Reabilitação respiratória na DPOC : efeito de duas intensidades de treino de exercício aeróbio nos resultados centrados no doente

RESUMO: Introdução: O treino de exercício assume uma importância fundamental nos programas de reabilitação respiratória, contudo permanece desconhecida qual a intensidade de treino efectiva na mudança dos resultados centrados no doente. Objectivos: Foram estudados os efeitos de duas intensidades de treino aeróbio na qualidade de vida relacionada com a saúde, no controlo de sintomas e na tolerância ao exercício, num programa de reabilitação respiratória para doentes com DPOC. Métodos: Trinta e quatro doentes com DPOC de estádios GOLD de ligeiro a muito grave, foram alocados aleatoriamente a intensidades de treino de exercício aeróbio de 60% ou 80% da intensidade máxima avaliada na prova de esforço num programa ambulatório de reabilitação respiratória de 20 sessões. Foram avaliados resultados centrados no doente pela aplicação do questionário respiratório de St.George, do índice de dispneia de Mahler, do questionário de actividades da vida diária do London Chest, da prova de 6 minutos, da prova de endurance a carga constante e da prova de esforço máxima incremental. Resultados: Apesar de existirem melhorias significativas em todos os resultados para ambos os grupos, a diferença média intergrupal por efeito da intensidade de treino aeróbio a 60% ou 80% da carga máxima em prova de esforço não foi significativa no questionário respiratório de St.George (p=0,306), no índice de dispneia de Mahler (p=0,378), no questionário de actividades da vida diária do London Chest (p=0,425), na prova de marcha de 6 minutos (p=0,917), na prova de endurance a carga constante (p=0,504) e na prova de esforço máxima incremental (p=0,117). Verificou-se ainda que a média das diferenças intergrupais na prova de endurance a carga constante e na prova de marcha de 6 minutos não apresentou qualquer associação com a idade dos doentes. Conclusões: O estudo permite concluir que não existem diferenças significativas nas alterações médias da qualidade de vida relacionada com a saúde, do controle de sintomas e da tolerância ao exercício em doentes com DPOC como efeito de duas intensidades de treino aeróbio. Os autores propõem para a prática clínica em reabilitação respiratória, a aplicação de intensidades de treino aeróbio individualmente adaptadas, de pelo menos 60% da carga máxima na prova de esforço inicial. -------------------------------ABSTRACT: Introduction: Exercise training is an important component of pulmonary rehabilitation, but it remains questionable as how training intensity changes patient-centered outcomes. Aims and objectives: The effects of two aerobic exercise training intensities in health-related quality of life, symptoms control and exercise tolerance in COPD patients were studied. Methods: Thirty-four COPD patients from mild to very severe GOLD stages were randomly assigned to a 60% or 80% aerobic exercise training intensity in a twenty-session outpatient pulmonary rehabilitation program. Patient-centered outcomes were assessed with St.George's respiratory questionnaire, Mahler dyspnoea index, London Chest activity of daily living, six minute walk test, constant work rate test and maximal incremental test. Results: Although there were significant improvements in all outcomes for both groups, there were no differences in mean change in St.George's respiratory questionnaire (p=0,306), Mahler dyspnoea index (p=0,378), London Chest activity of daily living (p=0,917), six-minute walk test (p=0,504), constant work rate test (p=0,504) and maximal incremental test (p=0,117), as an effect of aerobic exercise training intensity of 60% or 80%. Mean changes in constant work rate and six-minute walk test were not age-related. Conclusions: It is concluded that there are no differences in mean changes in health-related quality of life, symptoms control and exercise tolerance in COPD patients as an effect of two aerobic exercise training intensities. Therefore, the authors suggest that individually tailored exercise intensities above 60% should guide clinical practice in pulmonary rehabilitation.

Impacto do Exercício Físico Combinado na Percepção do Estado de Saúde da Pessoa com Doença Pulmonar Obstrutiva Crónica

AIM: The aim of the study was to evaluate the effectiveness of a 10-week combined training programme (aerobic and strength exercise) compared to an aerobic training programme, and respiratory physiotherapy on COPD patients' health. METHODS: Fifty subjects with moderate to severe COPD were randomly assigned to two groups. Combined group (CG, n=25) who underwent combined training, and aerobic group (AG, n=25) who underwent aerobic training. These were compared with fifty COPD subjects who underwent respiratory physiotherapy, breathing control and bronchial clearance techniques (RP group, n = 50). We evaluated health state through two questionnaires, St. George's Respiratory Questionnaire (SGRQ) and SF-36, at the beginning and at the end of the programme. RESULTS: The CG group showed differences (p<0.0001) in modification rates in state of health compared to the AG and RP groups in the activity (64 ± 9%, 19 ± 7%, 1 ± 15%) , impact (35 ± 5%, 20 ± 18%, 1 ± 14%) and total (41 ± 9%, 26 ± 17%, 1 ± 15%) domains assessed by the SGRQ, and the physical function (109 ± 74%, 22 ± 12%, 0.1 ± 18%), physical role (52 ± 36%, 11 ± 15%, 1.3 ± 21%) and vitality (83 ± 39%, 14 ± 38%) domains assessed by SF-36. CONCLUSION: These results suggest that combined training in subjects with COPD appears to be a more effective method, with better clinical changes, and improvements in health state perception.

A reabilitação respiratória para doentes com doença pulmonar obstrutiva crónica

RESUMO - CONTEXTO: A doença pulmonar obstrutiva crónica (DPOC) é uma doença de elevada prevalência a nível nacional e internacional, mas encontra-se presentemente subdiagnosticada e inadequadamente tratada. A reabilitação respiratória (RR), embora seja uma intervenção-padrão no tratamento da DPOC, é ainda pouco conhecida pelos profissionais e pelos doentes. Em Portugal existem doze instituições com programas de RR, mas terão os médicos de família conhecimento dos mesmos e do tratamento definido pelas guidelines para o doente com DPOC? Terão estes programas capacidade para dar resposta a todos os doentes que beneficiariam de RR? OBJECTIVOS: perceber como participam os doentes com DPOC em RR actualmente em Portugal; conhecer as percepções dos profissionais de saúde acerca da intervenção; identificar os factores que condicionam a acessibilidade do doente com DPOC a RR. MÉTODOS: desenvolvimento e aplicação de dois questionários: a coordenadores de USF – no sentido de avaliar o conhecimento, comportamentos e percepções dos médicos de família (MF) relativamente ao tratamento e gestão do doente com DPOC – e aos responsáveis pelos programas de RR – no sentido de avaliar a capacidade instalada de cada programa de RR, dificuldades de resposta e de participação de doentes com DPOC no mesmo. RESULTADOS: Poucos MF estiverem presentes em actividades de formação sobre a DPOC e parece existir um baixo nível de conhecimento dos MF acerca da RR, em geral, o que se verificou estar correlacionado (p=,000) com a baixa referenciação de doentes com DPOC para RR (9%). A oferta de RR é considerada pela maior parte dos profissionais (MF e responsáveis) como Insuficiente ou Muito insuficiente e o número de doentes com DPOC com recurso a RR anualmente nas instituições participantes é, na maior parte, reduzido (<80). Existe, além disso, um conjunto de importantes determinantes estruturais, associados ao profissional e ao doente que constituem barreiras à referenciação e participação dos doentes em RR. CONCLUSÕES: Verifica-se uma diferença significativa entre o número de doentes com DPOC registados nos cuidados de saúde primários (CSP) e o número de doentes com recurso a RR anualmente e apenas uma pequena percentagem de doentes com DPOC que beneficiariam da participação em RR está, actualmente, a ter acesso a esta intervenção em Portugal, o que pode ser justificado por diversos aspectos, como o grau de conhecimento do médico, dificuldades económicas do doente, entre outros.

Impacto da aplicação de um programa de educação em doentes com DOPC em fase estável

RESUMO: Relevância e Objectivos: A educação focada na auto-gestão tem sido cada vez mais valorizada como parte integrante da abordagem terapêutica dos doentes com DPOC. No entanto poucos resultados se encontram na literatura. Este estudo investiga se um programa de educação contribui para a melhoria da funcionalidade e do estado de saúde associados à DPOC estável. Metodologia: A amostra incluiu 18 indivíduos portadores de DPOC ligeira a moderada, de acordo com os critérios GOLD, com uma média de idades de 71 ± 8 anos. Os doentes foram distribuídos por 2 grupos: um grupo experimental, constituído por 10 doentes do sexo masculino, a receber os cuidados habituais e submetidos a um programa de educação, e um grupo de controlo formado por 7 doentes do sexo masculino e uma do sexo feminino, a receber apenas os cuidados habituais. Foram avaliados os dados sócio-demográficos relativos à amostra, o nível de conhecimentos sobre a patologia e a sua auto-gestão, a dispneia, o impacto nas AVD’s, a qualidade de vida relacionada com a saúde, a ansiedade e a depressão. Foram aplicados 8 questionários, 2 realizados pela invesstigadora, um destinado a recolher dados sociodemográficos e clínicos, outro para avaliar o conhecimento da doença pelo doente e os 6 restantes estandardizados: Medical Research Council, Índice de Dispneia Basal Modificado de Mahler, Índice de Dispneia de Transição de Mahler, St. George Respiratory Questionnaire, London Chest Activity of Daily Living e o Hospital Anxiety and Depression Scale. Incluíu-se também a realização de uma espirometria, de uma prova de marcha de 6 minutos e a aplicação de 1 checklist para avaliar a evolução dos conhecimentos do doente sobre a sua doença. Os dados foram recolhidos em dois momentos: em T0 e em T1, correspondendo ao início e o final do programa de educação. Resultados: Obteve-se uma diferença com significância na melhoria do nível de conhecimentos entre o grupo experimental e o grupo de controlo com um p = 0,001. Não se alcançaram resultados significativos na melhoria da distância percorrida, da dispneia, do impacto nas AVD’s, da QVRS, da ansiedade e da depressão. Conclusões: A aplicação de um programa de educação a doentes com DPOC estável contribuiu para a melhoria de conhecimentos sobre a doença, mas não se traduziu em modificações no estado de saúde e da funcionalidade na população estudada.------------ABSTRACT: Relevance and Objectives: Self-management interventions have been increased as an important part of therapeutic approach in COPD patients. However, few results are found in literature. This study investigates whether self-management program contributes to improve functionality and health status associated with stable COPD. Methods: The sample included 18 subjects with mild to moderate COPD, according to GOLD criteria, and a mean age of 71 ± 8 years. Patients were divided into 2 groups: one experimental group, consisting of 10 male patients receiving usual care plus an education program, and a control group consisting of one female and 7 male patients, receiving only usual care. We assessed socio-demographic data, level of knowledge about the pathology and selfmanagement, dyspnea, impact on ADLs, health related quality of life, anxiety and depression. Were administered 8 questionnaires, two made by the researcher, one to collect sociodemographic and clinical data, another to assess the knowledge of the disease by the patient and the remaining 6 standardized: Medical Research Council, baseline dyspnea index Modified Mahler's, Mahler Transitional (dyspnea), St. George Respiratory Questionnaire (HRQOL),London Chest Activity of Daily Living (ADL´s) and the Hospital Anxiety and Depression Scale (anxiety and depression). Performed a spirometry, a test of 6-minute walk and a checklist for monitoring progress of the patient's knowledge about their disease. Data were collected on two times: T0 and T1, beginning and end of self-management program. Results: We found a significant improvement in the level of knowledge between the experimental and control group with p = 0.001. We didn’t achieve significant results in improving distance, dyspnea, impact on ADLs, HRQOL, anxiety and depression. Conclusions: The application of an education program in stable COPD patients contributed to the improvement of knowledge about the disease, but didn’t translate into changes in health status and functionality in population of this study.

A doença pulmonar obstrutiva crónica e o exercício: impacto da doença no declínio funcional e importância do treino de exercício nos benefícios para a saúde

RESUMO: A reabilitação respiratória (RR) é uma intervenção abrangente e interdisciplinar dirigida aos doentes respiratórios crónicos e inclui o treino de exercício, programas de educação e de modificação comportamental, entre outros, desenhados individualmente para melhorar o desempenho físico e psicossocial e promover a adesão a longo prazo a comportamentos promotores de saúde. A doença pulmonar obstrutiva crónica (DPOC) é uma doença comum, afetando cerca de 210 milhões de pessoas em todo o mundo, com elevada mortalidade e com custos económicos significativos decorrentes do agravamento progressivo da doença, das hospitalizações e de reinternamentos frequentes. Apesar do crescente conhecimento da DPOC e do papel da RR nos benefícios para a saúde, existem aspetos ainda não esclarecidos que têm impacto na prática clínica e de investigação e nas decisões das autoridades de saúde. A primeira parte desta tese focou a DPOC e o seu impacto negativo e incluiu: o estudo da prevalência da DPOC em Portugal; os fatores clínicos e funcionais que se associam à mortalidade em doentes com DPOC avançada; a morbilidade, impacto funcional e risco dos doentes se tornarem dependentes para as atividades diárias e a influência da inflamação sistémica. A prevalência estimada da DPOC de 14,2% indica que esta é uma doença comum em Portugal e alerta para a necessidade de uma maior sensibilização da população, dos profissionais de saúde e autoridades de saúde com vista a um diagnóstico precoce e à alocação dos recursos terapêuticos adequados. A elevada taxa de mortalidade em doentes com DPOC avançada - 36,6% em 3 anos - associou-se a insuficiência respiratória, a elevado número de exacerbações, ao cancro do pulmão e a reduzida capacidade funcional para a marcha, salientando a importância da referenciação precoce para RR, a identificação e o tratamento das comorbilidades e a prevenção das exacerbações. A aplicação de um questionário que avaliou as atividades da vida diária básicas e instrumentais, permitiu identificar um marcador clínico do risco de dependência, complementando as avaliações funcionais e associando-se a outros marcadores de mau prognóstico, como as exacerbações. Em doentes com DPOC, com FEV1 médio de 46,76% (desvio padrão: 20,90%), 67% da categoria D do GOLD, verificou-se uma associação positiva entre a expressão de genes inflamatórios avaliada pela reação em cadeia da polimerase (ARN mensageiro de IFNg, IL1b, IL6, IL8, TNFa, TGFb1, iNOS) e o índice de massa corporal em repouso, acentuando-se após o exercício. Este estudo aponta a inflamação como o potencial elo de ligação entre a obesidade e a inflamação sistémica em doentes com DPOC. A segunda parte da tese focou a RR, nomeadamente os seus efeitos em doentes das categorias GOLD A, B, C e D; o impacto das comorbilidades nos resultados da RR e os resultados de diferentes intensidades de treino aeróbio. Após o programa de RR, verificaram-se melhorias significativas na capacidade de exercício funcional e de endurance e no estado geral de saúde dos doentes de todas as categorias GOLD. Esta classificação não distingue os doentes que melhor poderão beneficiar desta intervenção, indicando que devem ser referenciados para RR, os doentes sintomáticos ou com repercussão na qualidade de vida, independentemente da categoria da DPOC a que pertençam. A prevalência das comorbilidades no grupo de doentes com DPOC que é referenciado para RR, é elevada, sendo as mais frequentes, as cardiovasculares, as respiratórias e as psicológicas. Apesar de poderem diminuir o impacto da RR, os resultados desta foram semelhantes independentemente do número de comorbilidades. A identificação e o tratamento sistemáticos das comorbilidades conferem maior segurança clínica a esta intervenção terapêutica a qual, por apresentar bons resultados, não deve limitar a referenciação dos doentes. Com o programa de RR, verificou-se melhoria significativa em todos os resultados centrados no doente para ambas as intensidades de treino aeróbio, a 60% e a 80% da potência aeróbica máxima (Wmax), com melhoria do estado geral de saúde, nos sintomas e na capacidade para o exercício, o que questiona a indicação sistemática de elevadas intensidades de treino em doentes com DPOC para a obtenção de benefícios a curto prazo. Na terceira e última parte da tese foi estudado o papel da atividade física na DPOC, focando os fatores que influenciam a atividade física diária; a evolução da capacidade funcional e o estado de saúde 2 anos após um programa de RR e o papel da telemonitorização na quantificação e monitorização da atividade física. Confirmámos que os doentes com DPOC são marcadamente sedentários e os fatores que se associaram ao sedentarismo nestes doentes foram a dispneia e a distância percorrida na prova de marcha de seis minutos. Este estudo sublinha a importância do controlo sintomático, nomeadamente da dispneia, bem como, mais uma vez, o potencial papel da reabilitação respiratória no aumento da capacidade funcional para o exercício e na aquisição de hábitos de vida fisicamente ativa. Verificámos que, apesar de os doentes com DPOC apresentarem benefícios clinicamente significativos na capacidade funcional para o exercício e no estado geral de saúde com o programa de RR, apenas os que se mantêm ativos, podem, no final dos dois anos de seguimento, manter os efeitos benéficos desse programa. O sistema de telemonitorização que combina a oximetria e a quantificação da atividade física provou ser clinicamente útil na avaliação da necessidade de oxigenoterapia de longa duração (OLD) e na aferição do débito de oxigénio em repouso, no esforço e no sono, podendo contribuir para uma melhor adequação da prescrição da OLD. A monitorização dos níveis de atividade física regular é um importante instrumento de avaliação dos programas de RR e o seu uso potencial na telereabilitação permitirá prolongar a eficácia dos programas e reduzir os custos associados aos cuidados de saúde.---------------------------------------------------------------------------------------------------ABSTRACT: Pulmonary rehabilitation (PR) is a comprehensive interdisciplinary intervention that includes, but is not limited to, exercise training, education, and behavior change, individually designed to improve physical and psychological conditions of people with chronic respiratory disease and to promote long-term adherence to health-enhancing behaviors. Chronic obstructive pulmonary disease (COPD) is a common disease, affecting about 210 million people worldwide, with high mortality and significant health-related costs due to disease progression, hospitalizations and frequent hospital readmissions. Although the increasing knowledge about COPD and benefitial outcomes of PR, some aspects with impact in clinical practice, research and health authorities’ decisions, remain to be clarified. The first part of this thesis focused on COPD and its negative impact, including the study of COPD prevalence in Portugal; clinical and functional factors associated with mortality in advanced COPD patients; morbidity, functional impact and risk of others’ dependance to perform activities of daily living; and the role of systemic inflammation. The evidence of 14.2% estimated COPD prevalence as a common disease in Portugal raises the need of an increasing awareness of population, health care professionals and health authorities towards an earlier diagnosis and apropriate treatment resources allocation. High mortality in patients with advanced COPD – 36.6% in 3 years - was associated with respiratory failure, high frequency of exacerbations, lung cancer and a low functional capacity in walking. This highlightens the importance of an earlier referral to PR, comorbidity identification and treatment, and prevention of exacerbations. A questionnaire evaluated basic and instrumental activities of daily living, and identified a clinical marker of the risk of becoming dependent. This clinical marker complemented other functional evaluations and was associated with prognosis markers such as the number of exacerbations. In COPD patients with a mean FEV1 46.76% (SD 20.90%), 67% belonging to GOLD grade D, we found a positive association between inflammatory gene expression evaluated by polymerase chain reaction (IFNg, IL1b, IL6, IL8, TNFa, TGFb1, iNOS RNA messenger) and body mass index at rest, and a further increase with exercise. This study evidenced obesity as one potential link between COPD and systemic inflammation. The second part of this thesis focused PR, namely its outcomes in patients of GOLD categories A, B, C and D; comorbidities impact in PR outcomes, and the impact of different exercise training intensities in patient related outcomes. xviii With PR intervention, we found significant improvement in functional exercise capacity, endurance exercise capacity and health status in patients of all GOLD categories. This classification did not differentiate which patients would benefit more from PR, hence all symptomatic patients with a negative impact in health status should be referred to PR, regardless of the GOLD category they belong to. There is a high prevalence of comorbidities in COPD patients referred to PR, being cardiovascular, respiratory and psychological, the most prevalent. Although some comorbidities might reduce PR impact, the results were similar regardless of the number of comorbidities. Systematic comorbidities identification and treatment provides safety to PR intervention, and its good results should not preclude patients referral. With PR intervention we found a significant improvement in all patient reported outcomes for exercise training intensities at 60% and 80% maximum work rate (Wmax), namely in health status, symptoms and exercise capacity. These findings challenge the current systematic indication of high exercise training intensities to achieve PR short-term benefits. In the third and last part of the thesis, the role of physical activity in COPD was studied, focusing factors that may influence daily physical activity; the evolution of functional capacity and health status two years after a PR program, and the role of a telemonitoring system in physical activity quantification and monitoring. We confirmed that COPD patients are markedly inactive and factors associated with a sedentary lifestyle are dyspnea and 6 minute walking distance. This study emphasized the importance of symptom control, namely of dyspnea, as well as, once again, the potential role of PR in functional exercise improvement and in integrating physically active habits in daily life. We verified that, although COPD patients improve functional exercise capacity and health status after a PR program, only those who kept physical activity habits were able to maintain those effects after 2 years of follow-up. A telemonitoring system that combines oximetry and physical activity quantification proved to be clinically useful in the evaluation of long-term oxygen therapy (LTOT) indication, as well as in the titration of oxygen levels at rest, exertion, and sleeping, which might contribute to a more adequate LTOT prescription. Monitoring of daily physical activity levels is an important PR evaluation instrument and its potential use in telerehabilitation might allow lengthening programs efficacy, while reducing health-care costs.

Research needs in allergy: an EAACI position paper, in collaboration with EFA.

In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21st century.The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients' Associations (EFA) is a non-profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients' organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels.Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re-categorize clinical syndromes into more coherent, uniform and treatment-responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient-oriented diagnostic and treatment protocols. Several allergic diseases require well-controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult-to-manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders, including Patient Organizations and policy makers are necessary to achieve the aims emphasized herein.

Nutrition dans la bronchopneumopathie chronique obstructive [Nutrition in chronic obstructive bronchopneumopathy]

The respiratory system and nutrition are linked. Obesity is sometimes seen in chronic obstructive pulmonary disease (COPD), but its prevalence, the morbidity and mortality induced by it are not known. In addition, the prevalence of malnutrition is high in COPD and the more severe the COPD is, the higher percentage of malnutrition is present. Emphysematous patients are more frequently undernourished than those suffering from chronic bronchitis. Malnutrition is the consequence of the hypermetabolism induced by the higher cost of breathing in emphysema. The survival rate of these patients is negatively affected by malnutrition. A careful assessment of nutritional status must be performed in all COPD patients, especially during an episode of acute respiratory failure. When signs of malnutrition are present, a nutritional intervention should be initiated rapidly. An amount of calories sufficient to meet the energy expenditure increased by the disease must be given. Excessive intake may overstress the respiratory system whose functional reserve is limited in COPD. The diet must include a well balanced percentage of fat, carbohydrates and proteins. Preservation of the fat-free mass is the minimum goal to reach in acute respiratory failure. After the resolution of the acute phase, a gain of weight should be attempted within a rehabilitation program.

Macrophage elastase (MMP-12): a pro-inflammatory mediator?

As many metalloproteinases (MMPs), macrophage elastase (MMP-12) is able to degrade extracellular matrix components such as elastin and is involved in tissue remodeling processes. Studies using animal models of acute and chronic pulmonary inflammatory diseases, such as pulmonary fibrosis and chronic obstrutive pulmonary disease (COPD), have given evidences that MMP-12 is an important mediator of the pathogenesis of these diseases. However, as very few data regarding the direct involvement of MMP-12 in inflammatory process in the airways were available, we have instilled a recombinant form of human MMP-12 (rhMMP-12) in mouse airways. Hence, we have demonstrated that this instillation induced a severe inflammatory cell recruitment characterized by an early accumulation of neutrophils correlated with an increase in proinflammatory cytokines and in gelatinases and then by a relatively stable recruitment of macrophages in the lungs over a period of ten days. Another recent study suggests that resident alveolar macrophages and recruited neutrophils are not involved in the delayed macrophage recruitment. However, epithelial cells could be one of the main targets of rhMMP-12 in our model. We have also reported that a corticoid, dexamethasone, phosphodiesterase 4 inhibitor, rolipram and a non-selective MMP inhibitor, marimastat could reverse some of these inflammatory events. These data indicate that our rhMMP-12 model could mimic some of the inflammatory features observed in COPD patients and could be used for the pharmacological evaluation of new anti-inflammatory treatment. In this review, data demonstrating the involvement of MMP-12 in the pathogenesis of pulmonary fibrosis and COPD as well as our data showing a pro-inflammatory role for MMP-12 in mouse airways will be summarized.

Paper de l’ Haemophilus influenzae en les exacerbacions de la Malaltia Pulmonar Obstructiva Crònica (MPOC): tipificació molecular i factors de virulència

Objetivos: 1.-Identificar los factores clínicos y microbiológicos que ayuden a predecir la aparición de exacerbaciones en la EPOC. 2.-Diagnóstico y cuantificación de las especies bacterianas aisladas en esputo (fase de exacerbación y estable) .3.- Tipificación genotípica secuencial de las cepas de H. influenzae y P. aeruginosa. 4.- Impacto del tratamiento antibiótico en la aparición de resistencias en estos patógenos. 5.- Diseño: Estudio prospectivo (3 años). Ámbito del estudio: Hospital Universitario de tercer nivel. Pacientes con EPOC grave atendidos en la Consulta Monográfica de EPOC del Servicio de Neumología. Métodos microbiológicos: Cuantificación de la carga bacteriana en muestras respiratorias en fase estable y en exacerbación. Estudio de la sensibilidad “in vitro”. Tipificación molecular (PFGE y MLST) de H. influenzae y P. aeruginosa. Estudio de los genes de virulencia de H. influenzae mediante PCR. Resultados: Desde Febrero de 2010 a Julio de 2011 se han incluido 77 pacientes. Los microorganismos más frecuentemente aislados en fase de exacerbación fueron: P. aeruginosa (29.3%), H. influenzae (15.92%), M. catarrhalis (12.74%), S. pneumoniae (10.19%) y S. aureus (5.10%). En los 88 episodios por P. aeruginosa se detectaron 38 genotipos diferentes. En los 41 episodios por H. influenzae se detectaron 39 genotipos diferentes. El 10% de los episodios fueron polimicrobianos. Los episodios de EAEPOC y de fase estable tuvieron una distribución de microorganismos similar. Sin embargo, cuando se cuantificaron las cargas bacterianas fueron mayores en EAEPOC (intervalo 4x107 -2x108) que en fase estable (intervalo 2x105 -4x107). Conclusiones: El genotipo de las cepas de P. aeruginosa y H. influenzae aisladas en EAEPOC difieren de un paciente a otro, sin embargo la mayoría de los episodios de cada paciente están causados por un genotipo único.

End-tidal carbon dioxide monitoring using a naso-buccal sensor is not appropriate to monitor capnia during non-invasive ventilation.

BACKGROUND: In acute respiratory failure, arterial blood gas analysis (ABG) is used to diagnose hypercapnia. Once non-invasive ventilation (NIV) is initiated, ABG should at least be repeated within 1 h to assess PaCO2 response to treatment in order to help detect NIV failure. The main aim of this study was to assess whether measuring end-tidal CO2 (EtCO2) with a dedicated naso-buccal sensor during NIV could predict PaCO2 variation and/or PaCO2 absolute values. The additional aim was to assess whether active or passive prolonged expiratory maneuvers could improve the agreement between expiratory CO2 and PaCO2. METHODS: This is a prospective study in adult patients suffering from acute hypercapnic respiratory failure (PaCO2 ≥ 45 mmHg) treated with NIV. EtCO2 and expiratory CO2 values during active and passive expiratory maneuvers were measured using a dedicated naso-buccal sensor and compared to concomitant PaCO2 values. The agreement between two consecutive values of EtCO2 (delta EtCO2) and two consecutive values of PaCO2 (delta PaCO2) and between PaCO2 and concomitant expiratory CO2 values was assessed using the Bland and Altman method adjusted for the effects of repeated measurements. RESULTS: Fifty-four datasets from a population of 11 patients (8 COPD and 3 non-COPD patients), were included in the analysis. PaCO2 values ranged from 39 to 80 mmHg, and EtCO2 from 12 to 68 mmHg. In the observed agreement between delta EtCO2 and deltaPaCO2, bias was -0.3 mmHg, and limits of agreement were -17.8 and 17.2 mmHg. In agreement between PaCO2 and EtCO2, bias was 14.7 mmHg, and limits of agreement were -6.6 and 36.1 mmHg. Adding active and passive expiration maneuvers did not improve PaCO2 prediction. CONCLUSIONS: During NIV delivered for acute hypercapnic respiratory failure, measuring EtCO2 using a dedicating naso-buccal sensor was inaccurate to predict both PaCO2 and PaCO2 variations over time. Active and passive expiration maneuvers did not improve PaCO2 prediction. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01489150.

A systems biology approach identifies molecular networks defining skeletal muscle abnormalities in chronic obstructive pulmonary disease.

Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation. Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy. Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate. In this study, we have applied a network biology approach to model the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators. Our model shows that failure to co- ordinately activate expression of several tissue remodelling and bioenergetics pathways is a specific landmark of COPD diseased muscles. Our findings also suggest that this phenomenon may be linked to an abnormal expression of a number of histone modifiers, which we discovered correlate with oxygen utilization. These observations raised the interesting possibility that cell hypoxia may be a key factor driving skeletal muscle degeneration in COPD patients.

The ADO Index as a Predictor of Two-Year Mortality in General Practice-Based Chronic Obstructive Pulmonary Disease Cohorts.

BACKGROUND: Existing prediction models for mortality in chronic obstructive pulmonary disease (COPD) patients have not yet been validated in primary care, which is where the majority of patients receive care. OBJECTIVES: Our aim was to validate the ADO (age, dyspnoea, airflow obstruction) index as a predictor of 2-year mortality in 2 general practice-based COPD cohorts. METHODS: Six hundred and forty-six patients with COPD with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages I-IV were enrolled by their general practitioners and followed for 2 years. The ADO regression equation was used to predict a 2-year risk of all-cause mortality in each patient and this risk was compared with the observed 2-year mortality. Discrimination and calibration were assessed as well as the strength of association between the 15-point ADO score and the observed 2-year all-cause mortality. RESULTS: Fifty-two (8.1%) patients died during the 2-year follow-up period. Discrimination with the ADO index was excellent with an area under the curve of 0.78 [95% confidence interval (CI) 0.71-0.84]. Overall, the predicted and observed risks matched well and visual inspection revealed no important differences between them across 10 risk classes (p = 0.68). The odds ratio for death per point increase according to the ADO index was 1.50 (95% CI 1.31-1.71). CONCLUSIONS: The ADO index showed excellent prediction properties in an out-of-population validation carried out in COPD patients from primary care settings. © 2014 S. Karger AG, Basel.

Chronic obstructive pulmonary disease is underdiagnosed and undertreated in São Paulo (Brazil): results of the PLATINO study

Chronic obstructive pulmonary disease (COPD) is a common disease in adults over 40 years of age and has a great social and economic impact. It remains little recognized and undertreated even in developed countries. However, there are no data about its diagnosis and treatment in Brazil. The objectives of the present study were to evaluate the proportion of COPD patients who had never been diagnosed and to determine if the COPD patients who had been identified were receiving appropriate treatment. The Latin American Project for the Investigation of Obstructive Lung Disease (PLATINO) was a randomized epidemiological study of adults over 40 years living in five metropolitan areas, including São Paulo. The studied sample was randomly selected from the population after a division of the metropolitan area of São Paulo in clusters according to social characteristics. All subjects answered a standardized questionnaire on respiratory symptoms, history of smoking, previous diagnosis of lung disease, and treatments. All subjects performed spirometry. The criterion for the diagnosis of COPD was defined by a post-bronchodilator FEV1/FVC ratio lower than 0.7. A total of 918 subjects were evaluated and 144 (15.8%) met the diagnostic criterion for COPD. However, 126 individuals (87.5%) had never been diagnosed. This undiagnosed group of COPD patients had a lower proportion of subjects with respiratory symptoms than the previously diagnosed patients (88.9 vs 54.8%) and showed better lung function with greater FEV1 (86.8 ± 20.8 vs 68.5 ± 23.6% predicted) and FVC (106.6 ± 22.4 vs 92.0 ± 24.1% predicted). Among the COPD patients, only 57.3% were advised to stop smoking and 30.6% received the influenza vaccine. In addition, 82.3% did not receive any pharmacological treatment. In conclusion, COPD is underdiagnosed and a large number of COPD patients are not treated appropriately.

Breathing pattern and thoracoabdominal motion during exercise in chronic obstructive pulmonary disease

Subjects with chronic obstructive pulmonary disease (COPD) present breathing pattern and thoracoabdominal motion abnormalities that may contribute to exercise limitation. Twenty-two men with stable COPD (FEV1 = 42.6 ± 13.5% predicted; age 68 ± 8 years; mean ± SD) on usual medication and with at least 5 years of diagnosis were evaluated at rest and during an incremental cycle exercise test (10 watts/2 min). Changes in respiratory frequency, tidal volume, rib cage and abdominal motion contribution to tidal volume and the phase angle that measures the asynchrony were analyzed by inductive respiratory plethysmography at rest and during three levels of exercise (30-50, 70-80, and 100% maximal work load). Repeated measures ANOVA followed by pre-planned contrasts and Bonferroni corrections were used for analyses. As expected, the greater the exercise intensity the higher the tidal volume and respiratory frequency. Abdominal motion contributed to the tidal volume increase (rest: 49.82 ± 11.19% vs exercise: 64.15 ± 9.7%, 63.41 ± 10%, and 65.56 ± 10.2%, respectively, P < 0.001) as well as the asynchrony [phase angle: 11.95 ± 7.24° at rest vs 22.2 ± 15° (P = 0.002), 22.6 ± 9° (P < 0.001), and 22.7 ± 8° (P < 0.001), respectively, at the three levels of exercise]. In conclusion, the increase in ventilation during exercise in COPD patients was associated with the major motion of the abdominal compartment and with an increase in the asynchrony independent of exercise intensity. It suggests that cycling exercise is an effective way of enhancing ventilation in COPD patients.

Three-year follow-up study of respiratory and systemic manifestations of chronic obstructive pulmonary disease

Few studies show patient outcomes over time in chronic obstructive pulmonary disease (COPD). In the present study, we monitored forced expiratory volume in the first second (FEV1) and other manifestations of the disease over 3 years in 133 COPD patients (69% males, age = 65 ± 9 years, FEV1 = 59 ± 25%) evaluated at baseline. During follow-up, 15 patients (11%) died and 23 (17%) dropped out. Measurements for 95 (72%) COPD patients alive after 3 years were analyzed. FEV1, body mass index (BMI), 6-min walking distance (6MWD), Medical Research Council scale (MRC), Saint George’s Respiratory Questionnaire (SGRQ), Charlson Comorbidity index, and BODE index were obtained at baseline and after 3 years. At baseline, 17 patients (18%) presented mild, 39% moderate, 19% severe, and 24% very severe COPD. Predicted FEV1 % and BMI did not change over the period (P > 0.05). FEV1 in liters [1.25 (0.96-1.72) vs 1.26 (0.88-1.60) L; P < 0.001], 6MWD (438 ± 86 vs 412 ± 100 m; P < 0.001), MRC [1 (1-2) vs 2 (1-3); P = 0.002], Charlson index [3 (3-4) vs4 (3-5); P = 0.009], BODE index (2.2 ± 1.8 vs 2.6 ± 2.3; P = 0.008), and total SGRQ (42 ± 19 vs 44 ± 19%; P = 0.041) worsened after 3 years compared to baseline measurements. These data show that COPD patients deteriorated during the 3-year follow-up despite the fact that they had only minor modifications in airway obstruction and body composition. They support the need for comprehensive patient assessment to better identify disease progression.