Innate immune cell dysregulation drives inflammation and disease in aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease (AERD) is a complex inflammatory disorder that is not generally viewed as a disease involving the adaptive immune system but instead one largely driven by the innate immune system. This article focuses on the cellular dysregulation involving 4 central cell types: eosinophils, basophils, mast cells, and innate lymphoid type 2 cells. AERD can be envisioned as involving a self-perpetuating vicious circle in which mediators produced by a differentiated activated epithelial layer, such as IL-25, IL-33, and thymic stromal lymphopoietin, engage and activate each of these innate immune cells. The activation of these innate immune cells with their production of additional cytokine/chemokine and lipid mediators leads to further recruitment and activation of these innate immune cells. More importantly, numerous mediators produced by these innate immune cells provoke the epithelium to induce further inflammation. This self-perpetuating cycle of inflammation partially explains both current interventions suggested to ameliorate AERD (eg, aspirin desensitization, leukotriene modifiers, anti-IL-5/IL-5 receptor, anti-IL-4 receptor, and anti-IgE) and invites exploration of novel targets as specific therapies for this condition (prostaglandin D2 antagonists or cytokine antagonists [IL-25, IL-33, thymic stromal lymphopoietin]). Several of these interventions currently show promise in small retrospective analyses but now require definite clinical trials.

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.

Mepolizumab targets multiple immune cells in aspirin-exacerbated respiratory disease.

BACKGROUND: Eosinophilic asthma and nasal polyposis are hallmarks of aspirin-exacerbated respiratory disease (AERD), and IL-5 inhibition has been shown to provide therapeutic benefit. However, IL-5Rα is expressed on many cells in addition to eosinophils, and the mechanisms by which IL-5 inhibition leads to clinical benefit in eosinophilic asthma and nasal polyposis are unlikely to be due exclusively to antieosinophil effects. OBJECTIVE: We sought to identify the mechanisms by which anti-IL-5 treatment with mepolizumab improves respiratory inflammation in AERD. METHODS: The clinical characteristics, circulating granulocytes, nasal scraping transcripts, eosinophilic cationic protein, tryptase, and antibody levels, and urinary and nasal eicosanoid levels were measured for 18 subjects with AERD who were taking mepolizumab and compared with those of 18 matched subjects with AERD who were not taking mepolizumab. RESULTS: Subjects taking mepolizumab had significantly fewer peripheral blood eosinophils and basophils, and those cells that remained had higher surface CRTH2 expression than did the cells from subjects not taking mepolizumab. Nasal prostaglandin F2α, prostaglandin D2 metabolites, leukotriene B4, and thromboxane levels were lower in subjects taking mepolizumab, as were urinary levels of tetranor-prostaglandin D2 and leukotriene E4. The nasal epithelial cell transcripts that were overexpressed among subjects with AERD who were taking mepolizumab were enriched for genes involved in tight junction formation and cilium organization. Nasal and urinary prostaglandin E2, tryptase, and antibody levels were not different between the 2 groups. CONCLUSION: IL-5 inhibition in AERD decreases production of inflammatory eicosanoids and upregulates tight junction-associated nasal epithelial cell transcripts, likely due to decreased IL-5 signaling on tissue mast cells, eosinophils, and epithelial cells. These direct effects on multiple relevant immune cells contribute to the mechanism of benefit afforded by mepolizumab.

Effectiveness of endoscopic sinus surgery and aspirin therapy in the management of aspirin-exacerbated respiratory disease.

Background: Aspirin therapy and/or type 2 (T2) biologics are used in the management of aspirin-exacerbated respiratory disease (AERD). Objective: To identify the number of patients with AERD who tolerated aspirin therapy, yet due to persistent symptoms, incorporated T2 biologic management. Methods: A retrospective review was performed between July 2016 and June 2019. Patients with AERD and who underwent endoscopic sinus surgery (ESS), aspirin desensitization (AD), and at least 6 months of aspirin therapy (ATAD) after AD, and who remained biologic-naive up through this timepoint were included in the study. Introduction of a T2 biologic while on ATAD was the primary outcome. The secondary outcome was a change in a validated patient-reported outcome measure for chronic rhinosinusitis score between the postoperative predesensitization timepoint, and the 6-month postdesensitization timepoint, presented as means and compared by using the Student's t-test. Results: A total of 103 patients met inclusion criteria. Two patients (1.9%) ultimately supplemented ATAD with a T2 biologic. The mean outcomes measure test score after 6 months of ATAD for patients who received biologics was 40.5 versus 15 in those who did not receive biologics (p = 0.02). The mean differences between the postoperative predesensitization test score and the 6-month postdesensitization test score for patients who went on to receive biologics was an increase of 13 versus a decrease of 10 for those patients who did not receive biologics (p = 0.12). Conclusion: ESS, coupled with AD and ATAD, was successful in the long-term management of the majority of the patients with AERD, which rarely required the incorporation of T2 biologics. Patient questionnaires, such as outcomes measure test score, may identify aspirin therapy failures and help guide the practitioner in deciding when to introduce T2 biologics into the patient's treatment regimen.

Group 2 innate lymphoid cells in nasal polyposis.

OBJECTIVE: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a chronic type 2 inflammatory response in the paranasal sinuses. Group 2 innate lymphoid cells (ILC2s) are potent innate immune cells that contribute to type 2 inflammation by producing cytokines such as interleukin (IL)-4, IL-5, and IL-13. There is increasing evidence suggesting that ILC2s play an important role in the CRSwNP pathogenesis. DATA SOURCES: We reviewed published literature obtained through PubMed inquiries. STUDY SELECTIONS: Studies relevant to the presence, function, and activation of ILC2s in CRSwNP were included. RESULTS: Nasal polyps (NPs) are one of the first tissues in which human ILC2s were discovered, and many groups have since reported that these cells are highly elevated in NPs. ILC2s in NPs are also highly activated and produce type 2 cytokines in vivo. Mediators known to activate ILC2s, including receptor activator of nuclear factor kappa-Β ligand, thymic stromal lymphopoietin, various lipid mediators (including prostaglandin D2 and cysteinyl leukotrienes), IL-4, and IL-13 have also been shown to be elevated in NPs compared with healthy sinonasal tissue. Other well-known ILC2 activators, IL-25 and IL-33, are sometimes elevated in NPs in some countries. Furthermore, activation of ILC2s by means of 4 distinct transcriptional pathways (nuclear factor kappa-light-chain-enhancer of activated B cells, nuclear factor of activated T cells, signal transducer and activator of transcription 5, and signal transducer and activator of transcription 6) is needed for the most robust generation of type 2 cytokines. CONCLUSION: ILC2-mediated type 2 inflammation plays a crucial role in the pathogenesis of CRSwNP. Targeting the upstream mediators responsible for activating ILC2s and the downstream products that these cells release may play an important role in modifying the inflammatory response and improving clinical outcomes in CRSwNP.

Local immunoglobulin production in nasal tissues: A key to pathogenesis in chronic rhinosinusitis with nasal polyps and aspirin-exacerbated respiratory disease.

OBJECTIVE: Local activation of B cells and antibody production are important for protective and pathogenic immune responses. Furthermore, there is evidence that local activation of B cells and antibody production are important for pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) and a severe subset of CRSwNP, aspirin-exacerbated respiratory disease (AERD). This review summarizes these findings and the potential role of B cells and antibodies in disease pathogenesis. DATA SOURCES: Published literature from PubMed searches. STUDY SELECTIONS: Studies relevant to B cell development and the roles of B cells and antibodies in the pathogenesis of CRSwNP and AERD. RESULTS: Formation of tertiary lymphoid structures plays a key role in the local activation of B cells and antibody production. This process is important for fighting infections, but it also contributes to autoimmune disease. Furthermore, there is evidence to support a role for local B cell activation and antibody production in a variety of allergic diseases. Nasal polyp tissues from patients with CRSwNP and AERD have elevated levels of activated B cell subsets and locally produced antibodies. These locally produced antibodies may contribute to disease pathogenesis in a variety of ways, including activation of innate effector cells, whereas locally activated B cells may contribute to pathogenesis through the activation of T cells. CONCLUSION: More studies are needed to determine the role of B cells and antibodies in driving disease in these patients. However, targeting the processes that drive local B cell activation and antibody production may provide new therapeutic approaches and could help to reduce chronic inflammation.

Lipid-mediated innate lymphoid cell recruitment and activation in aspirin-exacerbated respiratory disease.

OBJECTIVE: To synthesize investigations into the role of lipid-mediated recruitment and activation of group 2 innate lymphoid cells (ILC2s) in aspirin-exacerbated respiratory disease (AERD). DATA SOURCES: A comprehensive literature review of reports pertaining to cellular mechanisms, cytokine, and lipid mediators in AERD, as well as ILC2 activation and recruitment, was performed using PubMed and Google Scholar. STUDY SELECTIONS: Selections of studies were based on reports of lipid mediators in AERD, cytokine mediators in AERD, type 2 effector cells in AERD, platelets in AERD, AERD treatment, ILC2s in allergic airway disease, and ILC2 activation, inhibition, and trafficking. RESULTS: The precise mechanisms of AERD pathogenesis are not well understood. Greater levels of proinflammatory lipid mediators and type 2 cytokines are found in tissues derived from patients with AERD relative to controls. After pathognomonic cyclooxygenase-1 inhibitor reactions, proinflammatory mediator concentrations (prostaglandin D2 and cysteinyl leukotrienes) are rapidly increased, as are ILC2 levels in the nasal mucosa. The ILC2s, which potently generate type 2 cytokines in response to lipid mediator stimulation, may play a key role in AERD pathogenesis. CONCLUSION: Although the literature suggests that lipid-mediated ILC2 activation may occur in AERD, there is a dearth of definitive evidence. Future investigations leveraging novel next-generation single-cell sequencing approaches along with recently developed AERD murine models will better define lipid mediator-induced ILC2 trafficking in patients with AERD.

Meta-analysis Exploring Sinopulmonary Outcomes of Aspirin Desensitization in Aspirin-Exacerbated Respiratory Disease.

OBJECTIVE: The objective of this study is to explore the sinopulmonary outcomes of aspirin desensitization through a systematic review and meta-analysis. DATA SOURCES: Embase and OVID Medline databases. REVIEW METHODS: A systematic review of published articles on outcomes following aspirin desensitization in any language for relevant articles was performed in February 2019. Outcomes included sinonasal quality-of-life assessment, sense-of-smell scores, FEV-1 (forced expiratory volume in 1 second), and medication/steroid use. RESULTS: Thirteen studies met the inclusion criteria out of 6055 articles screened. Aspirin desensitization resulted in significant improvement in FEV-1 and reduction in asthma medication/steroid use (P < .05). There was no significant improvement in the sinonasal quality of life of patients who underwent aspirin desensitization (P = .098). CONCLUSION: Aspirin desensitization appears to be effective in improving pulmonary outcomes and should be considered in the treatment of patients with aspirin-exacerbated respiratory disease. However, good-quality studies are still needed to determine the ideal protocol tailored to individual patients.

Activation of the 15-lipoxygenase pathway in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance of medications that inhibit cyclooxygenase-1. Patients with AERD have more severe upper and lower respiratory tract disease than do aspirin-tolerant patients with CRSwNP. A dysregulation in arachidonic acid metabolism is thought to contribute to the enhanced sinonasal inflammation in AERD. OBJECTIVE: Our aim was to utilize an unbiased approach investigating arachidonic acid metabolic pathways in AERD. METHODS: Single-cell RNA sequencing (10× Genomics, Pleasanton, Calif) was utilized to compare the transcriptional profile of nasal polyp (NP) cells from patients with AERD and patients with CRSwNP and map differences in the expression of select genes among identified cell types. Findings were confirmed by traditional real-time PCR. Lipid mediators in sinonasal tissue were measured by mass spectrometry. Localization of various proteins within NPs was assessed by immunofluorescence. RESULTS: The gene encoding for 15-lipooxygenase (15-LO), ALOX15, was significantly elevated in NPs of patients with AERD compared to NPs of patients with CRSwNP (P < .05) or controls (P < .001). ALOX15 was predominantly expressed by epithelial cells. Expression levels significantly correlated with radiographic sinus disease severity (r = 0.56; P < .001) and were associated with asthma. The level of 15-oxo-eicosatetraenoic acid (15-Oxo-ETE), a downstream product of 15-LO, was significantly elevated in NPs from patients with CRSwNP (27.93 pg/mg of tissue) and NPs from patients with AERD (61.03 pg/mg of tissue) compared to inferior turbinate tissue from controls (7.17 pg/mg of tissue [P < .001]). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-Oxo-ETE synthesis, was predominantly expressed in mast cells and localized near 15-LO+ epithelium in NPs from patients with AERD. CONCLUSIONS: Epithelial and mast cell interactions, leading to the synthesis of 15-Oxo-ETE, may contribute to the dysregulation of arachidonic acid metabolism via the 15-LO pathway and to the enhanced sinonasal disease severity observed in AERD.

The role of aspirin desensitization followed by oral aspirin therapy in managing patients with aspirin-exacerbated respiratory disease: A Work Group Report from the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the American Academy of Allergy, Asthma & Immunology.

Aspirin-exacerbated respiratory disease (AERD) is characterized by the clinical triad of chronic rhinosinusitis with nasal polyps, asthma, and an intolerance to medications that inhibit the cycloxgenase-1 enzyme. Patients with AERD on average have more severe respiratory disease compared with patients with chronic rhinosinusitis with nasal polyps and/or asthma alone. Although patients with AERD traditionally develop significant upper and lower respiratory tract symptoms on ingestion of cycloxgenase-1 inhibitors, most of these same patients report clinical benefit when desensitized to aspirin and maintained on daily aspirin therapy. This Work Group Report provides a comprehensive review of aspirin challenges, aspirin desensitizations, and maintenance aspirin therapy in patients with AERD. Identification of appropriate candidates, indications and contraindications, medical and surgical optimization strategies, protocols, medical management during the desensitization, and recommendations for maintenance aspirin therapy following desensitization are reviewed. Also included is a summary of studies evaluating the clinical efficacy of aspirin therapy after desensitization as well as a discussion on the possible cellular and molecular mechanisms explaining how this therapy provides unique benefit to patients with AERD.

Cellular interactions in aspirin-exacerbated respiratory disease.

PURPOSE OF REVIEW: The purpose of this review is to summarize the complex cellular interactions of aspirin-exacerbated respiratory disease (AERD) and how these interactions promote pathogenic mechanisms of AERD. RECENT FINDINGS: In addition to characteristic changes in eicosanoid levels, recent studies have identified increases in alarmin cytokines (IL-33, thymic stromal lymphopoietin) as well as activated innate lymphoid and plasma cell populations in samples from AERD patients. SUMMARY: Patients with AERD typically demonstrate high levels of proinflammatory eicosanoids including cysteinyl leukotrienes (CysLTs) and prostaglandin D2 (PGD2) and hyporesponsiveness to prostaglandin E2 (PGE2). CysLTs are released by mast cells, eosinophils, and adherent platelets and promote epithelial release of IL-33, which activates mast cells and group 2 innate lymphoid cells (ILC2s) in concert with CysLTs. TSLP induces PGD2 release from mast cells which activates and recruits eosinophils, basophils, Th2 cells, and ILC2s via CRTH2. In turn, ILC2s and other cell types produce Th2 cytokines IL-4, IL-5, and IL-13 that, along with CysLTs and PGD2, promote bronchoconstriction, eosinophilic tissue inflammation, and mucus production.

Inflammatory heterogeneity in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a mechanistically distinct subtype of chronic rhinosinusitis with nasal polyps (CRSwNP). Although frequently associated with type 2 inflammation, literature characterizing the milieu of inflammatory cytokines and lipid mediators in AERD has been conflicting. OBJECTIVE: We sought to identify differences in the upper airway inflammatory signature between CRSwNP and AERD and determine whether endotypic subtypes of AERD may exist. METHODS: Levels of 7 cytokines representative of type 1, type 2, and type 3 inflammation, and 21 lipid mediators were measured in nasal mucus from 109 patients with CRSwNP, 30 patients with AERD, and 64 non-CRS controls. Differences in inflammatory mediators were identified between groups, and patterns of inflammation among patients with AERD were determined by hierarchical cluster analysis. RESULTS: AERD could be distinguished from CRSwNP by profound elevations in IL-5, IL-6, IL-13, and IFN-γ; however, significant heterogeneity existed between patients. Hierarchical cluster analysis identified 3 inflammatory subendotypes of AERD characterized by (1) low inflammatory burden, (2) high type 2 cytokines, and (3) comparatively low type 2 cytokines and high levels of type 1 and type 3 cytokines. Several lipid mediators were associated with asthma and sinonasal disease severity; however, lipid mediators showed less variability than cytokines. CONCLUSIONS: AERD is associated with elevations in type 2 cytokines (IL-5 and IL-13) and the type 1 cytokine, IFN-γ. Among patients with AERD, the inflammatory signature is heterogeneous, supporting subendotypes of the disease. Variability in AERD immune signatures should be further clarified because this may predict clinical response to biologic medications that target type 2 inflammation.

Hypersensitivity to dipyrone in aspirin-exacerbated respiratory disease patients is associated with urticaria.

OBJECTIVE: To phenotype patients with aspirin-exacerbated respiratory disease (AERD) according to the presence of atopy, urticaria and level of peripheral eosinophils. METHODS: This study included adult asthmatic patients with AERD followed up at a tertiary hospital. They were classified according to atopy and/or urticaria, assessing clinical and laboratorial differences among the groups in order to identify possible aggravating factors of the disease. RESULTS: We included 73 patients, 78.1% being female with a mean age of 54.0 years. Severe asthma was observed in 68.5% and respiratory exacerbation with dipyrone in 67.1% of these patients. They had median total serum IgE of 191.6 IU/mL, mean peripheral eosinophils of 718.5 cells/mm3, and 50.7% were atopic. Urticaria was observed in 32.9% of them, and exacerbations were more often triggered by dipyrone (p = .016). Atopic patients were younger than nonatopic patients (p = .023), and had, on average, higher total serum IgE levels (p = .022). We observed a good correlation between asthma severity and peripheral eosinophils count (r2 = 026; p = .021). CONCLUSIONS: In this study, severe asthma was highly prevalent in AERD patients. Likewise, urticaria was quite prevalent and its presence was associated with dipyrone induced hypersensitivity reaction. Atopy was found in half of the patients, with no association with asthma severity. Patients with higher levels of peripheral eosinophils had more severe asthma. Dypirone hypersensitivity may be a marker for concomitant respiratory and cutaneous hypersensitivity reactions.

Aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease (AERD) classically presents with severe asthma, nasal polyposis, and respiratory exacerbations in response to cyclooxygenase (COX)-1 inhibition. Recent advances in our understanding of AERD have revealed multiple facets of immune dysregulation, including diminished prostaglandin E2 (PGE2) function and elevated levels of both cysteinyl leukotrienes (CysLTs) and innate cytokines such as interleukin 33 (IL-33). Inflammatory mediators in AERD heighten the recruitment and activation of innate lymphoid cells type 2 (ILC2), mast cells, eosinophils, and platelet-adherent leukocytes. This contributes to a cyclical pattern of type 2 inflammation. Here, we highlight current understanding of the immunopathogenesis of AERD.

Understanding the immunology of asthma: Pathophysiology, biomarkers, and treatments for asthma endotypes.

Asthma is a common disease in paediatrics and adults with a significant morbidity, mortality, and financial burden worldwide. Asthma is now recognized as a heterogeneous disease and emerging clinical and laboratory research has elucidated understanding of asthma's underlying immunology. The future of asthma is classifying asthma by endotype through connecting discernible characteristics with immunological mechanisms. This comprehensive review of the immunology of asthma details the currently known pathophysiology and clinical practice biomarkers in addition to forefront biologic and targeted therapies for all of the asthma endotypes. By understanding the immunology of asthma, practitioners will be able to diagnose patients by asthma endotype and provide personalized, biomarker-driven treatments to effectively control patients' asthma.