Management of CRSwNP in Latin America: A multidisciplinary consensus from an expert working group.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory condition of the nasal and paranasal tissues, characterized by the presence of bilateral nasal polyps. While etiology and pathogenetic mechanisms are heterogeneous and complex, in most patients, disease is mediated predominantly through type 2 inflammatory processes. Clinical management is challenging, and a multidisciplinary approach is preferred. Principal treatment approaches are the use of local/systemic corticosteroids and sinonasal surgery, although outcomes can be unsatisfactory. Recent availability of biological therapies targeting underlying inflammatory processes can offer effective treatment options in uncontrolled disease. Specialist guidelines greatly assist clinical decision-making, although as these are chiefly written from a global/international perspective, they may not wholly accommodate disease patterns and clinical practice at a regional level. An expert panel of specialists from Latin America was convened to develop regional guidance on the management of CRSwNP through a consensus approach. The present article presents the chief observations and recommendations which can provide guidance for clinicians in the Latin American region.

Adult Severe Asthma Registries: A Global and Growing Inventory.

Aim: The International Severe Asthma Registry (ISAR; http://isaregistries.org/) uses standardised variables to enable multi-country and adequately powered research in severe asthma. This study aims to look at the data countries within ISAR and non-ISAR countries reported collecting that enable global research that support individual country interests. Methods: Registries were identified by online searches and approaching severe asthma experts. Participating registries provided data collection specifications or confirmed variables collected. Core variables (results from ISAR's Delphi study), steroid-related comorbidity variables, biologic safety variables (serious infection, anaphylaxis, and cancer), COVID-19 variables and additional variables (not belonging to the aforementioned categories) that registries reported collecting were summarised. Results: Of the 37 registries identified, 26 were ISAR affiliates and 11 non-ISAR affiliates. Twenty-five ISAR-registries and 4 non-ISAR registries reported collecting >90% of the 65 core variables. Twenty-three registries reported collecting all optional steroid-related comorbidity variables. Twenty-nine registries reported collecting all optional safety variables. Ten registries reported collecting COVID-19 variables. Twenty-four registries reported collecting additional variables including data from asthma questionnaires (10 Asthma Control Questionnaire, 20 Asthma Control Test, 11 Asthma Quality of Life Questionnaire, and 4 EuroQol 5-dimension 5-level Questionnaire). Eight registries are linked to databases such as electronic medical records and national claims or disease databases. Conclusion: Standardised data collection has enabled individual severe asthma registries to collect unified data and increase statistical power for severe asthma research irrespective of ISAR affiliations.

Clinical Efficacy among Patients with Chronic Rhinosinusitis with Nasal Polyps and Clinical Features of Obstructive Lung Disease: Post Hoc Analysis of the Phase III SINUS-24 and SINUS-52 Studies.

Purpose: To provide a descriptive summary of clinical efficacy and health-related quality of life (HRQoL) measures in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and clinical features of obstructive lung disease in the Phase III dupilumab studies SINUS-24 and SINUS-52 (NCT02912468, NCT02898454). Patients and Methods: Patients met a "broad" definition of having clinical features of obstructive lung disease with any of 3 criteria: (i) pre-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <0.70 and smoking history; (ii) patient-reported medical history of chronic obstructive pulmonary disease (COPD); or (iii) asthma with >10 pack-years' smoking history. A "narrow" definition including criteria (i) or (ii) was also analyzed. CRSwNP and HRQoL measures were evaluated in all patients and lung function (FEV1; FEV1/FVC ratio) was captured and analyzed only in those patients who had a self-reported history of asthma. Results: Across both studies, 131 patients met the "broad" definition, of whom 90 also had asthma, and 115 patients met the "narrow" definition, of whom 74 had asthma. CRSwNP outcomes and HRQoL were improved with dupilumab vs placebo in both the broad and narrow subgroups. Among the 90 patients who met the broad definition and had asthma, dupilumab improved pre-bronchodilator FEV1 and FEV1/FVC ratio at Week 16 (least squares mean differences vs placebo: 0.38 L [95% confidence interval: 0.17, 0.59; p = 0.0004] and 4.8% [1.7%, 7.9%; p = 0.0024], respectively) sustained through Week 24. Similar results were seen in the "narrow" subgroup with asthma. Conclusion: In a population of patients with CRSwNP and clinical features of obstructive lung disease, dupilumab improved CRSwNP and HRQoL outcomes, and, among those with a history of asthma, also improved lung function. These results support further analyses of dupilumab in patients with evidence of type 2 inflammation and obstructive lung disease such as COPD.

Health-Related Quality of Life Impairment Among Patients with Severe Chronic Rhinosinusitis with Nasal Polyps in the SINUS-24 Trial.

Purpose: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease with a high symptom burden. Data are lacking on the comparative health status of patients with CRSwNP. This analysis compared baseline physical and mental health-related quality of life (HRQoL) and overall health status of patients with severe CRSwNP enrolled in a Phase 3 clinical trial with general population norms and with other chronic diseases. Methods: In this post hoc cross-sectional analysis of baseline data from the SINUS-24 study (NCT02912468), HRQoL was measured using the 36-item Short Form (SF-36) questionnaire and general health status was measured using the EuroQol-5 Dimension visual analog scale (EQ-VAS). Analyses included the intention-to-treat (ITT) population and subgroups defined by prior sinonasal surgery, systemic corticosteroid use, and coexisting asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Scores were compared with published values for population norms (50 for SF-36 physical component summary (PCS) and mental component summary (MCS), 70.4-83.3 for EQ-VAS) and for rheumatoid arthritis, type 2 diabetes, and asthma. Results: In the ITT population (n=276), mean SF-36 physical component summary (PCS), SF-36 mental component summary (MCS), and EQ-VAS scores were below general population norms (46.4, 48.6, and 66.0, respectively). Mean SF-36 PCS and EQ-VAS scores were below population norms across all subgroups; mean SF-36 MCS scores were below the population norm in all subgroups except no prior surgery. SF-36 PCS and MCS scores from SINUS-24 were generally similar to other chronic diseases, except SF-36 PCS which was lower in rheumatoid arthritis. EQ-VAS scores in SINUS-24 were lower than in other chronic diseases. HRQoL scores weakly correlated with objective measures of disease severity. Conclusion: In patients with severe CRSwNP, including those with coexisting asthma/NSAID-ERD, HRQoL was worse than population norms and as burdensome as diseases such as type 2 diabetes, asthma, and rheumatoid arthritis.

Rinitis alérgica en pediatría: recomendaciones para su diagnóstico y tratamiento / Allergic rhinitis in pediatrics: recommendations for diagnosis and treatment

La rinitis alérgica (RA) es una de las enfermedades crónicas más frecuentes de la infancia. Sin embargo, permanece subdiagnosticada y subtratada. Su prevalencia ha aumentado en los últimos años y varía del 2 % al 25 %. Los síntomas de la RA incluyen estornudos, prurito, rinorrea y congestión nasal. Un correcto diagnóstico y tratamiento de la RA y sus comorbilidades, tales como rinosinusitis con o sin poliposis nasal, conjuntivitis, otitis media, asma bronquial e infecciones del tracto respiratorio, son importantes para reducir el impacto negativo en la afectación de la calidad de vida del paciente y sus familiares, y los gastos sanitarios que ocasiona. La inmunoterapia alérgeno específica, en pacientes correctamente seleccionados, previene nuevas sensibilizaciones y reduce la hiperreactividad bronquial asociada a la RA. Considerando todos estos factores, el Comité Nacional de Alergia de la Sociedad Argentina de Pediatría propone recomendaciones basadas en la evidencia actual.

Allergic rhinitis (AR) is one of the most common chronic diseases in children. However, it remains underdiagnosed and undertreated. Its prevalence has increased in recent years and varies from 2 to 25 %. Symptoms include sneezing, itching, runny nose, and nasal congestion. A correct diagnosis and treatment of AR and its comorbidities such as rhinosinusitis with or without nasal polyposis, conjunctivitis, otitis media, bronchial asthma and respiratory tract infections, are important to reduce the negative impact on the quality of life of the patient and their relatives, and in medical costs. Specific allergen immunotherapy, in correctly selected patients, prevents new sensitizations and reduces bronchial hyperreactivity associated with AR. Taking into account all these reasons, the National Allergy Committee of the Sociedad Argentina de Pediatría proposes current evidence based recommendations

Efficacy of once-daily, single-inhaler, fixed-dose combination of mometasone/indacaterol/glycopyrronium in patients with asthma with or without persistent airflow limitation: Post hoc analysis from the IRIDIUM study.

BACKGROUND: A novel, once-daily, fixed-dose combination of mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY) delivered via Breezhaler® is the first inhaled corticosteroid/long-acting ꞵ2-agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) therapy approved for the maintenance treatment of asthma in adults inadequately controlled on ICS/LABA combination. In patients with asthma and persistent airflow limitation (PAL), maximal treatment, especially with combination is suggested. This post hoc analysis of data from the IRIDIUM study assessed the efficacy of MF/IND/GLY in asthma patients with and without PAL. METHODS: Patients with post-bronchodilator FEV1 ≤80% of predicted and FEV1/FVC ratio of ≤0.7 were categorised as PAL subgroup and the remaining as the non-PAL subgroup. Lung function parameters (FEV1, PEF, and FEF25%-75%) and annualised asthma exacerbations rates were evaluated in both subgroups across the treatment arms: once-daily high-dose MF/IND/GLY (160/150/50 µg), high-dose MF/IND (320/150 µg) and twice-daily high-dose fluticasone/salmeterol (FLU/SAL; 500/50 µg). RESULTS: Of the 3092 randomised patients, 64% (n = 1981) met the criteria for PAL. Overall, there was no evidence of treatment difference between PAL and non-PAL subgroups (interaction P-value for FEV1, FEF25%-75%, PEF, moderate or severe exacerbations, severe exacerbations and all exacerbations were 0.42, 0.08, 0.43 0.29, 0.35 and 0.12, respectively). In the PAL subgroup, high-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL improved trough FEV1 (mean difference: 102 mL [P < 0.0001] and 137 mL [P < 0.0001]) and reduced moderate or severe (16% and 32%), severe (25% and 39%) and all exacerbations (19% and 38%), respectively. CONCLUSIONS: Once-daily fixed-dose MF/IND/GLY was efficacious in asthma patients with and without persistent airflow limitation.

[Allergic rhinitis in pediatrics: recommendations for diagnosis and treatment]. / Rinitis alérgica en pediatría: recomendaciones para su diagnóstico y tratamiento.

Allergic rhinitis (AR) is one of the most common chronic diseases in children. However, it remains underdiagnosed and undertreated. Its prevalence has increased in recent years and varies from 2 to 25 %. Symptoms include sneezing, itching, runny nose, and nasal congestion. A correct diagnosis and treatment of AR and its comorbidities such as rhinosinusitis with or without nasal polyposis, conjunctivitis, otitis media, bronchial asthma and respiratory tract infections, are important to reduce the negative impact on the quality of life of the patient and their relatives, and in medical costs. Specific allergen immunotherapy, in correctly selected patients, prevents new sensitizations and reduces bronchial hyperreactivity associated with AR. Taking into account all these reasons, the National Allergy Committee of the Sociedad Argentina de Pediatría proposes current evidence based recommendations.

La rinitis alérgica (RA) es una de las enfermedades crónicas más frecuentes de la infancia. Sin embargo, permanece subdiagnosticada y subtratada. Su prevalencia ha aumentado en los últimos años y varía del 2 % al 25 %. Los síntomas de la RA incluyen estornudos, prurito, rinorrea y congestión nasal. Un correcto diagnóstico y tratamiento de la RA y sus comorbilidades, tales como rinosinusitis con o sin poliposis nasal, conjuntivitis, otitis media, asma bronquial e infecciones del tracto respiratorio, son importantes para reducir el impacto negativo en la afectación de la calidad de vida del paciente y sus familiares, y los gastos sanitarios que ocasiona. La inmunoterapia alérgeno específica, en pacientes correctamente seleccionados, previene nuevas sensibilizaciones y reduce la hiperreactividad bronquial asociada a la RA. Considerando todos estos factores, el Comité Nacional de Alergia de la Sociedad Argentina de Pediatría propone recomendaciones basadas en la evidencia actual.

Mepolizumab for chronic rhinosinusitis with nasal polyps: Treatment efficacy by comorbidity and blood eosinophil count.

BACKGROUND: In the phase III SYNAPSE study, mepolizumab reduced nasal polyp (NP) size and nasal obstruction in chronic rhinosinusitis with NP. OBJECTIVE: We sought to assess the efficacy of mepolizumab in patients from SYNAPSE grouped by comorbid asthma, aspirin-exacerbated respiratory disease (AERD), and baseline blood eosinophil count (BEC). METHODS: SYNAPSE, a randomized, double-blind, 52-week study (NCT03085797), included patients with severe bilateral chronic rhinosinusitis with NP eligible for surgery despite intranasal corticosteroid treatment. Patients received 4-weekly subcutaneous mepolizumab 100 mg or placebo plus standard of care for 52 weeks. Coprimary end points were change in total endoscopic NP score (week 52) and nasal obstruction visual analog scale score (weeks 49-52). Subgroup analyses by comorbid asthma and AERD status, and post hoc by BEC, were exploratory. RESULTS: Analyses included 407 patients (289 with asthma; 108 with AERD; 371 and 278 with BEC counts ≥150 or ≥300 cells/µL, respectively). The proportion of patients with greater than or equal to 1-point improvement from baseline in NP score was higher with mepolizumab versus placebo across comorbid diseases (asthma: 52.9% vs 29.5%; AERD: 51.1% vs 20.6%) and baseline BEC subgroups (<150 cells/µL: 55.0% vs 31.3%; ≥150 cells/µL: 49.5% vs 28.1%; <300 cells/µL: 50.7% vs 29.0%; ≥300 cells/µL: 50.4% vs 28.1%). A similar trend was observed in patients without comorbid asthma or AERD. More patients had more than 3-point improvement in nasal obstruction VAS score with mepolizumab versus placebo across comorbid subgroups. CONCLUSIONS: Mepolizumab reduced polyp size and nasal obstruction in chronic rhinosinusitis with NP regardless of the presence of comorbid asthma or AERD.

Efficacy and safety of dupilumab in patients with uncontrolled severe chronic rhinosinusitis with nasal polyps and a clinical diagnosis of NSAID-ERD: Results from two randomized placebo-controlled phase 3 trials.

BACKGROUND: About one-tenth of patients with difficult-to-treat chronic rhinosinusitis with nasal polyps (CRSwNP) have comorbid non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Dupilumab, a fully human monoclonal antibody that blocks the shared interleukin (IL)-4/IL-13 receptor component, is an approved add-on treatment in severe CRSwNP. This post hoc analysis evaluated dupilumab efficacy and safety in patients with CRSwNP with/without NSAID-ERD. METHODS: Data were pooled from the phase 3 SINUS-24 and SINUS-52 studies in adults with uncontrolled severe CRSwNP who received dupilumab 300 mg or placebo every 2 weeks. CRSwNP, nasal airflow, lung function, and asthma control outcomes at Week 24 were evaluated, and treatment-subgroup interactions were assessed for patients with and without NSAID-ERD. RESULTS: Of 724 patients, 204 (28.2%) had a diagnosis of NSAID-ERD. At Week 24, least squares mean treatment differences demonstrated significant improvements in nasal polyp score, nasal congestion (NC), Lund-Mackay computed tomography, 22-item Sinonasal Outcome Test (SNOT-22), Total Symptom Score (TSS), rhinosinusitis severity visual analog scale, peak nasal inspiratory flow (PNIF), six-item Asthma Control Questionnaire score, and improvement in smell with dupilumab versus placebo (all p < .0001) in patients with NSAID-ERD. Treatment comparisons demonstrated significantly greater improvements with dupilumab in patients with versus without NSAID-ERD for NC (p = .0044), SNOT-22 (p = .0313), TSS (p = .0425), and PNIF (p = .0123). CONCLUSIONS: In patients with uncontrolled severe CRSwNP, dupilumab significantly improved objective measures and patient-reported symptoms to a greater extent in the presence of comorbid NSAID-ERD than without. Dupilumab was well tolerated in patients with/without NSAID-ERD.

Efficacy and safety of fevipiprant in patients with uncontrolled asthma: Two replicate, phase 3, randomised, double-blind, placebo-controlled trials (ZEAL-1 and ZEAL-2).

BACKGROUND: These studies assessed the efficacy and safety of fevipiprant, an oral antagonist of the prostaglandin D2 (PGD2) receptor (DP2), compared with placebo when added to standard-of-care (SoC) asthma therapy in patients with uncontrolled asthma. METHODS: ZEAL-1 (NCT03215758) and ZEAL-2 (NCT03226392) are two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies in which fevipiprant 150 mg once daily (o.d.) or placebo was added to SoC asthma therapy in patients aged ≥12 years with uncontrolled asthma. Primary endpoint: change from baseline in pre-dose forced expiratory volume in 1 s (FEV1) after 12 weeks' treatment. Key secondary endpoints: daytime asthma symptom score, short-acting ß-agonist (SABA) use and Asthma Quality-of-Life Questionnaire (AQLQ+12) score after 12-weeks treatment. FINDINGS: 662 patients in ZEAL-1 and 685 patients in ZEAL-2 completed the treatment period. In ZEAL-1, the least squares (LS) mean change from baseline in pre-dose FEV1 was 112 mL in fevipiprant vs 71 mL in placebo group (difference [∆]:41 mL; 95% CI: -6, 88; adjusted p-value 0·088). In ZEAL-2, the LS mean change in pre-dose FEV1 was 126 mL and 157 mL in the fevipiprant and placebo groups, respectively (∆:-31 mL; 95% CI: -80, 18; adjusted p-value 0·214). For both studies, there were no statistically significant differences in the key secondary objectives between the treatment groups. INTERPRETATION: The ZEAL studies did not demonstrate significant improvement in lung function or other clinical outcomes. These results suggest that DP2 receptor inhibition with fevipiprant is not effective in the studied patient population.

Dupilumab improves upper and lower airway disease control in chronic rhinosinusitis with nasal polyps and asthma.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) and type 2 asthma share the same inflammatory pathophysiology and are frequent comorbidities. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin 4 and interleukin 13, which are key and central drivers of type 2 inflammation. OBJECTIVE: We report the effect of dupilumab vs placebo on outcome measures of the upper and lower airways and health-related quality of life (HRQoL) in the pooled population of patients with CRSwNP and comorbid asthma from the phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) studies. METHODS: In these randomized, double-blind, placebo-controlled trials, patients received subcutaneous dupilumab 300 mg (n = 438) or placebo (n = 286) every 2 weeks on a background of mometasone furoate nasal spray. Changes from baseline at week 24 in the upper and lower airway outcome measures are reported. RESULTS: Of the 724 patients randomized, 428 (59.1%) had comorbid asthma. In patients with asthma at week 24, dupilumab vs placebo improved the nasal polyp score (-2.04), patient-reported nasal congestion score (-1.04), Lund-Mackay computed tomography scan score (-6.43), peak nasal inspiratory flow (46.15 L/min), and 22-item sinonasal outcome test score (-21.42; all P < .001). The forced expiratory volume in 1 second and 6-item asthma control questionnaire scores were also markedly improved with dupilumab vs placebo. The most common adverse events (nasopharyngitis, headache, injection-site erythema, worsening of nasal polyposis, and asthma) were more frequent with placebo than dupilumab. CONCLUSION: Dupilumab improved upper and lower airway outcome measures and HRQoL in patients with severe CRSwNP and comorbid asthma and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02912468 (SINUS-24) and NCT02898454 (SINUS-52).

Alergia e intolerancia a antiinflamatorios no esteroideos en pediatría / Allergy and intolerance to nonsteroidal anti-inflammatory drugs in children

Los antiinflamatorios no esteroideos son ampliamente recetados en niños. Constituyen la segunda causa de reacciones a medicamentos en pediatría después de los antibióticos betalactámicos; sin embargo, solo una parte de estas son reacciones de hipersensibilidad. La prevalencia de dichas reacciones a antiinflamatorios no esteroideos en niños es del 0,3 % y aumenta al 5 % en asmáticos.Los mecanismos fisiopatológicos involucrados (inhibición de la ciclooxigenasa, hipersensibilidad mediada por inmunoglobulina E, linfocitos T reactivos y/o afectación de la inmunidad innata) darán lugar a diferentes entidades clínicas con sintomatología dispar.La confusión con síntomas propios de procesos virales y la variabilidad clínica hacen del diagnóstico de certeza un verdadero desafío. Una historia clínica detallada, análisis de laboratorio, pruebas cutáneas y de provocación controlada permitirán definir estrategias para cada paciente en particular sin etiquetar como alérgico a un niño que no lo es ni exponer a riesgos innecesarios a quien está sensibilizado.

Nonsteroidal anti-inflammatory drugs are widely prescribed in children. They are the second cause of drug ́s reactions in pediatrics after beta-lactam antibiotics, however only a part of them are hypersensitivity reactions. The prevalence of these reactions to nonsteroidal anti-inflammatory drugs in children is 0.3 %, increasing to 5 % in asthmatics.The different physiopathological mechanisms involved (inhibition of cyclooxygenase, immunoglobulin E-mediated hypersensitivity, reactive T lymphocytes and/or disturbance of innate immunity) will cause different clinical entities with diverse symptoms.The confusion between the common symptoms of a viral infection and a hypersensitivity reaction, and the variability of the clinical presentations make diagnosis a real challenge.A detailed clinical history, laboratory, skin and controlled provocation tests will provide strategies for each patient, without labeling a child who is not an allergic one, or taking unnecessary risks with those who are sensitized.

Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Sanofi and Regeneron Pharmaceuticals.

Asma de difícil control en niños y adolescentes: Estrategias diagnóstico-terapéuticas / Poorly controlled asthma: diagnosis and therapeutics in children and adolescents

El asma es una de las enfermedades crónicas más frecuentes en los niños. Si bien la mayoría de los niños con asma responden a bajas dosis de corticoides inhalados y/o antagonistas del receptor de leucotrienos, algunos de ellos permanecen sintomáticos independientemente de cualquier esfuerzo terapéutico, presentando una elevada morbilidad e inclusive mortalidad. Aunque la mayoría de los pacientes controlan los síntomas de forma adecuada, existe un grupo importante que presenta síntomas graves de la enfermedad difíciles de controlar (ADC). El objetivo de la presente revisión es discutir los aspectos clínicos, diagnósticos y terapéuticos del ACD en los menores de 18 años y su implicancia en la práctica clínica diaria.

Asthma is one of the most common chronic diseases in children. While most children with asthma respond to low doses of inhaled corticosteroids and /or leukotriene receptor antagonists, some of them remain symptomatic regardless of any therapeutic effort, showing a high morbidity and even mortality. While most of the patients control symptoms adequately, there is a large group with severe symptoms of the disease and difficult to control. The aim of this review is to discuss the clinical aspects, diagnosis and treatment of poorly controlled asthma in children and adolescents and its implications in daily clinical practice.

Urticaria crónica autoinmunitaria: tratamiento con omalizumab / Chronic autoimmune urticaria: treatment with omalizumab

Se presenta el caso de una niña con diagnóstico de urticaria autoinmunitaria y su evolución terapéutica con omalizumab. Caso clínico. Paciente de sexo femenino de 12 años de edad con un cuadro de urticaria crónica grave y angioedema de 14 meses de evolución, escasa respuesta a dosis máximas de 3 antihistamínicos combinados, antileucotrienos y corticoides, y gran afectación de su calidad de vida. Se realizó una prueba de suero autólogo, que fue positiva hasta la dilución 1:100, llegándose al diagnóstico de urticaria crónica autoinmunitaria. La falta de respuesta al tratamiento lleva a indicar terapia con omalizumab, con una reducción notable de los síntomas hacia la tercera dosis y ausencia de ellos tras 12 meses de tratamiento. Conclusión. El omalizumab podría ser una opción terapéutica para pacientes con urticaria autoinmunitaria que no responden a otros tratamientos.

We report the case of a child with diagnosis of chronic urticaria/angioedema and its evolution upon omalizumab treatment. Case report. Our patient is a 12-years-old female who suffered for 14 months severe chronic urticaria/angioedema. She had a poor response to the highest doses of combined therapy with 3 antihistamines, steroids and anti-leukotrienes and great impairmentof her quality of life. An autologous serum skin test was positive until 1:100 dilutions, leading to the diagnosis of chronic autoimmune urticaria. Due to the lack of response to treatment, therapy with omalizumab was administered. A notable reduction in symptoms toward the third dose was observed. After 12 months of this treatment, the patient is asymptomatic and has a negative autologousserum test. Conclusion. Omalizumab could be a therapeutic option for patients with autoimmune urticaria unresponsive to other treatments.

O que é um alergista? / What is an allergist?

Introdução: O alergista é o médico que concluiu com êxito um período de treinamento especializado em alergia e imunologia e um período de treinamento em medicina interna e/ou pediatria. Os alergistas também são imunologistas clínicos especializados, devido à base imunológica das doenças que diagnosticam e tratam. Na maioria dos países, o período aprovado de formação na especialidade em alergia e imunologia é de dois a três anos de treinamento intenso e específico. Dependendo dos sistemas de credenciamento nacionais, a conclusão desse treinamento será reconhecida por um certificado de treinamento especializado em alergia, em alergia e imunologia ou em alergia e imunologia clínica, outorgado por uma comissão diretiva. Em alguns países, isso acompanha a conclusão bem-sucedida de um exame de qualificação e, em outros, as competências apresentadas por um supervisor de treinamento. Os alergistas totalmente treinados fazem uma importante contribuição para o delineamento dos sistemas de atendimento local e proporcionam o atendimento necessário aos pacientes com doenças alérgicas. Os alergistas agem como defensores do paciente, e apóiam e questionam o caso para melhorar a educação dos médicos de atendimento primário e secundário, assim como de outros profissionais de saúde que também atendem pacientes alérgicos. Os alergistas devem estar disponíveis para fazer o atendimento dos casos mais complicados, que estão além do campo de ação de médicos de atendimento primário e secundário e de outros profissionais de saúde com bom treinamento. As principais características que definem um alergista são a apreciação da importância dos desencadeantes externos que causam a doença e o conhecimento de como identificar e tratar essas doenças, juntamente com a experiência nas terapias imunológicas e fármacos apropriados. Essa conduta no diagnóstico e na terapia é um valor essencial do especialista em alergia, e destaca o alergista entre muitos especialistas cujas bases de pacientes podem sobrepor-se com a especialidade...

Safety and efficacy of fluticasone furoate in pediatric patients with perennial allergic rhinitis.

OBJECTIVE: To evaluate the safety and efficacy of once-daily (QD) fluticasone furoate (FF) nasal spray in children with perennial allergic rhinitis (PAR). STUDY DESIGN: A global, randomized, double-blind, placebo-controlled study. SUBJECTS AND METHODS: Pediatric patients (aged 2-11 years; n = 558) with PAR received once-daily placebo, FF 110 microg, or FF 55 microg for 12 weeks. Efficacy was evaluated by nasal symptom scores. General safety and corticosteroid-specific safety (nasal and ophthalmic examinations, and hypothalamic-pituitary-adrenal assessments) were assessed. RESULTS: No findings of clinical concern were identified from the safety assessments. For primary efficacy analysis of mean change from baseline over the first 4 weeks of treatment in daily reflective total nasal symptom score, FF 55 microg demonstrated significant improvement (P = 0.003) compared with placebo; however, the improvement for FF 110 microg versus placebo did not reach statistical significance (P = 0.073). CONCLUSION: FF QD was well tolerated and demonstrated efficacy in children aged 2 to 11 years with PAR.

Asma por ejercicio: utilidad de marcadores en orina / Exercise induced asthma: utility of urinaria markers

Antecedentes: los metabolitos estables de la Prostaglandina D2 (PGD2) mastocitaria 9 Ó11ß Prostaglandina F2 (9 Ó11ßPGF2) y de los cis-leucotrienos (LTE4) medidos en orina reflejan la producción de estos mediadores. Objetivos: determinar el rol de los leucotrienos y de la Prostaglandina D2 a través de la relación existente entre la provocación del asma por ejercicio (AIE) y los niveles urinarios de Laucotrieno E4 (LTE4) y 9 Ó11ßPGF2. Materiales y métodos: fueron estudiados 24 niños con asma (6-14 años) y 9 niños sanos como control. En todos los asmáticos y en 5 controles se evaluó la presencia de AIE mediante prueba de carrera libre durante 7 min, alcanzando el 80 por ciento de frecuencia cardíaca máxima para la edad. Se realizaron espirometrías basales y post prueba (secuenciales) y se colectó orina inmediatamente antes y 45 minutos despues de la prueba. LTE4 y 9 Ó11ßPGF2 fue evaluada por enzimainmunoensayos específicos. Resultados: Los 5 controles normales no presentaron asma por ejercicio, de los 24 pacientes asmáticos 12 no presentaron AIE y en 12 la prueba fue posititva (VEF1s cae > 15 por ciento). Las medias de los valores basales y post ejercicio de LTE4 y 9 Ó11ßPGF2 en pg/mg creatinina se tabulan a continuación: Asma por ejercicio: 9 Ó11ßPGF2: Basal: 3,39; Post: 7,95; p=0,001; LTE4: Basal: 4,00; Post: 9,39; p=0,002. Asma sin ejercicio: 9 Ó11ßPGF2: Basal: 3,98; Post: 6,28; p=0,02; LTE4: Basal: 5,91; Post: 7,04; p=0,242. Los niveles de 9 Ó11ßPGF2 y LTE4 de los controles normales no variaron significativamente post ejercicio. Conclusión: en los pacientes con asma por ejercicio se verifica activación mastocitaria con liberación de PGD2 que se demuestra como aumento de 9 Ó11ßPGF2 urinaria, y de los leucotrienos aumento del LTE4. El aumento de LTE4 es específico para asma por ejercicio en tanto que la 9 Ó11ßPGF2 aumenta en ambos grupos