Background Aspirin desensitization followed by high-dose aspirin therapy is routinely performed for patients with aspirin-exacerbated respiratory disease (AERD). Little is known about the ...contributions of mediators other than cysteinyl leukotrienes to aspirin reactions and to the therapeutic benefit of high-dose aspirin therapy. Objective We investigated differences in urinary eicosanoid metabolite levels and blood eosinophil counts in patients with AERD who tolerate and those who fail aspirin desensitization and also in patients with AERD who were successfully treated with high-dose aspirin therapy. Methods Twenty-nine patients with AERD were stratified into those who tolerated aspirin desensitization (group I) and those who did not (group II). Urine was analyzed for eicosanoid metabolites at baseline, during aspirin reactions, and during high-dose aspirin therapy. Blood was analyzed for cell differentials at baseline and during aspirin therapy. Results Basal prostaglandin D2 metabolite (PGD-M; 13.6 ± 2.7 vs 7.0 ± 0.8 pmol/mg creatinine Cr, P < .05) and thromboxane metabolite (TX-M; 1.4 ± 0.3 vs 0.9 ± 0.1 pmol/mg Cr, P < .01) levels were higher in group II than in group I. During aspirin reactions, PGD-M levels remained unchanged, whereas TX-M levels (0.7 ± 0.1 pmol/mg Cr, P = .07) tended to decrease in group I. In contrast, PGD-M levels increased dramatically in group II (61.3 ± 19.9 pmol/mg Cr, P < .05), whereas TX-M levels did not change. The decrease in FEV1 inversely correlated with basal urinary levels of both leukotriene E4 and PGD-M. Blood eosinophil and basophil levels increased and urinary PGD-M levels (2.2 ± 0.8 pmol/mg Cr, P < .001) decreased on 2 months of high-dose aspirin therapy in group I. Conclusion Failure to tolerate aspirin desensitization in a subset of patients with AERD is associated with prostaglandin D2 overproduction. The increase in blood eosinophil and basophil counts during high-dose aspirin therapy might reflect the functional consequences of decreased prostaglandin D2 release and the therapeutic benefit of aspirin.
Barrier tissue dysfunction is a fundamental feature of chronic human inflammatory diseases
. Specialized subsets of epithelial cells-including secretory and ciliated cells-differentiate from basal ...stem cells to collectively protect the upper airway
. Allergic inflammation can develop from persistent activation
of type 2 immunity
in the upper airway, resulting in chronic rhinosinusitis, which ranges in severity from rhinitis to severe nasal polyps
. Basal cell hyperplasia is a hallmark of severe disease
, but it is not known how these progenitor cells
contribute to clinical presentation and barrier tissue dysfunction in humans. Here we profile primary human surgical chronic rhinosinusitis samples (18,036 cells, n = 12) that span the disease spectrum using Seq-Well for massively parallel single-cell RNA sequencing
, report transcriptomes for human respiratory epithelial, immune and stromal cell types and subsets from a type 2 inflammatory disease, and map key mediators. By comparison with nasal scrapings (18,704 cells, n = 9), we define signatures of core, healthy, inflamed and polyp secretory cells. We reveal marked differences between the epithelial compartments of the non-polyp and polyp cellular ecosystems, identifying and validating a global reduction in cellular diversity of polyps characterized by basal cell hyperplasia, concomitant decreases in glandular cells, and phenotypic shifts in secretory cell antimicrobial expression. We detect an aberrant basal progenitor differentiation trajectory in polyps, and propose cell-intrinsic
, epigenetic
and extrinsic factors
that lock polyp basal cells into this uncommitted state. Finally, we functionally demonstrate that ex vivo cultured basal cells retain intrinsic memory of IL-4/IL-13 exposure, and test the potential for clinical blockade of the IL-4 receptor α-subunit to modify basal and secretory cell states in vivo. Overall, we find that reduced epithelial diversity stemming from functional shifts in basal cells is a key characteristic of type 2 immune-mediated barrier tissue dysfunction. Our results demonstrate that epithelial stem cells may contribute to the persistence of human disease by serving as repositories for allergic memories.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common and heterogeneous inflammatory condition, for which the drivers of the underlying inflammation are not yet fully understood. The use of ...biologic therapies to target specifically relevant effector cells or cytokines in CRSwNP is a growing field of interest. The objectives of this review are to provide an update on the existing studies of biologics in CRSwNP and to identify potential future areas for further research.
An initial literature review of biologic therapies in CRS was performed through publications gathered from a PubMed search for title/abstract containing "biologic" and "chronic rhinosinusitis." Further manuscripts describing scientific premise for each biologic were then reviewed.
A detailed review of all studies describing biologic therapies targeting inflammation in CRSwNP was performed.
Biologic therapies targeting interleukin (IL)-4Rα, IL-5, IL-5Rα, IL-33, immunoglobulin (Ig)E, and thymic stromal lymphopoietin (TSLP) have all been developed and have been investigated for treatment in CRSwNP, or current research suggests that they may have utility in this area. Only dupilumab, which inhibits IL-4Rα, has gained Food and Drug Administration approval for the treatment of adults with inadequately controlled CRSwNP.
Recent advances in our understanding of the fundamental drivers of the chronic respiratory inflammation in CRSwNP has led to the identification of several potential therapeutic targets for this disease. Future clinical success will rely on the availability of biomarker-based endotyping and responder analyses so that clinicians can precisely match each patient to the appropriate biologic, thereby optimizing the proper treatment strategy.
NSAID‐exacerbated respiratory disease (N‐ERD) is a chronic eosinophilic, inflammatory disorder of the respiratory tract occurring in patients with asthma and/or chronic rhinosinusitis with nasal ...polyps (CRSwNP), symptoms of which are exacerbated by NSAIDs, including aspirin. Despite some progress in understanding of the pathophysiology of the syndrome, which affects 1/10 of patients with asthma and rhinosinusitis, it remains a diagnostic and therapeutic challenge. In order to provide evidence‐based recommendations for the diagnosis and management of N‐ERD, a panel of international experts was called by the EAACI Asthma Section. The document summarizes current knowledge on the pathophysiology and clinical presentation of N‐ERD pointing at significant heterogeneity of this syndrome. Critically evaluating the usefulness of diagnostic tools available, the paper offers practical algorithm for the diagnosis of N‐ERD. Recommendations for the most effective management of a patient with N‐ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed. Newly described sub‐phenotypes and emerging sub‐endotypes of N‐ERD are potentially relevant for new and more specific (eg, biological) treatment modalities. Finally, the document defines major gaps in our knowledge on N‐ERD and unmet needs, which should be addressed in the future.
Aspirin-exacerbated respiratory disease (AERD), a syndrome that includes asthma, recurrent nasal polyps, and pathognomonic reactions to aspirin and other nonselective cyclooxygenase inhibitors, is ...still not fully understood and lacks specific disease-modifying therapeutic options.
To review the most recent clinical updates in the evaluation and treatment of patients with AERD.
Recent clinical research studies relevant to patients with AERD were reviewed.
Multiple new biologics are available for the treatment of severe asthma, several of which have been specifically studied and determined to be efficacious in the subset of patients with asthma who are also aspirin sensitive. Zileuton continues to be underprescribed for AERD and is considered to be very effective by many patients with AERD. Dietary modifications toward a diet that is high in omega-3 fatty acids and low in omega-6 fatty acids can reduce the production of the inflammatory leukotriene and prostaglandin D₂ lipids and help improve symptoms for patients with AERD.
A lack of definitive understanding of the causative mechanisms of AERD and the absence of an AERD-specific patient-reported outcome measure are obstacles that remain in this field, but much progress has been made over the past decade.
Chronic Rhinosinusitis with Nasal Polyps and Asthma Laidlaw, Tanya M.; Mullol, Joaquim; Woessner, Katharine M. ...
The journal of allergy and clinical immunology in practice (Cambridge, MA),
March 2021, Letnik:
9, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) characterized by a type 2 immune signature often have severe and recurrent disease. Lower airway conditions such as asthma are common ...comorbidities and share similar pathophysiology. CRSwNP with asthma is characterized by tissue eosinophilia and high local IgE levels. Clinically, CRSwNP with comorbid asthma is associated with more severe sinonasal symptoms and worse quality of life, and it is more difficult to treat both medically and surgically. Asthma in the presence of nasal polyposis is also more difficult to control, being more exacerbation prone, with increased airway obstruction and more extensive eosinophilic inflammation. Aspirin/nonsteroidal anti-inflammatory drug–exacerbated respiratory disease (AERD) is a recognized phenotype of CRSwNP with comorbid asthma. Patients with CRSwNP with comorbid AERD are among those with the most severe and difficult-to-treat disease, and tend to have severe NP. The shared pathophysiology of the upper and lower airways has important implications for both the diagnosis and management of respiratory comorbidities. However, in clinical practice, the nose and lungs are often treated as separate entities. The underlying systemic inflammatory link between CRSwNP and asthma provides a compelling rationale for systemic treatment with novel biologics targeting shared underlying type 2 inflammatory pathways.
Aspirin-exacerbated respiratory disease has fascinated and frustrated specialists in allergy/immunology, pulmonology, and otorhinolaryngology for decades. It generally develops in previously healthy ...young adults and is unremitting and challenging to treat. The classical triad of asthma, nasal polyposis, and pathognomonic respiratory reactions to aspirin and other cyclooxygenase-1 inhibitors is accompanied by high levels of mast cell activation, cysteinyl leukotriene production, platelet activation, and severe type 2 respiratory inflammation. The “unbraking” of mast cell activation and further cysteinyl leukotriene generation induced by cyclooxygenase-1 inhibition reflect an idiosyncratic dependency on cyclooxygenase-1–derived products, likely prostaglandin E2, to maintain a tenuous homeostasis. Although cysteinyl leukotrienes are clear disease effectors, little else was known about their cellular sources and targets, and the contributions from other mediators and type 2 respiratory inflammation effector cells to disease pathophysiology were unknown until recently. The applications of targeted biological therapies, single-cell genomics, and transgenic animal approaches have substantially advanced our understanding of aspirin-exacerbated respiratory disease pathogenesis and treatment and have also revealed disease heterogeneity. This review covers novel insights into the immunopathogenesis of aspirin-exacerbated respiratory disease from each of these lines of research, including the roles of lipid mediators, effector cell populations, and inflammatory cytokines, discusses unanswered questions regarding cause and pathogenesis, and considers potential future therapeutic options.
Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) generally have a high symptom burden and poor health-related quality of life, often requiring recurring systemic corticosteroid use and ...repeated sinus surgery. Dupilumab is a fully human monoclonal antibody that inhibits signalling of interleukin (IL)-4 and IL-13, key drivers of type 2 inflammation, and has been approved for use in atopic dermatitis and asthma. In these two studies, we aimed to assess efficacy and safety of dupilumab in patients with CRSwNP despite previous treatment with systemic corticosteroids, surgery, or both.
LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 were two multinational, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies assessing dupilumab added to standard of care in adults with severe CRSwNP. SINUS-24 was done in 67 centres in 13 countries, and SINUS-52 was done in 117 centres in 14 countries. Eligible patients were 18 years or older with bilateral CRSwNP and symptoms despite intranasal corticosteroid use, receiving systemic corticosteroids in the preceding 2 years, or having had sinonasal surgery. Patients in SINUS-24 were randomly assigned (1:1) to subcutaneous dupilumab 300 mg or placebo every 2 weeks for 24 weeks. Patients in SINUS-52 were randomly assigned (1:1:1) to dupilumab 300 mg every 2 weeks for 52 weeks, dupilumab every 2 weeks for 24 weeks and then every 4 weeks for the remaining 28 weeks, or placebo every 2 weeks for 52 weeks. All patients were randomly assigned centrally with a permuted block randomisation schedule. Randomisation was stratified by asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease status at screening, previous surgery at screening, and country. Patients with or without comorbid asthma were included. Coprimary endpoints were changes from baseline to week 24 in nasal polyp score (NPS), nasal congestion or obstruction, and sinus Lund-Mackay CT scores (a coprimary endpoint in Japan), done in an intention-to-treat population. Safety was assessed in a pooled population of both dupilumab groups in SINUS-52 up to week 24 and the dupilumab group in SINUS-24 and the placebo groups in both studies until week 24. The trials are complete and registered at ClinicalTrials.gov, NCT02912468 and NCT02898454.
Between Dec 5, 2016, and Aug 3, 2017, 276 patients were enrolled in SINUS-24, with 143 in the dupilumab group and 133 in the placebo group receiving at least one study drug dose. Between Nov 28, 2016, and Aug 28, 2017, 448 patients were enrolled in SINUS-52, with 150 receiving at least one dose of dupilumab every 2 weeks, 145 receiving at least one dose of dupilumab every 2 weeks for 24 weeks and every 4 weeks until week 52, and 153 receiving at least one dose of placebo. Dupilumab significantly improved the coprimary endpoints in both studies. At 24 weeks, least squares mean difference in NPS of dupilumab treatment versus placebo was −2·06 (95% CI −2·43 to −1·69; p<0·0001) in SINUS-24 and −1·80 (−2·10 to −1·51; p<0·0001) in SINUS-52; difference in nasal congestion or obstruction score was −0·89 (−1·07 to −0·71; p<0·0001) in SINUS-24 and −0·87 (−1·03 to −0·71; p<0·0001) in SINUS-52; and difference in Lund-Mackay CT scores was −7·44 (−8·35 to −6·53; p<0·0001) in SINUS-24 and −5·13 (−5·80 to −4·46; p<0·0001) in SINUS-52. The most common adverse events (nasopharyngitis, worsening of nasal polyps and asthma, headache, epistaxis, and injection-site erythema) were more frequent with placebo.
In adult patients with severe CRSwNP, dupilumab reduced polyp size, sinus opacification, and severity of symptoms and was well tolerated. These results support the benefits of adding dupilumab to daily standard of care for patients with severe CRSwNP who otherwise have few therapeutic options.
Sanofi and Regeneron Pharmaceuticals.
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