Transcriptome Analysis Identifies Doublesex and Mab-3 Related Transcription Factor (DMRT3) in Nasal Polyp Epithelial Cells of Patients Suffering from Non-Steroidal Anti-Inflammatory Drug-Exacerbated Respiratory Disease (AERD).

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a syndrome characterised by chronic rhinosinusitis, nasal polyps, asthma and aspirin intolerance. An imbalance of eicosanoid metabolism with anover-production of cysteinyl leukotrienes (CysLTs) has been associated with AERD. However, the precise mechanisms underlying AERD are unknown. OBJECTIVE: To establish the transcriptome of the nasal polyp airway epithelial cells derived from AERD patients to discover gene expression patterns in this disease. METHODS: Nasal airway epithelial cells were isolated from 12 AERD polyps and 8 AERD non-polyp nasal mucosa samples as controls from the same subjects. Utilising the Illumina HiSeq 2500 platform, RNA samples were sequenced. Potential gene candidate DMRT3 was selected from the differentially-expressed genes for validation. RESULTS: Comparative transcriptome profiling of nasal epithelial cells was accomplished in AERD. A total of 20 genes had twofold mean regulation expression differences or greater. In addition, 8 genes were upregulated, including doublesex and mab-3 related transcription factor 3 (DMRT3), and 12 genes were downregulated. Differentially regulated genes comprised roles in inflammation, defence and immunity. Metabolic process and embryonic development pathways were significantly enriched. Enzyme-linked immune sorbent assay (ELISA) results of DMRT3 in AERD patients were significantly upregulated compared to controls (p = 0.03). Immunohistochemistry (IHC) of AERD nasal polyps localised DMRT3 and was predominantly released in the airway epithelia. CONCLUSION: Findings suggest that DMRT3 could be potentially involved in nasal polyp development in AERD patients. Furthermore, several genes are downregulated, hinting at the dedifferentiation phenomenon in AERD polyps. However, further studies are imperative to confirm the exact mechanism of polyp formation in AERD patients.

Staphylococcus aureus impairs sinonasal epithelial repair: Effects in patients with chronic rhinosinusitis with nasal polyps and control subjects.

BACKGROUND: The effect of Staphylococcus aureus on nasal epithelial repair has never been assessed in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVE: This study aimed to determine whether (1) nasal epithelial cell cultures from patients with CRSwNP and control subjects repair differently; (2) S aureus exoproducts compromise nasal epithelial repair; (3) S aureus alters lamellipodial dynamics; and (4) deleterious effects could be counteracted by the Rho-associated coiled-coil kinase inhibitor Y-27632. METHODS: Primary nasal epithelial cells (pNECs) collected during surgeries were cultured and injured under 3 conditions: (1) basal conditions, (2) exposed to S aureus exoproducts, and (3) exposed to S aureus exoproducts and Y-27632. Epithelial repair, lamellipodial dynamics, and cytoskeletal organization were assessed. RESULTS: Under basal conditions, pNEC cultures from patients with CRSwNP presented significantly lower repair rates and reduced lamellipodial protrusion length and velocity than those from control subjects. S aureus exoproducts significantly decreased repair rates and protrusion dynamics in both control subjects and patients with CRSwNP; however, the effect of S aureus on cell protrusions was more sustained over time in patients with CRSwNP. Under basal conditions, immunofluorescence assays showed significantly reduced percentages of cells with lamellipodia at the wound edge in patients with CRSwNP compared with control subjects. S aureus altered cell polarity and decreased the percentage of cells with lamellipodia in both groups. Finally, Y-27632 prevented the deleterious effects of S aureus exoproducts on CRSwNP repair rates, as well as on lamellipodial dynamics and formation. CONCLUSIONS: S aureus exoproducts significantly alter epithelial repair and lamellipodial dynamics on pNECs, and this impairment was more pronounced in patients with CRSwNP. Importantly, Y-27632 restored epithelial repair and lamellipodial dynamics in the presence of S aureus exoproducts.

Omalizumab for chronic rhinosinusitis. / Omalizumab para la rinosinusitis crónica.

INTRODUCTION: Chronic rhinosinusitis is a high prevalence chronic inflammatory disease that involves nasal mucosa and paranasal sinuses. Immunoglobulin E is an inflammatory mediator that plays an etiopathogenic role in this condition, so omalizumab, an anti-immunoglobulin E monoclonal antibody, might be a therapeutic alternative. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified five systematic reviews that included five primary studies overall, of which two correspond to randomized trials. We concluded it is not clear whether omalizumab leads to an improvement in the nasal polyps scale, quality of life, general well-being or nasal symptoms in patients with chronic rhinosinusitis, because the certainty of the evidence is very low. On the other hand, omalizumab is probably associated with frequent adverse effects.

INTRODUCCIÓN: La rinosinusitis crónica es una enfermedad inflamatoria crónica de alta prevalencia que compromete la mucosa de la cavidad nasal y senos paranasales. La inmunoglobulina E es un mediador inflamatorio que juega un rol etiopatogénico en esta condición, por lo que se ha planteado que omalizumab, un anticuerpo monoclonal anti-inmunoglobulina E, podría constituir una alternativa de tratamiento. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos cinco revisiones sistemáticas que en conjunto incluyeron cinco estudios primarios, de los cuales dos corresponden a ensayos controlados aleatorizados. Concluimos que en pacientes con rinosinusitis crónica, no está claro si omalizumab lleva a una mejoría en la escala de pólipos nasales, la calidad de vida, el bienestar general o los síntomas nasales porque la certeza de la evidencia es muy baja. Por otra parte, el uso de omalizumab probablemente se asocia a efectos adversos frecuentes.

Anti-interleukin 5 therapy for chronic rhinosinusitis with polyps. / Terapia anti interleukina 5 para la rinosinusitis crónica con pólipos.

INTRODUCTION: Chronic rhinosinusitis is the inflammation of sinonasal mucosa lasting longer than 12 weeks. Two clinical forms are distinguished: chronic rhinosinusitis with polyps and without polyps. Patients with chronic rhinosinusitis with polyps exhibit high levels of interleukin 5, which promotes differentiation and survival of eosinophils. So, minimizing their circulation has been proposed as a new treatment strategy. However, there is no clarity regarding its real effectiveness. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified three systematic reviews included three primary studies overall, all corresponding to randomized trials. We concluded inhibitors of interleukin 5 might decrease nasal polyps score. Although they might be associated with adverse effects, these would be infrequent and of low severity. However, the certainty of the evidence is low.

INTRODUCCIÓN: La rinosinusitis crónica es la inflamación de la mucosa nasosinusal de duración superior a 12 semanas. Se distinguen dos formas clínicas: rinosinusitis crónica con pólipos y sin pólipos. Los pacientes con rinosinusitis crónica con pólipos presentan niveles elevados de interleukina 5, la cual promueve la diferenciación y supervivencia de eosinófilos, por lo que se ha propuesto minimizar su circulación como una nueva estrategia de tratamiento. Sin embargo, no hay claridad respecto a su real efectividad. MÉTODOS: Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos tres revisiones sistemáticas que en conjunto incluyeron tres estudios primarios, todos correspondientes a ensayos aleatorizados. Concluimos que los inhibidores de interleukina 5 podrían disminuir el puntaje de pólipos nasales. Si bien podrían asociarse a efectos adversos, estos serían poco frecuentes y de baja severidad. Sin embargo, la certeza de la evidencia es baja.

Solitary chemosensory cells are a primary epithelial source of IL-25 in patients with chronic rhinosinusitis with nasal polyps.

BACKGROUND: IL-25 can function as an early signal for the respiratory type 2 response characteristic of allergic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). In the mouse gut, tuft cells are the epithelial source of IL-25. However, the source of human airway epithelial IL-25 has remained elusive. OBJECTIVE: In this study we sought to determine whether the solitary chemosensory cell (SCC) is the predominant source of IL-25 in the sinonasal epithelium. METHOD: Flow cytometry and immunofluorescence for SCCs and IL-25 were used to interrogate polyp and turbinate tissue from patients with CRSwNP. Mucus was collected during acute inflammatory exacerbations from patients with CRSwNP or chronic rhinosinusitis without nasal polyps and IL-25 levels determined by using ELISA. Lastly, sinonasal epithelial cultures derived from polyp and turbinate tissue were stimulated with IL-13 and analyzed for SCC proliferation and IL-25 production. RESULTS: This study demonstrates that a discrete cell type, likely an SCC, characterized by expression of the taste-associated G protein gustducin and the intestinal tuft cell marker doublecortin-like kinase 1, is the predominant source of IL-25 in the human upper airway. Additionally, we show that patients with CRSwNP have increased numbers of SCCs in nasal polyp tissue and that in vitro IL-13 exposure both increased proliferation and induced apical secretion of IL-25 into the mucosal layer. CONCLUSIONS: Inflammatory sinus polyps but not adjacent turbinate tissue show expansion of the SCC population, which is the source of epithelial IL-25.

Evolution in the surgical management of chronic rhinosinusitis: Current indications and pitfalls.

Chronic rhinosinusitis (CRS) consists of a range of inflammatory conditions in the sinuses that can result in clinical symptoms. The underlying pathophysiology and its relationship to lower airway disease are complex. Current definitions of CRS can serve more as an indication for potential surgical intervention rather than a marker of disease state. CRS can be asymptomatic and may require medical management to avoid disease progression and minimize the risk of lower airway disease. Endoscopic surgery has undergone a significant evolution and refinement, but the most common surgical complication remains persistent inflammation and disease recurrence. It is important to recognize that surgery alone rarely cures CRS and patients require long-term medical therapy for continued asymptomatic inflammation. Careful postoperative care and endoscopic follow-up to ensure resolution of inflammation are key to ensuring optimal surgical outcomes and reduce the risk of revision surgery. Future work on CRS endotypes will allow discovery of new therapies to treat CRS, as well as refine indications for medical or surgical intervention and postoperative care.

Terapia anti interleukina 5 para la rinosinusitis crónica con pólipos / Anti-interleukin 5 therapy for chronic rhinosinusitis with polyps

Resumen INTRODUCCIÓN: La rinosinusitis crónica es la inflamación de la mucosa nasosinusal de duración superior a 12 semanas. Se distinguen dos formas clínicas: rinosinusitis crónica con pólipos y sin pólipos. Los pacientes con rinosinusitis crónica con pólipos presentan niveles elevados de interleukina 5, la cual promueve la diferenciación y supervivencia de eosinófilos, por lo que se ha propuesto minimizar su circulación como una nueva estrategia de tratamiento. Sin embargo, no hay claridad respecto a su real efectividad. MÉTODOS: Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos tres revisiones sistemáticas que en conjunto incluyeron tres estudios primarios, todos correspondientes a ensayos aleatorizados. Concluimos que los inhibidores de interleukina 5 podrían disminuir el puntaje de pólipos nasales. Si bien podrían asociarse a efectos adversos, estos serían poco frecuentes y de baja severidad. Sin embargo, la certeza de la evidencia es baja.

Abstract INTRODUCTION: Chronic rhinosinusitis is the inflammation of sinonasal mucosa lasting longer than 12 weeks. Two clinical forms are distinguished: chronic rhinosinusitis with polyps and without polyps. Patients with chronic rhinosinusitis with polyps exhibit high levels of interleukin 5, which promotes differentiation and survival of eosinophils. So, minimizing their circulation has been proposed as a new treatment strategy. However, there is no clarity regarding its real effectiveness. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified three systematic reviews included three primary studies overall, all corresponding to randomized trials. We concluded inhibitors of interleukin 5 might decrease nasal polyps score. Although they might be associated with adverse effects, these would be infrequent and of low severity. However, the certainty of the evidence is low.

Omalizumab para la rinosinusitis crónica / Omalizumab for chronic rhinosinusitis

Resumen INTRODUCCIÓN: La rinosinusitis crónica es una enfermedad inflamatoria crónica de alta prevalencia que compromete la mucosa de la cavidad nasal y senos paranasales. La inmunoglobulina E es un mediador inflamatorio que juega un rol etiopatogénico en esta condición, por lo que se ha planteado que omalizumab, un anticuerpo monoclonal anti-inmunoglobulina E, podría constituir una alternativa de tratamiento. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos cinco revisiones sistemáticas que en conjunto incluyeron cinco estudios primarios, de los cuales dos corresponden a ensayos controlados aleatorizados. Concluimos que en pacientes con rinosinusitis crónica, no está claro si omalizumab lleva a una mejoría en la escala de pólipos nasales, la calidad de vida, el bienestar general o los síntomas nasales porque la certeza de la evidencia es muy baja. Por otra parte, el uso de omalizumab probablemente se asocia a efectos adversos frecuentes.

Abstract INTRODUCTION: Chronic rhinosinusitis is a high prevalence chronic inflammatory disease that involves nasal mucosa and paranasal sinuses. Immunoglobulin E is an inflammatory mediator that plays an etiopathogenic role in this condition, so omalizumab, an anti-immunoglobulin E monoclonal antibody, might be a therapeutic alternative. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified five systematic reviews that included five primary studies overall, of which two correspond to randomized trials. We concluded it is not clear whether omalizumab leads to an improvement in the nasal polyps scale, quality of life, general well-being or nasal symptoms in patients with chronic rhinosinusitis, because the certainty of the evidence is very low. On the other hand, omalizumab is probably associated with frequent adverse effects.

Denatonium-induced sinonasal bacterial killing may play a role in chronic rhinosinusitis outcomes.

BACKGROUND: Sinonasal bitter taste receptors (T2Rs) contribute to upper airway innate immunity and correlate with chronic rhinosinusitis (CRS) clinical outcomes. A subset of T2Rs expressed on sinonasal solitary chemosensory cells (SCCs) are activated by denatonium, resulting in a calcium-mediated secretion of bactericidal antimicrobial peptides (AMPs) in neighboring ciliated epithelial cells. We hypothesized that there is patient variability in the amount of bacterial killing induced by different concentrations of denatonium and that the differences correlate with CRS clinical outcomes. METHODS: Bacterial growth inhibition was quantified after mixing bacteria with airway surface liquid (ASL) collected from denatonium-stimulated sinonasal air-liquid interface (ALI) cultures. Patient ASL bacterial killing at 0.1 mM denatonium and baseline characteristics and sinus surgery outcomes were compared between these populations. RESULTS: There is variability in the degree of denatonium-induced bacterial killing between patients. In CRS with nasal polyps (CRSwNP), patients with increased bacterial killing after stimulation with low levels of denatonium undergo significantly more functional endoscopic sinus surgeries (FESSs) (p = 0.037) and have worse 6-month post-FESS 22-item Sino-Nasal Outcome Test (SNOT-22) scores (p = 0.012). CONCLUSION: Bacterial killing after stimulation with low levels of denatonium correlates with number of prior FESS and postoperative SNOT-22 scores in CRSwNP. Some symptoms of CRS in patients with hyperresponsiveness to low levels of denatonium may be due to increased airway immune activity or inherent disease severity.

Distinct characteristics of nasal polyps with and without eosinophilia / Diferenças nas características de pólipos nasais com e sem eosinofilia

Abstract Introduction Eosinophilic and noneosinophilic Nasal polyps (NPs) are different subtypes of NPs and require different treatment methods. Objective To compare the histologic characteristics, mRNA and protein expression between Nasal Polyps with and without eosinophilia. Methods NPs tissues were obtained from eighty-six NPs patients during surgery. Eosinophilic and noneosinophilic NPs were distinguished according to immunochemical results of the specimen. The histological, mRNA and protein expression features were compared between the two groups. Results In eosinophilic NPs, we observed a significantly higher GATA-3, IL-5, IL-4, IL-13 mRNA and protein expression. In noneosinophilic NPs, IL-17, IL-23 and RORc mRNA and protein expression were increased. Immunohistochemistry tests showed, more mast cells and less neutrophils in eosinophilic NPs compared with noneosinophilic NPs. Eosinophilic NPs patient presented more severe symptom scores when compared to noneosinophilic NPs. Conclusion We demonstrate for the first time that Th2 is the predominant reaction in eosinophilic NPs while Th17 is the predominant reaction in noneosinophilic NPs. Our study may provide new treatment strategy for NPs.

Resumo Introdução Pólipos nasais (PNs) eosinofílicos e não eosinofílicos são diferentes subtipos de PNs e requerem diferentes métodos de tratamento. Objetivo Comparar as características histológicas e a expressão de mRNAs e proteínas entre PNs com e sem eosinofilia. Método Amostras de PNs foram obtidos de 86 pacientes durante a cirurgia. PNs eosinofílicos e não eosinofílicos foram diferenciados segundo os resultados imunoistoquímicos de cada amostra. As características histológicas e de expressão de mRNAs e de proteínas foram comparadas entre os dois grupos. Resultados Em PNs eosinofílicos, observamos uma expressão significativamente maior dos mRNAs e proteínas GATA-3, IL-5, IL-4 e IL-13. Nos PNs não eosinofílicos, aumentou a expressão dos mRNAs e das proteínas IL-17, IL-23 e RORc. Nos testes imunoistoquímicos, observamos maior número de mastócitos e menor número de neutrófilos nos PNs eosinofílicos, em comparação com PNs não eosinofílicos. Os pacientes com PNs eosinofílicos obtiveram escores de sintomas mais graves vs. PNs não eosinofílicos. Conclusão Demonstramos, pela primeira vez, uma reação Th2 predominante em PNs eosinofílicos e uma reação Th17 predominante em PNs não eosinofílicos. Nosso estudo pode proporcionar novas estratégias terapêuticas para a rinossinusite crônica.

Dendritic cell subset expression in severe chronic rhinosinusitis with nasal polyps.

PURPOSE OF REVIEW: Two main pillars are implicated in nasal polyposis development: a severe imbalance in immunomodulation and a mechanical dysfunction because of an abnormal remodeling process. Dendritic cells play a crucial role in the link between innate and adaptive immune response and orchestrating the T-cell response and are implicated in the severe inflammatory process found in nasal polypoid tissue. This review summarizes the existent knowledge about dendritic cells in nasal polyposis. RECENT FINDINGS: Dendritic cells are found increased in nasal polyposis, regardless of subset. Of interest, plasmacytoid dendritic cells are decreased in patients with a more severe Th2 profile, suggesting an important role of the cytokines milieu in their functional response or that plasmacytoid dendritic cell could act mitigating the inflamed process found in polypoid tissue. SUMMARY: Understanding the dendritic cell subset expression in different environments, as well as the effect of these subsets on T-cell differentiation will greatly improve the development of new therapies in nasal polyposis.

Distinct characteristics of nasal polyps with and without eosinophilia.

INTRODUCTION: Eosinophilic and noneosinophilic Nasal polyps (NPs) are different subtypes of NPs and require different treatment methods. OBJECTIVE: To compare the histologic characteristics, mRNA and protein expression between Nasal Polyps with and without eosinophilia. METHODS: NPs tissues were obtained from eighty-six NPs patients during surgery. Eosinophilic and noneosinophilic NPs were distinguished according to immunochemical results of the specimen. The histological, mRNA and protein expression features were compared between the two groups. RESULTS: In eosinophilic NPs, we observed a significantly higher GATA-3, IL-5, IL-4, IL-13 mRNA and protein expression. In noneosinophilic NPs, IL-17, IL-23 and RORc mRNA and protein expression were increased. Immunohistochemistry tests showed, more mast cells and less neutrophils in eosinophilic NPs compared with noneosinophilic NPs. Eosinophilic NPs patient presented more severe symptom scores when compared to noneosinophilic NPs. CONCLUSION: We demonstrate for the first time that Th2 is the predominant reaction in eosinophilic NPs while Th17 is the predominant reaction in noneosinophilic NPs. Our study may provide new treatment strategy for NPs.

The role of aspirin desensitization in patients with aspirin-exacerbated respiratory disease (AERD) / O papel da dessensibilização à aspirina em pacientes portadores de doença respiratória exacerbada por aspirina (DREA)

ABSTRACT INTRODUCTION: Aspirin-exacerbated respiratory disease (AERD) consists of a classic tetrad: moderate/severe asthma, chronic rhinosinusitis, nasal polyps, and intolerance to aspirin or other nonsteroidal anti-inflammatory drugs. Clinical control with drugs, surgery, and desensitization are treatment options. OBJECTIVE: To evaluate the efficacy and tolerability of aspirin desensitization in patients with AERD. METHODS: Periodic symptom assessment and endoscopy in patients with AERD undergoing surgery who were desensitized. RESULTS: Seventeen patients were desensitized. Eight patients completed the desensitization and were followed for a minimum of a one-year period (mean 3.1 years). These patients showed improvement in all symptoms. Moreover, surgical reassessment was not indicated in any of these patients and there was a decrease in costs with medication and procedures. Eight patients did not complete desensitization, mainly due to procedure intolerance and uncontrolled asthma, whereas another patient was lost to follow-up. CONCLUSION: Aspirin desensitization, when tolerated, was effective in patients with AERD and with poor clinical/surgical response.

Resumo Introdução: A doença respiratória exacerbada por aspirina é composta pela tétrade clássica: asma moderada/grave, rinossinusite crônica, pólipos nasais e intolerância à aspirina ou outro anti-inflamatório não esteroide. Controle clínico com medicamentos, cirurgias e dessensibilização são opções de tratamento. Objetivo: Avaliar a eficácia e tolerabilidade da dessensibilização à aspirina em pacientes com doença exacerbada por aspirina. Método: Avaliação periódica dos sintomas e exame endoscópico em pacientes com doença respiratória exacerbada por aspirina submetidos à cirurgia e dessensibilizados. Resultados: Dezessete pacientes foram dessensibilizados, dos quais oito pacientes completaram a dessensibilização e foram acompanhados pelo tempo mínimo de 1 ano (média de 3,1 anos). Todos referiram melhora de todos os sintomas; não houve nenhuma indicação de reabordagem cirúrgica, e houve redução de gastos com medicações e procedimentos. Outros oito pacientes não completaram a dessensibilização, principalmente por intolerância ao procedimento e descontrole da asma, enquanto outro paciente perdeu o seguimento. Conclusão: A dessensibilização à aspirina, quando tolerada, mostrou-se eficaz nos pacientes com doença respiratória exacerbada por aspirina com resposta clínica/cirúrgica insatisfatória.

[Long-term efficacy of aspirin desensitization in aspirin-exacerbated respiratory disease. Review of two clinical cases]. / Eficacia a largo plazo de la desensibilización a aspirina en enfermedad respiratoria exacerbada por aspirina. Revisión de 2 casos clínicos.

BACKGROUND: The aspirin exacerbated respiratory disease (AERD) shows a prevalence of 7% among asthmatics and increases to 14% in patients with difficult to control asthma. Treatment includes the use of inhibitors of leukotriene receptor (), intranasal steroids, polypectomy, asthma management according to the severity and avoid taking nonsteroidal anti-inflammatory drugs (NSAIDs). In some patients it is necessary desensitization protocol to it. CLINICAL CASES: Two patients diagnosed with respiratory disease exacerbated by aspirin, with poor asthma control and need for multiple polypectomies, despite optimal pharmacological management, carrying out protocol desensitization to aspirin (AAS) successful, now after 4 years of having carried out, they have adequate asthma control without need for polypectomies with a maintenance dose of aspirin 150 mg/day.

Antecedentes: la prevalencia de enfermedad respiratoria exacerbada por aspirina es de 7% en pacientes asmáticos y se incrementa, incluso, a 14% en pacientes con asma de difícil control. El tratamiento incluye la prescripción de inhibidores de los receptores de leucotrienos, esteroides intranasales, polipectomías, tratamiento del asma según su severidad y evitar los antiinflamatorios no esteroides. En algunos pacientes es necesario realizar el protocolo de desensibilización a la aspirina. Casos clínicos: se describen 2 mujeres con diagnóstico de enfermedad respiratoria exacerbada por la administración de aspirina, con escaso control de los cuadros de asma y a quienes fue necesario realizar múltiples polipectomías, a pesar del manejo farmacológico óptimo. Se llevó a cabo protocolo de desensibilización a aspirina (AAS); la respuesta fue positiva. Después de cuatro años, las pacientes presentan adecuado control del asma, con una dosis de mantenimiento de AAS de 150 mg/ día y no han requerido polipectomías.

The role of aspirin desensitization in patients with aspirin-exacerbated respiratory disease (AERD).

INTRODUCTION: Aspirin-exacerbated respiratory disease (AERD) consists of a classic tetrad: moderate/severe asthma, chronic rhinosinusitis, nasal polyps, and intolerance to aspirin or other nonsteroidal anti-inflammatory drugs. Clinical control with drugs, surgery, and desensitization are treatment options. OBJECTIVE: To evaluate the efficacy and tolerability of aspirin desensitization in patients with AERD. METHODS: Periodic symptom assessment and endoscopy in patients with AERD undergoing surgery who were desensitized. RESULTS: Seventeen patients were desensitized. Eight patients completed the desensitization and were followed for a minimum of a one-year period (mean 3.1 years). These patients showed improvement in all symptoms. Moreover, surgical reassessment was not indicated in any of these patients and there was a decrease in costs with medication and procedures. Eight patients did not complete desensitization, mainly due to procedure intolerance and uncontrolled asthma, whereas another patient was lost to follow-up. CONCLUSION: Aspirin desensitization, when tolerated, was effective in patients with AERD and with poor clinical/surgical response.

The human leukocyte antigen G molecule (HLA-G) expression in patients with nasal polyposis.

INTRODUCTION: Sinonasal polyposis (NP) is a chronic inflammatory pathology of the nasal/paranasal cavities which affects from 1%-4% of the population. Although polyps seem to be a manifestation of chronic inflammation in both allergic and non-allergic subjects, the pathogenesis of nasal polyposis remains unknown. HLA-G molecules are a kind of no classic class I antigen with anti-inflammatory and tolerogenic properties. Little attention has been paid to the role of HLA-G chronic inflammatory disorders. OBJECTIVE: The aim of this study is to investigate the expression of HLA-G in the NP. MATERIALS AND METHODS: Prospective study involving samples of patients presenting with nasal polyposis that were subjected to the immunohistochemistry technique. After a skin prick test, all patients were divided into atopic and nonatopic groups and classified as asthmatic or non-asthmatic. RESULTS: Immunohistochemical staining demonstrated a higher expression of the HLA-G molecule in samples from nonatopic than in those from atopic patients, and was significantly lower in the non-asthmatic patients. CONCLUSION: These results indicate that HLA-G may play an important role in the pathology of nasal polyposis. Considering the anti-inflammatory properties of HLA-G, this study suggests that it could reduce susceptibility to atopy and asthma.

Expression of apoptosis mediators p53 and caspase 3, 7, and 9 in chronic rhinosinusitis with nasal polyposis.

BACKGROUND: The causal factor for the perpetuation of the inflammatory process in chronic rhinosinusitis with nasal polyps (CRSwNPs) has been extensively studied. However, little is known about the influence of cell death in this disease. Thus, the molecular assessment of mechanisms involved in apoptosis might shed light on the pathogenesis of CRSwNPs. This study was designed to evaluate the gene expression of different apoptotic factors in patients with NPs compared with control patients. METHODS: The mRNA expression of the apoptosis mediators caspase 3, 7, and 9 and of p53 protein was analyzed using quantitative reverse transcription-polymerase chain reaction in 25 NPs and 18 control samples. RESULTS: We observed significantly lower expression of p53 and caspase 3 and 9 in patients with CRSwNPs compared with the controls, whereas caspase 7 expression was not significantly different from the controls. CONCLUSION: The reduced expression of these apoptosis factors in CRSwNPs might be related to higher proliferation and the perpetuation of inflammatory cells hindering the control of the disease. A better understanding of the possible influence of apoptosis factors on CRSwNPs could provide rationale for future therapies.

The human leukocyte antigen G molecule (HLA-G) expression in patients with nasal polyposis / A expressão do antígeno humano leucocitário G (HLA-G) em pacientes com polipose nasossinusal

INTRODUCTION: Sinonasal polyposis (NP) is a chronic inflammatory pathology of the nasal/paranasal cavities which affects from 1%-4% of the population. Although polyps seem to be a manifestation of chronic inflammation in both allergic and non-allergic subjects, the pathogenesis of nasal polyposis remains unknown. HLA-G molecules are a kind of no classic class I antigen with anti-inflammatory and tolerogenic properties. Little attention has been paid to the role of HLA-G chronic inflammatory disorders. OBJECTIVE: The aim of this study is to investigate the expression of HLA-G in the NP. MATERIALS AND METHODS: Prospective study involving samples of patients presenting with nasal polyposis that were subjected to the immunohistochemistry technique. After a skin prick test, all patients were divided into atopic and nonatopic groups and classified as asthmatic or non-asthmatic. RESULTS: Immunohistochemical staining demonstrated a higher expression of the HLA-G molecule in samples from nonatopic than in those from atopic patients, and was significantly lower in the non-asthmatic patients. CONCLUSION: These results indicate that HLA-G may play an important role in the pathology of nasal polyposis. Considering the anti-inflammatory properties of HLA-G, this study suggests that it could reduce susceptibility to atopy and asthma. .

INTRODUÇÃO: Polipose nasossinusal (PNS) é uma patologia inflamatória crônica das cavidades nasais/paranasais que afeta 1%-4% da população. Embora os pólipos pareçam ser uma manifestação de inflamação crônica em ambos os indivíduos alérgicos e não alérgicos, a patogênese da polipose nasal permanece desconhecida. Moléculas HLA-G são antígenos não clássicos da classe I com propriedades anti-inflamatórias e tolerogênicas. Pouca atenção tem sido dada ao papel do HLA-G em doenças inflamatórias crônicas. OBJETIVO: Investigar a expressão de HLA-G na PNS. MATERIAIS E MÉTODOS: Estudo prospectivo de pacientes com polipose nasal que foram submetidas à técnica de imuno-histoquímica. Após realizarem teste cutâneo, os pacientes foram divididos em grupos atópicos e não atópicos e classificados como asmáticos ou não asmáticos. RESULTADO: A coloração imuno-histoquímica mostrou uma maior expressão da molécula HLA-G em pacientes não atópicos do que naqueles atópicos e foi significativamente inferior nos pacientes não asmáticos. CONCLUSÃO: Os resultados indicam que o HLA-G pode ter um papel importante na patologia da polipose nasal. Considerando as propriedades anti-inflamatórias do HLA-G, este estudo sugere que ele poderia reduzir a susceptibilidade a atopia e asma. .

Convergence of two major pathophysiologic mechanisms in nasal polyposis: immune response to Staphylococcus aureus and airway remodeling.

This review is addressed two pathophysiologic mechanisms implicated in the pathogenesis of nasal polyposis: the unique remodeling process found in nasal polyp tissue and the immune response of patients with nasal polyposis to Staphylococcus aureus. These two theories converge to the same direction in different aspects, including decreased extracellular matrix production, impaired T regulation and favoring of a Th2 immune response.In patients with nasal polyposis, an exaggerated immune response to Staphylococcus aureus may aggravate the airway remodeling process.

Impact of mitomycin C on the mRNA expression signatures of immunological biomarkers in eosinophilic nasal polyposis.

BACKGROUND: The topical application of mitomycin C has been evaluated as a complementary therapy for eosinophilic nasal polyposis (ENP). However, the mechanism underlying the additional benefits of mitomycin C for the control of eosinophilic inflammation and prevention of posttherapeutic relapse remains to be elucidated. In this work, the aim was to characterize the gene expression profile by quantitative real-time polymerase chain reaction (qPCR) of proinflammatory and regulatory biomarkers that are typically associated with ENP and to assess the impact of the topical application of mitomycin C on the nasal mucosal tissue immunologic milieu after ENP surgery. METHODS: We have selected 20 patients with ENP that were recommended to undergo surgical intervention. Normal mucosal tissue was obtained from healthy nasal mucosa from six patients with absence of eosinophilic infiltration. To test the effect of mitomycin C, one side of the maxillary sinus mucosa was selected for topical application of this drug and the other received no further treatment and acted as the control. The genes interleukin-4 (IL-4), IL-5, IL-10, IL-13, chemokine (C-C motif) ligand 5 (CCL5), CCL24, colony-stimulating factor 2 (CSF2), transforming growth factor beta 1 (TGFB1), tumor necrosis factor alpha (TNF-alpha), and beta actin (ACTB) were selected for gene expression analysis by qPCR. RESULTS: The data showed higher expression of proinflammatory biomarkers and lower levels of regulatory TGFB1 transcripts in ENP mucosal tissue. Surgery with topical application of mitomycin C induced a prominent transcriptional down-regulation of the immunologic biomarkers, CCL24, TNF-alpha, CSF2, and IL-5, in ENP mucosal tissue. Additionally, this treatment restored the levels of chemokines and cytokines to those observed in the nasal mucosal tissue of control subjects, except for TGFB1, which remained below the reference pattern. Moreover, CSF2 was identified as a putative biomarker with significant predictive value for complementary prophylactic purposes after surgery in ENP patients. CONCLUSION: After the characterization of the expression signatures of immunologic biomarkers in ENP, we observed that the topical use of mitomycin C is important for the reestablishment of the immunologic microenvironment of a normal expression profile of biomarkers involved in ENP mucosal tissue.