Guía práctica de seguimiento y manejo del paciente con asma grave tratado con biológicos / Practical guide for the follow-up and management of patients with severe asthma treated with biologics

El manejo del asma grave descontrolada con biológicos es un área de extrema dificultad, dada la escasez de información respecto a los criterios de inicio de los mismos, las variables a evaluar para determinar la eficacia y seguridad de su manejo, los puntos de corte para determinar el momento oportuno para cambiar o agregar otro biológico y el proceso para disminuir o retirar los esteroides. Esta revisión incorpora la información más reciente y realiza una propuesta con base en ella.

The management of severe uncontrolled asthma with biologics is an area of extreme difficulty given the scarcity of information regarding their starting criteria, the variables to be evaluated to determine the efficacy and safety of their management, the cut-off points to determine the timing to change or add another biological and the process to decrease or withdraw steroids. This review incorporates the latest information and makes a proposal based on it

The role of neutrophils in asthma / 浙江大学学报·医学版

Bronchial asthma is a chronic respiratory disease，characterized by airway inflammation，airway hyperresponsiveness，reversible airway obstruction and airway remodeling，in which a variety of cells including airway inflammatory cells and structural cells are involved. Previous studies have shown that asthma is mainly driven by Th2 cytokines IL-4，IL-5，and IL-13，leading to airway eosinophil inflammation. With further research，however，it has been found that neutrophils are also closely related to asthma. Numbers of neutrophils are elevated in airway through increased chemotaxis and decreased apoptosis，which is earlier than eosinophils，leading to airway neutrophilic inflammation. Neutrophils can produce elastase，myeloperoxidase，neutrophil extra- cellular traps，chemokines and cytokines，participating in the occurrence and development of asthma. The antagonists against these molecules，such as anti-IL-8 receptor antibody，anti-IL-17 antibody，and DNase，have shown positive effects on neutrophilic asthma，but further studies are needed to support their clinical application. This article mainly reviews the role of neutrophils in asthma and related mechanisms.

Caracterización clínica e inmunológica del Asma Neutrofílica / Clinical and immunological characterization of Neutrophilic asthma

RESUMEN Introducción: El asma bronquial es una enfermedad mucho más compleja de lo que inicialmente se consideraba, es multifactorial y se manifiesta en diferentes fenotipos clínicos, entre ellos, el asma neutrofílica. Objetivo: Caracterizar clínica e inmunológicamente el asma neutrofílica. Material y Métodos: Se realizó una revisión bibliográfica actualizada. Se empleó el motor de búsqueda Google Académico y se consultaron artículos de libre acceso en las bases de datos Pubmed y Scielo y se revisaron 50 artículos. Desarrollo: Los neutrófilos están presentes en las vías respiratorias del paciente con asma, se activan y pueden liberar mediadores que promueven y prolongan los síntomas del asma, la presencia de neutrófilos puede ser mediada por interleucina 17(IL-17), la hipótesis de cambios en la microbiota, la obesidad y las infecciones, constituyen elementos primordiales en este tipo de enfermedad. Para aliviar los síntomas de estos pacientes, se necesita una terapia dirigida a disminuir la inflamación dominada por neutrófilos. Conclusiones: El asma neutrofílica es una enfermedad crónica fenotípicamente heterogénea de las vías respiratorias, que implica la participación de numerosas células inflamatorias y más de cien mediadores con múltiples efectos inflamatorios, como el broncoespasmo, la exudación plasmática, la hipersecreción de moco y la activación sensorial. Actualmente existen pocas drogas dirigidas contra la inflamación neutrofílica y la mayoría se encuentran en estudio con el objetivo de aliviar y mejorar las condiciones de vida de cada uno de los pacientes que sufren esta enfermedad(AU)

ABSTRACT Introduction: Bronchial asthma is a much more complex disease than initially thought; it is multifactorial and manifests itself in different clinical phenotypes; among them, we can mention neutrophilic asthma. Objective: To characterize neutrophilic asthma from a clinical and immunological point of view. Material and methods: An updated bibliographic review was made. Google Scholar search engine was used; free access articles were consulted in PubMed and SciELO databases and 50 of them were reviewed. Development: Neutrophils are present in the respiratory tract of patients suffering from asthma; once those neutrophils are activated, they can release mediators that promote and prolong the symptoms of the disease. The presence of neutrophils can be mediated by IL-17. The hypothesis on changes in the microbiota, obesity and infections are key points in this kind of disease. To alleviate the symptoms of these patients, targeted therapy for neutrophil-dominated inflammation is needed. Conclusions: Neutrophilic asthma is a phenotypically heterogeneous chronic disease of the respiratory tract which involves numerous inflammatory cells and more than a hundred mediators with multiple inflammatory effects such as bronchospasm, plasma exudation, mucus hypersecretion and sensory activation. Currently, there are few drugs targeting neutrophilic inflammation and most of them are under study with the aim of alleviating and improving the living conditions in patients suffering from this disease(AU)

Pediatric asthma: impact of the disease in children receiving outpatient treatment in southern brazil / Asma pediátrica: impacto da doença em crianças em acompanhamento ambulatorial no sul do brasil

ABSTRACT Objective: To evaluate the impact of pediatric asthma on patients of a specialized outpatient clinic in Southern Brazil. Methods: The study included children aged 8 to 17 years old with asthma diagnosis (mild, moderate and severe) under treatment at the asthma clinic of Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Brazil. Measurements of spirometry, quality of life, disease control and atopy tests were applied. Results: A total of 66 children were included in the study and divided into groups, according to the severity of the disease: mild, moderate or severe asthma. The results showed similarities in both the treatment and the impact of asthma between groups, except for adherence to treatment: the group with mild asthma showed least adherence to treatment, and the group with severe asthma, greater adherence (p=0.011). As to school absenteeism, the group with severe asthma showed higher frequency (p=0.012), with over 10 days per year (p=0.043). Spirometry showed lower volume/capacity for the group with moderate asthma, followed by the groups with severe and mild asthma. All groups had a high prevalence of allergic asthma, with mites as the main allergens. For quality of life (QOL), and health-related quality of life (HRQOL) levels, there were no differences between groups. In addition, the values were close to the acceptable levels for the total score and for each one of the six domains. The same occurred for the HRQOL-asthma module. Conclusions: QOL and HRQOL present acceptable levels regardless of the severity of the disease.

RESUMO Objetivo: Avaliar o impacto da asma pediátrica de pacientes em acompanhamento ambulatorial em um centro de referência em pneumopediatria do Sul do Brasil. Métodos: Participaram do estudo crianças com idade entre oito e 17 anos, com diagnóstico de asma (leve, moderada e grave), em acompanhamento no ambulatório de asma do Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS). Foram verificadas medidas de espirometria, avaliação dos níveis de qualidade de vida, controle da doença e teste de atopia. Resultados: Sessenta e seis crianças participaram do estudo, divididas em três grupos (asma leve, moderada e grave). Evidenciaram-se semelhanças tanto no tratamento quanto no impacto da asma, exceto para a adesão ao tratamento (p=0,011), em que o grupo de asma leve é o que menos adere e o grupo de asma grave o que mais adere ao tratamento. Em relação ao absenteísmo escolar, o grupo de asma grave apresentou o maior valor (p=0,012), com mais de dez dias/ano (p=0,043). As espirometrias demonstram menor volume/capacidade para o grupo de asma moderada, seguido do grupo de asma grave e asma leve. Os grupos possuem alta prevalência de asma alérgica, tendo os ácaros como os principais alérgenos. Quanto à qualidade de vida (QV) e à qualidade de vida relacionada à saúde (QVRS), não houve diferença entre os grupos. Além disso, os valores apresentados estão próximos aos níveis aceitáveis, tanto para o escore total quanto para os seis domínios analisados. O mesmo ocorre para o módulo QVRS-asma. Conclusões: Os níveis de QV e de QVRS demonstram-se aceitáveis, independentemente da gravidade da doença.

Rol de los lisados bacterianos en asma, evidencia y proyección con especial referencia a OM-85 / Role of bacterial lysates in asthma, evidence and projection with special reference to OM-85

Existen diversos lisados bacterianos, siendo OM-85 (Broncho-Vaxom®) el que posee mayor evidencia en cuanto a su rol inmunoprotector sobre infecciones respiratorias en población pediátrica. Sus mecanismos de acción producen efectos inmunomoduladores que potencialmente podrían prevenir el asma en etapas precoces de la vida, actuar sobre la disminución de crisis y ser un aporte a la terapia convencional del asma. Este artículo expone las principales evidencias en relación con estos compuestos, con enfoque en la actualidad y el desarrollo futuro, en especial sobre OM-85.

There are several bacterial lysates, being OM-85 (Broncho-Vaxom®) the one with the greatest evidence regarding its immunoprotective role on respiratory infections in the pediatric population. Its mechanisms of action produce immunomodulatory effects that could potentially prevent asthma in early stages of life, act on the reduction of crisis and be a contribution to conventional asthma therapy. This article shows the main evidences in relation to these compounds, the current focus and future development, especially on OM-85.

Clinical differences between children with asthma and rhinitis in rural and urban areas / Diferencias clínicas entre niños con asma y rinitis de áreas rurales y urbanas

Abstract Background: Epidemiological studies have shown that children who grow up on traditional farms are protected from allergic diseases. However, less is known about if the environment influences the pharmacotherapy in these patients. Objective: To compare the treatment of asthmatic and rhinitis children from urban and rural areas in Medellín, Colombia. Methods: During one year, we follow up a group of children (6 to 14 years) with diagnostic of asthma or rhinitis living for more than five years in urban or rural area. A questionnaire with socio-demographic characteristics, pharmacotherapy treatments, was obtained each three months. Atopy evaluation, spirometry and clinical test for asthma and rhinitis severity were done at the beginning and one year later. Results: Eighty six point four percent patients completed the follow up (rural n: 134, urban n: 248). Patients in rural location required less salbutamol (p: 0.01), visit to emergency department (p <0.01) and have a less number of patients with FEV1 <80% (p: 0.05). For clinical control rural children require less pharmacotherapy than urban children (p: 0.01) and more patients with rhinitis (18% vs 8% p: 0.03) and asthma (23% vs 12% p: 0.01) in the rural group could suspended pharmacotherapy. Atopy (p: <0.07) and poli-sensitization (p: <0.08) was a little higher in urban than rural area. We observe that poverty/unhygienic indicators were risk factors for higher levels of specific IgE among patients from urban area. Conclusion: Patients with respiratory allergies located in urban area require more pharmacotherapy and have less clinical response than rural children.

Resumen Introducción: Los estudios epidemiológicos han demostrado que los niños que crecen en las granjas suelen tener menos frecuencia de enfermedades alérgicas. Sin embargo, se sabe menos si el tipo de ambiente (rural vs urbano) también puede influir en la respuesta clínica de a la farmacoterapia. Objetivo: Comparar un grupo de niños localizados en área rural y área urbana de Antioquia, Colombia, en cuanto al tratamiento farmacológico recibido para el asma y/o la rinitis. Métodos: Fueron incluidos niños con asma y/o rinitis que llevaran viviendo al menos 5 años en la misma zona rural o urbana con edades entre 6 a 14 años. A todos los pacientes se les realizó un seguimiento clínico cada 3 a 4 meses. La evaluación de la atopia, la espirometría y test para evaluar la gravedad del asma y la rinitis se realizaron al principio y al final del estudio. Resultados: De los pacientes candidatos, 382 (86.4%) completaron el seguimiento (rural n= 134 urbano n= 248). Los pacientes en área rural requirieron menos salbutamol (p: 0.01), visitas al departamento de emergencias (p <0.01) y tenían un menor número de pacientes con FEV1 <80% (p <0.05). Para el control clínico, los niños en zonas rurales requieren menos farmacoterapia que los niños en zona urbana (p: 0.01). Igualmente, para la rinitis (18% vs 8% p: 0.03) y el asma (23% vs 12% p= 0.01) un mayor número de los pacientes en zona rural pudieron suspender la farmacoterapia. La atopia (p <0.07) y la poli-sensibilización (p <0.08) fue mayor en las zonas urbanas que en las rurales. Se observó que los indicadores de pobreza y los servicios de aseo, eran factores de riesgo para mayores niveles de IgE entre los pacientes de área urbana. Conclusión: Los pacientes con asma o rinitis localizado en el área urbana tienen síntomas más severos y refractarios al tratamiento farmacológico, por lo que requieren más farmacoterapia que los niños rurales. Algunos factores ambientales intra y extra domiciliarios propios de la zona rural y urbana podrían influir en estos resultados.

Síntomas respiratorios asociados a alergia alimentaria / Respiratory symptoms associated with food allergy

In the last years the frequency of allergic diseases has risen in the world; however, their actual prevalence is unknown. In this context, current estimates of clinically relevant food allergy range from 1-3 % in children and adults in the general population. Respiratory symptoms associated with food allergy are described, but they are poorly evaluated by doctors probably because they are little known. This article is a review of the latest information described in the literature regarding this relationship.

La frecuencia de enfermedades alérgicas en el mundo ha aumentado en los últimos años, sin embargo, la prevalencia real de ellas no es conocida, dentro de este contexto la alergia alimentaria con manifestación clínica significativa se estima entre 1-3% en niños y adultos en la población general. Los síntomas respiratorios asociados a esta patología están descritos, pero son poco evaluados por los médicos probablemente debido a que son poco conocidos. Este artículo es una actualización de lo descrito en la literatura en relación a esta asociación.

Imbalance of γδT17/γδTreg cells in the pathogenesis of allergic asthma induced by ovalbumin

We aimed to explore the imbalance between the T helper 17 γδT cells (γδT17) and the regulatory γδT cells (γδTreg) in asthmatic mice. Male Balb/c mice were randomly divided into the normal control group and the asthmatic model group. The asthmatic model group mice were intraperitoneally injected with the mixture of ovalbumin (OVA)/Al(OH)3 and then activated by exposure of the animals to OVA atomization. Airway hyperresponsiveness (AHR) was determined by a non-invasive lung function machine. Hematoxylin and eosin and Alcian blue-periodic acid Schiff staining were done for histopathological analysis. Interleukin (IL)-17 and IL-35 levels in bronchoalveolar lavage fluid were detected by ELISA. The percentage of IL-17+ γδT cells and Foxp3+ γδT cells in spleen cells suspension were detected and the transcription levels of RORγt and Foxp3 in the lung tissue were determined. Compared with the normal control, the severity of airway inflammation and AHR were higher in the asthmatic mice. Furthermore, mice in the asthmatic group displayed significant increases of IL-17+ γδT cells, expression of IL-17A, and RORγt, whereas control mice displayed marked decreases of Foxp3+ γδT cells, expression of IL-35, and transcription factor Foxp3. In addition, the mRNA expression of RORγt was positively correlated with the percentage of IL-17+γδT cells, and the mRNA level of Foxp3 was positively correlated with the percentage of Foxp3+ γδT cells. The imbalance of γδT17/γδTreg in the asthmatic mice may contribute to the pathogenesis of OVA-induced asthma.

Deficiencia de anticuerpos específicos: inmunodeficiencia primaria asociada a alergia respiratoria / Specific antibody deficiency: primary immunodeficiency associated to respiratory allergy

La deficiencia de anticuerpos específicos con inmunoglobulinas séricas y linfocitos B normales (SAD) es una inmunodeficiencia primaria caracterizada por una capacidad alterada de responder a antígenos específicos, especialmente polisacáridos. OBJETIVO: Describir las características clínicas de pacientes con SAD y destacar la asociación entre una inmunodeficiencia primaria y enfermedades alérgicas. Pacientes y Método: Estudio descriptivo en enfermos con SAD atendidos en un hospital público entre agosto de 2007 y julio de 2015. Se descartó otra inmunodeficiencia primaria o secundaria. El diagnóstico se basó en infecciones recurrentes y una respuesta anormal a la vacuna neumocócica polisacárida con medición de IgG específica para 10 serotipos de neumococo. RESULTADOS: Se incluyeron 12 pacientes, 4 varones, con una edad promedio de 6 años; predominaron las neumonías recurrentes (91,7%) y otras infecciones respiratorias e invasivas. Los 12 enfermos con SAD tenían asma asociada; 11, rinitis alérgica y otras alergias. Tres pacientes no respondieron a ninguno de los 10 serotipos contenidos en la vacuna neumocócica polisacárida y la mayoría de los que lo hicieron fue a títulos bajos. El tratamiento con vacuna neumocócica conjugada fue favorable en 11/12 enfermos. CONCLUSIÓN: En niños mayores de 2 años con infecciones respiratorias recurrentes o infecciones invasivas por S. pneumoniae con inmunoglobulinas normales recomendamos investigar SAD, más aún si tienen enfermedad alérgica asociada.

Specific antibody deficiency (SAD) with normal immunoglobulin and normal B cells is a primary immunodeficiency characterized by reduced ability to produce antibodies to specific antigens especially polysaccharides. OBJECTIVE: To describe the characteristics of patients diagnosed with SAD emphasizing the association between primary immunodeficiency and allergic diseases. PATIENTS AND METHOD: Descriptive study showing patients with SAD treated at a public hospital between August 2007 and July 2015. Other secondary or primary immunodeficiency was discarded. The diagnosis of SAD was based on recurrent infections and abnormal response to pneumococcal polysaccharide vaccine assessed by specific IgG to 10 pneumococcal serotypes. Results: Twelve patients were included, 4 males, mean age 6 years, recurrent pneumonia predominated (91.7%) as well as other respiratory and invasive infections. All patients with SAD had associated asthma, 11 had allergic rhinitis, and other allergies. Three patients did not respond to any of the 10 serotypes contained in pneumococcal polysaccharide vaccine, and those who responded were with low titers. Treatment with conjugate pneumococcal vaccine was favorable in 11/12 patients. CONCLUSION: In children older than 2 years with recurrent respiratory infections or invasive S. pneumoniae infections with normal immunoglobulin we recommend to investigate SAD, especially if they have a concurrent allergic disease.

Sublingual immunotherapy in the treatment of allergic asthma: a systematic review with meta-analysis

Introduction: The guidelines for the management of allergic respiratory diseases oriented towards control from medical treatment combined with measures of environmental hygiene. Immunotherapy is one of several types of treatment, applied in combination with prophylactic drugs and environmental care. The aim of the study is to evaluate the efficacy of sublingual immunotherapy (SLIT) for house dust mites (HDM) in people with allergic asthma. Methods: The study is based on a systematic review with meta-analysis of randomized clinical trials, associating sublingual immunotherapy with the treatment of allergic patients with HDM. Results: The searches were applied in PubMed, ScienceDirect and Scielo databases. Initially, 98 articles were recovered, of which only nine were eligible. Of these, eight (88.9%) were conducted in Europe and only one (11.1%) in Asia. Comparing the outcomes expiratory volume in the first minute (FEV1 ) and sensitivity to allergens (HDM) between SLIT and placebo groups before and after intervention, no differences were observed between the groups. Conclusions: SLIT is not evidenced significantly by meta-analysis for the treatment of allergic asthma (AU)

Tangeretin has anti-asthmatic effects via regulating PI3K and Notch signaling and modulating Th1/Th2/Th17 cytokine balance in neonatal asthmatic mice

Asthma is a chronic allergic disease characterized by airway inflammation, airway hyper-responsiveness (AHR), and mucus hypersecretion. T-lymphocytes are involved in the pathogenesis of asthma, mediating airway inflammatory reactions by secreting cytokines. The phosphoinositide 3-kinase (PI3K) and Notch signaling pathways are associated with T cell signaling, proliferation, and differentiation, and are important in the progression of asthma. Thus, compounds that can modulate T cell proliferation and function may be of clinical value. Here, we assessed the effects of tangeretin, a plant-derived flavonoid, in experimental asthma. BALB/c mice at postnatal day (P) 12 were challenged with ovalbumin (OVA). Separate groups of mice (n=18/group) were administered tangeretin at 25 or 50 mg/kg body weight by oral gavage. Dexamethasone was used as a positive control. Tangeretin treatment reduced inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF) and also restored the normal histology of lung tissues. OVA-specific IgE levels in serum and BALF were reduced. AHR, as determined by airway resistance and lung compliance, was normalized. Flow cytometry analyses revealed a reduced Th17 cell population. Tangeretin reduced the levels of Th2 and Th17 cytokines and raised IFN-γ levels. PI3K signaling was inhibited. The expressions of the Notch 1 receptor and its ligands Jagged 1 and 2 were downregulated by tangeretin. Our findings support the possible use of tangeretin for treating allergic asthma.

Staphylococcal superantigen-specific IgE antibodies: degree of sensitization and association with severity of asthma / Anticorpos IgE específicos para superantígenos estafilocócicos: grau de sensibilização e associação com a gravidade da asma

ABSTRACT Objective: To determine the presence of staphylococcal superantigen-specific IgE antibodies and degree of IgE-mediated sensitization, as well as whether or not those are associated with the severity of asthma in adult patients. Methods: This was a cross-sectional study involving outpatients with asthma under treatment at a tertiary care university hospital in the city of Rio de Janeiro, Brazil. Consecutive patients were divided into two groups according to the severity of asthma based on the Global Initiative for Asthma criteria: mild asthma (MA), comprising patients with mild intermittent or persistent asthma; and moderate or severe asthma (MSA). We determined the serum levels of staphylococcal toxin-specific IgE antibodies, comparing the results and performing a statistical analysis. Results: The study included 142 patients: 72 in the MA group (median age = 46 years; 59 females) and 70 in the MSA group (median age = 56 years; 60 females). In the sample as a whole, 62 patients (43.7%) presented positive results for staphylococcal toxin-specific IgE antibodies: staphylococcal enterotoxin A (SEA), in 29 (20.4%); SEB, in 35 (24.6%); SEC, in 33 (23.2%); and toxic shock syndrome toxin (TSST), in 45 (31.7%). The mean serum levels of IgE antibodies to SEA, SEB, SEC, and TSST were 0.96 U/L, 1.09 U/L, 1.21 U/L, and 1.18 U/L, respectively. There were no statistically significant differences between the two groups in terms of the qualitative or quantitative results. Conclusions: Serum IgE antibodies to SEA, SEB, SEC, and TSST were detected in 43.7% of the patients in our sample. However, neither the qualitative nor quantitative results showed a statistically significant association with the clinical severity of asthma.

RESUMO Objetivo: Determinar a presença de anticorpos IgE específicos para superantígenos estafilocócicos e o grau de sensibilização mediada por esses, assim como se esses estão associados à gravidade da asma em pacientes adultos. Métodos: Estudo transversal incluindo asmáticos adultos em acompanhamento ambulatorial em um hospital universitário terciário no Rio de Janeiro (RJ). Os pacientes foram alocados consecutivamente em dois grupos de gravidade da asma segundo critérios da Global Initiative for Asthma: asma leve (AL), com asmáticos leves intermitentes ou persistentes, e asma moderada ou grave (AMG). Foram determinados os níveis séricos de anticorpos IgE antitoxinas estafilocócicas, e os resultados foram comparados por análise estatística. Resultados: Foram incluídos 142 pacientes no estudo: 72 no grupo AL (mediana de idade = 46 anos; 59 do sexo feminino) e 70 do grupo AMG (mediana de idade = 56 anos; 60 do sexo feminino). Na amostra geral, 62 pacientes (43,7%) apresentaram resultados positivos para dosagens de anticorpos IgE antitoxinas estafilocócicas: enterotoxina (TX) A, em 29 (20,4%); TXB, em 35 (24,6%); TXC, em 33 (23,2%); e toxic shock syndrome toxin (TSST), em 45 (31,7%). As médias das dosagens séricas de anticorpos IgE específicos anti-TXA, TXB, TXC e TSST foram, respectivamente, de 0,96 U/l, 1,09 U/l, 1,21 U/l, e 1,18 U/l. Não houve diferença estatisticamente significativa dos resultados qualitativos ou quantitativos entre os grupos. Conclusões: A presença de anticorpos IgE séricos anti-TXA, TXB, TXC e TSST, foi detectada em 43,7% nessa amostra de pacientes, mas não houve associação estatisticamente significativa entre seus resultados qualitativos ou quantitativos e gravidade clínica da asma.

Inflammatory and immunological profiles in patients with COPD: relationship with FEV 1 reversibility / Perfil inflamatório e imunológico em pacientes com DPOC: relação com a reversibilidade do VEF 1

ABSTRACT Objective: To determine whether COPD severity correlates with sputum cell counts, atopy, and asthma. Methods: This was a cross-sectional study involving 37 patients with COPD and 22 healthy subjects with normal lung function (controls). Sputum cell counts were determined by microscopy after centrifugation of samples. Skin prick tests were performed, and serum cytokines were determined by ELISA. Results: Patients were stratified by bronchodilator response: a non-reversible airflow limitation (nonRAL) group comprised 24 patients showing no significant post-bronchodilator change in FEV1; and a partially reversible airflow limitation (partialRAL) group comprised 13 patients showing FEV1 reversibility (post-bronchodilator FEV1 increase ≥ 12%). The proportion of eosinophils in sputum was higher in the partialRAL group than in the nonRAL group (p < 0.01), and there was an inverse correlation between the proportion of eosinophils and FEV1 (p < 0.05). However, none of the patients had a history of asthma and skin prick test results did not differ between the two groups. In the patient sputum samples, neutrophils predominated. Serum levels of TNF, IL-6, IL-8, and RANTES (CCL5) were higher in patients than in controls (p < 0.001) but did not differ between the two patient groups. Conclusions: COPD patients with partial FEV1 reversibility appear to have higher sputum eosinophil counts and greater airway hyperresponsiveness than do those with no FEV1 reversibility. However, we found that COPD severity did not correlate with atopy or with the cytokine profile.

RESUMO Objetivo: Determinar se a gravidade da DPOC se correlaciona com a contagem de células no escarro, atopia e asma. Métodos: Estudo transversal com 37 pacientes com DPOC e 22 indivíduos saudáveis com função pulmonar normal (controles). As contagens de células no escarro foram determinadas por microscopia após a centrifugação das amostras. Foram realizados testes cutâneos de puntura, e as citocinas séricas foram determinadas por ELISA. Resultados: Os pacientes foram estratificados pela resposta ao broncodilatador: o grupo de limitação ao fluxo aéreo não reversível (LFAnr) envolveu 24 pacientes sem alteração significativa do VEF1 pós-broncodilatador, e o grupo de limitação ao fluxo aéreo parcialmente reversível (LFApr) envolveu 13 pacientes com reversibilidade do VEF1 (aumento do VEF1 pós-broncodilatador ≥ 12%). A proporção de eosinófilos no escarro foi maior no grupo LFApr do que no LFAnr (p < 0,01), e houve uma correlação inversa entre a proporção de eosinófilos e VEF1 (p < 0,05). Entretanto, nenhum dos pacientes apresentou histórico de asma e os resultados dos testes cutâneos não diferiram entre os dois grupos. Nas amostras de escarro dos pacientes, os neutrófilos predominaram. Os níveis séricos de TNF, IL-6, IL-8 e RANTES (CCL5) foram maiores nos pacientes que nos controles (p < 0,001), mas não diferiram entre os dois grupos de pacientes. Conclusões: Pacientes com DPOC e reversibilidade parcial do VEF1 parecem apresentar maiores contagens de eosinófilos no escarro e maior hiper-responsividade das vias aéreas que aqueles sem reversibilidade do VEF1. Entretanto, a gravidade da DPOC não se correlacionou com atopia ou perfil das citocinas.

Perfil das células T Natural Killer (NKT)de indivíduos asmáticos desafiadas com antígenos solúvel do ovo de schistosoma mansoni / Natural Killer T cell (NKT) profile of asthmatic individuals challenged with soluble schistosoma mansoni egg antigens

INTRODUÇÃO: A asma é uma doença inflamatória crônica, caracterizada por hiper-reatividade das vias aéreas inferiores e por limitação variável e reversível ao fluxo aéreo. Apresenta manifestações clínicas na forma de sibilância, dispneia, sensação de aperto no peito e tosse, podendo ser considerada como atópica ou não atópica, de acordo com seus aspectos imunopatogênicos. Células do sistema imune, como neutrófilos, macrófagos, células dendríticas e as células T Natural Killer (NKT), apresentam importante papel no desenvolvimento ou regulação da resposta inflamatória da asma. Desta forma é possível que antígenos com propriedades regulatórias, como no caso dos antígenos de ovo do Schistosoma mansoni (SEA), sejam capazes de alterar o perfil destas células e regular a resposta imune da asma. OBJETIVOS: Avaliar a frequência de NKT e expressão de moléculas de ativação e coestimulação, além de citocinas nestas células, em indivíduos com asma. METODOLOGIA: Trata-se de um estudo de corte transversal realizado com 24 voluntários, sendo 14 indivíduos asmáticos e 10 voluntários não asmáticos. Células mononucleares de sangue periférico (PNMC)...

INTRODUCTION: Asthma is a chronic inflammatory disease characterized by hyperreactivity of lower airways and variable limitation and reversible airflow. The main clinical manifestations are wheezing, breathlessness, chest pain that feel like tightness and coughing, being considered as atopic or non-atopic, according to its immunopathogenic aspect. Immune cells, such as neutrophils, macrophages, dendritic cells and Natural Killer T cells (NKT) play an important role in the regulation or development of inflammatory response of asthma. Thus, it is possible that antigens with regulatory properties, such as Schistosoma mansoni soluble egg antigen (SEA), are able to alter the profile of these cells and regulate the immune response of asthma. AIM: To evaluate the frequency of NKT cells, expression of activation and costimulatory markers, as well as cytokine expression in NKT cells from individuals with asthma. METHODOLOGY: This is a cross-sectional study of 24 volunteers, of which 14 were asthmatic and 10 nonasthmatic volunteers. Peripheral blood mononuclear cells (PBMC)...

Sensitization by subcutaneous route is superior to intraperitoneal route in induction of asthma by house dust mite in a murine mode / Sensibilização por via subcutânea é superior à intraperitoneal na indução de asma por ácaro em modelo murino

ABSTRACT Objective To develop a new experimental model of chronic allergic pulmonary disease induced by house dust mite, with marked production of specific immunoglobulin E (IgE), eosinophilic inflammatory infiltrate in the airways and remodeling, comparing two different routes of sensitization. Methods The protocol lasted 30 days. BALB/c mice were divided into six groups and were sensitized subcutaneously or intraperitoneally with saline (negative control), Dermatophagoides pteronyssinus (Der p) 50 or 500mcg in three injections. Subsequently they underwent intranasal challenge with Der p or saline for 7 days and were sacrificed 24 hours after the last challenge. We evaluated the titration of specific IgE anti-Der p, eosinophilic density in peribronchovascular space and airway remodeling. Results Both animals sensitized intraperitoneally and subcutaneously produced specific IgE anti-Der p. Peribronchovascular eosinophilia increased only in mice receiving lower doses of Der p. However, only the group sensitized with Der p 50mcg through subcutaneously route showed significant airway remodeling. Conclusion In this murine model of asthma, both pathways of sensitization led to the production of specific IgE and eosinophilia in the airways. However, only the subcutaneously route was able to induce remodeling. Furthermore, lower doses of Der p used in sensitization were better than higher ones, suggesting immune tolerance. Further studies are required to evaluate the efficacy of this model in the development of bronchial hyperresponsiveness, but it can already be replicated in experiments to create new therapeutic drugs or immunotherapeutic strategies.

RESUMO Objetivo Desenvolver um novo modelo experimental de doença pulmonar alérgica crônica por ácaro, com proeminente produção de imunoglobulina E (IgE) específica, infiltrado inflamatório eosinofílico nas vias aéreas e remodelamento, comparando duas vias diferentes de sensibilização. Métodos O protocolo teve duração de 30 dias. Camundongos BALB/c foram divididos em seis grupos submetidos à sensibilização por via subcutânea ou intraperitoneal com solução salina (controles negativos),Dermatophagoides pteronyssinus (Der p) 50 ou 500mcg, em três aplicações. Posteriormente, foram submetidos à provocação intranasal com Der p ou salina por 7 dias e sacrificados 24 horas após o último desafio. Avaliamos a titulação de IgE específica anti-Der p, densidade eosinofílica no espaço peribroncovascular e remodelamento das vias aéreas. Resultados Tanto os animais sensibilizados por via subcutânea como intraperitoneal produziram IgE específica anti-Der p. Ocorreu aumento da eosinofilia peribroncovascular apenas nos animais que receberam menor dose de Der p. Porém apenas o grupo sensibilizado com Der p 50mcg subcutânea apresentou remodelamento significativo das vias aéreas. Conclusão Neste modelo murino de asma, as duas vias de sensibilização levaram à produção de IgE específica e eosinofilia nas vias aéreas. No entanto, apenas a via subcutânea foi capaz de induzir ao remodelamento. Além disso, doses menores de Der p utilizadas foram superiores às mais elevadas, sugerindo tolerância. Mais estudos são necessários para avaliar a eficácia deste modelo no desenvolvimento da hiperresponsividade brônquica, mas ele pode ser replicado em experimentos para criação de novas estratégias terapêuticas medicamentosas ou imunoterápicas.

Pesticide exposure and health conditions of terrestrial pesticide applicators in Córdoba Province, Argentina / Exposición a plaguicidas y condiciones de salud de agroaplicadores terrestres de la Provincia de Córdoba, Argentina / Exposição aos agrotóxicos e condições de saúde dos aplicadores de pesticidas da Província de Córdoba, Argentina

Agricultural workers represent a population that is highly vulnerable to the toxic effects of pesticide exposure. This cross sectional study aimed to describe the health conditions of terrestrial pesticide applicators in Córdoba Province, Argentina, their work practices and socio-demographic characteristics, by means of a standardized self-administered questionnaire (n = 880). A descriptive analysis reported a high prevalence of occasional or frequent symptoms: 47.4% had symptoms of irritation, 35.5% fatigue, 40.4% headache and 27.6% nervousness or depression. Using logistic regression models, risk and protective factors were found for symptoms of irritation, medical consultation and hospitalization. Among the occupational exposure variables, marital status, length of time in the job, low level of protection with regard to the use of personal protective equipment, combined use of different pesticides and the application of the insecticide endosulfan, were associated with a higher frequency of reported symptoms and higher consultation rates and hospitalization.

Los trabajadores agrícolas son una población altamente vulnerable a los efectos tóxicos de la exposición a plaguicidas. Con el objetivo de describir las condiciones de salud de agroaplicadores terrestres de plaguicidas de la Provincia de Córdoba, Argentina, sus prácticas laborales y características sociodemográficas, se realizó un estudio transversal, mediante cuestionario (n = 880). Un análisis descriptivo reportó alta prevalencia de sintomatología ocasional o frecuente: 47,4% síntomas irritativos, 35,5% cansancio, 40,4% cefalea y 27,6% ansiedad o depresión. Mediante modelos logísticos se detectaron factores protectores y de riesgo que explican la presencia de síntomas irritativos, la consulta médica y la hospitalización. El estado civil, la antigüedad en la tarea, el nivel de protección considerando uso de equipo de protección personal, la exposición múltiple a plaguicidas y la aplicación del insecticida endosulfán, se asociaron a mayor frecuencia de reporte de síntomas, consultas médicas y hospitalizaciones por causas relacionadas con la exposición a plaguicidas.

Os trabalhadores agrícolas são uma população altamente vulnerável aos efeitos tóxicos da exposição a pesticidas. Este estudo transversal teve o objetivo de descrever as condições de saúde de aplicadores terrestres de pesticidas da Província de Córdoba, Argentina, suas práticas de trabalho e características sociodemográficas, por meio de um questionário padronizado autoadministrado (n = 880). A análise descritiva relatou alta prevalência de sintomas ocasionais ou frequentes: 47,4% sintomas irritativos, 35,5% fadiga, 40,4% dor de cabeça e 27,6% ansiedade ou depressão. Mediante modelos logísticos foram detectados os fatores protetores e do risco que explicam a presença de sintomas irritativos, consulta médica e hospitalização. O estado civil, anos de trabalho, o nível de proteção considerando o uso de equipamentos de proteção individual, a exposição a vários pesticidas e aplicação do inseticida endosulfan, foram associados com maior frequência de sintomas, consultas médicas e hospitalização por causas relacionadas à exposição ao agrotóxico.

Determinants of peak VO2 in heart transplant recipients / Determinantes do pico de VO2 em transplantados cardíacos

Objective: To establish the determinants of the peak VO2 in heart transplant recipients. Methods: Patient's assessment was performed in two consecutive days. In the first day, patients performed the heart rate variability assessment followed by a cardiopulmonary exercise test. In the second day, patients performed a resting echocardiography. Heart transplant recipients were eligible if they were in a stable condition and without any evidence of tissue rejection diagnosed by endomyocardial biopsy. Patients with pacemaker, noncardiovascular functional limitations such as osteoarthritis and chronic obstructive pulmonary disease were excluded from this study. Results: Sixty patients (68% male, 48 years and 64 months following heart transplantation) were assessed. Multivariate analysis selected the following variables: receptor's gender (P=0.001), receptor age (P=0.049), receptor Body Mass Index (P=0.005), heart rate reserve (P <0.0001), left atrium diameter (P=0.016). Multivariate analysis showed r=0.77 and r2=0.6 with P <0.001. Equation: peakVO2=32.851 - 3.708 (receptor gender) - 0.067 (receptor age) - 0.318 (receptor BMI) + 0.145 (heart rate reserve) - 0.111 (left atrium diameter). Conclusion: The determinants of the peak VO2 in heart transplant recipients were: receptor sex, age, Body Mass Index, heart rate reserve and left atrium diameter. Heart rate reserve was the unique variable positively associated with peak VO2. This data suggest the importance of the sympathetic reinnervation in peak VO2 in heart transplant recipients. .

Objetivo: Estabelecer os determinantes do VO2 pico em transplantados de coração. Métodos: Avaliação do paciente foi realizada em dois dias consecutivos. No primeiro dia, os pacientes realizaram a avaliação da variabilidade da frequência cardíaca seguida de um teste de esforço cardiopulmonar. No segundo dia, os pacientes realizaram ecocardiografia de repouso. Os transplantados foram elegíveis se estivessem em uma condição estável e sem qualquer evidência de rejeição diagnosticada por biópsia endomiocárdica. Pacientes com marca-passo, limitações funcionais não cardiovasculares, tais como osteoartrite e doença pulmonar obstrutiva crônica foram excluídos deste estudo. Resultados: Sessenta pacientes (68% do sexo masculino, 48 anos e 64 meses após o transplante cardíaco) foram avaliados. A análise multivariada selecionou as seguintes variáveis: sexo (P=0,001), idade (P=0,049), Índice de Massa Corporal (P=0,005), frequência cardíaca de reserva (P <0,0001), diâmetro do átrio esquerdo (P=0,016), variáveis do receptor. A análise multivariada mostrou r=0,77 e r2=0,6, com P <0,001. Equação: VO2=32,851 - 3,708 (sexo receptor) - 0,067 (idade receptor) - 0,318 (IMC receptor) + 0,145 (frequência cardíaca de reserva) - 0,111 (diâmetro de átrio esquerdo). Conclusão: Os determinantes do pico de VO2 em transplantados de coração foram: sexo receptor, idade, Índice de Massa Corporal, frequência cardíaca de reserva e diâmetro do átrio esquerdo. A frequência cardíaca de reserva foi a única variável positivamente associada com o pico de VO2. Estes dados sugerem a importância da reinervação simpática no pico de VO2 em transplantados de coração. .

Implicancia de la inmunidad innata del epitelio bronquiolar en la modulación y prevención del asma / Implication of innate immunity in modulating bronchial epithelium and prevention of asthma

El asma alérgica ha incrementado su prevalencia, constituyéndose como un problema mundial de salud. Factores ambientales derivados de la vida moderna han sido vinculados a este fenómeno a través de la hipótesis de la higiene; la cual postula que la vida urbana disminuye la potenciación de la inmunidad innata, lograda a través del reconocimiento de estímulos microbianos por los receptores Toll-like (TLRs), conduciendo a la mayor prevalencia de respuestas alérgicas. Las investigaciones en asma en el último siglo han tenido como objetivo la disminución de la respuesta inmune adaptativa Th2 asociada a las alergias; sin embargo han conseguido escasos avances terapéuticos. Actualmente, es creciente el número de evidencias que implican a los componentes estructurales de la vía aérea en el inicio y progresión del asma; no obstante su rol en la prevención de la inflamación alérgica no ha sido suficientemente evaluado. Por lo tanto, el presente trabajo de Tesis Doctoral tuvo como objetivo general el estudio de la interacción de la inmunidad innata del epitelio bronquiolar y la inflamación alérgica del asma.

ABSTRACT: Recently, asthma rates have increased becoming a global health problem. The role of environmental factors in this increase, due to modern lifestyles, has been suggested by the hygiene hypothesis, which postulated that the urban hygienic conditions skip the early exposure to microbes hence that are clue to promote innate immune activation by signalling through the Toll-like receptors (TLRs) and thus preventing the allergic responses. Even though many investigations on asthma have been focused on the reduction of the allergic Th2-nflammatory response in the last century, the therapeutic advances have been scarce. Nowadays, there is increasing evidence of the involvement of the airway epithelial cells on the origin and progression of asthma. However, the role of these cells in preventing the triggering of allergic inflammation has not been evaluated. Therefore, the main objective of this thesis was to study the interaction of innate immunity of bronchiolar epithelium and allergic inflammation in asthma.

Padrão alimentar, asma e sibilo atópico e não atópico em crianças e adolescentes: estudo SCAALA, Salvador, Bahia, Brasil / Dietary pattern, asthma, and atopic and non-atopic wheezing in children and adolescents: SCAALA study, Salvador, Bahia State, Brazil / Patrón dietético, asma y sibilancias atópicas y no atópicas en niños y adolescentes: estudio SCAALA, Salvador, Bahía, Brasil

Avaliou-se, em estudo transversal, a influência do padrão alimentar sobre a ocorrência de sibilo e asma atópica e não atópica em 1.168 crianças e adolescentes em Salvador, Bahia, Brasil. Sibilo e sintomas de asma nos últimos 12 meses foram obtidos por meio do questionário ISAAC. Atopia foi definida pela presença de IgE específica a aerolérgenos. Questionário de frequência alimentar foi usado para definir padrões alimentares. Empregou-se regressões logística e logística politômica multivariadas. O consumo de pescados reduziu a ocorrência de sibilo em 27% (IC95%: 0,56-0,94) e asma em 37% (IC95%: 0,47-0,83); asma não atópica em 51% (IC95%: 0,31-0,79) e sibilo não atópico em 38% (IC95%: 0,46-0,83). O maior tercil do padrão alimentar reduziu o sibilo em 27% (IC95%: 0,57-0,95), sibilo atópico em 46% (IC95%: 0,30-0,98), asma em 36% (IC95%: 0,49-0,83) e asma atópica em 50% (IC95%: 0,28-0,89). O consumo de pescados pode conferir efeito protetor para sibilo e asma não atópica e o padrão alimentar para sibilo e asma atópica.

A cross-sectional study was conducted on dietary patterns and their influence on the occurrence of wheezing and atopic and non-atopic asthma in a sample of 1,168 children and adolescents in Salvador, Bahia State, Brazil. Wheezing and asthma symptoms in the previous 12 months were obtained using the ISAAC questionnaire. The presence of aeroallergen-specific IgE was identified. A food frequency questionnaire was used to define dietary patterns. The study applied logistic regression and multinomial polytomous logistic regression. Fish consumption was associated with a 27% reduction in wheezing (95%CI: 0.56-0.94), 37% in asthma (95%CI: 0.47-0.83), 51% in non-atopic asthma (95%CI: 0.31-0.79), and 38% in non-atopic wheezing (95%CI: 0.46-0.83). The highest tertile of dietary patterns reduced wheezing by 27% (95%CI: 0.57-0.95), atopic wheezing by 46% (95%CI: 0.30-0.98), asthma by 36% (95%CI: 0.49-0.83), and atopic asthma by 50% (95%CI: 0.28-0.89). Fish consumption may thus have a protective effect against wheezing and non-atopic asthma and dietary pattern against atopic asthma and wheezing.

Este estudio transversal se llevó a cabo para estudiar la influencia de los hábitos alimentarios en la aparición del asma y sibilancias atópicas y no atópicas en una muestra de 1.168 niños y adolescentes en Salvador, Bahía, Brasil. Las sibilancias y síntomas de asma en los últimos 12 meses se han obtenido a partir del cuestionario ISAAC. Se identificó la presencia de IgE específica de alérgeno aéreo. Se utilizó un cuestionario de frecuencia de alimentos para definir hábitos alimentarios. Se aplicó la regresión logística y el modelo logístico multinomial. El consumo de pescado redujo las sibilancias en un 27% (IC95%: 0,56-0,94) y el asma en un 37% (IC95%: 0,47-0,83), las sibilancias atópicas en un 51% (IC95%: 0,31-0,79) y no atópicas en un 38% (IC95%: 0,46-0,83). El tercil más alto de los hábitos alimentarios reduce sibilancias en un 27% (IC95%: 0,57-0,95), sibilancias atópicas en un 46% (IC95%: 0,30-0,98), el asma en un 36% (IC95%: 0,49-0,83) y un 50% en el asma atópico (IC95%: 0,28-0,89). El consumo de pescado puede promover un efecto protector, dentro el patrón de dieta, contra sibilancias atópicas y no atópicas y asma.