RESUMO
BACKGROUND: Chronic rhinosinusitis (CRS) is a prevalent inflammatory disease. No medications are Food and Drug Administration-approved for the most common form, CRS without nasal polyps (also called "chronic sinusitis"). Novel biomechanics of the exhalation delivery system deliver fluticasone (EDS-FLU; XHANCE) to sinonasal areas above the inferior turbinate, especially sinus drainage pathways not reached by standard-delivery nasal sprays. OBJECTIVE: Assess EDS-FLU efficacy for CRS (irrespective of nasal polyps). METHODS: Two randomized, EDS-placebo-controlled trials in adults with CRS irrespective of polyps (ReOpen1) or exclusively without polyps (ReOpen2) were conducted at 120 sites in 13 countries. Patients received EDS-FLU 1 or 2 sprays/nostril, or EDS-placebo, twice daily for 24 weeks. Coprimary measures were composite symptom score through week 4 and ethmoid/maxillary sinus percent opacification by computed tomography at week 24. RESULTS: ReOpen1 (N = 332) composite symptom score least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was -1.58 and -1.60 versus -0.62 (P < .001, P < .001); ReOpen2 (N = 223), -1.54 and -1.74 versus -0.81 (P = .011, P = .001). In ReOpen1, sinus opacification least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was -5.58 and -6.20 versus -1.60 (P = .045, P = .018), and in ReOpen2, -7.00 and -5.14 versus +1.19 (P < .001, P = .009). Acute disease exacerbations were reduced by 56% to 66% with EDS-FLU versus EDS-placebo (P = .001). There were significant, and similar magnitude, symptom reductions in patients using standard-delivery nasal steroid products just before entering the study (P < .001). Adverse events were similar to standard-delivery intranasal steroids. CONCLUSIONS: EDS-FLU is the first nonsurgical treatment demonstrated to reduce symptoms, intrasinus opacification, and exacerbations in replicate randomized clinical trials in CRS, regardless of polyp status.
Assuntos
Pólipos Nasais , Rinite , Rinossinusite , Sinusite , Adulto , Humanos , Doença Crônica , Fluticasona/uso terapêutico , Pólipos Nasais/tratamento farmacológico , Pólipos Nasais/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como Assunto , Rinite/tratamento farmacológico , Rinite/induzido quimicamente , Sinusite/tratamento farmacológico , Sinusite/induzido quimicamente , Esteroides/uso terapêuticoRESUMO
BACKGROUND: The impact of delayed hypersensitivity to Dermatophagoides pteronyssinus (DP) on comorbidities of allergic rhinitis (AR) is unknown. OBJECTIVE: The primary end point was to test the hypothesis that DP-induced AR could be divided into 2 subendotypes on the basis of presence or absence of a delayed-type mite sensitization detected by the positive result of atopy patch test for DP (DP-APT). The second end point was to evaluate differences in the long-term risk of respiratory comorbidities and nasal airway response to mite exposure. METHODS: In a prospective observational study, we included 472 patients with DP-induced AR. A total of 343 patients had positive results of skin prick test/serum specific IgE and DP-APT and were assigned to a subendotype with both IgE- and T-cell-mediated mite sensitization (BMSS). The remaining 129 patients without delayed-type mite sensitization were included in the subendotype with only IgE-mediated mite sensitization. Nasal allergen provocation test with active anterior rhinomanometry, paranasal sinuses computed tomography scan, nasal endoscopy, and spirometry were performed. RESULTS: At baseline, BMSS showed a larger increase in nasal airway resistance, total nasal score, and visual analogue scale score to mite exposure. During a 15-year follow-up, 56 patients developed chronic rhinosinusitis with nasal polyps, with higher incidence in BMSS than in the subendotype with only IgE-mediated mite sensitization (50 patients, 14.6% vs 6 patients, 12.4%; P < .001). BMSS also showed a higher incidence of conjunctivitis (25.7% vs 12.4%; P < .01). The rate of adult-onset asthma did not differ between groups, but patients with BMSS showed a more frequent link to chronic rhinosinusitis with nasal polyps (6 of 29 patients, 20.7% vs 0 of 10 patients, 0%). DP-APT independently predicted chronic rhinosinusitis with nasal polyps and conjunctivitis. CONCLUSIONS: Two subendotypes with significantly different clinical outcome can be identified among patients with DP-induced AR according to the presence of delayed-type mite sensitization detected by positive DP-APT result.
Assuntos
Conjuntivite , Pólipos Nasais , Rinite Alérgica Perene , Rinite Alérgica , Rinite , Sinusite , Adulto , Animais , Humanos , Dermatophagoides pteronyssinus , Rinite/epidemiologia , Rinite/induzido quimicamente , Pólipos Nasais/epidemiologia , Pólipos Nasais/induzido quimicamente , Rinite Alérgica/epidemiologia , Alérgenos , Testes Cutâneos , Sinusite/induzido quimicamente , Doença Crônica , Imunoglobulina E , Antígenos de DermatophagoidesRESUMO
Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has been considered an acquired condition. Positive first-degree family history has been reported in 1% of cases. The geographic and genetic isolation of the Finnish population offers exceptional opportunities for inheritance studies. In this questionnaire study, we explored the familial aggregation of N-ERD in 66 Finnish families of patients with N-ERD. The majority of patients (67%) had a positive family history of NSAID intolerance, asthma, nasal polyposis, or N-ERD. Furthermore, 55% had a positive first-degree family history of asthma, 21% nasal polyposis, 20% NSAID intolerance, and 11% N-ERD. The prevalence of asthma, nasal polyposis, NSAID intolerance, and N-ERD among first-degree relatives was 13%, 5%, 4%, and 2%, respectively. We present the pedigrees of the 44 affected families. According to our findings, Finnish patients with N-ERD seem to have a genetic susceptibility to it.
Assuntos
Asma Induzida por Aspirina , Asma , Pólipos Nasais , Sinusite , Humanos , Aspirina , Sinusite/cirurgia , Anti-Inflamatórios não Esteroides/efeitos adversos , Asma/epidemiologia , Pólipos Nasais/induzido quimicamente , Pólipos Nasais/genética , Pólipos Nasais/epidemiologia , Asma Induzida por Aspirina/epidemiologia , Asma Induzida por Aspirina/genéticaRESUMO
Aspirin-exacerbated respiratory disease (AERD) is characterized by abnormal arachidonic acid metabolism leading to chronic rhinosinusitis with nasal polyposis (CRSwNP), asthma, and upper and/or lower respiratory symptoms after ingestion of cyclooxygenase-1 inhibiting nonsteroidal antiinflammatory drugs. Diagnosis is clinical and may involve an aspirin challenge. Inflammatory biomarkers may be useful for diagnosis and treatment monitoring. Conventional medical management for asthma and CRSwNP is often inadequate. Endoscopic sinus surgery followed by continued medical management with or without aspirin desensitization frequently improves symptoms and objective disease measures. Biological agents targeting eosinophilic inflammation are promising alternatives to conventional management.
Assuntos
Asma Induzida por Aspirina , Asma , Pólipos Nasais , Rinite , Sinusite , Humanos , Rinite/induzido quimicamente , Rinite/diagnóstico , Rinite/terapia , Asma Induzida por Aspirina/diagnóstico , Asma Induzida por Aspirina/terapia , Sinusite/induzido quimicamente , Sinusite/terapia , Sinusite/diagnóstico , Pólipos Nasais/induzido quimicamente , Pólipos Nasais/terapia , Aspirina/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Doença CrônicaRESUMO
BACKGROUND: Dupilumab, a mAb targeting IL-4Rα, improves upper and lower airway symptoms in patients with aspirin-exacerbated respiratory disease (AERD), but the mechanisms leading to clinical improvement are not fully elucidated. OBJECTIVE: Our aim was to identify the mechanistic basis of clinical improvement in patients with AERD treated with dupilumab. METHODS: A total of 22 patients with AERD were treated with dupilumab for 3 months for severe asthma and/or chronic rhinosinusitis with nasal polyps. Clinical outcomes were assessed at baseline and at 1 and 3 months after initiation of dupilumab. Nasal fluid, urine, blood, and inferior turbinate scrapings were collected at the 3 time points for determination of mediator levels, cellular assays, and RNA sequencing. RESULTS: Participants had rapid improvement in clinical measures, including sense of smell, sinonasal symptoms, and lung function after 1 month of treatment with dupilumab; the improvements were sustained after 3 months of dupilumab. Baseline severity of smell loss was correlated with lower nasal prostaglandin E2 levels. Dupilumab increased nasal prostaglandin E2 level and decreased levels of nasal albumin, nasal and urinary leukotriene E4, and serum and nasal IgE. Transcripts related to epithelial dysfunction and leukocyte activation and migration were downregulated in inferior turbinate tissue after treatment with dupilumab. There were no dupilumab-induced changes in nasal eosinophilia. CONCLUSION: Inhibition of IL-4Rα in AERD led to rapid improvement in respiratory symptoms and smell, with a concomitant improvement in epithelial barrier function, a decrease in inflammatory eicosanoid levels, and an increase in the anti-inflammatory eicosanoid prostaglandin E2 level. The therapeutic effects of dupilumab are likely due to decreased IL-4Rα signaling on respiratory tissue granulocytes, epithelial cells, and B cells.
Assuntos
Asma Induzida por Aspirina , Pólipos Nasais , Rinite , Sinusite , Aspirina/efeitos adversos , Asma Induzida por Aspirina/diagnóstico , Doença Crônica , Eicosanoides , Humanos , Pólipos Nasais/induzido quimicamente , Pólipos Nasais/tratamento farmacológico , Prostaglandinas , Rinite/induzido quimicamente , Rinite/tratamento farmacológico , Sinusite/induzido quimicamente , Sinusite/tratamento farmacológicoRESUMO
BACKGROUND: Various studies have explored potential therapeutic applications of capsaicin in human medicine, for example in pain, obesity, cancer, cardiovascular and respiratory disease. The aim of this scoping review was to identify and chart available evidence on therapeutic applications of capsaicin in humans using any mode of capsaicin delivery to treat conditions of the respiratory system. METHODS: Electronic bibliographic databases (Web of Science, PubMed, Medline, ScienceDirect, Embase, Scopus) were searched from inception to 2021 to identify experimental studies reporting clinical outcomes of therapeutic applications of capsaicin. Studies with or without control group published in peer-reviewed journals were included. Animal studies, studies of human cell lines, and physiological proof of concept studies were excluded. Reviewer pairs independently double-screened 2799 search results for inclusion. RESULTS: Twenty-three original studies were included. Capsaicin has been investigated for the treatment of non-allergic rhinitis (n = 15), nasal polyposis (n = 3), allergic rhinitis (n = 2), unexplained chronic cough (n = 2), and prevention of aspiration pneumonia (n = 1). Modes of delivery included intranasal application (nasal spray, soaked pads, solution), inhalation, ingestion, and aural ointment. Seventeen studies reported positive effects of capsaicin on clinical outcomes for rhinitis, nasal polyposis, chronic cough, and pneumonia. Sixteen studies reported on the safety of capsaicin, with no reports of significant adverse events and overall fair to good patient acceptability. CONCLUSION: While the evidence identified in this review has limited implications for clinical practice, studies support the general safety of capsaicin as administered in these studies and highlight emerging strands of research and clinical hypotheses which warrant further examination.
Assuntos
Pólipos Nasais , Rinite Alérgica , Rinite , Animais , Capsaicina , Humanos , Pólipos Nasais/induzido quimicamente , Sistema Respiratório , Rinite/induzido quimicamente , Rinite Alérgica/tratamento farmacológicoRESUMO
Intranasal corticosteroid drugs are widely used in chronic rhinosinusitis with nasal polyps (CRSwNP). In contrast to classical delivery with nasal pump sprays, pulsating aerosols can deliver significant doses into superior and posterior sinonasal spaces. A case-control study was designed to assess the efficacy of corticosteroid transnasal nebulization on short-term mucosal recovery and quality of life (QoL) following endoscopic sinus surgery in CRSwNP. Thirty patients were prospectively enrolled to receive either 1-month budesonide nasal pump spray or 1-month budesonide 100-Hz acoustic pulsating nebulization at the first postoperative visit (day 8). Patients were evaluated with Lund-Kennedy endoscopic score at day 8 (D8) and 1 month later (M1). CRS-related QoL questionnaires (SNOT22 and RhinoQOL) were fulfilled at M1. The Lund-Kennedy endoscopic scores compared between D8 and M1 were suggestively improved in the group treated with budesonide nebulization (mean difference between groups, - 18.28 units; 95%CI, - 31.29 to - 5.28 units, p = 0.014). QoL measurements were comparable at M1 between the groups of patients. No unexpected adverse event was described with both budesonide delivery protocols. In the early postoperative period, patients with CRswNP may benefit from pulsating nebulization. Large studies should be conducted to confirm the results. Safety profile related to systemic steroid absorption and bioavailability in chronic respiratory diseases also need to be addressed for further use.
Assuntos
Pólipos Nasais , Rinite , Sinusite , Corticosteroides/uso terapêutico , Budesonida , Estudos de Casos e Controles , Doença Crônica , Humanos , Pólipos Nasais/induzido quimicamente , Pólipos Nasais/tratamento farmacológico , Pólipos Nasais/cirurgia , Sprays Nasais , Qualidade de Vida , Rinite/induzido quimicamente , Rinite/tratamento farmacológico , Rinite/cirurgia , Sinusite/induzido quimicamente , Sinusite/tratamento farmacológico , Sinusite/cirurgia , EsteroidesRESUMO
BACKGROUND: Eosinophilic inflammation has been implicated in the pathogenesis, severity, and treatment responsiveness of chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVE: We sought to assess the efficacy and safety of benralizumab-mediated eosinophil depletion for treating CRSwNP. METHODS: The phase 3 OSTRO study enrolled patients with severe CRSwNP who were symptomatic despite treatment with intranasal corticosteroids and who had a history of systemic corticosteroid (SCS) use and/or surgery for nasal polyps (NP). Patients were randomized 1:1 to treatment with benralizumab 30 mg or placebo every 4 weeks for the first 3 doses and every 8 weeks thereafter. Coprimary end points were change from baseline to week 40 in NP score (NPS) and patient-reported mean nasal blockage score reported once every 2 weeks. RESULTS: The study population comprised 413 randomized patients (207 in the benralizumab group and 206 in the placebo group). Benralizumab significantly improved NPS and nasal blockage score compared to placebo at week 40 (P ≤ .005). Improvements in Sinonasal Outcome Test 22 score at week 40, time to first NP surgery and/or SCS use for NP, and time to first NP surgery were not statistically significant between treatment groups. Nominal significance was obtained for improvement in difficulty in sense of smell score at week 40 (P = .003). Subgroup analyses suggested influences of comorbid asthma, number of NP surgeries, sex, body mass index, and baseline blood eosinophil count on treatment effects. Benralizumab was safe and well tolerated. CONCLUSION: Benralizumab, when added to standard-of-care therapy, reduced NPS, decreased nasal blockage, and reduced difficulty with sense of smell compared to placebo in patients with CRSwNP. TRIAL REGISTRATION: ClinicalTrials.gov NCT03401229.
Assuntos
Obstrução Nasal , Pólipos Nasais , Rinite , Sinusite , Anticorpos Monoclonais Humanizados/efeitos adversos , Doença Crônica , Humanos , Obstrução Nasal/induzido quimicamente , Obstrução Nasal/tratamento farmacológico , Pólipos Nasais/induzido quimicamente , Pólipos Nasais/complicações , Pólipos Nasais/tratamento farmacológico , Rinite/induzido quimicamente , Rinite/complicações , Rinite/tratamento farmacológico , Sinusite/induzido quimicamente , Sinusite/complicações , Sinusite/tratamento farmacológicoRESUMO
Aspirin-exacerbated respiratory disease (AERD) is a condition composed of chronic rhinosinusitis with nasal polyposis and asthma that is defined by respiratory hypersensitivity reactions to the cyclooxygenase 1-inhibitory effects of nonsteroidal anti-inflammatory drugs. It is diagnosed in 5% to 15% of patients with asthma and is even more common in those with comorbid nasal polyposis. Diagnosis is confirmed after an aspirin challenge procedure, yet many patients present with all components and can reliably be diagnosed by history. Patients with AERD commonly experience severe uncontrolled nasal polyposis and require multispecialty evaluation to properly stage and treat this condition. The presence of nasal polyposis plays a large component in the diminished quality of life in patients with AERD. In the last decade, multiple new therapeutic areas have been approved for type 2 airway diseases, offering patients with AERD many more options for control. This makes an early and accurate diagnosis of AERD important in the care of the larger population of type 2 airway diseases.
Assuntos
Asma Induzida por Aspirina , Pólipos Nasais , Sinusite , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Asma Induzida por Aspirina/diagnóstico , Asma Induzida por Aspirina/patologia , Asma Induzida por Aspirina/terapia , Humanos , Pólipos Nasais/induzido quimicamente , Pólipos Nasais/diagnóstico , Pólipos Nasais/patologia , Pólipos Nasais/terapia , Sinusite/induzido quimicamente , Sinusite/diagnóstico , Sinusite/patologia , Sinusite/terapiaRESUMO
BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by eosinophilic rhinosinusitis, nasal polyposis, and bronchial asthma, along with the onset of respiratory reactions after the ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA). In addition to the therapeutic routines and surgical options available, a low dietary intake of food salicylate has been suggested as adjunctive therapy for this condition. This study aimed to assess the influence of a short-term low salicylate diet on inflammatory markers in patients with AERD and whether that would result in symptomatic improvement. METHODS: Prospective study with randomization to either a high or low salicylate diet for 1 week, followed by cross-over to the other study arm. Participants were asked to record their dietary salicylate for each week of the study. Urinary creatinine, salicylate and leukotriene levels were measured at the time of recruitment, end of week one and end of week two and the SNOT-22 questionnaire was filled out at the same time points. RESULTS: A total of seven participants completed the study. There was no statistical difference in the urinary salicylate and leukotriene levels between the two diets; nevertheless, participants on low salicylate diet reported improved SNOT-22 symptoms scores (p = 0.04), mainly in the rhinologic, ear/facial, and sleep dysfunction symptom domains. In addition, these last two domains outcomes were more significant than the minimal clinically important difference. CONCLUSIONS: A short-term low salicylate diet may not result in biochemical outcomes changes but seems to provide significant symptomatic relief for patients with AERD. TRIAL REGISTRATION: NCT01778465 ( www.clinicaltrials.gov ).
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Asma Induzida por Aspirina/dietoterapia , Pólipos Nasais/dietoterapia , Salicilatos , Sinusite/dietoterapia , Adulto , Biomarcadores/urina , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/induzido quimicamente , Salicilatos/urina , Teste de Desfecho Sinonasal , Sinusite/induzido quimicamenteRESUMO
BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and intolerance to cyclooxygenase-1 enzyme inhibitors. The underlying mechanisms contributing to AERD pathogenesis are not fully understood, but AERD is characterized by an enhanced type 2 inflammatory phenotype. Basophils are potent type 2 effector cells, but their involvement in AERD pathophysiology remains unclear. OBJECTIVE: We sought to characterize the systemic and local basophil responses in patients with AERD compared with patients with CRSwNP. METHODS: Sinonasal tissues including inferior turbinate and/or nasal polyps (NPs) and peripheral blood were collected from controls, patients with AERD, and patients with CRSwNP. Expression of cell surface (CD45, FcεRI, CD203c), activation (CD63), and intracellular (2D7) markers associated with basophils was characterized using flow cytometry. Clinical data including Lund-Mackay scores and pulmonary function were obtained. RESULTS: The mean number of basophils (CD45+CD203c+FcεRI+CD117-) detected in AERD NPs (147 ± 28 cells/mg tissue) was significantly elevated compared with that detected in CRSwNP NPs (69 ± 20 cells/mg tissue; P = .01). The number of circulating basophils was significantly elevated in patients with AERD (P = .04). Basophils in NPs had significantly higher CD203c and CD63 mean fluorescence intensity compared with blood in both conditions (P < .01). Basophils from AERD NPs had lower expression of the granule content marker 2D7 compared with those from matched blood (P < .01) or NPs of patients with CRSwNP (P = .06), suggesting ongoing degranulation. Basophil 2D7 mean fluorescence intensity significantly correlated with pulmonary function (r = 0.62; P = .02) and inversely correlated with sinonasal inflammation (r = -0.56; P = .004). CONCLUSIONS: Increased basophil numbers and extent of ongoing degranulation in NPs of patients with AERD compared with patients with CRSwNP may contribute to the exaggerated disease pathogenesis and severity unique to AERD.
Assuntos
Asma/imunologia , Basófilos/imunologia , Inibidores de Ciclo-Oxigenase/efeitos adversos , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Adulto , Asma/induzido quimicamente , Asma/patologia , Basófilos/patologia , Doença Crônica , Inibidores de Ciclo-Oxigenase/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/induzido quimicamente , Pólipos Nasais/patologia , Rinite/induzido quimicamente , Rinite/patologia , Sinusite/induzido quimicamente , Sinusite/patologiaRESUMO
OBJECTIVE: Previous studies suggested that hypoxia-inducible factor-1α (HIF-1α) plays an important role in the progression of inflammation and remodeling of chronic rhinosinusitis with nasal polyposis. However, the molecule mechanisms of HIF-1α activation and regulation of cytokine expressions, such as interleukin (IL) 25 and IL-17RB, in nasal polyposis are not clear. METHOD: The IL-25 and IL-17RB levels in human nasal epithelial cells after stimulation by lipopolysaccharide (LPS) were detected by enzyme-linked immunosorbent assay method, and the proteins of HIF-1α and p-Akt were detected by Western blot method. Moreover, we evaluated the cytokine levels in the nasal mucosa of a murine model of nasal polyposis. RESULTS: The levels of IL-25 and IL-17RB showed dose- and time-dependent release in response to LPS stimulation. The proteins of HIF-1α and p-Akt were both increased significantly after LPS stimulation. After inhibition of PI3K/Akt pathway by PI3K inhibitor LY294002, the levels of IL-25 and IL-17RB and HIF-1α were decreased by LPS stimulation. CONCLUSIONS: Inhibition of PI3K or HIF-1α pathway could significantly reduce growth factor production and decrease nasal inflammation. The HIF-1α pathway could be a novel therapeutic approach for reducing nasal airway inflammation and remodeling in nasal polyposis.
Assuntos
Remodelação das Vias Aéreas/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pólipos Nasais/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Animais , Western Blotting , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/metabolismo , Humanos , Inflamação , Interleucina-17/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Mucosa Nasal/citologia , Pólipos Nasais/induzido quimicamenteRESUMO
BACKGROUND: Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is a chronic inflammatory condition, which is driven by an aberrant arachidonic acid metabolism. Macrophages are major producers of arachidonic acid metabolites and subject to metabolic reprogramming, but they have been neglected in N-ERD. OBJECTIVE: This study sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD. METHODS: Transcriptional, metabolic, and lipid mediator profiles in macrophages from patients with N-ERD and healthy controls were assessed by RNA sequencing, Seahorse assays, and LC-MS/MS. Metabolites in nasal lining fluid, sputum, and plasma from patients with N-ERD (n = 15) and healthy individuals (n = 10) were quantified by targeted metabolomics analyses. Genome-wide methylomics were deployed to define epigenetic mechanisms of macrophage reprogramming in N-ERD. RESULTS: This study shows that N-ERD monocytes/macrophages exhibit an overall reduction in DNA methylation, aberrant metabolic profiles, and an increased expression of chemokines, indicative of a persistent proinflammatory activation. Differentially methylated regions in N-ERD macrophages included genes involved in chemokine signaling and acylcarnitine metabolism. Acylcarnitines were increased in macrophages, sputum, nasal lining fluid, and plasma of patients with N-ERD. On inflammatory challenge, N-ERD macrophages produced increased levels of acylcarnitines, proinflammatory arachidonic acid metabolites, cytokines, and chemokines as compared to healthy macrophages. CONCLUSIONS: Together, these findings decipher a proinflammatory metabolic and epigenetic reprogramming of macrophages in N-ERD.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Asma/imunologia , Macrófagos/imunologia , Pólipos Nasais/imunologia , Anti-Inflamatórios não Esteroides/imunologia , Asma/induzido quimicamente , Humanos , Memória Imunológica/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/metabolismo , Pólipos Nasais/induzido quimicamenteRESUMO
NSAID-Exacerbated respiratory disease (also known as Samter's or Widal's triad, aspirin-exacerbated respiratory disease) is characte- rized by asthma, nasal polyposis and hypersensitivity to NSAIDs. The pathogenesis of this chronic inflammation arises from an imbalance in arachidonic acid metabolism, leading to an increase in pro- inflammatory cysteinyl-leukotrienes. The treatment is based on drug management of asthma and polyps and, in advanced situations, surgical management of polyposis. Monoclonal antibodies have shown promising results in the further medical treatment of this entity.
Le syndrome de Widal (SW) (également connu sous le nom de triade de Samter, maladie respiratoire exacerbée par l'Aspirine) est une entité clinique caractérisée par la triade comprenant un asthme, une polypose nasale et une intolérance aux AINS. La physiopathologie de cette maladie, bien qu'incomplètement élucidée, est caractérisée par un déséquilibre dans le métabolisme de l'acide arachidonique (AA) en faveur de la voie des cystéinyl- leucotriènes (cysLT). Son traitement repose sur une prise en charge médicamenteuse agressive de l'asthme et des polypes et, dans des situations avancées, la prise en charge chirurgicale de la polypose. L'avènement des traitements par anticorps monoclo- naux a montré des résultats encourageants pour les alternatives thérapeutiques futures.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Asma , Hipersensibilidade a Drogas , Pólipos Nasais , Sinusite , Anti-Inflamatórios não Esteroides/imunologia , Aspirina/efeitos adversos , Aspirina/imunologia , Asma/induzido quimicamente , Humanos , Pólipos Nasais/induzido quimicamente , Sinusite/induzido quimicamenteRESUMO
BACKGROUND: The cause of severe nasal polyposis in aspirin-exacerbated respiratory disease (AERD) is unknown. Elevated antibody levels have been associated with disease severity in nasal polyps, but upstream drivers of local antibody production in nasal polyps are undetermined. OBJECTIVE: We sought to identify upstream drivers and phenotypic properties of local antibody-expressing cells in nasal polyps from subjects with AERD. METHODS: Sinus tissue was obtained from subjects with AERD, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps, and controls without CRS. Tissue antibody levels were quantified via ELISA and immunohistochemistry and were correlated with disease severity. Antibody-expressing cells were profiled with single-cell RNA sequencing, flow cytometry, and immunofluorescence, with IL-5Rα function determined through IL-5 stimulation and subsequent RNA sequencing and quantitative PCR. RESULTS: Tissue IgE and IgG4 levels were elevated in AERD compared with in controls (P < .01 for IgE and P < .001 for IgG4 vs CRSwNP). Subjects with AERD whose nasal polyps recurred rapidly had higher IgE levels than did subjects with AERD, with slower regrowth (P = .005). Single-cell RNA sequencing revealed increased IL5RA, IGHG4, and IGHE in antibody-expressing cells from patients with AERD compared with antibody-expressing cells from patients with CRSwNP. There were more IL-5Rα+ plasma cells in the polyp tissue from those with AERD than in polyp tissue from those with CRSwNP (P = .026). IL-5 stimulation of plasma cells in vitro induced changes in a distinct set of transcripts. CONCLUSIONS: Our study identifies an increase in antibody-expressing cells in AERD defined by transcript enrichment of IL5RA and IGHG4 or IGHE, with confirmed surface expression of IL-5Rα and functional IL-5 signaling. Tissue IgE and IgG4 levels are elevated in AERD, and higher IgE levels are associated with faster nasal polyp regrowth. Our findings suggest a role for IL-5Rα+ antibody-expressing cells in facilitating local antibody production and severe nasal polyps in AERD.
Assuntos
Aspirina/efeitos adversos , Imunoglobulina E/metabolismo , Imunoglobulina G/metabolismo , Subunidade alfa de Receptor de Interleucina-5/metabolismo , Pólipos Nasais/metabolismo , Sinusite/metabolismo , Adulto , Idoso , Anticorpos/metabolismo , Feminino , Humanos , Interleucina-5/metabolismo , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/induzido quimicamente , Plasmócitos/efeitos dos fármacos , Plasmócitos/metabolismo , Análise de Sequência de RNA/métodos , Sinusite/induzido quimicamente , Adulto JovemRESUMO
BACKGROUND: Possible factors for cell atypia in nasal mucosa include noxious chemicals: ammonia, formaldehyde and heavy metals. AIMS: Case presentation of a nasal polyp with epithelial dysplasia in a worker exposed to nickel and copper salt dust. CASE REPORT: A 27-year-old man complained of impaired nasal breathing and mild right-sided epistaxis. He was exposed to copper and nickel salt dust for 6 years. Clinical examination showed a polypoid lesion arising from the right middle turbinate. Histopathological examination of the excised lesion showed high-grade epithelial dysplasia. Duration of exposure and concentration of heavy metals in serum suggest the biological plausibility of exposure to these factors and development of epithelial dysplasia in the nasal mucosa. CONCLUSIONS: Epithelial dysplasia may occasionally be noted in inflammatory nasal polyps, especially in workers exposed to heavy metals.
Assuntos
Cobre/efeitos adversos , Pólipos Nasais/induzido quimicamente , Níquel/efeitos adversos , Exposição Ocupacional/efeitos adversos , Adulto , Cobre/sangue , Humanos , Masculino , Metalurgia , Mucosa Nasal/citologia , Mucosa Nasal/patologia , Pólipos Nasais/patologia , Níquel/sangueRESUMO
La enfermedad respiratoria exacerbada por aspirina (EREA) es un síndrome inflamatorio de la vía aérea que se acompaña de asma, poliposis nasal y sinusitis crónica que suele requerir cirugía frecuentemente y en muchos casos, ciclos de corticoides sistémicos para controlar la enfermedad. Aunque su patogenia permanece aún desconocida, se cree que el principal causante pueda ser un metabolismo patológico del ácido araquidónico aparte de que existen múltiples factores externos que juegan un papel determinante en su desarrollo. Por otro lado, a pesar de que los pacientes refieran el antecedente de cualquier tipo de reacción previa a la aspirina o a algún otro antiinflamatorio no esteroideo (AINE), el diagnóstico definitivo ha de hacerse con una provocación protocolizada a la aspirina. Evitar la administración de aspirina y de otros AINEs es la primera medida terapéutica para estos pacientes. Sin embargo, dado que el uso de estos fármacos suele ser habitual, es preciso realizar un diagnóstico de certeza ante la mínima sospecha. La desensibilización a la aspirina puede ser una óptima opción terapéutica que además mejore el devenir clínico del paciente
The aspirin-exacerbated respiratory disease (AERD), is an inflammatory syndrome of the airway that is accompanied by asthma, nasal polyposis and chronic sinusitis that usually requires surgery and in many cases, cycles of systemic corticosteroids to control the disease. Although its pathogenesis remains unknown, it is believed that the main cause may be a pathological metabolism of arachidonic acid, apart from the fact that there are multiple external factors that play a determining role in its development. On the other hand, although patients refer history of any previous reaction to aspirin or some other non-steroidal anti-inflammatory drug (NSAIDs), the definitive diagnosis must be made with a protocolized challenge to aspirin. Avoiding the administration of aspirin and other NSAIDs is the first therapeutic measure for these patients. However, since the use of these drugs is usually habitual, it is necessary to make a diagnosis of certainty at the slightest suspicion. The desensitization to aspirin can be an optimal long term therapeutic option that also improves the clinical evolution of the patient
Assuntos
Humanos , Aspirina/efeitos adversos , Doenças Respiratórias/induzido quimicamente , Asma/induzido quimicamente , Pólipos Nasais/induzido quimicamente , Sinusite/induzido quimicamente , Doenças Respiratórias/diagnóstico , Doenças Respiratórias/fisiopatologia , Exacerbação dos Sintomas , Aspirina/uso terapêutico , Síndrome , Doença CrônicaRESUMO
BACKGROUND: Aspirin challenge and desensitization remains the criterion standard in diagnosis and treatment for patients with aspirin-exacerbated respiratory disease (AERD), but the protocols can be time and resource intensive. OBJECTIVE: To provide evidence that oral aspirin challenge and desensitization can be safely performed in an outpatient setting in 1 day. METHODS: Forty-four patients with a confirmed diagnosis of AERD, stable asthma, and baseline FEV1 value greater than or equal to 70% of predicted completed an oral aspirin challenge and desensitization protocol. The starting dose was 40.5 mg with escalating doses of aspirin (81, 162.5, 325 mg) at 90-minute intervals until symptoms were provoked. Desensitization was defined as tolerating a repeated administration of the provocative aspirin dose and at least 1 subsequent dose, bringing the total aspirin ingested during the in-clinic desensitization to 325 mg or more. RESULTS: Ninety-three percent of patients completed the challenge and desensitization in 1 day, with an average protocol completion time of 9 hours and 29 minutes. Two patients (4.6%) chose to complete the protocol over 2 days. One patient (2.3%) was discontinued from the protocol because of ongoing abdominal discomfort and diarrhea. No patient required epinephrine, emergency department visit, or hospitalization. CONCLUSIONS: Patients with AERD on a stable asthma regimen and with a baseline FEV1 value greater than or equal to 70% can be safely desensitized to aspirin using a 90-minute dose escalation protocol, starting at a dose of 40.5 mg, and defining desensitization as tolerance of the repeated provocation dose and at least 1 subsequent aspirin dose, bringing total cumulative daily dose to 325 mg or more. This protocol can routinely be completed in 1 day.