA2G4A) Polymorphisms Associated with Acute Urticaria/angioedema Induced by Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main triggers of drug hypersensitivity, probably due to their high consume worldwide, with NSAIDs-induced acute urticaria/angioedema (NIUA) being the most frequent clinical phenotype. Nevertheless, most studies have focused on NSAIDs-exacerbated respiratory disease. NSAID-hypersensitivity occurs only in some individuals, mainly by the increased release of cysteinyl-leukotrienes from arachidonic acid due to COX-1 inhibition. Thus, individual susceptibility to NSAID-hypersensitivity may be under the influence of genetic factors.

Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.

PurposeData on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.MethodsThe clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.ResultsMore than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.ConclusionsNIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.Trial RegistrationClinicalTrials.gov Identifier: NCT03849625

Lung function and side effects of Aspirin desensitization: a real world study

ABSTRACT Introduction: NSAID-exacerbated respiratory disease (N-ERD) is mainly treated with topical and oral corticosteroids, as well as acetylsalicylic acid (ASA) treatment after desensitization (ATAD). During desensitization and ATAD, it is common to experience an exacerbation of respiratory symptoms and other side effects, which may lead to cessation of treatment. Objectives: The aim of this retrospective follow-up study was to evaluate the effect of ATAD on lung functions and respiratory symptoms, and to clarify the occurrence of adverse events. Methods: We analysed the patient data of 67 patients treated with ASA desensitization between 2006 and 2016 in three hospitals, concerning adverse events, respiratory symptoms, lung function tests, and reasons for discontinuation. Results: 26 patients discontinued AD or ATAD. The most common reasons for discontinuation were lack of response (9%) and side effects (18%). ATAD did not affect lung function values in the follow-up of up to 5 years. Upper respiratory symptoms improved in 31 (52%) and lower respiratory symptoms (LRS) in 7 (10%) cases. Side effects occurred in 42 (63%) cases, the most common being dyspepsia and lower respiratory symptoms. Conclusion: Our study suggests that ATAD has little effect on lower airway functions. Side effects were common, and discontinuation rates high.

Role of systemic immune-inflammation index in asthma and NSAID-exacerbated respiratory disease.

Asthma is a heterogeneous disease characterized by chronic progressive airway inflammation. Although the disease has numerous phenotypes, there are no practical biomarkers for distinguishing the phenotypes from one another. To address this challenge, we aimed to reveal whether the systemic immune-inflammation index (SII), an important indicator of systemic inflammation and prognosis in various malignancies and vasculitis, can be used for distinguishing between asthma and NSAID-exacerbated respiratory disease (NERD). The study enrolled 105 patients (asthma: n = 69; NERD: n = 36). SII was calculated using the formula of neutrophil X platelet/lymphocyte number. Major risk factors, namely ACT score, eosinophil level, total IgE level, N-L ratio (NLR), P-L ratio (PLR), and SII, were evaluated by logistic regression analysis. No significant differences were found between the clinical features of the two study groups. Patients with an SII value ≥895.6 had a probability of having NERD with a sensitivity of 30.56%, whereas those with a lower SII had a probability of having asthma with a sensitivity of 92.65%. In the logistic regression analysis, no risk factor was determined for identifying asthma or NERD. The N-L ratio was found to be the risk factor affecting categorized SII (OR=264.2, 95% CI 9.9-7046.5, P=0.001). This is the first study to evaluate SII as a tool for differentiating asthma phenotypes. The presence of SII below the cutoff value can help exclude the diagnosis of NERD. There is a need for large-scale prospective studies to compare different phenotypes and determine the optimal cutoff value.

Platelet-Adherent Leukocytes Associated With Cutaneous Cross-Reactive Hypersensitivity to Nonsteroidal Anti-Inflammatory Drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most highly consumed drugs worldwide and the main triggers of drug hypersensitivity reactions. The most frequent reaction, named cross-reactive NSAID-hypersensitivity, is due to the pharmacological activity of these drugs by blocking the cyclooxygenase-1 enzyme. Such inhibition leads to cysteinyl-leukotriene synthesis, mainly LTE4, which are responsible for the reaction. Although the complete molecular picture of the underlying mechanisms remains elusive, the participation of platelet-adherent leukocytes (CD61+) and integrins have been described for NSAID-exacerbated respiratory disease (NERD). However, there is a lack of information concerning NSAID-induced urticaria/angioedema (NIUA), by far the most frequent clinical phenotype. Here we have evaluated the potential role of CD61+ leukocytes and integrins (CD18, CD11a, CD11b, and CD11c) in patients with NIUA, and included the other two phenotypes with cutaneous involvement, NSAID-exacerbated cutaneous disease (NECD) and blended reactions (simultaneous skin and airways involvement). A group NSAID-tolerant individuals was also included. During the acute phase of the reaction, the three clinical phenotypes showed increased frequencies of CD61+ neutrophils, eosinophils, and monocytes compared to controls, which correlated with urinary LTE4 levels. However, no correlation was found between these variables at basal state. Furthermore, increased expressions of CD18 and CD11a were found in the three CD61+ leukocytes subsets in NIUA, NECD and blended reactions during the acute phase when compared with CD61−leukocyte subpopulations. During the acute phase, CD61+ neutrophils, eosinophils and monocytes showed increased CD18 and CD11a expression when compared with CD61+ leukocytes at basal state. No differences were found when comparing controls and CD61+ leukocytes at basal state. Our results support the participation of platelet-adherent leukocytes and integrins in cutaneous cross-hypersensitivity to NSAIDs and provide a link between these cells and arachidonic acid metabolism. Our findings also suggest that these reactions do not involve a systemic imbalance in the frequency of CD61+ cells/integrin expression or levels of LTE4, which represents a substantial difference to NERD. Although further studies are needed, our results shed light on the molecular basis of cutaneous cross-reactive NSAID-hypersensitivity, providing potential targets for therapy through the inhibition of platelet-leukocyte interactions.

Evaluating nonadherence to preventer inhaler therapy in severe asthmatic patients receiving omalizumab.

Asthma is one of the most common chronic diseases worldwide and can often be controlled by existing treatments, but in the 5%-10% of patients with severe asthma, control is frequently more challenging. The aim of this paper is to evaluate the adherence to preventer inhaler therapy in severe asthmatic patients receiving omalizumab, a recombinant humanized monoclonal anti-IgE antibody indicated for moderate-to-severe asthma. This study included 29 patients who were receiving omalizumab treatment as maintenance therapy. All patients completed the six question Turkish Modified Morisky Scale. In addition, patients were classified by adherence to their prescribed preventer therapy, based on pharmaceutical and medical device institution records from the preceding one year. Of the 29 enrolled patients, 24.1% had NSAID-exacerbated respiratory disease; 75.9% were female and median age was 47.2±12.99years. Severe asthma patients demonstrated high levels of motivation (98.8%, n=28) and knowledge (86.2%, n=22) about asthma treatment. Nevertheless, the rate of nonadherence to preventer inhaler therapy was only 34.5% (n=10). There were no significant differences among the characteristics of the patients that might affect the adherence to inhaler therapy. In patients with severe asthma, suboptimal adherence to preventer inhaler therapy is common before and after omalizumab treatment. Although patients have high levels of motivation and knowledge about asthma treatment, adherence to inhaler preventer therapy declined after omalizumab therapy. Given these findings, it is important to decide whether preventer inhaler therapy should be continued as monotherapy or be discontinued inpatients exhibiting impaired adherence to biological agents, such as omalizumab.

Eosinophil/Neutrophil/Platelet-to-Lymphocyte Ratios in Various Types of Immediate Hypersensitivity to NSAIDs: A Preliminary Study

Background: The eosinophil/neutrophil/platelet-to-lymphocyte ratios (ELR, NLR, and PLR) have been used as clinical markers of systemic inflammation. However, they have not yet been tested in various subtypes of immediate hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs). Objectives: To assess the ELR, NLR, and PLR in various types of hypersensitivity to NSAIDs. Materials and Methods: A retrospective analysis of complete blood cell count and the ELR, NLR, and PLR was performed. Appropriate types of hypersensitivity to NSAIDs were diagnosed based on the anamnesis and drug provocation tests. The analysis covered 97 patients. Twenty were diagnosed with NERD (NSAID-exacerbated respiratory disease), 20 with NECD (NSAID-exacerbated cutaneous disease), 38 with NIUA (NSAID-inducted urticaria/angioedema), and 19 with SNIUAA (single-NSAID-induced urticaria/angioedema or anaphylaxis). Two controls groups were included: the first covered 15 patients with bronchial asthma and the second 28 patients with chronic spontaneous urticaria without NSAID hypersensitivity. Results: The NLR did not differ significantly between the NSAID hypersensitivity types. The ELR was significantly higher in NERD patients, and the PLR was significantly lower in NECD patients than in patients with other types of NSAID hypersensitivity and in controls. Conclusions: The ELR and PLR may be useful in differentiating various types of immediate hypersensitivity to NSAIDs. Moreover, the ELR may be helpful in differentiating patients with bronchial asthma with and without NSAID hypersensitivity and PLR in differentiating patients with chronic spontaneous urticaria from NECD.

Heterogeneity of lower airway inflammation in patients with NSAID-exacerbated respiratory disease

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) asthma is characterized by chronic rhinosinusitis and intolerance of aspirin and other COX1 inhibitors. Clinical data point to a heterogeneity within the N-ERD phenotype. Our aim was to investigate immune mediator profiles in the lower airways of patients with N-ERD. Levels of cytokines (determined by using Luminex assay) and eicosanoids (determined by using mass spectrometry) were measured in bronchoalveolar lavage fluid (BALF) from patients with N-ERD (n= 22), patients with NSAID-tolerant asthma (n= 21), and control subjects (n= 11). mRNA expression in BALF cells was quantified by using TaqMan low-density arrays. Lower airway eosinophilia was more frequent in N-ERD (54.5%) than in NSAID-tolerant asthma (9.5% [P= .009]). The type-2 (T2) immune signature of BALF cells was more pronounced in the eosinophilic subphenotype of N-ERD. Similarly, BALF concentrations of periostin and CCL26 were significantly increased in eosinophilic N-ERD and correlated with T2 signature in BALF cells. Multiparameter analysis of BALF mediators of all patients with asthma revealed the presence of 2 immune endotypes: T2-like (with an elevated level of periostin in BALF) and non-T2/proinflammatory (with higher levels of matrix metalloproteinases and inflammatory cytokines). Patients with N-ERD were classified mostly as having the T2 endotype (68%). Changes in eicosanoid profile (eg, increased leukotriene E4 level) were limited to patients with N-ERD with airway eosinophilia. Blood eosinophilia appeared to be a useful predictor of airway T2 signature (area under the curve [AUC]= 0.83); however, surrogate biomarkers had moderate performance in distinguishing eosinophilic N-ERD (for blood eosinophils, AUC= 0.72; for periostin, AUC= 0.75). Lower airway immune profiles show considerable heterogeneity of N-ERD, with skewing toward T2 response and eosinophilic inflammation. Increased production of leukotriene E4 was restricted to a subgroup of patients with eosinophilia in the lower airway.

NSAID-Exacerbated Respiratory Disease (NERD): From Pathogenesis to Improved Care.

Nonsteroidal antiinflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is characterized by moderate-to-severe asthma and a higher prevalence of chronic rhinosinusitis/nasal polyps, but is a highly heterogeneous disorder with various clinical manifestations. Two major pathogenic mechanisms are: (1) overproduction of cysteinyl leukotrienes with dysregulation of arachidonic acid metabolism and (2) increased type 2 eosinophilic inflammation affected by genetic mechanisms. Aspirin challenge is the gold standard to diagnose NERD, whereas reliable in vitro biomarkers have yet not been identified. Therapeutic approaches have been done on the basis of disease severity with the avoidance of culprit and cross-reacting NSAIDs, and when indicated, aspirin desensitization is an effective treatment option. Biologic approaches targeting Type 2 cytokines are emerging as potential therapeutic options. Here, we summarize the up-to-date evidence of pathophysiologic mechanisms and diagnosis/management approaches to the patients with NERD with its phenotypic classification.

Endotypes of chronic rhinosinusitis with nasal polyps with and without NSAID â€" intolerance.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2-dominated inflammatory disease of the upper air- ways. A subgroup of patients with CRSwNP suffer from intolerance to nonsteroidal anti-inflammatory drugs (NSAID) and develop NSAID-exacerbated respiratory disease (NERD). The aim of the study was to compare the cytokine based inflammatory endotype of nasal secretions of CRSwNP patients with and without NSAID intolerance. Nasal secretions were collected from twenty-six patients suffering from CRSwNP, thirteen with NERD and thirteen without NSAID intolerance. As control, nasal secretions were collected from fifteen healthy donors. Tryptase and ten human cyto- kines were analyzed: interleukin (IL)-4, IL-5, IL-6, IL-8, IL-12p70, IL-13, IL-17A, IL-23, IFN-g, and TNF-a by a cytokine multiple array on a Luminex 200 platform. Grade of polyposis and frequency of polyp surgery was more severe in NERD- compared to non-NERD patients. IL-6 and IL-5 in CRSwNP was significantly increased compared to healthy participants. IL-5 and IL-13 were significantly increased in subjects suffering from NERD compared to CRSwNP patients without NERD. We identified IL-13 as a possible specific biomarker in nasal secretions of patients with NERD, which allows us to differentiate between CRSwNP with vs. without NERD. The characterization of inflammatory endotypes in CRSwNP enables the introduction of the best available therapy in the context of precision medicine.

Dupilumab: A Review in Chronic Rhinosinusitis with Nasal Polyps.

Dupilumab (Dupixent®) is a fully human IgG4 monoclonal antibody against the interleukin (IL)-4receptor α (IL-4Rα) subunit, which is shared by the type I IL-4 and the type II IL-4/IL-13 receptor complexes. By binding to and blocking this subunit, dupilumab inhibits IL-4 and IL-13, which are the major drivers of human type 2 inflammatory disease [e.g. asthma, atopic dermatitis and chronic rhinosinusitis with nasal polyps (CRSwNP)]. Dupilumab, administered subcutaneously, is the first biological therapy to be approved for the treatment of adults with inadequately controlled CRSwNP in the EU and the USA. In two placebo-controlled, multinational, phase III studies of 24 and 52weeks' duration, the addition of dupilumab (300mg every 2weeks) to the intranasal corticosteroid treatment of adults with severe, inadequately controlled CRSwNP was generally well tolerated and improved nasal polyp size, sinus opacification and health-related quality of life (HR-QOL), relieved the major symptoms of CRSwNP (nasal congestion or obstruction, nasal discharge and loss of smell) and reduced the use of systemic corticosteroids and the need for nasal polyp surgery. Improvements in nasal polyp size, sinus opacification and nasal congestion or obstruction were achieved regardless of the presence of comorbid asthma or NSAID-exacerbated respiratory disease, or a history of previous nasal polyp surgery, with patients with comorbid asthma also demonstrating improvements in lung function and asthma control regardless of their baseline eosinophil count. Thus, add-on subcutaneous dupilumab is a valuable treatment option for adults with inadequately controlled CRSwNP.