Relationship between Asthma, Malocclusion and Mouth Breathing in Primary Health Care Children

Objective: To assess the relationship between asthma, malocclusion and mouth breathing. Material and Methods: This investigation was a cross-sectional study of 228 children between 6 and 12 years of age, of whom 112 were asthmatic and 116 were not, performed in two Primary Health Units of Porto Alegre, Brazil. The assessment consisted of a mouth exam performed by two calibrated dentists, an interview with parents/caregivers and medical chart data. Mouth breathing was determined through oral-facial changes related to Mouth Breathing Syndrome. Occlusion was assessed according to Angle's Classification for permanent or mixed teeth and regarding primary teeth were based on the canine relationships. The data were assessed by the Chi-square test and Poisson regression, with robust variation, at a p<0.05 significant level. Results: Asthma [PR = 2.12 (95% CI: 1.46-3.08), p<0.001] and the use of pacifiers [PR = 1.98 (95% CI: 1.27-3.07), p<0.001] were associated with mouth breathing, in the final multivariate model. Age [PR = 1.02 (95% CI: 1.00-1.03), p=0.039] and thumb sucking [PR = 1.08 (95% CI: 1.03-1.13), p=0.001] were associated with malocclusion in the final multivariate model, while there was no relationship between asthma and malocclusion (PR = 1.00; 95% CI: 0.94-1.07). Conclusion: This study provides evidence of the relationship between asthma and mouth breathing in children, demonstrating that knowledge regarding the oral health of populations with chronic diseases is fundamental for developing health programmes suitable to their needs and risks.

Chitosan and carboxymethylated derivative nanoparticles as delivery systems for biological products: preparation, characterization, stability and in vitro/in vivo evaluation / Nanopartículas de quitosana e derivado carboximetilado como sistemas de fornecimento (delivery) de produtos biológicos: preparo, caracterização, estabilidade e avaliação in vitro/in vivo

Chitosan is a biocompatible and biodegradable mucoadhesive polymer with unique advantages, such as the distinct trait of opening the junctions to allow paracellular transport of antigen and good tolerability. However, the poor solubility of chitosan in neutral or alkalinized media has restricted its applications in the pharmaceutical field. Chitosan can be easily carboxymethylated to improve its solubility in aqueous media, while its biodegradability and biocompatibility are preserved. Apart from this, carboxymethyl chitosan (CMCS) can be easily processed into nanoparticles which highlight its suitability and extensive usage for preparing different drug delivery formulations. The present study deals with the development and characterization of a delivery system based on CMCS nanoparticles using ovalbumin as model protein. We demonstrated that ovalbumin loaded nanoparticles were successfully synthetized using calcium chloride as a cross-linker by ionic gelation. The nanoparticles exhibited an average size of approximately 169 nm and presented a pseudo-spherical shape. The nanoparticles size increased according to the addition of CaCl2 due to the strong electrostatic attraction. During storage the nanoparticles size increased was attributed to swelling and aggregation. The loading efficiency of ovalbumin was found to be 17%. Confocal microscopy clearly showed the association between ovalbumin and CMCS chains into nanoparticles. Therefore, we suggest these nanoparticles can be considered as an attractive and promising carrier candidate for proteins and antigens. The major challenge that limits the use of such carriers is their instability in an aqueous medium. Thus, the next step of this work was to determine the robustness of several formulations using distinct freeze-drying protocols. This study demonstrated that mannitol in concentration of 10% (w/v) is well suited to preserve ovalbumin loaded CMCS nanocapsules from aggregation during lyophilization and subsequent reconstitution. Importantly, the results showed that an annealing step has a huge impact on porosity of freeze-dried cake by nearly complete crystallization of mannitol, once the crystalline matrix prevents the partial collapse and the formation of larger pores observed without annealing. Therefore, the usual observation that annealing increases the pore size due to growth of ice crystal size does not always apply, at least when crystallization of solute is involved. Since all characterizations and stability studies had been performed, the main purpose of this study was to develop a stable antigen delivery system for oral immunization using CMCS and inactivated rabies virus (RV) as the antigen. RV loaded nanoparticles was found to enhance both systemic (IgG) and local (IgA) immune responses against RV after oral delivery in mice. The effective doses 50% were 50-times higher than the negative controls, indicating that the immune response started only after the third boosting dose. Furthermore, enough neutralizing antibodies was produced to be protected against the harmful effects of the rabies virus. It is therefore concluded, that the CMCS nanoparticles formulated in this study, are suitable for oral vaccine delivery, and can be suggested as a promising delivery system for a diverse range of antigens as well as a gene/protein delivery system, especially for those positively charged. Since several approaches show that effective intervention in airway allergic inflammation can be achieved with allergen-activated interleukin-10-secreting cells, the final part of this work was dedicated to assessing whether IL-10 loaded chitosan nanoparticles (IL10-CSNPs) could be used as a possible inhalable therapeutic tool for preventing exacerbations in asthmatic patients. As positive controls, we also assess whether interleukin 17A and interleukin 9 have the ability to stimulate human airway smooth muscle (HASM) cell contractility using magnetic twisting cytometry (MTC). Significant decreased baseline cell stiffness was observed in HASM cells pre-treated with IL-10, but not with IL10-CSNPs, whereas treatment with IL-17A significantly enhanced baseline cell stiffening. Our findings reveal a previously unknown mechanism underlying immunotherapy for prevention and treatment of asthma

A quitosana é um polímero mucoadesivo biocompatível e biodegradável, com vantagens únicas, tais como a característica distinta de abrir as junções que permitim o transporte paracelular de antígenos e boa tolerabilidade. No entanto, sua baixa solubilidade em meios neutros ou alcalinizados tem restringido suas aplicações no campo farmacêutico. A quitosana pode ser facilmente carboximetilada para melhorar de sua solubilidade em meios aquosos, enquanto sua biodegradabilidade e biocompatibilidade são preservadas. Além disso, a carboximetilquitosana (CMCS) pode ser facilmente processada na forma de nanopartículas, o que destaca sua adequabilidade para uso extensivo no preparo de sistemas de delivery de medicamentos. O presente estudo trata do desenvolvimento e caracterização de um sistema de delivery baseado em nanopartículas de CMCS utilizando ovalbumina como proteína modelo. Nós demonstramos que as nanopartículas carregadas com ovalbumina foram sintetizadas com sucesso utilizando cloreto de cálcio como agente de reticulação por gelificação iônica. As nanopartículas exibiram um tamanho médio de aproximadamente 169 nm e apresentaram uma forma pseudo-esférica. O tamanho das nanopartículas aumentou de acordo com a adição de CaCl2 devido à forte atração eletrostática. Durante o armazenamento, o tamanho aumentado das nanopartículas foi atribuído a incorporação de água e agregação. A eficiência de encapsulamento da ovalbumina foi de aproximadamente 17%. A microscopia confocal mostrou claramente a associação entre ovalbumina e a cadeias de CMCS nas nanopartículas. Sugerimos, portanto, que tal sistema pode ser considerado como candidato atraente e promissor para o carreamento de proteínas e antígenos. O principal desafio que limita o uso desses carreadores consiste na instabilidade em meio aquoso. Assim, o próximo passo deste trabalho foi determinar a robustez de várias formulações utilizandose diferentes protocolos de liofilização. Este estudo demonstrou que o manitol em uma concentração de 10% (p/v) é adequado para preservar da agregação as nanocápsulas de CMCS carregadas com ovalbumina durante a liofilização e subsequente reconstituição. Mais importante, os resultados mostraram que uma etapa de annealing tem um enorme impacto sobre a porosidade da amostra liofilizada devido a quase completa cristalização do manitol, uma vez que a matriz cristalina evita o colapso parcial e a formação de poros maiores observados na ausência do annealing. Portanto, a observação comum de que o annealing aumenta o tamanho doporos devido ao crescimento dos cristais de gelo nem sempre se aplica, pelo menos quando a cristalização de um soluto está envolvida. Uma vez que todas as caracterizações e estudos de estabilidade foram realizados, o principal objetivo deste estudo foi desenvolver um sistema estável de delivery de antígeno para imunização oral utilizando CMCS e vírus rábico inativado (RV) como antígeno. Verificou-se que as nanopartículas carregadas com RV aumentam as respostas imune sistêmica (IgG) e local (IgA) contra o RV após administração oral em camundongos. As doses efetivas 50% foram 50 vezes maiores que os controles negativos, indicando que a resposta imune foi iniciada apenas após a terceira dose da vacina. Além disso, foram produzidos anticorpos neutralizantes suficientes para proteção contra os efeitos nocivos do vírus rábico. Conclui-se, portanto, que as nanopartículas de CMCS formuladas neste estudo, são adequadas para o delivery oral de vacinas, e podem ser sugeridas como um sistema promissor de delivery para uma gama diversa de antígenos, bem como para o delivery de genes/proteínas, especialmente para aqueles carregados positivamente. Uma vez que diversas abordagens mostram que uma intervenção efetiva em casos de inflamação alérgica de vias aéreas pode ser conseguida por meio de células secretoras de interleucina 10 (IL-10) mediante ativação por alergenos, a parte final deste trabalho esteve dedicada a avaliação de nanopartículas de quitosana carregadas com IL-10 (IL10-CSNPs) como possível ferramenta terapêutica inalável para prevenção de exacerbações em pacientes asmáticos. Como controles positivos, avaliou-se adicionalmente se as interleucinas 17A (IL-17A) e 9 (IL-9) possuem a capacidade de estimular a contratilidade de células humanas de músculo liso de vias aéreas humanas (HASM) por meio de citometria de torção magnética (MTC). Uma diminuição significativa da rigidez celular basal foi observada em células HASM pré-tratadas com IL-10, mas não com IL10-CSNPs, enquanto que o tratamento com IL-17A aumentou significativamente a magnitude rigidez celular basal. Nossos resultados revelam um mecanismo previamente desconhecido subjacente à imunoterapia para prevenção e tratamento da asma

Vitamin D3 levels and NLRP3 expression in murine models of obese asthma: association with asthma outcomes

Vitamin D (25(OH)D3) is an essential nutrient that plays a role in the immune system. Serum 25(OH)D3 is found to be associated with asthma. However, the role of vitamin D in obese asthma remains unclear. Therefore, we investigated the association between vitamin D levels and asthma outcomes in a murine model of obese asthma. We also evaluated NLRP3 inflammasome activity in the pathogenesis of obese asthma. We divided 20 male Balb/c mice (3-4 weeks old) into 4 groups: normal control, asthma, obese, and obese asthma and developed an obese asthma mouse model. Airway hyperreactivity, cytokine concentrations, 25(OH)D3 levels, NLRP3 mRNA and IL-1β mRNA expressions were measured. Lung histology and bronchoalveolar lavage fluid (BALF) cell count were also determined. Obese asthma mice showed a significant increase in airway hyper-responsiveness, airway inflammation, pro-inflammatory cytokine levels and NLRP3 mRNA, IL-1β mRNA expression. Both asthma and obese groups had lower 25(OH)D3 levels. Vitamin D levels in obese asthma were the lowest among all groups. Vitamin D levels correlated negatively with body weight, lung resistance levels at 25 mg/mL of methacholine, total inflammatory cells, and IL-1β and IL-17 concentrations in BALF. These data demonstrated an association between serum vitamin D levels and outcomes of obese asthma, and indicated that NLRP3 inflammasome may play a role in this disorder.

Cutaneous manifestations of Churg-Strauss syndrome: key to diagnosis

Abstract Churg-Strauss syndrome is a rare systemic vasculitis characterized by asthma and other allergy symptoms as well as eosinophilia and necrotizing vasculitis involving small and medium-sized vessels. Its prevalence in the general population ranges from 1-3 cases per million a year, varying according to the population studied. The authors describe a case of a female patient affected by the disease with important systemic manifestations and not very florid skin lesions.

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)...

Effects of Educational Interventions for Chronic Airway Disease on Primary Care

Education has been known to essential for management of chronic airway diseases. However the real benefits remain unclear. We evaluated the effectiveness of an organized educational intervention for chronic airway diseases directed at primary care physicians and patients. The intervention was a 1-month education program of three visits, during which subjects were taught about their disease, an action plan in acute exacerbation and inhaler technique. Asthma control tests (ACT) for asthma and, chronic obstructive pulmonary disease (COPD) assessment tests (CAT) for COPD subjects were compared before and after education as an index of quality of life. Educational effectiveness was also measured associated with improvement of their knowledge for chronic airway disease itself, proper use of inhaler technique, and satisfaction of the subjects and clinicians before and after education. Among the 285 participants, 60.7% (n = 173) were men and the mean age was 62.2 ± 14.7. ACT for asthma and CAT in COPD patients were significantly improved by 49.7% (n = 79) and 51.2% (n = 65) more than MCID respectively after education (P < 0.05). In all individual items, knowledge about their disease, inhaler use and satisfaction of the patients and clinicians were also improved after education (P < 0.05). This study demonstrates the well-organized education program for primary care physicians and patients is a crucial process for management of chronic airway diseases.

Influence of Asthma on the Longitudinal Trajectories of Cigarette Use Behaviors From Adolescence to Adulthood Using Latent Growth Curve Models / 예방의학회지

OBJECTIVES: While epidemiologic research indicates that the prevalence of risk-taking behaviors including cigarette smoking among young people with asthma is substantial, the longitudinal patterns of cigarette smoking in this vulnerable population have received little attention. The aim of this study was to evaluate differences in the longitudinal trajectories of cigarette use behaviors from adolescence to adulthood between young people with and without asthma. METHODS: Data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) during the years 1994 to 1995 (Wave I, adolescence), 2001 to 2002 (Wave III, young adulthood), and 2007 to 2008 (Wave IV, adulthood) were analyzed (n=12 244). Latent growth curve models were used to examine the longitudinal trajectories of cigarette use behaviors during the transition to adulthood according to asthma status. RESULTS: Regardless of asthma status, the trajectory means of cigarette use behaviors were found to increase, and then slightly decrease from adolescence to adulthood. In total participants, there were no statistically significant differences in initial levels and changes in cigarette use behaviors according to asthma status. However, in select sex and race subgroups (i.e., females and non-whites), former asthmatics showed greater escalation in cigarette use behaviors than did non-asthmatics or current asthmatics. CONCLUSIONS: This study indicated that the changing patterns of cigarette use behaviors during the transition to adulthood among young people with asthma are comparable to or even more drastic than those among young people without asthma.

Asma agudo severo en niños: ¿fenotipo diferente? / Severe asthma in children: a different phenotype?

Background: The magnitude of response to treatment of asthma exacerbations is variable and a significant proportion of them need hospitalization. Objectives: to define the profile of children that were hospitalized for severe asthma and the possible indicators and determinants of their poor responsiveness. Methods: a prospective study in 60 children 4 years or more of age with a search of the ethiology of the exacerbation and a study of the inflammatory profile in sputum. Results: 60 children between 4 and 15 years. 50 percent had a previous diagnosis of asthma without regular use of inhaled corticosteroids in two thirds. 40 percent had previous admissions for asthma. Etiology of the exacerbation was identified in 52 percent with Rhinovirus, human Metapneumovirus, RSV and Mycoplasma pneumoniae as the most frequent agents. Inflammatory profile was determined in 33 children: eosinophilic in 36 percent, eosinophilic/ neutrophilic in 64 percent. Conclusions: Severe asthma with serious exacerbations may be a phenotype whose outstanding aspects in this cohort were: previous hospitalizations, lack of prophylactic treatment, viral infections as frequent trigger, and combined inflammatory cell profile in sputum.

La magnitud de la respuesta al tratamiento de una exacerbación de asma es variable entre los pacientes y una proporción significativa de ellos debe hospitalizarse. Objetivos: Definir el perfil de los niños que se hospitalizaron por asma grave y los posibles indicadores y determinantes de la respuesta desfavorable al tratamiento. Método: Estudio prospectivo en niños de 4 años o más, con búsqueda etiológica de la exacerbación y estudio de perfil inflamatorio en esputo. Resultados: 60 niños entre 4 y 15 años. El 50 por ciento tenía diagnóstico previo de asma sin uso regular de corticoesteroides inhalados en dos tercios. Hospitalizaciones previas por asma en el 40 por ciento. La etiología de la exacerbación fue identificada en el 52 por ciento siendo los agentes más frecuentes Rhinovirus, Metapneumovius, VRS y Mycoplasma pneumoniae. El perfil inflamatorio fue determinado en 33 niños: eosinofílico en 36 por ciento y eosinoflico/neutroflico en 64 por ciento. Comentario: El asma severa con exacerbaciones graves sería un fenotipo cuyos aspectos destacados en esta cohorte serían: niños con hospitalizaciones previas, falta de tratamiento profiláctico, infección viral como desencadenante frecuente, patrón inflamatorio combinado del esputo y rinitis atópica.

Proposta de um modelo murino de curta duração de resposta pulmonar alérgica aguda sem utilização de adjuvante / Proposed short-term model of acute allergic response, without adjuvant use, in the lungs of mice

OBJETIVO: Determinar se um protocolo curto de sensibilização com ovalbumina subcutânea, sem adjuvante, induziria uma resposta pulmonar eosinofílica em pulmões de camundongos similar àquela encontrada em protocolos previamente estabelecidos. MÉTODOS: Fêmeas adultas de camundongos BALB/c foram randomizadas e divididas em grupos de acordo com o número de sensibilizações com ovalbumina e o número/dosagem de provocação intranasal. O protocolo curto (10 dias) consistiu de uma sensibilização e três provocações com ovalbumina (100 µg). A contagem total e diferencial de células no lavado broncoalveolar, o nível de peroxidase eosinofílica no tecido pulmonar e o exame histopatológico dos pulmões foram realizados 24 h após a última provocação. RESULTADOS: Não houve diferenças significativas entre os grupos em relação às variáveis estudadas. O protocolo curto, assim como os outros protocolos estudados, induziu uma resposta eosinofílica pulmonar semelhante àquela do grupo controle positivo. CONCLUSÕES: A sensibilização por ovalbumina subcutânea sem o uso de adjuvante resultou em uma significativa resposta pulmonar alérgica em ratos, mesmo no grupo de protocolo curto. Nossos achados sugerem que esse protocolo curto pode ser utilizado como teste pré-clínico de primeira linha para a pesquisa de novos fármacos, reduzindo custos e o tempo de observação.

OBJECTIVE: To determine whether a short-term protocol using subcutaneous sensitization with ovalbumin, without the use of adjuvants, would induce an eosinophilic response in the lungs of mice similar to that observed in previous, well-established protocols. METHODS: Adult female BALB/c mice were randomized and divided into groups according to the number of sensitizations with ovalbumin and the number/dosage of intranasal ovalbumin challenges. The short-term protocol (10 days) consisted of one sensitization with ovalbumin and three ovalbumin challenges (100 µg). Total and differential cell counts in BAL fluid, levels of eosinophil peroxidase in lung tissue, and histopathological examination of the lungs were performed 24 h after the last ovalbumin challenge. RESULTS: No significant differences were found among the groups regarding the variables studied. The short-term protocol, as well as the other protocols studied, induced an eosinophilic response similar to that obtained in the positive control. CONCLUSIONS: Subcutaneous sensitization with ovalbumin and without the use of adjuvants resulted in a significant allergic response in the lungs of mice, even in the short-term protocol group. Our findings suggest that this short-term protocol can be used as a first-line pre-clinical test for the study of new medications, reducing the costs and observation periods.

Bone mineral density in asthmatic patients on inhaled corticosteroids in a developing country

Prolonged use of oral corticosteroids is a risk factor for osteoporosis. However, the effect of inhaled corticosteroids [ICS] on bone mineral density [BMD] of asthmatic patients remains controversial. We aimed to determine the prevalence of osteopenia and osteoporosis in our patients with asthma receiving ICSs for more than one year compared with patients who did not have asthma and to determine the risk factors for osteopenia and osteoporosis among the asthmatic patients. This was a cross-sectional study conducted from August 2007 to July 2009. Asthmatic patients aged 18 years and older who had been on ICS for at least one year and a control group of subjects not on ICS were included. BMD was measured using DEXA [dual energy X-ray absorptiometry] scan. The WHO classification of T-scores for osteopenia and osteoporosis were used. A total of 143 subjects were recruited [69 asthmatics and 74 control subjects]. T-scores of the spine, femur, and hip of the asthmatics vs the control subjects were mean, -0.72 vs -0.57 [P=0.98]; median, -0.60 vs -0.80 [P=0.474]; and mean, 0.19 vs 0.06 [P=0.275]; respectively. T-scores of the spine, femur, and hip showed significant negative correlation with age and significant positive correlation with body mass index [BMI]. The risk factors for osteoporosis and osteopenia among asthmatic patients were older age and lower BMI, but not the cumulative dose of ICS. Asthmatic patients on ICS have no added risk of osteoporosis or osteopenia as compared with non-asthmatic subjects

Asthma pathogenesis / Patogênese da asma

A asma resulta de uma interação complexa entre genes e meio ambiente que leva à tríade característica de obstrução variável do fluxo aéreo, hiper-responsividade e inflamação da via aérea. Estímulos ambientais, como alérgenos e vírus, agindo em estágios críticos do desenvolvimento, promovem o início e a progressão da doença em pessoas geneticamente suscetíveis. O epitélio, ao interagir com estímulos ambientais e sinalizar para o mesênquima subjacente, direciona para o remodelamento da via aérea. Interações complexas entre subclasses de células T CD4+ efetoras, incluindo as tradicionais Th2 e as mais recentemente descobertas Th9 e Th17, células imunes e estruturais, desencadeiam inflamação e remodelamento da via aérea e são cruciais para a compreensão dos diversos fenótipos de asma. Novos fenótipos, como o de obesidade, podem ajudar a esclarecer mecanismos patogenéticos recentemente descritos na asma. A patogênese de fenótipos distintos de asma está começando a ser descoberta; esse esclarecimento será crucial para a compreensão dessa doença complexa. O desenvolvimento de uma abordagem biológica e sistemática, integrando biologia molecular e características clínicas, poderá levar a definição de alvos terapêuticos, especialmente na asma grave, e também avançar em busca de um tratamento personalizado na asma.

Asthma as a cause of death / Asma como causa de morte

Mortes causadas por asma são incomuns, mas, mesmo assim, respondem por cerca de 287.000 óbitos anuais mundialmente. Embora as taxas de mortalidade por asma venham diminuindo em diversos países, há grande disparidade na mortalidade por asma no mundo. A maior parte das mortes está relacionada ao manejo clinico subótimo. Fatores frequentemente envolvidos com asma quase fatal e fatal incluem história prévia de crises quase fatais, intubação/ventilação mecânica prévia, hospitalização ou admissão em UTI, falta de adesão ao tratamento, percepção falha de dispneia, distúrbios psicológicos e nível socioeconômico baixo. Na autópsia, os pulmões de pacientes que morreram de asma estão geralmente hiperinflados e os brônquios maiores e menores ocluídos por muco. Os achados histológicos incluem descolamento epitelial, espessamento da lâmina reticularis da membrana basal, glândulas submucosas e músculo liso aumentados e composição alterada da matriz extracelular nas vias aéreas grandes e pequenas. A inflamação brônquica é generalizada, sendo proeminente na camada adventícia das pequenas vias. Os mecanismos que levam à morte na asma não estão claros. O espasmo potente da musculatura lisa e a produção excessivade muco parecem ser os eventos chave que culminam em morte. Uma exacerbação aguda pode ser mortal em pacientes com asma mal controlada e subtratada e que tenham alterações estruturais nas vias aéreas pré-existentes

The diagnosis of asthma / O diagnóstico da asma

O diagnóstico de asma — como exposto em diversas diretrizes nacionais — é fundamentado na história clínica e corroborado pelo exame clínico e pela função pulmonar, que demonstra obstrução ao fluxo aéreo, reversível espontaneamente ou após o uso de broncodilatador ou corticosteroide. Diversos diagnósticos diferenciais devem ser cuidadosamente excluídos na avaliação clínica — incluindo bronquiolite viral na infância e DPOC nos adultos. Neste artigo, consideramos que o diagnóstico de asma deve agora avançar com o reconhecimento de que a asma é uma síndrome clínica heterogênea (casos individuais têm evolução e resposta ao tratamento diversos).Recomendamos que a broncoscopia e a biópsia brônquica devam participar do processo diagnóstico nos casos de pacientes que seguem o tratamento e, mesmo assim, não obtêm o controle da asma com doses moderadas de corticosteroides inalatórios. Desse modo, uma melhor caracterização da alteração clínica do paciente será obtida, visando o uso de terapias alternativas (disponíveis ou ainda a serem desenvolvidas)

Quercetin: a flavonoid with the potential to treat asthma

Allergic asthma is a complex inflammatory disorder characterized by airway hyperresponsiveness, eosinophilic inflammation and hypersecretion of mucus. Current therapies include β2-agonists, cysteinyl leukotriene receptor 1 antagonists and corticosteroids. Although these drugs demonstrate beneficial effects, their adverse side effects limit their long-term use. Thus, the development of new compounds with similar therapeutic activities and reduced side effects is both desirable and necessary. Natural compounds are used in some current therapies, as plant-derived metabolites can relieve disease symptoms in the same manner as allopathic medicines. Quercetin is a flavonoid that is naturally found in many fruits and vegetables and has been shown to exert multiple biological effects in experimental models, including the reduction of major symptoms of asthma: bronchial hyperactivity, mucus production and airway inflammation. In this review, we discuss results from the literature that illustrate the potential of quercetin to treat asthma and its exacerbations.

A asma alérgica é uma doença inflamatória complexa caracterizada por hiperresponsividade das vias aéreas, inflamação eosinofílica e hipersecreção de muco. As terapias atuais incluem β2-agonistas, antagonistas do receptor 1 de cisteinil leucotrienos e corticosteróides. Embora estes fármacos demonstrem efeitos benéficos, seus efeitos adversos limitam seus usos a longo prazo. Assim, o desenvolvimento de novos compostos com atividades terapêuticas similares e reduzido efeitos adversos é tanto desejável quanto necessário. Compostos naturais podem ser utilizados nas terapias atuais, uma vez que metabólitos derivados de plantas são capazes de aliviar os sintomas de forma comparável aos medicamentos alopáticos. A quercetina é um flavonóide que ocorre naturalmente em muitas frutas e vegetais e tem mostrado vários efeitos biológicos, principalmente em modelos experimentais, incluindo a redução dos principais fenótipos da asma: hiperreatividade brônquica, produção de muco e inflamação das vias aéreas. Nesta revisão, nós discutimos os resultados da literatura que revelam o potencial da quercetina para tratar a asma e suas exacerbações.

The morphological effects of asthma, as well as conventional and alternative asthma therapies on parietal and chief cells in the stomach of BALB/c Mice / Los efectos morfológicos del asma, así como de las terapias convencionales y alternativas del asma sobre las células parietales y principales en el estómago de ratones Balb/c

Scientific literature, although limited in this area, supports the hypothesis that asthma, by means of selective leukocyte trafficking between the various mucosal and glandular sites of the body, can have the same pathophysiological effects on the stomach as the airways. This study aimed to determine if asthma, in the absence and presence of various asthma therapies (Hydrocortisone and Modul8TM), imparted any morphological alteration on the stomach parietal and chief cells. The BALB/c murine asthmatic mouse model was the model of choice in this study. The asthma induction protocol as well as the asthma therapies were proved to be effective with the aid of bronchial lavage fluid leukocyte quantification. Fundic and pyloric biopsies were extracted at termination and assessed by means of transmission electron, scanning electron and light microscopy. The extracted fundic and pyloric biopsies revealed asthma alone induced parietal cell hypertrophy (increase in parietal cell size P < 0.000100 in both stomach regions) and chief cell hyper functioning. The use of Hydrocortisone and Modul8TM, as a therapy to correct the perceived gastric alterations were dismal; only in the case of fundic parietal cells were both treatments able to compensate for the hypertrophic effect caused by asthma, while in the pylorus parietal cell asthma- induced hypertrophy was only compensated for by Modul8TM.

La literatura científica, aunque limitada en esta área, apoya la hipótesis de que el asma, por medio del tráfico selectivo de leucocitos entre los diferentes sitios y la mucosa glandular del cuerpo, puede tener los mismos efectos fisiopatológicos en el estómago y las vías respiratorias. Este estudio tuvo como objetivo determinar si el asma, en ausencia y presencia de diversos tratamientos para el asma (hidrocortisona y Modul8 TM), generó alguna alteración morfológica en las céluals parietales y principales del estómago. El modelo murino BALB/c del ratón asmático fue el modelo de elección en este estudio. El protocolo de inducción de asma, así como el tratamiento del asma demostró ser eficaz con la ayuda de lavado bronquial y cuantificación leucocitaria del fluido. Biopsias de las regiones fúndica y pilórica fueron extraídas y evaluadas por medio de microscopía electrónica de transmisión, de barrido y de luz. Las biopsias extraídas de la región fúndica y pilórica revelaron que el asma solamente induce hipertrofia de las células parietales (aumento del tamaño de las células parietales P <0,00001 en ambas regiones del estómago) e hiperfuncionamiento de las células principales. El uso de hidrocortisona y Modul8 TM, como una terapia para corregir las alteraciones gástricas fue disimil, sólo en el caso de las células parietales fúndicas ambos tratamientos fueron capaces de compensar el efecto hipertrófico causado por el asma, mientras que en la célula parietal pílorica la hipertrofia inducida por el asma solamente se vio compensada por Modul8TM.

Neutrophil predominance in induced sputum from asthmatic patients: Therapeutic implications and role of clara cell 16-KD protein / Predominio de neutrófilos en esputo inducido de asmáticos: Implicancias terapéuticas y rol de la proteína 16-kD de la célula clara

Eosinophil is considered to be a main protagonist in asthma; however, often discordances between clinical manifestations and response to treatment are observed. We aimed to determine the occurrence of neutrophil predominance in asthma and to identify its characteristics on the basis of clinical-functional features, induced sputum cellular pattern and soluble molecules, to guide the appropriated anti-inflammatory therapy. A total of 41 patients were included in randomized groups: 21-40 year-old, with stable mild-to-severe asthma, steroid-naïve and non-smokers. An induced sputum sample was obtained under basal conditions, a second one after treatment with budesonide (400 µg b.i.d.) or montelukast (10 mg/d) for six weeks, and a final one after a 4-week washout period. By cytospin we evaluated eosinophil (EP) or neutrophil predominance (NP), and in supernatant we determined LTE4, and CC16. Peak expiratory flow variability (PEFV) was measured. A total of 23/41 patients corresponded to EP and 18/41 patients to NP. The PEFV was higher in EP than in NP. LTE4 was higher with NP than with EP. No difference was found for CC16. Montelukast reduced the predominant cell in both subsets, whereas budesonide only reduced eosinophils in EP. Budesonide and montelukast reduced PEFV in EP but not in NP. Considering the total treated-samples in each subset, CC16 level increased significantly in EP. In conclusion: a NP subset of asthmatic patients was identified. These patients show a lower bronchial lability; the leukotriene pathway is involved which responds to anti-leukotriene treatment. This phenotype shows a poor recovery of CC16 level after treatment.

El eosinófilo es considerado la célula protagonista principal en el asma; sin embargo, a menudo se observan discordancias entre las manifestaciones clínicas y la respuesta de los pacientes al tratamiento. Nos propusimos determinar la ocurrencia de predominio de neutrófilos en el asma e identificar las características clínico-funcionales, el patrón celular y las moléculas solubles del esputo inducido, para guiar el tratamiento apropiado anti-inflamatorio. Se incluyeron 41 pacientes: 21 a 40 años de edad, con asma estable leve a grave, no tratados con esteroides tópicos ni sistémicos y no fumadores. Se obtuvo una muestra de esputo inducido en condiciones basales, una segunda muestra después del tratamiento al azar con budesonida (400 µg dos veces al día) o el montelukast (10 mg/d) durante seis semanas, y una final después de un período de lavado de 4 semanas. En el frotis por citocentrifugado se evaluó el predominio de eosinófilos (EP) o neutrófilos (NP), y en el sobrenadante se determinó LTE4, y CC16. Se midió la variabilidad del flujo espiratorio máximo (PEFV). Un total de 23/41 pacientes correspondieron al EP y 18/41 pacientes con NP. El PEFV fue mayor en el EP que en NP. LTE4 fue mayor en NP que en EP. No se encontraron diferencias de los niveles de CC16 en ambos grupos. Montelukast redujo la célula predominante en ambos subgrupos, mientras que budesonida sólo redujo los eosinófilos en EP. Tanto budesonida como montelukast redujeron PEFV en EP, pero no en NP. El nivel de CC16 aumentó significativamente en el EP luego del tratamiento antiinflamatorio. En conclusión: se identificó un subgrupo de asmáticos NP que presentan una menor labilidad bronquial, la vía de los leucotrienos parece estar involucrada y responde al tratamiento anti-leucotrienos. Este fenotipo muestra una escasa recuperación del nivel de CC16 posterior al tratamiento.

Inactivation of capsaicin-sensitive nerves reduces pulmonary remodeling in guinea pigs with chronic allergic pulmonary inflammation

Pulmonary remodeling is an important feature of asthma physiopathology that can contribute to irreversible changes in lung function. Although neurokinins influence lung inflammation, their exact role in the extracellular matrix (ECM) remodeling remains to be determined. Our objective was to investigate whether inactivation of capsaicin-sensitive nerves modulates pulmonary ECM remodeling in animals with chronic lung inflammation. After 14 days of capsaicin (50 mg/kg, sc) or vehicle administration, male Hartley guinea pigs weighing 250-300 g were submitted to seven inhalations of increasing doses of ovalbumin (1, 2.5, and 5 mg/mL) or saline for 4 weeks. Seventy-two hours after the seventh inhalation, animals were anesthetized and mechanically ventilated and the lung mechanics and collagen and elastic fiber content in the airways, vessels and lung parenchyma were evaluated. Ovalbumin-exposed animals presented increasing collagen and elastic fiber content, respectively, in the airways (9.2 ± 0.9; 13.8 ± 1.2), vessels (19.8 ± 0.8; 13.4 ± 0.5) and lung parenchyma (9.2 ± 0.9; 13.8 ± 1.2) compared to control (P < 0.05). Capsaicin treatment reduced collagen and elastic fibers, respectively, in airways (1.7 ± 1.1; 7.9 ± 1.5), vessels (2.8 ± 1.1; 4.4 ± 1.1) and lung tissue (2.8 ± 1.1; 4.4 ± 1.1) of ovalbumin-exposed animals (P < 0.05). These findings were positively correlated with lung mechanical responses to antigenic challenge (P < 0.05). In conclusion, inactivation of capsaicin-sensitive nerve fibers reduces pulmonary remodeling, particularly collagen and elastic fibers, which contributes to the attenuation of pulmonary functional parameters.

Educación y asma en la escuela: la carga del asma: ausentismo y rendimiento escolar: [revisión] / Education and asthma in school: burden of asthma and truancy school performance: [review]

Asma es la enfermedad crónica más común en la infancia. Sus cifras de incidencia y prevalencia siguen aumentando a nivel mundial a pesar de los nuevos métodos diagnósticos y el arsenal terapéutico específico utilizado para lograr un control adecuado. El fracaso en dicho control depende, en alto grado, del poco conocimiento que tiene el paciente sobre su enfermedad y el tipo de tratamiento que debe realizar para lograrlo. Aun en países con excelentes sistemas de salud y suministro de medicamentos gratuitos, el ansiado control total ha sido difícil de alcanzar y las cifras de personas que manejan bien su asma son decepcionantes. Urge convocar equipos multidisciplinarios de salud, educación, deporte y desarrollo social, de sectores públicos y privados, para la elaboración de políticas públicas efectivas tendientes a enfrentar la gran carga que representa el asma en la economía estadal y doméstica, así como también el deterioro importante en la calidad de vida de quienes la sufren. Los programas de seguimiento y educación sanitaria del asmático y sus cuidadores deben constituir una prioridad para el Estado, quien está encargado de velar, gratuitamente, por el bienestar biopsicosocial de cada uno de sus miembros.

Asthma is the most common chronic disease during childhood. Despite the growing number of methods and techniques employed for diagnosis and medical treatments, asthma keeps growing in number of person who suffer it. Failure to control asthma will depend on the knowledge that the patient has about the disease and the treatment that is given by the medical team. Even in countries with excellent health systems and free supply of, the longed total control has been difficult to reach and the numbers of persons who deal well the disease are disappointing. It is urgent to summon multidisciplinary work teams in health, education, sport and social development in public and private sectors. These efforts should be aimed at the production of effective public policies tending to face the great load that asthma represents for the local and national economy, as well as to alleviate the important deterioration in the quality of life of those who suffer it. The programs of follow-up and sanitary education of the asthmatic patient and his keepers must constitute a priority for the State, who is entrusted to watch, free of cost, over the biopsicosocial well-being of each of his members.