Brazilian Journal of Pulmonology - Volume 38, number 5, September/October - 2012

pneumocócica PREVALÊNCIA

DESAFIO A doença causada pelo S. pneumoniae é a maior causa de doença e morte em crianças e adultos no mundo.3

Jornal Brasileiro de Pneumologia

A doença pneumocócica é a causa número 1 de mortes evitáveis por vacinação, a maioria devida à pneumonia.1 O S. pneumoniae é o agente da pneumonia adquirida na comunidade em cerca de 50% dos casos em adultos2

doença

ISSN 1806-3713

Published once every two months J Bras Pneumol. v.38, number 5, p. 539-680 September/October 2012

OFFICIAL PUBLICATION OF THE BRAZILIAN THORACIC ASSOCIATION

Highlight

ASTHMA Prevalence and duration of social security benefits allowed to workers with asthma in Brazil in 2008

CANCER Analysis and validation of probabilistic models for predicting malignancy in solitary pulmonary nodules in a population in Brazil

SURGERY Electric Ventilation: indications for and technical aspects of diaphragm pacing stimulation surgical implantation

SEVERIDADE

Quantitative assessment of the intensity of palmar and plantar sweating in patients with primary ­palmoplantar hyperhidrosis

O Streptococcus pneumoniae é o agente mais encontrado em pneumonia, inclusive em casos que necessitam de internação em unidade de terapia intensiva2

COPD

RISCOS

TEACHING

IMPACTO SOCIAL No ano de 2007, ocorreram 735.298 internações por pneumonia no Brasil, conforme o Sistema de Informações Hospitalares do Sistema Único de Saúde, correspondendo à primeira causa de internação por doença pelo CID-10 8

Muscle strength as a determinant of oxygen uptake efficiency and maximal metabolic response in patients with mild-to-moderate COPD

September/October 2012 volume 38 number 5

O risco de pneumonia pneumocócica aumenta com a idade , possivelmente devido ao declínio do sistema imunológico5, bem como ao aumento das comorbidades relacionadas com a idade.6,7 4

Responsiveness of the six-minute step test to a physical training program in patients with COPD

Maternal malnutrition during lactation in Wistar rats: effects on elastic fibers of the extracellular matrix in the trachea of offspring Proposed short-term model of acute allergic response, without adjuvant use, in the lungs of mice

PULMONARY FUNCTION Comparison among parameters of maximal respiratory pressures in healthy subjects

PEDIATRICS TUBERCULOSIS Correlation between resistance to pyrazinamide and resistance to other antituberculosis drugs in Mycobacterium tuberculosis strains isolated at a referral hospital Factors associated with pulmonary tuberculosis among patients seeking medical attention at referral clinics for tuberculosis

p.539-680

Referências Bibliográficas: 1. CDC. Vaccine Preventable Deaths and the Global Immunization Vision and Strategy, 2006--2015. MMWR 2006; 55(18):511-515. 2. Corrêa RA, Lundgren FLC, Pereira-Silva JL, et al. Diretrizes brasileiras para pneumonia adquirida na comunidade em adultos imunocompetentes – 2009. J Bras Pneumol. 2009;35(6):574-601. 3. WHO. 23-valent pneumococcal polysaccharide vaccine WHO position paper. WER 83(42):373-84. 4. Jokinen C, Heiskanen L, Juvonen H et al. Incidence of community-acquired pneumonia in the population of four municipalities in eastern Finland. Am J Epidemiol 1993;137:977-88 . 5. Schenkein JG, Park S, Nahm MH Pneumococcal vaccination in older adults induces antibodies with low opsonic capacity and reduced antibody potency Vaccine 26 (2008) 5521–5526. 6. Musher DM, Rueda AM, KakaAS , Mapara SMThe Association between Pneumococcal Pneumonia and Acute Cardiac Events. Clinical Infectious Diseases 2007; 45:158–65. 7. Jasti H, Mortensen EM, Obrosky DS. Causes and Risk Factors for Rehospitalization of Patients Hospitalized with Community-Acquired Pneumonia. Clinical Infectious Diseases 2008; 46:550–6. 8. Ministério da Saúde. Datasus. Tecnologia da Informação ao serviço do SUS. Morbidade Hospitalar do SUS - por local de internação - Brasil. Internações por pneumonia, 2007. Disponível em http://tabnet. datasus.gov.br/cgi/tabcgi.exe?sih/cnv/miuf.def. Acesso 22/09/2010.

EXPERIMENTAL

Factors associated with complications of community-acquired pneumonia in preschool children

493517 PRD1139 - Material produzido em Julho/11 Wyeth Indústria Farmacêutica Ltda Rua Verbo Divino, 1.400 Chácara Santo Antonio CEP: 04719-002 - São Paulo - SP www.wyeth.com.br

Pulmonary research recently published in Brazilian journals

Free Full Text in English www.jornaldepneumologia.com.br

Electric Ventilation

Alguns pacientes com asma

*

e DPOC não sabem como 1 a vida pode ser melhor.

Faça mais hoje 1

DAXAS.USOORAL,ADULTO.INDICAÇÕES:tratamentodemanutençãodepacientescomdoençapulmonarobstrutivacrônica(DPOC)grave(VEF1pós-broncodilatador < 50% do valor previsto) associada a bronquite crônica (tosse e expectoração crônicas) com histórico de exacerbações (crises) frequentes, em complementação ao tratamento com broncodilatadores. CONTRAINDICAÇÕES: hipersensibilidade ao roflumilaste ou a qualquer dos componentes da formulação. Este medicamento é contraindicado para pacientes com insuficiência hepática moderada e grave (classes ‘B’ e ‘C’ de Child-Pugh), pois não existem estudos sobre o uso do roflumilaste nestes pacientes. PRECAUÇÕES: DAXAS deve ser administrado apenas por via oral. DAXAS não é indicado para melhora de broncoespasmo agudo. Os comprimidos de DAXAS contêm 199 mg de lactose. Perda de peso: nos estudos de 1 ano (M-124, M-125), houve redução mais frequente do peso corporal em pacientes tratados com DAXAS versus placebo. Após a descontinuação de DAXAS, a maioria dos pacientes recuperou o peso corporal após 3 meses. Na ocorrência de perda de peso inexplicada e pronunciada, deve-se descontinuar a administração de DAXAS, se julgado necessário. Intolerância persistente: apesar das reações adversas como diarreia, náusea, dor abdominal e cefaleia serem transitórias e se resolverem espontaneamente com a manutenção do tratamento, o tratamento com DAXAS deve ser revisto em caso de intolerância persistente. Gravidez e lactação: as informações disponíveis sobre o uso de DAXAS em gestantes são limitadas, mas não indicaram eventos adversos do roflumilaste sobre a gestação ou a saúde do feto/recém-nato. Não são conhecidos outros dados epidemiológicos relevantes. Estudos em animais demonstraram toxicidade reprodutiva. O risco potencial para humanos ainda não está estabelecido. DAXAS não deve ser administrado durante a gestação. É possível que o roflumilaste e/ou seus metabólitos sejam excretados no leite materno durante a amamentação; estudos em animais (ratos) em fase de amamentação detectaram pequenas quantidades do produto e seus derivados no leite dos animais. Categoria B de risco na gravidez – este medicamento não deve ser utilizado por mulheres grávidas ou que estejam amamentando sem orientação médica ou do cirurgião dentista. Idosos: os cuidados com o uso de DAXAS por pacientes idosos devem ser os mesmos para os demais pacientes; não são recomendados ajustes na dosagem da medicação. Pacientes pediátricos (crianças e adolescentes menores de 18 anos de idade): o produto não é recomendado para este grupo de pacientes, pois não há dados disponíveis sobre a eficácia e a segurança da administração oral de DAXAS nesta faixa etária. Insuficiência hepática: não é necessário ajuste da dosagem para pacientes com insuficiência hepática leve (classe ‘A’ de Child-Pugh). No entanto, para pacientes com insuficiência hepática moderada ou grave (classes ‘B’ e ‘C’ de Child-Pugh), o uso deste medicamento não é recomendado, pois não existem estudos sobre o uso nesses pacientes.

Insuficiência renal: não é necessário ajuste da dose para pacientes com insuficiência renal crônica. Fumantes com DPOC: não é necessário ajuste da dose. Habilidade de dirigir e operar máquinas: é improvável que o uso desse medicamento cause efeitos na capacidade de dirigir veículos ou de usar máquinas. Pacientes com doenças imunológicas graves, infecciosas graves ou tratados com imunossupressores: deve-se suspender ou não iniciar o tratamento com DAXAS nesses casos. Pacientes com insuficiência cardíaca classes III e IV (NYHA): não existem estudos nessa população de pacientes, portanto não se recomenda o uso nesses pacientes. Pacientes com doenças psiquiátricas: DAXAS não é recomendado para pacientes com histórico de depressão associada com ideação ou comportamento suicida. Os pacientes devem ser orientados a comunicar seu médico caso apresentem alguma ideação suicida. INTERAÇÕES MEDICAMENTOSAS: estudos clínicos de interações medicamentosas com inibidores do CYP3A4 (eritromicina e cetoconazol) não resultaram em aumento da atividade inibitória total de PDE4 (exposição total ao roflumilaste e ao N-óxido roflumilaste); com o inibidor do CYP1A2 fluvoxamina e os inibidores duplos CYP3A4/1A2 enoxacina e cimetidina, os estudos demonstraram aumento na atividade inibitória total de PDE4. Dessa forma, deve-se esperar aumento de 20% a 60% na inibição total de PDE4 quando o roflumilaste for administrado concomitantemente com potentes inibidores do CYP1A2, como a fluvoxamina, embora não sejam esperadas interações com inibidores do CYP3A4, como cetoconazol. Não são esperadas interações medicamentosas clinicamente relevantes. A administração de rifampicina (indutor enzimático de CYP450) resultou em redução na atividade inibitória total de PDE4 de cerca de 60% e o uso de indutores potentes do citocromo P450 (como fenobarbital, carbamazepina, fenitoína) pode reduzir a eficácia terapêutica do roflumilaste.

Não se observou interações clinicamente relevantes com: salbutamol inalado, formoterol, budesonida, montelucaste, digoxina, varfarina, sildenafil, midazolam. A coadministração de antiácidos não altera a absorção nem as características farmacológicas do produto. A coadministração com teofilina aumentou em 8% a atividade inibitória sobre a fosfodiesterase 4. Quando utilizado com contraceptivo oral com gestodeno e etinilestradiol, a atividade inibitória sobre a fosfodiesterase 4 aumentou 17%.

Não há estudos clínicos que avaliaram o tratamento concomitante com xantinas, portanto não se recomenda o uso combinado a esse fármaco. REAÇÕES ADVERSAS: DAXAS foi bem avaliado em estudos clínicos e cerca de 16% dos indivíduos apresentaram reações adversas com o roflumilaste versus 5,7% com o placebo. As reações adversas mais frequentemente relatadas foram diarreia (5,9%), perda de peso (3,4%), náusea (2,9%), dor abdominal (1,9%) e cefaleia (1,7%). A maior parte dessas reações foram leves ou moderadas e desapareceram com a continuidade do tratamento. Os eventos adversos classificados por frequência foram: Reações comuns (> 1/100 e < 1/10):perda de peso, distúrbios do apetite, insônia, cefaleia, diarreia, náusea, dor abdominal. Reações incomuns (> 1/1.000 e < 1/100): hipersensibilidade, ansiedade, tremor, vertigem, tontura, palpitações, gastrite, vômitos, refluxo gastroesofágico, dispepsia, erupções cutâneas, espasmos musculares, fraqueza muscular, mal-estar, astenia, fadiga, dor muscular, lombalgia. Reações raras (> 1/10.000 e < 1/1.000): depressão e distúrbios do humor, ginecomastia, disgeusia, hematoquesia, obstipação intestinal, aumento de Gama – GT, aumento de transaminases, urticária, infecções respiratórias (exceto pneumonia), aumento de CPK. POSOLOGIA E ADMINISTRAÇÃO: a dose recomendada de DAXAS é de um comprimido uma vez ao dia. Não é necessário ajuste posológico para pacientes idosos, com insuficiência renal ou com insuficiência hepática leve (classes ‘A’ de Child-Pugh). DAXAS não deve ser administrado a pacientes com insuficiência hepática moderada ou grave (classe ‘B’ou ‘C’ de Child-Pugh). Os comprimidos de DAXAS devem ser administrados com a quantidade de água necessária para facilitar a deglutição e podem ser administrados antes, durante ou após as refeições. Recomenda-se que o medicamento seja administrado sempre no mesmo horário do dia, durante todo o tratamento. Este medicamento não deve ser partido ou mastigado. A PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. VENDA SOB PRESCRIÇÃO MÉDICA. REGISTRO MS: 1.0639.0257.

DX_0710_0211_VPS . *Marca Depositada.

Seus pacientes podem se beneficiar com uma ação anti-inflamatória e broncodilatadora por 12 horas, que é uma opção terapêutica segura, inclusive para crianças de 4

Componentes Parcerias confiáveis2

a 11 anos.

2

O Doutor pode oferecer aos seus pacientes uma dose consistente num dispositivo fácil de usar, com opção de spray com contador de doses.2,4

Dispositivo2 fácil de usar

A dosag em cert

a para c a pacient 2 da e

Um corpo extenso de evidências no qual o Doutor pode basear-se. Eficácia que definiu o padrão no tratamento da asma e da DPOC.3

Dados

es o padrõ5 definind to n e m de trata

6,7

Reduz a mortalidade e a progressão da DPOC, mesmo em pacientes moderados.

Seretide® é a terapia combinada que provou alcançar e manter o controle 3 da asma a longo prazo.

5,8

Ajude-os a sentir como a vida pode ser melhor.

O uso de Seretide® é contraindicado em pacientes com hipersensibilidade conhecida a qualquer componente da fórmula. Aconselha-se cautela ao coadministrar inibidores potentes do CYP3A4 (p. ex., cetoconazol).

Referências: 1. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease.Br J Pharmacol. 2011;163(1):53-67 Antes de prescrever DAXAS, recomendamos a leitura da Circular aos Médicos (bula) completa para informações detalhadas sobre o produto.

Contraindicações: alergia aos componentes da fórmula e pacientes com insuficiência hepática moderada ou grave. Interações Medicamentosas: a administração de indutores do citocromo

P450, como rifampicina e anticovulsivantes, pode reduzir a eficácia terapêutica do roflumilaste. Não existem estudos clínicos que avaliaram o tratamento concomitante com metilxantinas, portanto seu uso em associação não está recomendado.

Março/2012 - MC 707/11 05-2013-DAX-11-BR-707-J

Material de distribuição exclusiva para profissionais de saúde habilitados a prescrever ou dispensar medicamentos. Recomenda-se a leitura da bula e da monografia do produto, antes da prescrição de qualquer medicamento. Mais informações à disposição, sob solicitação do Serviço de Informação Médica (0800 701 2233 ou http://www.sim-gsk.com.br). Minibula do medicamento na próxima página desta edição.

REPENSE BR/SFC/0080/11 – FEV/12 Nycomed Pharma Ltda.

Rua do Estilo Barroco, 721 - CEP 04709-011 - São Paulo - SP Mais informações poderão ser obtidas diretamente com o nosso Departamento Médico ou por meio de nossos representantes.

Produto de uso sob prescrição médica.

A PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO.

A escolha de dosagem possibilita dar passos acima ou abaixo no tratamento da asma, se necessário.

No tratamento da DPOC, tem a força que o Doutor precisa para cada paciente.2,3

SERVIÇO DE INFORMAÇÃO MÉDICA 0800 701 2233 www.sim-gsk.com.br

www.gsk.com.br Estrada dos Bandeirantes, 8.464 • Jacarepaguá Rio de Janeiro • RJ • CEP 22783-110 CNPJ 33247743/0001-10

Published once every two months

J Bras Pneumol. v.38, number 5, p. 539-680 September/October 2012

Editor Chefe Carlos Roberto Ribeiro Carvalho – Universidade de São Paulo, São Paulo, SP

Editores Executivos

Associação Brasileira de Editores Científicos

Bruno Guedes Baldi - Universidade de São Paulo, São Paulo, SP Carlos Viana Poyares Jardim - Universidade de São Paulo, São Paulo, SP Pedro Caruso - Universidade de São Paulo, São Paulo, SP

Editores Associados Afrânio Lineu Kritski – Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ Álvaro A. Cruz – Universidade Federal da Bahia, Salvador, BA Celso Ricardo Fernandes de Carvalho - Universidade de São Paulo, São Paulo, SP Fábio Biscegli Jatene – Universidade de São Paulo, São Paulo, SP Geraldo Lorenzi-Filho – Universidade de São Paulo, São Paulo, SP Ilma Aparecida Paschoal – Universidade de Campinas, Campinas, SP José Alberto Neder – Universidade Federal de São Paulo, São Paulo, SP Renato Tetelbom Stein – Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS Sérgio Saldanha Menna-Barreto – Universidade Federal do Rio Grande do Sul, Porto Alegre, RS

Publicação Indexada em: Latindex, LILACS, Scielo Brazil, Scopus, Index Copernicus, ISI Web of Knowledge e MEDLINE Disponível eletronicamente nas versões português e inglês: www.jornaldepneumologia.com.br e www.scielo.br/jbpneu

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Alberto Cukier – Universidade de São Paulo, São Paulo, SP Ana C. Krieger – New York School of Medicine, New York, USA Ana Luiza Godoy Fernandes – Universidade Federal de São Paulo, São Paulo, SP Antonio Segorbe Luis – Universidade de Coimbra, Coimbra, Portugal Brent Winston – Department of Critical Care Medicine, University of Calgary, Calgary, Canada Carlos Alberto de Assis Viegas – Universidade de Brasília, Brasília, DF Carlos M. Luna – Hospital de Clinicas, Universidad de Buenos Aires, Buenos Aires, Argentina Carmen Silvia Valente Barbas – Universidade de São Paulo, São Paulo, SP Chris T. Bolliger – University of Stellenbosch, Stellenbosch, South Africa Dany Jasinowodolinski – Universidade Federal de São Paulo, São Paulo, SP Douglas Bradley – University of Toronto, Toronto, ON, Canadá Denis Martinez – Universidade Federal do Rio Grande do Sul, Porto Alegre, RS Edson Marchiori - Universidade Federal Fluminense, Niterói, RJ Emílio Pizzichini – Universidade Federal de Santa Catarina, Florianópolis, SC Frank McCormack – University of Cincinnati School of Medicine, Cincinnati, OH, USA Gustavo Rodrigo – Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Montevidéu, Uruguay Irma de Godoy – Universidade Estadual Paulista, Botucatu, SP Isabela C. Silva – Vancouver General Hospital, Vancouver, BC, Canadá J. Randall Curtis – University of Washington, Seattle, Wa, USA John J. Godleski – Harvard Medical School, Boston, MA, USA José Antonio Baddini Martinez - Universidade de São Paulo, Ribeirão Preto, SP José Dirceu Ribeiro – Universidade de Campinas, Campinas, SP, Brazil José Miguel Chatkin – Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS José Roberto de Brito Jardim – Universidade Federal de São Paulo, São Paulo, SP José Roberto Lapa e Silva – Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ Kevin Leslie – Mayo Clinic College of Medicine, Rochester, MN, USA Luiz Eduardo Nery – Universidade Federal de São Paulo, São Paulo, SP Marc Miravitlles – Hospital Clinic, Barcelona, España Marcelo Alcântara Holanda – Universidade Federal do Ceará, Fortaleza, CE Marcos Ribeiro – University of Toronto, Toronto, ON, Canadá Marli Maria Knorst – Universidade Federal do Rio Grande do Sul, Porto Alegre, RS Marisa Dolhnikoff – Universidade de São Paulo, São Paulo, SP Mauro Musa Zamboni – Instituto Nacional do Câncer, Rio de Janeiro, RJ Nestor Muller – Vancouver General Hospital, Vancouver, BC, Canadá Noé Zamel – University of Toronto, Toronto, ON, Canadá Paul Noble – Duke University, Durham, NC, USA Paulo Francisco Guerreiro Cardoso – Pavilhão Pereira Filho, Porto Alegre, RS Paulo Pego Fernandes – Universidade de São Paulo, São Paulo, SP Peter J. Barnes – National Heart and Lung Institute, Imperial College, London, UK Renato Sotto-Mayor – Hospital Santa Maria, Lisboa, Portugal Richard W. Light – Vanderbili University, Nashville, TN, USA Rik Gosselink – University Hospitals Leuven, Bélgica Robert Skomro – University of Saskatoon, Saskatoon, Canadá Rubin Tuder – University of Colorado, Denver, CO, USA Sonia Buist – Oregon Health & Science University, Portland, OR, USA Rogério de Souza – Universidade de São Paulo, São Paulo, SP Talmadge King Jr. – University of California, San Francisco, CA, USA Thais Helena Abrahão Thomaz Queluz – Universidade Estadual Paulista, Botucatu, SP Vera Luiza Capelozzi – Universidade de São Paulo, São Paulo, SP

SOCIEDADE BRASILEIRA DE PNEUMOLOGIA E TISIOLOGIA

Secretaria: SCS Quadra 01, Bloco K, Asa Sul, salas 203/204. Edifício Denasa, CEP 70398-900 - Brasília - DF, Brasil.

Telefone (55) (61) 3245-1030/ 0800 616218. Site: www.sbpt.org.br. E-mail: sbpt@sbpt.org.br O Jornal Brasileiro de Pneumologia ISSN 1806-3713, é uma publicação bimestral da Sociedade

Brasileira de Pneumologia e Tisiologia. Os conceitos e opiniões emitidos nos artigos são de inteira responsabilidade de seus autores. Permitida a reprodução total ou parcial dos artigos, desde que mencionada a fonte.

Diretoria da SBPT (Biênio 2010-2012): Presidente: Roberto Stirbulov (SP) Secretária-Geral: Terezinha Lima (DF) Diretora de Defesa Profissional: Clarice Guimarães Freitas (DF) Diretora Financeira: Elizabeth Oliveira Rosa Silva (DF) Diretor Científico: Bernardo Henrique F. Maranhão (RJ) Diretor de Ensino e Exercício Profissional: José Roberto de Brito Jardim (SP) Diretor de Comunicação: Adalberto Sperb Rubin (RS) Presidente do Congresso SBPT 2012: Renato Maciel (MG) Presidente Eleito (Biênio 2012/2014): Jairo Sponholz Araújo (PR) Presidente do Conselho Deliberativo: Jussara Fiterman (RS) CONSELHO FISCAL: Efetivos: Carlos Alberto Gomes dos Santos (ES), Marcelo Alcântara Holanda (CE), Saulo Maia Davila Melo (SE) Suplentes: Antônio George de Matos Cavalcante (CE), Clóvis Botelho (MT), Valéria Maria Augusto (MG) COORDENADORES DOS DEPARTAMENTOS DA SBPT: Ações Programáticas – Alcindo Cerci Neto (PR) Cirurgia Torácica – Fábio Biscegli Jatene (SP) Distúrbios Respiratórios do Sono – Simone Chaves Fagondes (RS) Endoscopia Respiratória – Ascedio José Rodrigues (SP) Função Pulmonar – Roberto Rodrigues Junior (SP) Imagem – Domenico Capone (RJ) Patologia Pulmonar – Rimarcs Gomes Ferreira (SP) Pesquisa Clínica – Oliver Augusto Nascimento (SP) Pneumologia Pediátrica – Marcus Herbert Jones (RS) Residência Médica – José Roberto de Brito Jardim (SP) COORDENADORES DAS COMISSÕES CIENTÍFICAS DA SBPT: Asma – Marcia Margareth Menezes Pizzichini (SC) Câncer Pulmonar – Guilherme Jorge Costa (PE) Circulação Pulmonar – Daniel Waetge (RJ) Doença Pulmonar Avançada – Valéria Maria Augusto (MG) Doenças intersticiais – Bruno Guedes Baldi (SP) Doenças Respiratórias Ambientais e Ocupacionais – Hermano Albuquerque de Castro (RJ) DPOC – Fernando Luiz Cavalcanti Lundgren (PE) Epidemiologia – Antônio George de Matos Cavalcante (CE) Fibrose Cística – José Dirceu Ribeiro (SP) Infecções Respiratórias e Micoses – Mara Rúbia Fernandes de Figueiredo (CE) Pleura – Cyro Teixeira da Silva Júnior (RJ) Relações Internacionais – Mauro Musa Zamboni (RJ) Tabagismo – Alberto José de Araújo (RJ) Terapia Intensiva – Octávio Messeder (BA) Tuberculose – Marcelo Fouad Rabahi (GO) SECRETARIA ADMINISTRATIVA DO JORNAL BRASILEIRO DE PNEUMOLOGIA Endereço: SCS Quadra 01, Bloco K, Asa Sul, salas 203/204. Edifício Denasa, CEP 70398-900 - Brasília - DF, Brasil. Telefone (55) (61) 3245-1030/ 0800 616218.

Secretária: Luana Maria Bernardes Campos. E-mail: jpneumo@jornaldepneumologia.com.br Revisão de português, assessoria técnica e tradução: Precise Editing Editoração: Editora Cubo Site, sistema de submissão on-line e marcação em linguagem SciELO: GN1 - Genesis Network Tiragem: 1100 exemplares Distribuição: Gratuita para sócios da SBPT e bibliotecas Impresso em papel livre de ácidos APOIO:

Published once every two months

J Bras Pneumol. v.38, number 5, p. 539-680 September/October 2012

EDITORIAL

539 - Cardiopulmonary exercise testing: beyond maximal oxygen uptake

Teste cardiopulmonar de exercício na DPOC: indo além do consumo máximo de oxigênio Eloara Vieira Machado Ferreira

ORIGINAL ARTICLES / ARTIGOS ORIGINAIS 541 - Muscle strength as a determinant of oxygen uptake efficiency and maximal metabolic response in patients with mild-to-moderate COPD

Força muscular como determinante da eficiência do consumo de oxigênio e da máxima resposta metabólica ao exercício em pacientes com DPOC leve/moderada Paulo de Tarso Guerrero Müller, Carlos Alberto de Assis Viegas, Luiz Armando Pereira Patusco

550 - Prevalence and duration of social security benefits allowed to workers with asthma in Brazil in 2008

Prevalência e duração dos benefícios auxílio-doença decorrentes de asma no Brasil em 2008 Anadergh Barbosa de Abreu Branco, Simone de Andrade Goulart Ildefonso

559 - Analysis and validation of probabilistic models for predicting malignancy in solitary pulmonary nodules in a population in Brazil

Análise e validação de modelos probabilísticos de malignidade de nódulo pulmonar solitário em uma população no Brasil Cromwell Barbosa de Carvalho Melo, João Aléssio Juliano Perfeito, Danilo Félix Daud, Altair da Silva Costa Júnior, Ilka Lopes Santoro, Luiz Eduardo Villaça Leão

566 - Electric Ventilation: indications for and technical aspects of diaphragm pacing stimulation surgical implantation

Ventilação elétrica: indicações e aspectos técnicos do implante cirúrgico do marca-passo de estimulação diafragmática

Miguel Lia Tedde, Raymond P Onders, Manoel Jacobsen Teixeira, Silvia Gelas Lage, Gerson Ballester, Mario Wilson Iersolino Brotto, Erica Mie Okumura, Fabio Biscegli Jatene 573 - Quantitative assessment of the intensity of palmar and plantar sweating in patients with primary palmoplantar hyperhidrosis

Avaliação quantitativa da intensidade da transpiração palmar e plantar em pacientes portadores de hiperidrose palmoplantar primária Bruno Yoshihiro Parlato Sakiyama, Thaís Vera Monteiro, Augusto Ishy, José Ribas Milanez de Campos, Paulo Kauffman, Nelson Wolosker

579 - Responsiveness of the six-minute step test to a physical training program in patients with COPD

Responsividade do teste do degrau de seis minutos a um programa de treinamento físico em pacientes com DPOC Kamilla Tays Marrara, Diego Marmorato Marino, Maurício Jamami, Antônio Delfino de Oliveira Junior, Valéria Amorim Pires Di Lorenzo

588 - Maternal malnutrition during lactation in Wistar rats: effects on elastic fibers of the extracellular matrix in the trachea of offspring

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J Bras Pneumol. v.38, number 5, p. 539-680 September/October 2012

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Editorial Cardiopulmonary exercise testing in COPD patients: beyond maximal oxygen uptake Teste cardiopulmonar de exercício na DPOC: indo além do consumo máximo de oxigênio

Eloara Vieira Machado Ferreira Worldwide, COPD is one of the leading causes of morbidity and mortality, causing significant impairment in quality of life and an enormous resource burden due to increased outpatient and inpatient costs. One of the main characteristics of the disease is the presence of dyspnea on exertion, which becomes increasingly limiting as the disease progresses. In COPD, exercise intolerance is multifactorial and integrally involves the respiratory, cardiovascular, and musculoskeletal systems, with the presence of airflow limitation (due to reduced ventilatory capacity), respiratory muscle dysfunction, lung hyperinflation, metabolic abnormalities, gas exchange abnormalities, peripheral muscle dysfunction, and cardiovascular abnormalities.(1) All of these factors contribute to dyspnea and fatigability at low exercise intensities, therefore limiting activities of daily living.

A variety of tests of proven prognostic importance are available to assess COPD patients during exercise, including the six-minute walk test combined with the Body mass index, airway Obstruction, Dyspnea, and Exercise capacity (BODE) index. However, the six-minute walk distance is only a marker of functional capacity, given that it does not evaluate the mechanisms of exercise limitation. In contrast, cardiopulmonary exercise testing (CPET) can provide more useful information regarding multiple limiting factors.(1) Traditionally, oxygen uptake at peak incremental CPET has been the variable to which the most weight has been given. However, because this variable is highly effort-dependent and because the determinants of exercise intolerance are nonspecific, other variables, particularly those measured during testing (i.e., submaximal variables), have been progressively incorporated into clinical assessment

by CPET. In 1996, Baba et al.(2) proposed that the slope of the linear relationship between oxygen uptake (y) and the logarithm of minute ventilation (x) be used as a marker—the oxygen uptake efficiency

slope (OUES)—a steeper slope translating to greater oxygen uptake efficiency. At least theoretically, the OUES involves the integration of multiple systems during exercise and is influenced by oxygen supply and use, as well as by the muscle mass involved and the ventilatory response to exercise. It is known that the ventilatory response to exercise depends on the metabolic demand (carbon dioxide production and lactic acidosis), as well as on ventilatory efficiency (dead space to tidal volume ratio) and on factors affecting the respiratory drive (hypoxemia and the carbon dioxide set point). Therefore, the OUES is influenced by various systems, constituting an indirect marker of cardiopulmonary reserve.(2,3) The OUES has been studied especially in patients with cardiovascular dysfunction, its importance as a prognostic factor in chronic heart failure having been demonstrated.(4) However, it is of note that, despite being considered a submaximal variable, the OUES is influenced by exercise intensity, and it should be given weight especially when patients with chronic heart failure have exercised enough, as indicated by a ratio of carbon dioxide production to oxygen uptake > 1.0.(3) In the current issue of the Brazilian Journal of Pulmonology, Müller et al.(5) investigated cardiovascular impairment and the role of peripheral and respiratory muscle strength in reducing the OUES in patients with mild-tomoderate COPD. This approach makes sense within the current concept that such patients have various comorbidities, including cardiovascular dysfunction.(6,7) Nutritional changes, weight loss, and skeletal muscle dysfunction can also occur, especially in the later stages of the disease.(8) However, in the study in question, the authors found that the OUES was within the predicted range for normal individuals. This finding suggests that cardiopulmonary reserve was adequate in the study population. In fact, the patients evaluated had relatively preserved aerobic capacity, their anaerobic threshold was within the expected J Bras Pneumol. 2012;38(5):539-540

540

range, they had no cardiovascular impairment, and most had no signs of airflow limitation, meaning that the factors that could have affected oxygen uptake efficiency were absent or only slightly altered. In addition, peripheral muscle strength and respiratory muscle strength were found to be relatively preserved. These findings are in contrast with those reported by Terziyski et al.(9) and, in particular, with those reported by Tzani et al.(10) in patients with more advanced disease, in whom the OUES was actually reduced.

A joint analysis of the results of the study

by Müller et al.(5) and those reported in the abovementioned studies(9,10) allows us to conclude that evaluating the OUES seems to be more relevant in patients with COPD that is more severe, in whom airflow limitation and cardiovascular limitation are more common, and in those with mild COPD and underlying cardiovascular disease.

In that same line of thought, it is expected that reduced OUES, together with other CPET variables, can assist in the prognostic evaluation of this population, especially if we take into consideration the central role that cardiovascular comorbidities play in COPD mortality. These questions remain unanswered, and more studies like the study

by Müller et al.(5) will certainly contribute to incorporating CPET into the clinical assessment of COPD patients.

Eloara Vieira Machado Ferreira Pulmonologist, Pulmonary Circulation Group/ Pulmonary Function and Exercise Physiology Section, Department of Pulmonology,

Universidade Federal de São Paulo/ Escola Paulista de Medicina – UNIFESP/ EPM, Federal University of São Paulo/ Paulista School of Medicine – São Paulo, Brazil

J Bras Pneumol. 2012;38(5):539-540

References 1. ERS Task Force, Palange P, Ward SA, Carlsen KH, Casaburi R, Gallagher CG, et al. Recommendations on the use of exercise testing in clinical practice. Eur Respir J. 2007;29(1):185-209. PMid:17197484.

2. Baba R, Nagashima M, Goto M, Nagano Y, Yokota M, Tauchi N, et al. Oxygen uptake efficiency slope: a new index of cardiorespiratory functional reserve derived from the relation between oxygen uptake and minute ventilation during incremental exercise. J Am Coll Cardiol. 1996;28(6):1567-72. http://dx.doi.org/10.1016/ S0735-1097(96)00412-3 3. Hollenberg M, Tager IB. Oxygen uptake efficiency slope: an index of exercise performance and cardiopulmonary reserve requiring only submaximal exercise. J Am Coll Cardiol. 2000;36(1):194-201. http://dx.doi.org/10.1016/ S0735-1097(00)00691-4 4. Davies LC, Wensel R, Georgiadou P, Cicoira M, Coats AJ, Piepoli MF, et al. Enhanced prognostic value from cardiopulmonary testing in chronic heart failure by non-linear analysis: oxygen uptake efficiency slope. Eur Heart J. 2006;27(6):684-90. PMid:16338939. http:// dx.doi.org/10.1093/eurheartj/ehi672 5. Mueller PT, Viegas CA, Patusco LA. Muscle strength as a determinant of oxygen uptake efficiency and maximal metabolic response in patients with mild-to-moderate COPD. J Bras Pneumol. 2012;38(5):541-549.

6. Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J. 2009;33(5):1165-85. PMid:19407051. http://dx.doi. org/10.1183/09031936.00128008 7. Miranda EF, Malaguti C, Corso SD. Peripheral muscle dysfunction in COPD: lower limbs versus upper limbs.

J Bras Pneumol. 2011;37(3):380-8. PMid:21755195. http://dx.doi.org/10.1590/S1806-37132011000300016 8. Borghi-Silva A, Oliveira CC, Carrascosa C, Maia J, Berton DC, Queiroga F Jr, et al. Respiratory muscle unloading improves leg muscle oxygenation during exercise in patients with COPD. Thorax. 2008;63(10):910-5. PMid:18492743. http://dx.doi.org/10.1136/thx.2007.090167 9. Terziyski KV, Marinov BI, Aliman OI, St Kostianev S. Oxygen uptake efficiency slope and chronotropic incompetence in chronic heart failure and chronic obstructive pulmonary disease [abstract]. Folia Med (Plovdiv). 2009;51(4):18-24.

10. Tzani P, Aiello M, Elia D, Boracchia L, Marangio E, Olivieri D, et al. Dynamic hyperinflation is associated with a poor cardiovascular response to exercise in COPD patients.

Respir Res. 2011;12:150. PMid:22074289 PMCid:3225311. http://dx.doi.org/10.1186/1465-9921-12-150

Original Article Muscle strength as a determinant of oxygen uptake efficiency and maximal metabolic response in patients with mild-to-moderate COPD* Força muscular como determinante da eficiência do consumo de oxigênio e da máxima resposta metabólica ao exercício em pacientes com DPOC leve/moderada

Paulo de Tarso Guerrero Müller, Carlos Alberto de Assis Viegas, Luiz Armando Pereira Patusco

Abstract Objective: To compare the behavior of the oxygen uptake efficiency slope (OUES) with that of oxygen uptake at peak exertion (VO2peak). Methods: This was a prospective cross-sectional study involving 21 patients (15 men) with mild-to-moderate COPD undergoing spirometry, handgrip strength (HGS) testing, cardiopulmonary exercise testing, and determination of lactate at peak exertion (LACpeak). Results: Mean weight was 66.7 ± 13.6 kg, and mean age was 60.7 ± 7.8 years. With the exception of FEV1 and FEV1/FVC ratio (75.8 ± 18.6% of predicted and 56.6 ± 8.8%, respectively), all spirometric variables were normal, as was HGS. The patients exhibited significant metabolic and hemodynamic stress, as evidenced by the means (% of predicted) for VO2peak (93.1 ± 15.4), maximum HR (92.5 ± 10.4), and OUES (99.4 ± 24.4), as well as for the gas exchange rate (1.2 ± 0.1). The correlation between VO2peak and OUES was significant (r = 0.747; p < 0.0001). The correlation between HGS and VO2peak (r = 0.734; pX< 0.0001) was more significant than was that between HGS and OUES (r = 0.453; p < 0.05). Similar results were found regarding the correlations of VO2peak and OUES with MIP. Although LACpeak correlated significantly with VO2peak (r = −0.731; p < 0.0001), only LACpeak/maximum power correlated significantly with OUES (r = −0.605; p = 0.004). Conclusions: Our findings suggest that, in mild-to-moderate COPD, VO2 determinants other than overall muscle strength have a greater impact on OUES than on VO2peak.

Keywords: Respiratory function tests; Pulmonary disease, chronic obstructive; Muscle strength; Oxygen consumption.

Resumo Objetivo: Comparar o comportamento de oxygen uptake efficiency slope (OUES, inclinação da eficiência do consumo de oxigênio) com o do consumo de oxigênio no pico do exercício (VO2pico). Métodos: Estudo prospectivo transversal envolvendo 21 pacientes (15 homens) com DPOC leve/moderada que foram submetidos a espirometria, dinamometria de preensão palmar (DIN), teste cardiopulmonar de exercício e medida de lactato no pico do exercício (LACpico). Resultados: A média de peso foi 66,7 ± 13,6 kg, e a de idade foi 60,7 ± 7,8 anos. Com exceção de VEF1 e relação VEF1/CVF (75,8 ± 18,6 do previsto e 56,6 ± 8,8, respectivamente), as demais variáveis espirométricas foram normais, assim como DIN. As médias, em % do previsto, para VO2pico (93,1 ± 15,4), FC máxima (92,5 ± 10,4) e OUES (99,4 ± 24,4), assim como a da taxa de troca respiratória (1,2 ± 0,1), indicaram estresse metabólico e hemodinâmico importante. A correlação entre o VO2pico e a OUES foi elevada (r = 0,747; p < 0,0001). A correlação entre DIN e VO2pico (r = 0,734; p < 0,0001) foi mais expressiva do que com aquela entre DIN e OUES (r = 0,453; p < 0,05). Resultados semelhantes ocorreram em relação às correlações de VO2pico e OUES com PImáx. Houve correlação significativa entre VO2pico e LACpico (r = −0,731; p < 0,0001), mas essa só ocorreu entre OUES e LACpico/potência máxima (r = −0,605; p = 0,004). Conclusões: Nossos resultados sugerem que, na DPOC leve/moderada, determinantes do VO2, além da força muscular global, têm um maior impacto na OUES do que no VO2pico.

Descritores: Testes de função respiratória; Doença pulmonar obstrutiva crônica; Força muscular; Consumo de oxigênio.

* Study carried out at the Federal University of Mato Grosso do Sul, Campo Grande, Brazil.

Correspondence to: Paulo de Tarso Guerrero Müller. Avenida Filinto Müller, s/n, Campus da Universidade Federal de Mato Grosso do Sul, Faculdade de Medicina, Vila Ipiranga, CEP 79070-900, Campo Grande, MS, Brasil.

Tel. 55 67 3345-3149 or 55 67 9291-0441. E-mail: paulo.muller@ufms.br Financial support: None.

Submitted: 8 March 2012. Accepted, after review: 15 August 2012.

J Bras Pneumol. 2012;38(5):541-549

542

Mueller PT, Viegas CAA, Patusco LAP

Introduction Worldwide, COPD is one of the leading causes of morbidity and mortality, causing significant musculoskeletal morbidity and reducing quality of life.(1) The main methods for evaluating and monitoring the effectiveness of COPD treatment are assessment of exercise capacity and assessment of respiratory and peripheral muscle strength.

(1) Cardiopulmonary exercise testing (CPET) is one of the most important methods in this context because it combines comprehensive cardiopulmonary and metabolic analyses, including oxygen consumption (VO2) and gas exchange; however, useful variables such as oxygen uptake efficiency have been little studied in patients with COPD. Oxygen uptake efficiency, i.e., the VO2 required in order to meet a given ventilatory demand, can be determined by calculating the ratio between VO2 and minute ventilation (VE) or by log-transforming VE (log10VE), thus obtaining the derivative of the VO2/VE ratio—known as the oxygen uptake efficiency slope (OUES)—as proposed by Baba et al.(2) A more recent study has described another way of determining the relationship between VO2 and VE, i.e., by calculating the oxygen uptake efficiency plateau.(3) The OUES can play an important role in the assessment of aerobic capacity based on submaximal data obtained after pharmacological or non-pharmacological intervention in patients whose exercise capacity is more limited. Maximal effort on CPET might be inappropriate, increasing risks and patient discomfort. In addition, stage I/II COPD commonly overlaps with other diseases, such as heart failure, diabetes, and peripheral vascular disease, the presence of multiple comorbidities therefore compromising the assessment of maximal exercise capacity.(4) Although some studies have analyzed the OUES in normal individuals and in adults with heart failure,(5,6) only one study has done so in patients with COPD.(7) The study focused on the role of dynamic hyperinflation (DH) in reducing the OUES, the role of muscle strength not having been evaluated. Considering that the OUES is independent of maximal effort, the authors suggested that DH plays an important role in decreasing cardiac output (indirectly assessed by measuring SpO2) and in peripheral perfusion; DH was reported as being the principal cause of J Bras Pneumol. 2012;38(5):541-549

reduced OUES, and the role of overall muscle strength was not taken into consideration.(7) The OUES depends on the development of metabolic acidosis, on muscle mass, on oxygen extraction and use, and on physiological pulmonary dead space, which is affected by lung perfusion and structural integrity.(8) It has been suggested that the relationship between muscle strength and OUES depends on muscle mass. However, to our knowledge, this has never been investigated.

Maximal metabolic response to CPET depends on the exercise protocol, encouragement, type of ergometer, peripheral muscle strength, and respiratory muscle strength.(8,9) (Overall) muscle strength is more preserved in the early stages of COPD.(9,10) Therefore, a relevant question is the extent to which a more preserved muscle function, less susceptible to the limiting influence of DH in patients with mild-to-moderate COPD,(11) is a determinant of maximal metabolic response, as evaluated by the lactate level and peak VO2 (VO2peak), in comparison with a submaximal variable reported as being independent of maximal effort, i.e., OUES. The objective of the present study was to compare the behavior of the OUES with that of the gold standard (VO2peak) in a population of outpatients diagnosed with stage I/II COPD in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. We chose to study patients with stage I/II COPD in order to avoid the strong effects of DH on the cardiocirculatory profile of patients with severe COPD. Considering that VO2 efficiency is a variable that depends less on maximal effort during exercise in order to be assessed, we hypothesized that the correlation of this variable with parameters of (peripheral and respiratory) muscle strength at rest and maximal lactate levels was lower.

Methods This was a prospective cross-sectional study involving patients recruited from among those being treated at a COPD outpatient clinic or at a smoking outpatient clinic and referred for spirometry. All patients had been diagnosed with stage I/II COPD in accordance with the GOLD criteria(1) and had a post-bronchodilator FEV1/FVC ratio < 70% of predicted and an FEV1 > 50% of predicted, in accordance with reference values for the Brazilian population.(12)

Muscle strength as a determinant of oxygen uptake efficiency and maximal metabolic response in patients with mild-to-moderate COPD

The criteria for patient selection were as follows: being ≥ 40 years of age; having a smoking history or being a smoker of ≥ 10 pack-years; having experienced no exacerbations in the four weeks preceding the tests; being able to perform exercise tests; being able, from a cardiovascular and metabolic standpoint, to perform the exercise tests; not having coronary/peripheral ischemia, diabetes, hypothyroidism, hyperthyroidism, rheumatic disease, neurological disease, asthma, cognitive deficit, or obstructive sleep apnea; and not using beta-blockers to control mild systemic arterial hypertension. All of the patients gave written informed consent. The study protocol was approved by the Human Research Ethics Committee of the Federal University of Mato Grosso do Sul. In the first visit, the patients received information on the tests and the following were performed: physical examination; anthropometric data collection; anamnesis (including history of comorbidities and current use of medications); spirometry; measurement of lung volumes and maximal respiratory pressures; handgrip strength (HGS) testing; and arterial blood gas analysis, with appropriate intervals between tests in order to prevent muscle fatigue or discomfort. In the second visit, the patients underwent CPET, capillary blood samples being collected before and after testing. Spirometry and bronchodilator testing were performed in accordance with national guidelines,(13) with a MasterScreen PFT spirometer (Jaeger, Würzburg, Germany). For bronchodilator testing, 400 µg of inhaled albuterol were used.

Lung volumes were determined with the same spirometer and the multiple-breath closed-circuit helium dilution technique for calculating functional residual capacity in accordance with national guidelines and reference values for the Brazilian population.(13,14) Maximal respiratory pressures were measured in accordance with national guidelines,(13) with a digital manometer (model MVD 300; Globalmed, Porto Alegre, Brazil), the signals being read and recorded through individual ducts and precision of 1 cmH2O. A 2-mm hole in the circuit prevented false measurements due to involuntary contractions of the cheeks. The results were provided in cmH2O, and the graphs obtained gave us an idea of the quality of the test. Before the actual test, each patient performed 2-3 measurements in order

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to become familiar with it. The predicted values were those of Neder et al.(15) A dynamometer (Jamar; Preston, Jackson, MI, USA) was used in order to measure HGS. The patients were placed in a sitting position, with the arm adducted and parallel to the trunk, the elbow flexed at 90°, and the forearm and wrist in a neutral position. Three measurements were performed, at least 1 min apart, alternating between the dominant and non-dominant arms; the highest value was recorded.(16) Reference values for the Brazilian population were derived from those of Novaes et al.(17) In order to measure blood gases and arterial blood pH, we used an ABL 5 gas analyzer (Radiometer, Copenhagen, Denmark) under anaerobic conditions, through radial artery puncture, in accordance with international recommendations.(18) For CPET, we used the criteria and protocols recommended in national guidelines.(13) The test was performed in a metabolic system (Oxycon Delta system; Jaeger, Würzburg, Germany) with a mixing chamber for proportional ergospirometry. The system was connected to a program (OxyconLAB; Jaeger) and a cycle ergometer (ER 900; ergoline GmbH., Bitz, Germany) with electromagnetic brakes, the workload and protocol being generated by the program. Calibration was performed before each test, in accordance with the manufacturer protocols, and biological calibration was performed every three months. We defined VO2peak as the mean of the last 15 s at peak exertion. Symptomlimited maximal exercise tolerance was defined as intolerable shortness of breath or leg fatigue preventing cycling at > 50 breaths/min. Maximal voluntary ventilation (MVV) was estimated by multiplying FEV1 by 37.5.(15) The anaerobic threshold (AT) was determined by the V-slope method.(19) The test protocol (incremental ramp protocol) was individualized on the basis of the Wasserman formula to increase the workload and on the basis of the predicted maximal VO2,(20) the predicted value being based on the reference values for the Brazilian population proposed by Neder et al.(21) Lactate was determined from a fingertip blood sample by reflectance photometry (660 nm) with a portable system (Accutrend Lactate; Roche, Mannheim, Germany).

The results are expressed as mean ± SD, and the normality of data distribution was evaluated by the Kolmogorov-Smirnov test. Correlations among variables were established by Pearson’s J Bras Pneumol. 2012;38(5):541-549

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correlation coefficient. In order to calculate the OUES, we log-transformed VE (log10VE) and performed a simple regression analysis: VO2 = a × logVE + b where “a” represents the OUES in L and “b” is a constant.

For this calculation, we used the entire period of exercise, because it has been shown that the logarithmic transformation of VE reduces the slope because of the anaerobic wave.(2) Maximal metabolic response was measured by VO2peak and by the ratio between lactate at peak exertion (LACpeak), in mM, and maximum power, in W. Maximum power was used in order to adjust for possible gender bias in aerobic capacity.

Results The data related to anthropometric variables, spirometry, lung volumes, muscle strength, and blood gas analysis in the study population are shown in Table 1. The study sample consisted of 21 patients (15 men), the mean age being 60.7 ± 7.8 years. Lung volumes, peripheral muscle strength, and respiratory muscle strength (all in % of predicted) were within the normal range, as were PaO2 and PaCO2 at rest.

The means of the metabolic, ventilatory, and hemodynamic values selected at peak exertion are shown in Table 2. The values of VO2peak, maximum power, and maximum HR, all in% of predicted, were consistent with those expected for a population of patients with mild-to-moderate COPD. Only 2 patients showed a > 4% drop in SpO2 during exercise, and 7 patients showed evidence of airflow limitation. Of those 7 patients, 1 was female (VE/MVV > 0.75) and 6 were male (VE/MVV > 0.85).

It was impossible to determine the AT in 1 patient only (FEV1 = 51.2% of predicted). For the remaining patients, the mean VO2 at the AT was 1.1 ± 0.3 L/min, its correlation with the OUES being unusually high (r = 0.899; p < 0.0001).

The OUES correlated significantly with VO2peak (r = 0.747; p < 0.0001). Although there are no reference values for the OUES in the Brazilian population, the mean OUES found in the present study (99.4 ± 24.4% of predicted) was consistent with the normal range reported in one study.(21) Table 3 presents the coefficients of correlation of variables at rest/during exercise with peripheral/ respiratory muscle strength variables in the study J Bras Pneumol. 2012;38(5):541-549

population. As can be seen in Table 3, OUES and weight-indexed OUES, respectively, showed a weaker correlation with peripheral muscle strength (r = 0.453, p < 0.05; and r = 0.345, p > 0.05) and MIP (r = 0.532 and r = 0.454; p < 0.05 for both) than did VO2peak and weight-indexed VO2peak, respectively (r = 0.734, p < 0.0001 and r = 0.641, p < 0.01; and r = 0.733, p < 0.0001 and r = 0.681, p < 0.01; Figure 1).

We found no significant correlation between OUES and LACpeak. However, we found a significant negative correlation between OUES and LACpeak corrected for maximum exercise power (r = −0.605 and p = 0.004; Figure 2), as well as between

Table 1 - Anthropometric variables and pulmonary function variables at rest in the patients studied.a Variable Result Weight, kg 66.7 ± 13.6 Height, cm 163.8 ± 8.7 BMI, kg/m2 24.8 ± 4.4 Age, years 60.7 ± 7.8 M/F gender, n/n 15/6 Spirometry FEV1, L 2.2 ± 0.8 FEV1, % of predicted 75.8 ± 18.6 FVC, L 3.7 ± 1.1 FVC, % of predicted 102.9 ± 16.5 IC, L 2.5 ± 0.7 IC, % of predicted 89.1 ± 21.0 FEV1/FVC, % 56.6 ± 8.8 Lung volumes RV, L 2.5 ± 0.7 RV, % of predicted 135.9 ± 26.3 FRC, L 3.7 ± 1.1 FRC, % of predicted 112.0 ± 24.8 TLC, L 6.4 ± 1.5 TLC, % of predicted 105.5 ± 10.6 Muscle strength MIP, cmH2O 98.0 ± 27.9 MIP, % of predicted 101.5 ± 25.4 MEP, cmH2O 125.1 ± 25.8 MEP, % of predicted 119.9 ± 18.9 HGS, kgf 35.5 ± 11.6 HGS, % of predicted 102.6 ± 18.6 Arterial blood gas analysis PaO2, mmHg 77.0 ± 9.0 PaCO2, mmHg 37.4 ± 3.7 BMI: body mass index; IC: inspiratory capacity; FRC: functional residual capacity; and HGS: handgrip strength. a Values expressed as mean ± SD, except where otherwise indicated.

Muscle strength as a determinant of oxygen uptake efficiency and maximal metabolic response in patients with mild-to-moderate COPD

Table 2 - Variables at peak exertion during incremental cycle ergometer exercise in the patients studied.a Variable Result VO2peak, L/min 1.5 ± 0.5 VO2peak, % of predicted 93.1 ± 15.4 VO2 at the AT, L/min 1.1 ± 0.3 OUES, L/min/log(L/min) 2.0 ± 0.7 OUES/weight, L/min/log(L/min)/kg 30.0 ± 7.7 OUES, % of predicted 99.4 ± 24.4 SpO2peak, mL/heartbeat 9.1 ± 2.8 SpO2peak, % 95.0 ± 1.9 Wmax, watts 105.0 ± 45.5 Wmáx,% of predicted 86.5 ± 30.7 VTpeak, L 1.7 ± 0.6 RRmax, breaths/min 34.1 ± 5.8 VEmax, L/min 58.8 ± 20.4 VEmax, % of predicted 73.8 ± 15.9 VEmáx/VVM, % 73.7 ± 0.1 HRmax, bpm 147.4 ± 17.3 HRmax, % of predicted 92.5 ± 10.4 RER 1.2 ± 0.1 PASmax, mmHg 210.8 ± 27.9 PADmax, mmHg 101.2 ± 22.2 LACpeak, mM 7.1 ± 2.1 VO2peak: oxygen uptake at peak exertion; AT: anaerobic threshold; OUES: oxygen uptake efficiency slope; SpO2peak: SpO2 at peak exertion; Wmax: maximum power; VTpeak: tidal volume at peak exertion; RRmax: maximum RR; VEmax: minute ventilation at peak exertion; MVV: maximal voluntary ventilation; HRmax: maximum HR; RER: respiratory exchange ratio at peak exertion; SBPmax: maximum systolic blood pressure; DBPmax: maximum diastolic blood pressure; and LACpeak: lactate at peak exertion. aValues expressed as mean ± SD.

LACpeak/maximum power and VO2peak (r = −0.720 and p < 0.0001; Figure 2). In addition, we found moderate correlations between HGS and SpO2 at peak exertion (r = 0.653 and p < 0.01; Table 3) and between SpO2 at peak exertion and MIP (r = 0.585 and p < 0.01; Table 3).

Discussion The principal finding of the present study is that VO2peak correlates better with peripheral and respiratory muscle strength than with the OUES in patients with mild-to-moderate COPD. In addition, the mean OUES was found to be normal for this group of patients with mild-tomoderate COPD, although one third of the patients showed some degree of airflow limitation during

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cycle ergometer exercise. Some of our findings are consistent with previous findings showing generally preserved aerobic capacity (VO2peak) in patients with mild-to-moderate COPD.(22) Some of the advantages of using the OUES in healthy and ill individuals alike are as follows: • There are no significant differences between the results obtained with a cycle ergometer and those obtained with a treadmill.(3) • Reproducibility studies have found an extremely high coefficient of variation for the submaximal variable VO2 at the AT, which varies according to the calculation method used.(8) • The OUES can be obtained with submaximal exercise, showing high correlation with VO2peak.(8,23,24) • The OUES has been shown to be more stable and reproducible than VO2peak, especially after training and rehabilitation.(8) However, further studies involving patients with COPD are needed.

Regarding the correlation between OUES and VO2peak, our findings are consistent with those reported in a recent review of the OUES, in which the correlation coefficient was found to range from 0.72 to 0.96 across the studies.(8) However, our finding of an unexpectedly strong correlation between VO2 at the AT and OUES is at odds with those of that review, in which the correlation coefficient was found to range from 0.66 to 0.78 across the studies.(8) Possible explanations for this difference include the type of disease studied, the size of the clinical population, and the criteria for determining VO2 at the AT. In this aspect, because OUES is a submaximal measurement, it has the advantage of reflecting the effects of metabolic acidosis and those of physiological pulmonary dead space, whereas VO2 at the AT primarily reflects the distribution of blood flow to the exercising muscles.(2) The OUES estimates the efficiency of ventilation in relation to VO2, a higher slope translating to greater ventilatory efficiency. In fact, the OUES reflects the absolute rate of increase in VO2 for a tenfold increase in ventilation.(25) The increase in ventilation in patients with mild-to-moderate COPD is also limited by DH.(26,27) Because a greater ventilatory demand is one of the determinants of DH, it is reasonable to assume that a proportion of patients in the present study showed DH during exercise, given that 33% of the patients J Bras Pneumol. 2012;38(5):541-549

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Table 3 - Correlations of variables during exercise and at rest with parameters of peripheral and respiratory muscle strength.

HGS, kgf MIP, cmH2O Variable r p r p OUES, L/min/log(L/min) 0.453 < 0.05 0.532 < 0.05 OUES/weight, L/min/log(L/min)/kg NS 0.454 < 0.05 OUES/BS, L/min/log(L/min)/m2 NS 0.492 < 0.05 VO2peak, L/min 0.734 < 0.0001 0.733 < 0.0001 VO2peak, mL/kg/min 0.641 < 0.01 0.681 < 0.01 VO2peak, % of predicted NS 0.440 < 0.05 VO2 at the AT, mL/min 0.542 < 0.05 0.506 < 0.05 LACpeak, mmol/L 0.637 < 0.01 0.437 < 0.05 FEV1, % of predicted 0.434 < 0.05 0.527 < 0.05 TLC, % of predicted 0.486 < 0.05 0.593 < 0.01 PaO2, mmHg 0.479 < 0.05 0.530 < 0.05 Wmax, watts 0.756 < 0.0001 0.577 < 0.01 VEmax, L/min 0.738 < 0.0001 0.654 < 0.01 HRmax, bpm 0.491 < 0.05 0.636 < 0.01 SpO2peak, mL/bpm 0.653 < 0.01 0.585 < 0.01 HGS: handgrip strength; OUES: oxygen uptake efficiency slope; NS: not significant; BS: body surface; VO2peak: oxygen uptake at peak exertion; AT: anaerobic threshold; LACpeak: lactate at peak exertion; Wmax: maximum power; VEmax: minute ventilation at peak exertion; HRmax: maximum HR; and SpO2peak: SpO2 at peak exertion.

Figure 1 - Relationship of the submaximal variable oxygen uptake efficiency slope (OUES) with peripheral muscle strength (in A), as measured by handgrip strength (HGS) testing, and with respiratory muscle strength (in B), as measured by MIP, followed by the relationship of oxygen uptake at peak exertion (VO2peak) with HGS (in C) and MIP (in D).

J Bras Pneumol. 2012;38(5):541-549

Muscle strength as a determinant of oxygen uptake efficiency and maximal metabolic response in patients with mild-to-moderate COPD

Figure 2 - In A, relationship of oxygen uptake at peak exertion (VO2peak) with the ratio between lactate at peak exertion (LACpeak) and the maximum power achieved (Wmax). In B, relationship of the oxygen uptake efficiency slope (OUES) with the ratio between LACpeak and Wmax.

showed evidence of airflow limitation (VE/MVV > 0.75). In theory, this can lead to decreased venous return, worsening the uneven distribution of ventilation, as has been suggested to occur in patients with mild COPD.(26) This could generate a ventilatory inefficiency that is disproportionate to the relatively preserved muscle strength of these patients. However, we do not believe that this effect was significant in our study sample; the mean OUES was found to be within the normal range, and only 1 patient had SpO2 < 80% of the predicted value. Therefore, if any given patient in our sample did present with DH, it probably did not affect the OUES significantly, unlike what was seen in patients with moderate-tosevere COPD, in whom DH caused a significant reduction in the OUES.(7)

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Although we found a high correlation between LACpeak and variables such as VO2peak and maximum power, we found no significant correlation between maximal lactate levels and OUES. There are two possible explanations for this finding. First, because OUES is a submaximal variable, it might represent an independent linear system, as was demonstrated for other submaximal variables, such as the variable tau in the analysis of oxygen deficit and the primary gain of aerobic efficiency (∆VO2/∆power) during exercise testing at a constant workload, these variables having been found to be independent of the maximal lactate levels achieved.(28) Second, the OUES might be significantly lower in females.

(29) The latter hypothesis gains strength when LACpeak is adjusted for maximum power, LACpeak thus correlating significantly with the OUES. This indicates that the oxidative capacity of the muscles adjusted for the workload, at maximal metabolic rate during exercise, significantly reflects oxygen uptake efficiency. The small number of individuals in our sample does not allow us to perform a separate analysis of the possible causes of this difference.

We found a correlation between peripheral muscle strength (HGS) and SpO2 at peak exertion.

This finding is consistent with those reported

by Celli et al.(30) in patients with moderate-tosevere COPD at peak exertion. Those authors also found a significant correlation between muscle strength and SpO2 at rest, suggesting a more direct relationship between loss of peripheral muscle function and loss of cardiac muscle function. Although COPD was more severe in the patients investigated in the abovementioned study, mean SpO2 values were higher in that study than in ours (10.6 ± 3.7 mL/heartbeat vs. 9.1 ± 2.8 mL/heartbeat), as were mean HGS values (37.8 ± 7.5 kgf vs. 35.5 ± 11.6 kgf). This can be partly attributed to the fact that that study included male patients only.

One of the limitations of the present study is the small number of patients in our clinical sample, which was partly due to the difficulty in finding patients in the early stages of the disease for inclusion in the study. Another limitation is the type of peripheral muscle strength studied. Although there is a controversial correlation between muscle strength as assessed by HGS testing and muscle strength as assessed by isokinetic dynamometry of leg muscles, arm muscle strength is more J Bras Pneumol. 2012;38(5):541-549

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preserved in patients with COPD and does not reflect well the potential impact of the various etiologic factors involved in muscle function loss.

Nevertheless, changes in arm muscle strength limit activities of daily living in such patients and are involved in ventilatory adjustments; in addition, for an equal work rate, ventilation and VO2 are generally higher for arm exercises than for leg exercises.(10) Because our laboratory is not equipped for isokinetic dynamometry, we were unable to evaluate leg muscle strength. We also recognize that the inclusion of female patients in the present study posed a challenge for the analysis of the results. However, it is known that the respiratory pattern of healthy females during incremental exercise is a tachypneic pattern, which therefore results in greater ventilatory inefficiency during submaximal exercise.(20) Further studies are needed in order to determine whether greater ventilatory inefficiency during submaximal exercise in females is accompanied by lower OUES values.

On the basis of the results of the present study, we conclude that the correlations of OUES with peripheral muscle strength and respiratory muscle strength are weaker than are those of VO2peak with peripheral muscle strength and respiratory muscle strength in patients with mild-to-moderate COPD. The high correlation between OUES and VO2peak suggests that the former is a physiological variable that is more dependent on other determinants of VO2, such as gas exchange and lung perfusion, and less dependent on the baseline muscle strength of individuals.

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Respir Res. 2011;12:150. PMid:22074289. PMCid:3225311. http://dx.doi.org/10.1186/1465-9921-12-150 8. Akkerman M, van Brussel M, Hulzebos E, Vanhees L, Helders PJ, Takken T. The oxygen uptake efficiency slope: what do we know? J Cardiopulm Rehabil Prev. 2010;30(6):357‑73.

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11. Freitas CG, Pereira CA, Viegas CA. Inspiratory capacity, exercise limitation, markers of severity, and prognostic factors in chronic obstructive pulmonary disease. J Bras Pneumol. 2007;33(4):389-96. PMid:17982530. http:// dx.doi.org/10.1590/S1806-37132007000400007 12. Pereira CA, Sato T, Rodrigues SC. New reference values for forced spirometry in white adults in Brazil. J Bras Pneumol. 2007;33(4):397-406. PMid:17982531. http:// dx.doi.org/10.1590/S1806-37132007000400008 13. Sociedade Brasileira de Pneumologia e Tisiologia.

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About the authors Paulo de Tarso Guerrero Müller

Professor. Federal University of Mato Grosso do Sul School of Medicine, Campo Grande, Brazil.

Carlos Alberto de Assis Viegas

Professor. University of Brasília School of Medicine, Brasília, Brazil.

Luiz Armando Pereira Patusco

Professor. Federal University of Mato Grosso do Sul School of Medicine, Campo Grande, Brazil.

J Bras Pneumol. 2012;38(5):541-549

Original Article Prevalence and duration of social security benefits allowed to workers with asthma in Brazil in 2008* Prevalência e duração dos benefícios auxílio-doença decorrentes de asma no Brasil em 2008

Anadergh Barbosa de Abreu Branco, Simone de Andrade Goulart Ildefonso

Abstract Objective: To determine the prevalence and duration of social security benefit (SSB) claims granted to registered workers with asthma in Brazil by the Brazilian National Institute of Social Security in 2008. Methods: This was a retrospective, descriptive study, based on information obtained from the Brazilian Unified Benefit System database, on the number of SSB claims granted to registered workers with asthma in 2008. The reference population was the monthly mean number of workers registered in the Brazilian Social Registry Database in 2008. The variables studied were type of economic activity, gender, age, and type/duration of the SSB allowance.

The relationship between work and asthma was evaluated by the prevalence ratio (PR) between work-related and non-work-related SSB claims for asthma. Results: In 2008, 2,483 SSB claims were granted for asthma, with a prevalence of 7.5 claims per 100,000 registered workers. The prevalence was higher among females than among males (PR = 2.1 between the sexes). Workers ≥ 40 years of age were 2.5 times more likely to be granted an SSB allowance for asthma than were younger workers. The prevalence was highest among workers engaged in the following types of economic activity: sewage, wood and wood product manufacturing, and furniture manufacturing (78.8, 22.4, and 22.2 claims/100,000 registered workers, respectively). The median (interquartile range) duration of SSB claims for asthma was 49 (28-87) days. Conclusions: Asthma is a major cause of sick leave, and its etiology has a strong occupational component. This has a major impact on employers, employees, and the social security system. Being female, being ≥ 40 years of age, and working in the areas of sewage, wood and wood product manufacturing, and furniture manufacturing increase the chance of sick leave due to asthma.

Keywords: Asthma; Social security; Prevalence; Occupational exposure; Occupational health.

Resumo Objetivo: Determinar a prevalência e a duração dos benefícios auxílio-doença (BAD) decorrentes de asma concedidos pelo Instituto Nacional de Seguro Social aos empregados no Brasil em 2008. Métodos: Estudo descritivo e retrospectivo a partir do banco de dados do Sistema Único de Benefícios sobre os BAD decorrentes de asma concedidos em 2008. A população de referência consistiu da média mensal dos empregados registrados no Cadastro Nacional de Informações Sociais em 2008. Foram estudadas as variáveis ramo de atividade econômica, sexo, idade, tipo e duração dos BAD. A relação trabalho-doença foi avaliada por razão de prevalência (RP) entre BAD acidentários e previdenciários. Resultados: Em 2008, foram concedidos 2.483 BAD por asma, com prevalência de 7,5 BAD por 100.000 empregados. A prevalência foi maior em mulheres que em homens (RP = 2,1 entre os sexos). Empregados com ≥ 40 anos tinham 2,5 vezes maior probabilidade de receber BAD por asma do que aqueles com < 40 anos. Os ramos esgoto e atividades relacionadas, fabricação de produtos de madeira e fabricação de móveis tiveram as maiores prevalências (78,8; 22,4; e 22,2 BAD/100.000 empregados, respectivamente). A mediana (intervalo interquartílico) da duração dos BAD foi de 49 (28-87) dias. Conclusões: A asma é uma importante causa de afastamento do trabalho com forte componente ocupacional na sua etiologia, resultando em grande impacto para empregadores, empregados e previdência social. Ser mulher, ter ≥ 40 anos e trabalhar nos segmentos de esgoto, fabricação de produtos de madeira e de fabricação de móveis aumentam a probabilidade de afastamento do trabalho por asma.

Descritores: Asma; Previdência social; Prevalência; Exposição ocupacional; Saúde do trabalhador.

* Study carried out in the Department of Collective Health, University of Brasília School of Health Sciences, Brasília, Brazil.

Correspondence to: Anadergh Barbosa-Branco. 22 Cedar Springs Grove, M3H 5L2, Toronto, ON, Canada.

Tel. 1 416 901-1243. E-mail: anadergh@hotmail.com Financial support: None.

Submitted: 9 January 2012. Accepted, after review: 23 July 2012.

J Bras Pneumol. 2012;38(5):550-558

Prevalence and duration of social security benefits allowed to workers with asthma in Brazil in 2008

Introduction Asthma is a major cause of work disability in various countries. In the USA, with the exception of musculoskeletal diseases, asthma is the disease that is most frequently associated with work disability among individuals in the 18-44 year age bracket, more so than are conditions such as diabetes and arterial hypertension. This is due to the fact that asthma is a disease that is chronic and highly prevalent, being characterized by frequent exacerbations and habitually affecting working-age individuals.(1,2) Another factor that should be taken into consideration is that the work environment is a source of exposure to a wide variety of inhaled agents that can trigger or worsen asthma. In 2000, it was estimated that there had been 38,000 deaths from asthma worldwide and 1,621,000 disabilityadjusted life years attributable to occupational exposure to airborne particulates, over 400 agents having been reported as causing occupational asthma.(3) Those agents have been implicated in 9-15% of all cases of adult asthma in industrialized countries, asthma having become the most common occupational respiratory disease in those countries.(4) Asthma-related work disability (ARWD) has major socioeconomic consequences, having high direct and indirect costs. The number of lost workdays, vocational rehabilitation, changes in the number of hours worked per day, and the need for changing jobs (onset or worsening of symptoms due to exposure to aerosols) have all been used in order to quantify ARWD, which can lead to work cessation (disability retirement).(1,5) In Brazil, data related to occupational asthma and ARWD are scarce. In 1995, the incidence of occupational asthma in the city of São Paulo, Brazil, was reported to be 17/1,000,000 workers, an incidence that was unquestionably underestimated.

(6) Occupational asthma is underdiagnosed, partly because many health professionals are unaware of or underestimate the occupational component of the etiology of asthma. The fact that many of the clinicians who manage adults with newly diagnosed asthma do not ask their patients about their occupations or take incomplete occupational histories constitutes an obstacle to establishing the correct diagnosis.(7) In this context, the objective of the present study was to determine the prevalence and duration of social security benefit (SSB) claims granted to

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registered workers with asthma in Brazil in 2008, as well as to identify personal and occupational factors related to ARWD.

Methods This was a retrospective, descriptive study on the number of SSB claims granted by the Brazilian Instituto Nacional de Seguro Social (INSS, National Institute of Social Security) in 2008 to workers whose disability was attributed to a clinical diagnosis of asthma in accordance with the tenth revision of the International Classification of Diseases (ICD-10; code J45).

The data were obtained from the INSS Unified Benefit System database.

The study variables were type of economic activity, as defined by the National Classification of Economic Activities (NCEA, version 2.0.), gender, age, and type/duration of the SSB allowance.

The reference population was the monthly mean number of workers registered in the Brazilian Social Registry Database in 2008. The Brazilian Social Registry Database is managed by the Brazilian National Ministry of Social Security. Companies are required by law to update the Brazilian Social Registry Database monthly (online) using the payment form of the Social Security Severance Pay Indemnity Fund. Although some workers had two or more jobs concurrently (or several jobs consecutively) in 2008, the number of such individuals was low and we therefore considered each employment record separately.

In Brazil, when workers who are insured by the Social Security system have a health problem resulting in work disability for more than 15 days, they are entitled to receive an SSB allowance, which can be classified as non-occupational (non-work-related) or occupational (work-related).

Each SSB allowance request resulting in an SSB allowance granted is registered in the Brazilian Unified Benefit System database under a single identification number that allows access to information regarding the company and its type of economic activity (as defined by the NCEA), as well as information regarding the worker (including the clinical diagnosis in accordance with the ICD-10), the type of SSB allowance, and the duration of the SSB allowance. The SSB claims under study were those granted by the INSS in 2008.

We determined the prevalence of ARWD by type of economic activity (as defined by the J Bras Pneumol. 2012;38(5):550-558

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NCEA), gender, age, type of SSB allowance, and duration of the SSB allowance. The relationship between work and work disability (or lack thereof) was evaluated by the prevalence of non-workrelated and work-related SSB claims (by type of economic activity, gender, and age group), as well as by the prevalence ratio (PR) between the two types of SSB claims.

The prevalence of SSB claims (per 100,000 registered workers) was calculated by summing all of the SSB claims granted to workers with asthma in 2008 and dividing the sum by the monthly mean number of workers registered in the Brazilian Social Registry Database in 2008.

The duration of the SSB claims was evaluated by measures of central tendency (first quartile, median, and third quartile).

Results In 2008, 2,483 SSB claims were granted for asthma. Those claims were granted to a population of 32,590,239 registered workers, with a prevalence of 7.5 claims/100,000 registered workers.

Table 1 shows the prevalence of SSB claims for asthma by gender, age, and type of economic activity. The prevalence was higher among females than among males, the PR between the genders being 2.1.

With regard to the effect of age on the prevalence of SSB claims for asthma, we found that workers ≥ 40 years of age were 2.5 times more likely to be granted an allowance than were younger workers (< 40 years of age).

The prevalence was highest among workers engaged in the following types of economic activity: sewage, wood and wood product manufacturing, and furniture manufacturing (78.8, 22.4, and 22.2 claims/100,000 registered workers, respectively). Individuals working in those areas were, respectively, 10.4, 3.0, and 2.9 times more likely to be granted an SSB allowance for asthma than were those working in other areas.

Table 2 shows the prevalence of SSB claims for asthma by type of economic activity, type of benefit, and gender. The prevalence of non-workrelated SSB claims for asthma was higher than was that of work-related SSB claims (5.3 claims/100,000 registered workers vs. 2.2 claims/100,000 registered workers), the PR between the two types of claims being 2.4. The technical relationship between work and asthma was stronger among males than among females (PR = 2.2 vs. PR = 2.6). The J Bras Pneumol. 2012;38(5):550-558

strength of the technical relationship between work and asthma varied widely across types of economic activity. We found high PRs (a weak relationship between work and asthma) for the following types of economic activity: provision of health care services to individuals in collective and private households (PR = 11.6); radio and television broadcasting (PR = 7.4); and postal service and other delivery services (PR = 6.5). In contrast, we found low PRs (a strong relationship between work and asthma) for the following types of economic activity: textile manufacturing (PR = 0.8); chemical manufacturing (PR = 0.9), and machinery and equipment manufacturing (PR = 0.9).

Table 3 shows the median (interquartile range [IQR]) duration of the SSB claims for asthma by type of economic activity, gender, and type of SSB allowance. The overall median duration of the SSB claims for asthma was 49 days (IQR, 28-87 days).

In general, the duration of the work-related SSB claims was longer than was that of the non-workrelated claims. The median duration of SSB claims was highest for the following types of economic activity: clerical services, administrative support, and other services provided to companies; and wood and wood product manufacturing. The median duration of the SSB claims granted to males was longest for those working in the area of construction and infrastructure. The median duration of the SSB claims granted to females was longest for those working in the area of motor vehicle manufacturing. The duration of non-work-related SSB claims was longest for those granted to registered workers engaged in wood and wood product manufacturing.

The duration of work-related SSB claims was longest for those granted to registered workers engaged in the manufacturing of plastics and rubber products.

Discussion The present study revealed certain particularities and limitations that should be taken into consideration so that the results can be fully understood. It should be emphasized that the results of the present study refer to SSB claims granted to registered workers (in accordance with the Consolidation of Labor Laws), meaning that individuals working in the informal sector (individuals who are probably exposed to worse working conditions and who have higher levels

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Table 1 - Prevalence (per 100,000 workers) of social security benefit claims granted to registered workers with asthma,a by type of economic activity,b gender, and age bracket, Brazil, 2008.

Age bracket Total < 40 years ≥ 40 years By age bracket By gender Economic activity Total M F M F < 40 years ≥ 40 years M F Sewage and related activities 26.4 144.8 75.5 544.3 42.0 147.1 44.5 308.2 78.8 Wood and wood product 13.3 50.0 28.5 69.4 19.2 33.8 17.9 54.8 22.4 manufacturing Furniture manufacturing 11.0 35.7 50.3 26.6 16.1 45.3 20.7 33.4 22.2 Radio and television 0.0 62.9 13.3 6.1 22.3 8.3 5.5 20.9 21.0 broadcasting Textile manufacturing 9.8 34.7 9.6 47.8 18.8 23.4 9.8 38.4 19.2 Building construction 10.2 13.4 35.8 2.1 10.7 13.4 19.8 3.6 19.1 Garment manufacturing 6.7 16.5 4.0 29.0 13.8 24.9 6.2 20.2 15.8 Services for buildings and 2.8 23.5 7.4 13.2 10.1 11.4 4.7 15.9 15.1 landscaping Home health carec 0.0 12.4 10.2 16.7 8.4 15.6 3.9 15.0 15.1 Other personal services 5.1 9.5 19.9 8.8 7.8 10.2 9.2 9.0 13.4 Plastics and rubber products 7.7 18.7 19.3 18.1 10.8 19.0 10.5 18.6 12.2 manufacturing Lodging 0.0 13.5 16.1 8.0 7.4 9.3 4.8 10.0 12.0 Food manufacturing 7.4 14.7 14.0 37.2 9.5 19.5 9.1 19.6 11.4 Infrastructure construction 8.0 17.6 14.9 1.2 9.0 5.6 10.4 2.8 11.0 Forest products manufacturing 4.4 11.2 18.0 102.4 5.2 26.0 8.4 33.7 10.6 Chemical manufacturing 6.7 15.2 6.7 43.1 9.1 13.5 6.7 21.7 10.2 Postal service and other 4.5 4.2 20.9 1.1 4.4 8.0 11.4 1.8 9.7 delivery services Agriculture, livestock 2.7 9.1 19.5 40.0 3.9 23.2 7.9 18.1 9.4 production, and related activities Human health 1.1 7.7 9.4 7.0 6.0 7.3 3.8 7.3 9.3 Leather goods preparation and 4.4 12.0 11.4 19.1 8.1 14.9 6.0 13.4 8.9 manufacturing Metal manufacturing and 5.8 12.7 11.9 34.5 6.9 14.6 7.6 17.8 8.7 production, except for M/E M/E manufacturing 5.9 16.0 10.4 32.4 7.2 12.3 7.3 19.7 8.6 Feeding 2.6 5.8 6.6 6.7 4.2 6.7 3.4 6.4 8.5 Non-metallic mineral product 5.4 20.2 9.3 31.8 7.3 11.6 6.6 23.0 8.3 manufacturing Surveillance, security, and 6.9 11.0 9.7 0.3 7.3 3.0 7.8 1.3 8.0 investigation Motor vehicle manufacturing 3.6 7.3 18.1 33.6 4.2 19.7 7.5 12.0 8.0 Selection, representation, and 2.7 6.1 20.0 3.1 4.1 5.4 6.4 4.0 7.7 leasing of HRs Brazil 3.6 8.2 9.8 20.0 5.4 13.4 5.6 11.6 7.5 M/E: machinery and equipment; and HRs: human resources. aCode J45, in accordance with the tenth revision of the International Classification of Diseases. bAs defined by the National Classification of Economic Activities, version 2.0. c Health care provided to individuals in collective and private households.

of exposure) were not included in our study. In addition, we limited the study population to adults (in the 16-65 year age bracket). Furthermore, it should be taken into consideration that studies involving populations of workers are vulnerable

to the “healthy worker effect”, in which there is a selection of susceptible individuals outside the workforce. This fact could underestimate the exposure effects. The working population usually has high levels of exposure and therefore J Bras Pneumol. 2012;38(5):550-558

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Table 2 - Prevalence (per 100,000 workers) of social security benefit claims granted to registered workers with asthma,a by type of economic activity,b gender, and type of allowance, Brazil, 2008.

Type of allowance Non-work-related Work-related Economic activity M F Total M F Total Sewage and related activities 36.1 256.7 64.9 8.3 51.3 13.9 Wood and wood product manufacturing 12.3 24.0 13.4 5.6 30.8 9.0 Furniture manufacturing 10.6 17.8 11.6 10.0 15.6 10.7 Radio and television broadcasting 3.7 53.1 18.5 1.8 4.1 2.5 Textile manufacturing 3.3 18.2 8.3 6.5 20.2 10.9 Building construction 14.9 11.8 14.0 4.9 7.8 5.1 Garment manufacturing 1.4 13.3 9.7 4.8 7.0 6.1 Services for buildings and landscaping 3.3 20.8 9.4 1.3 13.9 5.7 Home health carec 3.9 18.9 13.9 0.0 1.7 1.2 Other personal services 5.5 10.2 8.0 3.7 6.8 5.3 Plastics and rubber products manufacturing 5.8 14.0 7.7 4.8 4.7 4.6 Lodging 4.8 13.2 9.2 0.0 5.1 2.8 Food manufacturing 7.0 14.8 8.7 2.1 4.8 2.7 Infrastructure construction 6.3 15.5 7.0 4.0 5.2 4.0 Forest products manufacturing 7.3 25.3 8.9 1.0 8.4 1.8 Chemical manufacturing 3.4 10.0 4.9 3.4 11.7 5.3 Postal service and other delivery services 10.5 2.7 8.4 0.9 2.7 1.3 Agriculture, livestock production, and related activities 6.1 9.0 6.4 1.8 9.0 3.1 Human health 2.7 9.6 7.6 1.1 1.8 1.6 Leather goods preparation and manufacturing 3.0 7.5 4.8 3.0 5.9 4.1 Metal manufacturing and production, except for M/E 5.0 9.7 5.4 2.6 8.1 3.3 M/E manufacturing 3.0 12.3 4.0 4.3 7.4 4.6 Feeding 2.9 12.0 7.3 0.5 2.0 1.2 Non-metallic mineral product manufacturing 3.1 15.3 4.4 3.5 7.7 3.8 Surveillance, security, and investigation 7.2 6.0 7.0 0.5 6.0 1.0 Motor vehicle manufacturing 4.7 7.5 5.0 2.8 4.5 3.0 Selection, representation, and leasing of HRs 4.2 7.2 5.2 2.1 3.4 2.5 Brazil 3.8 8.3 5.3 1.7 3.2 2.2 M/E: machinery and equipment; and HRs: human resources. aCode J45, in accordance with the tenth revision of the International Classification of Diseases. bAs defined by the National Classification of Economic Activities, version 2.0. c Health care provided to individuals in collective and private households.

provides a poor estimate of the impact of the disease on the general population.(8) It should also be highlighted that our data refer exclusive to disease that had moderate to severe clinical consequences, i.e., disease that led to work disability for more than 15 days. In addition to the severity of the disease/injury, the administrative operationalization capacity of the social security institution and even legal issues for the recognition of the technical relationship between work and the disease/injury can have an impact on the duration of the SSB claims.

Furthermore, the number of SSB claims granted might not represent the number of registered workers with ARWD covered by social security, J Bras Pneumol. 2012;38(5):550-558

given that SSB claims might have been granted more than once to the same workers in the study period.

The prevalence of SSB claims for asthma was found to be 7.5 claims/100,000 registered workers. Worldwide, the prevalence of asthma has increased in the last decades,(2,3,9,10) which results in a higher number of asthma patients joining the workforce. This poses new challenges to the industries that traditionally excluded asthma patients from their workforce.(3) In Brazil, the high prevalence of asthma is the primary cause of excessive sick leave due to respiratory diseases and, consequently, ARWD. Asthma accounts for 350,000 annual hospitalizations in the country,

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Table 3 - Duration of the social security benefit claims granted to registered workers with asthma, a by type of economic activity,b gender, and type of allowance, Brazil, 2008.

Duration of the allowance, daysc Claims Gender Type of allowance Economic activity granted, Total Non-workn M F Work-related related Retail 303 47 (30-95) 48 (29-84) 47 (30-83) 52 (29-119) 47 (30-91) Public administration, 204 59 (32-93) 50 (29-80) 50 (26-77) 59 (35-99) 51 (29-81) defense, and social security Food manufacturing 147 45 (18-76) 54 (32-77) 48 (27-80) 45 (21-76) 47 (25-77) Services for buildings and 145 51 (30-93) 56 (29-91) 52 (31-93) 58 (25-92) 53 (29-93) landscaping Human health 97 39 (32-84) 47 (20-74) 46 (20-72) 46 (36-95) 46 (21-76) Garment manufacturing 96 41 (6-48) 38 (22-71) 39 (20-71) 38 (23-61) 39 (20-70) Feeding 84 40 (27-62) 52 (31-84) 48 (30-85) 56 (39-64) 49 (31-83) Land transportation 76 48 (35-77) 48 (36-90) 48 (37-84) 60 (29-69) 51 (33-82) Building construction 75 51 (35-84) 57 (34-64) 47 (33-71) 65 (49-86) 52 (35-78) Wholesale, except for vehicles 67 45 (16-90) 46 (26-65) 52 (25-97) 45 (17-56) 46 (20-77) Office services and 66 65 (30-148) 64 (41-105) 55 (32-97) 97 (54-120) 64 (33-108) administrative support for companies Education 63 65 (38-180) 37 (17-82) 36 (16-68) 65 (30-166) 46 (17-89) Activities of associations and 61 49 (33-84) 47 (32-85) 47 (32-72) 60 (32-147) 47 (31-85) societies Textile manufacturing 58 43 (33-94) 58 (35-80) 58 (37-87) 46 (34-75) 55 (34-85) Plastics and rubber products 51 41 (24-77) 43 (28-94) 32 (21-49) 115 (40-174) 41 (26-84) manufacturing Furniture manufacturing 50 45 (24-76) 31 (20-69) 44 (21-95) 43 (22-59) 43 (21-73) Wood and wood product 45 59 (46-101) 91 (33-135) 64 (33-108) 66 (49-139) 64 (45-123) manufacturing Infrastructure construction 44 69 (39-90) 32 (19-51) 51 (37-81) 77 (29-121) 59 (33-89) Trade and repair of motor 41 45 (33-86) 34 (22-45) 40 (27-57) 62 (37-88) 45 (30-70) vehicles Agriculture, livestock 40 65 (45-119) 32 (28-68) 60 (34-129) 45 (31-74) 56 (31-95) production, and related activities Brazil 2,458 48 (29-93) 49 (28-83) 46 (27-81) 57 (30-100) 49 (28-87) Code J45, in accordance with the tenth revision of the International Classification of Diseases. bAs defined by the National Classification of Economic Activities, version 2.0. cValues expressed as median (interquartile range). a

being the fourth leading cause of hospitalization via the Brazilian Unified Health Care System. In 2005, hospitalizations for asthma accounted for 18.7% of all hospitalizations for respiratory diseases and for 2.6% of all hospitalizations in the period. In 2005, the Brazilian Unified Health Care System spent 96 million Brazilian reals on hospitalizations for asthma, which accounted for 1.4% of the overall expenditures on all diseases.(9) In addition to the high prevalence of asthma, we should consider the characteristics of the disease; asthma is a chronic inflammatory disease characterized by frequent exacerbations and

limiting symptoms, such as dyspnea, wheezing, and chest tightness,(9) affecting working-age individuals and having a major impact on ARWD rates.

In addition to the abovementioned factors, the present study clearly shows that occupational risk factors can have a major impact on ARWD. The types of economic activity observed in our study sample confirmed that occupational exposure to chemicals, endotoxins, and sawdust plays an important role as potential causative agents of asthma. These results are supported by the scientific literature.(6,10,11) J Bras Pneumol. 2012;38(5):550-558

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Disease severity is another important predictor of ARWD. We had no direct contact with the disabled workers investigated in the present study.

Therefore, we were unable to evaluate disease severity by clinical history taking or functional tests. However, we believe that the long sick leave periods, as evidenced by the SSB claims granted, constitute indirect evidence of the severity of the clinical profiles.

Cohort studies involving asthma patients found the prevalence of complete work disability to be 7-14%.(2,12) Among registered workers, the prevalence of ARWD was found to be 10-38%, ARWD having been characterized as sick leave, reduced work productivity, and need for changing job functions.(2,12) Of the unemployed workers, 26% left their jobs because of asthma.(12) Risk factors associated with ARWD were smoking,(1,12) occupational exposure,(2,12) disease severity,(2,12) and physical exertion at work.(2) In the present study, the PR between non-work-related and work-related SSB claims was found to be 2.4, which clearly shows the impact that the implementation of the Nexo Técnico Epidemiológico Previdenciário (NTEP, Technical-Epidemiological Social Security Benefit Nexus) system had on the characterization of SSB claims. The NTEP system is regulated by Decree no. 6042, which was issued on February 12, 2007, and which established a complementary way of characterizing the technical and epidemiological nexus of disabling diseases/injuries (> 15 days) for each type of economic activity. Before the implementation of the NTEP system, the relationship between work and disease was determined exclusively by the Comunicação de Acidente do Trabalho (CAT, Occupational Accident Report), which was issued exclusively by the employer, although the legislation provided a wider range of possibilities. By issuing a CAT, employers formally take responsibility for the disease/injury.

Therefore, it is clear that employers have no interest in issuing a CAT characterizing a disease/injury as being work-related (occupational accident). The NTEP system was implemented with the objective of correcting existing distortions in the process of characterizing the relationship between work and a given disease/injury. Therefore, the analysis of the SSB claims granted for asthma in 2008 allows a more realistic view of the epidemiological profile of ARWD in Brazil, as well as of the relationship between asthma and work.

J Bras Pneumol. 2012;38(5):550-558

A study analyzing the prevalence of SSB claims granted to workers with respiratory disease in the 2003-2004 period clearly showed that the relationship between work and diseases, particularly chronic diseases, is underestimated.

(13) The study in question found the PR between non-work-related and work-related SSB claims for asthma to be 41.5.

The fact that work disability due to respiratory disease is more common in females than in males might be primarily due to the fact that the prevalence of asthma is higher in females than in males, particularly among working-age adults.(10) It is known that gender influences the distribution of occupational lung diseases because there are activities that are performed exclusively by one gender or the other. Therefore, there are differences between the genders in term of exposure to the causative agents. Exposure to cleaning products, biological agents, and textile fibers is significantly greater among females than among males. Among females, the risk of developing asthma is higher after exposure to paper dust and textile materials, whereas among men, the risk of developing asthma is higher after exposure to wheat flour, solder, synthetic mineral fibers, and solvents.(4) A study involving 779 asthma patients found that the female gender was associated with a higher risk of ARWD (OR = 2.8).(14) The finding of a higher prevalence of respiratory disease in individuals over 40 years of age might be due to the duration of exposure to risk factors and to the fact that asthma is a chronic disease that can manifest at any age.

One study demonstrated that 11-20 years of employment correlated positively with work absenteeism due to respiratory disease in groups of workers with high-risk occupational exposure, including welders.(15) In older individuals, there is the possibility of longer occupational exposure or even non-occupational exposure, including smoking and air pollution. In addition, the workforce is aging, particularly in European countries, where the prevalence of respiratory symptoms has been reported to be higher in workers over 55 years of age than in younger workers.(3) We found that the prevalence of asthma was highest among individuals working in the areas of sewage, wood and wood product manufacturing, and furniture manufacturing, in which risk factors

Prevalence and duration of social security benefits allowed to workers with asthma in Brazil in 2008

for asthma have been reported. The area of sewage includes collection and transportation of domestic or industrial sewage and storm water; management of sewer networks; operation of treatment plants, sewage treatment through physical, chemical, and biological processes; wastewater treatment for pollution prevention; emptying and cleaning infiltration tanks, septic tanks, sinks, and sewage pits; cleaning sewage holding tanks, storm sewer, and pipelines; and chemical toilet sludge removal and cleaning.(16) Chemicals include chlorinated organic solvents, pesticides, polycyclic aromatic hydrocarbons, petroleum hydrocarbons, nitrosamines, heavy metals, asbestos, dioxins, and radioactive material.

(17) In addition, organic waste generates bioaerosols containing bacteria, fungal spores, and microbial components, such as endotoxins and β(1-3) glucans, which can induce an inflammatory response in the lower airways. Endotoxin inhalation induces inflammation characterized by neutrophil influx and IL-8 secretion, both of which cause changes in lung function.(18) The presence of flies of the family Psychodidae in environments rich in organic waste might be associated with respiratory allergies.(17) Sawdust (especially from hardwoods), is one of the most common causative agents of occupational asthma. Carpenters, lumberjacks, and workers in the furniture industry are considered to be at risk.(6,10) Various types of wood are associated with asthma, including red cedar, white cedar, oak, Brazilian walnut, mahogany, trumpet-tree, pau-marfim, sequoia, and cedar of Lebanon.(10,11) Exposure can occur during planting and deforestation (felling trees and transporting timber), as well as in sawmills, wood plank industries, and furniture manufacturing facilities, as well as in workspaces for cabinet makers and carpenters. In wood and wood product manufacturing, production processes include wood preservation and treatment, which involve immersing the wood in or injecting oil-based pesticides, metal salts, and organic compounds, production of boards or panels, in which wood chips are mixed with glue and pressed at high temperatures; use of machines such as saws, planers, and slotters to work on natural woods or boards that release barbs/chips and dust; and finishing (sanding, bleaching, varnishing, and painting). These processes expose workers to sawdust and chemical substances that are

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associated with occupational asthma. A study conducted in woodworking facilities in the city of São Paulo and employing symptom questionnaires showed that 3, 7, and 10 of the 58 workers under study presented with symptoms that were consistent with chronic bronchitis, asthma, and sinusitis, respectively.(19) In the context of work disability, it is likely that the prevalence of asthma is underestimated because of comorbidities. The present study was based on secondary data and on the primary cause of disability (as diagnosed by medical expert examination). Therefore, it is likely that many cases of asthma were diagnosed as being cases of diseases that are associated with asthma, including pneumonia and bronchitis.

We found that the duration of the SSB claims was longest among workers engaged in economic activities in which the prevalence of occupational asthma was highest, including wood and wood product manufacturing (risk factors mentioned above), plastics and rubber products manufacturing (exposure to phthalic anhydride, formaldehyde, ethylene, toluene, and other agents), and motor vehicle manufacturing (exposure to diisocyanates and fumes/metal dust). Exposure to occupational factors is associated with a more severe clinical course of asthma,(20) which is possibly why the duration of the work-related SSB claims for asthma was longer.

In conclusion, asthma is a major cause of sick leave, being strongly related to the type of economic activity. Asthma seems to be related to its prevalence in the population and to occupational risk factors. Improved management of asthma in the population and the control of risk factors and occupational exposure will have a positive impact on social, occupational, and social security spheres.

References 1. Blanc PD, Ellbjär S, Janson C, Norbäck D, Norrman E, Plaschke P, et al. Asthma-related work disability in Sweden. The impact of workplace exposures. Am J Respir Crit Care Med. 1999;160(6):2028-33. PMid:10588624.

2. Blanc PD, Cisternas M, Smith S, Yelin EH. Asthma, employment status, and disability among adults treated by pulmonary and allergy specialists.

Chest. 1996;109(3):688‑96. http://dx.doi.org/10.1378/ chest.109.3.688 3. Sigsgaard T, Nowak D, Annesi-Maesano I, Nemery B, Torén K, Viegi G, et al. ERS position paper: work-related respiratory diseases in the EU. Eur Respir J. 2010;35(2):234-8. http:// dx.doi.org/10.1183/09031936.00139409

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4. Mapp CE, Boschetto P, Maestrelli P, Fabbri LM. Occupational asthma. Am J Respir Crit Care Med. 2005;172(3):280-305. http://dx.doi.org/10.1164/ rccm.200311-1575SO 5. Blanc PD, Burney P, Janson C, Torén K. The prevalence and predictors of respiratory-related work limitation and occupational disability in an international study.

Chest. 2003;124(3):1153-9. http://dx.doi.org/10.1378/ chest.124.3.1153 6. Fernandes AL, Stelmach R, Algranti E. Occupational asthma [Article in Portuguese]. J Bras Pneumol. 2006;32(Suppl 2):S45-52. http://dx.doi. org/10.1590/S1806-37132006000800006 7. Shofer S, Haus BM, Kuschner WG. Quality of occupational history assessments in working age adults with newly diagnosed asthma. Chest. 2006;130(2):455-62. http:// dx.doi.org/10.1378/chest.130.2.455 8. Le Moual N, Kauffmann F, Eisen EA, Kennedy SM. The healthy worker effect in asthma: work may cause asthma, but asthma may also influence work. Am J Respir Crit Care Med. 2008;177(1):4-10. http://dx.doi. org/10.1164/rccm.200703-415PP 9. IV Brazilian Guidelines for the management of asthma [Article in Portuguese]. J Bras Pneumol. 2006;32(Suppl 7):S447-74. PMid:17420905.

10. Global Initiative for asthma – GINA [homepage on the internet]. Bethesda: Global Initiative for asthma. [cited 2011 Jan 20]. Global strategy for asthma management and prevention. Available from: http://www.ginasthma.org/ guidelines-gina-report-global-strategy-for-asthma.html 11. Asthme professional [homepage on the Internet]. Quebec: Asthme professional. [cited 2011 Jan 20]. Agents causing occupational asthma with key references. [Adobe Acrobat document, 51p.]. Available from: http://www.asthme. csst.qc.ca/document/Info_Med/IdCauses/Bernstein/ AgentsAnglais.pdf 12. Eisner MD, Yelin EH, Katz PP, Lactao G, Iribarren C, Blanc PD. Risk factors for work disability in severe adult asthma. Am J Med. 2006;119(10):884-91. http://dx.doi. org/10.1016/j.amjmed.2006.01.016

13. Ildefonso Sde A, Barbosa-Branco A, AlbuquerqueOliveira PR. Prevalence of temporary social security benefits due to respiratory disease in Brazil. J Bras Pneumol. 2009;35(1):44-53. PMid:19219330.

14. Torén K, Zock JP, Kogevinas M, Plana E, Sunyer J, Radon K, et al. An international prospective general population-based study of respiratory work disability.

Thorax. 2009;64(4):339-44. http://dx.doi.org/10.1136/ thx.2008.105007 15. Szubert Z, Sobala W. Some occupational determinants of work disability [Article in Polish]. Med Pr. 1999;50(1):43‑50.

PMid:10399717.

16. Instituto Brasileiro de Geografia e Estatística – IBGE [homepage on the internet]. Brasília: Instituto Brasileiro de Geografia e Estatística. [cited 2011 Jan 20]. Estrutura detalhada e notas explicativas da CNAE 2.0. [Adobe Acrobat document, 284p.]. Available from: www.ibge. gov.br/concla/pub/revisao2007/PropCNAE20/CNAE20_ NotasExplicativas.pdf 17. DigitalCommons@ILR [homepage on the internet].

Ithaca: Cornell University. [cited 2011 Jan 18]. Manuals and user guides - Health Hazard Manual: Wastewater Treatment Plant and Sewer Workers. Available from: http://digitalcommons.ilr.cornell.edu/manuals/2 18. Heldal KK, Halstensen AS, Thorn J, Eduard W, Halstensen TS. Airway inflammation in waste handlers exposed to bioaerosols assessed by induced sputum. Eur Respir J. 2003;21(4):641-5. http://dx.doi.org/10.1183/0903 1936.03.00059702 19. Rosa EA, Brito ME, Almeida AM, Baroni TM. Avaliação dos riscos respiratórios desencadeados por poeira de madeira em indústria de móveis e madeira na cidade de São Paulo. In: São Paulo (Estado). Secretaria da Saúde.

Divisão de Saúde do Trabalhador. Rede Especial - Revista do Projeto de Cooperação Técnica Brasil-Itália: Proteção à saúde nos ambientes de trabalho - 1998. São Paulo: IMESP; 1998. p. 127-44.

20. Le Moual N, Siroux V, Pin I, Kauffmann F, Kennedy SM; Epidemiological Study on the Genetics and Environment of Asthma. Asthma severity and exposure to occupational asthmogens. Am J Respir Crit Care Med. 2005;172(4):440-5. http://dx.doi.org/10.1164/rccm.200501-111OC

About the authors Anadergh Barbosa de Abreu Branco

Associate Professor. Department of Collective Health, University of Brasília School of Health Sciences, Brasília, Brazil.

Simone de Andrade Goulart Ildefonso

Pulmonologist. Department of Collective Health, University of Brasília School of Health Sciences, Brasília, Brazil.

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Original Article Analysis and validation of probabilistic models for predicting malignancy in solitary pulmonary nodules in a population in Brazil* Análise e validação de modelos probabilísticos de malignidade de nódulo pulmonar solitário em uma população no Brasil

Cromwell Barbosa de Carvalho Melo, João Aléssio Juliano Perfeito, Danilo Félix Daud, Altair da Silva Costa Júnior, Ilka Lopes Santoro, Luiz Eduardo Villaça Leão

Abstract Objective: To analyze clinical and radiological findings that influence the pathological diagnosis of solitary pulmonary nodule (SPN) and to compare/validate two probabilistic models for predicting SPN malignancy in patients with SPN in Brazil. Methods: This was a retrospective study involving 110 patients diagnosed with SPN and submitted to resection of SPN at a tertiary hospital between 2000 and 2009. The clinical characteristics studied were gender, age, presence of systemic comorbidities, history of malignancy prior to the diagnosis of SPN, histopathological diagnosis of SPN, smoking status, smoking history, and time since smoking cessation.

The radiological characteristics studied, in relation to the SPN, were presence of spiculated margins, maximum transverse diameter, and anatomical location. Two mathematical models, created in 1997 and 2007, respectively, were used in order to determine the probability of SPN malignancy. Results: We found that SPN malignancy was significantly associated with age (p = 0.006; OR = 5.70 for age > 70 years), spiculated margins (p = 0.001), and maximum diameter of SPN (p = 0.001; OR = 2.62 for diameters > 20 mm). The probabilistic model created in 1997 proved to be superior to that created in 2007—area under the ROC curve, 0.79 ± 0.44 (95% CI: 0.70‑0.88) vs. 0.69 ± 0.50 (95% CI: 0.59-0.79). Conclusions: Advanced age, greater maximum SPN diameter, and spiculated margins were significantly associated with the diagnosis of SPN malignancy. Our analysis shows that, although both mathematical models were effective in determining SPN malignancy in our population, the 1997 model was superior.

Keywords: Solitary Pulmonary Nodule; Risk Factors; Carcinoma, Non-Small-Cell Lung.

Resumo Objetivo: Analisar características clínicas e radiográficas que influenciaram o diagnóstico anatomopatológico de nódulo pulmonar solitário (NPS) e comparar/validar dois modelos probabilísticos de malignidade do NPS em pacientes com NPS no Brasil. Métodos: Análise retrospectiva de 110 pacientes com diagnóstico de NPS submetidos à ressecção em um hospital terciário no período entre 2000 e 2009. As características clínicas estudadas foram gênero, idade, presença de comorbidades sistêmicas, história de neoplasia maligna ao diagnóstico de NPS, diagnóstico histopatológico do NPS, tabagismo, carga tabágica e tempo de cessação do tabagismo. As características radiográficas avaliadas em relação ao NPS foram presença de margens espiculadas, tamanho do maior diâmetro transversal e localização anatômica do NPS. Foram utilizados dois modelos matemáticos, criados em 1997 e 2007, respectivamente, para determinar a probabilidade de malignidade do NPS. Resultados: Houve associações significantes entre malignidade do NPS e idade (p = 0,006; OR = 5,70 para idade >70 anos), presença de margens espiculadas (p = 0,001) e diâmetro maior do NPS (p = 0,001; OR = 2,62 para diâmetro >20 mm).

O modelo probabilístico de 1997 mostrou-se superior ao de 2007 — área sob a curva [ASC] ROC = 0,79 ± 0,44 (IC95%: 0,70-0,88) vs. ASC = 0,69 ± 0,50 (IC95%: 0,59-0,79). Conclusões: Idade elevada, maior diâmetro do NPS e presença de margens espiculadas tiveram associações significantes ao diagnóstico de malignidade do NPS. Nossa análise mostrou que, embora os dois modelos matemáticos sejam eficazes na determinação de malignidade do NPS nessa população, o modelo de 1997 mostrou-se superior.

Descritores: Nódulo pulmonar solitário; Fatores de risco; Carcinoma pulmonar de células não pequenas. * Study carried out at the Universidade Federal de São Paulo/Escola Paulista de Medicina – UNIFESP/EPM, Federal University of São Paulo/Paulista School of Medicine – São Paulo, Brazil.

Correspondence to: Cromwell Barbosa de Carvalho Melo. Rua Napoleão de Barros, 715, 4º andar, Disciplina de Cirurgia Torácica.

Vila Clementino, CEP 04023-002, São Paulo, SP, Brasil.

Tel. 55 11 5576-4295. E-mail: cromwellmelo@hotmail.com Financial support: None.

Submitted: 15 May 2012. Accepted, after review: 14 August 2012.

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Introduction

Methods

Pulmonary nodules have always represented a major diagnostic challenge, which is cause for justified concern given the incidence of malignant (metastatic or primary) lung tumors. In recent decades, there has been an increase in the incidence of, and consequently, in the mortality from, primary lung cancer, concomitantly with advances in imaging techniques, which have resulted in increased detection of pulmonary nodules. In this context, the finding of a solitary pulmonary nodule (SPN) has become crucial for the early detection of primary lung cancer, which, according to data from the Brazilian National Ministry of Health Mortality Database, is the leading cause of cancer death, surpassing the number of deaths from prostate and breast cancer when gender is not taken into account.

An SPN is defined as a more or less spherical lung opacity that is less than 3 cm in diameter. It usually has well-defined margins, is completely surrounded by lung parenchyma, and is without other radiological abnormalities, such as atelectasis and mediastinal lymph node enlargement.(1,2) Several ways to estimate the malignant potential of SPNs have been devised. Among the most widespread are two mathematical models based on multivariate analysis of the clinical characteristics of patients with SPNs and the radiological characteristics of SPNs, one of which was published by Swensen et al.

(3) in 1997 and one of which was published by Gould et al.(4) in 2007. In those two studies, the authors developed mathematical formulas to calculate the probability of SPN malignancy with the purpose of providing guidance for attending physicians, the probabilistic models having been extensively tested and approved, especially in populations in the USA and Europe.(3-5) In a study conducted in the Philippines, the high prevalence of tuberculosis made it impossible to repeat that finding, demonstrating the ineffectiveness of the models for that population.(6) Since, to date, there have been no studies in Brazil aimed at evaluating these models in a population in the country, the objective of the present study was to analyze clinical and radiological variables that influence the pathological diagnosis of SPN and to compare and validate the two aforementioned mathematical models(3,4) for calculating the probability of SPN malignancy in patients with SPN in Brazil.

This was a retrospective study involving all of the patients submitted to resection of SPN at the Hospital São Paulo, located in the city of São Paulo, Brazil, between 2000 and 2009. The study was based on data from medical charts. We studied the following variables: gender; age; presence of systemic comorbidities; history of malignancy prior to the diagnosis of SPN; histopathological diagnosis of SPN (malignant disease vs. benign disease); smoking status (current smokers and former smokers); smoking history (in pack-years); and number of years since smoking cessation.

In addition, we studied CT features of SPNs, including presence of spiculated margins, maximum transverse diameter (in mm), and anatomical location, as described in CT reports.

After data collection, we used the following inclusion criteria: having a confirmed diagnosis of SPN; having undergone surgical resection of SPN; having a medical chart containing the data needed for the analysis; and having a pathological diagnosis of SPN. Of the 127 patients who were initially screened for inclusion in the study, 110 met the aforementioned criteria. The main reason for exclusion was having an incomplete medical chart, followed by having been diagnosed with multiple pulmonary nodules.

We determined the probability of SPN malignancy by using the mathematical models developed in the aforementioned studies and applying the equations defined by the authors.

Equations developed by Swensen et al.(3):

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Probability of malignancy = ex/(1+ ex) (1) x = −6.8272 + (0.0391 × age) + + (0.7917 × smoke ) + + (1.3388 × cancer ) + + (0.1274 × diameter) + + (1.0407 × spiculation) + +(0.7838 × location)

(2)

where age is the age of the patient in years; smoke = 1 if the patient is a current or former smoker (otherwise, smoke = 0); cancer = 1 if the patient has a history of an extrathoracic cancer that was diagnosed more than five years ago (otherwise, cancer = 0); diameter is the diameter of the nodule in mm; spiculation = 1 if the edge of the nodule has spicules (otherwise,

Analysis and validation of probabilistic models for predicting malignancy in solitary pulmonary nodules in a population in Brazil

spiculation = 0); and location = 1 if the nodule is located in an upper lobe (otherwise, location = 0).

Equations developed by Gould et al.(4): Probability of malignant SPN = ex/(1+ ex) (1)

x = −8.404 + (0.779 × age) + + (2.061 × smoke ) + (0.112 × diameter) − (2) − (0.567 × Y) where age is age in years; smoke is 1 if a current or former smoker (otherwise 0); diameter is the largest diameter of the nodule in mm; and Y is the number of years since quitting smoking divided by 10.

For the statistical analysis, we used the Statistical Package for the Social Sciences, version 13.0 for Windows (SPSS Inc., Chicago, IL, USA), and the Statistical Package for the Social Sciences, version 20.0 for Mac. We also used BioEstat, version 5.0 for Windows, for complementary analyses and for constructing the ROC curves.

In order to determine possible differences among the groups studied, we used the Student’s t-test for parametric variables, Pearson’s chi-square test for nonparametric variables, and Fisher’s exact test for dichotomous variables.(7) The level of significance was set at 5% for all statistical tests.

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Diagnostic performance and the best cut-off point for both mathematical models were determined by analysis of the ROC and two-graph ROC curves.(8) For the cut-off points, we calculated the sensitivity, specificity, accuracy, negative predictive value, and positive predictive value of the models. We also calculated the area under the curve and compared the models.

Results We evaluated 110 patients. Of those, 59 were male and 51 were female. We found no significant association between gender and the diagnosis of SPN malignancy. The same was true for presence of comorbidities, history of malignancy prior to the diagnosis of SPN, and smoking status.

Neither the number of years since smoking cessation nor smoking history in pack-years had any influence on the pathological diagnosis of SPN. The only clinical characteristic that was significantly associated with SPN malignancy was age (p = 0.006), when it was stratified into groups, with increasing ORs, culminating in an OR of 5.70 for the > 70 year age group (Table 1).

Among the radiological characteristics, presence of spiculated margins (p = 0.001) and lesion diameter (p = 0.001) were significantly associated

Table 1 - Clinical characteristics of the patients and radiological characteristics of the nodules.

SPN malignancy Characteristic No Yes % % Male gender 55.93 44.07 Age bracket, years 21-50 40.00 16.36 51-60 18.18 23.67 61-70 30.91 34.54 > 70 10.91 25.45 Presence of comorbidities 49.12 50.88 History of malignancy 35 65 Ever smoking 46.91 53.09 Time since smoking cessation (former smokers), years 8.58 ± 11.98a 10.12 ± 7.67a Smoking history, pack-years 48.51 ± 28.44a 50.15 ± 35.12a SPNs in the ULs 51.78 48.21 Presence of spiculated margins 33.34 66.66 SPN diameter, mm 15.87 ± 7.37a 20.60 ± 6.69a ≤ 10 34.55 21.82 10.1-20.0 43.64 41.82 > 20,1 21.81 36.36

solitary pulmonary

p

OR

0.18 0.006

1.00 3.18 2.73 5.70

0.85 0.14 0.28 0.09 0.82 0.70 0.001 0.001

1.00 1.52 2.64

SPN: solitary pulmonary nodule; and UL: upper lobe. aValues expressed as mean ± SD.

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with SPN malignancy. Stratification of this analysis by lesion diameter revealed increasing ORs, with SPNs of 20.1-30 mm in diameter reaching an OR of 2.64 (Table 1).

After calculating the probability of SPN malignancy with the mathematical model of Swensen et al.,(3) we constructed a ROC curve, the area under the ROC curve (AUC) being 0.79 ± 0.44 (95% CI: 0.70-0.88; Figure 1). The construction of a two-graph ROC curve allowed us to determine an optimal cut-off point in relation to the various cut-off points along the ROC curve (Figure 2), with higher sensitivity and specificity being obtained below 15% or above 66.5% (a yield higher than 95%; Table 2).

For the model of Gould et al.,(4) we obtained an AUC of 0.69 ± 0.50 (95% CI: 0.59-0.79; Figure 3). By analyzing the two-graph ROC curve, we observed the behavior of the various cut-off points in relation to sensitivity and specificity; for a maximum yield (greater than 95%), the calculated cut-off points were below 8.5% and above 82.3% (Table 2).

to establish a definitive pathological diagnosis and identified three independent risk factors for SPN malignancy: advanced age; presence

Figure 2 - Two-graph ROC curve for the probabilistic model for predicting malignancy of Swensen et al.(3) in our sample.

Discussion The diagnosis of SPN remains a major challenge in medical practice. In the present study, we evaluated a sample of patients who had undergone surgical resection of SPN in order

Figure 3 - Two-graph ROC curve for the probabilistic model for predicting malignancy of Gould et al.(4) in our sample.

Figure 1 - ROC curve comparing the models of Swensen et al.(3) and Gould et al.(4) #A: ROC curve for the probabilistic model of Swensen et al.,(3) with an area under the curve (AUC) of 0.79 ± 0.44 (95% CI: 0.70-0.88); #B: ROC curve for the probabilistic model of Gould et al.,(4) with an AUC of 0.69 ± 0.50 (95% CI: 0.59-0.79); and d: distance to the leftmost point of the ROC curve (d = 0.39) of the model of Swensen et al.(3)

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Table 2 - Values derived from the two-graph ROC curve for the cut-off points determined in the analysis of the mathematical models of Swensen et al.(3) and Gould et al.(4) Modelsa Statistical analysis Swensen et al. Gould et al.

Cut-off point 37.00 40.81 Sensitivity 71.40 65.50 Specificity 72.50 67.30 Positive predictive value 71.38 66.70 Negative predictive value 72.52 66.11 Accuracy of the test 71.96 66.40 a

Values expressed as %.

Analysis and validation of probabilistic models for predicting malignancy in solitary pulmonary nodules in a population in Brazil

of spiculated margins; and SPN diameter. The other clinical and radiological characteristics of the patients with SPN showed no significant associations with SPN malignancy in our sample.

In several recent studies, age has been reported to be one of the major risk factors for SPN malignancy.(3,4,9,10) Stratification by age revealed a statistically significant association between age and malignancy, as well as increasing ORs. This finding corroborates current findings demonstrating that older individuals, especially those over 50 years of age, are at a higher risk for malignant SPN. Spiculated (corona radiata) margins are predictive of SPN malignancy, the positive predictive value being as high as 94%, whereas lobulated margins have a positive predictive value for malignancy of up to 80%.(11-13) This was also true in the present study, in which we found that two thirds of the malignant lesions had irregular, spiculated edges or irregular, lobulated edges, a finding that was statistically significant (p = 0.001).

The mean lesion diameter is also an important risk factor for malignancy, especially when it increases and approaches 30 mm. Numerous studies have confirmed this finding, always associating lesion growth with its malignant potential.

Nodules of more than 20 mm in diameter have a greater than 50% chance of being diagnosed as malignant.(14,15) This is consistent with the findings of the present study, in which we found a significant association between lesion diameter and malignancy when we compared the mean lesion diameters among the stratified groups, stratification having revealed increasing ORs. We also evaluated two mathematical models for predicting the likelihood of SPN malignancy.

Although both models are widely disseminated, we found no studies investigating either model in a population in Brazil. One group of authors recently tested the model of Swensen et al.(3) in a population in the Philippines and found that the model was not valid as a predictor of malignancy, a finding that was associated with the high rate of tuberculosis in the study population.(6) In our study population, both models proved effective in predicting the malignant potential of SPNs, the model of Swensen et al.(3) being more accurate than that of Gould et al.(4) The results obtained with the use of the equations developed by Swensen et al.(3) showed

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that the AUC found in the present study (0.79 ± 0.44; 95% CI: 0.70-0.88) was nearly identical to the values reported by other groups of researchers, who validated both probabilistic models in similar studies.(16,17) This AUC allows us to state that the aforementioned mathematical model showed good accuracy (AUC > 0.70), which supports the use of that model as a diagnostic test, as has been proposed.(18) By analyzing the ROC and two-graph ROC curves, we observed the behavior of the various cut-off points: the values at the ends of the curves, i.e., the cut-off points below 15.0% and above 66.5%, are the values with the highest yield, a sensitivity of 95.9% and a specificity of 35.3% having been found for the cut-off points below 15.0% and a sensitivity of 36.7% and a specificity of 94.1% having been found for the cut-off points above 66.5%. In brief, in patients for whom the probability of malignancy was ≤ 15.0%, the rates of true positives were so high (showed such a high sensitivity) that, in theory, they would have allowed us to withhold treatment in our sample, whereas, in patients for whom the probability of malignancy was ≤ 11.0%, sensitivity was 100%, this being therefore the lowest possible rate of false negatives. At the other end of the curve, we found patients for whom the probability of malignancy was ≥ 66.5%; at this cut-off point, sensitivity was 36.7% and specificity was 94.1%, i.e., they reached values that allow referral for surgical resection of SPN because of a high diagnostic rate, which increases after that percentile, reaching a specificity of 100% above the cut-off point of 80.5% (i.e., minimizing the occurrence of false negatives). For patients with intermediate probability of malignancy (i.e., those for whom the probability was between 15.0% and 66.5%), the model was found to be ineffective in predicting the probability of SPN malignancy, being therefore an unreliable diagnostic test. For such patients, further tests, including positron emission tomography and biopsy (transbronchial or transthoracic biopsy), are necessary.

For the model of Gould et al.,(4) our analysis of the ROC curve revealed an AUC of 0.69 ± 0.50 (95% CI: 0.59-0.79) and an accuracy of 66.40%.

Reliable cut-off points were obtained only with values ≤ 8.36% (sensitivity of 94.4% and specificity of 21.4%) and values ≥ 82.3% (sensitivity of 13.0% and specificity of 94.6%). Therefore, for J Bras Pneumol. 2012;38(5):559-565

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cases within the range between these cut-off points, it is impossible to draw reliable conclusions based on the model, and further investigation being therefore necessary.

For our sample, we found that the mathematical model of Swensen et al.(3) was superior to that of Gould et al;(4) through analysis of superimposed ROC curves, we observed a greater AUC for the former, as well as a narrower range between the reliable cut-off points. This behavior demonstrated that, in our sample, the mathematical model proposed by Swensen et al.(3) had a higher diagnostic accuracy. Recently, in a study conducted in the USA, the two models were compared and were found to have very similar behaviors,(16) a finding that is in disagreement with ours.

In conclusion, of the clinical and radiological characteristics related to SPNs, three showed a statistically significant association with SPN malignancy: advanced age; presence of spiculated margins on chest CT; and greater maximum SPN diameter.

By comparing the model of Swensen et al.(3) and that of Gould et al.,(4) we found that the former had a higher yield, with higher sensitivity, specificity, and accuracy.

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Chest. 2007;132(3 Suppl):108S-130S. 10. Clements WM, DeRosimo JF, Reed CE. Solitary pulmonary nodule. In: Shields TW, LoCicero J, Reed CE, Feins RH, editors. General Thoracic Surgery. Philadelphia: Lippincott Williams & Wilkins; 2009. p. 1205-11.

11. Soubani AO. The evaluation and management of the solitary pulmonary nodule. Postgrad Med J. 2008;84(995):459‑66. PMid:18940947. http://dx.doi. org/10.1136/pgmj.2007.063545 12. Stark P. Computed tomographic and positron emission tomographic scanning of pulmonary nodules. In: UpToDate, Basow DS, editor, UpToDate: Waltham, MA; 2012.

13. Seemann MD, Seemann O, Luboldt W, Bonél H, Sittek H, Dienemann H, et al. Differentiation of malignant from benign solitary pulmonary lesions using chest radiography, spiral CT and HRCT. Lung Cancer. 2000;29(2):105-24. http://dx.doi.org/10.1016/S0169-5002(00)00104-5 14. Henschke CI, Yankelevitz DF, Naidich DP, McCauley DI, McGuinness G, Libby DM, et al. CT screening for lung cancer: suspiciousness of nodules according to size on baseline scans. Radiology. 2004;231(1):164-8.

PMid:14990809. http://dx.doi.org/10.1148/ radiol.2311030634 15. MacMahon H, Austin JH, Gamsu G, Herold CJ, Jett JR, Naidich DP, et al. Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology. 2005;237(2):395‑400.

PMid:16244247. http://dx.doi.org/10.1148/ radiol.2372041887 16. Schultz EM, Sanders GD, Trotter PR, Patz EF Jr, Silvestri GA, Owens DK, et al. Validation of two models to estimate the probability of malignancy in patients with solitary pulmonary nodules. Thorax. 2008;63(4):335‑41.

PMid:17965070 PMCid:2882437. http://dx.doi. org/10.1136/thx.2007.084731 17. Herder GJ, van Tinteren H, Golding RP, Kostense PJ, Comans EF, Smit EF, et al. Clinical prediction model to characterize pulmonary nodules: validation and added value of 18F-fluorodeoxyglucose positron emission tomography. Chest. 2005;128(4):2490-6. PMid:16236914. http://dx.doi.org/10.1378/chest.128.4.2490 18. Martinez EZ, Louzada-Neto F, Pereira BB. A curva ROC para testes diagnósticos. Cad Saude Coletiva (Rio J.). 2003;11(1):7-31.

Analysis and validation of probabilistic models for predicting malignancy in solitary pulmonary nodules in a population in Brazil

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About the authors Cromwell Barbosa de Carvalho Melo

Thoracic Surgeon. Hospital São Paulo, Universidade Federal de São Paulo/Escola Paulista de Medicina – UNIFESP/EPM, Federal University of São Paulo/Paulista School of Medicine – São Paulo, Brazil.

João Aléssio Juliano Perfeito

Adjunct Professor. Universidade Federal de São Paulo/Escola Paulista de Medicina – UNIFESP/EPM, Federal University of São Paulo/Paulista School of Medicine – São Paulo, Brazil.

Danilo Félix Daud

Thoracic Surgeon. Hospital São Paulo, Universidade Federal de São Paulo/Escola Paulista de Medicina – UNIFESP/EPM, Federal University of São Paulo/Paulista School of Medicine – São Paulo, Brazil.

Altair da Silva Costa Júnior

Attending Physician. Hospital São Paulo, Universidade Federal de São Paulo/Escola Paulista de Medicina – UNIFESP/EPM, Federal University of São Paulo/Paulista School of Medicine – São Paulo, Brazil.

Ilka Lopes Santoro

Affiliate Professor. Universidade Federal de São Paulo/Escola Paulista de Medicina – UNIFESP/EPM, Federal University of São Paulo/Paulista School of Medicine – São Paulo, Brazil.

Luiz Eduardo Villaça Leão

Full Professor. Universidade Federal de São Paulo/Escola Paulista de Medicina – UNIFESP/EPM, Federal University of São Paulo/ Paulista School of Medicine – São Paulo, Brazil.

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Original Article Electric Ventilation: indications for and technical aspects of diaphragm pacing stimulation surgical implantation*,** Ventilação elétrica: indicações e aspectos técnicos do implante cirúrgico do marca-passo de estimulação diafragmática

Miguel Lia Tedde, Raymond P Onders, Manoel Jacobsen Teixeira, Silvia Gelas Lage, Gerson Ballester, Mario Wilson Iersolino Brotto, Erica Mie Okumura, Fabio Biscegli Jatene

Abstract Objective: Patients with high cervical spinal cord injury are usually dependent on mechanical ventilation support, which, albeit life saving, is associated with complications and decreased life expectancy because of respiratory infections. Diaphragm pacing stimulation (DPS), sometimes referred to as electric ventilation, induces inhalation by stimulating the inspiratory muscles. Our objective was to highlight the indications for and some aspects of the surgical technique employed in the laparoscopic insertion of the DPS electrodes, as well as to describe five cases of tetraplegic patients submitted to the technique. Methods: Patient selection involved transcutaneous phrenic nerve studies in order to determine whether the phrenic nerves were preserved. The surgical approach was traditional laparoscopy, with four ports. The initial step was electrical mapping in order to locate the “motor points” (the points at which stimulation would cause maximal contraction of the diaphragm). If the diaphragm mapping was successful, four electrodes were implanted into the abdominal surface of the diaphragm, two on each side, to stimulate the branches of the phrenic nerve. Results: Of the five patients, three could breathe using DPS alone for more than 24 h, one could do so for more than 6 h, and one could not do so at all.

Conclusions: Although a longer follow-up period is needed in order to reach definitive conclusions, the initial results have been promising. At this writing, most of our patients have been able to remain ventilator-free for long periods of time.

Keywords: Spinal cord injuries; Quadriplegia; Respiration, artificial; Pacemaker, artificial; Diaphragm.

Resumo Objetivo: Pacientes com lesão medular cervical alta em geral são dependentes de ventilação mecânica, que, embora salve vidas, está associada a complicações e redução da expectativa de vida devido a infecções respiratórias.

A estimulação do diafragma por marca-passo, às vezes chamada de ventilação elétrica, induz a inspiração por estimulação dos músculos inspiratórios. Nosso objetivo foi destacar as indicações e alguns aspectos da técnica cirúrgica empregada no implante laparoscópico dos eletrodos, assim como descrever cinco casos de pacientes tetraplégicos submetidos à técnica. Métodos: A seleção dos pacientes envolveu estudos de condução do nervo frênico por via transcutânea para determinar se os nervos estavam preservados. A abordagem cirúrgica foi laparoscopia clássica com quatro trocartes. A técnica foi iniciada com o mapeamento elétrico para encontrar os “pontos motores” (pontos de contração máxima do diafragma). Se o mapeamento era bem-sucedido, dois eletrodos eram implantados na face abdominal de cada lado do diafragma para estimular ramos do nervo frênico. Resultados: Dos cinco pacientes, três e um, respectivamente, eram capazes de respirar somente com o uso do marca-passo por períodos superiores a 24 e 6 h, enquanto um não era capaz. Conclusões: Embora seja necessário um acompanhamento mais longo para chegar a conclusões definitivas, os resultados iniciais são promissores, pois, no momento, a maioria dos nossos pacientes pode permanecer sem ventilação mecânica por longos períodos de tempo.

Descritores: Traumatismos da medula espinal; Quadriplegia; Respiração artificial; Marca-passo artificial; Diafragma.

* Study carried out in the Department of Thoracic Surgery, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Correspondence to: Miguel L. Tedde. Rua Itambé, 367, apto. 151A, Higienópolis, CEP 01239-001, São Paulo, SP, Brasil.

Tel. 55 11 99653-5030. Fax: 55 11 2661-5197. E-mail: tedde@usp.br Financial support: This study received financial support from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, São Paulo Research Foundation; Grant no. 2010/50785-6) and from Synapse Biomedical International.

Submitted: 25 June 2012. Accepted, after review: 12 July 2012. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

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Electric Ventilation: indications for and technical aspects of diaphragm pacing stimulation surgical implantation

Introduction Patients with high cervical spinal cord injury (SCI) are usually dependent on mechanical ventilation (MV) support, which, despite being life saving, is associated with a myriad of significant complications, such as increased secretions, difficulty with speech, constant noise, increased anxiety, loss of smell, and inability to find living facilities or nursing care. In addition, patients using ventilators have a significant reduction in their life expectancy because of respiratory infections, mainly caused by poor ventilation of the posterior lobe. From an economic standpoint, the average annual health care and living expenses due to ventilator dependence in tetraplegic patients in the United States are more than US$ 170,000.(1) Phrenic nerve pacing has been used with mixed success for over 40 years in ventilatordependent patients.(2) However, a recent long-term follow-up study has demonstrated a reduction in respiratory infections, improved cost-benefit ratio, and improved quality of life in those submitted to diaphragm pacing stimulation (DPS).(3) In the past, the traditional method of phrenic nerve pacing required bilateral cervical exploration or thoracotomy followed by phrenic nerve dissection and mobilization.(4,5) The implantation of the electrodes at these sites can be difficult, and, if the phrenic nerve is injured, the diaphragm will be nonfunctional. However, the more recent approach to DPS (i.e., via laparoscopy) avoids bilateral thoracotomy, allows the evaluation of the diaphragm in real time, and permits the intramuscular implantation of the electrodes into the motor points of the branches of the right and left hemidiaphragms.(6) Electric ventilation, most commonly known as DPS, is the production of inhalation by applying rhythmic stimulation to the motor nerves and inspiratory muscles. It is a technique designed to replace, delay, or reduce the need for MV by natural negative pressure ventilation using the diaphragm of the patient. However, phrenic nerve function needs to be preserved for DPS to be successful.(6,7) In addition to being used in patients with SCI or congenital central hypoventilation syndrome, the laparoscopic approach to DPS has been used in patients with motor neuron disease or amyotrophic lateral sclerosis (ALS),(8) as well as in difficult-to-wean patients in the ICU.(9)

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The indications for DPS vary depending on the case. In patients with SCI, DPS is used when there is respiratory insufficiency due to the injury, whereas, in patients with ALS, DPS is used when the respiratory symptoms begin.(10) We have recently developed a funded pilot project for diaphragm pacing via intramuscular diaphragm electrode implantation in patients who have become ventilator-dependent after SCI.(11) To the best of our knowledge, these are the first reported cases of intramuscular DPS in Latin America. The objective of the present study was to highlight the indications for and some aspects of the surgical technique employed in the laparoscopic insertion of the DPS electrodes.

Here, we describe the most current version of the laparoscopic insertion technique and the results of the modifications that were made over the course of more than 500 implantation procedures performed worldwide. We hope that by improving the understanding of the procedure the present study can be used not only as a guide for surgeons involved in implantation procedures but also as a tool for nonsurgeons taking care of such patients.

Methods Between October and November of 2011, five patients who had suffered high cervical SCI (C4 or higher) and who were on long-term ventilation were evaluated to determine whether they could undergo diaphragm pacing with the DPS system (NeuRx®; Synapse Biomedical, Oberlin, OH, USA), in a trial conducted in the Thoracic Surgery and Neurosurgery Departments of the University of São Paulo School of Medicine Hospital das Clínicas Heart Institute, located in the city of São Paulo, Brazil. All of the patients gave written informed consent, and the study was approved by the research ethics committee of the institution (Process no. 0551/10).

Specific investigations were carried out for patient selection, including chest X-rays and transcutaneous phrenic nerve studies in order to determine whether the phrenic nerves were preserved. The characteristics of the patients, including gender, age, level of SCI, duration of MV, electromyographic response of the right and left phrenic nerves (as determined by electroneurography), and degree of ventilator dependence, are summarized in Table 1.

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The anesthetic technique employed has been described in one study.(12) All of the patients selected had permanent tracheostomies, arrived at the operating room connected to their usual ventilator, and were transferred to the anesthesia ventilator (the settings of which were the same as those of the mechanical ventilator). This process was reversed at the end of the surgical procedure. The patients were monitored by electrocardiography, oximetry, and noninvasive arterial pressure measurement.

The surgical approach was traditional laparoscopy, with pneumoperitoneum and four ports. The patients were placed in the supine position, with arms outstretched, and elevated 30° during most of the procedure. Exposure of the diaphragm started with the placement of one 10-mm supraumbilical port and two 5-mm ports at the right and left subcostal incisions.

After the falciform ligament was excised, one 12-mm subxiphoid port was placed.

The initial step was electrical mapping in order to locate the points at which stimulation would cause maximal contraction of the diaphragm.

Diaphragm mapping was the key step in the procedure, given that it shows where the DPS electrodes should be implanted. A standard Maryland dissector, coupled to the Clinical Station (Synapse Biomedical, Oberlin, OH, USA) by an alligator clip, was used in order to perform the mapping. The mapping technique involves working in parallel lines to the central tendinous portion of the diaphragm. After one line was completed, the surgeon moved upward away from the central tendon in order to identify areas of maximal contraction, which are usually close to the motor points (Figure 1).

Qualitative assessment was based on the degree of diaphragm contraction, as seen intraoperatively.

Quantitative assessment of intra-abdominal pressure changes was performed with a tube that was attached to one of the laparoscopic ports, which in turn was attached to a pressure transducer.

If the diaphragm mapping was successful, four electrodes were implanted into the abdominal surface of the diaphragm, two on each side, in order to stimulate the branches of the phrenic nerve. The implantation device was passed through the subxiphoid midline port. This allowed easy access to both hemidiaphragms. The laparoscopic implant instrument is retractable, with a hollow bore needle that is capable of angulations and full retraction. It allows safe, dependable, and accurate positioning of the electrode in the commonly thin wall of the atrophied diaphragm muscle (Figure 2).

After the electrodes had been implanted, Maryland dissectors were used in order to hold the wires in the abdomen as the implantation device was backed out through the midline port.

Those pacing wires were passed out percutaneously

Figure 1 - Dissector being used in order to map the diaphragm. Note diaphragmatic contraction.

Table 1 - Patient characteristics. right phrenic nerve left phrenic nerve EMGR EMGR MV Duration Latency, Amplitude, Latency, Amplitude, ms ms ms ms C3 9 years 7.8 460 8.8 750 C2-C3 14 years 7.6 200 7.9 240 C4 1year 7.6 240 6.7 320 C4-C5 10 months Undetermined 8.3 180

Age, SCI Patient Gender years level 1 2 3 4

F F M M

26 35 27 16

5

F

40

C3

6 years

9.1

68

9.0

35

SCI: spinal cord injury; MV: mechanical ventilation; and EMGR: electromyographic response.

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Ventilator dependence Complete Complete Complete Partial (with supplemental oxygen) Complete

Electric Ventilation: indications for and technical aspects of diaphragm pacing stimulation surgical implantation

and attached to the external pacing device in a manner somewhat similar to epicardial pacing after cardiac surgery.(6,7,13,14) The Clinical Station that was used for electrode stimulation during the surgical procedure was also used in order to program the pacing unit to maximize patient ventilation. This unit allowed pacing to be turned on and off and provided the stimulus at the required amplitude and frequency (Figure 3).

The DPS electrodes were then attached to the clinical station, and the diaphragm was tested to confirm that the electrodes had been correctly positioned. The tail of the first electrode was brought back into the abdomen prior to the implantation of the second electrode on the same side. The tail of the second electrode was subsequently passed entirely into the abdomen, and the procedure was transitioned to the opposite side. The four electrodes were withdrawn

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through the subxiphoid port, care being taken to ensure that the right and left side wires were not inadvertently crossed.

The wire routing process involves tunneling the implanted electrodes from the subxiphoid exit site to a laterally located site on the skin. Four separate tunnels were created with the tunneling devices, one for each implanted electrode. An additional ground electrode was implanted at a remote location with a separate tunneling device. The tunneling devices were flushed with saline to ensure that they were free of tissue, and the electrodes were passed through each of the tunneling devices, in a pattern according to their location in the diaphragm, with an electrode coupling device (Figure 4).

With the electrodes tunneled in their appropriate positions, the excess slack was pulled back into the abdominal cavity with the Maryland dissector. This was carefully done in order to prevent inadvertent placement of the electrodes exceedingly back into the abdominal cavity, pulling the exposed portion of each electrode back into the subcutaneous tunnel, the electrodes therefore becoming irretrievable.

The laparoscopic ports were withdrawn under direct visualization, fascia and skin incisions were closed, and the wounds were dressed. Gold pin connectors were attached to the ends of the electrodes, which were subsequently inserted into the connector block. The connector block was

Figure 2 - Electrode being implanted into the right hemidiaphragm.

Figure 3 - The Clinical Station used during surgery and for device programming.

Figure 4 - External pacing device showing the attachments to the electrodes that are transcutaneously implanted into the diaphragm.

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secured to the skin by a customized connector holder. The patient was again connected to the computer stimulator to ensure that all electrical connections were working.

Results Of the five patients selected, two presented with capnothorax related to intra-abdominal carbon dioxide insufflation (carbon dioxide pneumothorax). One of the patients developed bilateral carbon dioxide pneumothorax during anesthesia; this was rapidly diagnosed by evaluation of the pulmonary pressures. The patient required higher pressures for ventilation, which were difficult to achieve because the patient had an uncuffed endotracheal tube. The problem was quickly solved by puncturing the right side in order to drain the carbon dioxide pneumothorax and deflate the pneumoperitoneum. In the other patient, the carbon dioxide pneumothorax was detected by a postoperative chest X-ray. We decided to perform pleural drainage using a pigtail catheter.

The chest tube was removed the following day.

During the surgical procedure, in one patient with elevated hemidiaphragm, a Valsalva maneuver, performed in order to produce downward force to help insert the permanent electrode, produced hypotension. The complication resolved with the interruption of the maneuver.

Six months after the procedures, three of the five patients were able to use DPS continuously.

Another patient, who had been ventilatordependent for 14 years, was able to use DPS 6 h a day. However, stimulation had to be interrupted after the onset of neuropathic pain that remained uncontrolled at this writing. The fifth patient, with the weakest electromyographic response, was unable to sustain ventilation with the DPS system.

Discussion Because the five patients had been tracheostomized, access to the airways was not a problem for the anesthesiologists. However, one of the patients had an uncuffed endotracheal tube, which jeopardized ventilation when capnothorax occurred (because of the air leak around the tube). Although ventilation can be maintained with an uncuffed tube, we recommend that it be replaced by a cuffed tube prior to the surgical procedure because of the risk of capnothorax.

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Two patients presented with capnothorax, a finding that has been reported in the literature. In a recent report of SCI patients implanted with the DPS system,(6) the most common complication was capnothorax, which was seen in 42%. However, the capnothorax had clinical consequences in only 4%. Although electrode infection and migration have been reported,(6) they are uncommon; none of our patients had these complications.

Diaphragm mapping is the key step in the implantation procedure, and it is the step that has changed the most over time. Previously, a suction electrode catheter was used in order to identify points of contraction; currently, a standard Maryland dissector is used in order to do the mapping. The latter method has proven to be easy, reproducible, and faster than the former.

During diaphragm mapping, it is advisable to stimulate additional abdominal wall musculature if the diaphragm shows weak stimulation, in order to confirm that the electrode and the computer-based stimulator are working properly.

During diaphragm pacing, it is important to confirm whether there is no electrical interference that might affect the cardiac rhythm. Right and left side DPS electrodes should be tested.

Subsequently, the four electrodes should be tested with the stimulator at maximum output settings. In addition to these tests, we used electrocardiography in order to confirm that there was no electrical interference. If interference is observed, DPS can be isolated to a single electrode, and appropriate modifications can be made by moving the electrode or programming stimulation to lower levels.

Another point of concern is the use of DPS and cardiac pacing. The use of DPS and cardiac pacemakers has been shown to be safe.

The interaction between the devices can be clearly identified and avoided by changing the programming or the placement of the intramuscular electrodes. Because such patients present with increased cardiac susceptibility, which caused them to have a cardiac pacemaker in the first place, they should be treated with extra caution.

Any increases in the DPS settings should be carried out in a monitored setting to ensure that there is no cardiac rhythm capture, as is the case during the initial electrode implantation in all patients.(15) One group of authors, postulating that sleep-related disturbances are early clues to

Electric Ventilation: indications for and technical aspects of diaphragm pacing stimulation surgical implantation

diaphragmatic dysfunction and therefore can provide a sensitive marker, assessed the effects of DPS on FVC.(10) After four months of diaphragm conditioning, patients with ALS exhibited significant sleep improvements. It is possible that the number of SCI or ALS patients submitted to DPS will increase in the future.(10) Although a longer follow-up period is necessary in order to reach definitive conclusions, the initial results have been promising, since most of our patients could remain ventilator-free for long periods of time at this writing. Of the five patients, three could breathe using DPS alone for more than 24 h.

In conclusion, the implementation of preoperative testing, together with the surgical technique employed and the postoperative recovery protocol, does not require any extraordinary preparations or follow-up for the implantation of the electrodes and the DPS system. This is a procedure that can be readily repeated in a costeffective manner. This is an important finding especially for patients with SCI, since the DPS procedure is usually more challenging in those patients than in ALS patients.

References 1. National Spinal Cord Injury Statistical Center [homepage on the Internet]. Birmingham: The University of Alabama at Birmingham. [cited 2012 Jun 4]. Spinal Cord Injury Facts and Figures at a Glance February 2011. [Adobe Acrobat document, 2p.]. Available from: https://www. nscisc.uab.edu/PublicDocuments/fact_figures_docs/ Facts%202012%20Feb%20Final.pdf 2. Miko I, Gould R, Wolf S, Afifi S. Acute spinal cord injury.

Int Anesthesiol Clin. 2009;47(1):37-54. PMid:19131751. http://dx.doi.org/10.1097/AIA.0b013e3181950068 3. Hirschfeld S, Exner G, Luukkaala T, Baer GA. Mechanical ventilation or phrenic nerve stimulation for treatment of spinal cord injury-induced respiratory insufficiency.

Spinal Cord. 2008;46(11):738-42. PMid:18475279. http:// dx.doi.org/10.1038/sc.2008.43 4. Glenn WW, Hogan JF, Loke JS, Ciesielski TE, Phelps ML, Rowedder R. Ventilatory support by pacing of the conditioned diaphragm in quadriplegia. N Engl J Med. 1984;310(18):1150-5. PMid:6608692. http:// dx.doi.org/10.1056/NEJM198405033101804 5. DiMarco AF, Onders RP, Kowalski KE, Miller ME, Ferek S, Mortimer JT. Phrenic nerve pacing in a tetraplegic patient via intramuscular diaphragm electrodes. Am J Respir Crit Care Med. 2002;166(12 Pt 1):1604-6. PMid:12471076. http://dx.doi.org/10.1164/rccm.200203-175CR

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6. Onders RP, Elmo M, Khansarinia S, Bowman B, Yee J, Road J, et al. Complete worldwide operative experience in laparoscopic diaphragm pacing: results and differences in spinal cord injured patients and amyotrophic lateral sclerosis patients. Surg Endosc. 2009;23(7):1433‑40.

PMid:19067067. http://dx.doi.org/10.1007/ s00464-008-0223-3 7. Onders RP, DiMarco AF, Ignagni AR, Mortimer JT. The learning curve for investigational surgery: lessons learned from laparoscopic diaphragm pacing for chronic ventilator dependence. Surg Endosc. 2005;19(5):633-7.

PMid:15776209. http://dx.doi.org/10.1007/ s00464-004-8934-6 8. Onders RP, Carlin AM, Elmo M, Sivashankaran S, Katirji B, Schilz R. Amyotrophic lateral sclerosis: the Midwestern surgical experience with the diaphragm pacing stimulation system shows that general anesthesia can be safely performed. Am J Surg. 2009;197(3):386‑90.

PMid:19245920. http://dx.doi.org/10.1016/j. amjsurg.2008.11.008 9. Onders R, McGee MF, Marks J, Chak A, Schilz R, Rosen MJ, et al. Diaphragm pacing with natural orifice transluminal endoscopic surgery: potential for difficult-to-wean intensive care unit patients. Surg Endosc. 2007;21(3):475-9. PMid:17177078. http:// dx.doi.org/10.1007/s00464-006-9125-4 10. Gonzalez-Bermejo J, Morélot-Panzini C, Salachas F, Redolfi S, Straus C, Becquemin MH, et al. Diaphragm pacing improves sleep in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2012;13(1):4454. PMid:22023158. http://dx.doi.org/10.3109/17482 968.2011.597862 11. ClinicalTrials.gov [homepage on the Internet]. Bethesda: U.S. National Institutes of Health. [cited 2012 Jun 4].

Diaphragmatic Pacemaker in Tetraplegic Patients With Spinal Cord Injuries. Available from: http://clinicaltrials. gov/ct2/show/NCT01385384?term=tedde&rank=1 12. Tedde ML, Vasconcelos-Filho P, Hajjar LA, Almeida JP, Flora GF, Okumura EM, et al. Diaphragmatic pacing stimulation in spinal cord injury: anesthetic and perioperative management. Clinics (Sao Paulo).

In press 2012.

13. Onders RP, Aiyar H, Mortimer JT. Characterization of the human diaphragm muscle with respect to the phrenic nerve motor points for diaphragmatic pacing. Am Surg. 2004;70(3):241-7; discussion 247. PMid:15055848.

14. Reade MC. Temporary epicardial pacing after cardiac surgery: a practical review: part 1: general considerations in the management of epicardial pacing. Anaesthesia. 2007;62(3):264-71. Erratum in: Anaesthesia. 2007;62(6):644. PMid:17300304. http:// dx.doi.org/10.1111/j.1365-2044.2007.04950.x 15. Onders RP, Khansarinia S, Weiser T, Chin C, Hungness E, Soper N, et al. Multicenter analysis of diaphragm pacing in tetraplegics with cardiac pacemakers: positive implications for ventilator weaning in intensive care units. Surgery. 2010;148(4):893-7; discussion 897-8.

PMid:20797750. http://dx.doi.org/10.1016/j. surg.2010.07.008

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About the authors Miguel Lia Tedde

Attending Physician. Department of Thoracic Surgery, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Raymond P Onders

Director. Department of Minimally Invasive Surgery, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland (OH) USA.

Manoel Jacobsen Teixeira

Full Professor. Department of Neurosurgery, Laboratório de Investigação Médica 26 (LIM-26, Laboratory for Medical Research 26), University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Silvia Gelas Lage

Tenured Professor. Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Gerson Ballester

Physician. Department of Neurosurgery, Laboratório de Investigação Médica 26 (LIM-26, Laboratory for Medical Research 26), University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Mario Wilson Iersolino Brotto

Physician. Department of Neurology, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Erica Mie Okumura

Physiotherapist. Department of Thoracic Surgery, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Fabio Biscegli Jatene

Full Professor. Department of Thoracic Surgery, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

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Original Article Quantitative assessment of the intensity of palmar and plantar sweating in patients with primary palmoplantar hyperhidrosis* Avaliação quantitativa da intensidade da transpiração palmar e plantar em pacientes portadores de hiperidrose palmoplantar primária

Bruno Yoshihiro Parlato Sakiyama, Thaís Vera Monteiro, Augusto Ishy, José Ribas Milanez de Campos, Paulo Kauffman, Nelson Wolosker

Abstract Objective: To compare individuals with and without hyperhidrosis in terms of the intensity of palmar and plantar sweating. Methods: We selected 50 patients clinically diagnosed with palmoplantar hyperhidrosis and 25 normal individuals as controls. We quantified sweating using a portable noninvasive electronic device that has relative humidity and temperature sensors to measure transepidermal water loss. All of the individuals had a body mass index of 20-25 kg/cm2. Subjects remained at rest for 20-30 min before the measurements in order to reduce external interference. The measurements were carried out in a climate-controlled environment (21-24°C).

Measurements were carried out on the hypothenar region on both hands and on the medial plantar region on both feet. Results: In the palmoplantar hyperhidrosis group, the mean transepidermal water loss on the hands and feet was 133.6 ± 51.0 g/m2/h and 71.8 ± 40.3 g/m2/h, respectively, compared with 37.9 ± 18.4 g/m2/h and 27.6 ± 14.3 g/m2/h, respectively, in the control group. The differences between the groups were statistically significant (p < 0.001 for hands and feet). Conclusions: This method proved to be an accurate and reliable tool to quantify palmar and plantar sweating when performed by a trained and qualified professional.

Keywords: Hyperhidrosis; Sweat; Dermatology/instrumentation.

Resumo Objetivo: Comparar a intensidade de transpiração em palmas das mãos e planta dos pés de indivíduos portadores de hiperidrose com a de um grupo controle. Métodos: Foram selecionados 50 pacientes com diagnóstico clínico de hiperidrose palmoplantar e 25 indivíduos controles. Um método objetivo de quantificação da transpiração foi utilizado com um aparelho eletrônico portátil, não invasivo, com sensores de umidade relativa e de temperatura capazes de quantificar a perda de água transepidérmica. Todos os indivíduos apresentavam índice de massa corpórea de 20-25 kg/cm2 e permaneceram em repouso por 20-30 min antes das medições para reduzir a interferência externa. A mensuração foi realizada em sala climatizada com a temperatura de 21-24°C. Os locais determinados para a aferição foram região hipotenar da face palmar e região medial da face plantar. Resultados: No grupo com hiperidrose palmoplantar, as médias da intensidade de transpiração nas mãos e nos pés foram de, respectivamente, 133,6 ± 51,0 g/m2/h e 71,8 ± 40,3 g/m2/h, enquanto, no grupo controle, essas foram de 37,9 ±18,4 g/m2/h e 27,6 ± 14,3 g /m2/h. As diferenças das médias entre os grupos foram estatisticamente significativas (p < 0,001).

Conclusões: Este método de quantificação mostrou-se uma ferramenta precisa e confiável na avaliação da transpiração palmar e plantar, quando operado por um profissional treinado e capacitado.

Descritores: Hiperidrose; Suor; Dermatologia/instrumentação.

* Study carried out in the Department of Thoracic Surgery, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Correspondence to: Bruno Yoshihiro Parlato Sakiyama Rua Caraíbas, 326, apto. 171, Vila Pompéia, CEP 05020-000, São Paulo, SP, Brasil.

Tel. 11 38039774. E-mail: brunoyps@yahoo.com.br Financial support: None.

Submitted: 7 March 2012. Accepted, after review: 13 July 2012.

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Sakiyama YPS, Monteiro TV, Ishy A, de Campos JRM, Kauffman P, Wolosker N

Introduction Hyperhidrosis is a disorder characterized by excessive sweating (i.e., beyond what is physiologically necessary), especially on the palms, the axillae, the soles, and the face.(1,2) The etiology of hyperhidrosis is unknown and is associated with severe emotional, occupational, and social stress.(3) Hyperhidrosis begins in childhood or adolescence(4) and leads to significant loss of quality of life.(5) Between 12.5% and 56.5% of all patients with hyperhidrosis have a family history of the disease.(6) The treatment of hyperhidrosis aims at reducing sweating on the regions where there is sweat hypersecretion. Among clinical treatments are anticholinergic drugs—which inhibit the sympathetic impulses and whose side effects include dry mouth, visual disorders, urinary retention, constipation, and difficulty in chewing and swallowing(7)—and dermatological treatments, including application of astringent solutions or creams,(8) iontophoresis(9) (electrical saltwater baths applied to the affected area), which can reduce sweating on specific areas for a short period, and subcutaneous injection of botulinum toxin.

(10) In contrast, surgical treatment is definitive and consists of bilateral thoracic sympathectomy by video-assisted thoracoscopy, in which there is resection, thermal cauterization, or clipping of the sympathetic chain that is responsible for activating sweat glands in the region where one wants to eliminate profuse sweating.(11,12) The major side effect of the procedure is compensatory hyperhidrosis.(13,14) Most studies investigating the intensity or progression of hyperhidrosis after the different types of treatment are based on subjective assessment, meaning that they depend entirely on patient-reported data.(15) However, tests have been developed in order to measure the intensity of sweating in an objective manner.

The Delfin VapoMeter (Delfin Technologies Ltd., Kuopio, Finland), a portable device that can measure water vapor loss through the skin, has recently been used in order to evaluate the results of treating primary hyperhidrosis.(16,17) In Brazil, reference values for palmoplantar sweating (based on objective measurements of sweating) have yet to be established.

The objective of the present study was to compare individuals with and without hyperhidrosis in terms of the intensity of palmar and plantar J Bras Pneumol. 2012;38(5):573-578

sweating, as measured by the abovementioned portable device.

Methods Between February and May of 2011, we measured the intensity of sweating in 50 patients clinically diagnosed with palmoplantar hyperhidrosis (study group) and 25 individuals without hyperhidrosis (control group) by using the abovementioned portable device. The study was conducted in accordance with the guidelines of the local human research ethics committee.

None of the patients had hyperhidrosis on other areas of the body. All of the patients had a body mass index of 20-25 kg/cm2.

We measured palmoplantar sweating with the abovementioned device, which is a portable noninvasive instrument that has a closed measurement chamber that eliminates any interference from drafts (air conditioning and breathing, as well as the opening and closing of doors and windows), allowing accurate measurement of transepidermal water loss.

The chamber contains relative humidity and temperature sensors. For the measurements, the device was positioned perpendicular to the skin, remaining in contact with the skin surface until signaling that the reading was finished. The evaporation rate was automatically calculated by the device on the basis of an increase in relative humidity in the closed chamber. This measurement expresses the increase in water mass (in g) in relation to the area of evaporation (in m2) per unit of time (in h), the unit of measurement being therefore g/m2/h.

In order to standardize the quantification of sweating, all of the patients remained at rest for 20-30 min before the measurements in order to reduce external interference. The measurements were carried out in a climatecontrolled environment (21-24°C) at the hyperhidrosis outpatient clinic of the institution.

Measurements were carried out on the hypothenar region on both hands (Figure 1) and on the medial plantar region on both feet (Figure 2).

We compared individuals with and without hyperhidrosis in terms of the intensity of palmar and plantar sweating.

In the statistical analysis, we evaluated the mean transepidermal water loss on the hands and feet for each group of patients, the intensity of palmoplantar sweating having been measured

Quantitative assessment of the intensity of palmar and plantar sweating in patients with primary palmoplantar hyperhidrosis

575

with the Mann-Whitney U test. For all inferential analyses, the probability of a type I (α) error was set at 0.05.

Results The results of the quantification of palmoplantar sweating in the palmoplantar hyperhidrosis group and in the control group are shown in Table 1. In the palmoplantar hyperhidrosis group, the mean transepidermal water loss on the hands and feet was 133.6 ± 51.0 g/m2/h and 71.8 ± 40.3 g/m2/h, respectively, compared with 37.9 ± 18.4 g/m2/h and 27.6 ± 14.3 g/m2/h, respectively, in the control group.

The mean values were higher in the palmoplantar hyperhidrosis group than in the control group, the differences between the groups being statistically significant (p < 0.001).

Figure 1 - Measurement of the intensity of palmar sweating.

Discussion The quantification of sweating plays an extremely important role in the evaluation of treatments for hyperhidrosis and other diseases in which transepidermal water loss on areas such as the face, the hands, the feet, the trunk, and the back might be altered, as is the case of carpal tunnel syndrome(18) and diabetes.(19) Currently, quality-of-life questionnaires and indicators of patient satisfaction are often used for measuring the intensity of hyperhidrosis. On the basis of such reports, various attempts have been made to modify the extent of resection of sympathetic ganglia in thoracic sympathectomy in order to eliminate or reduce compensatory hyperhidrosis. However, the information thus obtained is subjective and varies from patient to patient, including symptom duration, symptom severity, extent and distribution of the sites of sweating, previous interventions, and postoperative results.(20-22)

Figure 2 - Measurement of the intensity of plantar sweating.

Table 1 - Transepidermal water loss on the hands and feet in the hyperhidrosis and control groups.a Group Hyperhidrosis Control Variable p* (n = 50) (n = 25) Mean ± SD Median Range Mean ± SD Median Range Transepidermal water loss 133.6 ± 51.0 129.0 55.6-256.0 37.9 ± 18.4 29.6 19.1-83.2 < 0.001 on the hands, g/m2/h Transepidermal water loss 71.8 ± 40.3 62.3 18.4-228.0 27.6 ± 14.3 26.0 10.6-82.5 < 0.001 on the feet, g/m2/h a

For each individual, measurements were performed on both hands and on both feet. *Mann-Whitney U test.

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Sakiyama YPS, Monteiro TV, Ishy A, de Campos JRM, Kauffman P, Wolosker N

There are few methods for the quantification of sweating. In 1996, Kalkan et al.(23) described an objective method for measuring transepidermal water loss, known as the “pad glove” method.

The method involved the use of special gloves (gauze gloves worn under surgical gloves) that were previously weighed on an electronic scale.

The participants put on the gloves (on both hands) and then rested in a comfortable, stress-free environment where temperature and humidity were kept constant (19-22°C and 45-55%, respectively).

After a given period of time, the gloves were carefully removed (in order to prevent the collected sweat from evaporating) and immediately weighed.

The difference between the final weight and the initial weight of the gloves corresponded to the amount of transepidermal water loss, measured in g/h.

Another technique for the quantification of sweating is the use of a ventilated capsule system (SKD 1000, Skinos Co., Nagoya, Japan) through which the contents of the gas that fills the space between the skin surface and the capsule placed on it are measured by two humidity sensors; therefore, the resulting measurement indicates the amount of transepidermal water loss in µg/ cm2/min.(17,18) Kuwabara et al.(18) used the ventilated capsule system in order to assess the sympathetic sweat response in patients with carpal tunnel syndrome, whereas Asahina et al.(19) used it in order to measure transepidermal water loss in cases of autonomic dysfunction in patients with diabetes.

In order to evaluate changes in the sweating patterns of 17 patients submitted to bilateral thoracic sympathectomy by video-assisted thoracoscopy, Bonde et al.(22) used a ventilated capsule system connected to both palms, the left sole, and the chest wall. Preoperative and postoperative measurements of transepidermal water loss were conducted under different experimental conditions. In addition to measuring baseline sweating (at 29°C), those authors measured the intensity of sweating after conversation (at 29°C), after a mental arithmetic challenge (at 29°C), after thermal stimulation (at 40°C), and after physical exercise (at 40°C). The study reported absence of primary palmoplantar hyperhidrosis in the long term and increased intensity of compensatory hyperhidrosis on the chest wall in situations of mental stress, in situations of thermal stimulation, and after physical exercise.

J Bras Pneumol. 2012;38(5):573-578

The quantitative sweat measurement system (Q-sweat, model 1.0; WR Medical Electronics Co., Stillwater, MN, USA) was developed to measure transepidermal water loss on small skin surfaces in humans. Rand et al.(24) used it in order to assess the sweat response during electrical stimulation in patients with diabetes.

More recently, a device known as VapoMeter (Delfin Technologies Ltd.) was used in order to evaluate the results of sympathectomy by video-assisted thoracoscopy in the treatment of primary palmar and plantar hyperhidrosis.(15,16) The use of this device has been validated by De Paepe et al.,(25) who demonstrated that the measurements obtained by the device are more accurate and reliable than are those obtained by an open chamber device known as the Tewameter (Courage & Khazaka, Cologne, Germany), which is regarded as the reference standard.

To date, there have been no studies specifically focusing on measuring baseline sweating in hyperhidrosis patients or healthy individuals.

By using a portable device, we measured sweat rates in 50 hyperhidrosis patients and 25 healthy individuals and found that the former had much higher rates, the differences being statistically significant. We now have baseline data on the sweating response in normal individuals and in hyperhidrosis patients. These data can be used as a reference by professionals who might be interested in using the device in the evaluation of patients with hyperhidrosis.

Transepidermal water loss as measured by the device under study proved to be a very rapid, practical, and reliable technique for quantifying palmoplantar sweating when performed by a trained and qualified professional. Therefore, the technique can be used in medical practice and can be an ancillary test in the diagnosis of hyperhidrosis and in the assessment of disease severity.

References 1. Lear W, Kessler E, Solish N, Glaser DA. An epidemiological study of hyperhidrosis. Dermatol Surg. 2007;33(1 Spec No.):S69-75. PMid:17241417.

2. Vorkamp T, Foo FJ, Khan S, Schmitto JD, Wilson P. Hyperhidrosis: evolving concepts and a comprehensive review. Surgeon. 2010;8(5):287-92. PMid:20709287.

3. de Campos JR, Kauffman P, Werebe Ede C, Andrade Filho LO, Kusniek S, Wolosker N, et al. Quality of life, before and after thoracic sympathectomy: report on 378 operated patients. Ann Thorac Surg. 2003;76(3):886-91.

PMid:12963223.

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4. Stolman LP. Hyperhidrosis: medical and surgical treatment.

Eplasty. 2008;8:e22. PMid:18488053.

5. Weber A, Heger S, Sinkgraven R, Heckmann M, Elsner P, Rzany B. Psychosocial aspects of patients with focal hyperhidrosis. Marked reduction of social phobia, anxiety and depression and increased quality of life after treatment with botulinum toxin A. Br J Dermatol. 2005;152(2):342-5.

PMid:15727649.

6. Ro KM, Cantor RM, Lange KL, Ahn SS. Palmar hyperhidrosis: evidence of genetic transmission. J Vasc Surg. 2002;35(2):382-6. PMid:11854739.

7. Harmsze AM, Houte M, Deneer VH, Tupker RA. Exerciseinduced sweating in healthy subjects as a model to predict a drug’s sweat-reducing properties in hyperhydrosis: a prospective, placebo-controlled, double-blind study. Acta Derm Venereol. 2008;88(2):108-12. PMid:18311434.

8. Goh CL, Yoyong K. A comparison of topical tannic acid versus iontophoresis in the medical treatment of palmar hyperhidrosis. Singapore Med J. 1996;37(5):466-8.

PMid:9046194.

9. Köstler E. Significance of iontophoresis in dermatology. With special reference to the management of lymphedemas [Article in German]. Dermatol Monatsschr. 1977;163(9):689-99. PMid:336427.

10. Grunfeld A, Murray CA, Solish N. Botulinum toxin for hyperhidrosis: a review. Am J Clin Dermatol. 2009;10(2):87‑102. PMid:19222249.

11. Munia MA, Wolosker N, Kauffman P, de Campos JR, Puech-Leão P. A randomized trial of T3-T4 versus T4 sympathectomy for isolated axillary hyperhidrosis. J Vasc Surg. 2007;45(1):130-3. PMid:17210397.

12. Munia MA, Wolosker N, Kaufmann P, de Campos JR, Puech-Leão P. Sustained benefit lasting one year from T4 instead of T3-T4 sympathectomy for isolated axillary hyperhidrosis. Clinics (Sao Paulo). 2008;63(6):771-4. http://dx.doi.org/10.1590/S1807-59322008000600011 13. Yazbek G, Wolosker N, Kauffman P, Campos JR, PuechLeão P, Jatene FB. Twenty months of evolution following sympathectomy on patients with palmar hyperhidrosis: sympathectomy at the T3 level is better than at the T2 level. Clinics (Sao Paulo). 2009;64(8):743-9. http:// dx.doi.org/10.1590/S1807-59322009000800006 14. Lyra Rde M, Campos JR, Kang DW, Loureiro Mde P, Furian MB, Costa MG, et al. Guidelines for the prevention, diagnosis and treatment of compensatory hyperhidrosis.

J Bras Pneumol. 2008;34(11):967-77. http://dx.doi. org/10.1590/S1806-37132008001100013 15. Wolosker N, Yazbek G, Ishy A, de Campos JR, Kauffman P, Puech-Leão P. Is sympathectomy at T4 level better

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than at T3 level for treating palmar hyperhidrosis? J Laparoendosc Adv Surg Tech A. 2008;18(1):102-6.

PMid:18266585.

16. Ishy A, de Campos JR, Wolosker N, Kauffman P, Tedde ML, Chiavoni CR, et al. Objective evaluation of patients with palmar hyperhidrosis submitted to two levels of sympathectomy: T3 and T4. Interact Cardiovasc Thorac Surg. 2011;12(4):545-8. http://dx.doi.org/10.1510/ icvts.2010.252015 17. Tetteh HA, Groth SS, Kast T, Whitson BA, Radosevich DM, Klopp AC, et al. Primary palmoplantar hyperhidrosis and thoracoscopic sympathectomy: a new objective assessment method. Ann Thorac Surg. 2009;87(1):267‑74; discussion 274-5. PMid:19101310.

18. Kuwabara S, Tamura N, Yamanaka Y, Misawa S, Isose S, Bae JS, et al. Sympathetic sweat responses and skin vasomotor reflexes in carpal tunnel syndrome. Clin Neurol Neurosurg. 2008;110(7):691-5. PMid:18485585.

19. Asahina M, Yamanaka Y, Akaogi Y, Kuwabara S, Koyama Y, Hattori T. Measurements of sweat response and skin vasomotor reflex for assessment of autonomic dysfunction in patients with diabetes. J Diabetes Complications. 2008;22(4):278-83. PMid:18413213.

20. Wolosker N, Yazbek G, de Campos JR, Munia MA, Kauffman P, Jatene FB, et al. Quality of life before surgery is a predictive factor for satisfaction among patients undergoing sympathectomy to treat hyperhidrosis.

J Vasc Surg. 2010;51(5):1190-4. PMid:20299178.

21. Ribas Milanez de Campos J, Kauffman P, Wolosker N, Munia MA, de Campos Werebe E, Andrade Filho LO, et al. Axillary hyperhidrosis: T3/T4 versus T4 thoracic sympathectomy in a series of 276 cases. J Laparoendosc Adv Surg Tech A. 2006;16(6):598-603. PMid:17243877.

22. Bonde P, Nwaejike N, Fullerton C, Allen J, Mcguigan J. An objective assessment of the sudomotor response after thoracoscopic sympathectomy. J Thorac Cardiovasc Surg. 2008;135(3):635-41. PMid:18329485.

23. Kalkan M, Aydemir E, Karakoç Y, Körpinar M. The measurement of sweat intensity using a new technique.

Turk J Med Sci 1998;28(5):515-7.

24. Rand S, Petrofsky JS., Zimmerman G. Diabetes: sweat response and heart rate variability during electrical stimulation in controls and people with diabetes. The J Appl Res. 2008;8(1):48-54.

25. De Paepe K, Houben E, Adam R, Wiesemann F, Rogiers V. Validation of the VapoMeter, a closed unventilated chamber system to assess transepidermal water loss vs. the open chamber Tewameter. Skin Res Technol. 2005;11(1):61-9.

PMid:15691261.

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About the authors Bruno Yoshihiro Parlato Sakiyama

Physician. University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Thaís Vera Monteiro

Physician. University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Augusto Ishy

Thoracic Surgeon. University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

José Ribas Milanez de Campos

Thoracic Surgeon. University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Paulo Kauffman

Vascular Surgeon. University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Nelson Wolosker

Vascular Surgeon. University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

J Bras Pneumol. 2012;38(5):573-578

Original Article Responsiveness of the six-minute step test to a physical training program in patients with COPD* Responsividade do teste do degrau de seis minutos a um programa de treinamento físico em pacientes com DPOC

Kamilla Tays Marrara, Diego Marmorato Marino, Maurício Jamami, Antônio Delfino de Oliveira Junior, Valéria Amorim Pires Di Lorenzo

Abstract Objective: To evaluate the responsiveness of the six-minute step test (6MST) to an aerobic physical training program (PTP) and to determine the efficacy of the PTP regarding spirometric variables during the 6MST, as well as physical performance, sensation of dyspnea, and SpO2 during the 6MST and the six-minute walk test (6MWT), in patients with COPD. Methods: This was a controlled, prospective randomized study involving patients clinically diagnosed with COPD, with an FEV1/FVC ratio < 70%, and having been clinically stable in the last two months.

The patients were randomized to undergo a PTP on a treadmill, three times a week, for six weeks (PTP group) or not (control group). Histories were taken from all of the patients, who received regular respiratory therapy during the study period, undergoing physical examination and spirometry before and after bronchodilator use; incremental symptom-limited cardiopulmonary exercise testing; the 6MST; and the 6MWT. Results: Of the 36 patients that completed the study, 21 and 15 were in the PTP and control groups, respectively. In the PTP group, there was a significant increase in the number of steps climbed during the 6MST and in the six-minute walk distance (in m and % of predicted), as well as a significant decrease in the sensation of dyspnea during the 6MWT. Conclusions: The 6MST showed responsiveness to the PTP. However, the 6MWT appears to be more responsive to the PTP proposed.

Keywords: Exercise test; Exercise; Pulmonary disease, chronic obstructive.

Resumo Objetivo: Avaliar a responsividade do teste do degrau de seis minutos (TD6) a um programa de treinamento físico (PTF) aeróbio e verificar a eficácia do PTF quanto às variáveis ergoespirométricas no TD6, assim como ao desempenho físico, sensação de dispneia e SpO2 no TD6 e no teste de caminhada de seis minutos (TC6) em pacientes com DPOC. Métodos: Estudo controlado, prospectivo e randomizado com pacientes com diagnóstico clínico de DPOC que apresentassem relação VEF1/CVF < 70% e condições clinicamente estáveis nos últimos dois meses. Os pacientes foram randomizados em grupo PTF, que realizaram um PTF em esteira por seis semanas, três vezes por semana, e grupo controle. Todos os participantes receberam cuidados usuais de fisioterapia respiratória durante o período de estudo e foram submetidos a anamnese, exame físico, espirometria antes e após o uso de broncodilatador, teste cardiopulmonar incremental sintoma limitado, TD6 e TC6 nos momentos basal e final. Resultados: Dos 36 pacientes que completaram o estudo, 21 e 15 foram distribuídos nos grupos PTF e controle, respectivamente. Verificou-se um aumento significativo do número de subidas no degrau no TD6, da distância percorrida no TC6 (em m e % do previsto), assim como uma redução significativa da sensação de dispneia durante o TC6 somente no grupo PTF. Conclusões: O TD6 apresentou responsividade ao PTF. No entanto, acreditamos que o TC6 seja mais responsivo ao PTF proposto.

Descritores: Teste de esforço; Exercício; Doença pulmonar obstrutiva crônica.

* Study carried out at the Universidade Federal de São Carlos – UFSCar, Federal University of São Carlos – São Carlos, Brazil.

Correspondence to: Kamilla Tays Marrara. Avenida Filomeno Rispoli, 179, Parque Santa Marta, CEP 13564-200, São Carlos, SP, Brasil.

Tel. 55 16 3351-8343. E-mail: kmarrara@hotmail.com Financial support: None.

Submitted: 17 November 2011. Accepted, after review: 16 July 2012.

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Marrara KT, Marmorato D, Jamami M, Oliveira Junior AD, Pires di Lorenzo VA

Introduction Clinical tests have been shown to be appropriate for assessing patients with COPD and are considered representative of an activity of daily living. Among these tests, the six-minute step test (6MST) has been used as an alternative for assessing such patients, having the advantages of requiring little physical space to be carried out(1) and only a single step for use as an ergometer.(2) However, Dal Corso et al.(1) and Swinburn et al.(3) reported that step climbing involves working against gravity and the use of muscle groups that are not frequently used during activities of daily living, which produces physiological responses that are different from those of the walk test, making the metabolic and ventilatory demands of step climbing more intense.

In addition, it should be borne in mind that the leg muscles in patients with COPD are impaired in terms of strength and endurance because of a reduction in muscle mass and aerobic capacity,(4) compromising performance. For this reason, it is important that leg muscle exercises be performed to improve the functional performance of these patients. Therefore, the inclusion of aerobic physical training in rehabilitation programs for patients with COPD has been essential, and the benefits of such training are observed regardless of disease stage. To Bourjeily & Rochester,(5) training programs should last an average of 6 to 12 weeks, at a frequency of three sessions per week and with exercise intensity ranging from 60% to 80% of maximal capacity. However, it is of note that although there is no scientific evidence in the literature to support that the 6MST is responsive to an aerobic physical training program (PTP) in patients with COPD, this type of program has been reported to be an additional advantage in clinical practice, involving reduced costs and the use of little physical space.

The primary objective of the present study was to evaluate the responsiveness of the 6MST to aerobic physical training in patients with stage II or III COPD. The secondary objective of the study was to determine the efficacy of this training regarding oxygen consumption (VO2); metabolic demand, as measured by the ratio between VO2 and peak oxygen consumption (VO2peak); pulmonary ventilation (VE); ventilatory demand, as measured by the ratio between VE and maximal voluntary ventilation (MVV); and ventilatory equivalent for carbon dioxide, as measured by the ratio J Bras Pneumol. 2012;38(5):579-587

between VE and carbon dioxide production (VCO2), all of which during the 6MST. In addition, we assessed physical performance, dyspnea, and SpO2 during the 6MST and the six-minute walk test (6MWT). Our hypothesis was that the 6MST would be responsive to aerobic physical training on a treadmill in terms of physiological variables, performance on the test, and dyspnea.

Methods This was a controlled, prospective randomized study conducted at the Universidade Federal de São Carlos (UFSCar, Federal University of São Carlos) Special Unit for Respiratory Therapy, located in the city of São Carlos, Brazil. The patients were referred to the unit by an attending pulmonologist. The inclusion criteria were having been clinically diagnosed with COPD, having an FEV1/FVC ratio < 70%, and having been clinically stable in the last two months (no disease exacerbations).

Pulmonary function testing (MasterScope®; Jaeger, Hoechberg, Germany) was conducted by the attending pulmonologist before and after bronchodilator use in order to assess reversibility, which was based on changes in FEV1, with an increase of more than 12% and at least 0.2 L(6); in addition, an FEV1/FVC ratio < 70% and the FEV1 value were used in order to classify patients as having moderate obstruction (50% ≤ FEV1 < 80% of predicted) or severe obstruction (30% ≤ FEV1 < 50% of predicted), as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD).(7) All technical procedures, as well as the acceptability and reproducibility criteria, were in accordance with the recommendations of the American Thoracic Society.(8) At least three technically acceptable expiratory curves were obtained for measuring slow vital capacity, FVC, and MVV, and the predicted values used were those of Pereira et al.(9) The exclusion criteria were as follows: having decompensated cardiovascular disease, rheumatic disease, neuromuscular disease, or orthopedic disease that prevented the performance of the tests by limiting exercise capacity; having attended a regular physical exercise program for six months prior to the study period; and not having performed a test or protocol of the present study for any reason.

Histories were taken from all patients, who underwent physical examination, pulmonary

Responsiveness of the six-minute step test to a physical training program in patients with COPD

function testing before and after bronchodilator use, incremental symptom-limited cardiopulmonary exercise testing (CPET), the 6MST, and the 6MWT. All tests were performed within a one-week period and were repeated after six weeks of physical training.

The tests were performed on different days, with the initial evaluation being performed at the study outset, CPET being performed on day 2, the 6MST being performed on day 3, and the 6MWT being performed on day 4. The same test sequence was used in reassessment.

For CPET, an incremental treadmill protocol was used, starting at 2 km/h for 2 min for warm-up and increasing the speed by 0.5 km/h every 2 min, with the slope being kept constant at 3%.(10-12) Testing was performed on a treadmill ergometer at incrementally increasing speeds because this approach is more specific, is functional, and is similar to an activity of daily living. Testing was stopped if the patient felt unable to proceed or if there were signs or symptoms that made it impossible to continue.(12) The 6MST was performed on a 20-cm-high step,(1) which was 80 cm in length and 40 cm in width and was covered with anti-slip flooring.

The test started from a standing position, and the patients were instructed to step up and down the step at their own pace for 6 min, to stop the test temporarily if necessary, and to alternate their legs without the support of their arms, which remained stationary at their sides; the patients performed the test at a freely chosen cadence.(1) The general principles of the 6MST were based on the recommendations of the American Thoracic Society,(13) and functional capacity on the 6MST was measured by the total number of steps climbed with both feet and by calculating work (VO2/number of steps climbed).

The 6MST and CPET included analysis of expired gases by means of a Medical Graphics VO2000 metabolic system (Medical Graphics Inc., St. Paul, MN, USA), which was operated with Aerograph® software for capture (analogdigital converter) and storage of signals with the 20-second method. Patients remained seated while a mouthpiece was put in place and was attached to the metabolic system, which was supported by a head fastener to relieve the weight of the mouthpiece, and the nostrils were blocked by a nose clip. The following parameters were evaluated:

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VO2 (L/min) at standard temperature and pressure, dry; the VO2/VO2peak ratio, as calculated by using the VO2 obtained during each activity evaluated and the VO2peak obtained during CPET; VE (L/min) at body temperature, pressure, saturated, as measured with a bidirectional pneumotachograph; the VE/MVV ratio, as calculated by using the VE obtained during each activity and by MVV as measured by direct spirometry(14); and the VE/ VCO2 ratio.

The 6MST and CPET were performed in the afternoon in order to prevent different physiological responses because of circadian changes, and in a climate-controlled environment (temperature, 22-24°C; and relative humidity, 50-60%).(15) In addition, all patients were initially instructed not to ingest caffeine, alcoholic beverages, or any other stimulating foods/drinks on the day of data collection and not to perform strenuous activities one day prior to data collection.

The 6MWT was performed in a 30-m level corridor. At each minute, standard encouragement was given; SpO2 and HR were measured with a portable pulse oximeter (Model 8500A; Nonin Medical Inc., Plymouth, MN, USA) and a frequency meter (Polar Electro Co., Kempele, Finland), respectively; and the patient was asked about dyspnea and fatigue/pain by means of a modified Borg CR10 scale. Functional capacity during the 6MWT was measured by the six-minute walk distance (6MWD, in m), which was recorded at the end of the test, as well as by the percent predicted 6MWD. Predicted 6MWD was calculated by the following formula(16): Predicted 6MWD (in m) = 622.461 − (1.846 × age) + (61.503 × gender) where age was measured in years, male gender = 1, and female gender = 0.

Two tests were performed 30 min apart in order to eliminate the learning effect, the higher of the two values obtained being used in the analysis.(13) The patients included in the study were randomized, by means of sealed, sequentially numbered envelopes, into two groups: PTP group (n = 22 participants) and control group (n = 21 participants).

The patients in the PTP group completed a 5-min warm-up at 2 km/h on a treadmill, followed by 30 min of aerobic physical training, with the slope being kept constant at 3%. The J Bras Pneumol. 2012;38(5):579-587

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training speed was 70% of the maximum speed achieved during CPET,(17) being adjusted during the sessions according to patient tolerance. The sessions were individual and were supervised by a physical therapist.

The patients in the control group and those in the PTP group received regular respiratory therapy, which involved education on diaphragmatic breathing, free arm and leg exercises, and stretching of the neck, trunk, arm, and leg muscles.

In addition, the two groups of patients underwent bronchial hygiene therapy, if necessary.

The treatment program for both groups consisted of three sessions per week, on alternate days, for six consecutive weeks, totaling 18 sessions. At the beginning of the sessions, pulmonary auscultation was performed and blood pressure, SpO2, and HR were measured.

In addition, during the sessions, SpO2 and HR were measured for monitoring.

The present study was approved by the local human research ethics committee (Protocol no.

008/2006), and all participants gave written informed consent after having been informed of the proposed protocol, in compliance with Brazilian National Health Council Resolution 196/96.

Statistical analysis was carried out with the Statistical Package for the Social Sciences, version 18.0 (SPSS Inc., Chicago, IL, USA). Normality of data distribution was assessed by the Shapiro-Wilk test, which revealed normal distribution. Values are expressed as means and standard deviations, except for dyspnea values, which are expressed as median (range). Anthropometric and spirometric variables were analyzed by the paired t-test.

The remaining study variables were analyzed by two-way ANOVA and the Tukey-Kramer post hoc test. The Kruskal-Wallis test and Dunn’s post hoc test were used for quantitative analysis of dyspnea. The level of statistical significance was set at p < 0.05 for all tests.

The two groups were compared in terms of the differences between post-intervention values and pre-intervention values, in order to assess clinical improvement in response to physical training.

In one study, 6MST responsiveness was evaluated by the difference between the mean number of steps climbed after the intervention and the mean number of steps climbed before the intervention in relation to the pre-intervention J Bras Pneumol. 2012;38(5):579-587

standard deviation.(18) In the present study, we used the difference between the mean number of steps climbed after the intervention and that of those climbed before the intervention.

The power of our sample was calculated by the program Ene, version 2.0 (GlaxoSmithKline, Madrid, Spain), which suggested a sample size of 11 patients per group, assuming a loss of 15% and a power of over 80% for the variable minimum clinically significant 6MWD, which corresponds to a minimum increase of 35 m between pre- and post-intervention values.(18)

Results We recruited 51 patients clinically diagnosed with COPD. Of those, 8 were excluded: 4 because they had mild obstruction; 2 because they did not participate in all evaluations; and 2 because they were unavailable to attend the proposed treatment program. Therefore, 43 male patients remained in the study. Initially, the PTP and controls groups consisted of 22 and 21 patients, respectively; however, only 21 and 15 patients, respectively, completed the study (Figure 1).

The patients who completed the study attended 18 physical therapy sessions, and the groups were found to be homogeneous in terms of anthropometric and pulmonary function data (Table 1). In addition, the groups were similar in terms of baseline MVV, VO2, VE, ventilatory demand, metabolic demand, ventilatory equivalent for carbon dioxide, dyspnea, and SpO2 (Table 1).

In the PTP and control groups, 10 and 9 patients, respectively, were classified as GOLD stage II, whereas 11 and 6 were classified as GOLD stage III.(7) Table 2 shows the pre- and post-intervention results; in either group, there were no significant differences between pre- and post-intervention VO2, VO2/VO2peak, VE, VE/MVV, or VE/VCO2peak. In addition, there were no significant differences between the two groups in terms of those variables.

The number of steps climbed increased significantly in the PTP group and remained similar in the control group, the same being true for the 6MWD (in m and % of predicted; Table 3). In addition, dyspnea was reduced during the 6MST and the 6MWT in the PTP group and remained the same in the control group. Preand post-intervention SpO2 values were similar, with no significant differences in either group (Table 3).

Responsiveness of the six-minute step test to a physical training program in patients with COPD

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Figure 1 - Flowchart of the study. PTPG: physical training program group; CG: control group.

Table 1 - Anthropometric, spirometric, metabolic, and ventilatory characteristics of the patients at baseline.a Groups Characteristic Physical training Control (n = 21) (n = 15) Age, years 70.5 ± 8.5 68.3 ± 8.7 Weight, kg 62.2 ± 13.2 63.9 ± 11.1 Height, cm 165.5 ± 4.8 164.5 ± 5.5 BMI, kg/m2 22.8 ± 3.4 23.4 ± 3.2 FEV1, L 1.2 ± 0.4 1.2 ± 0.5 FEV1, % of predicted 48.5 ± 15.4 45.4 ± 16.7 FVC, L 2.3 ± 0.6 2.4 ± 0.8 FVC, % of predicted 72.5 ± 20.5 71.3 ± 18 FEV1/FVC, % 51.9 ± 10 49 ± 11.8 MVV, L/min 47.7 ± 15.9 46.9 ± 19.8 MVV, % of predicted 49.9 ± 17.8 45.4 ± 17.1 VO2 at rest, mL/min 257 ± 11.2 230 ± 68.9 VO2peak during CPET, mL/min 1,000.6 ± 415.5 1,055.3 ± 546.8 Ventilatory equivalent for CO2 at rest 40.2 ± 9.8 37.5 ± 11.2 Dyspnea, modified Borg scaleb 2 (0.5-5.0) 1 (0.5-5.0) SpO2 at rest, % 93.3 ± 2.5 93.3 ± 3.3 BMI: body mass index; MVV: maximal voluntary ventilation; VO2: oxygen consumption; VO2peak: peak oxygen consumption; and CPET: incremental symptom-limited cardiopulmonary exercise testing. aData expressed as mean ± SD, except where otherwise indicated. bData expressed as median (range).

By comparing the two groups, we found significantly higher 6MWD values (in m and % of predicted) in the PTP group.

In the PTP group, dyspnea was significantly reduced, although only during the 6MWT. There were no significant changes in the degree of dyspnea during the 6MST in either group. By

comparing the two groups, we found that the degree of dyspnea was significantly lower in the PTP group, although only during the 6MWT (Table 3).

There were no significant differences between pre- and post-intervention SpO2 values during the 6MST or during the 6MWT in either group, J Bras Pneumol. 2012;38(5):579-587

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Table 2 - Peak metabolic and ventilatory variables during the six-minute step test before and after the intervention in the groups studied.a Groups Physical training Control Variable (n = 21) (n = 15) PrePostPrePost∆ ∆ intervention intervention intervention intervention VO2peak, mL/min 977 ± 320.9 980.3 ± 356.8 21.3 ± 343.7 895.5 ± 557.9 827 ± 187.6 −49.3 ± 483.4 VO2/VO2peak, % 116.9 ± 41.3 115.2 ± 57 −6.1 ± 40.5 89 ± 24.9 84.3 ± 38.2 −5 ± 51.4 VEpeak, L/min 25.9 ± 6.7 27.6 ± 9.5 1.5 ± 7.6 20.2 ± 11.1 19.6 ± 4.5 −1.4 ± 10.6 VE/MVV, % 53.3 ± 11.3 56.2 ± 15.7 0.7 ± 6.9 48.7 ± 13.1 43.3 ± 10.8 −6.5 ± 19.4 VE/VCO2peak 30.8 ± 12.1 31.3 ± 10.3 0.5 ± 6.2 26 ± 3.4 25.7 ± 5.2 −1.9 ± 7.7 ∆: post-intervention − pre-intervention; VO2peak: peak oxygen consumption; VO2/VO2peak: metabolic demand; VEpeak: peak pulmonary ventilation; VE/MVV: ventilatory demand; VE/VCO2: ventilatory equivalent for carbon dioxide. aData expressed as mean ± SD.

Table 3 - Results obtained for the study variables during the six-minute step test before and after the intervention in the groups studied.a Groups Physical training Result (n = 21) ∆ PrePostPreintervention intervention intervention Steps climbed 43.1 ± 16.2 54.6 ± 12.9 10.6 ± 13.2* 42.6 ± 28.7 during the 6MST, n Work efficiency 26.5 ± 9.2 22 ± 11.1 −4.6 ± 8.0 22.6 ± 5.2 during the 6MST, mL/min/ number of steps climbed Dyspnea during the 1 (0.5-5.0) 0 (0-2) 0 (−4 to 1) 0.5 (0.5-5.0) 6MST, modified Borg scaleb SpO2 during the 88.4 ± 5.4 89.5 ± 4.6 0.3 ± 3.7 88.8 ± 7.7 6MST, % 6MWD, m 387.3 ± 159.0 452.1 ± 133.6 64.9 ± 79.3* 387.5 ± 222.1 6MWD, % of 69.9 ± 28.2 81.9 ± 23.9 12.0 ± 14.9* 72.3 ± 27.1 predicted Dyspnea during the 2 (0.5-5.0) 0 (0-1) 0 (−5 to 0)* 1 (0.5-5.0) 6MWT, modified Borg scaleb SpO2 during the 86.2 ± 6 86.8 ± 7.1 0.7 ± 6.4 86.1 ± 6.2 6MWT, %

test and the six-minute walk

Control (n = 15) Postintervention 45.8 ± 30.4

2.2 ± 15.4

21.4 ± 10.6

−0.74 ± 11.4

0 (0-5)

0 (−2 to 3)

88.1 ± 7.0

−0.8 ± 6.9

∆

396.7 ± 221.0 9.2 ± 133.8** 69.8 ± 39.7 −2.6 ± 21.0** 2 (0-5)

0 (−2 to 5)**

85.7 ± 6.5

−0.4 ± 3.4

∆: post-intervention − pre-intervention; 6MST: six-minute step test; DTC6: six-minute walk distance; and 6MWT: six-minute walk test. aData expressed as mean ± SD, except where otherwise indicated. bData expressed as median (range). *p < 0.05 of the within-group difference. **p < 0.05 of the between-group difference.

and there were no significant differences between the two groups, as shown in Table 3.

The effect size for responsiveness of the 6MST was found to be approximately 11 steps and 2 steps for the PTP and control groups, respectively.

J Bras Pneumol. 2012;38(5):579-587

Discussion To our knowledge, the present study was the first study to evaluate the responsiveness of the 6MST to aerobic physical training, having

Responsiveness of the six-minute step test to a physical training program in patients with COPD

demonstrated improved physical performance.

In addition, the training led to an increase in the 6MWD (in m and % of predicted), although the degree of dyspnea was reduced only during the 6MWT. The reduction in physical exertion in patients with COPD tends to promote disease progression and worsening, and this contributes to a spiral of inactivity, physical deconditioning, and dyspnea.

(19) In the present study, aerobic physical training on a treadmill was found to result in increased physical activity levels, a finding that was confirmed by the increase in the number of steps climbed during the 6MST and by the increase in the 6MWD. Improved physical performance is, according to one group of authors,(20) an important indicator in the evaluation of the effectiveness of treatment programs in patients with COPD. Data in the literature(21) have demonstrated that aerobic physical training results in an increase in the 6MWD and in improved exercise tolerance in patients with COPD. One study(22) also demonstrated a significant increase in the 6MWD after a program involving aerobic physical training, as did a study by Cooper,(23) who demonstrated that physical training for six weeks, three times a week, results in improved physical performance.

Puhan et al.(18) reported that an increase of 35 m in the 6MWD in relation to pre-intervention values is a clinically significant improvement.

In the present study, the mean increase in the 6MWD was 64.9 m.

In the present study, metabolic energy expenditure during the 6MST was found to be high, surpassing the VO2peak achieved during CPET. However, it is of note that pre- and post-training metabolic energy expenditures were similar, with performance on the test being better in the postintervention phase. According to one group of authors,(1) VO2/VO2max has been shown to be high during step tests in comparison with the values obtained during other field tests in patients with COPD. This is probably due to the fact that step climbing requires work against gravity.(24) In addition, it should be borne in mind that although pre- and post-intervention VO2peak values during the 6MST were similar for both groups (as was work), the PTP group showed improved physical performance, with an increase of approximately 11 steps and a trend toward decreased work.

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According to Ferrazza et al.,(25) it is expected that, in addition to high VO2/VO2max, patients with COPD show high VE/MVV as factors limiting exercise capacity, with VE/MVV behaving similarly to VO2/VO2max even after intervention. Therefore, the use of the 6MST to assess patients with COPD makes it possible to quantify the limitation to exercise involving the legs alone, as well as allowing quantification of functional capacity.

We found that VE/VCO2 values were similar during the 6MST for an increase, on average, of 11 steps after training. According to some studies, VE/ VCO2 has been used as an indicator of ventilatory efficiency, which makes it possible to assess the efficiency of ventilation in eliminating carbon dioxide, being a marker of the appropriateness of the ventilatory response to metabolic stimuli.(26) Airflow limitation during exercise is assessed by the perception of dyspnea, dyspnea being a symptom attributed to airflow limitation due to a chronic imbalance between increased ventilatory demand and reduced capacity to meet the demand,(7) which is one of the factors limiting exercise capacity. Therefore, one of the goals of COPD treatment is to reduce dyspnea.

In the present study, we found that aerobic physical training led to a significant reduction in the perception of dyspnea during the 6MWT. This finding corroborates those reported by one group of authors,(11) who observed a reduction in dyspnea (from 1.10 ± 1.90 to 0.05 ± 0.20) in COPD patients submitted to a treadmill test after six weeks of physical training on a treadmill.

It is known that patients with moderate to severe COPD can experience a decrease in SpO2 during functional tests,(27) SpO2 monitoring being therefore indispensable during such tests. In the present study, we found that, at the peak of both tests, patients in the two groups had desaturation, characterizing gas exchange dysfunction associated with chronic airway obstruction. This abnormality in gas exchange is one of the determining factors for stopping physical exercise in patients with COPD. In addition, when reporting on the step test, one group of authors(28) recommends considering the weight and height of the patients, as well as the height of the step, because, unlike in the 6MWT, in which there is only a horizontal component in the work performed, in the step test there is the addition of vertical displacement, which tends to increase the demand level of the J Bras Pneumol. 2012;38(5):579-587

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test. However, in the present study, the patients performed the 6MST at a freely chosen cadence.

Karsten & Lima(29) emphasized that a freely chosen cadence allows patients to adjust their pace during exercise according to their limitations, preventing early termination of the test.

Some studies have employed the same step test duration as that employed in the present study, i.e., 6 minutes.(1) Data in the literature also recommend this duration for a better evaluation of the test results, a recommendation that was confirmed by one group of authors,(30) because there is a correlation with the 6MWT; this correlation was more evident in the last minutes of the test with respect to the variables related to the subjective perception of exertion, increasing the sensitivity of the test and facilitating its comparison with the 6MWT. However, the type of protocol used for CPET in the present study might have influenced the responses to exercise in the patients with COPD, although the protocol has been developed in the laboratory and used in several previous studies. In addition, CPET was performed on a treadmill, as was physical training. Although walking on a treadmill reflects an activity of daily living, it is not a specific training protocol for the muscle group involved in performing the 6MST, as it is for the muscle group involved in performing the 6MWT. On the basis of our results, we can conclude that the 6MST showed responsiveness to aerobic physical training on a treadmill in terms of physical performance and that it can be recommended in clinical practice, although there is no scientific evidence that defines a clinically significant increase in the number of steps climbed. Aerobic physical training was shown to be beneficial for patients with stage II or III COPD. However, because the 6MWT was more specific than the 6MST, we believe that the former was more responsive to the proposed training protocol, as evidenced by improved physical performance and reduced dyspnea.

References 1. Dal Corso S, Duarte SR, Neder JA, Malaguti C, de Fuccio MB, de Castro Pereira CA, et al. A step test to assess exercise-related oxygen desaturation in interstitial lung disease. Eur Respir J. 2007;29(2):330-6. http://dx.doi. org/10.1183/09031936.00094006 2. Andrade CH, Cianci RG, Malaguti C, Corso SD. The use of step tests for the assessment of exercise capacity in healthy subjects and in patients with chronic lung

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disease. J Bras Pneumol. 2012;38(1):116-24. http:// dx.doi.org/10.1590/S1806-37132012000100016 3. Swinburn CR, Cooper BG, Mould H, Corris PA, Gibson GJ. Adverse effect of additional weight on exercise against gravity in patients with chronic obstructive airways disease. Thorax. 1989;44(9):716-20. PMid:462051.

4. Miranda EF, Malaguti C, Corso SD. Peripheral muscle dysfunction in COPD: lower limbs versus upper limbs. J Bras Pneumol. 2011;37(3):380-8. http://dx.doi.org/10.1590/ S1806-37132011000300016 5. Bourjeily G, Rochester CL. Exercise training in chronic obstructive pulmonary disease. Clin Chest Med. 2000;21(4):763-81.

6. Lung function testing: selection of reference values and interpretative strategies. American Thoracic Society. Am Rev Respir Dis. 1991;144(5):1202-18. PMid:1952453.

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10. Pires Di Lorenzo VA, Silva AB, Sampaio LM, Jamami M, Oishi J, Costa D. Efeitos do treinamento físico e muscular respiratório em pacientes com doença pulmonar obstrutiva crônica (COPD) grave submetidos a BiPAP. Rev Bras Fisioter. 2003;7(1):69-76.

11. Marrara KT, Marino DM, de Held PA, de Oliveira Junior AD, Jamami M, Di Lorenzo VA. Different physical therapy interventions on daily physical activities in chronic obstructive pulmonary disease. Respir Med. 2008;102(4):505-1. PMid:18242069.

12. II Diretrizes da Sociedade Brasileira de Cardiologia sobre teste ergométrico. Arq Bras Cardiol. 2002;78(Suppl. II):3-17. http://dx.doi.org/10.1590/S0066-782X2010000800001 13. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111-7. PMid:12091180.

14. Neder JA, Nery LE. Fisiologia clínica do exercício: Teoria e Prática. São Paulo: Artes Médicas; 2003.

15. Guimarães JI, Stein R, Vilas-Boas F. Normatização de técnicas e equipamentos para realização de exames em ergometria e ergoespirometria. Arq Bras Cardiol. 2003;80(4):457-64.

16. Iwama AM, Andrade GN, Shima P, Tanni SE, Godoy I, Dourado VZ. The six-minute walk test and body weightwalk distance product in healthy Brazilian subjects.

Braz J Med Biol Res. 2009;42(11):1080-5. Erratum in: Braz J Med Biol Res. 2010;43(3):324. http://dx.doi. org/10.1590/S0100-879X2009005000032 17. Maltais F, Simard AA, Simard C, Jobin J, Desgagnés P, LeBlanc P. Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD. Am J Respir Crit Care Med. 1996;153(1):288-93. PMid:8542131.

18. Puhan MA, Mador MJ, Held U, Goldstein R, Guyatt GH, Schünemann HJ. Interpretation of treatment changes

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in 6-minute walk distance in patients with COPD. Eur Respir J. 2008;32(3):637-43. PMid:18550610.

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26. Pasqualoto AS. Comparação das respostas fisiológicas no teste de exercício cardiopulmonar e em três testes de exercício submáximo em pacientes com doença pulmonar obstrutiva crônica [thesis]. Porto Alegre: Universidade Federal do Rio Grande do Sul; 2009.

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About the authors Kamilla Tays Marrara

Professor. Centro Universitário Central Paulista – UNICEP, Central Paulista University Center – São Carlos, Brazil.

Diego Marmorato Marino

Doctoral Student in Physical Therapy. Universidade Federal de São Carlos – UFSCar, Federal University of São Carlos – São Carlos, Brazil.

Maurício Jamami

Professor. Department of Physical Therapy, Universidade Federal de São Carlos – UFSCar, Federal University of São Carlos – São Carlos, Brazil.

Antônio Delfino de Oliveira Junior

Pulmonologist. São Carlos Unimed Hospital, São Carlos, Brazil.

Valéria Amorim Pires Di Lorenzo

Professor. Department of Physical Therapy, Universidade Federal de São Carlos – UFSCar, Federal University of São Carlos – São Carlos, Brazil.

J Bras Pneumol. 2012;38(5):579-587

Original Article Maternal malnutrition during lactation in Wistar rats: effects on elastic fibers of the extracellular matrix in the trachea of offspring*,** Desnutrição materna durante a lactação em ratos Wistar: efeitos sobre as fibras elásticas da matriz extracelular na traqueia dos filhotes

Filipe Moreira de Andrade, Luiz Felippe Judice, Gilberto Perez Cardoso, Rafael Cisne, Cristiane da Fonte Ramos, Marcio Antonio Babinski

Abstract Objective: To investigate the effects of maternal protein malnutrition during lactation on the elastic fibers in the tracheas of Wistar rat pups. Methods: At delivery, 12 male pups of two Wistar rat dams were equally divided into two groups: control, in which the dam received water and standard rat chow ad libitum during lactation; and protein-restricted (PR), in which the dam received water ad libitum and an isoenergetic PR diet (8% protein). At 21 days of age, the pups were killed and their tracheas were excised. The elastic fibers were stained with Weigert’s resorcin-fuchsin (after oxidation) and evaluated under light microscopy. Morphometric determinations were performed by stereology, with the point-counting method, and expressed as volumetric densities. Results: Elastic fibers, most having a longitudinal distribution, were identified beneath the tracheal mucosa. In addition, well-defined circular layers of elastic fibers were found around the inner and outer surfaces of the cartilaginous ring. There were no differences between the groups regarding the organization and distribution of the elastic fibers. The volumetric density of the elastic fibers of the pups in the control and PR groups was 2.46 ± 0.99% and 3.25 ± 1.13%, respectively (p < 0.01). Conclusions: The volumetric density of elastic fibers appears to be greater in rat pups breastfed by dams receiving a PR diet than in those breastfed by dams receiving a normal diet.

Keywords: Trachea/growth and development; Trachea/anatomy and histology; Extracellular matrix; Airway remodeling; Malnutrition.

Resumo Objetivo: Investigar os efeitos da desnutrição proteica materna durante a lactação sobre as fibras elásticas da traqueia de filhotes de ratos Wistar. Métodos: Ao nascimento, 12 filhotes machos de duas ratas Wistar foram igualmente divididos em dois grupos: grupo controle, cuja mãe recebeu água e dieta padrão de laboratório ad libitum durante a lactação, e grupo restrição proteica (RP), cuja mãe recebeu água ad libitum e dieta isoenergética com RP (8% de proteína). Aos 21 dias de vida, os filhotes foram sacrificados, e suas traqueias foram ressecadas. As fibras elásticas foram coradas pelo método de resorcina-fucsina de Weigert (precedido de oxidação) e avaliadas sob microscopia óptica. As determinações morfométricas foram feitas por estereologia, utilizando o método de contagem de pontos, e expressas em densidade volumétrica. Resultados: As fibras elásticas foram identificadas abaixo da mucosa traqueal, sendo a maioria em distribuição longitudinal. Além disso, camadas circulares bem definidas de fibras elásticas envolviam as superfícies interna e externa do anel cartilaginoso. Não houve diferenças entre os grupos quanto à organização e distribuição das fibras elásticas.

A densidade volumétrica das fibras elásticas dos filhotes nos grupos controle e RP foi de, respectivamente, 2,46 ± 0,99% e 3,25 ± 1,13% (p < 0,01). Conclusões: Nossos resultados sugerem que a densidade volumétrica de fibras elásticas é maior em filhotes de ratos alimentados por fêmeas submetidas a dieta com RP do que naqueles de mães recebendo dieta normal.

Descritores: Traqueia/crescimento e desenvolvimento; Traqueia/anatomia e histologia; Matriz extracelular; Remodelação das vias aéreas; Desnutrição.

* Study carried out in the Department of Surgery, Division of Thoracic Surgery. Antonio Pedro University Hospital, Fluminense Federal University, Niterói, Brazil.

Correspondence to: Filipe Moreira de Andrade. Rua Visconde do Rio Branco, 755/812, Centro, CEP 24020-006, Niterói, RJ, Brasil.

Tel. 55 21 9500-1503. Fax: 55 21 3628-5795. E-mail: filipeandrade_torax@hotmail.com Financial support: None.

Submitted: 7 March 2012. Accepted, after review: 3 July 2012. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

J Bras Pneumol. 2012;38(5):588-594

Maternal malnutrition during lactation in Wistar rats: effects on elastic fibers of the extracellular matrix in the trachea of offspring

Introduction Malnutrition is the most prevalent form of nutritional disorder among children in developing countries. In hospitalized patients, the reported prevalence of malnutrition is as high as 75%.(1,2) In addition, hospitalization further worsens the nutritional status. Malnutrition has been associated with increases in the risk of in-hospital morbidity/ mortality, the length of hospital stay, the costs, and the use of health care resources.(3) Therefore, studying malnutrition is relevant and timely.

Some investigators have shown that the nutritional status of the mother during gestation and lactation is essential to normal growth and development in humans and in experimental animals.(4,5) Previous studies have shown that maternal malnutrition during lactation might change milk composition, serum hormone levels in pups at weaning, and the reproductive system in females. Interestingly, some of these changes can persist into adulthood.(6) The rat has long been used as a model when studying the human respiratory tract and major airway diseases. The composition of the elastic fibers in the tracheas of rats is similar to that of those in the tracheas of humans.(7) In addition, the rat is considered a good model for nutritional research.(5) Few studies have focused on the morphology of the trachea, especially regarding its extracellular matrix and elastic fibers.(7,8) Although considerable attention has been given to the elastic properties of the lung and chest wall, there have been no studies investigating the elastic network of the major airways.(9) We consider that the lack of studies on this topic is relevant, since procedures involving the trachea and the airways are emerging and becoming more complex. Tracheal resection with anastomosis, the utilization of a wide range of airway stents, and, recently, the attempts at tracheal transplantation and replacement with allografts(10-12) make it essential to improve the understanding of the extracellular matrix. In addition, the effects of protein malnutrition on tracheal histology are worth studying, given the prevalence of this condition in hospitalized patients, especially in those in developing countries.(1,3,6) An understanding of the effects of protein malnutrition on the elastic fibers in the tracheas of rats might improve the scientific knowledge base on the composition and organization of

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the extracellular matrix in this organ. Studies of tracheal transplantation and tracheal replacement with aortic allografts have demonstrated that the development of mature respiratory epithelium and newly formed cartilage occurs in the extracellular matrix, particularly amid the elastic fibers.(10,11) This finding supports the key roles of the extracellular matrix and elastic fibers in the healing process. The objective of present study was to investigate the effects of maternal protein malnutrition during lactation on the elastic fibers in the tracheas of Wistar rat pups. In our analysis, we characterized and quantified the elastic fibers in the trachea.

Our quantitative analyses focused on volumetric density determination by stereological methods.(13)

Methods The study design and experimental protocols were approved by the Animal Care and Use Committee of the Fluminense Federal University, located in the city of Niterói, Brazil, and were in accordance with the American Physiological Society guidelines.(14) The experiments described herein were performed in accordance with the guidelines of the Brazilian College for Animal Experimentation.(15) Wistar rats obtained from the Experimental Morphology Laboratory of the Fluminense Federal University were housed at 25 ± 1°C on a 12/12-h light/dark cycle (lights on from 7:00 a.m. to 7:00 p.m.) throughout the experiment. Two three-month-old virgin female rats were housed in individual cages with two male rats, at a proportion of 1:1. After mating, each female was placed in an individual cage. The two females had a normal pregnancy, having received food and water ad libitum until delivery. All of the pups were born in good health.

At delivery, one of the Wistar rat dams—the control dam—was started on water and standard rat chow ad libitum and the other—the proteinrestricted (PR) dam—was started on water ad libitum and an isoenergetic PR diet during that period. The quantity of diet that the PR dam received each day was calculated on the basis of the mean intake by the control dam in order to prevent the PR dam from “compensating” for the reduced protein intake by ingesting a greater quantity of the diet.(5) The low-protein diet was prepared in our laboratory, and its composition is shown in Table 1.

This diet has been used in previous studies.(5) The J Bras Pneumol. 2012;38(5):588-594

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vitamin and mineral mixtures were formulated in order to meet the American Institute of Nutrition AIN-93G recommendations for rodent diets.(16) In order to evaluate the nutritional status, the body weight of the pups and dams were monitored throughout the experiment. Twenty-four hours after birth, excess pups were removed in order to reduce the size of each litter (group) to six, since this procedure maximizes lactation.(5,7) At delivery, the PR diet started to be offered to the PR dam, this having been defined as lactation day 0 (D0). At 21 days of age (weaning), all pups were killed with an overdose of sodium pentobarbital (0.15 mL/100 g of body weight) in the morning and perfused through the left ventricle with PBS, followed by a formalin solution.

After perfusion, the tracheas were dissected from the adjacent structures, excised, fixed in a solution of 4% formalin in 0.1 mol/L PBS (pH 7.4) for 24 h at room temperature, processed in accordance with routine histological methods, and embedded in paraffin. From the paraffin-embedded samples, 5-µm-thick sections were initially stained with H&E in order to confirm sample adequacy.

Weigert’s resorcin-fuchsin, preceded by oxidation with potassium peroxymonosulfuric acid (Oxone®), was used for the demonstration and evaluation of elastic fibers, which were stained violet, producing a sharp contrast.

Table 1 - Diet composition for the control dam and protein-restricted dams.

ProteinVariable Controla restrictedbc Total protein, g/kgc 230.0 80.0 Corn starch, g/kg 676.0 826.0 Soybean oil, g/kg 50.0 50.0 Vitamin mixture, g/kgd 4.0 4.0 Mineral mixture, g/kgd 40.0 40.0 Macronutrient composition, % Protein 23.0 8.0 Carbohydrate 66.0 81.0 Fat 11.0 11.0 Total energy, kJ/kg 17,038.7 17,038.7 Standard rat chow (Nuvilab-Nuvital Ltd., Curitiba, Brazil).

The protein-restricted diet was prepared in our laboratory by replacing part of the protein content of the control diet with corn starch. The amount of starch was calculated to provide the same energy content as that provided by the control diet. cThe main protein sources were soy, wheat, beef, fish, and amino acids. dVitamin and mineral mixtures were formulated to meet the American Institute of Nutrition AIN-93G recommendations for rodent diets.(16)

From each specimen, five tissue sections were analyzed, and from each section, five random fields were evaluated; therefore, we analyzed 25 test areas for each individual. The analyzed fields were digitized using a video camera coupled to a light microscope, with a final magnification of ×400. The quantification was carried out by using a specific test grid system (M42) on the digitized fields on the screen of a color monitor.

The volume density of the histological components was calculated by the following formula:

Vv = Pp/Pt where Vv is the volume density, p is the tissue component to be taken into consideration, Pp is the number of test points associated with p, and Pt is the number of points of the test system.

The stereological methods employed have been described in detail elsewhere.(7,13) The data are expressed as mean ± SD, with the respective 95% CIs. The Mann-Whitney test was used in order to compare the results between the groups. We used the program GraphPad Prism, version 4 (GraphPad Inc., San Diego, CA, USA).

Results The body weight gain of the pups throughout the study is depicted in Figure 1. At the end of the study (D21), the body weight of the pups of the PR dam (PR group) was approximately 61% lower than was that of those of the control dam (control group; p < 0.01). The body weight of the PR dam at D21 was approximately 37% lower than was that of the control dam (p < 0.01).

a

b

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Figure 1 - Body weight gain of the rat pups in the control and protein-restricted (PR) groups, sacrificed at 21 days of age (p < 0.01).

Maternal malnutrition during lactation in Wistar rats: effects on elastic fibers of the extracellular matrix in the trachea of offspring

Elastic fibers, most having a longitudinal distribution, were identified beneath the tracheal mucosa in both groups. Bundles of oblique fibers were found in this region, forming an irregular network of elastic tissue (Figure 2). In close contact with the inner surface of the cartilaginous ring, a well-defined and organized circular layer was present, surrounding the cartilage (Figure 3).

Outside the cartilaginous rings, the elastic fibers were exclusively arranged in a circular

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layer, following the circular cartilaginous rings (Figure 3). In that topography, there was no longitudinal or oblique arrangement of elastic fibers. There were no differences between the groups regarding the organization and distribution of the elastic fibers in the trachea.

Regarding quantitative stereological analysis, our study revealed that the volumetric density of the elastic fibers of the pups in the control and PR groups was 2.46 ± 0.99% (95% CI: 2.05-2.87; p < 0.01) and 3.25 ± 1.13 (95% CI: 2.78-3.71; p < 0.01), respectively. A comparison of the volumetric density between the groups is shown in Figure 4.

Discussion C

* **

*

*

50 µm

Figure 2 - Photomicrograph of a tracheal section showing the epithelium (single white asterisk) and the basal layer (double white asterisks). Note the longitudinal distribution of elastic fibers beneath the basal layer (black asterisks), with a few oblique bundles (Weigert’s resorcin-fuchsin; magnification, ×600). C: cartilage.

Figure 3 - Photomicrograph of a tracheal segment showing the epithelium (single white asterisk) and the basal layer (double white asterisks). A circular layer of elastic fibers is in close contact with the inner surface of the cartilaginous ring (single black asterisk). Outside the cartilage (C), there is a single circular layer (double black asterisks) of elastic fibers (Weigert’s resorcin-fuchsin; magnification, ×600).

Since the advent of computer-aided image analysis programs, most studies attempting to quantify linear structures have used area density.

(7) These programs use the color properties of the elements (pixels) of an image in order to determine a threshold level for inclusion. However, in very thin linear structures, such as elastic fibers, the contrast between the structural elements (e.g., fibers) and the background is low; therefore, there is a high error rate when such programs are used.(7,13) The point-counting method (stereology) used in our study has proven to be quite effective in avoiding the bias that frequently occurs when computer-based image analyses are performed.

This method has been widely used in order to determine the amount of elastic fibers when analyzing the morphological composition of a tissue.(7,13) This quantification is expressed as

Figure 4 - Volumetric density (Vv), expressed as percentage, of the elastic fibers in the tracheas of the rat pups in the control and protein-restricted (PR) groups, at 21 days of age (p < 0.01).

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the proportion of the volumetric density of the tissue that is occupied by elastic fibers.

Elastic fibers are characterized by major extensibility and elastic recoil. The location and arrangement of these fibers are related to their functionality, which reflects the mechanical properties of the local tissue.(17,18) Extensibility and elastic recoil in the human trachea are remarkably age-dependent, decreasing from a maximum of 50% in children to approximately 20% at 70 years of age.(18) Although the aging-related decrease in the elastic properties of the lungs and chest wall has been extensively studied, studies involving the elastic tissue of the major airways are still scarce.(9,18) The importance of normal tracheal morphology is highlighted by congenital and acquired tracheal deformities, such as tracheobronchomegaly, tracheomalacia, and benign tracheal stenosis.

The extracellular matrix plays a pivotal role in these remodeling processes, and the elastic fibers make a special contribution to that role.(10,11) The objective of the present study was to evaluate the effects of a PR diet during lactation on the elastic fibers in the tracheas of Wistar rats.

The Wistar rat has been by far the most used as a model for the human respiratory tract and major airway diseases. We performed a qualitative analysis of the distribution and organization of the elastic fibers (Figures 2 and 3). More importantly, we performed a quantitative evaluation (Figure 4), providing stereological data on the concentration of elastic fibers in the tracheas of the rats. The findings in the PR group were compared with those in the control group.

The nutritional status of a relevant proportion of patients undergoing surgical procedures is far from ideal, and malnutrition can affect the outcomes of such procedures.(2,3) According to previous studies, the first week of life is a critical period regarding the nutritional status, and the weight of an animal at an early age can influence the food intake and body weight of that animal for the rest of its life. Therefore, the degree of malnutrition during the fetal or neonatal period can determine the extent to which there will be recovery of the nutritional status during the periods of growth and development.(6,19) Regarding the relationship between elastic fibers and surgical procedures involving the airways, new findings have emerged from recently attempted experiments involving tracheal J Bras Pneumol. 2012;38(5):588-594

replacement in pigs.(11) In the study in question, the authors used aortic allografts to replace a tracheal segment and found that the normal aortic tissue in the allograft was replaced by a morphological structure that resembled a “new trachea”, with mature ciliated respiratory epithelium, respiratory glands, islets of cartilage, and even well-formed cartilage arches. Interestingly, this new trachea developed amid islets of elastic fibers in the extracellular matrix of the aortic allograft.(11) The extracellular matrix and the elastic fibers in particular seem to play an important role in the process of tissue regeneration and cellular ingrowth of recipient progenitor cells in the trachea.(10,11) Tracheal replacement might be an option in the future, when radical surgery for primary tracheal tumors, with resection of more than half of the tracheal length, is necessary. In one study on tissue-engineered replacement of a major airway, the authors discussed the active role of the extracellular matrix in regulating various aspects of cell biology that are essential to normal tissue function.(10) Therefore, research on the extracellular matrix of the airway is needed in order to improve the understanding of the morphological changes in this matrix during the process of inflammation and healing. In addition, experiments in the field of bioengineering have emphasized the role of elastic fibers in the development of new extracellular matrixderived prosthetic materials, such as bioreactive substrates.(10,20) Regarding airway elastic fibers, previous studies have shown major changes related to the aging process. Age-related changes in the elastic fibers have been found beneath the epithelium of the human larynx.(18) Interestingly, there is an increase in the concentration of elastin in geriatric patients in comparison with that in young adults, although it is well known that the trachea loses its elastic properties with age.(18,21) Elastin increases continuously and progressively as individuals age. This phenomenon has also been reported to occur during the aging of the arteries and larynx, as well as regarding the extensibility of the lung.(9,21,22) Some studies have suggested that elasticity decreases in the elderly because the calcium-binding ability of elastin increases with age, although no histological changes can be detected in the elastic fibers.(21,22) An increasing number of patients are being submitted to interventional procedures involving

Maternal malnutrition during lactation in Wistar rats: effects on elastic fibers of the extracellular matrix in the trachea of offspring

the airways.(10,12,23) The nutritional status of several of these patients is abnormal; therefore, a deeper and more detailed understanding of the effects of malnutrition on the trachea is necessary. In addition, especially in developing countries, a poor socioeconomic status can lead to malnutrition during different periods of life, such as gestation, suckling, and weaning (or even later), and the effects of malnutrition on the organs might be irreversible.(2,5,6) Figures 2 and 3 depict the qualitative evaluation of the elastic fibers in both groups of pups, which were identical. Regarding the quantitative evaluation by means of stereology, we found that the volumetric density of the elastic fibers was significantly higher in the PR group than in the control group (Figure 4). Previous studies have shown increased concentrations of elastic fibers and elastin during the aging process.

Although further investigation is needed in order to establish a direct correlation between normal aging and malnutrition as an influence on the process of tissue remodeling over the lifetime of individuals, the effects of malnutrition on Wistar rats during the initial periods of life might resemble the effects of the aging process. In addition, recent advances in the field of tracheal replacement by allografts, tissue-engineered airway replacement, and the development of new extracellular matrix-derived prosthetic materials demand a better understanding of the morphology of elastic fibers in the trachea and the changes that might occur in patients submitted to invasive procedures involving the airways.(10,11,20) In conclusion, our study showed that maternal malnutrition during lactation can affect the development of elastic fibers in the tracheas of Wistar rat pups. Our morphometric analysis by stereology (quantitative evaluation) demonstrated a significant increase in the volumetric density of elastic fibers in the rat pups breastfed by the dam receiving a PR diet, when compared with those in the control group. The organization and distribution (qualitative evaluation) of the elastic fibers in the tracheas of the rat pups were similar between the groups.

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2. Correia MI, Campos AC; ELAN Cooperative Study. Prevalence of hospital malnutrition in Latin America: the multicenter ELAN study. Nutrition. 2003;19(10):823-5. http://dx.doi. org/10.1016/S0899-9007(03)00168-0 3. Naber TH, Schermer T, de Bree A, Nusteling K, Eggink L, Kruimel JW, et al. Prevalence of malnutrition in nonsurgical hospitalized patients and its association with disease complications. Am J Clin Nutr. 1997;66(5):1232-9.

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10. Macchiarini P, Jungebluth P, Go T, Asnaghi MA, Rees LE, Cogan TA, et al. Clinical transplantation of a tissueengineered airway. Lancet. 2008;372(9655):2023-30. http://dx.doi.org/10.1016/S0140-6736(08)61598-6 11. Makris D, Holder-Espinasse M, Wurtz A, Seguin A, Hubert T, Jaillard S, et al. Tracheal replacement with cryopreserved allogenic aorta. Chest. 2010;137(1):60-7.

PMid:19801581. http://dx.doi.org/10.1378/chest.09-1275 12. Andrade FM, Abou-Mourad OM, Judice LF, Carvalho-Filho AB, Schau B, Carvalho AC. Endotracheal inflammatory pseudotumor: the role of interventional bronchoscopy.

Ann Thorac Surg. 2010;90(3):e36-7. PMid:20732473. http://dx.doi.org/10.1016/j.athoracsur.2010.06.013 13. Mandarim-de-Lacerda CA. Stereological tools in biomedical research. An Acad Bras Cienc. 2003;75(4):469-86. Erratum in: An Acad Bras Cienc. 2007;79(1):51. http://dx.doi. org/10.1590/S0001-37652003000400006 14. Bayne K. Revised Guide for the Care and Use of Laboratory Animals available. American Physiological Society.

Physiologist. 1996;39(4):199, 208-11. PMid:8854724.

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changes in human vocal folds. Otolaryngol Head Neck Surg. 1998;119(4):314-22. http://dx.doi.org/10.1016/ S0194-5998(98)70071-3 19. Alippi RM, Meta MD, Olivera MI, Bozzini C, Schneider P, Meta IF, et al. Effect of protein-energy malnutrition in early life on the dimensions and bone quality of the adult rat mandible. Arch Oral Biol. 2002;47(1):47-53. http://dx.doi.org/10.1016/S0003-9969(01)00089-9 20. Conconi MT, De Coppi P, Di Liddo R, Vigolo S, Zanon GF, Parnigotto PP, et al. Tracheal matrices, obtained by a detergent-enzymatic method, support in vitro the adhesion of chondrocytes and tracheal epithelial cells.

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About the authors Filipe Moreira de Andrade

Assistant Professor of Thoracic Surgery. Department of Surgery, Division of Thoracic Surgery, Fluminense Federal University, Niterói, Brazil. Visiting Professor of Thoracic Surgery. University of Alabama at Birmingham, Birmingham, AL, USA.

Luiz Felippe Judice

Full Professor of Thoracic Surgery. Department of Surgery, Division of Thoracic Surgery, Fluminense Federal University, Niterói, Brazil.

Gilberto Perez Cardoso

Full Professor of Clinical Medicine. Department of Clinical Medicine, Fluminense Federal University, Niterói, Brazil.

Rafael Cisne

Substitute Professor of Human Anatomy. Department of Morphology, Fluminense Federal University, Niterói, Brazil.

Cristiane da Fonte Ramos

Adjunct Professor of Human Anatomy. Rio de Janeiro State University, Rio de Janeiro, Brazil.

Marcio Antonio Babinski

Adjunct Professor of Human Anatomy. Department of Morphology, Fluminense Federal University, Niterói, Brazil.

J Bras Pneumol. 2012;38(5):588-594

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

Andrea Mendonça Rodrigues, Camila Zanelatto Parreira Schmidt, Lucien Peroni Gualdi, Raquel Giacomelli Cao, Rodrigo Godinho de Souza, Ana Cláudia Pereira, Nailê Karine Nuñez, Alisson Passos Schleich, Paulo Márcio Condessa Pitrez

Abstract 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.

Keywords: Ovalbumin; Mice; Asthma.

Resumo 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.

Descritores: Ovalbumina; Camundongos; Asma.

* Study carried out at the Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS, Pontifical Catholic University of Rio Grande do Sul – Porto Alegre, Brazil.

Correspondence to: Andrea M Rodrigues. Centro Infant, Avenida Ipiranga, 6681, Prédio 60 (HSL), 2º andar, Parthenon, CEP 90619‑900, Porto Alegre, RS, Brasil.

Tel. 55 51 3320-3000, extension 2313, or 55 51 3320-3353. E-mail: andream_rodrigues@hotmail.com Financial support: Andrea Mendonça Rodrigues, Lucien Peroni Gualdi, and Raquel Giacomelli Cao are recipients of doctoral scholarships from the Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development). Nailê Karine Nuñez is the recipient of a master’s scholarship from CNPq. Submitted: 26 March 2012. Accepted, after review: 3 August 2012.

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Introduction Asthma is a chronic lower airway disease that affects approximately 300 million people worldwide, resulting in high morbidity and substantial costs to society. Asthma is characterized by infiltration of CD4+ Th2 cells and eosinophils in the airways, associated with production of allergen-specific IgE.(1) In the study of new therapies for asthma, as well as for a better understanding of the pathophysiology of the disease, animal models have been used for decades.(2) Murine models involving systemic sensitization to antigens, with subsequent airway challenge, have been developed in order to trigger an allergic response in the lungs similar to that of asthma.(3) These models are still the most commonly used in experimental asthma research, despite some recent criticisms of factors related to current animal models of asthma, which do not develop phenotypic characteristics similar to those of asthma in humans.(4) Among the animals studied, isogenic mice are the most popular, because they are inexpensive, there is detailed knowledge of their genetics, and there is a clear Th2 immune response in their lungs when they are exposed to specific allergens.

(3) Classically, BALB/c mice are intraperitoneally sensitized with ovalbumin twice, 14 days apart, together with an adjuvant, i.e., aluminum hydroxide (alum); although this method is routinely used, it is an artificial way of boosting the allergic response in the lungs.(5) In the literature, this has been the standard protocol most commonly used as a murine model of asthma. Overcoming two frequently reported limitations (use of adjuvants and prolonged protocol duration) would be attractive for performing murine models of asthma that are more sophisticated, especially in pre-clinical testing of new drugs.

In an attempt to find an alternative to the use of adjuvants in murine models of asthma, Conrad et al. have recently demonstrated that subcutaneous sensitization with ovalbumin, without the use of adjuvants, results in an allergic response in the lungs similar to that observed in previously, well-established protocols.(6,7) The results of that study allow the exclusion of the use of adjuvants in murine models of asthma in future studies; the artificial way in which asthma is currently studied in animal models, with the use of adjuvants, has been justifiably criticized. However, in that study, there were three sensitizations, 7 J Bras Pneumol. 2012;38(5):595-604

days apart, and the protocol remained too long.

To date, there have been no studies testing short-term protocols for use in murine models of asthma, particularly without the use adjuvants.

If proven viable, this type of model would be an interesting means to evaluate, preliminarily, new therapies for asthma, particularly those related to an eosinophilic response in the lungs, such a response being a key outcome in therapeutic targets of atopic asthma. In the pharmaceutical industry setting, long-term protocols have been a significant limitation in the study of new drugs.(8) Therefore, the objective of the present study was to find alternative protocols for animal models of asthma, i.e., protocols that are shorter and less artificial. A 10-day protocol with only one subcutaneous sensitization with ovalbumin and without the use of adjuvants was compared with standard protocols described in previous studies.

Methods A total of 44 isogenic BALB/c mice (adult females 6-8 weeks of age) were obtained from the Rio Grande do Sul State Foundation for Health Science Research. The animals were fed a balanced chow diet and had ad libitum access to water, being housed in cages and maintained on a 12/12-h light/dark cycle. The animals were divided into the following groups: • five study groups of 7 animals each, in which different models of induction of an allergic response in the lungs were tested • one positive control (C+) group of 5 animals • one negative control (C−) group of 4 animals The groups were classified according to the type of sensitization (intraperitoneal or subcutaneous sensitization with ovalbumin, with or without the use of adjuvants), the number of sensitizations (one or two), the number of intranasal ovalbumin challenges (two or three), the dosage of intranasal ovalbumin challenge (40 µg or 100 µg), and the observation period (21 or 10 days). The control groups were observed for 28 days.

Sensitization with ovalbumin and intranasal ovalbumin challenge were performed with total volumes of 200 µL and 50 µL, respectively, diluted in Dulbecco’s PBS (DPBS). The dose of ovalbumin used for sensitization was 20 µg in all groups except the C− group. For intranasal ovalbumin challenge, the animals were anesthetized with isoflurane in an anesthesia chamber to allow pulmonary aspiration.

Proposed short-term model of acute allergic response, without adjuvant use, in the lungs of mice

The animals in the study groups underwent the following: • 2sc2in-100 group—two subcutaneous sensitizations with ovalbumin (days 0 and 7) and two intranasal ovalbumin challenges (100 µg) on consecutive days (days 19 and 20) • 2sc3in-100 group—two subcutaneous sensitizations with ovalbumin (days 0 and 7) and three intranasal ovalbumin challenges (100 µg) on consecutive days (days 18, 19, and 20) • 2sc3in-40 group—two subcutaneous sensitizations with ovalbumin (days 0 and 7) and three intranasal ovalbumin challenges (40 µg) on consecutive days (days 18, 19, and 20) • 2sc2in-40 group—two subcutaneous sensitizations with ovalbumin (days 0 and 7) and two intranasal ovalbumin challenges (40 µg) on consecutive days (days 19 and 20) • 1sc3in-100 group (with a short observation period, which was the primary objective of the present study)—one subcutaneous sensitization with ovalbumin (day 0) and three intranasal ovalbumin challenges (100 µg) on consecutive days (days 7, 8, and 9) The first four groups were observed for 21 days, whereas the 1sc3in-100 group was observed for 10 days (short-term protocol).

The animals in the control groups underwent the following: • C+ group: two intraperitoneal sensitizations with 1 mg of ovalbumin + alum (days 0 and 14) and three intranasal ovalbumin challenges (100 µg) on consecutive days (days 25, 26, and 27) • C− group: two subcutaneous administrations of DPBS (days 0 and 14) and three intranasal instillations of DPBS on consecutive days (days 25, 26, and 27) The protocols are shown in Figure 1.

For BAL, the animals were anesthetized with a solution of xylazine (100 mg/mL) and ketamine (100 mg/mL), at a ratio of 1:9 (dose, 0.1 mL), and the trachea was cannulated with a blunt needle. A DPBS solution (1 mL) was instilled intratracheally and immediately aspirated. This procedure was performed three consecutive times. After the BAL procedure, the animals were euthanized with lethal doses of the drugs used for anesthesia (dose, 0.3 mL i.p.) and were

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disposed of in accordance with the norms of the institution.

The BAL fluid was weighed and centrifuged at 1,500 rpm for 10 min at 4°C. The precipitate was resuspended in 1 mL of DPBS. For all samples, total cell count and cell viability in the suspension were determined by the trypan blue exclusion test with a Neubauer chamber (BOECO, Hamburg, Germany). For the differential cytologic analysis, the precipitate suspension (30 g) was placed in a cytospin centrifuge for 5 min.

The cells were analyzed for their morphology by the May-Grünwald-Giemsa method. The cell types observed under an optical microscope are expressed as percentages, after the counting of 200 cells.

After BAL and lung resection, we used orthophenylenediamine (a chromogenic substrate) in order to produce a chemical reaction and measure eosinophil activity in lung tissue. As demonstrated by Strath et al.,(9) this method allows us to quantify eosinophil activity on the basis of the eosinophil peroxidase (EPO) reaction, by measuring optical absorbance, without interference from other peroxidases that might be present in the tissue analyzed. In brief, lung tissue fragments were frozen and thawed three times in liquid nitrogen. After centrifugation for 10 min at 4°C, the supernatant was serially diluted five times in 96-well plates (50 µL/well).

Subsequently, 100 mL of substrate (1.5 mM ortho-phenylenediamine and 6.6 mM hydrogen peroxide diluted in 0.05 M Tris-HCl buffer, pH 8.0) were added. After 30 min, at room temperature, the reaction was stopped by the addition of 1 M sulfuric acid, and the absorbance of the samples was measured at 492 nm.

After having been removed, the lungs were perfused with 10% buffered formalin on a gravity column (20 mmHg). The specimens were embedded in paraffin blocks, cut into 4-µm sections, stained with H&E, and mounted on slides. In order to determine the severity of eosinophilic inflammation, we performed a qualitative assessment of bronchial inflammatory response under an optical microscope, by counting the number of eosinophils in a given field, in three different bronchi.

The statistical analysis was performed with the Statistical Package for the Social Sciences, version 17.0 (SPSS Inc., Chicago, IL, USA). After descriptive analysis of the variables, we used the J Bras Pneumol. 2012;38(5):595-604

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Figure 1 - Protocols used in order to induce an acute allergic response in the lungs of BALB/c mice. OVA: ovalbumin; i.n.: intranasal; C−: negative control; C+: positive control; DPBS: Dulbecco’s PBS; and alum: aluminum hydroxide. Groups: 2sc2in-100: two subcutaneous sensitizations with ovalbumin and two intranasal challenges with ovalbumin (100 µg) on consecutive days; 2sc3in-100: two subcutaneous sensitizations with ovalbumin and three intranasal challenges with ovalbumin (100 µg) on consecutive days; 2sc3in-40: two subcutaneous sensitizations with ovalbumin and three intranasal challenges with ovalbumin (40 µg) on consecutive days; 2sc2in-40, two subcutaneous sensitizations with ovalbumin and two intranasal challenges with ovalbumin (40 µg) on consecutive days; and 1sc3in-100: one subcutaneous sensitization with ovalbumin and three intranasal challenges with ovalbumin (100 µg) on consecutive days.

Kruskal-Wallis test with Dunn’s post hoc test for comparisons that reached statistical significance.

The C− group was statistically tested separately for each study group by the Mann-Whitney test, J Bras Pneumol. 2012;38(5):595-604

with adjustment for multiple comparisons. The level of statistical significance was set at 0.05.

The eosinophil count in BAL fluid was used as the primary outcome measure because eosinophils

Proposed short-term model of acute allergic response, without adjuvant use, in the lungs of mice

are the most important immune effector cells in this experimental model.

The sample size was calculated at 7 animals per study group. This calculation was based on the following: absolute eosinophil count in BAL fluid for a mean of 0.7 × 106 cells/mL as the primary outcome measure; a standard deviation of 0.34; a value of p = 0.05; and a power of 80%, the difference among the means for the groups having been estimated at 80%.

The present study was approved by the local animal research ethics committee and was conducted in accordance with current ethical norms for animal model research, following the guidelines of the Brazilian Association for Laboratory Animal Science, using as few animals as possible, and managing pain and suffering during all procedures, including euthanasia.

Results In the present study, models that induce an acute allergic response in the lungs of mice by using subcutaneous sensitization with ovalbumin and different numbers and doses of intranasal ovalbumin challenges were compared with one another and with the traditional model (C+ group). The primary goal of the study was to determine whether the use of a short-term (10-day) protocol consisting of one sensitization would induce an allergic response in the lungs similar to that observed in standard protocols in the literature. The mean BAL fluid return volume for all animals was 0.55 ± 0.15 mL, and the mean cell viability was 100%. The mean eosinophil count in the C− and C+ groups was 2.5 ± 3.0% and 40.1 ± 10.0%, respectively.

There were no significant differences between the study groups and the C+ group regarding total cell count (p = 0.1), lymphocyte count (p = 0.36), macrophage count (p = 0.24), or neutrophil count (p = 0.059) in BAL fluid. The eosinophil count was higher in the 2sc3in-40 group than in the 2sc2in-40 group (p = 0.032; Figure 2).

There were no significant differences in cellular inflammatory response in the lungs between the animals undergoing the short-term protocol, without the use of adjuvants, and those undergoing the 21-day protocol that is widely used in animal models of asthma. In comparison with the C− group, the study groups showed significantly higher total and differential cell counts (p < 0.05).

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Histological examination revealed intense peribronchovascular inflammatory infiltrates in all groups, with a predominance of lymphocytes and the presence of more than 100 peribronchial eosinophils per field. The anatomy of the animals in the C− group was preserved, without inflammatory changes, a finding that is characteristic of healthy animals. From a histological standpoint, there was no difference in the severity of pulmonary inflammation among the groups, including the group undergoing the short-term protocol (Figure 3). Analysis of EPO levels in lung tissue, which reflect eosinophil activity in the lungs, revealed no differences among the groups studied (Figure 4).

Discussion Animal models of asthma with shorter-term protocols and without the use of adjuvants seem to be an attractive alternative for experimental studies of asthma in certain situations. Using the outcome variables that are more directly related to the presence and activity of eosinophils in the lung, we compared different groups of BALB/c mice sensitized with ovalbumin and found no significant differences among the different protocols studied, including a short-term (10-day) protocol.

The most important finding of the present study, especially if we take into consideration that no adjuvants were used, is that there were no differences among the protocols despite their differences in duration (10, 21, or 28 days). We demonstrated for the first time that a shorterterm protocol, without the use of adjuvants, can induce an allergic response in the lungs of mice similar to that observed in previous, wellestablished protocols. The use of a 10-day protocol inducing the same eosinophilic response in the lungs as that observed in previous, longer-term protocols widely used in the literature can facilitate pre-clinical trials (particularly those investigating new therapeutic targets), reducing the costs and the duration of experiments. In addition, shorter-term protocols are in accordance with all ethical principles currently guiding the use of animals in research, reducing the duration of the experimental procedures that animals undergo.

There were no significant differences between the short-term protocol tested in the present study and the protocol used in the C+ group in terms of total cell counts and eosinophil counts J Bras Pneumol. 2012;38(5):595-604

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Figure 2 - Comparison of total and differential cell counts in BAL fluid (in absolute numbers and percentages) among the groups studied. The Kruskal-Wallis test (with Dunn’s post hoc test) was used. *p < 0.05. In order to compare the study groups with the negative control group, we used the Mann-Whitney test corrected for multiple comparisons (p = 0.035). The values for all variables were significantly higher in the study groups than in the negative control group. TCC: total cell count; and BALF: BAL fluid. Groups: 2sc2in-100: two subcutaneous sensitizations with ovalbumin and two intranasal challenges with ovalbumin (100 μg) on consecutive days; 2sc3in-100: two subcutaneous sensitizations with ovalbumin and three intranasal challenges with ovalbumin (100 µg) on consecutive days; 2sc3in-40: two subcutaneous sensitizations with ovalbumin and three intranasal challenges with ovalbumin (40 µg) on consecutive days; 2sc2in-40: two subcutaneous sensitizations with ovalbumin and two intranasal challenges with ovalbumin (40 µg) on consecutive days; 1sc3in-100: one subcutaneous sensitization with ovalbumin and three intranasal challenges with ovalbumin (100 µg) on consecutive days; C−: negative control; and C+: positive control.

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Figure 3 - Histological examination of the lungs of the mice in the groups studied: 2sc2in-40 group (in A); 2sc2in-100 group (in B); 2sc3in-40 group (in C); 2sc3in-100 group (in D); short-term protocol group (in E); C+ group (in F); and C− group (in G). Presence of an intense peribronchial and perivascular inflammatory infiltrate (A-F, black arrows) in all sensitized groups. The short-term protocol group (in E) has histopathological changes similar to those found in the other sensitized groups. Histology of the lungs of the animals in the C− group (in G) shows bronchi with normal wall thickness, vessels containing normally distributed perivascular lymphoid aggregates, and permeability and aeration of the alveolar space (H&E; magnification, ×100). In the peribronchovascular cell infiltrates (black arrows), there are more than 100 eosinophils per field in all groups, which is characteristic of an allergic response in the lungs of mice in these models. In the short-term protocol group (in H, light arrows), there are intense eosinophilic interstitial infiltrates (H&E; magnification, ×1,000). 2sc2in-100: two subcutaneous sensitizations with ovalbumin and two intranasal ovalbumin challenges (100 µg) on consecutive days; 2sc3in-100: two subcutaneous sensitizations with ovalbumin and three intranasal ovalbumin challenges (100 µg) on consecutive days; 2sc3in-40: two subcutaneous sensitizations with ovalbumin and three intranasal ovalbumin challenges (40 µg) on consecutive days; 2sc2in-40: two subcutaneous sensitizations with ovalbumin and two intranasal ovalbumin challenges (40 µg) on consecutive days; C−: negative control; and C+: positive control.

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Figure 4 - Comparison of the groups in terms of eosinophil peroxidase activity in lung tissue. There were no statistically significant differences among the groups studied. 2sc2in-100: two subcutaneous sensitizations with ovalbumin and two intranasal ovalbumin challenges (100 µg) on consecutive days; 2sc3in-100: two subcutaneous sensitizations with ovalbumin and three intranasal ovalbumin challenges (100 µg) on consecutive days; 2sc3in-40: two subcutaneous sensitizations with ovalbumin and three intranasal ovalbumin challenges (40 µg) on consecutive days; 2sc2in-40: two subcutaneous sensitizations with ovalbumin and two intranasal ovalbumin challenges (40 µg) on consecutive days; 1sc3in-100: one subcutaneous sensitization with ovalbumin and three intranasal ovalbumin challenges (100 µg) on consecutive days; and C+: positive control.

in BAL fluid or in terms of EPO levels in lung tissue. In addition, for the short-term protocol, histological examination revealed a significant peribronchovascular inflammatory cell infiltrate, with a predominance of eosinophils, with the same characteristics as those observed for the other protocols.

In 2008, Hahn & Erb published an article questioning the time it takes to identify and develop new treatments for asthma; this process begins with identifying a molecule and determining whether it is actually involved in the disease process, and it is followed by identification of the structural components and synthetic modification of the molecule, culminating in pre-clinical testing in animals.(8) In addition to this long and costly process, there are long periods of experiments in mice. It is of note that the results obtained with the model proposed in the present study are related to the analysis of acute response to a single allergen (i.e., ovalbumin).

It is also of note that experimental models of asthma involving chronic exposure have been proposed and are important in the study of new drugs, being probably performed in a later sequence of experiments, when therapeutic targets are sought.(10,11) Shorter-term protocols can nevertheless be an interesting screening model for new therapeutic targets.

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In 2004, Cates et al. conducted a study involving a short-term (10-day) protocol of sensitization with house dust mites (HDM) and demonstrated eosinophilic inflammation in the lungs of mice, as well as increased expression of Th2 effector cells (CD3+, CD4+, and T1/ST2+), together with increased levels of total IgE and HDM-specific IgG1.(12) The results of that study and those of our study demonstrate that it is possible to perform a short-term (10-day) protocol using either ovalbumin or HDM. Various authors have criticized the use of alum in murine models of asthma because alum is an artificial substance for the induction of an immune response, inducing pro-inflammatory cytokine production and activating Th2 lymphocytes.(5,13,14) Alum also activates the immune system via dendritic cell maturation and by co-stimulation of expression molecules.(15,16) In addition, alum has been shown to cause major stress in animals up to 4 h after exposure.(6) Studies in which alum was not used demonstrated that this substance is not necessary for the induction of an allergic response in the lungs of mice and that there is no difference between subcutaneous sensitization without the use of adjuvants and intraperitoneal sensitization with alum. Those studies, involving protocols without the use of adjuvants, demonstrated different levels of

Proposed short-term model of acute allergic response, without adjuvant use, in the lungs of mice

inflammation, different levels of immune tolerance to the allergen, or protocols that were often too long.(7,17-20) More recently, Conrad et al. found no significant differences in BAL cellularity, lung histology, or interleukin (IL-5, IL-10, and IL-13) levels using subcutaneous sensitization with ovalbumin and no adjuvants.(6) However, in that study, there were three sensitizations, which makes the experiment relatively long for an acute model of asthma. The mechanism by which subcutaneous sensitization is effective without the use of adjuvants still needs to be clearly characterized. One hypothesis is that the subcutaneous tissue compartment has a larger and more effective number of antigen-presenting cells, which results in a more robust response to a given allergen, no adjuvants being required.

The cell counts in BAL fluid in the present study showed that eosinophil counts were lower in the groups undergoing subcutaneous sensitization with ovalbumin (21 days) and two intranasal ovalbumin challenges (40 µg) than in the group undergoing three ovalbumin challenges (Figure 2).

This finding can be explained by the fact that fewer intranasal ovalbumin challenges induce less inflammation in the animal. However, in the context of the primary objectives of our study, this finding does not seem to be of great relevance.

One limitation of the present study was the fact that we did not measure cytokines or ovalbumin-specific IgE or conduct pulmonary function testing. Because we did not investigate any disease mechanism or any mechanism of antigen sensitization in the present study, we believe that the analysis performed, with a major focus on eosinophil activity in the lungs (eosinophil levels in BAL fluid, eosinophil levels in histological sections, and EPO levels in lung tissue), does not significantly change the final interpretation of the results in general. However, we understand that further studies involving a better characterization of the inflammatory response in the lungs are needed in order to validate our model. One question that remains unanswered is whether this short period is sufficient for a significant production of ovalbumin-specific IgE. In conclusion, new models of asthma using lower doses of ovalbumin, a smaller number of sensitizations, a smaller number of intranasal challenges, and no adjuvants have shown an inflammatory response in the lungs, with a predominance of eosinophils (key effector cells

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in Th2 immune response). Our proposed model, of shorter duration, can be a future option for pre-clinical testing and the study of therapeutic targets in asthma, reducing the duration and cost of studies, provided that new studies are carried out and the appropriateness of the model is confirmed.

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PMid:19561139 PMCid:2739768. http://dx.doi.org/10.1152/ ajplung.00027.2009 3. Zosky GR, Sly PD. Animal models of asthma. Clin Exp Allergy. 2007;37(7):973-88. http://dx.doi. org/10.1111/j.1365-2222.2007.02740.x 4. Szelenyi I. Animal models of bronchial asthma. Inflamm Res. 2000;49(12):639-54. PMid:11211914. http://dx.doi. org/10.1007/s000110050642 5. Eisenbarth SC. Use and limitations of alum-based models of allergy. Clin Exp Allergy. 2008;38(10):1572-5. http:// dx.doi.org/10.1111/j.1365-2222.2008.03069.x 6. Conrad ML, Yildirim AO, Sonar SS, Kiliç A, Sudowe S, Lunow M, et al. Comparison of adjuvant and adjuvant-free murine experimental asthma models.

Clin Exp Allergy. 2009;39(8):1246-54. http://dx.doi. org/10.1111/j.1365-2222.2009.03260.x 7. Renz H, Smith HR, Henson JE, Ray BS, Irvin CG, Gelfand EW. Aerosolized antigen exposure without adjuvant causes increased IgE production and increased airway responsiveness in the mouse. J Allergy Clin Immunol. 1992;89(6):1127-38. http://dx.doi. org/10.1016/0091-6749(92)90296-E 8. Hahn C, Erb KJ. The preclinical testing strategy for the development of novel chemical entities for the treatment of asthma. Curr Drug Targets. 2008;9(6):443-51. PMid:18537583. http:// dx.doi.org/10.2174/138945008784533552 9. Strath M, Warren DJ, Sanderson CJ. Detection of eosinophils using an eosinophil peroxidase assay. Its use as an assay for eosinophil differentiation factors. J Immunol Methods. 1985;83(2):209-15. http://dx.doi. org/10.1016/0022-1759(85)90242-X 10. Johnson JR, Wiley RE, Fattouh R, Swirski FK, Gajewska BU, Coyle AJ, et al. Continuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling. Am J Respir Crit Care Med. 2004;169(3):378‑85. PMid:14597485. http:// dx.doi.org/10.1164/rccm.200308-1094OC 11. Fattouh R, Al-Garawi A, Fattouh M, Arias K, Walker TD, Goncharova S, et al. Eosinophils are dispensable for allergic remodeling and immunity in a model of house dust mite-induced airway disease. Am J Respir Crit Care Med. 2011;183(2):179-88. PMid:20732990. http://dx.doi.org/10.1164/rccm.200905-0736OC 12. Cates EC, Fattouh R, Wattie J, Inman MD, Goncharova S, Coyle AJ, et al. Intranasal exposure of mice to house dust mite elicits allergic airway inflammation via a GM-CSFmediated mechanism. J Immunol. 2004;173(10):6384-92.

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About the authors Andrea Mendonça Rodrigues

Doctoral Student. Graduate Program in Pediatrics and Child Health, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS, Pontifical Catholic University of Rio Grande do Sul – Porto Alegre, Brazil.

Camila Zanelatto Parreira Schmidt

Pediatric Pulmonologist. Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS, Pontifical Catholic University of Rio Grande do Sul – Porto Alegre, Brazil.

Lucien Peroni Gualdi

Doctoral Student. Graduate Program (Joint Doctoral Program) in Pediatrics and Child Health, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS, Pontifical Catholic University of Rio Grande do Sul – Porto Alegre, Brazil.

Raquel Giacomelli Cao

Doctoral Student. Graduate Program (Joint Doctoral Program) in Pediatrics and Child Heath, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS, Pontifical Catholic University of Rio Grande do Sul – Porto Alegre, Brazil.

Rodrigo Godinho de Souza

Technician. Laboratory of Pediatric Pulmonology, Biomedical Research Institute, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS, Pontifical Catholic University of Rio Grande do Sul – Porto Alegre, Brazil.

Ana Cláudia Pereira

Biology Student. Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS, Pontifical Catholic University of Rio Grande do Sul – Porto Alegre, Brazil.

Nailê Karine Nuñez

Master’s Student. Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS, Pontifical Catholic University of Rio Grande do Sul – Porto Alegre, Brazil.

Alisson Passos Schleich

Biology Student. Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS, Pontifical Catholic University of Rio Grande do Sul – Porto Alegre, Brazil.

Paulo Márcio Condessa Pitrez

Professor. Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS, Pontifical Catholic University of Rio Grande do Sul – School of Medicine, Porto Alegre, Brazil.

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Original Article Comparisons among parameters of maximal respiratory pressures in healthy subjects* Comparação entre parâmetros de pressões respiratórias máximas em indivíduos saudáveis

Cristina Martins Coelho, Rosa Maria de Carvalho, David Sérgio Adães Gouvêa, José Marques Novo Júnior

Abstract Objective: To investigate four parameters defining maximal respiratory pressures and to evaluate their correlations and agreements among those parameters for the determination of MIP and MEP. Methods: This was a crosssectional study involving 49 healthy, well-nourished males and females. The mean age was 23.08 ± 2.5 years.

Measurements were carried out using a pressure transducer, and the estimated values for the parameters peak pressure (Ppeak), plateau pressure (Pplateau), mean maximal pressure (Pmean), and pressure according to the area (Parea) were determined with an algorithm developed for the study. To characterize the study sample, we used descriptive statistics, followed by repeated measures ANOVA and Bonferroni post hoc test or by the Friedman test and the Wilcoxon post hoc test, as well as by Pearson’s or Spearman’s correlation coefficients, depending on the normality of the data. The agreement between the variables was assessed with Bland & Altman plots. Results: There were significant differences among all of the parameters studied for MIP (Ppeak = 95.69 ± 27.89 cmH2O; Parea = 88.53 ± 26.45 cmH2O; Pplateau = 82.48 ± 25.11 cmH2O; Pmean = 89.01 ± 26.41 cmH2O; p < 0.05 for all) and for MEP (Ppeak = 109.98 ± 40.67 cmH2O; Parea = 103.85 ± 36.63 cmH2O; Pplateau = 98.93 ± 32.10 cmH2O; Pmean = 104.43 ± 36.74 cmH2O; p < 0.0083 for all). Poor agreement was found among almost all of the parameters. Higher pressure values resulted in larger differences between the variables. Conclusions: The maximal respiratory pressure parameters evaluated do not seem to be interchangeable, and higher pressure values result in larger differences among the parameters.

Keywords: Respiratory system; Muscle strength; Respiratory function tests.

Resumo Objetivo: Investigar quatro parâmetros de definição de pressão respiratória máxima e avaliar suas correlações e concordância para medidas de PImáx e PEmáx. Métodos: Estudo transversal com 49 sujeitos saudáveis, eutróficos, de ambos os sexos, com média de idade de 23,08 ± 2,50 anos. As medidas foram realizadas utilizando-se um transdutor de pressão, e os parâmetros foram estimados a partir de um algoritmo matemático desenvolvido para a pesquisa: pressões de pico (Ppico), de platô (Pplatô), média máxima (Pmédia) e segundo a área (Párea). Foi empregada a estatística descritiva para caracterização da amostra, seguida por ANOVA para medidas repetidas e teste post hoc de Bonferroni ou teste de Friedman e teste post hoc de Wilcoxon, assim como correlações de Pearson ou Spearman, segundo a normalidade dos dados. A concordância entre as variáveis foi avaliada pelo método gráfico de Bland & Altman. Resultados: Houve diferenças significativas entre todos os parâmetros, tanto para PImáx (Ppico = 95,69 ± 27,89 cmH2O; Párea = 88,53 ± 26,45 cmH2O; Pplatô = 82,48 ± 25,11 cmH2O; Pmédia = 89,01 ± 26,41 cmH2O; p < 0,05 entre todos) quanto para PEmáx (Ppico = 109,98 ± 40,67 cmH2O; Párea = 103,85 ± 36,63 cmH2O; Pplatô = 98,93 ± 32,10 cmH2O; Pmédia = 104,43 ± 36,74 cmH2O; p < 0,0083 entre todos). Houve baixa concordância entre a maior parte das medidas, sendo as diferenças entre os parâmetros maiores quanto mais elevados os valores pressóricos considerados. Conclusões: Os parâmetros avaliados não são intercambiáveis, sendo as diferenças entre eles maiores à medida que valores pressóricos mais elevados são atingidos.

Descritores: Sistema respiratório; Força muscular; Testes de função respiratória.

* Study carried out at the Federal University of Juiz de Fora School of Physical Education and Sports, Juiz de Fora, Brazil.

Correspondence to: Cristina Martins Coelho. Rua Carlita de Assis Pereira, 30, Bosque dos Pinheiros, CEP 36062-050, Juiz de Fora, MG, Brasil.

Tel/Fax: 55 32 3215-1385. E-mail: cristina_fisiojf@yahoo.com.br Financial support: This study received financial support from the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG, Foundation for the Support of Research in the state of Minas Gerais).

Submitted: 19 December 2011. Accepted, after review: 5 September 2012.

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Introduction Chief among the available methods for evaluating respiratory muscle strength is the measurement of maximal respiratory pressures at the mouth (i.e., MIP and MEP), a method that is widely used in clinical practice. The methodological basis for this method of assessment and the first reference values for healthy individuals date from the 1960s.(1,2) Since then, various reference values and predictive equations have been proposed,(3) all having the common characteristic of yielding widely varying results. This can be attributed, at least in part, to differences in methodology across studies.(4,5) Methodological factors influencing the results include the number of maneuvers performed by individuals,(6-8) the choice of mouthpiece(9) and interfaces,(10) the presence of an air leak and the size of it,(11) and the parameters used in order to define maximal pressure.(12) In 2002, the American Thoracic Society (ATS), in partnership with the European Respiratory Society (ERS),(5) proposed that the methods for measuring maximal respiratory pressures be standardized.

Among the proposed recommendations was the use of pressure transducers in place of aneroid manometers, which, despite their historical use, have major limitations.(13) However, the parameters defining maximal pressure as measured by pressure transducers remain a matter of debate. On the basis of the pressure curve generated during the tests, maximal pressure can be defined as the highest pressure value obtained—peak pressure (Ppeak)—the highest pressure value sustained over a minimum period—plateau pressure (Pplateau)—or the highest mean pressure value sustained for one second—mean maximal pressure (Pmean).(4) Because it is more reproducible, Pmean has been recommended over Ppeak.(13) However, that recommendation was not based on evidence, which is why a large study(12) comparing the use of Ppeak with the use of Pplateau for the characterization of MIP was conducted. Although absolute Ppeak values were significantly higher, the two variables were found to be similar in terms of reproducibility. Similar results were reported by other authors for Ppeak and Pplateau,(14,15) as well as for Ppeak and Pmean.(10) The choice of parameter defining maximal pressure is believed to have a direct influence on the interpretation and reliability of test results.

However, we found no studies systematically comparing the use of Ppeak, Pplateau, and Pmean J Bras Pneumol. 2012;38(5):605-613

for MIP and MEP measurements. Therefore, the objective of the present study was to investigate four parameters defining maximal respiratory pressures and to evaluate the correlations and agreements among those parameters for the determination of MIP and MEP.

Methods Healthy young individuals over 18 years of age and studying physiotherapy or physical education at the Federal University of Juiz de Fora, located in the city of Juiz de Fora, Brazil, were selected to participate in the present study after advertisement of the study by word of mouth. After one of the researchers had personally contacted the individuals who were interested in participating in the study, those who met the inclusion criteria were invited to undergo testing, the study sample being therefore a convenience sample. The exclusion criteria were as follows: being a current smoker; being obese, obesity having been defined as a body mass index (BMI) ≥ 30 kg/m2; being underweight, malnutrition having been defined as a BMI < 18.5 kg/m2(16); having had upper airway infection in the two weeks preceding data collection(17,18); having reported a diagnosis of lung, cardiovascular, or neuromuscular disease(3); and continuously using oral/inhaled corticosteroids or any other medication that could interfere with skeletal muscle contractility.(19) The present study was approved by the Human Research Ethics Committee of the Federal University of Juiz de Fora University Hospital (Ruling no.

0121/2009), and all of the participants gave written informed consent.

Initially, we evaluated the anthropometric characteristics of all volunteers (body mass, height, and BMI) using an anthropometric scale with a stadiometer (LD1050; Líder, Araçatuba, Brazil).

Subsequently, we measured blood pressure and HR at rest.(20) Because these measurements are highly effort-dependent and with the objective of ensuring the safety of the tests, subsequent testing was performed only if blood pressure was below 180/110 mmHg(10) and HR was below 85% of the age-predicted maximal HR.(10,21) All of the participants underwent spirometry (MasterScreen PFT; Jaeger, Würzburg, Germany).

Volume calibration of the equipment was performed daily, prior to the tests, with a 3-L syringe (Jaeger).

We analyzed the following parameters: FVC; FEV1;

Comparisons among parameters of maximal respiratory pressures in healthy subjects

and FEV1/FVC. All tests were conducted by the same examiner, in accordance with the acceptability and reproducibility criteria recommended by the ATS.(22) We used the reference values reported

by Knudson et al.(23) Maximal respiratory pressures were measured with the individuals in a sitting position and using a nose clip and a scuba-type, semirigid rubber mouthpiece (Jaeger) with an orifice of 2 mm in internal diameter.(5) We used a pressure transducer (EMG System do Brasil Ltda., São José dos Campos, Brazil)—the distal end of which was closed—equipped with a 16-bit analogdigital converter, high-pass filters at a cut-off frequency of 20 Hz, and low-pass filters at a cut-off frequency of 500 Hz (two-pole analog Butterworth filter) and a sampling frequency of 240 Hz. Before data collection, the equipment was calibrated against a water column by the manufacturer. This generated a calibration file, which was saved and used in all subsequent evaluations. Although some of the volunteers reported being familiar with maximal respiratory pressure measurements, none of the volunteers reported having previously used scuba-type mouthpieces during testing. The volunteers were blinded to the objectives of the study, and all tests were conducted by the same examiner.

The decision of whether to measure MIP or MEP first was made by random drawing. For the measurement of MIP, the participants were asked to exhale to RV; subsequently, they were asked to put on the mouthpiece and perform a maximal inspiratory maneuver. For the measurement of MEP, the participants were asked to inhale to TLC; subsequently, they were asked to put on the mouthpiece and perform a maximal expiratory maneuver(24) while supporting the cheeks with the hands. For each variable, there were two learning trials,(3) followed by three test trials.

In order to ensure the reproducibility of the measurements, we established that the difference between the two highest values obtained in the three test trials should not be greater than 10%.(24) If the difference between those values was found to be no greater than 10%, the tests were repeated (a maximum of six attempts) until two reproducible values were obtained. In order to evaluate reproducibility, we used the peak value.(12) Given the possibilities offered by the program used, this was the only parameter that could be objectively measured during testing. In

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addition, in order to be accepted, the maneuvers had to last ≥ 5 s, as determined by a digital stopwatch (Cronobio SW2018; Pastbio, São Paulo, Brazil). This was due to the fact that, during the test trials, some of the volunteers were unable to reach their peak values before 3 s into the maneuver. Furthermore, there should be no air leaks around the mouthpiece while the maneuvers were being performed.(24) The volunteers received strong verbal encouragement from the examiner and were allowed to rest for 1 min or more between trials,(24,25) on the basis of self-reported fatigue.

After the tests, the maximal respiratory pressure curves were selected by the program WinDaq®, version 3.36 (Dataq Instruments, Akron, OH, USA), were saved in electronic format (Microsoft Excel), and were then exported for analysis with the mathematical program Matlab® R2009a (The MathWorks®; Natick, MA, USA, user license having been obtained via FAPEMIG project no. APQ 01284/09), the algorithm having been developed for the present study.

Of the three respiratory pressure curves that met the acceptability and reproducibility criteria for each of the measurements of MIP and MEP, the curve with the highest absolute peak value was used for subsequent calculations, its values being expressed in absolute terms. On the basis of the definitions proposed by Evans and Whitelaw,(4) the parameters Ppeak, Pplateau, and Pmean were calculated. We defined Ppeak as the highest pressure value obtained during testing. We defined Pplateau as the highest pressure value sustained for 1 s. We calculated Pplateau by using a sliding window of 240 samples in length (equivalent to 1 s), thus seeking to identify, along the entire curve, pressure values that were sustained for 1-s intervals, the highest value being selected. We defined Pmean as the highest mean value of the samples within one 1-s interval. We calculated Pmean by using a sliding window of 240 samples in length, thus seeking to identify, along the entire curve, the mean values that were within 1-s intervals. In order to calculate Pmean, we summed all pressure values within the window and subsequently divided each result by 240, the highest value being selected for analysis. In addition to the aforementioned parameters, we calculated the maximal pressure according to the area (Parea), as suggested by Windisch et al.(12) We calculated Parea by using a sliding window of J Bras Pneumol. 2012;38(5):605-613

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240 samples in length, the trapezoid method(26) being used in order to calculate the areas. After having obtained all area values within 1-s intervals of the pressure curve, we selected the highest value for analysis. For all cases, maximum values were defined as those obtained at any given time point during testing.

In the statistical analysis, the anthropometric and spirometric variables, as well as the age of the volunteers, were used in order to characterize the sample, being expressed as mean and standard deviation. Data normality was tested with the Kolmogorov-Smirnov test. For variables with normal distribution, we used repeated measures ANOVA, followed by the Bonferroni post hoc test.

For variables with non-normal distribution, we used the Friedman test, followed by the Wilcoxon post hoc test with Bonferroni correction (the level of significance being set at p < 0.0083). We also calculated Pearson’s or Spearman’s correlation coefficients (depending on the normality of the data) for the study variables. For all tests except the Wilcoxon post hoc test, the level of significance was set at 5%. The agreement among the different parameters was evaluated

by Bland & Altman plots.(27)

Results Of the individuals who agreed to participate in the present study, 50 met the inclusion criteria.

Of those 50 individuals, 1 was unable to attend all testing sessions for personal reasons, being therefore excluded from the analysis of the results. Therefore, the final sample consisted of 49 healthy individuals (23 males and 26 females). Mean age was 23.08 ± 2.50 years, mean body mass was 66.63 ± 11.05 kg, mean height was 168.9 ± 8.56 cm, and mean BMI was 23.22 ± 2.44 kg/m2. Mean spirometric values (in % of predicted)(23) were as follows: FEV1 = 103.8 ± 11.14%; FVC = 102.47 ± 9.46%; and FEV1/FVC = 98.63 ± 7.11%.

Table 1 - Parameters defining maximal pressure.a Variables Ppeak Parea MEP* 109.98 ± 40.67 103.85 ± 36.63 MIP*** 95.69 ± 27.89 88.53 ± 26.45

Of the 49 individuals evaluated, 3 reported having smoked in the past. However, all had quit smoking and had spirometric values that were within the normal range, having therefore remained in the study sample.

Table 1 shows the values of the parameters Ppeak, Parea, Pplateau, and Pmean, all of which were obtained during the measurement of MIP and MEP. There were significant differences among all of the parameters defining MIP and MEP. Figure 1 shows the box plots for the study variables.

The limits of agreement among the parameters, defined as mean ± 1.96 × SD of the difference between the variables, were calculated by Bland & Altman plots(27) and can be seen in Figures 2 and 3. Visual analysis of the plots revealed a trend toward a relationship of the differences between variables with their mean values. This hypothesis was tested by Spearman’s correlation coefficient, and the results are shown in Figures 2 and 3.

Discussion Previous studies involving healthy individuals(10,12,15) or individuals with chronic lung disease(14) found Ppeak values that were significantly higher than were Pplateau and Pmean values. The results of the present study corroborate those findings, and their clinical relevance is evident because most of the reference values for MIP and MEP published to date are based on Pplateau sustained for 1 s.(4) Therefore, the use of different parameters defining maximal pressures in prediction equations or tables derived from Pplateau values can lead to a misinterpretation of the respiratory muscle strength of the individuals evaluated. However, because the present study involved healthy individuals, further studies are needed in order to determine whether the use of different parameters defining maximal pressure can influence the detection and classification of respiratory muscle weakness in individuals with respiratory muscle impairment.

Pplateau 98.93 ± 32.1 82.48 ± 25.11

Pmean 104.43 ± 36.74 89.01 ± 26.41

p < 0.05** < 0.05****

Ppeak: peak pressure; Parea: maximal pressure according to the area; Pplateau: plateau pressure; and Pmean: mean maximal pressure. aValues expressed as mean ± SD (cmH2O).*Wilcoxon post hoc test. **Friedman test, with significant differences among all values. ***Bonferroni post hoc test. ****Repeated measures ANOVA, with significant differences among all values.

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Comparisons among parameters of maximal respiratory pressures in healthy subjects

The calculation of linear correlations among the variables showed that the variables were strongly correlated, with values above 0.9 (Table 2). In fact, given that the different parameters studied were derived from the same pressure curve, it is not surprising that they were found to be strongly correlated. These results are consistent with the reported Ppeak and Pplateau values for MIP.(12) According to the authors of that study, the strong correlation between the two variables suggests that they are interchangeable.

However, as was reported in that study,(12) the parameters, although strongly correlated, were statistically different from one another, indicating that choosing one over the other might influence the characterization of respiratory muscle strength in the individuals evaluated.

Regarding the agreement among the parameters investigated (Figures 2 and 3), we found that, in

Figure 1 - Parameters defining maximal pressure. The central horizontal lines represent the medians, whereas the lower and upper horizontal lines represent the first and third quartiles, respectively. The symbols o and * represent, respectively, the outlier value and extreme values. Ppeak: peak pressure; Parea: maximal pressure according to the area; Pplateau: plateau pressure; and Pmean: mean maximal pressure. †Significantly different from Ppeak. ‡Significantly different from Parea. ¥Significantly different from Pplateau. For MEP, we used the Friedman test with the Wilcoxon post hoc test; for MIP, we used repeated measures ANOVA with the Bonferroni post hoc test.

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general, there was poor agreement between the study variables, especially between Ppeak and the remaining variables. This was expected, given that there were statistically significant differences among the parameters evaluated. However, the narrow limit of agreement between the variables Parea and Pmean for MIP and MEP is of note.

Therefore, the question remains as to whether the difference between the parameters Parea and Pmean, although statistically significant, is relevant from a clinical standpoint, given the strong agreement between these two variables.

The differences between the study variables were significantly correlated with the means of the study variables, indicating that higher pressure values resulted in larger differences between the variables. Therefore, the question is whether the differences among the parameters defining maximal pressure would also be significant in individuals with respiratory muscle impairment, in whom lower pressure values are expected.

Further studies are needed in order to answer this question.

Studies aiming at investigating different parameters defining maximal pressure should take into consideration the various methods for calculating the variables. In the literature, Ppeak has been defined as the maximal pressure sustained for 0.01 s after the initiation of pressure recording(14) and as the highest pressure value obtained during the test.(10,12) Pplateau has been defined as the pressure sustained for 1.0 s(14) and as the pressure sustained for 0.5 s.(12) Pmean has been defined as the mean of the pressure values recorded at peak pressure over a 1-s period.(10) Therefore, there is a clear need for standardizing

Table 2 - Linear correlation among the parameters defining maximal pressure.

Variables Correlation Ppeak Parea Pplateau Pmean MEP Ppeak 0.99* 0.98* 0.99* Parea 0.99* 0.99* 1* Pplateau 0.98* 0.99* 0.99* Pmean 0.99* 1* 0.99* MIP Ppeak 0.99** 0.97** 0.99** Parea 0.99** 0.99** 0.99** Pplateau 0.97** 0.99** 0.99** Pmean 0.99** 0.99** 0.99** Ppeak: peak pressure; Parea: maximal pressure according to the area; Pplateau: plateau pressure; and Pmean: mean maximal pressure. *Spearman’s correlation coefficient (p < 0.05). **Pearson’s correlation coefficient (p < 0.05).

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Figure 2 - Bland & Altman plots for the limits of agreement among the parameters defining MEP. The solid line represents the mean of the differences between the parameters, whereas the dashed lines represent the limits of agreement (mean ± 1.96 × SD of the difference between the variables). EPpeak: peak expiratory pressure; EParea: maximal expiratory pressure according to the area; EPplateau: plateau expiratory pressure; and EPmean: mean maximal expiratory pressure. ρ: Spearman’s correlation coefficient. *p < 0.05.

the use of and the criteria for calculating the various parameters defining maximal pressure.

However, further studies are needed in order to investigate whether different criteria for calculating J Bras Pneumol. 2012;38(5):605-613

the same variable can significantly influence the pressure values obtained.

The limitations of the present study include the reference values for spirometry used in order

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Figure 3 - Bland & Altman plots for the limits of agreement among the parameters defining MIP. The solid line represents the mean of the differences between the parameters, whereas the dashed lines represent the limits of agreement (mean ± 1.96 × SD of the difference between the variables). IPpeak: peak inspiratory pressure; IParea: maximal inspiratory pressure according to the area; IPplateau: plateau inspiratory pressure; and IPmean: mean maximal inspiratory pressure. ρ: Spearman’s correlation coefficient. *p < 0.05.

to characterize the sample,(23) given that the latest reference values for the Brazilian population(28) are, on average, higher than are those proposed

by Knudson et al.(23) However, the latter values

are similar to those obtained experimentally in a sample of normal individuals in Brazil, the only significant difference between the sets of values being the FVC for males.(29) Therefore, J Bras Pneumol. 2012;38(5):605-613

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because the mean spirometric values in our study sample were quite similar to or higher than the predicted maximum values, it is unlikely that individuals showing values below the normal range were selected.

Another possible limitation of the present study is related to the number of trials used for measuring maximal respiratory pressures (two learning trials plus three test trials, totaling five maneuvers). In fact, studies involving children with respiratory disorders(8) or adults with chronic lung disease(6,7) found that nine to ten maneuvers are needed in order to measure MIP adequately.

However, aiming to bring the results obtained in the present study closer to those obtained in clinical practice, we chose to use the most current methodological recommendations for the assessment of maximal respiratory pressures, i.e., a minimum of three attempts(13) and a maximum of five attempts.(24) In conclusion, the maximal respiratory pressure parameters evaluated do not seem to be interchangeable, given that there was poor agreement among the parameters (except between Parea and Pmean) and that there were significant differences among them. In addition, higher pressure values resulted in larger differences between the variables. Further studies are needed in order to determine whether the use of different parameters can influence the characterization of muscle strength in individuals with respiratory muscle weakness.

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About the authors Cristina Martins Coelho

Physiotherapist. Federal University of Juiz de Fora, Juiz de Fora, Brazil.

Rosa Maria de Carvalho

Professor. Federal University of Juiz de Fora, Juiz de Fora, Brazil.

David Sérgio Adães Gouvêa

Professor. Federal University of Juiz de Fora, Juiz de Fora, Brazil.

José Marques Novo Júnior

Professor. Federal University of São Carlos, São Carlos, Brazil.

J Bras Pneumol. 2012;38(5):605-613

Original Article Factors associated with complications of community-acquired pneumonia in preschool children* Fatores associados às complicações em crianças pré-escolares com pneumonia adquirida na comunidade

Pollyana Garcia Amorim, André Moreno Morcillo, Antônia Teresinha Tresoldi, Andréa de Melo Alexandre Fraga, Ricardo Mendes Pereira, Emílio Carlos Elias Baracat

Abstract Objective: To identify socioeconomic factors and clinical factors associated with the development of complications in preschool children hospitalized with community-acquired pneumonia (CAP). Methods: This was a prospective longitudinal study involving children (12-59 months of age) diagnosed with CAP and admitted to the pediatric wards of two hospitals in the metropolitan area of Campinas, Brazil. Children with cystic fibrosis, heart disease, pulmonary malformations, neurological disorders, or genetic diseases were excluded. The diagnosis of CAP was based on clinical and radiological findings. Data were collected from the medical records and with a semistructured questionnaire. The subjects were divided into two groups (complicated and uncomplicated CAP).

Socioeconomic and clinical variables were compared, and multivariate logistic regression analysis was performed.

Results: Of the 63 children included, 29 and 34, respectively, presented with uncomplicated and complicated CAP. No statistically significant differences were found between the groups regarding age at admission, gestational age, birth weight, gender, or socioeconomic variables. Significant differences were found between the groups regarding history of pneumonia (p = 0.03), previous antibiotic therapy (p = 0.004), time elapsed since the onset of CAP (p = 0.01), duration of fever prior to admission (p < 0.001), duration of antibiotic therapy (p < 0.001), and length of hospital stay (p < 0.001). In the multivariate analysis, only duration of fever prior to admission remained in the model (OR = 1.97; 95% CI: 1.36-2.84; p < 0.001). Conclusions: Biological variables, especially duration of fever prior to admission, appear to be associated with the development of complications in children with CAP. Keywords: Community-acquired infections; Pneumonia; Pleural Effusion.

Resumo Objetivo: Identificar os fatores socioeconômicos e clínicos associados à evolução para complicações em crianças internadas com pneumonia adquirida na comunidade (PAC). Métodos: Estudo longitudinal prospectivo em crianças diagnosticadas com PAC (12-59 meses de idade) internadas em enfermarias gerais de pediatria de dois hospitais na região de Campinas (SP). Os critérios de exclusão foram ter fibrose cística, cardiopatia, malformação pulmonar, neuropatias e doenças genéticas. PAC foi diagnosticada por características clínicas e radiológicas.

Os dados foram coletados dos prontuários médicos e por um questionário semiestruturado. Os sujeitos foram divididos em dois grupos (PAC complicada e não complicada). Foram comparadas variáveis socioeconômicas e clínicas, e foi realizada análise de regressão logística multivariada. Resultados: Das 63 crianças incluídas, 29 e 34, respectivamente, apresentaram PAC não complicada e PAC complicada. Não houve diferenças estatisticamente significantes entre os grupos quanto a idade na admissão, idade gestacional, peso ao nascer, gênero ou variáveis socioeconômicas. Houve diferenças significantes entre os grupos em relação a pneumonia anterior (p = 0,03), antibioticoterapia prévia (p = 0,004), tempo de início da doença (p = 0,01), duração da febre antes da internação (p < 0,001), duração da antibioticoterapia (p < 0,001) e tempo de internação (p < 0,001). Na análise multivariada, somente permaneceu no modelo a duração da febre antes da internação (OR = 1,97; IC95%: 1,36-2,84; p < 0,001). Conclusões: Variáveis biológicas, com destaque para o tempo de febre anterior à internação, parecem estar associadas com a evolução para complicação em crianças com PAC. Descritores: Infecções comunitárias adquiridas; Pneumonia; Derrame pleural. * Study carried out at the Universidade Estadual de Campinas – Unicamp, State University at Campinas – Campinas, Brazil.

Correspondence to: Pollyana Garcia Amorim. Rua Tessália Vieira de Camargo, 126, Cidade Universitária “Zeferino Vaz”, CEP 13083-887, Campinas, SP, Brasil.

Tel. 55 19 7829-3950. E-mail: pollyanag@gmail.com Financial support: Pollyana Garcia Amorim is the recipient of a master’s degree grant from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Office for the Advancement of Higher Education).

Submitted: 5 June 2012. Accepted, after review: 7 August 2012.

J Bras Pneumol. 2012;38(5):614-621

Factors associated with complications of community-acquired pneumonia in preschool children

Introduction Acute respiratory infection is one of the five leading causes of death among children under 5 years of age in developing countries, accounting for approximately three million deaths/year.(1-4) Community-acquired pneumonia (CAP) is the most severe form of acute respiratory infection, accounting for 80% of all deaths from acute respiratory infection.(1) The impact of CAP on childhood mortality is a cause for concern, especially in developing countries.(1,2,5-7) Factors associated with CAP-related mortality include clinical signs of cyanosis, sensory abnormalities, wheezing, intercostal retractions, inability to drink fluids at hospital admission, and comorbidities, including heart disease, anemia, and rickets.(6,8) It is estimated that the worldwide incidence of CAP among children under 5 years of age is 0.29 cases/year, the annual incidence of CAP being therefore 150.7 million cases, over 11 million of which require hospitalization.(9) Factors such as day care center attendance, a high number of individuals residing in the same location, and passive smoke exposure, as well as a history of wheezing and pneumonia, are associated with an increased risk of CAP.(6,10,11) In Brazil, 373,622 children ≤ 14 years of age were hospitalized for pneumonia in 2004; of those children, 48% were in the 1-4 year age bracket.(12) In this year age bracket, bacterial pneumonia gains importance, being associated with an increased risk of complications, such as pleural effusion and pulmonary parenchymal injury.(13,14) These complications are the main determinants of clinical worsening and risk of death in children under 5 years of age.(2,15) Factors associated with CAP-related complications have been studied, maternal age, level of maternal education, acute malnutrition, lack of breastfeeding, and age of the child being of note.(10,16) In recent years, there has been an epidemiological transition from acute infectious diseases (including CAP) to chronic diseases. This raises the question of whether the abovementioned factors still have an impact on the incidence of complications, morbidity, and mortality due to acute bacterial pneumonia in children living in developed regions of Brazil. Therefore, it is relevant to determine the clinical and epidemiological profile of children with CAP requiring hospitalization in those regions and the factors associated with

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CAP-related complications. The objective of the present study was to identify the socioeconomic, environmental, and clinical factors that were associated with complicated and uncomplicated CAP in preschool children hospitalized with CAP.

Methods This was a prospective longitudinal study of a cohort of children (12-59 months of age) diagnosed with CAP and admitted to the pediatric wards of two university hospitals in the metropolitan area of Campinas, Brazil, namely the São Paulo State Hospital at Sumaré and the State University at Campinas Hospital de Clínicas. The study was conducted between June of 2010 and November of 2011.

In 2007, the mortality rates for children under 1 year of age in the state of São Paulo, Brazil, and in the metropolitan area of Campinas were, respectively, 13.4 and 11.55 deaths/1,000 live births. In Campinas, the gross domestic product per capita was 21,549.20 Brazilian reals in that year.

Children with cystic fibrosis, heart disease with hemodynamic repercussions, pulmonary malformations, neurological disorders, or genetic diseases were excluded from the study. Data were collected from the medical records and with a semi-structured questionnaire comprising closed questions. The questionnaire was administered to the parents/legal guardians of the CAP patients at the time of admission to the pediatric ward.

The main variables studied were gestational age at birth, breastfeeding, chronological age at admission, gender, level of maternal education, maternal employment status, family income, day care center attendance, smoking, housing conditions, comorbidities (a history of pneumonia and recurrent wheezing), previous use of antibiotics, complications, clinical variables, and variables related to disease progression. The children were divided into two groups (complicated and uncomplicated CAP).

The diagnosis of pneumonia was based on clinical findings (fever, cough, and difficulty breathing), physical examination findings (chest retraction and decreased breath sounds or rales), and radiological findings (unilateral or bilateral homogeneous consolidation on chest X-ray).(8) Pleural effusion, pneumothorax, pneumatocele, and lung abscess were considered complications of CAP. The patients who were included in the J Bras Pneumol. 2012;38(5):614-621

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complicated CAP group presented with such complications at admission.

The sample size was calculated on the basis of the two main epidemiological variables, i.e., family income and level of maternal education, at least 12 and 14 children being required for each group.

The data were processed by the Statistical Package for the Social Sciences, version 16.0 (SPSS Inc., Chicago, IL, USA) and presented in tables showing the absolute frequency (n) and relative frequency (%) of qualitative variables, as well as showing the means, standard deviations, minimum values, medians, and maximum values of quantitative variables. In order to evaluate the association between the dependent variable and qualitative independent variables, we used the chi-square test or Fisher’s exact test, as appropriate. In addition, we determined the crude OR and its 95% CI using the program Epi Info, version 6.04d. We performed a multivariate unconditional logistic regression analysis using the Wald method (forward stepwise technique), the probability of inclusion in the model being 0.05 and the probability of exclusion from the model being 0.10. All of the variables with a value of p < 0.200 in the bivariate analysis were preselected for inclusion in the model. In all cases, the level of significance was set at α = 5%.

The present study was approved by the Research Ethics Committee of the State University at Campinas School of Medical Sciences and the Education and Research Committee of the São Paulo State Hospital at Sumaré (CEP-FCM Ruling no. 616/2010).

Results A total of 63 children were included in the present study. Of those, 29 were included in the uncomplicated CAP group and 34 were included in the complicated CAP group. Of the 34 children with complicated CAP, 33 presented with pleural effusion (associated with pneumothorax in 3 and with pneumatoceles in 2) and 1 presented with pneumothorax alone. The procedures performed in order to treat the complications included pleural drainage (in 13 patients) and pleural puncture (in 4). Of the 34 patients, 10 were submitted to mechanical ventilation.

There were no statistically significant differences between the complicated CAP group and the uncomplicated CAP group regarding J Bras Pneumol. 2012;38(5):614-621

age (p = 0.36), gestational age (p = 0.60), birth weight (p = 0.32), or gender (p = 0.99; Table 1).

In addition, there were no statistically significant differences between the groups regarding the epidemiological variables (Table 1). Regarding housing conditions, most of the patients in both groups lived in homes in areas where there was garbage collection, a sewage system, and running water.

As can be seen in Table 2, there were statistically significant differences between the groups regarding history of pneumonia (p = 0.03) and previous antibiotic therapy (p = 0.004). As can be seen in Table 3, there were statistically significant differences between the groups regarding time elapsed since the onset of CAP (p = 0.01), duration of fever prior to admission (p < 0.001), duration of antibiotic therapy (p < 0.001), and length of hospital stay (p < 0.001).

Variables with a value of p < 0.200 were used as predictor variables in the multivariate analysis, including history of pneumonia, wheezing, previous antibiotic therapy, onset of CAP, number of individuals sharing the bedroom with the child, number of children under 5 years of age living in the household, time elapsed since the onset of CAP, and duration of fever prior to admission. After adjustment, duration of fever prior to admission was the only variable that remained in the model (adjusted OR = 1.97; 95% CI: 1.36-2.84; p < 0.001).

Of the total of children included in the present study, 1 died (on postadmission day 3). The child was 27 months of age and had a history of wheezing. She developed extensive pleural effusion (which was drained) and required ventilatory support.

Discussion The present study described the characteristics of patients who were diagnosed with complicated or uncomplicated CAP and who were admitted to the pediatric wards of two university hospitals in the metropolitan area of Campinas. We sought to identify variables associated with the development of complications and to determine whether epidemiological or clinical conditions played a role in this unfavorable outcome. The most common complication was pleural effusion, a finding that is consistent with those of other authors.(12,14,17,18)

Factors associated with complications of community-acquired pneumonia in preschool children

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Table 1 - Distribution of epidemiological variables and gender according to the groups of children hospitalized with complicated or uncomplicated community-acquired pneumonia (CAP).

Groups Total Complicated CAP Uncomplicated CAP Variables p* Crude OR 95% CI n % n % n % Gender Male 21 55.3 17 44.7 38 100.0 0.996 1.14 0.37-3.55 Female 13 52.0 12 48.0 25 100.0 Level of maternal education, years <5 3 60.0 2 40.0 5 100.0 1.000** 1.33 0.15-13.38 5-8 12 52.2 11 47.8 23 100.0 0.830 0.97 0.29-3.20 ≥9 18 52.9 16 47.1 34 100.0 1.00 Work Formal 10 47.6 11 52.4 21 100.0 0.647 0.66 0.19-2.31 Informal 6 54.5 5 45.5 11 100.0 1.000** 0.87 0.18-4.26 No work 18 58.1 13 41.9 31 100.0 1.00 Per capita income, number of times the national minimum wage < 0.5 24 68.6 11 31.4 35 100.0 1.000** 1.45 0.14-13.32 0.5-1.0 7 30.4 16 69.6 23 100.0 0.315** 0.29 0.03-2.93 ≥ 1.0 3 60.0 2 40.0 5 100.0 1.00 Breastfeeding No 3 50.0 3 50.0 6 100.0 1.000** 0.84 0.12-5.83 Yes 31 54.4 26 45.6 57 100.0 Day care center attendance Full time 17 54.8 14 45.2 31 100.0 0.819 1.34 0.38-4.71 Part time 7 63.6 4 36.4 11 100.0 0.624 1.92 0.34-11.25 No time 10 47.6 11 52.4 21 100.0 1.00 Smokers in the household Yes 16 61.5 10 38.5 26 100.0 0.451 1.69 0.54-5.33 No 18 48.6 19 51.4 37 100.0 Individuals living in the household, n >4 13 68.4 6 31.6 19 100.0 0.594 1.77 0.40-8.08 4 10 41.7 14 58.3 24 100.0 0.562 0.58 0.15-2.28 <4 11 55.0 9 45.0 20 100.0 1.00 Rooms in the household, n >4 10 45.5 12 54.5 22 100.0 0.974 0.83 0.20-3.48 4 15 65.2 8 34.8 23 100.0 0.507 1.88 0.45-8.06 <4 9 50.0 9 50.0 18 100.0 1.00 Individuals sharing the bedroom with the child, n ≥3 13 68.4 6 31.6 19 100.0 1.000** 0.54 0.02-7.78 2 9 33.3 18 66.7 27 100.0 0.131** 0.13 0.00-1.54 1 8 66.7 4 33.3 12 100.0 1.000** 0.50 0.02-8.82 0 4 80.0 1 20.0 5 100.0 1.00 Children under 5 years of age living in the household, n 2 5 100.0 0 0 5 100.0 0.067** No data No data 1 2 25.0 6 75.0 8 100.0 0.252** 0.28 0.04-1.81 0 27 54.0 23 46.0 50 100.0 1.00 *Chi-square test, except where otherwise indicated. **Fisher’s exact test.

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Table 2 - Previous findings in the groups of children hospitalized with community-acquired pneumonia (CAP).

Groups Total Previous Complicated CAP Uncomplicated CAP findings n % n % n % Pneumonia Yes 4 26.7 11 73.3 15 100.0 No 30 62.5 18 37.5 48 100.0 Wheezing Yes 4 30.8 9 69.2 13 100.0 No 30 60.0 20 40.0 50 100.0 Antibiotic therapy Yes 23 74.2 8 25.8 31 100.0 No 11 34.4 21 65.6 32 100.0

complicated or uncomplicated

p*

Crude OR

95% CI

0.033

0.22

0.05-0.90

0.116

0.30

0.07-1.26

0.004

5.49

1.64-19.06

*Chi-square test.

Table 3 - Clinical/disease progression variables in the groups of children hospitalized with uncomplicated community-acquired pneumonia (CAP).

Variables Groups n Mean SD Min Md Onset of CAP Complicated CAP 34 8.15 6.81 1 7 Uncomplicated CAP 29 4.86 2.67 2 4 Duration of fever prior to Complicated CAP 34 6.35 3.23 1 6 admission Uncomplicated CAP 29 3.21 1.40 1 3 Duration of antibiotic therapy Complicated CAP 34 10.21 6.66 3 9 during hospitalization Uncomplicated CAP 29 5.24 2.17 2 5 Length of hospital stay Complicated CAP 34 12.18 9.34 3 9 Uncomplicated CAP 29 5.52 1.90 3 5

complicated or Max p* 30 0.017 13 15 < 0.001 7 33 < 0.001 11 44 < 0.001 11

Min: minimum; Md: median; and Max: maximum. *Mann-Whitney test.

In the present study, age was not associated with the development of complications. Some studies support this finding,(15,18,19) whereas others have found a direct relationship between low age and the development of complications in children with CAP, the relationship being due to the fact that these patients have narrower airways and limited defense mechanisms of the airways, which are still immature.(10,13,16,20) Our finding might be due to the fact that patients under 12 months of age were excluded from the present study. We had to exclude patients in that age bracket because of the higher prevalence of viral pneumonia among such patients and because of the inclusion of children in the 1-4 year age bracket in most CAP studies defined by the World Health Organization.(21) We found no association between gender and complications of CAP in our sample. There is no consensus in the literature. Some studies have reported that complications of CAP are more common in males,(6,16,22) whereas others J Bras Pneumol. 2012;38(5):614-621

have reported that such complications are more common in females(18) or that there is no association between gender and complications of CAP.(14,23) Most of the patients investigated in the present study were children with no history of prematurity or low birth weight. This reflects the ease of access to health care in the study area, where health care facilities offer good coverage for prenatal care and delivery. Therefore, we were unable to determine whether the risk of complications was higher in such patients. In children with CAP and a history of prematurity and low birth weight, studies have shown an increased risk of death(6,10,16,24) rather than an increased risk of complications.(18) Breast milk seems to play a protective role against infectious diseases.(6,10) Early weaning and lack of breastfeeding have been associated with an increase in the number of cases of severe pneumonia.(16,23) Most of the patients in our sample were breastfed, a finding that supports

Factors associated with complications of community-acquired pneumonia in preschool children

the hypothesis that the study population had good nutritional status and easy access to health care, including clinical follow-up and nutritional guidance in the first year of life.

We found that epidemiological variables such as age, level of maternal education, mothers working outside the home, and day care center attendance had no impact on the development of CAP-related complications, a finding that is consistent with those reported by other authors.(15,18) One group of authors(25) found higher mortality in children with CAP attending a day care center; however, the authors reported no association between day care center attendance and an increased risk of complications. Although children attending a day care center are more exposed to bacterial agents and show a high rate of colonization by Streptococcus pneumoniae (the major etiologic agent of CAP), day care center attendance appears to influence the acquisition of CAP rather than the complications thereof. The same seems to be true for the variables associated with close living quarters, including family size and number of rooms in the household, which were also found to have no association with complications of CAP. We also found that income had no influence on the development of CAP-related complications.

Although the study population had a low income, the impact of having a low income appears to have been minimized by the good health care coverage provided by the facilities in the study area.

Passive smokers are at a higher risk of respiratory morbidity and mortality because cigarette pollutants act on the defense mechanisms of the respiratory mucosa, affecting mucociliary transport and alveolar macrophage activity; this induces pulmonary infections, as well as leading to an increase in the allergic response to inhaled antigens.(10) Studies have shown that children whose parents smoke have a higher risk of having pneumonia and being hospitalized for it.(16,26) However, no studies have established a direct relationship between smoking and a higher occurrence of CAP-related complications.(6,15) Although epidemiological variables were not associated with the development of CAP-related complications in the present study, biological variables such as history of pneumonia and wheezing and previous use of antibiotics were found to be associated with such complications.

The association of biological variables (particularly

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a history of pneumonia and wheezing) with complications of CAP has been reported by other authors. In one study,(16) children with a history of recurrent respiratory infections and wheezing were found to be up to five times more likely to be hospitalized for pneumonia.

Other authors(14) found that children who had used aminopenicillins before hospitalization had more complications than did those who used other types of antibiotics. This finding might be due to the fact that amoxicillin is widely used in patients with acute respiratory infections at doses that are insufficient to have an effect on S. pneumoniae, particularly on bacterial serotypes showing intermediate resistance to penicillin. The question is whether the use of higher doses of amoxicillin in patients with CAP whose etiology is probably bacterial can prevent this unfavorable outcome.

The longer hospital stays in the patients with complicated CAP in the present study were due to the need for maintaining intravenous antibiotic therapy until patients had been afebrile for 48 h, as well as being due to the need for additional care in cases in which pleural drainage was performed. It is of note that most of the patients included in the present study received betalactam antibiotics at admission and responded well to the treatment.

Our multivariate analysis revealed that duration of fever prior to admission was the only variable that was more closely related to the development of complications, with an OR of nearly 2. Other authors have reported the risk of complications in such cases, given that a timely diagnosis can prevent progression to pleural effusion in patients with CAP.(14,17,19,27-29) A delay in the initiation of antibiotic therapy, an inappropriate choice of antibiotics, and the use of lower than recommended doses of antibiotics can have a negative impact on the clinical course of bacterial pneumonia.

However, there is a concern about the incorrect indication of penicillins in viral processes; this is a commonplace practice in emergency rooms and can lead to increased bacterial resistance to the antibiotics that are widely used in pediatric patients.(30) In summary, the present study showed that the development of complications in children with CAP is directly associated with biological variables such as patient history, previous use J Bras Pneumol. 2012;38(5):614-621

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of antibiotics, and, first and foremost, duration of fever prior to admission.

The limitations of the present study include the difficulty in determining the etiology of localized CAP (even in patients with pleural effusion) and the number of patients included in the study.

However, empirical antibiotic therapy remains the most common approach to CAP, being based on age and on clinical and radiological data. In the present study, this was the therapeutic approach to CAP. Failure to determine the etiology of CAP should not be an obstacle to the decision-making process regarding antibiotic therapy. Clinical follow-up studies involving a higher number of patients and the use of various methods for bacterial identification can confirm or refute our findings.

Acknowledgements The authors would like to thank the staff of the pediatric wards of the São Paulo State Hospital at Sumaré and the State University at Campinas Hospital de Clínicas.

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26. Pereira ED, Torres L, Macêdo J, Medeiros MM. Effects of environmental tobacco smoke on lower respiratory system of children under 5 years of age [Article in Portuguese]. Rev Saude Publica. 2000;34(1):39-43. http://dx.doi.org/10.1590/S0034-89102000000100008

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27. Byington CL, Spencer LY, Johnson TA, Pavia AT, Allen D, Mason EO, et al. An epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema: risk factors and microbiological associations. Clin Infect Dis. 2002;34(4):434-40. http://dx.doi.org/10.1086/338460 28. Wexler ID, Knoll S, Picard E, Villa Y, Shoseyov D, Engelhard D, et al. Clinical characteristics and outcome of complicated pneumococcal pneumonia in a pediatric population.

Pediatr Pulmonol. 2006;41(8):726-34. http://dx.doi. org/10.1002/ppul.20383 29. Tan TQ, Mason EO Jr, Wald ER, Barson WJ, Schutze GE, Bradley JS, et al. Clinical characteristics of children with complicated pneumonia caused by Streptococcus pneumoniae. Pediatrics. 2002;110(1 Pt 1):1-6. http:// dx.doi.org/10.1542/peds.110.1.1 30. Wolkers PC, Mantese OC, Paula A, Almeida VV, Aguiar PA, Alvares JR, et al. New susceptibility breakpoints in antimicrobial resistance rates of invasive pneumococcal strains. J Pediatr (Rio J). 2009;85(5):421-5. http://dx.doi. org/10.2223/JPED.1931

About the authors Pollyana Garcia Amorim

Master’s Student in Child and Adolescent Health. Universidade Estadual de Campinas – Unicamp, State University at Campinas – Campinas, Brazil.

André Moreno Morcillo

Associate Professor. Department of Pediatrics, Universidade Estadual de Campinas – Unicamp, State University at Campinas – School of Medical Sciences, Campinas, Brazil.

Antônia Teresinha Tresoldi

Associate Professor. Department of Pediatrics, Universidade Estadual de Campinas – Unicamp, State University at Campinas – School of Medical Sciences, Campinas, Brazil.

Andréa de Melo Alexandre Fraga

Attending Physician. Department of Pediatrics, Universidade Estadual de Campinas – Unicamp, State University at Campinas – School of Medical Sciences, Campinas, Brazil.

Ricardo Mendes Pereira

Professor. Department of Pediatrics, Universidade Estadual de Campinas – Unicamp, State University at Campinas – School of Medical Sciences, Campinas, Brazil.

Emílio Carlos Elias Baracat

Associate Professor. Department of Pediatrics, Universidade Estadual de Campinas – Unicamp, State University at Campinas – School of Medical Sciences, Campinas, Brazil.

J Bras Pneumol. 2012;38(5):614-621

Original Article Factors associated with pulmonary tuberculosis among patients seeking medical attention at referral clinics for tuberculosis*,** Fatores associados à tuberculose pulmonar em pacientes que procuraram serviços de saúde de referência para tuberculose

Cid Carlos Soares de Alcântara, Afrânio Lineu Kritski, Valéria Goes Ferreira, Mônica Cardoso Façanha, Ricardo Soares Pontes, Rosa Salani Mota, Terezinha do Menino Jesus Silva Leitão

Abstract Objective: The identification of behavioral and clinical factors that are associated with pulmonary tuberculosis might improve the detection and treatment of the disease, thereby reducing its duration and transmission. Our objective was to identify sociodemographic, clinical, and behavioral factors that are associated with the diagnosis of pulmonary tuberculosis. Methods: This was a cross-sectional study conducted between April of 2008 and March of 2009 at three health care clinics in the city of Fortaleza, Brazil. We selected 233 patients older than 14 years of age who spontaneously sought medical attention and presented with cough for ≥ 2 weeks. Sociodemographic, clinical, and behavioral data were collected. Sputum smear microscopy for AFB and mycobacterial culture were also carried out, as were tuberculin skin tests and chest X-rays. The patients were divided into two groups (with and without pulmonary tuberculosis). The categorical variables were compared by the chi-square test, followed by logistic regression analysis when the variables were considered significant. Results: The prevalence of pulmonary tuberculosis was 41.2%. The unadjusted OR showed that the following variables were statistically significant risk factors for pulmonary tuberculosis: fever (OR = 2.39; 95% CI, 1.34-4.30), anorexia (OR = 3.69; 95% CI, 2.03-6.75), and weight loss (OR = 3.37; 95% CI, 1.76-6.62). In the multivariate analysis, only weight loss (OR = 3.31; 95% CI, 1.78-6.14) was significantly associated with pulmonary tuberculosis. Conclusions: In areas with a high prevalence of tuberculosis, weight loss could be used as an indicator of pulmonary tuberculosis in patients with chronic cough for ≥ 2 weeks.

Keywords: Mycobacterium tuberculosis; Tuberculosis, pulmonary/epidemiology; Risk factors.

Resumo Objetivo: A identificação de fatores comportamentais e clínicos associados à tuberculose pulmonar pode melhorar a detecção e o tratamento dessa doença, consequentemente reduzindo sua duração e transmissão.

Nosso objetivo foi identificar fatores sociodemográficos, clínicos e comportamentais associados à tuberculose pulmonar. Métodos: Estudo transversal realizado entre abril de 2008 e março de 2009 em três unidades de saúde na cidade de Fortaleza (CE). Foram selecionados 233 pacientes maiores de 14 anos que procuraram atendimento médico espontaneamente e que apresentavam tosse por ≥ 2 semanas. Foram coletados dados sociodemográficos, clínicos e comportamentais. Foram realizadas baciloscopia direta para BAAR e cultura de micobactérias, bem como testes tuberculínicos e radiografias de tórax. Os pacientes foram divididos em dois grupos (com e sem tuberculose pulmonar). As variáveis categóricas foram comparadas com o teste do qui-quadrado, seguido de análise de regressão logística quando as variáveis foram consideradas significativas. Resultados: A prevalência de tuberculose pulmonar foi 41,2%. As OR não ajustadas indicaram que as seguintes variáveis foram fatores de risco significativos para tuberculose pulmonar: febre (OR = 2,39; IC95%: 1,34-4,30), anorexia (OR = 3,69; IC95%: 2,03-6,75) e perda de peso (OR = 3,37; IC95%: 1,76-6,62). Na análise multivariada, apenas perda de peso (OR = 3,31; IC95%: 1,78-6,14) associou-se significativamente com tuberculose pulmonar. Conclusões: Em áreas com elevada prevalência de tuberculose, a perda de peso poderia ser utilizada como um indicador de tuberculose pulmonar em pacientes com tosse crônica por ≥ 2 semanas.

Descritores: Mycobacterium tuberculosis; Tuberculose pulmonar/epidemiologia; Fatores de risco. * Study carried out in the Department of Community Health, Federal University of Ceará School of Medicine, Fortaleza, Brazil.

Correspondence to: Terezinha do Menino Jesus Silva Leitão. Avenida dos Expedicionários, 4435, Montese, CEP 60410-411, Fortaleza, CE, Brasil.

Tel. 55 85 9994-6710. Fax: 55 85 3366-8044. E-mail: tsilva@ufc.br Financial support: This study received financial support from the International Clinical Operational and Health Services Research and Training Award (ICOHRTA AIDS/TB Grant no. 5 U2R TW006883-02), the Edital Doenças Negligenciadas (Neglected Diseases Mandate) of the Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development; Grant no. 410538/2006-0), and the Edital Institutos Milênio (Millennium Institutes Mandate; Grant no. 420121/2005-6).

Submitted: 19 December 2011. Accepted, after review: 2 July 2012. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

J Bras Pneumol. 2012;38(5):622-629

Factors associated with pulmonary tuberculosis among patients seeking medical attention at referral clinics for tuberculosis

Introduction A delay in the diagnosis of pulmonary tuberculosis can accelerate the progression of the disease, increase the risk of death, and contribute to the transmission of tuberculosis in the community.(1) Various studies have investigated risk factors for pulmonary tuberculosis in an attempt to accelerate the identification of cases.(2-4) The intention was to identify hospitalized patients in a timely manner in order to reduce transmission(2,3) or to establish diagnostic criteria for tuberculosis among patients with AFB-negative sputum smears.

(4) Similarly, various studies have investigated the impact of demographic, socioeconomic, and cultural factors on active tuberculosis,(5) as well as variables related to the development of tuberculosis in HIV-infected patients.(6) Given the high worldwide incidence of respiratory diseases and the millions of people with latent tuberculosis, a 2-3 week history of cough in patients residing or working in areas where tuberculosis is common is a finding that can contribute to earlier diagnosis, thus improving the outcomes and reducing the transmission of the disease.(7) In a study involving patients seeking medical attention at a primary health care clinic in the city of Rio de Janeiro, Brazil, the authors compared those with cough for ≥ 1 week and those with cough for ≥ 3 weeks in terms of the impact of tuberculosis screening on the rate of diagnosis.(8) The authors found that the probability of detecting tuberculosis was influenced by the reason for seeking medical attention rather than by the duration of cough. The probability of detecting pulmonary tuberculosis was significantly higher among those seeking medical attention for respiratory symptoms than among those seeking attention for other reasons (7.9% vs.

0.3%). The authors suggested that tuberculosis screening in patients seeking medical attention for respiratory symptoms and presenting with cough for ≥ 1 week in settings with a high prevalence of tuberculosis might significantly increase the detection of tuberculosis cases. The identification of other variables that can hasten the laboratory investigation and increase the detection of pulmonary tuberculosis might contribute to early treatment initiation and therefore become a useful tool in health care clinics.

In the state of Ceará, Brazil, the crude incidence of pulmonary tuberculosis increased from 41.9 cases per 100,000 population in 2007

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to 45.5 per 100,000 population in 2010. Ceará ranks fourth among the Brazilian states with the highest number of pulmonary tuberculosis cases,(9) the cure rate for the state being 69%.

This rate is much lower than that recommended by the World Health Organization (i.e., 85%) (10) and lower than that reported for Brazil (i.e., 73%).(10) Patients seeking medical attention at any of three referral health care clinics in the city of Fortaleza, Brazil, and presenting with cough for ≥ 2 weeks were invited to participate in the present study. Our objective was to identify sociodemographic, clinical, and behavioral factors that are associated with the diagnosis of pulmonary tuberculosis.

Methods This was a cross-sectional study conducted between April of 2008 and March of 2009 at three health care clinics in the city of Fortaleza, which is the capital of the state of Ceará, in northeastern Brazil, and has a population of 2,473,614 inhabitants. The patients included in the present study were selected from among those being treated at the Centro de Saúde Cesar Cals (a primary health care clinic), the Centro de Saúde Carlos Ribeiro (a primary health care clinic), or the Messejana Hospital Outpatient Clinic.

The three health care clinics are referral centers for tuberculosis, and the vast majority of individuals with suspected tuberculosis are referred to those clinics for routine investigation.

The patients were enrolled in the study when they presented to one of the abovementioned clinics for a medical consultation and were interviewed by trained investigators.

The eligibility criteria were as follows: being older than 14 years of age; having sought medical attention spontaneously; presenting with a ≥ 2 week history of cough; being willing to provide at least one sputum sample and undergo chest X-ray. The exclusion criteria included being pregnant and having declined to give written informed consent. All of the adult participants gave written informed consent, as did the parents/ guardians of the children included in the present study. The study project was approved by the Research Ethics Committees of the Federal University of Ceará (Protocol no. 158/08) and the Messejana Hospital (Protocol no. 547/08) in October of 2008.

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Patients with pulmonary tuberculosis were defined either as those with a positive culture for Mycobacterium tuberculosis or an AFB-positive sputum smear or as those who had clinical and radiological characteristics suggestive of pulmonary tuberculosis and who showed improvement (as determined by the study coordinator) after six months of antituberculosis treatment alone.

Patients without pulmonary tuberculosis were defined as those with an AFB-negative sputum smear and a negative culture for M. tuberculosis and no chest X-ray changes after a six-month follow-up period. Six months after having interviewed the patients without pulmonary tuberculosis, we searched the Brazilian Ministry of Health Sistema Nacional de Informação de Agravos de Notificação (SINAN, National Case Registry Database) in order to determine whether any of those patients had been diagnosed with tuberculosis elsewhere.

Sociodemographic data included age, gender, marital status, level of education of the head of the household, place of birth, place of residence, prior institutionalization, housing, and employment status. Smoking and illicit drug use were evaluated as behavioral variables; alcohol consumption was evaluated by the Cut down, Annoyed, Guilty, and Eye-opener (CAGE) questionnaire.(11) Household contacts with tuberculosis cases were also investigated.

We gathered clinical information (including history of tuberculosis, previous hospitalization, and presence of other chronic respiratory diseases) and asked the participants whether they had experienced any of the following symptoms: cough, pulmonary secretion, hemoptysis, night sweats, chest pain, fever, anorexia, weakness, hoarseness, dyspnea, or adenopathy. In addition, we collected information regarding past and present body weight (as reported by the study participants).

The participants underwent chest X-ray and tuberculin skin test (with PPD RT23).

Sputum samples for smear microscopy for AFB and mycobacterial cultures were collected on the day of the medical consultation at one of the clinics and in the following morning, the study participants having been instructed on how to collect sputum properly. Cultures for M. tuberculosis were performed on LöwensteinJensen medium and were followed by biochemical speciation.(12) The chest X-rays were evaluated by a J Bras Pneumol. 2012;38(5):622-629

radiologist working at the clinic where the patient was being treated. The chest X-ray reports were reviewed by the study coordinator, who used a standardized form in order to classify the findings in accordance with previously established criteria.(13) Findings that were considered characteristic of pulmonary tuberculosis included the presence of infiltrates, consolidations, or cavities (unilateral or bilateral in the upper lungs), with or without mediastinal or hilar lymphadenopathy, and bilateral miliary infiltrates.

In order to construct a database, we used Epi Info, version 6.04b. The patients were divided into two groups (i.e., with and without pulmonary tuberculosis). We used contingency tables in order to describe the categorical variables, which were organized by group. We used the chi-square test in order to compare the categorical variables, which were grouped into sociodemographic characteristics, living conditions, behavioral aspects, history of tuberculosis, and symptoms.

After adjustment for possible confounding factors, a stepwise logistic regression analysis was carried out. The final model was constructed in three steps. First, we selected variables within each group, the criterion being a value of p < 0.20; second, we obtained a model with dummy variables, the OR being adjusted by multiple logistic regression; and third, we used an adjusted logistic regression model in order to create a reduced model with dummy variables. A value of p < 0.05 was considered statistically significant.

Data analysis was performed with the STATA program, version 7 (StataCorp LP, College Station, TX, USA), the level of significance being set at 5%.

Results The initial sample consisted of 265 patients selected from among those being treated at any of the abovementioned health care clinics. Of those 265 patients, 32 were excluded: 15 did not provide a sputum sample, and 17 did not undergo chest X-ray. The final sample therefore consisted of 233 patients, the prevalence of pulmonary tuberculosis being 41.2% (n = 96).

Most of the participants resided in Fortaleza (97.42%). In addition, most of the participants were either single (37.77%) or married (30.47%).

The median age was 42.62 years, and there was a slight predominance of females (51.93%).

As shown in Table 1, the patients who reported having been cured of tuberculosis after previous

Factors associated with pulmonary tuberculosis among patients seeking medical attention at referral clinics for tuberculosis

treatment were significantly less likely to be diagnosed with pulmonary tuberculosis (OR = 0.45; 95% CI, 0.20-0.98).

The unadjusted OR showed that the variables age, gender, place of birth, level of education of the head of the household, and employment status were not statistically significant risk factors for pulmonary tuberculosis. In addition, illicit drug or alcohol use, a history of smoking, previous hospitalization, emphysema, housing, and household contact with a tuberculosis patient were found to have no significant association with pulmonary tuberculosis (Table 1). In our sample, only 4 patients were homeless. Illicit drug use (OR = 2.35; 95% CI, 1.14-4.94), cachaça consumption—cachaça being a popular Brazilian spirit (alcohol by volume, 40-50%)— (OR = 15.09; 95% CI, 4.31-79.87), and a history of imprisonment (OR = 11.76; 95% CI, 1.61514.62) were significantly more common in males than in females.

Certain symptoms, such as anorexia (OR = 3.69; 95% CI, 2.03-6.75), weight loss (OR = 3.37; 95% CI, 1.76-6.62), and fever (OR = 2.39; 95% CI, 1.34-4.30), were significantly associated with pulmonary tuberculosis. However, classic symptoms such as hemoptysis (OR = 1.84; 95% CI, 0.923.67), weakness (OR = 1.66; 95% CI, 0.92-2.99), night sweats (OR = 1.24; 95% CI, 0.71-2.17), and chest pain (OR = 1.59; 95% CI, 0.88-2.89) were not (Table 2).

Among the patients with tuberculosis, the disease was diagnosed by sputum smear microscopy or culture in 78.2% and by clinical, radiological, and epidemiological characteristics followed by clinical and radiological improvement after tuberculosis treatment alone in 21.8%. Although HIV testing was offered to all 233 participants, only 141 (60.5%) agreed to be tested. Of those, only 3 tested positive. Of those 3 patients, 1 had tuberculosis. None of the patients classified as not having pulmonary tuberculosis matched the tuberculosis cases included in the SINAN database.

The variables with a value of p > 0.2 were used to construct a logistic regression model (Tables 1 and 2). After the model was adjusted at a level of significance of 5%, only weight loss remained significantly associated with pulmonary tuberculosis (OR = 3.31; 95% CI, 1.78-6.14; Table 3).

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Discussion The proportion of pulmonary tuberculosis cases was higher in the present study (41.2%) than in other studies. Façanha et al. studied a group of patients with respiratory symptoms in a poor community in Fortaleza and found the prevalence of tuberculosis to be 8%.(14) In our study, rather than recruiting patients with respiratory symptoms, we included only those who were suspected of having active pulmonary tuberculosis and who sought medical attention for chronic cough and other respiratory or systemic symptoms.

In our sample (patients over 14 years of age seeking medical attention at a referral clinic in an endemic area and presenting with a ≥ 2 week history of cough), weight loss was the only symptom that was found to be significantly associated with pulmonary tuberculosis. Similarly, in a recent study involving 1,435 children living in an area with a high burden of tuberculosis in Africa, where the prevalence of the disease was 1.3%, weight loss was the only clinical variable that differed significantly between the patients with tuberculosis and those without.(15) Unlike other studies,(8,16,17) the present study found that patients under 40 years of age were similar to those over 40 years of age in terms of the prevalence of active tuberculosis. Carvalho et al. found that tuberculosis/HIV co-infection was significantly more common among patients over 40 years of age and among those with a lower level of education (i.e., fewer than 8 years of schooling).(6) In our study, although HIV testing was offered to all of the patients who were suspected of having tuberculosis, only 141 (60.5%) agreed to be tested. This underscores the importance of policy decisions targeting that specific population.

We found that the 44 patients with a history of tuberculosis treatment and cure were less likely to present with pulmonary tuberculosis. This finding differs from those reported in South Africa, where high rates of tuberculosis were found among those who had previously received treatment; indeed, 75% of the cases of postprimary disease were attributable to exogenous reinfection.(18) Our results are in line with the unitary concept of pathogenesis, which states that previously treated patients are at a lower risk of developing tuberculosis because most tuberculosis cases result from endogenous reactivation.

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Table 1 - Epidemiological characteristics of the patients with and without pulmonary tuberculosis.

Diagnosis of pulmonary tuberculosis Unadjusted OR Yes No Variable (95% CI) n (%) n (%) Gender Male 52 (46.43) 60 (53.57) 1.51 (0.86-2.65) Female 44 (36.36) 77 (63.64) 1 Age, years < 40 51 (48.11) 55 (51.89) 1.68 (0.96-2.96) ≥ 40 45 (35.43) 82 (64.57) 1 Place of birth Fortaleza 60 (42.86) 80 (57.14) 1.13 (0.63-2.05) Ceará state 33 (39.76) 50 (60.24) 1 Other states 03 (30.00) 07 (70.00) 0.57 (0.09-2.64) Level of education of head of household, years of schooling 0 12 (42.85) 16 (57.15) 1.08 (0.44-02.57) 1-4 29 (37.18) 49 (62.82) 0.77 (0.42-01.40) 5-12 45 (45.45) 54 (54.54) 1.35 (0.77-02.37) > 12 09 (40.90) 13 (59.09) 0.98 (0.35-02.62) No data 01 (16.67) 05 (83.33) 1 Employment status Unemployed 32 (45.71) 38 (54.29) 1.13 (0.53-2.40) Self-employed 12 (48.00) 13 (52.00) 1.34 (0.35-5.10) Employed 26 (42.62) 35 (57.38) 1 No data 26 (33.76) 51 (66.24) Household contact with tuberculosis Yes 33 (46.48) 38 (53.52) 1.36 (0.74-2.48) No 63 (38.89) 99 (61.11) 1 Smoking status Current smoker 25 (37.88) 41 (62.12) 1.03 (0.50-2.10) Former smoker 38 (48.72) 40 (51.28) 1.61 (0.83-3.13) Never smoker 33 (37.08) 56 (62.92) 1 Illicit drug use Yes 021 (45.65) 25 (54.35) 1.25 (0.61-2.52) No 075 (40.10) 112 (59.90) 1 Alcohol consumption (CAGE) Heavy 22 (50.00) 22 (50.00) 1.50 (0.57-3.90) Sporadic 16 (40.00) 24 (60.00) 1 Nondrinker 58 (38.92) 91 (61.08) History of tuberculosis followed by full treatment Yes 12 (27.27) 32 (72.73) 0.45 (0.20-0.98) No 84 (44.91) 103 (55.09) 1 No data 00 (00.00) 02 (100.00) Hospitalization in the last two years Yes 24 (50.00) 24 (50.00) 1.56 (0.78-3.12) No 72 (38.92) 113 (61.08) 1 Emphysema Yes 56 (45.53) 67 (54.47) 1.47 (0.84-2.60) No 39 (36.11) 69 (63.89) 1 Uncertain 01 (50.00) 01 (50.00) CAGE: Cut down, Annoyed, Guilty, and Eye-opener (questionnaire).

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p

0.11 0.05

0.65 0.42 0.84 0.37 0.25 0.97

0.72 0.61

0.27

0.91 0.12

0.49

0.35

0.03

0.16

0.14

Factors associated with pulmonary tuberculosis among patients seeking medical attention at referral clinics for tuberculosis

Table 2 - Symptoms reported by the patients with and without pulmonary Diagnosis of pulmonary tuberculosis Yes No Variable n (%) n (%) Anorexia Yes 69 (55.20) 56 (44.80) No 27 (25.00) 81 (75.00) Weight loss Yes 78 (50.32) 77 (49.68) No 18 (23.08) 60 (76.92) Fever Yes 64 (50.79) 62 (49.21) No 31 (30.10) 72 (69.90) Uncertain 01 (33.33) 03 (66.67) Hemoptysis Yes 26 (53.06) 23 (46.94) No 68 (37.99) 111 (62.01) Uncertain 02 (40.00) 03 (60.00) Weakness Yes 66 (45.83) 78 (54.17) No 30 (33.71) 59 (66.29) Chest pain Yes 67 (45.27) 81 (54.73) No 29 (34.12) 56 (65.88) Table 3 - Independent variables associated with pulmonary tuberculosis, as determined by logistic regression analysis.

Adjusted Variable p 95% CI OR Complete model Weight loss 0.002 2.78 1.44-5.34 Hemoptysis 0.12 1.70 0.86-3.38 Fever 0.14 1.61 0.84-3.06 Weakness 0.64 1.16 0.60-2.22 Chest pain 0.85 0.94 0.49-1.79 Model adjusted to p < 0.05 Weight loss 0.0002 3.31 1.78-6.14

In the present study, the diagnosis of tuberculosis was based on clinical, radiological, and epidemiological evidence in 21.8% of the patients, a proportion that is similar to those reported by other authors.(5,19) Gordin et al. evaluated 139 patients who had undergone tuberculosis treatment on the basis of a presumptive diagnosis of pulmonary tuberculosis. Of those 139 patients, 66 (48%) had active tuberculosis, 16 (24%) had positive culture results, 43 (65%) showed radiological improvement after treatment, and 7 (11%) showed clinical improvement. In the

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tuberculosis.

Unadjusted OR (95% CI)

p

3.69 (2.03-6.75) 1

0.001

3.37 (1.76-6.62) 1

0.001

2.39 (1.34-4.30) 1

0.001

1.84 (0.92-3.67) 1

0.05

1.66 (0.92-2.99) 1

0.06

1.59 (0.88-2.89) 1

0.09

present study, all of the patients who received a diagnosis of pulmonary tuberculosis were followed for at least 6 months and showed clinical or radiological improvement.(19) The association between active pulmonary tuberculosis and males has been previously described.(5) This might due to the fact that males are more likely to be exposed to certain risk factors for infections, including consuming alcoholic beverages, using illegal drugs, being an ex-convict, and smoking. Although we found that the proportion of males with pulmonary tuberculosis was higher than was that of females, we found no association between the male gender and pulmonary tuberculosis. It is of note that the four risk factors mentioned above were found to be significantly associated with the male gender.

In our study, neither smoking nor a history of smoking was significantly associated with pulmonary tuberculosis. Tobacco has been shown to be a factor that not only increases the risk of pulmonary tuberculosis but also delays its diagnosis because coughing is commonly attributed to smoking.(20) Machado et al. studied 218 pulmonary tuberculosis patients in the state of Rio de Janeiro, Brazil, and reported that those J Bras Pneumol. 2012;38(5):622-629

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with cough were over eleven times more likely to delay seeking medical attention.(21) Approximately 10% of all tuberculosis cases worldwide can be attributed to alcohol consumption. In a recent systematic review of 53 studies, Rehm et al. reported a strong correlation between heavy alcohol use/alcohol use disorders and tuberculosis.(22) We found no association between pulmonary tuberculosis and alcohol use, which is probably due to our sample size.

In addition, in order to detect alcohol use, we used the CAGE screening questionnaire, which is a tool that mainly identifies patients who drink heavily.

Our univariate analysis showed that anorexia, weight loss, and fever were associated with pulmonary tuberculosis. Although Bastos et al.

(8) found that fever, weight loss, and night sweats were significantly associated with pulmonary tuberculosis in patients seeking medical attention at primary health care clinics, they found no associations between hemoptysis and pulmonary tuberculosis or between anorexia and pulmonary tuberculosis in those patients.(8) Our logistic regression analysis with a significance level of 5% showed that weight loss was independently associated with a diagnosis of pulmonary tuberculosis. In areas with a high incidence of common respiratory diseases and tuberculosis, weight loss could aid in establishing an early diagnosis of pulmonary tuberculosis in patients with cough for ≥ 2 weeks, thus contributing to the control of the disease in regions with limited resources.

In conclusion, weight loss could be used as an indicator of pulmonary tuberculosis in patients with chronic cough for ≥ 2 weeks in areas with a high prevalence of tuberculosis.

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Chest. 2006;129(1 Suppl):197S-201S. PMid:16428710. http://dx.doi.org/10.1378/chest.129.1_suppl.197S 8. Bastos LG, Fonseca LS, Mello FC, Ruffino-Netto A, Golub JE, Conde MB. Prevalence of pulmonary tuberculosis among respiratory symptomatic subjects in an out-patient primary health unit. Int J Tuberc Lung Dis. 2007;11(2):156‑60.

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10. World Health Organization. Global tuberculosis control: a short update to the 2009 report. Geneva: World Health Organization; 2009. PMid:10888972.

11. Fiellin DA, Reid MC, O’Connor PG. Screening for alcohol problems in primary care: a systematic review. Arch Intern Med. 2000;160(13):1977-89. http://dx.doi.org/10.1001/ archinte.160.13.1977 12. Ministério da Saúde. Secretaria de Vigilância em Saúde.

Departamento de Vigilância Epidemiológica. Manual nacional de vigilância laboratorial da tuberculose e outras micobactérias. Brasília: Ministério da Saúde; 2008.

13. Ministério da Saúde. Fundação Nacional de Saúde.

Centro Nacional de Pneumologia Sanitária. Manual de recomendações para o controle da tuberculose no Brasil.

Brasília: Ministério da Saúde; 2010. PMid:19547855.

14. Façanha MC, Melo MA, Vasconcelos Fde F, Sousa JR, Pinheiro Ade S, Porto IA, et al. Health team training and active community surveillance: strategies for the detection of TB cases. J Bras Pneumol. 2009;35(5):449‑54.

PMid:16243872. PMCid:1720178.

15. Marais BJ, Obihara CC, Gie RP, Schaaf HS, Hesseling AC, Lombard C, et al. The prevalence of symptoms associated with pulmonary tuberculosis in randomly selected children from a high burden community. Arch Dis Child. 2005;90(11):1166-70. http://dx.doi.org/10.1136/ adc.2004.060640 16. Rodrigues JL, Fiegenbaum M, Martins AF. Prevalência de coinfecção tuberculose/HIV em pacientes do Centro de Saúde Modelo de Porto Alegre, Rio Grande do Sul. Sci Med (Porto Alegre). 2010;20(3):212-7. PMid:15994262.

PMCid:1747449.

17. den Boon S, van Lill SW, Borgdorff MW, Verver S, Bateman ED, Lombard CJ, et al. Association between smoking and tuberculosis infection: a population survey in a high tuberculosis incidence area. Thorax. 2005;60(7):555-7.

PMid:15831840. http://dx.doi.org/10.1136/ thx.2004.030924 18. Verver S, Warren RM, Beyers N, Richardson M, van der Spuy GD, Borgdorff MW, et al. Rate of reinfection tuberculosis after successful treatment is higher

Factors associated with pulmonary tuberculosis among patients seeking medical attention at referral clinics for tuberculosis

than rate of new tuberculosis. Am J Respir Crit Care Med. 2005;171(12):1430-5. PMid:2496633. http:// dx.doi.org/10.1164/rccm.200409-1200OC 19. Gordin FM, Slutkin G, Schecter G, Goodman PC, Hopewell PC. Presumptive diagnosis and treatment of pulmonary tuberculosis based on radiographic findings. Am Rev Respir Dis. 1989;139(5):1090-3.

20. Arantes GR, Trivelatto, LB. Cadastramento bacteriológico antituberculose: estudo preliminar para sua implantação em uma comunidade do estado de São Paulo (Brasil).

Rev Saude Publica. 1976;10:167-76. http://dx.doi. org/10.1590/S0034-89101976000200004

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21. Machado AC, Steffen RE, Oxlade O, Menzies D, Kritski A, Trajman A. Factors associated with delayed diagnosis of pulmonary tuberculosis in the state of Rio de Janeiro, Brazil. J Bras Pneumol. 2011;37(4):512-20. http://dx.doi. org/10.1590/S1806-37132011000400014 22. Rehm J, Samokhvalov AV, Neuman MG, Room R, Parry C, Lönnroth K, et al. The association between alcohol use, alcohol use disorders and tuberculosis (TB). A systematic review. BMC Public Health. 2009;9:450. http://dx.doi. org/10.1186/1471-2458-9-450

About the authors Cid Carlos Soares de Alcântara

Master’s Student. Department of Community Health, Federal University of Ceará School of Medicine, Fortaleza, Brazil.

Afrânio Lineu Kritski

Full Professor. Federal University of Rio de Janeiro School of Medicine, Rio de Janeiro, Brazil.

Valéria Goes Ferreira

Associate Professor. Federal University of Ceará School of Medicine, Fortaleza, Brazil.

Mônica Cardoso Façanha

Associate Professor. Federal University of Ceará School of Medicine, Fortaleza, Brazil.

Ricardo Soares Pontes

Associate Professor. Federal University of Ceará School of Medicine, Fortaleza, Brazil.

Rosa Salani Mota

Adjunct Professor. Department of Statistics and Mathematics, Federal University of Ceará, Fortaleza, Brazil.

Terezinha do Menino Jesus Silva Leitão

Associate Professor. Federal University of Ceará School of Medicine, Fortaleza, Brazil.

J Bras Pneumol. 2012;38(5):622-629

Brief Communication Correlation between resistance to pyrazinamide and resistance to other antituberculosis drugs in Mycobacterium tuberculosis strains isolated at a referral hospital*,** Correlação entre a resistência a pirazinamida e a resistência a outros fármacos antituberculose em cepas de Mycobacterium tuberculosis isoladas em um hospital de referência

Leila de Souza Fonseca, Anna Grazia Marsico, Gisele Betzler de Oliveira Vieira, Rafael da Silva Duarte, Maria Helena Féres Saad, Fernanda de Carvalho Queiroz Mello

Abstract The correlation between resistance to pyrazinamide (PZA) and resistance to other first-line antituberculosis drugs was investigated in 395 Mycobacterium tuberculosis strains isolated from clinical specimens, representing 14% of the overall number of M. tuberculosis isolates obtained between 2003 and 2008 at the laboratory of a referral university hospital for tuberculosis. A high correlation was found between resistance to PZA and multidrug resistance, as well as between PZA resistance and resistance to rifampin, isoniazid, and ethambutol (p < 0.01 for all). These results highlight the importance of performing PZA susceptibility testing prior to the prescription of this drug in order to treat drug-resistant and multidrug-resistant tuberculosis.

Keywords: Tuberculosis/drug therapy; Tuberculosis/microbiology; Antibiotics, antitubercular.

Resumo A correlação entre a resistência à pirazinamida (PZA) e a resistência a outros fármacos antituberculose de primeira linha foi investigada em 395 cepas de Mycobacterium tuberculosis provenientes de espécimes clínicos, que representavam 14% do total de isolados de M. tuberculosis no período entre 2003 e 2008 no laboratório de um hospital universitário de referência para tuberculose. Uma alta correlação foi encontrada entre resistência a PZA e multirresistência, assim como entre resistência a PZA e resistência a rifampicina, isoniazida e etambutol (p < 0,01 para todos). Esses resultados enfatizam a importância da realização do teste de sensibilidade a PZA antes de prescrever a droga para o tratamento de tuberculose resistente e multirresistente.

Descritores: Tuberculose/quimioterapia; Tuberculose/microbiologia; Antibióticos antituberculose.

Pyrazinamide (PZA) is classified as a first-line oral antituberculosis drug and has been widely used in the intensive phase of antituberculosis treatment, which involves the use of isoniazid (INH), rifampin (RMP), ethambutol (EMB), and PZA for two months, followed by the use of INH and RMP for another four months. In addition,

chemotherapeutic regimens that include PZA have been associated with the success of the directly observed treatment, short-course strategy. Unlike conventional antibiotics that are active mainly against growing bacteria, PZA appears to kill at least 95% of the semidormant population of Mycobacterium tuberculosis that persists in acidic

* Study carried out in the Mycobacteriology Laboratory of the Hospital Universitário Clementino Fraga Filho/Instituto de Doenças do Tórax da Universidade Federal do Rio de Janeiro – HUCFF/IDT-UFRJ, Clementino Fraga Filho University Hospital/Thoracic Diseases Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Correspondence to: Leila de Souza Fonseca. Laboratório de Micobactérias do Hospital Universitário Clementino Fraga Filho/ Instituto de Doenças do Tórax da Universidade Federal do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco, 255, 6º andar, CEP 21941-913, Rio de Janeiro, Brasil.

Tel. 55 21 2562-6746. E-mail: lsfonseca@micro.ufrj.br Financial support: This study received financial support from the International Clinical, Operational and Health Services Research and Training Award (ICOHRTA) Mandate (AIDS/TB Grant no. 5 U2R TW006883-02), the Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development), and the Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ, Rio de Janeiro Research Foundation).

Submitted: 26 March 2012. Accepted, after review: 14 June 2012. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

J Bras Pneumol. 2012;38(5):630-633

Correlation between resistance to pyrazinamide and resistance to other antituberculosis drugs in Mycobacterium tuberculosis strains isolated at a referral hospital

pH environments inside macrophages.(1) Therefore, PZA susceptibility testing in M. tuberculosis isolates is highly recommended.

Although resistance to other first-line drugs can be easily determined by laboratory susceptibility testing, PZA resistance remains difficult to determine; PZA is active only in acidic environments (e.g., pH = 5.5), and testing is not routinely performed. However, screening for PZA resistance is essential in order to identify multidrug-resistant (MDR) tuberculosis patients who have been exposed to the drug.

Despite the recent advances in controlling tuberculosis, Brazil ranked 19th among highburden countries, with 87,000 cases per year and a mortality rate of 7.5 per 100,000 population, according to estimates by the World Health Organization.(2) In 2009, 75,040 cases of tuberculosis were identified. Of those, 10,286 were cases of retreatment. Rio de Janeiro was the Brazilian state that had the largest proportion of retreatment cases (15.2%).(3) The objective of the present study was to determine the prevalence of PZA resistance in M. tuberculosis isolates and to identify a possible correlation between resistance to PZA and resistance to other first-line antituberculosis drugs. The strains used in the present study were isolated in the laboratory of a referral university hospital for tuberculosis, located in the city of Rio de Janeiro, Brazil. To our knowledge, this is the first study to evaluate the correlation between PZA resistance and resistance to other first-line drugs in Brazil.

Drug susceptibility tests were performed by the proportion method on Löwenstein-Jensen medium. Critical concentrations for resistance were as follows: streptomycin, 4 µg/mL; INH, 0.2 µg/mL; RMP, 40 µg/mL; and EMB, 2 µg/mL. We performed PZA susceptibility testing using Löwenstein-Jensen medium (pH = 5.5) containing 100 µg/mL of PZA. We defined MDR M. tuberculosis isolates as those resistant to INH and RMP.(4) Statistical analyses were performed with the Epi Info statistical package, version 6.0. The corrected chi-square test and Fisher’s exact test were used in order to compare resistance to PZA with resistance to the other drugs studied. The level of significance was set at p ≤ 0.05. The local research ethics committee approved the study.

Between 2003 and 2008, 2,821 M. tuberculosis clinical isolates (from 28,298 clinical samples

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sent to the laboratory) were submitted to drug susceptibility testing. Of those 2,821 isolates, 395 were selected from stock cultures on the basis of their viability. Of those 395 isolates, 285 (72.2%) were pansusceptible (i.e., susceptible to INH, RMP, EMB, and streptomycin) and 110 (27.8%) were resistant to at least one of the four first-line drugs. Of the 285 pansusceptible M. tuberculosis isolates, 22 (7.7%) showed monoresistance to PZA, and 38 (34.5%) of the 110 isolates that were resistant to at least one of the four firstline drugs were also resistant to PZA. There were 53 MDR isolates, 30 (56.6%) of which were also resistant to PZA. Resistance to PZA showed a strong correlation with concomitant resistance to other first-line antituberculosis drugs (Table 1).

Resistance to PZA correlated most significantly with resistance to INH, EMB, and RMP, as well as with multidrug resistance (p < 0.01 for all).

A key drug in the treatment of tuberculosis, PZA acts on dormant bacilli and plays a unique role in killing a subpopulation of semidormant bacilli that are not easily killed by other antibiotics.

(1) Concomitant resistance to different firstline antituberculosis drugs, including PZA, is not uncommon. Because of the difficulties in performing PZA susceptibility tests, information regarding PZA resistance is not routinely obtained in clinical settings. The rate of PZA resistance among pansusceptible clinical isolates (7.7%) in the present study was similar to those reported in two studies (range, 6-8%).(5) We found a high correlation between resistance to PZA and resistance to INH, RMP, and EMB (p < 0.01); however, the correlation between resistance to PZA and resistance to streptomycin was lower (p = 0.04). This can be explained by the fact that streptomycin is no longer part of the standard treatment for treatment-naïve patients in Brazil.

Recent studies of MDR M. tuberculosis strains in South Africa, Thailand, and Taiwan(5-7) have found the rate of resistance to PZA to be approximately 50%, a finding that is similar to ours (i.e., 56.6%).

The fact that studies conducted in different regions of the world (Africa, Asia, and South America) have found similar rates of resistance to PZA among MDR strains despite the use of different methods, such as the proportion method and BACTEC Mycobacteria Growth Indicator Tube, suggests that this is a general phenomenon J Bras Pneumol. 2012;38(5):630-633

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Fonseca LS, Marsico AG, Vieira GBO, Duarte RS, Saad MHF, Mello FCQ

Table 1 - Pyrazinamide resistance among 110 Mycobacterium tuberculosis clinical isolates resistant to at least one first-line drug.a Pyrazinamide susceptibility test results Resistant Susceptible Resistance p* (n = 38) (n = 72) Streptomycin resistance 0.04 Yes 16 (42.1) 45 (63.4)b No 22 (57.9) 26 (36.6) Isoniazid resistance < 0.01 Yes 36 (94.7) 43 (59.7) No 2 (5.3) 29 (40.3) Ethambutol resistance < 0.01 Yes 22 (57.9) 8 (11.3)b No 16 (42.1) 63 (88.7) Rifampin resistance < 0.01 Yes 31 (81.6) 25 (34.7) No 7 (18.4) 47 (65.3) Multidrug resistance % < 0.01 Yes 30 (78.9) 23 (31.9) No 8 (21.1) 49 (68.1) a

Values expressed as n (%). bn = 71 clinical isolates. *Fisher’s exact test.

and should be taken into consideration when treatment regimens are devised.

In 2008, the World Health Organization released an emergency update on guidelines for the treatment of drug-resistant tuberculosis.(8) The updated guidelines recommend that treatment of MDR/extensively drug-resistant tuberculosis should include at least four drugs with either certain or almost certain effectiveness.(8) Treatment regimens can be individualized or standardized if resistance patterns for a specific country are known.(8) Finally, PZA must not be counted as one of the four effective drugs.(8) Our data support and reinforce that recommendation, given the strong evidence of high levels of resistance to PZA associated with MDR tuberculosis. If we assume that approximately half of the MDR strains are resistant to PZA, nearly half of those are susceptible to PZA; therefore, it is important to identify the MDR tuberculosis isolates that are susceptible to PZA so that the drug can be added to the combination of antituberculosis drugs for patients with MDR tuberculosis. We conclude that PZA susceptibility tests should be performed prior to starting or adjusting treatment regimens for patients with MDR tuberculosis.

Our results indicate that PZA resistance is far more common than is currently appreciated.

Therefore, the inclusion of PZA in the treatment of J Bras Pneumol. 2012;38(5):630-633

MDR tuberculosis should be based on susceptibility test results in order to avoid disease progression to extensively drug-resistant tuberculosis. Further surveillance studies are needed in order to estimate the prevalence of PZA resistance in M. tuberculosis strains in Brazil.

Acknowledgments We thank Dr. Joseph Marr for his valuable assistance with the manuscript.

References 1. Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis. 2003;7(1):6-21.PMid:12701830.

2. World Health Organization [homepage on the Internet].

Geneva: World Health Organization. [cited 2011 Dec 8].

Global tuberculosis control: a short update to the 2009 report. Available from: http://www.who.int/tb/publications/ global_report/2009/update/en/index.html 3. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2011 Dec 8]. Available from: http://portalsaude.saude.gov.br/portalsaude/ 4. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica.

Manual nacional de vigilância laboratorial da tuberculose e outras micobactérias. Brasília: Ministério da Saúde; 2008.

5. Jonmalung J, Prammananan T, Leechawengwongs M, Chaiprasert A. Surveillance of pyrazinamide susceptibility among multidrug-resistant Mycobacterium tuberculosis isolates from Siriraj Hospital, Thailand. BMC Microbiol. 2010;10:223.

Correlation between resistance to pyrazinamide and resistance to other antituberculosis drugs in Mycobacterium tuberculosis strains isolated at a referral hospital

Erratum in: BMC Microbiol. 2010;10:278. http://dx.doi. org/10.1186/1471-2180-10-223 6. Mphahlele M, Syre H, Valvatne H, Stavrum R, Mannsåker T, Muthivhi T, et al. Pyrazinamide resistance among South African multidrug-resistant Mycobacterium tuberculosis isolates. J Clin Microbiol. 2008;46(10):3459-64.

PMid:18753350. http://dx.doi.org/10.1128/JCM.00973-08

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7. Chiu YC, Huang SF, Yu KW, Lee YC, Feng JY, Su WJ. Characteristics of pncA mutations in multidrug-resistant tuberculosis in Taiwan. BMC Infect Dis. 2011;11:240. http://dx.doi.org/10.1186/1471-2334-11-240 8. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis, Emergency update 2008. Geneva: World Health Organization; 2008.

About the authors Leila de Souza Fonseca

Full Professor. Professor Paulo de Góes Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Anna Grazia Marsico

Pharmacist. Mycobacteriology Laboratory of the Hospital Universitário Clementino Fraga Filho/Instituto de Doenças do Tórax da Universidade Federal do Rio de Janeiro – HUCFF/IDT-UFRJ, Clementino Fraga Filho University Hospital/Thoracic Diseases Institute, Federal University of Rio de Janeiro – Rio de Janeiro, Brazil.

Gisele Betzler de Oliveira Vieira

Pharmacist. Mycobacteriology Laboratory of the Hospital Universitário Clementino Fraga Filho/Instituto de Doenças do Tórax da Universidade Federal do Rio de Janeiro – HUCFF/IDT-UFRJ, Clementino Fraga Filho University Hospital/Thoracic Diseases Institute, Federal University of Rio de Janeiro – Rio de Janeiro, Brazil.

Rafael da Silva Duarte

Associate Professor. Professor Paulo de Góes Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Maria Helena Féres Saad

Senior Researcher. Laboratory of Cellular Microbiology. Fundação Instituto Oswaldo Cruz – Fiocruz, Oswaldo Cruz Institute Foundation – Rio de Janeiro, Brazil.

Fernanda de Carvalho Queiroz Mello

Associate Professor. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

J Bras Pneumol. 2012;38(5):630-633

Special Article Pulmonary research recently published in Brazilian journals*,** Pesquisas em pneumologia recentemente publicadas em revistas brasileiras

Ariane Maris Gomes, Daniela Aquemi Higa

Abstract We reviewed original articles in the field of pulmonary medicine that had been recently published in 12 Brazilian journals—general or specialty journals—excluding the Brazilian Journal of Pulmonology. All were journals indexed for the Institute for Scientific Information Web of Knowledge. The selection of articles was based on the “continuously variable rating” concept. We have organized the articles by category.

Keywords: Pulmonary medicine; Medical oncology; Research; Infectious disease medicine.

Resumo Revisamos estudos originais no campo da pneumologia que foram recentemente publicados em 12 publicações gerais ou de especialidades — que não o Jornal Brasileiro de Pneumologia — indexadas no Institute for Scientific Information Web of Knowledge. A seleção dos artigos foi baseada no conceito de continuously variable rating, e os artigos foram classificados em categorias.

Descritores: Pneumologia; Oncologia; Pesquisa; Infectologia.

Introduction We reviewed original articles in the field of pulmonary medicine that had been recently published in 12 Brazilian journals—general or specialty journals—excluding the Brazilian Journal of Pulmonology.

All were journals indexed for the Institute for Scientific Information Web of Knowledge. The selection of articles was based on the “continuously variable rating” concept.(1) The selected articles were divided into categories, which are listed here in descending order of frequency.

Mechanical ventilation Among the articles selected, the most common topic was that of mechanical ventilation (MV).

We found thirteen recently published articles dealing with that topic.

According to Pantoni et al.,(2) the level of continuous positive airway pressure alters postoperative HR variability and breathing pattern in patients submitted to coronary artery bypass

grafting. The authors also demonstrated that 8-12 cmH2O of continuous positive airway pressure provides the best pulmonary and cardiac autonomic function.

Vidotto et al.(3) showed that, in patients undergoing neurosurgery, extubation failure significantly increases the risk of death, as well as that of post-operative pulmonary complications and tracheostomy. The authors stated that, among the risks evaluated, only that of post-operative pulmonary complications was significantly increased by prolonged MV. Casaroli et al.(4) evaluated a rat model of bacterial peritonitis. The authors found that pneumoperitoneum alone or in combination with controlled ventilation does not modify bacterial clearance via the peritoneal lymphatic system.

Ferreira et al.(5) compared a sigmoidal model and an exponential model to fit pressure-volume curves from mechanically ventilated patients under general anesthesia with idiopathic pulmonary fibrosis. The results suggest that respiratory system

* Study carried out at the University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Correspondence to: Ariane M Gomes. Rua Dr. Ovídio Pires de Campos, 225, 6º andar, ECP 05403-010, São Paulo, SP, Brasil.

Tel. 55 11 2661-6235. E-mail: ariane.gomes@hc.fm.usp.br or daniela.higa@hc.fm.usp.br Financial support: None.

Submitted: 6 September 2012. Accepted, after review, 14 September 2012. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

J Bras Pneumol. 2012;38(5):634-642

Pulmonary research recently published in Brazilian journals

compliance is decreased close to end-expiratory lung volume in those patients.

According to Lopez et al.,(6) the need for more than 2 h of MV predicts the development of bronchopulmonary dysplasia in preterm infants with a gestational age > 26 weeks. The authors also suggested that the need for prolonged MV is an early marker of bronchopulmonary dysplasia.

Nery et al.(7) suggested that daily screening of patients in order to identify those able to breathe without support, combined with noninvasive positive-pressure ventilation, reduces the duration of MV and total ventilatory support without increasing the risk of reintubation. That intervention was identified as an independent factor associated with survival.

Schifelbain et al.(8) compared two weaning methods (pressure support ventilation and T-tube) and found no differences between the two methods in terms of Doppler echocardiographic, electrocardiographic, or other cardiorespiratory variables prior to and 30 min after weaning from MV, regardless of the outcome of the weaning.

However, the authors found that cardiac structures were smaller, isovolumetric relaxation time was longer, and oxygenation level was greater in successfully weaned patients than in those who failed.

According to Almeida et al.,(9) the increase in the phase III slope normalized to tidal volume in asthma patients suggests that these patients have ventilation inhomogeneity in the distal air spaces. The authors speculated that this reflects chronic structural disorders or reversible acute changes seen on the bronchial provocation test.

According to Araujo et al.,(10) stress ulcer prophylaxis is a common practice in pediatric ICUs in the city of Porto Alegre, Brazil, ranitidine being the drug most commonly used. Chief among the various reasons given for providing the prophylactic treatment were the increased risk in patients on MV and the fact that it is part of the informal routine in those ICUs. Carvalho et al.(11) reported that the mean accidental extubation density was 5.34/100 patient‑days on MV in a tertiary neonatal ICU, and that the duration of assisted ventilation was its only independent predictor.

The authors also stated that the best accuracy for the occurrence of accidental extubation was achieved at 10.5 days of assisted ventilation.

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Hanashiro et al.(12) studied the impact that transferring a pediatric MV-dependent population from the ICU to MV dependency units or to home MV had on bed availability in the ICU. Their results suggest that the transfer of such patients increases ICU bed availability and that the survival rates for patients who are sent home on MV are similar to those for patients who remain hospitalized on MV. Hentges et al.(13) reported that detectable levels of caffeine in umbilical cord blood did not decrease the occurrence of apnea of prematurity but had a borderline effect on delaying its occurrence. That finding suggests that even low levels of caffeine in umbilical cord blood delays the occurrence of apnea spells.

According to Sukys et al.,(14) rapid sequence intubation is the method of choice for tracheal intubations performed in the emergency room, because it has proven to be safe and had a low incidence of severe complications. However, in that study, there was a low success rate, which the authors attributed to poor preparation for the procedure and limited experience on the part of the practitioner.

Diagnostic procedures The second most commonly addressed topic was that of diagnostic procedures. Among the recently published articles evaluated, eleven dealt with that topic.

Anciães et al.(15) induced experimental emphysema in BALB/c mice. The authors found that morphometric parameters are more reliable for detecting the presence of emphysema than are functional parameters measured by respiratory mechanics.

Bosch et al.(16) described the functioning of a quick diagnosis unit in a Spanish public university hospital. The authors concluded that this type of unit represents a useful and costsaving model for the diagnostic study of patients with potentially severe diseases.

Boskabady et al.(17) evaluated individuals engaged in carpentry work in the city of Mashhad (northeast Iran). The authors found that such work is associated with a high frequency of respiratory symptoms, particularly after exposure to irritating chemicals during work.

Costa et al.(18) studied the application of the pediatric risk of mortality score. The authors concluded that the score shows adequate J Bras Pneumol. 2012;38(5):634-642

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Gomes AM, Higa DA

discriminatory capacity, being a useful tool for the assessment of prognosis in pediatric patients admitted to tertiary pediatric ICUs. Faria et al.(19) studied the use of the forced oscillation technique to investigate the mechanical properties of the respiratory system in order to detect early smoking-induced respiratory involvement, when pathologic changes are still potentially reversible. The authors concluded that the technique is a versatile clinical tool for the prevention, diagnosis, and treatment of COPD. Guimarães et al.(20) evaluated CT-guided percutaneous fine needle aspiration biopsy of pulmonary lesions. The authors found that the rate of complications was 14.4%, and that the rate was significantly higher when the lesions had no pleural contact than when they did.

Pimenta et al.(21) proposed a new composite index (the desaturation-distance ratio), using continuous SpO2 and the distance covered on the six-minute walk test. The authors concluded that the desaturation-distance ratio is a promising, reliable physiologic tool for the evaluation of interstitial lung disease.

Rocha et al.(22) found that differences in renal function and tubular handling of potassium and phosphorus are present during the first week of life among preterm neonates who will develop bronchopulmonary dysplasia. The authors also found that patent ductus arteriosus and increased indomethacin use accentuate those differences.

Schachner et al.(23) evaluated patients undergoing isolated coronary artery bypass grafting. The authors found that, among such patients, pre-operative levels of N-terminal pro-brain natriuretic peptide > 502 ng/mL predict mid-term mortality, as well as being associated with significantly higher rates of in-hospital mortality and peri-operative complications.

Vieira et al.(24) developed and validated a predictive score for clinical complications during intra-hospital transport of infants treated in neonatal units. That score presented adequate discriminative power and calibration.

Boechat et al.(25) performed a cross-sectional study of intra- and inter-observer reliability of HRCT images of very-low-birth-weight infants and concluded that there was quite good intraand inter-observer concordance.

J Bras Pneumol. 2012;38(5):634-642

Infectious diseases Among the articles evaluated, infectious diseases were quite frequently addressed. We found nine articles dealing with the diagnosis or treatment of infectious diseases.

Arslan et al.(26) studied patients with community-acquired pneumonia. The authors found that plasma D-dimer levels, which are directly related to the intra- and extra-vascular coagulation that occurs in acute and chronic lung damage, were increased in those patients, regardless whether they had an accompanying disease that would normally cause such an increase.

Capelozzi et al.(27) report a detailed histopathological analysis of open lung biopsy specimens from five patients with acute respiratory distress syndrome and confirmed H1N1 infection, which was evidenced by viral-like particles in lung tissue, as identified through ultrastructural examination. Bronchioles and epithelium, rather than endothelium, seem to be the primary targets of H1N1 infection.

According to Chung et al.,(28) various risk factors can predict pulmonary function deterioration following tuberculosis treatment. The authors stated that patients with significant respiratory symptoms and multiple risk factors require pulmonary function testing in order to monitor the progression of functional impairment, especially within the first 18 months after the completion of the treatment.

Soeiro et al.(29) reviewed the autopsies of 4,710 patients with acute respiratory failure.

The authors found that bronchopneumonia and cancer were the two most common diagnoses.

The most prevalent pulmonary histopathological pattern was diffuse alveolar damage, which was associated with different inflammatory conditions.

In a study conducted in Brazil by da Silva et al.,(30) 51 Rhodococcus equi isolates were identified in the sputum samples of 546 individuals suspected of having pulmonary tuberculosis.

The authors described the epidemiology of the infection, as well as the phenotypic characteristics and drug susceptibility profile of the isolates.

Dias et al.(31) found that, in BALB/c mice co-infected with tuberculosis and the intestinal helminth Strongyloides venezuelensis, interleukin-17A production by lung cells was reduced and susceptibility to Mycobacterium bovis was increased. The authors suggested

Pulmonary research recently published in Brazilian journals

that intestinal infection with the helminth has a detrimental effect on the control of tuberculosis.

Boechat et al.(32) described a scoring system based on abnormalities identified on HRCT scans of premature infants and measured the predictive validity of the score in relation to respiratory morbidity during the first year of life. According to the authors, the scoring system is reproducible and easy to apply, allowing HRCT comparisons among premature infants by the identification of patients with different risk factors for respiratory morbidity.

Toufen et al.(33) evaluated patients with acute respiratory distress syndrome. The authors reported that, despite the marked severity of lung disease at admission, the patients in whom the acute respiratory distress syndrome was caused by infection with the swine-origin influenza A (H1N1) virus presented a late but substantial recovery over six months of follow-up.

De Paulis et al.(34) compared isolated infection with respiratory syncytial virus (RSV) and co-infection with RSV and other viruses, in terms of severity. The authors concluded that viral co-infections do not seem to affect the prognosis of hospitalized infants with acute RSV infection.

Oncology A number of recently published articles dealt with the field of oncology. We identified six such articles.

According to Ardengh et al.,(35) transesophageal ultrasound-guided fine needle aspiration is an alternative to surgical procedures. The authors stated that, in the vast majority of cases, the former can be used for the investigation of mediastinal lesions.

Miziara et al.(36) evaluated the combination of standard CT scans and Tc-99m sestamibi single-photon emission CT scans for the nodal staging of patients with non-small cell lung cancer. The authors found that, although the combination showed high specificity, its sensitivity and accuracy were quite low.

Parra et al.(37) studied the lungs of BALB/c mice after chemical carcinogenesis and found a direct link between low amounts of type V collagen and decreased cell apoptosis, which might favor neoplasia. The authors therefore suggested that strategies aimed at preventing decreased type V collagen synthesis or local responses that reduce

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apoptosis might have a significant impact on the control of lung cancer.

Pereira et al.(38) studied urethane-induced lung tumors in Swiss mice. The authors found that even low levels of exposure to fine particulate matter increased the risk of developing such tumors.

Sardenberg et al.(39) evaluated the treatment of patients with non-lung primary tumors. The authors concluded that pulmonary metastasectomy is a safe and potentially curative procedure for such patients, and that select patients can achieve long-term survival after lung resection.

Terra et al.(40) studied the use of talc pleurodesis carried out entirely on an outpatient basis in patients with recurrent malignant pleural effusions and Karnofsky performance status < 70. The authors found that, in such cases, outpatient talc pleurodesis is a safe, efficacious procedure, has low complication rates, and reduces hospital admissions.

Zhang et al.(41) found that tumor-associated macrophages in lung adenocarcinoma have an M2-polarized subtype and are associated with poor prognoses. The authors suggested that this results from accelerated lymphangiogenesis and lymph node metastasis.

Exercise One somewhat popular topic among the articles evaluated was that of exercise. Four articles addressed the relationships among diseases, treatments, and exercise.

Gimenes et al.(42) studied the oxygen uptake to work rate ratio in relation to various indicators of aerobic dysfunction during ramp incremental exercise in patients with mitochondrial myopathy and controls. The authors concluded that that ratio is a readily available, effort-independent index of aerobic dysfunction.

Mainenti et al.(43) investigated the effects of levothyroxine on cardiopulmonary exercise reserve and recovery in patients with subclinical hypothyroidism. The authors found that levothyroxine improved exercise cardiopulmonary reserve but had no effect on cardiopulmonary recovery after exercise during the 6-month study period.

Castro et al.(44) compared respiratory responses during progressive cardiopulmonary exercise tests performed on cycle or arm ergometers. Those authors found that, although not influencing the timing of breathing, the type of exercise J Bras Pneumol. 2012;38(5):634-642

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influences time-domain ventilatory variability in young, healthy individuals.

Myers et al.(45) found that impaired cardiac output recovery kinetics can identify heart failure patients with greater disease severity, lower exercise capacity, and inefficient ventilation. Estimating cardiac output during recovery from exercise might provide additional insight into the cardiovascular status of patients with heart failure.

Allergy Among the recently published articles evaluated, only three dealt with the topic of allergic diseases. Nevertheless, we found those articles quite interesting.

Boskabady et al.(46) studied the effect of hydroethanolic extract of Nigella sativa in ovalbumin-sensitized guinea pigs. The authors found that the extract had a preventive effect on the tracheal responsiveness, as well as on the white blood cell count in the BAL fluid.

Gomieiro et al.(47) found that, in elderly individuals with asthma, a respiratory exercise program increased muscle strength and was associated with a positive effect on health and quality of life. The authors concluded that such a program should be included in the therapeutic approach to those patients.

Guimarães et al.(48) assessed pulmonary function and the prevalence of atopy in school-age children who had been very-low-birth-weight infants. The authors found that there were no significant differences between the children with and without bronchopulmonary dysplasia in terms of lung function parameters, nor was there any evidence of an association between atopy and bronchopulmonary dysplasia.

Epidemiology Epidemiology continues to be the object of much research worldwide. Among the articles evaluated, we found three dealing with epidemiological issues.

Mamishi et al.(49) determined the most common infectious causes of hospital admissions in select Iranian patients with primary antibody deficiencies.

The authors found that respiratory tract infections were the most common cause of hospitalization among those patients.

Lamy et al.(50) evaluated neonatal ICUs at public hospitals in the city of São Luis, Brazil. Those J Bras Pneumol. 2012;38(5):634-642

authors found that staff work overload increases the occurrence of intermediate adverse effects in newborns and suggested that work overload be taken into consideration when evaluating outcomes in such ICUs. Marba et al.(51) studied the treatment of very-low-birth-weight neonates over a period of 15 years. The authors found that the incidence of periventricular/intraventricular hemorrhage declined significantly over the study period.

Obstructive sleep apnea Obstructive sleep apnea (OSA) has long been of interest to pulmonologists. Among the recently published articles evaluated, there were two dealing with that topic.

Neves et al.(52) evaluated the effects of sildenafil on the autonomic nervous system in patients with severe OSA. The authors found evidence to suggest that, in addition to worsening sleep apnea, sildenafil has potentially immediate and negative cardiac effects in patients with severe OSA. According to Romano et al.,(53) the determination of flow limitation (exhaled air volume in 0.2 s) by a negative expiratory pressure test during wakefulness might be a highly sensitive and reliable method of identifying OSA. When the test is positive, mild OSA can be presumed; when it is negative, moderate and severe OSA can be excluded.

COPD The treatment of COPD constitutes a major challenge for pulmonologists. Here, we evaluated two articles on the topic of COPD. Reis et al.(54) found that patients with COPD present impaired sympathetic-vagal balance at rest. Those authors also found that autonomic control of HR is associated with inspiratory muscle weakness in COPD. Silva et al.(55) found that, in patients with severe COPD, respiratory alterations can be identified by increased respiratory system impedance, which is more evident in the expiratory phase.

Their results seem to confirm the potential of within-breath analysis of respiratory impedance for the assessment of COPD-related respiratory alterations.

Pulmonary research recently published in Brazilian journals

Trauma Trauma can have disastrous effects on the respiratory system. Of the recently published articles evaluated, two dealt with those effects and their treatment.

Dong et al.(56) reported that victims of the Sichuan earthquake who had sustained crushrelated thoracic trauma exhibited life-threatening conditions, with a high incidence of bone fractures in the thorax. Bilateral involvement of the ribs was common, as were severe types of fractures, which were accompanied by non-rib fractures and injury to the lung parenchyma or pleura.

According to Sincos et al.,(57) endovascular treatment is a safe method for repairing blunt aortic trauma, with immediate and mid-term results that were comparable to those obtained with surgical repair. No complications caused by the stent graft were identified during the follow-up period (mean, 33 months).

Other Among the recently published articles selected, there were some that dealt with topics other than those listed above. We evaluated six such articles.

Ranzani et al.(58) evaluated a group of critically ill patients with systemic lupus erythematosus and a group of patients with other systemic rheumatic diseases. The authors found that the incidence of severe respiratory dysfunction at admission was lower in the former group, whereas the incidence of severe hematologic dysfunction was lower in the latter.

Barbalho-Moulim et al.(59) studied a group of obese women undergoing open bariatric surgery.

The authors showed that pre-operative inspiratory muscle training attenuates the impact that the trauma of bariatric surgery has on respiratory muscle strength without altering lung volumes or diaphragmatic excursion.

In a murine model of hemorrhagic shock, Costantini et al.(60) evaluated the use of hypertonic saline, which has hemodynamic and immune benefits, in combination with the phosphodiesterase inhibitor pentoxifylline, which has anti-inflammatory effects, as a hemorrhagic shock resuscitation strategy. The authors found that the use of that combination resulted in less lung injury than did the use of Ringer’s lactate.

Dogan et al.(61) evaluated rats exposed to smoke (tobacco smoke and biomass smoke).

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The authors reported that tobacco smoke caused severe damage to the respiratory histopathology, particularly when there was concomitant exposure to biomass smoke.

Otsuki et al.,(62) compared two preparations of the anesthetic sevoflurane (with water and with propylene glycol) in pigs. The authors found the two preparations to be equal regarding their hemodynamic and pulmonary effects.

Silva et al. (63) tested the effects that mycophenolate sodium, one of the most commonly used immunosuppressive drugs in lung transplantation, has on mucociliary clearance in rats. The authors found that the drug had no effect on transportability but significantly reduced mucociliary transport velocity in situ.

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Pulmonary research recently published in Brazilian journals

35. Ardengh JC, Bammann RH, Giovani Md, Venco F, Parada AA. Endoscopic ultrasound-guided biopsies for mediastinal lesions and lymph node diagnosis and staging. Clinics (Sao Paulo). 2011;66(9):1579-83. http://dx.doi.org/10.1590/ S1807-59322011000900013 36. Miziara JM, da Rocha ET, Miziara JE, Garcia GF, Simões MI, Lopes MA, et al. Preoperative nodal staging of non-small cell lung cancer using 99mTc-sestamibi spect/ ct imaging. Clinics (Sao Paulo). 2011;66(11):1901-9. http://dx.doi.org/10.1590/S1807-59322011001100009 37. Parra ER, Bielecki LC, Ribeiro JM, Andrade Balsalobre F, Teodoro WR, Capelozzi VL. Association between decreases in type V collagen and apoptosis in mouse lung chemical carcinogenesis: a preliminary model to study cancer cell behavior. Clinics (Sao Paulo). 2010;65(4):425-32. http://dx.doi.org/10.1590/S1807-59322010000400012 38. Pereira FA, Lemos M, Mauad T, Assunção JV, Saldiva PH. Urban, traffic- related particles and lung tumors in urethane treated mice. Clinics (Sao Paulo). 2011;66(6):1051-4. http://dx.doi.org/10.1590/S1807-59322011000600022 39. Sardenberg RA, Figueiredo LP, Haddad FJ, Gross JL, Younes RN. Pulmonary metastasectomy from soft tissue sarcomas. Clinics (Sao Paulo). 2010;65(9):871-6. http:// dx.doi.org/10.1590/S1807-59322010000900010 40. Terra RM, Teixeira LR, Bibas BJ, Pego-Fernandes PM, Vargas FS, Jatene FB. Effectiveness and safety of outpatient pleurodesis in patients with recurrent malignant pleural effusion and low performance status.

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M2-polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymphangiogenesis in lung adenocarcinoma. Clinics (Sao Paulo). 2011;66(11):1879-86. http://dx.doi.org/10.1590/ S1807-59322011001100006 42. Gimenes AC, Neder JA, Dal Corso S, Nogueira CR, Nápolis L, Mello MT, et al. Relationship between work rate and oxygen uptake in mitochondrial myopathy during ramp-incremental exercise. Braz J Med Biol Res. 2011;44(4):354-60.

43. Mainenti MR, Teixeira PF, Oliveira FP, Vaisman M. Effect of hormone replacement on exercise cardiopulmonary reserve and recovery performance in subclinical hypothyroidism.

Braz J Med Biol Res. 2010;43(11):1095-101. http:// dx.doi.org/10.1590/S0100-879X2010007500116 44. Castro RR, Pedrosa S, Nóbrega AC. Different ventilatory responses to progressive maximal exercise test performed with either the arms or legs. Clinics (Sao Paulo). 2011;66(7):1137-42. http://dx.doi.org/10.1590/ S1807-59322011000700003 45. Myers JN, Gujja P, Neelagaru S, Hsu L, Burkhoff D. Noninvasive measurement of cardiac performance in recovery from exercise in heart failure patients. Clinics (Sao Paulo). 2011;66(4):649-56. http://dx.doi.org/10.1590/ S1807-59322011000400021 46. Boskabady MH, Keyhanmanesh R, Khamneh S, Ebrahimi MA. The effect of Nigella sativa extract on tracheal responsiveness and lung inflammation in ovalbumin-sensitized guinea pigs. Clinics (Sao Paulo). 2011;66(5):879-87. http://dx.doi.org/10.1590/ S1807-59322011000500027 47. Gomieiro LT, Nascimento A, Tanno LK, Agondi R, Kalil J, Giavina-Bianchi P. Respiratory exercise program for elderly individuals with asthma. Clinics (Sao

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Paulo). 2011;66(7):1163-9. http://dx.doi.org/10.1590/ S1807-59322011000700007 48. Guimarães H, Rocha G, Pissarra S, Guedes MB, Nunes T, Vitor B. Respiratory outcomes and atopy in school-age children who were preterm at birth, with and without bronchopulmonary dysplasia. Clinics (Sao Paulo). 2011;66(3):425-30. http://dx.doi.org/10.1590/ S1807-59322011000300011 49. Mamishi S, Eghbali AN, Rezaei N, Abolhassani H, Parvaneh N, Aghamohammadi A. A single center 14 years study of infectious complications leading to hospitalization of patients with primary antibody deficiencies. Braz J Infect Dis. 2010;14(4):351-5. http://dx.doi.org/10.1590/ S1413-86702010000400007 50. Lamy Filho F, Silva AA, Lopes JM, Lamy ZC, Simões VM, Dos Santos AM. Staff workload and adverse events during mechanical ventilation in neonatal intensive care units. J Pediatr (Rio J). 2011;87(6):487-92.

51. Marba ST, Caldas JP, Vinagre LE, Pessoto MA. Incidence of periventricular/intraventricular hemorrhage in very low birth weight infants: a 15-year cohort study. J Pediatr (Rio J). 2011;87(6):505-11.

52. Neves C, Tufik S, Chediek F, Poyares D, Cintra F, Roizenblatt M, et al. Effects of sildenafil on autonomic nervous function during sleep in obstructive sleep apnea.

Clinics (Sao Paulo). 2010;65(4):393-400. http://dx.doi. org/10.1590/S1807-59322010000400008 53. Romano S, Salvaggio A, Lo Bue A, Marrone O, Insalaco G. A negative expiratory pressure test during wakefulness for evaluating the risk of obstructive sleep apnea in patients referred for sleep studies. Clinics (Sao Paulo). 2011;66(11):1887-94. http://dx.doi.org/10.1590/ S1807-59322011001100007 54. Reis MS, Arena R, Deus AP, Simões RP, Catai AM, Borghi-Silva A. Deep breathing heart rate variability is associated with respiratory muscle weakness in patients with chronic obstructive pulmonary disease. Clinics (Sao Paulo). 2010;65(4):369-75. http://dx.doi.org/10.1590/ S1807-59322010000400004 55. Silva KK, Lopes AJ, Jansen JM, de Melo PL. Total inspiratory and expiratory impedance in patients with severe chronic obstructive pulmonary disease. Clinics (Sao Paulo). 2011;66(12):2085-91. http://dx.doi.org/10.1590/ S1807-59322011001200014 56. Dong ZH, Yang ZG, Chen TW, Chu ZG, Deng W, Shao H. Thoracic Injuries in earthquake-related versus non-earthquake-related trauma patients: differentiation via Multi-detector Computed Tomography. Clinics (Sao Paulo). 2011;66(5):817-22. http://dx.doi.org/10.1590/ S1807-59322011000500018 57. Sincos IR, Aun R, Belczak SQ, Nascimento LD, Mioto Netto B, Casella I, et al. Endovascular and open repair for blunt aortic injury, treated in one clinical institution in Brazil: a case series. Clinics (Sao Paulo). 2011;66(2):267-74. http://dx.doi.org/10.1590/S1807-59322011000200015 58. Ranzani OT, Battaini LC, Moraes CE, Prada LF, Pinaffi JV, Giannini FP, et al. Outcomes and organ dysfunctions of critically ill patients with systemic lupus erythematosus and other systemic rheumatic diseases. Braz J Med Biol Res. 2011;44(11):1184-93. http://dx.doi.org/10.1590/ S0100-879X2011007500132 59. Barbalho-Moulim MC, Miguel GP, Forti EM, Campos Fdo A, Costa D. Effects of preoperative inspiratory muscle training in obese women undergoing open bariatric surgery: respiratory muscle strength, lung

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volumes, and diaphragmatic excursion. Clinics (Sao Paulo). 2011;66(10):1721-7. http://dx.doi.org/10.1590/ S1807-59322011001000009 60. Costantini TW, Deree J, Martins JO, Putnam JG, Campos T, Coimbra R. A novel fluid resuscitation strategy modulates pulmonary transcription factor activation in a murine model of hemorrhagic shock. Clinics (Sao Paulo). 2010;65(6):621-8. http://dx.doi.org/10.1590/ S1807-59322010000600010 61. Dogan OT, Elagoz S, Ozsahin SL, Epozturk K, Tuncer E, Akkurt I. Pulmonary toxicity of chronic exposure to tobacco and biomass smoke in rats. Clinics (Sao

Paulo). 2011;66(6):1081-7. http://dx.doi.org/10.1590/ S1807-59322011000600027 62. Otsuki DA, Fantoni DT, Holms C, Auler JO Jr. Minimum alveolar concentrations and hemodynamic effects of two different preparations of sevoflurane in pigs. Clinics (Sao Paulo). 2010;65(5):531-7. http://dx.doi.org/10.1590/ S1807-59322010000500011 63. Silva VF, Pazetti R, Soto Sde F, Siqueira MM, Correia AT, Jatene FB, et al. Effects of mycophenolate sodium on mucociliary clearance using a bronchial section and anastomosis rodent model. Clinics (Sao Paulo). 2011;66(8):1451-6. http://dx.doi.org/10.1590/ S1807-59322011000800024

About the authors Ariane Maris Gomes

Editorial Assistant. Clinics, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Daniela Aquemi Higa

Editorial Assistant. Clinics, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

J Bras Pneumol. 2012;38(5):634-642

Review Article Air pollution and the respiratory system* A poluição do ar e o sistema respiratório

Marcos Abdo Arbex, Ubiratan de Paula Santos, Lourdes Conceição Martins, Paulo Hilário Nascimento Saldiva, Luiz Alberto Amador Pereira, Alfésio Luis Ferreira Braga

Abstract Over the past 250 years—since the Industrial Revolution accelerated the process of pollutant emission, which, until then, had been limited to the domestic use of fuels (mineral and vegetal) and intermittent volcanic emissions—air pollution has been present in various scenarios. Today, approximately 50% of the people in the world live in cities and urban areas and are exposed to progressively higher levels of air pollutants. This is a non-systematic review on the different types and sources of air pollutants, as well as on the respiratory effects attributed to exposure to such contaminants. Aggravation of the symptoms of disease, together with increases in the demand for emergency treatment, the number of hospitalizations, and the number of deaths, can be attributed to particulate and gaseous pollutants, emitted by various sources. Chronic exposure to air pollutants not only causes decompensation of pre-existing diseases but also increases the number of new cases of asthma, COPD, and lung cancer, even in rural areas. Air pollutants now rival tobacco smoke as the leading risk factor for these diseases. We hope that we can impress upon pulmonologists and clinicians the relevance of investigating exposure to air pollutants and of recognizing this as a risk factor that should be taken into account in the adoption of best practices for the control of the acute decompensation of respiratory diseases and for maintenance treatment between exacerbations.

Keywords: Respiratory System; Air pollution; Pregnancy; Pulmonary disease, chronic obstructive; Asthma; Respiratory tract Infections.

Resumo A poluição atmosférica encontra-se presente nos mais diferentes cenários ao longo dos últimos 250 anos, desde que a Revolução Industrial acelerou o processo de emissão de poluentes que, até então, estava limitado ao uso doméstico de combustíveis vegetais e minerais e às emissões vulcânicas intermitentes. Hoje, aproximadamente 50% da população do planeta vivem em cidades e aglomerados urbanos e estão expostas a níveis progressivamente maiores de poluentes do ar. Este estudo é uma revisão não sistemática sobre os diferentes tipos e fontes de poluentes do ar e os efeitos respiratórios atribuídos à exposição a esses contaminantes. Podem ser creditados aos poluentes particulados e gasosos, emitidos por diferentes fontes, aumentos nos sintomas de doenças, na procura por atendimentos em serviços de emergência e no número de internações e de óbitos. Mais do que descompensar doenças pré-existentes, exposições crônicas têm ajudado a aumentar o número de casos novos de asma, de DPOC e de câncer de pulmão, tanto em áreas urbanas quanto em áreas rurais, fazendo com que os poluentes atmosféricos rivalizem com a fumaça do tabaco pelo papel de principal fator de risco para estas doenças. Na rotina de clínicos e pneumologistas, esperamos contribuir para consolidar a importância da investigação sobre a exposição aos poluentes do ar e o reconhecimento de que esse fator de risco merece ser levado em conta na adoção da melhor terapêutica para o controle das descompensações agudas das doenças respiratórias e para a sua manutenção entre as crises.

Descritores: Sistema respiratório; Poluição do ar; Gravidez; Doença pulmonar obstrutiva crônica; Asma; Infecções respiratórias.

* Study carried out at the Center for Environmental Epidemiology Studies, Air Pollution Laboratory, Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil.

Correspondence to: Marcos Abdo Arbex. Rua Dr. Arnaldo, 455, sala 1304, CEP 01246-903, São Paulo, SP, Brasil.

Tel. 55 11 3061-8530 or 55 16 9714-2882. Email: arbexma@techs.com.br Financial support: None.

Submitted: 23 July 2012. Accepted, after review: 22 August 2012.

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Introduction Although the effects of pollution had been described since antiquity, pollution began to have a major impact on the population with the advent of the Industrial Revolution. The rapid urbanization seen worldwide brought about a large increase in energy consumption and in pollutant emissions from stationary fossil fuel burning sources, such as industries, and from mobile sources, such as motor vehicles. Currently, approximately 50% of the people in the world live in cities and urban areas and are exposed to progressively higher levels of air pollutants.(1) The other half, especially in developing countries, uses solid fuels derived from biomass (wood, charcoal, dried animal dung, and agricultural residues) and, to a lesser extent, liquid fuels, as a source of energy for cooking, heating, and lighting.(1,2) Because of the large contact area between the surface of the respiratory system and the environment, air quality directly affects respiratory health. In addition, a significant quantity of inhaled pollutants reach the systemic circulation through the lungs and can cause deleterious effects on various organs and systems.(3) Global estimates suggest that external environmental pollution (outdoor pollution) causes 1.15 million deaths worldwide (corresponding to nearly 2% of the total number of deaths) and is responsible for 8.75 million disability-adjusted life years,(4) whereas pollution inside homes causes approximately 2 million premature deaths and results in 41 million disability-adjusted life years.

(5) For Brazil, the World Health Organization has estimated that air pollution causes nearly 20,000 deaths/year, a value that is five times as high as the estimated number of deaths from environmental/passive smoking, and that indoor air pollution leads to 10,700 deaths/year.(4,5)

Air pollution: sources, site of action, and pathophysiology Air pollution is a mixture of particles— particulate matter (PM)—and gases released into the atmosphere mainly by industries, motor vehicles, and thermoelectric power plants, as well as from biomass and fossil fuel burning.

Pollutants can be classified as primary or secondary.

Primary pollutants are released directly into the J Bras Pneumol. 2012;38(5):643-655

atmosphere, whereas secondary pollutants result from chemical reactions among primary pollutants.

The major primary pollutants monitored by the major environmental agencies in Brazil and worldwide are nitrogen oxides (NO2 or NOx), volatile organic compounds (VOCs), carbon monoxide (CO), and sulfur dioxide (SO2). One example of a secondary pollutant is ozone (O3), formed by the photo-oxidation-induced chemical reaction of VOCs and NO2 in the presence of ultraviolet rays from sunlight.(6,7) The most studied pollutant is PM, which can be primary or secondary. It varies in number, size, shape, surface area, and chemical composition depending on its place of production and its emission source. The deleterious effects of PM on human health depend on PM size and chemical composition. The multiple chemical components of PM include a core of elemental or organic carbon; inorganic compounds, such as sulfates and nitrates; transition metal oxides; soluble salts; organic compounds, such as polycyclic aromatic hydrocarbons; and biological materials, such as pollen, bacteria, spores, and animal remains. On the basis of total suspended particle size, PM is classified as follows: constituent particles of up to 30 µm in diameter; constituent particles of less than 10 µm in diameter (PM10 or inhalable fraction); constituent particles of less than 2.5 µm in diameter (PM2.5 or fine PM); and constituent particles of less than 10 nm in diameter (PM0.1 or ultrafine PM).(6,7) Chart 1 shows the major pollutants monitored by environmental protection agencies in urban areas, as well as their sources, their sites of action in the respiratory system, and their effects on human health.

How air pollutants affect the respiratory system Several mechanisms have been suggested to explain the adverse effects of air pollutants.

The most consistent and most widely accepted explanation is that, once in contact with the respiratory epithelium, high concentrations of oxidants and pro-oxidants in environmental pollutants such as PM of various sizes and compositions and in gases such as O3 and nitrogen oxides cause the formation of oxygen and nitrogen free radicals, which in turn induce oxidative stress in the airways. In other words, an increase in free radicals that are not neutralized

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Chart 1 - Major air pollutants, their sources, their sites of action in the respiratory system, and their effects on human health.

Pollutants TSP PM10

PM2.5 PM0.1 O3

Source

Penetration into the respiratory system

Anthropogenic sources: street Nose and throat dust; road dust; agricultural Trachea, bronchi, and activities; and construction bronchioles activities. Natural sources: sea salt; pollen; spores; fungi; and volcanic ash.

Burning of fossil fuels and biomass; thermoelectric power plants

Alveoli

Pathophysiology It impairs mucociliary and macrophage activity. It causes airway irritation.

It induces oxidative stress and, consequently, pulmonary and systemic inflammation. Chronic exposure causes bronchial remodeling and COPD. It can be carcinogenic.

Alveoli, lung tissue, and bloodstream

It is not emitted directly into Trachea, bronchi, the atmosphere. It is produced bronchioles, and by complex chemical reactions alveoli between volatile organic compounds (VOCs) and nitrogen oxides (NOx) in the presence of sunlight. Sunlight and temperature stimulate such reactions, so that, on hot sunny days, O3 concentrations peak.

The sources of VOC and NOx emissions are vehicles, chemical industries, laundries, and activities that use solvents.

It is a photochemical oxidant that is extremely irritating. It induces respiratory tract mucosal inflammation.

At high concentrations, it irritates the eyes, the nasal mucosa, and the oropharynx. It causes cough and chest discomfort. Exposure for several hours produces damage to the epithelium lining the airways. It induces inflammation and airway obstruction in the presence of stimuli such as cold and exercise.

NOx, NO2

Anthropogenic sources: nitric acid; Trachea, bronchi, sulfuric acid; and combustion bronchiole, and engine industries (major source); alveoli fuel burning at high temperatures, in thermal power plants that use gas or incineration. Natural sources: electrical discharges in the atmosphere.

An irritant. It affects the mucosa of the eyes, nose, throat, and lower respiratory tract. It increases bronchial reactivity and increases susceptibility to infections and allergens. It is considered a good marker of vehicular pollution.

SO2

Anthropogenic sources: petroleum Upper airways, refineries; diesel vehicles; furnaces; trachea, bronchi, and metallurgy; and papermaking. bronchioles Natural sources: volcanic activity.

An irritant. It affects the mucosa of the eyes, nose, throat, and respiratory tract. It causes cough and increases bronchial reactivity, facilitating bronchoconstriction.

CO

Anthropogenic sources: forest Alveoli and fires; incomplete combustion bloodstream of fossil fuels or other organic materials; and road transportation.

Urban areas with heavy traffic are the major contributing source of CO emissions.

It binds to hemoglobin, interfering with oxygen transport. It causes headache, nausea, and dizziness. It has a deleterious effect on the fetus.

It is associated with low birth weight neonates and fetal death.

Natural sources: volcanic eruptions and chlorophyll decomposition.

TSP: total suspended particles; PM: particulate matter; PM10: PM of less than10 µm in diameter; PM2.5: PM of less than 2.5 µm in diameter; and PM0.1: PM of less than 0.1 µm in diameter. Adapted from Kunzli et al.(6)

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by antioxidant defenses initiates an inflammatory response with release of inflammatory cells and mediators (cytokines, chemokines, and adhesion molecules) that reach the systemic circulation, leading to subclinical inflammation, which not only has a negative effect on the respiratory system but also causes systemic effects.(6,7)

Latency effects The effects of pollutants on health can be acute or chronic. Acute effects are manifest shortly after exposure (hours or days). Chronic effects are usually assessed in longitudinal studies over years or decades.(8) Chart 2 summarizes the acute and chronic effects of pollutants on the respiratory system.

Susceptible groups Children Children are highly susceptible to exposure to air pollutants. Minute ventilation is higher in children than in adults because children have higher basal metabolic rates and engage in more physical activity than do adults, as well as because children spend more time outdoors than do adults. On the basis of body weight, the volume of air passing through the airways of a child at rest is twice that of an adult under similar conditions. Pollutant-induced irritation producing a weak response in adults can result in significant obstruction in children. In addition, the fact that their immune system is not fully developed increases the possibility of respiratory infections.(6,7,9)

Elderly individuals Elderly individuals are susceptible to the adverse effects of exposure to air pollutants because they have a less efficient immune system (immunosenescence) and a progressive decline in pulmonary function that can lead to airway obstruction and exercise limitation.

There is decreased chest wall compliance and lung hyperinflation requiring additional energy expenditure to perform respiratory movements, as well as functional decline of organ systems.(10) J Bras Pneumol. 2012;38(5):643-655

Individuals with pre-existing chronic diseases The third most susceptible group, regardless of age, comprises individuals with pre-existing chronic diseases affecting mainly the respiratory system (asthma, COPD, and fibrosis) or the circulatory system (arrhythmias, hypertension, and ischemic heart diseases), as well as those with chronic diseases such as diabetes and collagen diseases.(3)

Genetic susceptibility The production of free radicals and the induction of inflammatory response by pollutants in the respiratory system can be neutralized by the antioxidant agents present in the aqueous layer lining the respiratory epithelium—glutathione S-transferase (GST), superoxide dismutase, catalase, tocopherol, ascorbic acid, and uric acid—which can prevent oxidative stress and represent the first line of defense against the adverse effects of pollutants.(11) Of the antioxidant agents present in the respiratory epithelium, GST is considered the most important(11) and is represented by three major classes of enzymes: GSTM1; GSTP1; and GSTT1.(11) Polymorphisms in genes encoding the enzymes of the GST family can change the expression or function of these enzymes in the lung tissue and result in different responses to inflammation and oxidative stress and, consequently, in increased susceptibility to the adverse effects of air pollutants.(11) Studies conducted in Mexico showed that children with asthma with a deletion polymorphism of genes encoding the GSTM1 and GSTP1 enzymes had increased susceptibility to O3 exposure, this increased susceptibility being characterized by an increase in biomarkers of nasal inflammation, reduced peak expiratory flow, and increased dyspnea.(12,13)

Effects of air pollution during pregnancy Exposure to air pollutants during pregnancy can impair fetal development and cause intrauterine growth retardation, prematurity, low birth weight, congenital anomalies, and, in cases that are more severe, intrauterine or perinatal death.(14) The biological mechanisms underlying the effects of air pollutants during pregnancy have yet to be fully elucidated. Extensive cell

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Chart 2 - Acute and chronic effects of pollutants on the respiratory system.

Effects of acute exposure (hours and days after increasing pollution) Increased mortality Symptom exacerbation in individuals with COPD or asthma Increased mortality from respiratory diseases Higher frequency of acute respiratory infections Increased number of hospitalizations for pneumonia Increased prevalence of symptoms and signs of eye, nose, and throat irritation Increased prevalence of acute respiratory symptoms (wheezing, cough, and expectoration) Need for increasing the dose of medication Acute changes in pulmonary function Increased number of medical visits, emergency room visits, and hospitalizations Higher rates of work and school absenteeism Effects of chronic exposure (years of chronic exposure) Increased mortality from respiratory diseases Increased incidence and prevalence of asthma and COPD Increased incidence of and mortality from lung cancer Increased incidence of and mortality from pneumonia and influenza Chronic changes in pulmonary function Chronic reduction in FEV1 and FVC Impaired lung development in children and youths Increased prevalence of below-normal FEV1 Increased rate of decline in FEV1 Other effects Low birth weight Preterm delivery Changes in the cognitive development of children Adapted from Kunzli et al.(6)

proliferation, physiological immaturity, accelerated organ development, and changes in metabolism increase fetal susceptibility to maternal inhalation of air pollutants, and the maternal respiratory system can, in turn, be compromised by the action of pollutants, thereby affecting placental transport of oxygen and glucose.(15) In addition, pollutants can affect maternal blood coagulation because of an inflammatory response resulting from oxidative stress, increasing the possibility of placental infarction and chronic villitis.(16) A meta-analysis of studies published between 1994 and 2003 revealed that a 10-µg/m3 increase in PM10 exposure was associated with a 5% increase in postnatal mortality from all causes and a 22% increase in mortality from respiratory diseases.(17) A study conducted in São Paulo, Brazil, revealed that a 1-µg/m3 increase in PM10 concentration and a 1-ppm increase in CO concentration were associated with a 0.6-g and a 12-g reduction in birth weight, respectively.(18) A study conducted in California, USA, and evaluating 81,186 births found an increased risk of maternal preeclampsia

and fetal prematurity associated with higher levels of traffic-generated NOx and PM2.5.(19)

Effects of pollutants on the respiratory system Effects on respiratory symptoms Epidemiological studies have shown that exposure to gaseous pollutants and PM is associated with a higher incidence of upper airway symptoms, such as rhinorrhea, nasal obstruction, cough, laryngospasm, and vocal fold dysfunction,(20) and lower airway symptoms, such as cough, dyspnea, and wheezing, especially in children.(21) This exposure is also associated with an increase in cough and wheezing in adults with chronic lung disease and in healthy adults.(21)

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population, as well as being an early, objective, and quantitative predictor of cardiorespiratory morbidity and mortality. Studies have demonstrated the acute and chronic effects of pollutants on pulmonary function in children, adolescents, healthy adults, and individuals with a history of respiratory disease.(6,7)

Effects associated with acute exposure Chang et al.(22) investigated the effects of variations in daily concentrations of PM10, SO2, CO, and NO2 on the pulmonary function of 2,919 students in the 12-16 year age bracket in the city of Taipei, Taiwan. A 1-ppm increase in CO concentration was associated with a 69.8-mL reduction in FVC (95% CI: −115.0 to −24.4) and a 73.7-mL reduction in FEV1 (95% CI: −118.0 to −29.7), with a 1-day lag effect. A 1-ppb increase in SO2 concentration was associated with a 12.9-mL reduction in FVC (95% CI: −20.7 to −5.1) and an 11.7-mL reduction in FEV1 (95% CI: −19.3 to −4.2), also with a 1-day lag effect. Variations in O3 and PM10 concentrations showed a small but significant negative association with FVC and FEV1 on the day of exposure.

A study conducted in London, England, compared pulmonary function parameters in 60 adults with mild or moderate asthma on two different occasions: after a two-hour walk along Oxford Street, the city’s main commercial corridor, where only diesel-powered buses and taxis are allowed; and after a two-hour walk through Hyde Park (a city park). At the time of the study, PM2.5 and NO2 levels were, respectively, 3.0 and 6.5 times higher on Oxford Street than in Hyde Park. There was a 6.1% reduction in FEV1 (p = 0.04) and a 5.4% reduction in FVC (p = 0.001) after exposure on Oxford Street in relation to exposure in Hyde Park.(23)

Effects associated with chronic exposure Gauderman et al. conducted a prospective study following 1,759 children in the 10-18 year age bracket in 12 communities in California, USA, with different levels of NO2, acid vapor, PM2.5, and elemental carbon. After controlling for confounding factors, the authors found that children residing in areas with higher environmental levels of PM showed a significant decline in FEV1 (of approximately 100 mL) when compared J Bras Pneumol. 2012;38(5):643-655

with those residing in less polluted areas. The effects were significant even in children without bronchial asthma. The proportion of children with an FEV1 < 80% at age 18 years was five times higher in more polluted communities than in less polluted communities (mean PM2.5 concentrations of 29.0 µg/m3 and 6.0 µg/m3, respectively).(24) Those same authors investigated pulmonary function in 3,677 individuals, who were followed over an 8-year period (between ages 10 and 18 years) and who lived within 500 m or 1,500 m of a high-traffic road. At age 18 years, the adolescents living closer to the high-traffic road showed an 81.0-mL deficit in FEV1 and a 127.0-mL/s deficit in FEF25-75% when compared with those living farther away.(25) A cross-sectional study conducted in Germany evaluated 2,593 women (mean age, 54.5 years) in 7 communities. Levels of NO2 and PM10 showed significant negative associations with FEV1, FVC, and FEV1/FVC. An annual increase of 7.0 µg/m3 in PM10 was associated with a 5.0% reduction in FEV1 and a 1.0% reduction in FEV1/FVC, and, for an annual increase of 16.0% in NO2, there was a 4.0% reduction in FEV1 and a 1.0% reduction in FEV1/FVC.(26) A prospective study conducted in Switzerland evaluated 4,742 adults in the 18-60 year age bracket in 8 communities over an 11-year period.

Over the study period, there was a mean drop of 5.3 μg/m3 in PM10 levels. A 10-μg/m3 decline in the mean annual PM10 concentration was associated with statistically significant reductions in the annual rates of decline in FEV1 (of 9%), FEF25-75% (of 16%), and FEV1/FVC (of 6%).(27)

Pollution and bronchial asthma Epidemiological and toxicological studies have demonstrated the association between air pollution and bronchial asthma.(21) Air pollutants are associated with an increase in the number of emergency room visits and hospitalizations for acute asthma attacks, as well as with an increase in expiratory wheezing, respiratory symptoms, and use of rescue medication.(21) The prevalence of bronchial asthma has increased worldwide, especially in highly industrialized urban areas. Prospective studies suggest that exposure to air pollutants can lead to the development of new cases of asthma.

One example of this is the large increase in the incidence of asthma in China after the recent

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industrial development and, consequently, the large increase in the concentration of pollutants.(28)

Effects associated with acute exposure In Athens, Greece, one group of researchers investigated the acute effects of PM10 and SO2 exposure on the number of emergency room visits by children and adolescents in the 0-14 year age bracket between 2001 and 2004. A 10-μg/m3 increase in PM10 and SO2 levels was associated with a 2.2% increase (95% CI: 0.1-5.1) and a 6.0% increase (95% CI: 0.9-11.3), respectively, in the number of asthma-related visits.(29) A study involving children and adolescents in the 0-18 year age bracket and conducted in Copenhagen, Denmark, between 2001 and 2008, revealed an increase in the number of asthmarelated hospitalizations due to increased levels of NOx (OR = 1.11; 95% CI: 1.05-1.17), NO2 (OR = 1.10; 95% CI: 1.04-1.16), PM10 (OR = 1.07; 95% CI: 1.03-1.12), and PM2.5 (OR = 1.09; 95% CI: 1.04-1.13).(30) An association between increased pollutant levels and hospitalizations for asthma has been observed in the city of Araraquara, located in the center of the sugarcane-producing area of the state of São Paulo, Brazil. During the harvest period, when sugarcane straw burning is the largest pollutant emission source, the number of hospitalizations for asthma was 50% higher than was that during the period when there is no burning (p < 0.001). A 10-µg/m3 increase in the concentrations of PM of up to 30 µm in diameter was associated with an 11.6% increase in the number of hospitalizations (95% CI: 5.4-17.7), with a 1-day lag effect.(31) A study conducted in the city of Rio Branco, Brazil, showed that, in the forest biomass burning season, the number of asthma-related visits among children under 10 years of age increased in parallel with the increase in PM2.5 concentrations measured in the city.(32) During the Olympic Games in Atlanta, USA, measures to reduce urban pollution were implemented. During the three weeks of games, traffic counts dropped around 22%. Peak daily levels of O3, NO2, CO, and PM10 decreased 28%, 7%, 19%, and 17%, respectively, in comparison with the three weeks before and the three weeks after the Games. There was a 40% reduction in the number of consultations for asthma among children and an 11-19% decline in the number

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of asthma-related visits to the emergency rooms of the city among individuals of all ages.(33) During the Olympic Games in Beijing, PM2.5 and O3 concentrations decreased from 78.8 µg/m3 to 46.7 µg/m3 and from 65.8 ppb to 61 ppb, respectively, and the number of asthma-related emergency rooms visits decreased by 41.6%.(34)

Effects associated with chronic exposure In a prospective study conducted in 12 communities with different O3 levels in California, USA, 3,535 schoolchildren with no history of asthma were followed over a 5-year period. In the follow-up period, 265 children developed asthma. In communities with high O3 concentrations, the risk of developing asthma was 3.3 times higher (95% CI: 1.9-5.8) in children who played three or more sports than in those who did not play any sports. In areas with low O3 concentrations, the number of sports played was not a risk factor for the development of asthma.

The same was true for time spent outdoors, which was shown to be a direct risk factor for the development of asthma only in areas with high O3 concentrations.(35) Ghering et al. followed the first 8 years of life of 3,863 children in communities in the north, west, and center of the Netherlands. At age 8 years, the children underwent allergy testing and bronchial hyperresponsiveness testing. Levels of PM2.5 were associated with a 28% increase in the incidence of asthma, a 29% increase in the prevalence of asthma, and a 15% increase in asthma symptoms.(36) In Munich, Germany, 2,860 children were followed from birth to age 4 years and 3,061 were followed to age 6 years. The authors categorized residential distance to a main road as follows: < 50 m; 50-250 m; 250-1,000 m; and > 1,000 m. The study showed significant inverse associations between residential distance to a main road and the outcomes analyzed.

Among those living less than 50 m from a main road, the highest ORs were for asthma (OR = 1.6; 95% CI: 1.03-2.37), hay fever (OR = 1.6; 95% CI: 1.1-2.3), and allergic sensitization to pollen (OR = 1.4; 95% CI: 1.2-1.6).(37) A cohort study conducted in Switzerland between 1991 and 2002 and evaluating 2,725 nonsmoking adults in the 18-60 year age bracket showed that those living in more polluted J Bras Pneumol. 2012;38(5):643-655

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areas were at a higher risk of developing asthma (a 30% increase in risk for every 1-µg/m3 increase in the concentration of traffic-generated PM10).(38)

Pollution and COPD Patients with COPD are particularly vulnerable to additional stress on the airways caused by aggressive agents. Smoking is recognized as the most important factor for the development of COPD, especially in developed countries. However, over the last 10 years, an increasing number of studies have suggested that there are risk factors other than smoking in the genesis of COPD. These factors include exposure to indoor and outdoor air pollutants, occupational exposure to dust and fumes, history of recurrent respiratory infections in childhood, history of pulmonary tuberculosis, chronic asthma, intrauterine growth retardation, poor nutrition, and low socioeconomic status.(1) Exposure to air pollution is associated with an increase in respiratory morbidity from COPD, including an increase in respiratory symptoms and a decrease in pulmonary function, as well as being a common cause of exacerbations leading to emergency room visits or hospitalizations.(39) Indoor biomass burning is a significant cause of COPD in nonsmoking women who are exposed to high concentrations of pollutants during cooking activities, especially in rural areas of developing countries, and this significantly contributes to the global increase in the disease.(1,2) While women with COPD caused by smoking have emphysema and goblet cell metaplasia more commonly than do those exposed to biomass burning, the latter group has more severe interlobular septal thickening, more pigment deposition in the lung parenchyma, more small airway fibrosis, and more severe intimal thickening of the pulmonary artery.(39)

Effects associated with acute exposure An ecological study conducted in Hong Kong, China, investigated the association between air pollutants and hospitalizations for COPD between 2000 and 2004. Significant associations were observed between hospitalizations for COPD and levels of pollutants. The relative risk (RR) of hospitalization for every 10-µg/m3 increase in SO2, NO2, O3, PM10, and PM2.5 concentrations was, respectively, 1.007, 1.026, 1.040, 1.024, and 1.031. The effect started on the day of exposure and lasted until the fifth day, as well J Bras Pneumol. 2012;38(5):643-655

as being more pronounced in the winter than in the summer.(40) A study conducted between 1986 and 1999 and involving 36 American cities showed that a 5-ppb increase in O3 levels and a 10-µg/m3 increase in PM10 levels were associated with an increase of 0.27% (95% CI: 0.1-0.5) and 1.5% (95% CI: 0.9-2.0), respectively, in the number of hospitalizations for COPD. Use of central air conditioning was found to reduce the adverse effects of air pollution.(41) A study conducted between 2001 and 2003 in city of São Paulo, Brazil, and evaluating 1,769 patients over 40 years of age showed that an increase in the number of COPD-related emergency room visits was associated with increases in air concentrations of PM10 and SO2. Variations in PM10 and SO2 concentrations (28.2 µg/m3 and 7.8 µg/m3, respectively) were associated with a cumulative 6-day increase of 19% and 16% in COPD admissions, respectively. A 10-µg/m3 increase in PM10 concentration was associated with a 6.7% increase in the number of visits on the day of exposure.(42)

Effects of chronic exposure Schikowski et al. followed 4,757 women in the 54-55 year age bracket in Germany, using diagnostic criteria for COPD established by the Global Initiative for Chronic Obstructive Lung Disease. The prevalence of COPD (stages I-IV) was found to be 4.5 %. A 7-µg/m3 increase in the 5-year mean PM10 concentration was associated with a 1.33 OR (95% CI: 1.03-1.72) for the development of COPD and a 5.1% decline in FEV1 (95% CI: 2.5-7.7). Women living less that 100 m from a high-traffic road were at a higher risk of developing COPD than were those living farther away (OR = 1.8; 95% CI: 1.1-3.0).(26) Those authors suggest that chronic exposure to traffic-generated PM10 increases the risk of developing COPD and accelerates pulmonary function loss.

A study conducted in Denmark followed 57,053 individuals between 1993 and 2004 and showed that 1,786 (3.4%) developed COPD. The authors found a positive association between COPD and exposure to traffic-generated pollutants after controlling for confounding factors, including smoking. The incidence of COPD was associated with the 35-year NO2 mean

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concentration (RR = 1.08; 95% CI: 1.02-1.14 for an interquartile range of 5.8 µg/m3).(43) A meta-analysis of 15 studies showed that individuals exposed to biomass burning have a 2.4 higher OR (95% CI: 1.9-3.3) for the development of COPD than do those who were not exposed.(44) A recent meta-analysis of 25 studies showed that the risk in women exposed to biomass burning is similar to that in women who used another type of fuel (OR = 2.4; 95% CI: 1.5-9.9).(2) In a meta-analysis, Kurmi et al. showed a positive association of use of solid fuel with COPD (OR = 2.8; 95% CI: 1.8-4.0) and chronic bronchitis (OR = 2.3; 95% CI: 1.9-2.8) when compared with use of other types of fuels.(45) The risk is similar to that reported for smokers who developed COPD (OR = 2.5) and is higher than that for individuals who developed COPD because of passive smoking or alpha-1 antitrypsin deficiency. On the basis of a comparison of the 1.1 billion smokers with the 3 billion individuals exposed to high concentrations of pollutants generated by solid fuel burning, Kodgule & Salvi hypothesized that the latter exposure is a more significant risk factor for the development of COPD.(46)

Pollution and acute respiratory infection Acute lower respiratory tract infection is the leading cause of death in children up to 5 years of age. In this age group, this type of infection causes 2 million deaths per year.

Half of such deaths are attributed to indoor exposure to pollutants from solid fuel burning.

(46) A meta-analysis of 24 studies showed that indoor exposure to biomass burning increases the risk of pneumonia in children (OR = 1.8; 95% CI: 1.5-2.1).(47) Similarly, a recent meta-analysis of 25 studies found a significant and robust association between indoor biomass burning and acute respiratory infection in children (OR = 3.5; 95% CI: 1.9-6.4).(2)

Effects associated with acute exposure Host et al. investigated the association of PM10 and PM2.5 concentrations with hospitalization for respiratory infection in 6 French cities between 2000 and 2003. The excess RR of hospitalization for respiratory infection for every 10-µg/m3 increase in PM10 and PM2.5 concentrations was 4.4%

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(95% CI: 0.9-8.0) and 2.5% (95% CI: 0.1-4.8), respectively. Children under 15 years of age constituted the most susceptible age group.(48) Belleudi et al. investigated the effects of PM on the number of hospitalizations for pneumonia among individuals over 35 years of age admitted to any of five Roman hospitals between 2001 and 2005. A 10-µg/m3 increase in PM2.5 concentration was associated with a 2.8% increase in the number of hospitalizations for pneumonia, with a 2-day lag effect.(49) Medina-Ramón et al., in a study conducted between 1986 and 1999 and involving 36 American cities, showed that, during the hottest period, a cumulative 2-day increase of 5 ppb in O3 concentration was associated with a 0.41% increase (95% CI: 0.26-0.57) in the number of hospitalizations for pneumonia. Similarly, a 10-µg/m3 increase in PM10 concentration was associated with a 0.8% increase in the number of hospitalizations for pneumonia on the day of exposure (95% CI: 0.5-1.2).(41)

Effects associated with chronic exposure Between 2003 and 2005, Neupane et al. conducted a case-control study in Canada in which they investigated long-term exposure to NO2, PM2.5, and SO2 and the risk of hospitalization for pneumonia in individuals over 65 years of age. They evaluated 365 elderly individuals with radiologically confirmed community-acquired pneumonia and 494 controls. The groups were compared on the basis of individual exposure to NO2, PM2.5, and SO2 in the previous year.

Long-term (≥ 1-year) exposure to high levels of NO2 and PM2.5 was significantly associated with hospitalization for community-acquired pneumonia.(50) A cohort study conducted in the USA showed that a 10-µg/m³ increase in PM2.5 concentration was associated with a 20% increase in the risk of death from pneumonia and influenza in nonsmokers.(51)

Pollution and lung cancer The World Health Organization estimates that, in 2008, there were 12.7 million new cases of cancer that caused 7.6 million deaths worldwide, the number of new cases of lung cancer and the number of deaths from lung J Bras Pneumol. 2012;38(5):643-655

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cancer being 1.61 million and 1.18 million, respectively.(52) Studies have shown the effects of exposure to pollutants and the development of lung cancer, which is attributed to the direct action of carcinogens present in pollution and to the chronic inflammation induced by such carcinogens.(7,53) A prospective study involving 500,000 adults in 50 states in the USA(54) showed that a 14% increase in the incidence of lung cancer was associated with a 10-μg/m3 in PM2.5 concentration.

In a study conducted in European countries, 5% and 7% of the various types of lung cancer in nonsmokers and former smokers, respectively, were attributed to the effects of pollution.(55) An analysis of several cohort and case-control studies suggested that, on average, chronic exposure to air pollution increases the risk of lung cancer incidence by 20-30%.(7,56)

Air pollution and mortality In a review of studies conducted in various countries and investigating the effects of acute changes in pollution levels, it was suggested that a 0.4-1.3% increase in the RR of death is associated with a 10-µg/m3 increase in PM2.5 levels or a 20-µg/m3 increase in PM10 levels.(57) The largest impact on mortality occurs among children under 5 years of age (RR = 1.6%) and among elderly individuals (RR = 2.0%), for every 10-µg/m3 increase in PM10 concentration.(57) In the USA, the most relevant studies on the chronic effects of air pollution on mortality have estimated a 6-17% increase in cardiopulmonary mortality for a 10-µg/m³ increase in PM2.5 levels.(57)

Effects of air pollution on exercise Air pollution and physical exercise - risks and benefits During aerobic exercise, the inhaled air enters the airways mostly through the mouth and minute volume and diffusing capacity increase, facilitating the penetration of pollutants.(58) The quantity of ultrafine particles deposited in the respiratory tract is nearly five times higher during moderate exercise than at rest and increases as particle size decreases.(59) Exercising near a high-traffic road increases carboxyhemoglobin levels (a 30-min run can increase carboxyhemoglobin levels to levels J Bras Pneumol. 2012;38(5):643-655

equivalent to those resulting from smoking 10 cigarettes/day) and reduces aerobic performance in athletes.(58) Although the major recommendations of sports medicine societies do not include precautions against exercising in polluted environments, a recent statement from the American Heart Association(3) on the effects of pollution recommends that intensive exercise be avoided when air quality is unsatisfactory.

A recent review(60) investigating the effects of pollution on athlete performance concluded that exercising in environments with high levels of pollutants sharply reduces pulmonary and vascular function in individuals with asthma and in healthy individuals, and that long-term exercise in polluted environments is associated with reduced pulmonary function and can induce vascular dysfunction, probably due to systemic and airway oxidative stress, leading to reduced exercise performance. In brief, it is recommended that susceptible individuals (those with asthma, those with COPD, patients with cardiovascular disease, elderly individuals, and children) avoid exercising when air quality is poor.

Final considerations Exposure to air pollutants poses a risk to human health as early as in intrauterine life.

Health professionals should recognize the importance of the effects of pollutants in clinical practice and properly assess the exposure profile of patients at home, in the workplace, and in the region of residence. If it is not possible to reduce the emission of pollutants in the short or medium term, it is perfectly possible to counsel patients regarding the adoption of preventive measures to reduce the effects of indoor and outdoor pollutants, reducing the adverse effects associated with this exposure. In addition, physicians should, as appropriate, not only make adjustments to the standard treatment when increases in air pollutant concentrations can aggravate pre-existing diseases but also, as citizens, use their knowledge to promote the adoption of measures to reduce pollutant levels in urban and rural areas.

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About the authors Marcos Abdo Arbex

Senior Researcher. Center for Environmental Epidemiology Studies, Air Pollution Laboratory, Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil; and Professor of Pulmonology. Centro Universitário de Araraquara – Uniara, Araraquara University Center – School of Medicine, Araraquara, Brazil.

Ubiratan de Paula Santos

Senior Researcher. Center for Environmental Epidemiology Studies, Air Pollution Laboratory, Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil.

Lourdes Conceição Martins

Senior Researcher. Center for Environmental Epidemiology Studies, Air Pollution Laboratory, Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil; and Assistant Professor. Graduate Program in Public Health, Universidade Católica de Santos – UNISANTOS, Catholic University of Santos – Santos, Brazil.

Paulo Hilário Nascimento Saldiva

Full Professor. Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil.

Luiz Alberto Amador Pereira

Senior Researcher. Center for Environmental Epidemiology Studies, Air Pollution Laboratory, Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil; and Assistant Professor. Graduate Program in Public Health, Universidade Católica de Santos – UNISANTOS, Catholic University of Santos – Santos, Brazil.

Alfésio Luis Ferreira Braga

Senior Researcher. Center for Environmental Epidemiology Studies, Air Pollution Laboratory, Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil; and Assistant Professor. Graduate Program in Public Health, Universidade Católica de Santos – UNISANTOS, Catholic University of Santos – Santos, Brazil.

J Bras Pneumol. 2012;38(5):643-655

Review Article The chest and aging: radiological findings* O tórax e o envelhecimento: manifestações radiológicas

Bruno Hochhegger, Gustavo Pontes de Meireles, Klaus Irion, Gláucia Zanetti, Eduardo Garcia, José Moreira, Edson Marchiori

Abstract In the elderly (conventionally defined as individuals ≥ 60 years of age), it is often difficult to establish what normality is, because of the numerous anatomical and physiological modifications that occur during the aging process. As a result, the greatest challenge is to differentiate between the normal aging process and the onset of disease. Healthy elderly people commonly present borderline findings on chest imaging. We systematically reviewed the medical literature on the subject, covering the period between 1950 and 2011, including articles in Portuguese, English, French, Italian, and Spanish. We searched the PubMed, LILACS, and SciELO databases, using the search terms “age”, “aging”, “lung”, “thorax”, “chest”, “X-ray”, “radiography”, “pulmonary”, and “computed tomography”—as well as their corresponding translations—in various combinations. We included only original or review articles on aging-related chest imaging findings. In broad terms, aging results in physiological modifications that must be recognized so as not to be erroneously interpreted as pathological.

Keywords: Aging; Thorax; Lung; Diagnostic imaging.

Resumo Nos idosos (convencionalmente definidos como indivíduos com idade ≥ de 60 anos), é muitas vezes difícil estabelecer o que é normal devido a inúmeras modificações anatômicas e fisiológicas que ocorrem durante o processo de envelhecimento. Como resultado, o principal problema consiste em diferenciar o ponto em que o envelhecimento é normal daquele no qual a doença começa. Os achados radiológicos do tórax de pessoas idosas sadias são comumente limítrofes. Revisamos sistematicamente a literatura médica sobre o assunto, abrangendo o período entre 1950 e 2011, incluindo artigos em português, inglês, francês, italiano e espanhol. A busca foi feita através das bases de dados PubMed, LILACS e SciELO, utilizando os seguintes termos: age, aging, lung, thorax, chest, X-ray, radiography, pulmonary, computed tomography e suas traduções correspondentes, em combinações variadas. Os critérios de inclusão foram artigos originais e de revisão de achados radiológicos no tórax relacionados ao envelhecimento. Em linhas gerais, o envelhecimento resulta em modificações fisiológicas que devem ser reconhecidas de forma a não serem erroneamente interpretadas como patologias.

Descritores: Envelhecimento; Tórax; Pulmão; Diagnóstico por imagem.

Introduction With increasing frequency, imaging tests are performed in elderly patients; this is due to a progressive increase in life expectancy, which in turn is due to improved living conditions and medical advances.(1,2) In the elderly, it is often difficult to establish what normality is, or rather, what changes are consistent with the aging process. This is due to the numerous anatomical and physiological changes that occur during the aging process. In clinical practice, the challenge

is to determine the extent to which the changes found in elderly individuals are due to the aging process.(3) The objective of the present review was to describe the most common aging-related chest imaging findings.

We conducted a systematic review of the medical literature on the subject, covering the period between 1950 and 2011 and including articles in Portuguese, English, French, Italian, and Spanish. We search the PubMed, LILACS,

* Study carried out at the Pereira Filho Medical Center, Santa Casa Hospital Complex in Porto Alegre, Porto Alegre, Brazil.

Correspondence to: Bruno Hochhegger. Rua João Alfredo, 558/301, Cidade Baixa, CEP 90050-230, Porto Alegre, RS, Brasil.

Tel. 55 51 3314-3665 E-mail: brunohochhegger@gmail.com Financial support: None.

Submitted: 15 August 2011. Accepted, after review: 5 September 2012.

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The chest and aging: radiological findings

and SciELO databases for relevant references, using the search terms “age”, “aging”, “lung”, “thorax”, “chest”, “X-ray”, “radiography”, “pulmonary”, and “computed tomography”— as well as their corresponding translations—in various combinations. In addition, review articles on the subject were hand searched for articles for inclusion in the present review, as were the references in all of the articles that were considered relevant. We included original or review articles on aging-related chest imaging findings. We found 152 articles. Of those, 12 were selected by reading the abstract. In addition to the articles on aging-related chest imaging findings, we included 39 articles on clinical, pathological, and functional aspects in order to underpin the discussion.

The imaging findings were didactically divided into three major groups: findings in the chest wall; findings in the mediastinum; and findings in the lung parenchyma.

Aging-related changes in radiological findings in the chest wall One of the most common imaging findings in the aging chest wall is a reduction in the thickness of the parietal muscles, particularly when compared with that of those in younger individuals, a change that can be easily seen on CT scans (Figure 1). This reduction is one of the major causes of increased pulmonary transparency on chest X-rays in the elderly. Although no

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studies have established the age at which this finding is first seen, this is known to be due to aging-related muscle mass loss, becoming more pronounced with age.(4-10) However, there are no objective criteria for the diagnosis of this imaging finding. Another common finding is costal cartilage calcification, which is seen as small islands of compact bone tissue or as nodules, being mistaken for solitary pulmonary nodules in some cases.(3) The spinal column is another site where age-related degenerative changes are common. The main changes are osteoporosis and spondylosis.

The term spondylosis refers to degenerative changes of the spinal column, including reduced intervertebral space, bone sclerosis adjacent to the intervertebral discs, and marginal vertebral osteophytes. In general, vertebral osteophytes are more commonly seen on the right side of the spinal column, which is due to the presence of the descending aorta on the left side. The association of pronounced dorsal kyphosis with a more convex sternum contributes to the so-called “barrel chest” deformity, a phenotypic configuration of the chest in elderly individuals.

When combined, these parietal changes cause stiffening of the chest wall, having an unfavorable impact on respiratory mechanics.(11-13) Barrel chest is an imaging finding that is typically (but not exclusively) seen in elderly individuals. The differential diagnosis should be made primarily with COPD. The diagnosis of COPD should be based on other findings, such as pulmonary emphysema, bronchial wall

Figure 1 - CT Images. In A, a 25-year-old individual, and in B, an 86-year-old individual. Note the difference between the two in terms of the thickness of the parietal muscles. Note also the liposubstitution (hypodense areas) of the longissimus thoracis in B (arrows).

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thickening, and bronchiectasis.(14,15) In patients with COPD, age is a factor that certainly contributes to disease progression. However, the individual roles of age and COPD in barrel chest cannot be determined by imaging tests.

Common imaging findings in the elderly include diaphragmatic bulging due to muscle hypertrophy and dyskinesia in some areas, particularly on the right side, probably caused by the effort of the hemidiaphragm to maintain the anatomical relationship between the lung and the liver.(11,13)

Aging-related changes in radiological findings in the mediastinum Approximately 10% of the elderly population presents with changes that are exclusively related to cardiac aging. This select group of individuals is characterized by the exclusive presence of primary findings of cardiac aging, i.e., radiological findings that are not related to common comorbidities in this age group (arterial hypertension, COPD, atherosclerosis, diabetes, and renal failure).(16,17) The most common physiological change related to cardiovascular aging is diastolic dysfunction, which is due to increased left ventricular muscle

mass (due to hypertrophy) and age-related changes in the elastic properties of the myocardium.(18,19) The principal radiological features of the “aging heart” include increased myocardial muscle mass and thickness (in particular, increased left ventricular muscle mass) due to myocyte hypertrophy and increased connective tissue matrix (Figure 2); marginal thickening of the heart valves (commonly the mitral and aortic valves) due to fat, collagen, and calcium salt deposition, causing wear of the valve annulus and, consequently, mild heart valve regurgitation in 90% of healthy patients over 80 years of age; and coronary sclerosis, possibly leading to changes in myocardial perfusion.(16,17,20-23) Although most of these changes have no clinical significance in healthy patients, they can contribute to decompensation in cases of cardiac overload due to external factors, such as infectious processes.

In most cases, the signs of right heart overload are due to increased pulmonary capillary resistance (as occurs in COPD and mitral valve dysfunction) and generally have a pathological basis; in contrast, the signs of left heart overload (left ventricular hypertrophy) are exclusively associated with cardiac aging in some cases.(22)

Figure 2 - Cardiac CT scan. In A, reconstruction of an aortic valve during systole, showing thickening of the valve leaflets in an 88-year-old patient with no history of cardiovascular disease. Valve leaflet thickening is a finding that is considered to be characteristic of normal cardiovascular aging. In B, three-dimensional reconstruction of these findings.

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Changes in the aorta include elongation and dilation, which are the major factors responsible for the chest X-ray finding of upper mediastinal enlargement in the elderly. In most patients, parietal calcifications of the aorta are most commonly seen in the aortic arch and in the descending portion of the aorta, constituting nonspecific radiological findings. However, in elderly individuals, calcification of the thoracic aorta, heart valves, and coronary arteries indicates a higher risk of cardiovascular diseases.(3,22,23)

Aging-related changes in radiological findings in the lung parenchyma During the first two decades of life, the lungs grow and mature. The maximum number of alveoli is reached at approximately 10-12 years of age, and maturation of the respiratory system occurs at approximately 20 years of age in females and at approximately 25 years of age in males.

Decreased lung function is due to imbalances triggered by changes in the ventilation/perfusion ratio in patients at a more advanced age; however, together, these changes account for less than 3% of the total cardiac output, leading to a minimal (6-mmHg) decrease in PaO2 and having no clinical significance unless pulmonary function is affected by an underlying disease.(24-30) One of the major aging-related physiological changes is decreased lung compliance. The two components of the elastic properties of the lung are surface and tissue forces.(31) There is no evidence that the surface-active lining of terminal respiratory units changes its basic mechanical behavior with age. No changes in the quality or quantity of alveolar surfactant have been described, and there is no evidence of changes in type II pneumocyte function.(32) However, changes in the lung parenchyma and chest wall are functionally significant.

Chest wall compliance decreases with age, which is principally due to musculoskeletal limitations, such as vertebral fractures, spondylosis, and progressive loss of respiratory muscle strength.

(31,32) Lung parenchymal compliance normally decreases with age.(33,34) These changes are generally attributed to changes in lung connective tissue.

However, biochemical studies have suggested that the total collagen and elastin content of the lung does not change with age.(35) Rather,

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collagen becomes more stable because of an increase in the number of intermolecular crosslinks. The most widely accepted hypothesis is that lung elastic recoil is lost because of changes in the spatial arrangement of the network of collagen fibers or because of a protein known as pseudoelastin.(31) Studies of the senescence-accelerated mouse have shown remarkably increased alveolar duct size during the aging process. Enlarged terminal air spaces have also been reported, having been characterized as a relatively homogeneous destruction, with few cellular infiltrates in the alveoli, suggesting that, unlike what occurs in emphysema, air space enlargement was not due to inflammation of the lung parenchyma.(36,37) Turner et al.(34) found that the ratio of lung weight to body weight does not decrease with age in individuals in the 20-60 year age bracket, a finding that suggests little or no lung destruction, or tissue replacement.(34,36,37) During the aging process, the alveolar ducts increase in diameter and the alveoli become larger and shallower.

After the fourth decade of life, part of the elastic fibers in the respiratory bronchioles and alveoli degenerate, their complacency therefore decreasing.(38) These changes are more pronounced around the alveolar ducts. Consequently, there is alveolar duct dilatation, followed by air space enlargement.(32) This enlargement is remarkably homogeneous, unlike the irregular distribution of air space enlargement in emphysema (Figures 3 and 4).

Morphometric studies have shown a progressive increase in the average distance between air space walls, as well as a decrease in the surface area of air space wall per unit of lung volume.

(34,39,40) These changes begin in the third decade of life and progress linearly and continuously, resulting in a 25-30% decrease in the surface area of air space wall per unit of lung volume in nonagenarians.(39,40) Although these changes are histologically different from those seen in pulmonary emphysema, in which there is destruction of the alveolar walls, they result in similar changes in lung compliance. As occurs with pulmonary emphysema, these changes cause a reduction in the supporting tissues around the airways, where there is a trend toward collapse of small (< 2-mm) airways and, consequently, changes in airflow. These morphostructural changes in the lung parenchyma constitute an agingJ Bras Pneumol. 2012;38(5):656-665

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Figure 3 - Three-dimensional CT scan showing (in A) areas of increased small airway volume, known as senile emphysema (blue areas), in an 85-year-old patient. Note the homogeneous distribution of emphysematous areas. In B, three-dimensional CT scan of a healthy 23-year-old patient. Note that there are no areas suggestive of pulmonary emphysema.

Figure 4 - Axial CT scan in a 78-year-old individual (in A) and in a six-month-old child (in B). Note the difference between the two in terms of parenchymal attenuation (denser in the child).

related phenomenon that has been designated “senile emphysema” (Figure 3).(38) Aging-related parenchymal changes are caused by reduced blood flow from the systemic circulation through the bronchial arteries, as well as by the aforementioned quantitative/ J Bras Pneumol. 2012;38(5):656-665

qualitative changes in collagen and in lung compliance.(11,13) The extent of the influence of each of these factors has yet to be determined.

The initial pathophysiological consequence of these changes is air trapping due distal airway closure, with a progressive increase in RV. This

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Figure 5 - Asymptomatic 87-year-old female patient. In A, axial CT scan of the left lower lobe showing laminar atelectasis at the lung bases. In B, sagittal reconstruction of this finding.

Figure 6 - Asymptomatic 83-year-old female patient.

Axial CT scan taken in the prone position, showing subpleural linear septal thickening (arrows). These radiological findings are indistinguishable from those seen in patients with interstitial lung disease due to other causes.

Figure 7 - Asymptomatic 87-year-old female patient.

Axial CT scan with minimum intensity projection reconstruction, a technique that highlights the lowest density areas of the lung parenchyma, showing extensive areas of air trapping. The patient had normal pulmonary function test results.

mechanism is analogous to that of pulmonary emphysema, with no signs of inflammation and no significant increase in TLC. At the same time, the ventilation/perfusion ratio changes because of a reduction in the number of alveoli with normal gas exchange; this has two pathophysiological consequences: increased physiological dead space and the shunt effect, both of which lead to a decrease in PaO2.(39,41) In addition, there is mild

pulmonary hypertension (a clinical manifestation of mild vascular sclerosis) that can redistribute pulmonary flow cranially and be mistaken for early signs of cardiac decompensation.(41-43) The major determinants of static lung volumes are chest wall compliance and lung parenchymal compliance. Loss of lung parenchymal compliance and, to a lesser degree, decreased respiratory muscle strength result in an increase in RV (air J Bras Pneumol. 2012;38(5):656-665

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Figure 8 - Asymptomatic 79-year-old patient. In A, axial CT scan of the left lower lobe, showing areas of bronchial thickening and ectasia. In B, multiplanar reconstruction of a CT scan taken along the bronchial axis, showing bronchial ectasia. Note loss of normal bronchial tapering. In C, the same CT image with minimum intensity projection reconstruction, a technique that highlights the low density areas of the lung parenchyma and allows a better view of the loss of normal bronchial tapering.

trapping), which increases by approximately 50% between ages 20 and 70 years. Conversely, VC progressively decreases to approximately 75% of optimal values. Therefore, TLC remains constant throughout life.(44) The closing volume of the small airways (volume at which the small airways begin to close during exhalation) increases with age.

This premature closure begins to exceed functional residual capacity at age 44 years and exceeds it at age 65 years,(45) being closely related to the loss of supporting tissues around the airways.

This is one of the theories for the aging-related decrease in the ventilation/perfusion ratio.(46-49) A CT scan of the lung parenchyma shows findings that are quite common in the elderly, and it is speculated that these findings are related to collagen changes. These findings are laminar atelectasis, mostly posterior and basal, located in the dependent regions of the lungs (Figure 5); subpleural linear thickening (Figure 6); areas of air trapping (Figure 7); bronchial thickening and ectasia (Figure 8); and lung cysts.(41,50-53) The differential diagnosis between normal, aging-related imaging findings and imaging findings secondary to disease is quite difficult, and it is often impossible to distinguish between the two types of findings using imaging tests alone.

Monitoring these lesions is often necessary, and comparison with previous tests is indispensable.

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Likewise, correlation with pulmonary function test results (particularly DLCO) can demonstrate how gas exchange is occurring and guide a conservative approach. Another fact that should be taken into consideration in the elderly is life expectancy and the metabolic need for gas exchange, given that patients whose activity is limited by extrathoracic disease have lower physiological needs. This brings us to the well-known Hippocratic principle of primum non nocere (above all, do no harm), which is increasingly true today, given the various choices of procedures and the increase in survival of the population.

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About the authors Bruno Hochhegger

Thoracic Radiologist. Department of Pulmonology, Santa Casa Hospital Complex in Porto Alegre; and Professor of Radiology.

Universidade Federal de Ciências da Saúde de Porto Alegre – UFSCPA, Federal University of Health Sciences of Porto Alegre – Porto Alegre, Brazil.

Gustavo Pontes de Meireles

Radiologist. Fleury Medicina Diagnóstica, São Paulo, Brazil.

Klaus Irion

Consultant Radiologist. Liverpool Heart and Chest Hospital, Liverpool, United Kingdom.

Gláucia Zanetti

Professor of Pulmonology. Petrópolis School of Medicine, Petrópolis, Brazil.

Eduardo Garcia

Professor of Pulmonology and Geriatrics. Universidade Federal de Ciências da Saúde de Porto Alegre – UFSCPA, Federal University of Health Sciences of Porto Alegre – Porto Alegre, Brazil.

José Moreira

Professor of Pulmonology. Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – School of Medicine, Porto Alegre, Brazil.

Edson Marchiori

Professor of Radiology. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

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Case Report Hemophagocytic syndrome due to pulmonary sarcoidosis*,** Síndrome hemofagocítica devido a sarcoidose pulmonar

Thiago Prudente Bártholo, José Gustavo Pugliese, Thiago Thomaz Mafort, Vinicius Lemos da Silva, Cláudia Henrique da Costa, Rogério Rufino

Abstract Although hemophagocytic syndrome is a rare clinical condition, it is associated with high mortality and the number of cases described in the literature has progressively increased. The diagnosis of hemophagocytic syndrome is made on the basis of a finding of hemophagocytosis. Sarcoidosis is a highly prevalent disease whose course and prognosis might correlate with the initial clinical presentation and the extent of the disease. We report the case of a patient with long-standing sarcoidosis who presented with intermittent fever and fatigue.

The diagnosis of hemophagocytic syndrome was made by bone marrow aspiration, and specific treatment was ineffective. This is the third case of sarcoidosis-related hemophagocytic syndrome reported in the literature and the first reported in Latin America. All three cases had unfavorable outcomes.

Keywords: Lymphohistiocytosis, hemophagocytic; Ferritins; Sarcoidosis, pulmonary; Macrophage activation syndrome.

Resumo Embora seja uma condição clínica rara, a síndrome hemofagocítica é associada com alta mortalidade e o número de casos descritos na literatura vem aumentando progressivamente. O diagnóstico de síndrome hemofagocítica depende da presença de hemofagocitose. A sarcoidose é uma doença de alta prevalência cujo curso e prognóstico podem correlacionar-se com a apresentação clínica inicial e a extensão da doença. Relatamos o caso de um paciente com sarcoidose de longa duração que apresentava febre intermitente e fadiga. O diagnóstico de síndrome hemofagocítica foi realizado por aspirado de medula óssea, e o tratamento específico foi ineficaz. Trata-se do terceiro caso de síndrome hemofagocítica relacionada a sarcoidose na literatura mundial e o primeiro na literatura latino-americana. Os três casos tiveram desfecho desfavorável.

Descritores: Linfohistiocitose hemofagocítica; Ferritinas; Sarcoidose pulmonar; Síndrome de ativação macrofágica.

Introduction Sarcoidosis is a chronic granulomatous inflammatory disease of unknown etiology and heterogeneous outcomes. On the basis of the natural history of the disease or the course of clinical treatment, the outcomes of cases can be divided into spontaneous regression (self-limited disease), progression of extensive fibrotic lesions as postgranulomatous fibrosis, or association of sarcoidosis with other hematologic diseases, such as myelodysplastic syndrome, acute myeloid leukemia, IgG4-related disease, lymphoma, hypogammaglobulinemia, Castleman’s disease,

and, less frequently, solid tumors. Spontaneous regression occurs in nearly two thirds of cases, the remaining one third being the most challenging to treat and follow.(1-4)

Case report A 56-year-old man who had been diagnosed with sarcoidosis in 1991 on the basis of skin biopsy findings presented with pulmonary and cutaneous lesions. Since the diagnosis of sarcoidosis, the patient had been receiving daily

* Study carried out at the Pedro Ernesto University Hospital, State University of Rio de Janeiro, Rio de Janeiro, Brazil.

Correspondence to: Rogério Rufino. Avenida 28 de Setembro, 77, 2º andar, Departamento de Pneumologia, CEP 20551-030, Rio de Janeiro, RJ, Brasil.

Tel/Fax: 55 21 2868-8248. E-mail: rrufino@uerj.br Financial support: None.

Submitted: 19 February 2012. Accepted, after review: 3 April 2012. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

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doses of prednisone (10 mg/day) in order to control the activity of the disease. The patient had been well until March of 2010, when he had episodes of fever. He received emergency room treatment, the amoxicillin-clavulanate combination having been prescribed. The fever did not subside. Ten days later, the patient sought emergency room treatment again (in the same emergency room) and received levofloxacin. The fever persisted, followed by mild dyspnea, and the patient lost 5 kg in one month. Two weeks after the end of the second course of antibiotics, the patient returned for an unscheduled visit.

Physical examination revealed normal respiration and stable hemodynamic parameters. However, the patient remained febrile. The dose of prednisone was increased to 40 mg/day. One month later, the symptoms persisted, and the patient returned. A Table 1 - Laboratory test results.

Variable Glucose, mg/dL Hematocrit, % Hemoglobin, g/dL Leukocytes, mm3 Platelets, mm3 Creatinine, mg/dL Urea, mg/dL ALT, U/L AST, U/L Total protein, g/dL Albumin, g/dL GGT, U/L Alkaline phosphatase, U/L LDH, U/L Total bilirubin, mg/dL Direct bilirubin, mg/dL Indirect bilirubin, mg/dL PTT, s INR Total cholesterol, mg/dL HDL, mg/dL LDL, mg/dL Triglycerides, mg/dL ESR, mm/h Calcium, mg/dL Iron, mg/dL Ferritin, ng/dL Sodium, mEq/L Potassium, mEq/L

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blood workup revealed leukocytosis (neutrophils, 32%). Anemia and thrombocytopenia were found.

Electrolytes, creatinine, and urea were normal, and blood and urine cultures were negative (Table 1). The patient was hospitalized for further investigation. He had a medical history of diabetes and dyslipidemia but reported no allergies, blood transfusions, smoking, or alcohol consumption.

At admission, the patient was febrile (39°C) and a little anxious. He had no jaundice, rash, or lymphadenopathy. His blood pressure was 130/70 mmHg, his RR was 21 breaths/min, his SaO2 was 96%, and his HR was 88 bpm.

Cardiovascular examination was normal. Pulmonary examination revealed normal breath sounds.

Physical examination was otherwise unremarkable.

Laboratory test results at admission were similar

At admission 108 38.5 13.7 6,300 201,000 0.6 25 28 56 7.4 3.7 34 ND 234 0.53 0.23 0.35 28 0.7 242 31 141 202 ND 8.8 ND ND 141 4.1

10 days after admission 65 21 7.2 41,000 25,000 3.8 128 298 65 4.6 1.8 536 7,960 ND 12.9 9 3.9 ND 1.3 ND ND ND ND 52 ND 50 690.6 144 4.7

ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyl transpeptidase; ND: not determined; LDH: lactate dehydrogenase; PTT: partial thromboplastin time; and INR: international normalized ratio.

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to those previously reported. Chest X-ray was normal.

At admission, ceftriaxone, amikacin, and vancomycin were prescribed. New cultures of blood and urine specimens were negative. On postadmission day 10, the patient presented with jaundice and flapping tremor. There were no remarkable changes in the level of consciousness or in the hemodynamic parameters. Laboratory test results were considerably worse (Table 1). A HRCT scan of the chest revealed no abnormalities, and a transthoracic echocardiogram was unremarkable.

Abdominal ultrasound and CT scan were normal.

Serology for HIV, Epstein-Barr virus, and hepatitis was negative, as were rheumatologic markers (antinuclear antibodies, rheumatoid factor, and antineutrophil cytoplasmic antibody). Blood smear microscopy revealed leukocytosis (41,100 cells/ mm3), thrombocytopenia (25,000 platelets/mm3), and anemia (hemoglobin, 7.2 g/dL; hematocrit, 21%; ferritin, 690.6 ng/dL; and serum iron, 50 mg/dL). On postadmission day 20, the patient presented with decreased urine output and developed liver failure (with hepatomegaly and splenomegaly) and respiratory failure. He was started on mechanical ventilation, hemodialysis, and vasopressors. Four blood cultures were negative.

Serology for ehrlichiosis, bartonellosis, and Q fever was negative. Ferritin determination was repeated (1,619 ng/dL). A myelogram was requested because of unexplained fever, thrombocytopenia, and elevated serum ferritin, revealing red cell phagocytosis by macrophages (Figure 1). A diagnosis of hemophagocytic syndrome (HPS) was established, and the patient was started on methylprednisolone pulse therapy in the

department of hematology, with no success.

The patient died four days after the initiation of corticosteroid therapy.

Discussion Albeit rare, HPS is a potentially fatal condition. The diagnosis of HPS is based on a combination of clinical and biological signs, requiring histological/cytological examination for hemophagocytosis and an exhaustive etiologic investigation.(5) The disease is classified as primary or secondary HPS.(6) The two forms are clinically indistinguishable, being characterized by a sepsis-like presentation with splenomegaly, cytopenia, hyperferritinemia, bleeding disorder, and hemophagocytosis. Consequently, multiorgan failure often develops, leading to high mortality.

(7) Primary HPS is hereditary, and most patients present with symptoms within two years after birth, being treated in the pediatric field.(6) The primary form of HPS has an autosomal recessive pattern of inheritance, with an incidence of approximately 1/50,000 live births.(7) Primary HPS can result from autosomal defects or be associated with immune deficiencies, such as Chediak-Higashi syndrome, X-linked lymphoproliferative syndrome, and Griscelli syndrome.(8) Five types of familial HPS have been described.(9) The prognosis is unfavorable. Secondary HPS develops during adulthood in most patients. The incidence of infection-associated HPS (particularly that of virus-associated HPS) is high, as is that of lymphoma-associated HPS.(6) Other conditions associated with secondary HPS include autoimmune diseases such as rheumatoid arthritis, Still’s disease, dermatomyositis, sarcoidosis, systemic

Figure 1 - Findings in bone marrow aspirate (H&E; magnification, ×40). Photomicrographs showing active macrophages with signs of hemophagocytosis, mainly engulfed erythrocytes (white arrows).

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lupus erythematosus, and vasculitis. Drugs such as beta blockers and chemotherapeutic agents have also been described as causing secondary HPS.(6,7,10) Diffuse alveolar hemorrhage has been described as a manifestation of HPS.(11,12) The syndrome is characterized by the proliferation of benign macrophages that are responsible for extensive phagocytosis of hematopoietic cells, which is due to a hyperinflammatory response that can affect the cytotoxic function of T lymphocytes and natural killer (NK) cells.(13) This inflammatory response is induced by a “cytokine storm” and is characterized by the proliferation and activation of macrophages in the reticuloendothelial system.(14,15) Normal histiocyte function includes phagocytosis, antigen presentation, and activation of the adaptive immune system through contact and cytokine signaling. Although abnormalities in the function of NK cells have been reported in patients with HPS, the number of NK cells is rarely increased.

The syndrome is a reactive process resulting from prolonged and excessive activation of antigenpresenting cells (macrophages, histiocytes, and CD8+ T cells). As stated by Filipovich,(16) “hemophagocytosis, which is mediated through the CD163 heme-scavenging receptor, is a hallmark of activated macrophages/histiocytes and is the characteristic finding for which the disorder was named. The majority of genetic causes identified to date affect the cytotoxic function of NK and T cells, crippling immunologic mechanisms that

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mediate natural immune contraction. NK and NK T cells play a major role in maintaining a healthy threshold of immune responsiveness to noxious external stimuli and are critical to prevent and control autoimmune conditions and severe reactions to viral infections.”

Diagnostic criteria for HPS, developed by the Histiocyte Society, are described in Chart 1.(17) Hemophagocytosis can be established not only in bone marrow but also in lymphoid tissues such as the liver, spleen, and lymph nodes. Histological identification of hemophagocytosis is considered the gold standard for the diagnosis of HPS; however, in up to 20% of patients, histological examination of the first bone marrow biopsy specimen does not reveal hemophagocytosis.

Because hemophagocytosis can occur at different sites during the course of the disease, repeated biopsies are sometimes required for the diagnosis of HPS.(7) Okamoto et al.(6) investigated 28 patients with secondary HPS and without a history of hyperlipidemia. Their results suggest that the triglyceride level is useful for diagnosing HPS and evaluating treatment response.(6) Ferritin levels constitute an important diagnostic parameter.

However, slightly elevated ferritin levels can be found in various inflammatory diseases, being therefore nonspecific. Nevertheless, ferritin levels greater than 10,000 µg/L are found only in patients with HPS, Still’s disease, or malignant histiocytosis, as well as in those who have received multiple blood transfusions.(7) According to Knovich et al.,(18)

Chart 1 - Diagnostic criteria for hemophagocytic syndrome.a Clinical criteria 1. Fever 2. Splenomegaly Biochemical criteria 3. Cytopenia (affecting at least 2 of 3 lineages in the peripheral blood) 3a. Hemoglobin < 90 g/L 3b. Platelets < 100 × 109 cells/L 3c. Neutrophils < 1.0 × 109 cells/L 4. Hypertriglyceridemia or hypofibrinogenemia 4a. Fasting triglycerides > 265 mg/dL 4b. Fibrinogen ≤ 1.5 g/L 5. Ferritin ≥ 500 µg/L 6. Low or absent natural killer cell activity (in accordance with the criteria of a local referral laboratory) 7. Soluble CD25 ≥ 2,400 U/ml Histopathological criteria 8. Hemophagocytosis in bone marrow, spleen, or lymph nodes (no evidence of malignancy) a

The diagnosis is dependent on 5 of the 8 criteria being met. Adapted from Henter et al.(17)

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“in a prospective study of adult HPS patients, the percentage of glycosylated ferritin was lower in patients with HPS, suggesting that low glycosylated ferritin could be a marker of severe HPS. The elevated ferritin is hypothesized to be due to passive release from cell damage in the liver and spleen, increased secretion by macrophages or hepatocytes, or decreased clearance due to lower glycosylation or down regulation of ferritin receptors.” Without intensive treatment, severe HPS is fatal. In adult patients, early intensive treatment can increase the chances of survival.(7) Cases of HPS secondary to sarcoidosis are very rare. Dhote et al. studied 26 patients with secondary HPS, one of whom had pulmonary sarcoidosis.(19) The authors of another study reported a case of miliary tuberculosis complicated

by HPS in a patient who had been diagnosed with sarcoidosis.(20) In those two cases (sarcoidosis and HPS), the patients died, having presented with fever, thrombocytopenia, and elevated triglyceride levels.

In the present case, the patient developed a sepsis-like syndrome after a period of two months with fever, mild dyspnea, and weight loss. After a thorough investigation, we found hemophagocytic cells in bone marrow aspirate.

Bone marrow aspiration is a common and safe hematologic procedure that should be performed in patients with thrombocytopenia or leukopenia of unknown cause, as was the case in our patient.

In accordance with the literature, our patient had to be transferred to an ICU. Nevertheless, he died from multiple organ dysfunction. The patient had been diagnosed with sarcoidosis nine years prior to the onset of HPS. However, he was dependent on corticosteroids for symptom control. It is impossible to determine whether this was a case of primary HPS in a patient with sarcoidosis or whether HPS appeared as a complication of a still active disease.

In summary, the association of HPS and sarcoidosis is very rare. A diagnosis of HPS should be considered in patients with unexplained fever and high levels of ferritin and triglycerides. In the present case, bone marrow aspiration was an essential tool for the diagnosis of HPS.

References 1. Nagai S, Handa T, Ito Y, Ohta K, Tamaya M, Izumi T. Outcome of sarcoidosis. Clin Chest Med. 2008;29(3):565‑74, x. PMid:18539245.

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2. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med. 1999;160(2):736-55.

3. Swigris JJ, Olson AL, Huie TJ, Fernandez-Perez ER, Solomon J, Sprunger D, et al. Sarcoidosis-related mortality in the United States from 1988 to 2007. Am J Respir Crit Care Med. 2011;183(11):1524-30. http://dx.doi. org/10.1164/rccm.201010-1679OC 4. Alexandrescu DT, Kauffman CL, Ichim TE, Riordan NH, Kabigting F, Dasanu CA. Cutaneous sarcoidosis and malignancy: An association between sarcoidosis with skin manifestations and systemic neoplasia. Dermatol Online J. 2011;17(1):2. PMid:21272493.

5. Ben Dhaou Hmaidi B, Derbali F, Boussema F, Ketari Jamoussi S, Baili L, Kochbati S, et al. Hemophagocytic syndrome: report of 4 cases [Article in French]. Tunis Med. 2011;89(1):70-5. PMid:21267834.

6. Okamoto M, Yamaguchi H, Isobe Y, Yokose N, Mizuki T, Tajika K, et al. Analysis of triglyceride value in the diagnosis and treatment response of secondary hemophagocytic syndrome. Intern Med. 2009;48(10):775‑81. PMid:19443971. http:// dx.doi.org/10.2169/internalmedicine.48.1677 7. Wijsman CA, Roeters van Lennep JE, von dem Borne PA, Fogteloo AJ. A diagnostic difficulty: two cases of haemophagocytic syndrome in adults. Neth J Med. 2009;67(1):29-31. PMid:19155545.

8. Congyang L, Xuexin H, Hao L, Chunge L, Yingye M. Plasma cells increased markedly in lymph node in hemophagocytic syndrome: a case report. Cases J. 2009;2:9096. PMid:2803893. http://dx.doi. org/10.1186/1757-1626-2-9096 9. Cetica V, Pende D, Griffiths GM, Aricò M. Molecular basis of familial hemophagocytic lymphohistiocytosis.

Haematologica. 2010;95(4):538-41. PMid:2857182. http://dx.doi.org/10.3324/haematol.2009.019562 10. Phillips J, Staszewski H, Garrison M. Successful treatment of secondary hemophagocytic lymphohistiocytosis in a patient with disseminated histoplasmosis.

Hematology. 2008;13(5):282-5. http://dx.doi. org/10.1179/102453308X316013 11. Müller C, Mänhardt LB, Willaschek C, Schneider EM, Stuth EA, Buchhorn R. Beta-blocker therapy and hemophagocytic lymphohistiocytosis: a case report.

Cardiol Res Pract. 2010;2010:912757. http://dx.doi. org/10.4061/2010/912757 12. Brandão-Neto RA, Santana AN, Danilovic DL, Bernardi Fdel C, Barbas CS, de Mendonça BB. A very rare cause of dyspnea with a unique presentation on a computed tomography scan of the chest: macrophage activation syndrome. J Bras Pneumol. 2008;34(2):118-20. PMid:18345456.

13. Santana AN, Kairalla RA, Carvalho CR. Remembering other causes of alveolar siderophages: macrophage activation syndrome. Chest. 2008;133(4):1055. PMid:18398137. http://dx.doi.org/10.1378/chest.07-2668 14. Melo RA, Fonseca A, Brochado M, Quinaz JM. Hemophagocytic Syndrome Associated with Hodgkin’s Lymphoma First Presenting as Fever and Pancytopenia.

Case Report Med. 2010;759651. http://dx.doi. org/10.1155/2010/759651

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15. Szyper-Kravitz M. The hemophagocytic syndrome/ macrophage activation syndrome: a final common pathway of a cytokine storm. Isr Med Assoc J. 2009;11(10):633-4.

PMid:20077953.

16. Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am Soc Hematol Educ Program. 2009:127-31. PMid:20008190.

17. Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-31. PMid:16937360.

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18. Knovich MA, Storey JA, Coffman LG, Torti SV, Torti FM. Ferritin for the clinician. Blood Rev. 2009;23(3):95-104.

PMid:18835072.

19. Dhote R, Simon J, Papo T, Detournay B, Sailler L, Andre MH, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum. 2003;49(5):633-9. PMid:14558048.

20. Lam KY, Ng WF, Chan AC. Miliary tuberculosis with splenic rupture: a fatal case with hemophagocytic syndrome and possible association with long standing sarcoidosis.

Pathology. 1994;26(4):493-6. PMid:7892057.

About the authors Thiago Prudente Bártholo

Pulmonologist. Pedro Ernesto University Hospital, State University of Rio de Janeiro, Rio de Janeiro, Brazil.

José Gustavo Pugliese

Pulmonologist. Pedro Ernesto University Hospital, State University of Rio de Janeiro, Rio de Janeiro, Brazil.

Thiago Thomaz Mafort

Pulmonologist. Pedro Ernesto University Hospital, State University of Rio de Janeiro, Rio de Janeiro, Brazil.

Vinicius Lemos da Silva

Professor of Clinical Medicine. State University of Rio de Janeiro, Rio de Janeiro, Brazil.

Cláudia Henrique da Costa

Adjunct Professor. Department of Pulmonology and Tuberculosis, State University of Rio de Janeiro, Rio de Janeiro, Brazil.

Rogério Rufino

Adjunct Professor. Department of Pulmonology and Tuberculosis, State University of Rio de Janeiro, Rio de Janeiro, Brazil.

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Letter to the Editor Tailored intracuff pressures Valores individualizados de pressão intracuff

Armando Carlos Franco de Godoy, Mariana Del Grossi Moura, Monique Louise Adame, Gustavo Pereira Fraga

To the Editor: Adult invasive mechanical ventilation requires the use of an endotracheal tube with an inflatable cuff at its distal end. It is important to ensure adequate pressure within the device because its objective is to seal the interface between the tracheal mucosa and the cuff in order to prevent microaspiration of oropharyngeal secretions and pressure-induced ischemic injury due to obliteration of the tracheal mucosal arteries.(1) Therefore, the III Consenso Brasileiro de Ventilação Mecânica (III CBVM, Third Brazilian Consensus on Mechanical Ventilation) recommends intracuff pressures between 15 and 25 mmHg (20-34 cmH2O), with a grade of recommendation of D.(2) However, other authors recommend the use of the minimal occlusive volume (MOV) technique in order to reach a minimum pressure to seal the interface between the cuff and the tracheal mucosa, because it is known that lower cuff pressures on the tracheal mucosa translate to a lower risk of tracheal mucosal injury and, in the event of injury, to less severe injury.(3) In order to compare the intracuff pressures that can be obtained by the MOV technique with the pressures recommended by the III CBVM, we conducted a prospective descriptive study at the Adult ICU of the State University at Campinas Hospital de Clínicas between August and December of 2011. The study was approved by the Research Ethics Committee of the State University at Campinas School of Medical Sciences (Protocol no. 542/2011). We measured intracuff pressures using the MOV technique in 29 adult patients on mechanical ventilation. We included patients over 18 years of age who had been on mechanical ventilation with a high-volume, low-pressure cuffed endotracheal tube for less than 48 h. We excluded patients with a history of intubation.

For the use of the MOV method, the study patients were placed in the supine position, with the neck in a neutral position, and their

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oropharyngeal cavity was cleaned and aspirated.

Subsequently, the cuff was deflated and inflated with a 20-mL syringe, which was attached to one of the ports of a three-way stopcock. Of the two remaining stopcock ports, one was connected to an endotracheal tube cuff and the other was attached to a mercury-filled glass column, calibrated in mmHg (Figure 1). The cuff was inflated until auscultation with a stethoscope placed on the suprasternal notch of the patient showed the absence of adventitious sounds, at which point mercury manometer readings were taken.(3) Data were analyzed with the one-sample Student’s t-test, and values of p < 0.05 were considered significant.

The patients studied were in the 26-83 year age bracket (mean age, 56 ± 14 years). The reasons for intubation were as follows: postoperative period of neurovascular surgery, in 31% of the cases; pulmonary focus, in 34%; postoperative period of general surgery, in 10%; trauma, in 7%; and other reasons, in 18%. All tracheal tubes had an internal diameter of 7.5-9.0 mm and had a low-pressure cuff.

The mean intracuff pressure obtained by the MOV method was 15 ± 4 mmHg, the minimum value being 7 mmHg and the maximum value being 22 mmHg (2nd quartile, 14 mmHg, and 3rd quartile, 17 mmHg; Figure 2). Data analysis revealed a statistically significant difference (p < 0.001) between the mean intracuff pressures recommended by the III CBVM and the pressures obtained by the MOV method.

We found that the intracuff pressures obtained by the MOV method did not remain the same in all patients. All of the 29 study patients received intracuff pressures that were lower than the maximum pressure recommended by the III CBVM (25 mmHg), and, in 20 patients (69%), the lowest recommended intracuff pressure (15 mmHg) could have been used. For those patients, we could have reduced the pressure on the tracheal

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Armando Carlos Franco de Godoy Physical Therapist, Adult ICU, State University at Campinas Hospital de Clínicas, Campinas, Brazil Mariana Del Grossi Moura Physical Therapist, Adult ICU, State University at Campinas Hospital de Clínicas, Campinas, Brazil

Figure 1 - Diagram of the apparatus used in the present study. In A, three-way stopcock. In B, endotracheal tube cuff. In C, 20-mL graduated plastic syringe. In D, mercury-filled glass column calibrated in mmHg.

Figure 2 - Intracuff pressures obtained by the minimal occlusive volume method. The dashed lines indicate the pressure range recommended by the Third Brazilian Consensus on Mechanical Ventilation. The mean pressure obtained by minimal occlusive volume is indicated by the triangle in the middle of the graph.

mucosa in contact with the cuff by 10.6 g/cm2 if they had been receiving the highest pressure recommended by the III CBVM (25 mmHg).

Only one patient (3%) required the maximum pressure of 22 mmHg, which is still lower than that recommended by the III CBVM. We conclude that the MOV method can be used in order to obtain tailored intracuff pressures within the pressure range recommended by the III CBVM, thereby minimizing the risk of tracheal mucosal injury and, in the event of injury, the severity of the injury.

Monique Louise Adame Physical Therapist, Adult ICU, State University at Campinas Hospital de Clínicas, Campinas, Brazil Gustavo Pereira Fraga Coordinator of the Division of Trauma Surgery, Department of Surgery, State University at Campinas School of Medical Sciences, Campinas, Brazil

References 1. Seegobin RD, van Hasselt GL. Endotracheal cuff pressure and tracheal mucosal blood flow: endoscopic study of effects of four large volume cuffs. Br Med J (Clin Res Ed). 1984;288(6422):965-8. PMid:1442489. http:// dx.doi.org/10.1136/bmj.288.6422.965 2. Sociedade Brasileira de Pneumologia e Tisiologia. III Consenso Brasileiro de Ventilação Mecânica. J Bras Pneumol. 2007;33(Suppl 2):S1-S150.

3. Guyton DC, Barlow MR, Besselievre TR. Influence of airway pressure on minimum occlusive endotracheal tube cuff pressure. Crit Care Med. 1997;25(1):91-4.

PMid:8989182.

Submitted: 22 February 2012. Accepted, after review: 1 March 2012.

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Letter to the Editor Osteitis in a female infant after vaccination with BCG Moreau in the neonatal period Osteíte por BCG Moreau em uma menina vacinada ao nascer

Nelson Morrone, Cláudio do Amaral Antonio, Claudio Santilli, Beatriz Tavares Costa-Carvalho, Denise Rodrigues

To the Editor: A female infant (age, 2 years and 4 months) from the city of São Paulo, Brazil, had been vaccinated with BCG in the maternity ward and presented with a 15-day history of pain in the right leg and impaired ambulation. The patient was treated with a nonsteroidal anti-inflammatory drug and showed improvement. However, two weeks after the drug had been discontinued, she showed worsening. An X-ray of the knee showed an osteolytic lesion in the right distal femoral epiphysis. Magnetic resonance imaging (Figure 1) revealed a centromedial lesion in the right distal femoral epiphysis, with multiple areas of cortical erosion; there was significant cortical discontinuity, and there was no effusion in the posteroinferior portion of the medial femoral condyle. The patient was treated with ceftriaxone for 14 days, with no improvement. A punch biopsy of the right knee showed a granuloma with no AFB. The patient was started on isoniazid, rifampin, and pyrazinamide. Investigation of her parents, siblings, and nannies showed no exposure to pulmonary or extrapulmonary tuberculosis.

At admission to our facility, a few days after treatment initiation, the patient was in good general health. The only abnormality on physical examination was right knee edema (distal and proximal to the tibia). The edema was cold and painful on palpation, being accompanied by functional disability.

The following tests were performed: tuberculin skin testing with PPD, the induration being 14 mm; X-ray and magnetic resonance imaging of the right knee; enzyme-linked immunospot (ELISPOT) assay, the results being negative; knee biopsy, revealing very little bone tissue with two epithelioid granulomas (one of which had caseous necrosis) and chronic lymphoplasmacytic inflammatory infiltrate; AFB testing, the results being negative; mycobacterial culture, the results being positive; PCR testing, revealing the presence J Bras Pneumol. 2012;38(5):674-676

of insertion sequence 6110 (which is characteristic of mycobacteria) and duplication of spacer 33 in the DR region (172-bp amplicon), present only in the Mycobacterium bovis BCG strain and absent in M. tuberculosis; PCR testing, the results being negative for M. tuberculosis; routine tests (complete blood count, ESR determination, HIV testing, and evaluation of liver and kidney function), the results being normal; humoral and cellular immune response testing, the results being normal (Table 1); and chest CT, the findings being normal.

The patient achieved a satisfactory clinical improvement and was discharged after 18 months of treatment, at which point an X-ray of the right femur showed normal findings.

The BCG vaccine is used in many countries, and there are no strict rules regarding the age of vaccination, the groups that should be vaccinated, the type of vaccine, the concentration of bacilli, the ratio of live to dead bacilli, or the mode of administration. Many strains are used; however, there is uncertainty regarding the total number of viable and nonviable bacilli (which could potentiate the immunity induced by the former) and the ability of PPD to induce allergy, both of which are factors that can have an impact on the potency and complications of the vaccine.

(1,2) In Brazil, vaccination with BCG Moreau is given intradermally (at the insertion of the right deltoid) in the first days of life, at concentrations of 300,000-1,000,000 bacilli/dose.

Severe side effects are rare and include persistent ulceration at the vaccination site, surrounding adenopathy, osteitis, and disseminated disease, which can occur in severely immunocompromised individuals (including the cases of locally administered vaccine in patients with bladder carcinoma). In the Czech Republic, the incidence of complications has decreased with the use of lower doses of the vaccine.(3)

Osteitis in a female infant after vaccination with BCG Moreau in the neonatal period

In Russia, the incidence of bone tuberculosis has been reported to be higher than that of primary tuberculosis, BCG having been confirmed as the cause of osteitis in 46% of the patients who presented with the disease.(4) In Japan, the incidence of osteitis has been reported to be 0.2 cases/100,000 vaccinations, varying according to the BCG strain(5) and the use of vaccines that are less reactogenic.(6) In Finland, the incidence of osteitis has also been reported to vary according to the BCG strain.(7) We found no reports of osteitis caused

by BCG Moreau. However, it should be noted that BCG Moreau is not as widely used as are other strains, particularly BCG Glaxo and BCG Pasteur-Paris. In Brazil, one group of authors(8) recently reported the case of a normal-weight,

Figure 1 - Magnetic resonance imaging of the right femur showing osteolytic lesions.

Table 1 - Immune status of the patient.

Test Determination of antibodies against rubella, measles, and pneumococci Dihydrorhodamine oxidation test Total lymphocyte count Total T lymphocyte count CD4 count CD8 count Natural killer lymphocyte count CD56/16 CD3 count

675

immunocompetent child who presented with radial and ulnar lesions and who was highly suspected of having BCG osteitis, although the bacillus was not identified.(8) The diagnosis of BCG osteitis in our patient is indisputable. Tuberculin skin testing confirmed that PPD positivity does not depend on M. tuberculosis, given that ELISPOT assay results were negative.

Biopsy showed a caseating granuloma, no bacilli having been identified. However, culture was positive, confirming mycobacteriosis. The presence of BCG was confirmed by PCR revealing insertion sequence IS6110, which is characteristic of the vaccine. Therefore, this seems to be the first confirmed case of osteitis after vaccination with BCG Moreau. The classic criteria of Foucard & Hjelmstedt(9) are useful in raising the suspicion of BCG osteitis, because they include vaccination in the neonatal period, development of symptomatic disease up to four years after vaccination, no contact with tuberculosis, a clinical profile consistent with tuberculosis, and histopathological findings consistent with tuberculosis. Our patient met those criteria. However, the current gold standard is the detection of the presence of M. bovis.

The patient was treated with isoniazid, rifampin, and pyrazinamide because of the presumptive diagnosis of tuberculosis. The hypothesis of osteitis after BCG vaccination was raised later, pyrazinamide being discontinued because BCG is resistant to the drug. The treatment continued for 18 months, and complete cure was achieved.

However, treatment with only isoniazid and rifampin for 6 months has been reported to be successful. Recurrence is rare.

Osteitis after BCG vaccination is slightly more common in boys than in girls. Humeral osteitis results from contiguous spread, which

Result Normal 241 units (reference value, > 80 units) 5,880 cells/mm3 3,587 cells/mm3 (61%; reference value, 64%) 37% 24% 5,849 cells/mm3 (13%) 781 (14%; normal range, 6-29%)

Note: BCG was isolated in the Clinical Laboratory of the Hospital Israelita Albert Einstein, in the city of São Paulo, Brazil, as described by Yeboah-Manu D et al.(14)

J Bras Pneumol. 2012;38(5):674-676

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Morrone N, Antonio CA, Santilli C, Costa-Carvalho BT, Rodrigues D

was impossible in our patient. Osteitis resulting from hematogenous spread is more likely, occurring primarily in the epiphyses of long bones in the arms and legs (which are highly vascularized) and being usually solitary.(5,10) Involvement of other bones, such as the sternum(11) and the sacrum,(12) is extremely rare. The unilaterality of the disease suggests that circulation was increased (by minimal trauma, for instance) prior to the onset of the bacilli. However, it is strange that other highly vascularized organs are more resistant.

Dissemination of BCG is facilitated by immunosuppression, which was not observed in our patient. She had a normal complete blood count and normal counts of lymphocytes, CD4, CD8, and natural killer lymphocytes, as well as having normal levels of antibodies against rubella, measles, and pneumococci. In addition, she had a normal dihydrorhodamine oxidation test result.

Unfortunately, it was impossible to determine IL-12 levels, and deficiency/absence of IL-12 might be related to mycobacterial disease. In Brazil, this condition was found in two brothers with BCG adenitis and deficient IL-12 production after stimulation with INF-γ.(13)

Nelson Morrone Collaborator, Clemente Ferreira Institute, São Paulo State Department of Health, São Paulo, Brazil Cláudio do Amaral Antonio Physician, Clemente Ferreira Institute, São Paulo State Department of Health, São Paulo, Brazil Cláudio Santilli Physician,

Hospital Israelita Albert Einstein, São Paulo, Brazil

Beatriz Tavares Costa Carvalho Adjunct Professor, Division of Allergy and Immunology and Division of Rheumatology, Department of Pediatrics, Federal University of São Paulo, São Paulo, Brazil

Denise Rodrigues Physician, Clemente Ferreira Institute, São Paulo State Department of Health, São Paulo, Brazil

References 1. World Health Organization [homepage on the Internet].

Geneva: World Health Organization. [cited 2011 Sep 9].

Fine PE, Carneiro IA, Milstien JB, Clements CJ. Issues relating to the use of BCG in immunization programmes.

A discussion document [Adobe Acrobat document, 45p.].

Available from: http://www.who.int/vaccines-documents/ DocsPDF99/www9943.pdf 2. Milstien JB, Gibson JJ. Quality control of BCG vaccine

by WHO: a review of factors that may influence vaccine effectiveness and safety. Bull World Health Organ. 1990;68(1):93-108. PMid:2393003.

3. Vítková E, Galliová J, Krepela K, Kubín M. Adverse reactions to BCG. Cent Eur J Public Health. 1995;3(3):138-41.

PMid:8535371.

4. Kamaeva NG, Chugaev IuP, Grinberg LM, Anisimova NA, Golubeva TV, Kamaev EIu. Clinical and epidemiological features of tuberculosis ostitis in BCG-vaccinated children [Article in Russian]. Probl Tuberk Bolezn Legk. 2009;(1):1620. PMid:19253678.

5. Koyama A, Toida I, Nakata S. Osteitis as a complication of BCG vaccination [Article in Japanese].

Kekkaku. 2009;84(3):125-32. PMid:19364044.

6. Jou R, Huang WL, Su WJ. Tokyo-172 BCG vaccination complications, Taiwan. Emerg Infect Dis. 2009;15(9):1525-6.

7. Kröger L, Korppi M, Brander E, Kröger H, Wasz-Höckert O, Backman A, et al. Osteitis caused by bacille CalmetteGuérin vaccination: a retrospective analysis of 222 cases.

J Infect Dis. 1995;172(2):574-6. PMid:7622909.

8. Yamada AF, Pellegrini JB, Cunha LM, Fernandes Ada R. Osteitis after BCG vaccination. J Bras Pneumol. 2009;35(3):285-9. PMid:19390729. http:// dx.doi.org/10.1590/S1806-37132009000300015 9. Foucard T, Hjelmstedt A. BCG-osteomyelitis and -osteoarthritis as a complication following BCG-vaccination.

Acta Orthop Scand. 1971;42(2):142-51. PMid:4939582.

10. Marík I, Kubát R, Filipský J, Galliová J. Osteitis caused

by BCG vaccination. J Pediatr Orthop. 1988;8(3):333-7.

PMid:3284907.

11. Saifudheen K, Anoop TM, Mini PN, Ramachandran M, Jabbar PK, Jayaprakash R. Primary tubercular osteomyelitis of the sternum. Int J Infect Dis. 2010;14(2):e164-6.

PMid:19524467.

12. Meurice JC, Dore P, Lamotte F, Bataille B, Levard G, Castets M, et al. Sacral tuberculous osteitis [Article in French]. Rev Mal Respir. 1994;11(4):418-20.

13. Lawrence TC, Carvalho BC. Adenite pós vacina BCG em dois pacientes com imunodeficiência de receptor 1 do INFgama. Rev Bras Alerg Imunopatol. 2006;29(1):18-23.

14. Yeboah-Manu D, Yates MD, Wilson SM. Application of a simple multiplex PCR to aid in routine work of the mycobacterium reference laboratory. J Clin Microbiol. 2001;39(11):4166-8. http://dx.doi.org/10.1128/ JCM.39.11.4166-4168.2001

Submitted: 16 February 2012. Accepted, after review: 8 March 2012.

J Bras Pneumol. 2012;38(5):674-676

Letter to the Editor Noninvasive mechanical ventilation in a patient with acute pancreatitis and respiratory failure Ventilação mecânica não invasiva em uma paciente com pancreatite aguda e insuficiência respiratória

Armando Carlos Franco de Godoy, Thiago Rodrigues Araújo Calderan, Gustavo Pereira Fraga

To the Editor: Respiratory failure in acute pancreatitis is one of the prognostic factors for mortality and can lead to death in the first week of treatment.

Therefore, much attention has been devoted to the respiratory complications of this condition.

The most common pleuropulmonary complications of acute pancreatitis are inflammatory response syndrome, atelectasis, alveolar consolidation, and diaphragmatic dysfunction.(1,2) Noninvasive mechanical ventilation (NIMV) is an advance in intensive care in specific cases of acute respiratory failure, such as in COPD exacerbation and in cardiogenic pulmonary edema.(3) In such cases, NIMV is used in order to reduce the work of breathing and improve pulmonary gas exchange, as well as to avoid tracheal intubation.(3) In the Adult ICU of the State University at Campinas Hospital de Clínicas, located in the city of Campinas, Brazil, we had the opportunity to treat a 35-year-old female patient who had been admitted with a diagnosis of acute biliary pancreatitis and signs of respiratory failure. The scores obtained were as follows: Simplified Acute Physiology Score II = 30; Ranson scoring system (48 h) = 5.8; and Balthazar CT score = B-C 3, D-E 12. At admission, the patient presented with severe abdominal pain, sweating, dyspnea (RR = 35 breaths/min), contraction of accessory respiratory muscles, nasal flaring, and paradoxical breathing.

The patient received ventilatory support by NIMV for three consecutive days, requiring no endotracheal intubation or invasive mechanical ventilation. She was started on NIMV at 7:30 a.m. on postadmission day 2, NIMV being delivered via a face mask connected to a ventilator (BiPAP Vision; Respironics Inc., Murrysville, PA, USA) set in spontaneous mode. Initially, expiratory positive airway pressure (EPAP) was set at 25 cmH2O and

inspiratory positive airway pressure (IPAP) was set at 12 cmH2O, oxygen being delivered at 7 L/min via a catheter connected to the ventilator circuit.

After the patient’s adaptation to the ventilator, the EPAP levels were periodically adjusted to obtain an SaO2 greater than 94% and the IPAP levels were adjusted to obtain a tidal volume of 5-8 mL/kg and an RR below 30 breaths/min.

Weaning from NIMV was achieved after three consecutive days by gradually reducing the EPAP and IPAP levels in order not to increase the RR and reduce the tidal volume and SaO2. On the fifth day of treatment, the patient received oxygen at 7 L/min via a nebulizer mask, showing no signs of respiratory distress. There was no need for NIMV for the remainder of her hospital stay.

Before starting the treatment with NIMV, the patient was dyspneic because of the presence of bilateral alveolar infiltrates in the lung bases, microatelectasis, and abdominal distension. The last of the three led to a restrictive ventilatory pattern, with a reduction in diaphragmatic strength and mobility, which was due to cephalic displacement of the diaphragm. After the initiation of NIMV, her arterial pO2 increased and her RR stabilized. On the first day of NIMV, there was clearly an increase in RR (> 40 breaths/min) and a fall in SaO2 (< 85%) whenever the face mask was removed for oral hygiene, communication, adjustment, or administration of medications.

According to the recommendations of the Third Brazilian Consensus on Mechanical Ventilation, NIMV can be beneficial in cases of hypoxemic respiratory failure; however, caution should be exercised when using NIMV in such patients, because this treatment modality has a grade B recommendation.(3) Ventilatory support by NIMV is safe and efficient as long as patients are closely monitored and promptly intubated if their clinical condition deteriorates; however, J Bras Pneumol. 2012;38(5):677-678

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Godoy ACF, Calderan TRA, FRAGA GP

when used incorrectly, NIMV can delay the use of invasive mechanical ventilation and increase mortality.(1,3) In conclusion, NIMV can be part of the therapeutic armamentarium for patients with acute pancreatitis and respiratory failure as long as there are no contraindications to its use and patients are closely monitored.

References

Armando Carlos Franco de Godoy Physical Therapist, Adult ICU, Universidade Estadual de Campinas – Unicamp, State University at Campinas – Hospital das Clínicas, Campinas, Brazil Thiago Rodrigues Araújo Calderan Physician, Division of Trauma Surgery,

Universidade Estadual de Campinas – Unicamp,

State University at Campinas – School of Medical Sciences, Campinas, Brazil Gustavo Pereira Fraga Coordinator of the Division of Trauma Surgery, Department of Surgery,

Universidade Estadual de Campinas – Unicamp,

State University at Campinas – School of Medical Sciences, Campinas, Brazil

Submitted: 8 March 2012. Accepted, after review: 20 March 2012.

J Bras Pneumol. 2012;38(5):677-678

1. Jaber S, Chanques G, Sebbane M, Salhi F, Delay JM, Perrigault PF, et al. Noninvasive positive pressure ventilation in patients with respiratory failure due to severe acute pancreatitis. Respiration. 2006;73(2):166-72.

PMid:16432295. http://dx.doi.org/10.1159/000088897 2. Pneumatikos I, Bouros D. Noninvasive ventilation in acute pancreatitis respiratory failure: deus ex machina?

Respiration. 2006;73(2):147-8. PMid:16549943. http:// dx.doi.org/10.1159/000091531 3. Sociedade Brasileira de Pneumologia e Tisiologia. III Consenso Brasileiro de Ventilação Mecânica. J Bras Pneumol. 2007;33(Suppl 2):S1-S150.

Letter to the Editor Urine in the pleural cavity: an unexpected finding Urina em cavidade pleural: um achado inesperado

Melike Demir, Gülistan Karadeniz, Ebru Uz

To the Editor: Urinothorax is an infrequent cause of pleural effusion and is caused by urine leakage into the pleural cavity through an anatomical defect in the diaphragm or via the lymphatic system.(1) Urinothorax is usually secondary to obstructive uropathy or traumatic (typically iatrogenic) injury of the urinary system.(2) A 61-year-old female with a history of nephrolithiasis was admitted to our institution with high-grade fever, decreased urine output, progressive shortness of breath, and right-sided chest pain for two days. The patient had undergone right-sided percutaneous nephrolithotomy three days prior to admission and had no history of pulmonary disease.

Physical examination revealed pallor and a body temperature of 38.4°C. Her chest movements were decreased. In the right hemithorax, there was a dull percussion note and breath sounds were absent, both of which are findings consistent with pleural effusion. No abnormalities were found regarding the other systems.

A chest X-ray demonstrated significant rightsided pleural effusion (Figure 1), and a CT scan of the chest revealed right pleural effusion, thin septa, and atelectasis of the underlying lung (Figure 2). Serum levels of urea and creatinine were 132 mg/dL and 3.9 mg/dL, respectively.

Because the respiratory distress developed suddenly and soon after percutaneous nephrolithotomy, urinothorax was suspected. The diagnosis was confirmed after thoracocentesis, which yielded approximately 1,100 mL of pleural fluid, with a ratio between the creatinine content in pleural fluid and that in serum of 1.78 (normal, < 1). A 28 Fr chest tube was inserted into the right fifth intercostal space in order to drain the effusion.

The patient was started on broad spectrum antibiotics and carefully observed. Intravenous urography did not reveal any obstructive uropathy caused by kidney stones. Because the diagnosis of urinothorax had been confirmed, we did not perform radionuclide imaging in order to show

a connection between the urinary system and the pleural cavity. There was a gradual increase in urine output, accompanied by a simultaneous decrease in serum levels of urea and creatinine.

The urine drainage from the chest tube stopped seven days after the procedure, and the tube was withdrawn. On post-admission day 9, the

Figure 1 - Posteroanterior chest X-ray showing pleural effusion in the right hemithorax.

Figure 2 - CT scan of the thorax revealing right pleural effusion, thin septa, and atelectasis of the underlying lung.

J Bras Pneumol. 2012;38(5):679-680

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Demir M, Karadeniz G, Uz E

patient was asymptomatic and was discharged, remaining asymptomatic throughout a fourweek follow-up period. Clinical characteristics and chest X-ray findings, as well as serum levels of urea and creatinine, were normal.

Urinothorax is probably more common than is supposed, because it is not usually included in the differential diagnosis of pleural effusion. For the definitive diagnosis of urinothorax, creatinine content should be determined in pleural fluid and in serum, a pleural/serum creatinine ratio of > 1 being considered diagnostic of the condition.(3) Because creatinine is not routinely measured in pleural fluid, some patients with urinothorax might recover without having been correctly diagnosed.

The history of percutaneous nephrolithotomy in our patient led us to determine the creatinine levels, and the diagnosis was established. It was our good fortune that the condition developed only a few days after that procedure.

In summary, given that urinothorax can develop several weeks after urologic procedures or without any apparent cause in cases of obstructive uropathy, we emphasize the importance of the clinical suspicion of urinothorax for its early diagnosis and treatment. Once urinothorax has been definitively diagnosed, we recommend that, with certain exceptions, radionuclide imaging should not be performed, thereby avoiding unnecessary radiation exposure and costs.

Melike Demir Pulmonologist, Sanatoryum Cd, Kecioren, Ankara, Turkey Gülistan Karadeniz Pulmonologist, Sanatoryum Cd, Kecioren, Ankara, Turkey Ebru Uz Nephrologist, Sanatoryum Cd, Kecioren, Ankara, Turkey

References 1. Handa A, Agarwal R, Aggarwal AN. Urinothorax: an unusual cause of pleural effusion. Singapore Med J. 2007;48(11):e289-92. PMid:17975679.

2. Garcia-Pachon E, Padilla-Navas I. Urinothorax: case report and review of the literature with emphasis on biochemical diagnosis. Respiration. 2004;71(5):533-6.

PMid:15467335. http://dx.doi.org/10.1159/000080642 3. Hooper C, Lee YC, Maskell N; BTS Pleural Guideline Group.

Investigation of a unilateral pleural effusion in adults: British Thoracic Society Pleural Disease Guideline 2010.

Thorax. 2010;65 Suppl 2:ii 4-17.

Submitted: 04 February 2012. Accepted, after review: 22 February 2012.

J Bras Pneumol. 2012;38(5):679-680

A eficácia do antileucotrieno 1 A eficácia do antileucotrieno para o tratamento das vias aéreas combinadas 1

para crianças de 6 meses a 5 anos de idade.2

Contribui para a redução de: Uso de corticóides 1 Crises de Asma 1 Número de hospitalizações 1

montelucaste de sódio 4 mg/granulado 3, 4

Contraindicações: Hipersensibilidade a qualquer componente do produto. Interações medicamentosas: MONTELAIR pode ser administrado com outros medicamentos na profilaxia e tratamento crônico da asma e tratamento de rinite alérgica. Em estudos de interações medicamentosas, a dose terapêutica recomendada não teve efeitos clinicamente importantes na farmacocinética dos medicamentos: teofilina, prednisona, prednisolona, contraceptivos orais (etinilestradiol/noretindrona 35 µg/1 mg), terfenadina, digoxina e varfarina. Embora não tenham sido realizados outros estudos específicos de interação, o montelucaste de sódio foi usado em estudos clínicos concomitantemente à ampla variedade de medicamentos comumente prescritos (hormônios tireoidianos, sedativos hipnóticos, agentes anti-inflamatórios não esteróides, benzodiazepínicos e descongestionantes),sem evidência de interações. Não é recomendado ajuste posológico.

Referências bibliográficas: 1. BORDERIAS, Luis et al. Asthma control in patients with asthma and allergic rhinitis receiving add-on montelukast therapy for 12 months: a retrospective observational study. Current medical research and options. v. 23, n. 4, p. 721-730, 2007. 2. Bula do produto MONTELAIR® GRANULADO 4MG. Responsável técnico: Wilson R. Farias. Aché Laboratórios Farmacêuticos SA. Guarulhos, SP. 3. Comparação feita com base no produto Singulair Baby®, marca registrada do laboratório Merck Sharp & Dohme. 4. Revista KAIROS. Junho 2012 - PMC ICMS 18%.

MONTELAIR (montelucaste de sódio - comprimidos revestidos 10 mg - Uso adulto. Granulado 4mg - Uso pediátrico acima de 6 meses de idade). Uso oral. Indicações: MONTELAIR é indicado para a profilaxia e o tratamento crônico da asma, incluindo a prevenção de sintomas diurnos e noturnos, broncoconstrição induzida pelo exercício e pacientes asmáticos sensíveis a aspirina. Pode ser utilizado concomitantemente a corticosteróides inalatórios com efeitos aditivos no controle da asma e para reduzir a dose deste corticosteróide inalatório num quadro clínico estável. MONTELAIR é indicado para o alivio dos sintomas da rinite alérgica; lacrimejamento e hiperemia ocular. Precauções e Advertências: MONTELAIR não deve ser usado para o tratamento das crises agudas de asma. Os pacientes devem ser aconselhados a ter disponível medicamento de resgate.

MONTELAIR não deve substituir abruptamente os corticosteróides inalatórios ou orais.Gravidez e lactação: Categoria de risco na gravidez: B. Este medicamento não deve ser utilizado por mulheres grávidas sem orientação médica ou do cirurgião-dentista. O montelucaste de sódio não foi estudado em gestantes, portanto, deve ser usado durante a gravidez somente se claramente necessário. Não há informações sobre a excreção de montelucaste no leite humano. Como muitos medicamentos são excretados no leite humano, deve-se ter cautela quando administrado a nutrizes. Reações adversas: O montelucaste de sódio tem sido bem tolerado. As reações adversas, usualmente leves, geralmente não requereram descontinuação da terapia. A incidência global das reações adversas foi comparável à do placebo. Posologia: MONTELAIR deve ser administrado uma vez ao dia. Para asma, a dose deve ser administrada à noite. Para rinite alérgica, o horário da administração pode ser individualizado para atender às necessidades do paciente. Montelair 4mg granulado: Pacientes pediátricos de 6 meses a 2 anos de idade com asma e pacientes de 2 a 5 anos com asma e/ou rinite alérgica: a posologia é de um sachê de grânulos orais de 4 mg diariamente. Administração dos grânulos orais: os grânulos orais de MONTELAIR podem ser administrados diretamente na boca ou misturados com uma colher cheia de alimentação leve (por exemplo, papinha de maçã) à temperatura ambiente ou fria. A embalagem deve ser mantida fechada até o uso e, depois de aberta, toda a dose deve ser administrada imediatamente (no período de 15 minutos). Se misturado com algum alimento, MONTELAIR não deve ser armazenado para uso posterior. Os grânulos orais de MONTELAIR não foram desenvolvidos para serem dissolvidos em líquidos, mas podem ser administrados após o uso do medicamento. Montelair 10mg comprimido revestido: Adultos e adolescentes a partir de 15 anos de idade com asma e/ou rinite alérgica: a posologia é de 1 comprimido de 10 mg diariamente. “SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO.” VENDA SOB PRESCRIÇÃO MÉDICA. MS - 1.0573.0405 – Montelair granulado MB_03 e comrev MB_02. Para informações completas, consultar a bula na íntegra através da Central de Atendimento ao Cliente.

Material técnico-científico de distribuição exclusiva a profissionais de saúde habilitados à prescrição e/ou dispensação de medicamentos.

Out/2012

Referências bibliográficas: 1) Bula do Produto. 2) Haughney, J. et al. Patient-centred outcomes in primary care management of COPD - what do recent clinical trial data tell us? Prim Care Respir J, 2004; 13(4):185-97. 3) Halpin, D.M.G. et al. Identifying COPD patients at increased risk of mortality: Predictive value of clinical study baseline data. Respiratory Medicine, 2008; 102: 1615-1624.

Symbicort® Turbuhaler® (fumarato de formoterol diidratado/budesonida) 6/100 mcg/inalação é composto por substâncias que possuem diferentes modos de ação e que apresentam efeitos aditivos em termos de redução das exacerbações asmáticas. A budesonida é um glicocorticosteróide e o formoterol é um agonista beta-2-adrenérgico seletivo de início de ação rápida e longa duração. Indicações: Symbicort®Turbuhaler® está indicado no tratamento da ASMA nos casos em que o uso de uma associação (corticosteróide inalatório com um beta-2 agonista de ação prolongada) é apropriado. Contraindicações: Hipersensibilidade à budesonida, ao formoterol ou à lactose inalatória. Cuidados e Advertências: Advertências: A deterioração súbita e progressiva no controle da ASMA pode potencialmente representar risco de vida e o paciente deve passar por uma avaliação médica com urgência. O tratamento não deve ser iniciado para tratar uma exacerbação grave. Deve-se tomar cuidado especial em pacientes que são transferidos de esteróides orais para inalatórios, uma vez que podem permanecer riscos de função adrenal prejudicada durante um tempo considerável. Pacientes que necessitaram de terapia corticosteróide de alta dose emergencial também podem estar em risco. Estes pacientes podem exibir sinais e sintomas de insuficiência adrenal quando expostos a situações de estresse grave. Administração de corticosteróide sistêmico adicional deveria ser considerada durante situações de estresse ou cirurgia eletiva. Symbicort® Turbuhaler® deve ser administrado com cautela em pacientes com graves transtornos cardiovasculares (incluindo anomalias do ritmo cardíaco), diabetes mellitus, hipocalemia não tratada ou tireotoxicose. A administração de doses elevadas de um beta-2 agonista pode diminuir o potássio sérico, por induzir a redistribuição de potássio do meio extracelular para o meio intracelular, via estimulação da Na+/K+-ATPase nas células musculares. Uso durante a gravidez e a lactação: Symbicort® Turbuhaler® só deve ser utilizado durante a gravidez após ponderação cuidadosa da situação, em especial durante os primeiros três meses da gestação e pouco tempo antes do parto. Deve ser usada a menor dose eficaz de budesonida de modo a permitir o controle adequado da ASMA. Só deverá considerar-se a hipótese de utilizar Symbicort® Turbuhaler® em mulheres lactantes se os benefícios esperados para a mãe superarem qualquer possível risco para a criança (para maiores informações vide bula completa do produto). Interações medicamentosas: Os inibidores da enzima CYP3A4, como o cetoconazol, podem aumentar a exposição sistêmica à budesonida. Os bloqueadores beta-adrenérgicos (incluindo os colírios oftálmicos) podem atenuar ou inibir o efeito do formoterol. Não foi observado que a budesonida e o formoterol interajam com outros fármacos usados no tratamento da ASMA (para maiores informações vide bula completa do produto). Reações adversas: As reações adversas mais freqüentes relacionadas com a droga consistem em efeitos colaterais farmacologicamente previsíveis da terapêutica beta-2 agonista, tais como tremor e palpitações. Estes tendem a ser leves e a desaparecer após alguns dias de tratamento.

As reações adversas que foram associadas à budesonida ou ao formoterol são candidíase na orofaringe, cefaléia e tremor e leve irritação na garganta, tosse e rouquidão (para outras reações adversas, vide bula completa do produto). Posologia: A dose de Symbicort® Turbuhaler® deve ser individualizada conforme a gravidade da doença. Quando for obtido o controle da ASMA, a dose deve ser titulada para a menor dose que permita manter um controle eficaz dos sintomas. Os pacientes devem ser instruídos a usar o medicamento mesmo quando estiverem assintomáticos para obter o benefício máximo da terapia. Terapia com um único inalador: Adultos e adolescentes (a partir de 12 anos de idade): a dose de manutenção diária usual é de 2 inalações uma vez ao dia ou 1 inalação duas vezes ao dia. Alguns pacientes podem precisar de uma dose de manutenção de 2 inalações duas vezes ao dia. Os pacientes devem administrar inalações adicionais, conforme sua necessidade, em resposta aos sintomas. Uma dose diária total de até 12 inalações pode ser usada temporariamente. Crianças (a partir de 4 anos de idade): a dose de manutenção diária usual é de 1 inalação uma vez ao dia. Alguns pacientes podem precisar de uma dose de manutenção de 1 inalação duas vezes ao dia. Os pacientes devem administrar inalações adicionais, conforme sua necessidade, em resposta aos sintomas. Uma dose diária total de até 8 inalações pode ser usada temporariamente. Terapia de Manutenção Regular: Adultos (a partir de 18 anos de idade): 1- 2 inalações uma ou duas vezes ao dia. Adolescentes (12-17 anos de idade): 1-2 inalações uma ou duas vezes ao dia.

Crianças (a partir de 4 anos de idade): 1-2 inalações duas vezes ao dia. Dose máxima diária: 4 inalações. Instruções de Uso: vide bula completa do produto. Superdose: A superdosagem de formoterol provoca tremor, cefaléias, palpitações e taquicardia. Poderá igualmente ocorrer hipotensão, acidose metabólica, hipocalemia e hiperglicemia. Não é esperado que uma superdosagem aguda de budesonida, mesmo em doses excessivas, constitua um problema clínico. Quando utilizado cronicamente em doses excessivas, podem ocorrer efeitos glicocorticosteróides sistêmicos. Apresentações: Pó inalante 6/100 mcg/inalação em embalagem com 1 tubo contendo 60 doses. USO ADULTO e PEDIÁTRICO. USO POR INALAÇÃO ORAL. VENDA SOB PRESCRIÇÃO MÉDICA. Para maiores informações, consulte a bula completa do produto (CDS 06.11.03 Jul/07). AstraZeneca do Brasil Ltda., Rod. Raposo Tavares, Km 26,9 - Cotia SP - CEP 06707-000 Tel.: 0800-0145578. www.astrazeneca.com.br Symbicort® MS – 1.1618.0106.

Symbicort® Turbuhaler® fumarato de formoterol diidratado/budesonida 6/200 mcg/inalação é composto por substâncias que possuem diferentes modos de ação e que apresentam efeitos aditivos em termos de redução das exacerbações da ASMA e da doença pulmonar obstrutiva crônica (DPOC). A budesonida é um glicocorticosteróide e o formoterol é um agonista beta-2-adrenérgico seletivo de início de ação rápida e longa duração. Indicações: ASMA: Symbicort® Turbuhaler® está indicado no tratamento da ASMA nos casos em que o uso de uma associação (corticosteróide inalatório com um beta-2 agonista de ação prolongada) é apropriado. DPOC: Symbicort® Turbuhaler® está indicado no tratamento regular de pacientes com DPOC de moderada a grave, com sintomas freqüentes e história de exacerbações.

Contra-indicações: Hipersensibilidade à budesonida, ao formoterol ou à lactose inalatória. Cuidados e Advertências: Advertências: A deterioração súbita e progressiva no controle da ASMA ou DPOC pode potencialmente representar risco de vida e o paciente deve passar por uma avaliação médica com urgência. O tratamento não deve ser iniciado para tratar uma exacerbação grave. Deve-se tomar cuidado especial em pacientes que são transferidos de esteróides orais para inalatórios, uma vez que podem permanecer riscos de função adrenal prejudicada durante um tempo considerável. Pacientes que necessitaram de terapia corticosteróide de alta dose emergencial também podem estar em risco. Estes pacientes podem exibir sinais e sintomas de insuficiência adrenal quando expostos a situações de estresse grave. Administração de corticosteróide sistêmico adicional deveria ser considerada durante situações de estresse ou cirurgia eletiva. Symbicort® Turbuhaler® deve ser administrado com cautela em pacientes com graves transtornos cardiovasculares (incluindo anomalias do ritmo cardíaco), diabetes mellitus, hipocalemia não tratada ou tireotoxicose. A administração de doses elevadas de um beta-2 agonista pode diminuir o potássio sérico, por induzir a redistribuição de potássio do meio extracelular para o meio intracelular, via estimulação da Na+/K+-ATPase nas células musculares. Uso durante a gravidez e a lactação: Symbicort® Turbuhaler® só deve ser utilizado durante a gravidez após ponderação cuidadosa da situação, em especial durante os primeiros três meses da gestação e pouco tempo antes do parto. Deve ser usada a menor dose eficaz de budesonida de modo a permitir o controle adequado da ASMA. Só deverá considerar-se a hipótese de utilizar Symbicort® Turbuhaler® em mulheres lactantes se os benefícios esperados para a mãe superarem qualquer possível risco para a criança (para maiores informações vide bula completa do produto). Interações medicamentosas: Os inibidores da enzima CYP3A4, como o cetoconazol, podem aumentar a exposição sistêmica à budesonida. Os bloqueadores beta-adrenérgicos (incluindo os colírios oftálmicos) podem atenuar ou inibir o efeito do formoterol. Não foi observado que a budesonida e o formoterol interajam com outros fármacos usados no tratamento da ASMA (para maiores informações vide bula completa do produto). Reações adversas: As reações adversas mais frequentes relacionadas com a droga, consistem em efeitos colaterais farmacologicamente previsíveis da terapêutica beta-2 agonista, tais como tremor e palpitações. Estes tendem a ser leves e a desaparecer após alguns dias de tratamento. As reações adversas que foram associadas à budesonida ou ao formoterol são candidíase na orofaringe, cefaléia e tremor e leve irritação na garganta, tosse e rouquidão (outras reações adversas, vide bula completa do produto). Posologia: A dose de Symbicort® Turbuhaler® deve ser individualizada conforme a gravidade da doença. Quando for obtido o controle dos sintomas, a dose deve ser titulada para a menor dose que permita manter um controle eficaz dos sintomas. Os pacientes devem ser instruídos a usar o medicamento mesmo quando estiverem assintomáticos para obter o benefício máximo da terapia. Terapia com um único inalador: Adultos e adolescentes (a partir de 12 anos de idade): a dose de manutenção diária usual é de 2 inalações uma vez ao dia ou 1 inalação duas vezes ao dia.

Alguns pacientes podem precisar de uma dose de manutenção de 2 inalações duas vezes ao dia. Os pacientes devem administrar inalações adicionais, conforme sua necessidade, em resposta aos sintomas.

Uma dose diária total de até 12 inalações pode ser usada temporariamente. Terapia de Manutenção Regular: ASMA: Adultos (a partir de 18 anos de idade): 1-2 inalações uma ou duas vezes ao dia. Em alguns casos, pode ser necessário um máximo de 4 inalações, duas vezes ao dia, como dose de manutenção ou temporariamente durante uma piora da ASMA. Adolescentes (12-17 anos de idade): 1-2 inalações uma ou duas vezes ao dia. Durante uma piora da ASMA, a dose pode ser temporariamente aumentada para um máximo de 4 inalações, duas vezes ao dia. Crianças (a partir de 4 anos de idade): 1 inalação duas vezes ao dia. Dose máxima diária: 2 inalações. DPOC: Adultos (a partir de 18 anos de idade): 2 inalações duas vezes ao dia. Dose máxima diária: 4 inalações. Instruções de Uso: vide bula completa do produto.

Superdose: A superdosagem de formoterol provoca tremor, cefaléias, palpitações e taquicardia. Poderá igualmente ocorrer hipotensão, acidose metabólica, hipocalemia e hiperglicemia. Não é esperado que uma superdosagem aguda de budesonida, mesmo em doses excessivas, constitua um problema clínico. Quando utilizado cronicamente em doses excessivas, podem ocorrer efeitos glicocorticosteróides sistêmicos. Apresentações: Pó inalante 6/200 mcg/inalação em embalagem com 1 tubo contendo 60 doses. USO ADULTO e PEDIÁTRICO. USO POR INALAÇÃO ORAL. VENDA SOB PRESCRIÇÃO MÉDICA. Para maiores informações, consulte a bula completa do produto (CDS 06.11.03 Jul/07). AstraZeneca do Brasil Ltda., Rod. Raposo Tavares, Km 26,9 - Cotia SP - CEP 06707-000 Tel.: 0800-0145578. www.astrazeneca.com.br Symbicort® MS – 1.1618.0106.

Symbicort® Turbuhaler® fumarato de formoterol diidratado/budesonida 12/400 mcg/inalação é composto por substâncias que possuem diferentes modos de ação e que apresentam efeitos aditivos em termos de redução das exacerbações da ASMA e da doença pulmonar obstrutiva crônica (DPOC). A budesonida é um glicocorticosteróide e o formoterol é um agonista beta-2-adrenérgico seletivo de ação rápida e longa duração. Indicações: ASMA: Symbicort® Turbuhaler® está indicado no tratamento da ASMA nos casos em que o uso de uma associação (corticosteróide inalatório com um beta-2 agonista de ação prolongada) é apropriado. DPOC: Symbicort® Turbuhaler® está indicado no tratamento regular de pacientes com DPOC de moderada a grave, com sintomas freqüentes e história de exacerbações. Contraindicações: Hipersensibilidade à budesonida, ao formoterol ou à lactose inalatória. Cuidados e Advertências: Advertências: Os pacientes devem ser aconselhados a ter sempre à disposição o seu broncodilatador de ação rápida. O tratamento não deve ser iniciado para tratar uma exacerbação grave. Deve-se tomar cuidado especial em pacientes que são transferidos de esteróides orais para inalatórios, uma vez que podem permanecer riscos de função adrenal prejudicada durante um tempo considerável. Pacientes que necessitaram de terapia corticosteróide de alta dose emergencial também podem estar em risco. Estes pacientes podem exibir sinais e sintomas de insuficiência adrenal quando expostos a situações de estresse grave. Administração de corticosteróide sistêmico adicional deveria ser considerada durante situações de estresse ou cirurgia eletiva. Symbicort® Turbuhaler® deve ser administrado com cautela em pacientes com graves transtornos cardiovasculares (incluindo anomalias do ritmo cardíaco), diabetes mellitus, hipocalemia não tratada ou tireotoxicose. A administração de doses elevadas de um beta-2 agonista pode diminuir o potássio sérico, por induzir a redistribuição de potássio do meio extracelular para o meio intracelular, via estimulação da Na+/K+-ATPase nas células musculares. Uso durante a gravidez e a lactação: Symbicort® Turbuhaler® só deve ser utilizado durante a gravidez após ponderação cuidadosa da situação, em especial durante os primeiros três meses da gestação e pouco tempo antes do parto. Deve ser usada a menor dose eficaz de budesonida de modo a permitir o controle adequado da ASMA. Só deverá considerar-se a hipótese de utilizar Symbicort® Turbuhaler® em mulheres lactantes se os benefícios esperados para a mãe superarem qualquer possível risco para a criança (para maiores informações vide bula completa do produto). Interações medicamentosas: Inibidores da enzima CYP3A4, como o cetoconazol, podem aumentar a exposição sistêmica à budesonida. Os bloqueadores beta-adrenérgicos (incluindo os colírios oftálmicos) podem atenuar ou inibir o efeito do formoterol. Não foi observado que a budesonida e o formoterol interajam com outros fármacos usados no tratamento da ASMA (para maiores informações vide bula completa do produto). Reações adversas: As reações adversas mais freqüentes relacionadas com a droga consistem em efeitos colaterais farmacologicamente previsíveis da terapêutica beta-2 agonista, tais como tremor e palpitações. Estes tendem a ser leves e a desaparecer após alguns dias de tratamento. As reações adversas que foram associadas à budesonida ou ao formoterol são candidíase na orofaringe, cefaléia e tremor e leve irritação na garganta, tosse e rouquidão (para outras reações adversas, vide bula completa do produto). Posologia: A dose de Symbicort® Turbuhaler® deve ser individualizada conforme a gravidade da doença. Quando for obtido o controle dos sintomas, a dose deve ser titulada para a menor dose que permita manter um controle eficaz dos sintomas. Os pacientes devem ser instruídos a usar o medicamento mesmo quando estiverem assintomáticos para obter o benefício máximo da terapia. Terapia de Manutenção Regular: ASMA: Adultos (a partir de 18 anos de idade) 1 inalação uma ou duas vezes ao dia. Em alguns casos, pode ser necessário um máximo de 2 inalações, duas vezes ao dia, como dose de manutenção ou temporariamente durante uma piora da ASMA. Adolescentes (12-17 anos de idade): 1 inalação uma ou duas vezes ao dia. Durante uma piora da ASMA, a dose de manutenção pode ser temporariamente aumentada para um máximo de 2 inalações, duas vezes ao dia. DPOC 1 inalação duas vezes ao dia. Dose máxima diária: 2 inalações. Instruções de Uso: vide bula completa do produto. Superdose: A superdosagem de formoterol provoca tremor, cefaléias, palpitações e taquicardia. Poderá igualmente ocorrer hipotensão, acidose metabólica, hipocalemia e hiperglicemia. Não é esperado que uma superdosagem aguda de budesonida, mesmo em doses excessivas, constitua um problema clínico. Quando utilizado cronicamente em doses excessivas, podem ocorrer efeitos glicocorticosteróides sistêmicos. Apresentações: Pó inalante 12/400 mcg/inalação em embalagem com 1 tubo contendo 60 doses. USO ADULTO. USO POR INALAÇÃO ORAL. VENDA SOB PRESCRIÇÃO MÉDICA. Para maiores informações, consulte a bula completa do produto (CDS 06.11.03 Jul/07). AstraZeneca do Brasil Ltda., Rod. Raposo Tavares, Km 26,9 - Cotia SP - CEP 06707-000 Tel.: 0800-0145578. www.astrazeneca.com.br Symbicort® MS – 1.1618.0106

Contraindicações: Hipersensibilidade à budesonida, ao formoterol ou à lactose inalatória. Interações medicamentosas: Os bloqueadores beta-adrenérgicos (incluindo os colírios oftálmicos) podem atenuar ou inibir o efeito do formoterol.

10.000 horas para você

se tornar um especialista.

Horas que trazem conhecimento

para o controle da ASMA e DPOC.

ESPECIALISTA QUE INSPIRA CONFIANÇA. • Especialista em ASMA.

1

Controle com manutenção e alívio em um único inalador.

• Especialista em DPOC.

2,3

Melhor controle da DPOC hoje e no futuro.

Symbicort ® 6/100: 60 doses - ASMA Crianças a partir dos 4 anos, adolescentes e adultos.1

Symbicort ® 12/400: 60 doses - ASMA e DPOC Adolescentes e adultos a partir de 12 anos.1

Cód.: SY.11.C.120

Symbicort ® 6/200: 60 doses - ASMA e DPOC Crianças a partir dos 4 anos, adolescentes e adultos.1

Contraindicações: Hipersensibilidade à budesonida, ao formoterol ou à lactose inalatória. Interações medicamentosas: Os bloqueadores beta-adrenérgicos (incluindo os colírios oftálmicos) podem atenuar ou inibir o efeito do formoterol.

A PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO.

INTERVIR COM SPIRIVA® para ajudar os pacientes com DPOC a manter um amanhã mais ativo.1, 2

Redução rápida e sustentada da falta de ar3 Prevenção de exacerbações da DPOC3, 4

2 puffs

consecutivos, uma vez ao dia 3

Melhora da qualidade de vida3, 5 Dispositivo inovador para seu paciente com DPOC6 SPIRIVA® RESPIMAT® (brometo de tiotrópio) - uso adulto. Apresentação: frasco com 4ml. Indicação: DPOC. Contraindicações: hipersensibilidade aos seus componentes.

Reações adversas: boca ou pele seca, tontura, arritmias, disfonia, epistaxe, tosse, faringite, laringite, gengivite, glossite, estomatite, candidíase orofaríngea, disfagia, dispepsia, prurido, hipersensibilidade, rash, urticária, broncoespasmo, edema angioneurótico, glaucoma, visão embaçada, infecção e úlcera de pele, retenção e infecção urinária, disúria, desidratação, insônia, sinusite, constipação, obstrução intestinal, íleo paralítico, edema articular. Precauções: pacientes com distúrbios de ritmo cardíaco devem utilizar Spiriva® Respimat® com cautela; não usar como terapia de resgate; cuidado no glaucoma de ângulo fechado, hiperplasia da próstata, obstrução do colo da bexiga, clearance de creatinina ≤50ml/min, tontura ou visão embaçada podem alterar habilidade de dirigir e operar máquinas, não usar em mulheres grávidas ou lactantes (risco C). Interações: medicações anticolinérgicas. Posologia: inalar 2 puffs/dia.

SEM NECESSIDADE DE REFRIGERAÇÃO.3 VENDA SOB PRESCRIÇÃO MÉDICA. MS-1.0367.0137. Boehringer Ingelheim do Brasil Química e Farmacêutica Ltda. Rod. Regis Bittencourt (BR116), km 286. Itapecerica da Serra – SP. SAC 0800-7016633. Se persistirem os sintomas, o médico deverá ser consultado.

ESTE MEDICAMENTO É CONTRAINDICADO EM PACIENTES COM HISTÓRIA DE HIPERSENSIBILIDADE À ATROPINA OU A SEUS DERIVADOS. A ADMINISTRAÇÃO CRÔNICA DE OUTROS FÁRMACOS ANTICOLINÉRGICOS COM SPIRIVA® NÃO FOI ESTUDADA E, PORTANTO, NÃO É RECOMENDADA. SPIRIVA® É UM MEDICAMENTO. DURANTE SEU USO, NÃO DIRIJA VEÍCULOS OU OPERE MÁQUINAS, POIS SUA AGILIDADE E ATENÇÃO PODEM ESTAR PREJUDICADAS. MATERIAL DESTINADO EXCLUSIVAMENTE A PROFISSIONAIS HABILITADOS A PRESCREVER MEDICAMENTOS.

Referências: 1. Decramer M et al. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomized controlled trial. Lancet, published on-line August 28, 2009, DOI:10.16/S0140-6736(09)61298-8. 2. Decramer M et al. Tiotropium as essential maintenance therapy in COPD. Eur Respir Rev 2006; 15: 99, 51–7. 3. Bula de Spiriva® Respimat® 4. Vogelmeier C et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011; 364 (12) : 1093-103. 5. Tashkin DP et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008; 9 (15) : 1543-54. 6. Dalby RN et al. Development of Respimat Soft Mist Inhaler and its clinical utility in respiratory disorders. Medical Devices: Evidence and Research. 2011; 4: 145-55.

Eficácia superior na função pulmonar vs

formoterol e salmeterol desde a primeira dose.1,2

Melhora significativa da dispneia, da qualidade de vida e do uso de medicação de resgate vs formoterol, salmeterol e tiotrópio.1,2,3 Contraindicações: hipersensibilidade ao princípio ativo ou a qualquer um dos excipientes. ONBRIZETM é contraindicado para pacientes asmáticos. Interações medicamentosas: deverá ser administrado com cautela em pacientes sendo tratados com inibidores da monoamino oxidase, antidepressivos tricíclicos ou medicamentos conhecidos por prolongar o intervalo QT e outros agentes simpatomiméticos, agentes hipocalêmico.

ONBRIZE TM maleato de indacaterol. Forma farmacêutica e apresentações: Cápsulas com pó para inalação contendo 150 ou 300 microgramas de indacaterol. Caixas com 10 ou 30 cápsulas acompanhadas de um inalador. Indicações: ONBRIZE TM é um beta2-agonista de ação prolongada, indicado para o tratamento broncodilatador de manutenção em longo prazo, em dose única diária, da obstrução ao fluxo aéreo em pacientes com doença pulmonar obstrutiva crônica (DPOC) moderada a grave, definida como um VEF1 pós-broncodilatador < 80% e ≥ 30%TMdo valor normal previsto e um VEF1/CVF pós-broncodilatador inferior a 70%. Posologia: Adultos – A dose recomendada de ONBRIZE é uma inalação uma vez ao dia doTMconteúdo de uma cápsula de ONBRIZE 150 mcg usando o seu inalador. A dose deve ser aumentada apenas sob orientação médica. A inalação do conteúdo, uma vez ao dia, de uma cápsula de ONBRIZE 300 mcg usando o inalador trouxe benefícios clínicos adicionais para alguns pacientes, por exemplo, com relação à respiração, particularmente para pacientes com DPOC grave. A dose máxima é 300 mcg uma vez ao dia. Crianças (menores de 18 anos) – Não deve ser utilizado em pacientes abaixo de 18 anos de idade. População especial – Nenhum ajuste de dose é necessário para pacientes idosos, com disfunção hepática leve e moderada ou disfunção renal. Não há dado disponível para pacientes com disfunção hepática grave.TMMétodo de administração: As cápsulas de ONBRIZE TM devem ser administradas apenas por via inalatória oral e apenas usando o inalador. As cápsulas de ONBRIZE TM não devem deve ser administrado no mesmo horário todos os dias. Se uma dose for esquecida, a próxima dose deve ser tomada no dia seguinte no horário usual. As cápsulas devem ser ser engolidas. ONBRIZE armazenadas no blíster, e apenas removidas imediatamente antes do uso. Contraindicações: Hipersensibilidade ao princípio ativo ou a qualquer um dos excipientes. ONBRIZE TM é contraindicado para pacientes asmáticos. Precauções e Advertências: Asma – ONBRIZE TM não deve ser usado em casos de asma devido à ausência de dados com resultados de longa duração para esta indicação (veja “Contraindicações”).

Broncoespasmo paradoxal – Assim como com outras terapias inalatórias, a administração pode resultar em broncoespasmo paradoxal que pode ocasionar risco à vida. Se ocorrer broncoespasmo paradoxal, ONBRIZE TM deve ser descontinuado imediatamente e um tratamento alternativo deve ser instituído. Deterioração da doença – No caso de deterioração da DPOC durante o tratamento, deve-se reconsiderar uma reavaliação do paciente e o regime de tratamento da DPOC deve ser combinado. Efeitos sistêmicos – Assim como outros agonitas beta2-adrenérgicos, indacaterol deve ser utilizado com precaução em pacientes com distúrbios cardiovasculares (doença coronariana arterial, infarto do miocárdio agudo, arritmia cardíaca, hipertensão), em pacientes com distúrbios convulsivos ou tireotoxicose e em pacientes que têm resposta exacerbada aos agonistas beta2-adrenérgicos. Efeitos cardiovasculares – Como outros agonistas beta2-adrenérgicos, indacaterol pode produzir um efeito cardiovascular clinicamente significante em alguns pacientes medido pelo aumento da pulsação, da pressão sanguínea e/ou sintomas, alterações no ECG. Hipocalemia – Os agonitas beta2-adrenérgicos podem produzir hipocalemia significante em alguns pacientes, o que pode produzir efeitos adversos cardiovasculares. Em pacientes com DPOC grave, a hipocalemia pode ser potencializada por hipóxia ou tratamento concomitante que podem aumentar a susceptibilidade de arritmias cardíacas. Hiperglicemia – Alterações clinicamente notáveis na glicose sanguínea foram geralmente de 1 a 2% mais frequentes no grupo de ONBRIZE TM nas doses recomendadas do que no placebo. Não deverá ser utilizado concomitantemente com outros beta2-agonista de longa duração ou medicamentos contendo agonistas beta2-agonista de ação prolongada. Gravidez – só deve ser utilizado durante a gravidez se os benefícios esperados justificarem o risco potencial ao feto. Embora o indacaterol não tenha afetado a capacidade reprodutiva geral em um estudo de fertilidadeTMcom ratos, verificou-se uma diminuição do número de gravidezes na geração F1 em estudo de pré e pós-desenvolvimento em ratos, com uma exposição 14 vezes superior à de humanos tratados com ONBRIZE . Lactação – o uso de ONBRIZE TM deve ser considerado apenas se o benefício esperado para a mulher for maior que qualquer possível risco ao bebê. Fertilidade – Estudos de reprodução ou outros dados em animais não revelaram problema ou potencial problema em relação a fertilidade tanto em homens como em mulheres. Interações medicamentosas: Deverá ser administrado com cautela em pacientes sendo tratados com inibidores da monoamino oxidase, antidepressivos tricíclicos ou medicamentos conhecidos por prolongar o intervalo QT. Administração concomitante com outros agentes simpatomiméticos pode potencializar os efeitos indesejáveis. Tratamento concomitante com derivados da metilxantina, esteroides, ou diuréticos depletores de potássio, pode potencializar os possíveis efeitos hipocalemicos dos agonistas beta2adrenérgicos. Não deverá ser administrado concomitantemente com outros bloqueadores beta-adrenérgicos (incluindo colírios) a menos que haja razões para a utilização. A inibição dos principais contribuintes para o clearance do indacaterol, CYP3A4 e P-gp, não teve impacto sobre a segurança de doses terapêuticas.

Reações adversas: Comuns (1 a 10%): nasofaringite, infecção do trato respiratório superior, tosse, espasmo muscular, dor orofaríngea, sinusite, mialgia, edema periférico, doença cardíaca isquêmica, diabetes mellitus e hiperglicemia, boca seca, rinorreia, dor musculoesquelética, dor no peito. Incomuns (0,1 a 1%): fibrilação atrial, desconforto no peito, vertigo e parestesia. VENDA SOB PRESCRIÇÃO MÉDICA. Reg. MS – 1.0068.1073.

Informações completas para prescrição disponíveis mediante solicitação ao Departamento Médico da Novartis.

Referências bibliográficas: 1) Dahl R, Chung KF, Buhl R et al. Efficacy of a new once-daily long-acting inhaled b2-agonist indacaterol versus twice-daily formoterol in COPD (INVOLVE). Thorax 2010; 65:473-479. 2) Donohue JF, Fogarty C, Lotvall J, Mahler DA et al. Once Daily Bronchodilators for Chronic Obstructive Pulmonary Disease (INHANCE). Indacaterol versus Tiotropium. American Journal of Respiratory and Critical Care Medicine 2010; vol 182: 155-162. 3) Kornmann O, Dahl R et al. Once-daily indacaterol vs twice-daily salmeterol for COPD: a placebo-controlled comparison (INLIGHT-2). European Respiratory Journal 2011;37:273-279.

Material destinado a profissionais de saúde habilitados a prescrever e/ou dispensar medicamentos. Produzido em julho de 2012.

Instruções aos Autores O Jornal Brasileiro de Pneumologia (J Bras Pneumol) ISSN-1806-3713, publicado bimestralmente, é órgão oficial da Sociedade Brasileira de Pneumologia e Tisiologia destinado à publicação de trabalhos científicos referentes à Pneumologia e áreas correlatas.

Todos os manuscritos, após análise inicial pelo Conselho Editorial, serão avaliados por revisores qualificados, sendo o anonimato garantido em todo o processo de julgamento. Os artigos podem ser submetidos em português, espanhol ou inglês. Na versão eletrônica do Jornal (www.jornaldepneumologia.com.br, ISSN‑1806‑3756) todos os artigos serão disponibilizados tanto em língua latina como em inglês. A impressão de figuras coloridas é opcional e os custos relativos a esse processo serão transferidos aos autores. Favor entrar em contato com a secretaria do Jornal para esclarecimentos adicionais.

O Jornal Brasileiro de Pneumologia apóia as políticas para registro de ensaios clínicos da Organização Mundial da Saúde (OMS) e do International Committee of Medical Journal Editors (ICMJE), reconhecendo a importância dessas iniciativas para o registro e divulgação internacional de informações sobre estudos clínicos em acesso aberto. Sendo assim, somente serão aceitos para publicação ensaios clínicos que tenham recebido um número de identificação em um dos Registros de Ensaios Clínicos validados pelos critérios estabelecidos pela OMS e ICMJE. O número de identificação deverá ser registrado ao final do resumo.

Apresentação e submissão dos manuscritos Os manuscritos deverão ser obrigatoriamente encaminhados via eletrônica a partir da própria home-page do Jornal. As instruções estão disponíveis no endereço ­www­.­­jornaldepneumologia.com.br/sgp. Pede-se aos autores que sigam rigorosamente as normas editoriais da revista, particularmente no tocante ao número máximo de palavras, tabelas e figuras permitidas, bem como às regras para confecção das referências bibliográficas. Com exceção de trabalhos de excepcional complexidade, a revista considera 6 o número máximo aceitável de autores. No caso de maior número de autores, enviar carta a Secretaria do Jornal descrevendo a participação de cada um no trabalho. Com exceção das unidades de medidas, siglas e abreviaturas devem ser evitadas ao máximo, devendo ser utilizadas apenas para termos consagrados. Estes termos estão definidos na Lista de Abreviaturas e Acrônimos aceitos sem definição, disponível no site da revista. Quanto a outras abreviaturas, sempre defini-las na primeira vez em que forem citadas, por exemplo: proteína C reativa (PCR). Com exceção das abreviaturas aceitas sem definição, elas não devem ser utilizadas nos títulos e evitadas no resumo dos manuscritos. Ao longo do texto evitar a menção ao nome de autores, dando-se sempre preferência às citações numéricas apenas. Quando os autores mencionarem qualquer substância ou equipamento incomum, deverão incluir o modelo/número do catálogo, o nome do fabricante, a cidade e o país, por exemplo: “. . . esteira ergométrica (modelo ESD-01; FUNBEC, São Paulo, Brasil) . . .” No caso de produtos provenientes dos EUA e Canadá,

o nome do estado ou província também deverá ser citado; por exemplo: “ . . . tTG de fígado de porco da Guiné (T5398; Sigma, St. Louis, MO, EUA) . . .” A não observância das instruções redatoriais implicará na devolução do manuscrito pela Secretaria da revista para que os autores façam as correções pertinentes antes de submetê-lo aos revisores. Os conceitos contidos nos manuscritos são de responsabilidade exclusiva dos autores. Instruções especiais se aplicam para confecção de Suplementos Especiais e Diretrizes, e devem ser consultadas pelos autores antes da confecção desses documentos na homepage do jornal.

A revista reserva o direito de efetuar nos artigos aceitos adaptações de estilo, gramaticais e outras.

A página de identificação do manuscrito deve conter o título do trabalho, em português e inglês, nome completo e titulação dos autores, instituições a que pertencem, endereço completo, inclusive telefone, fax e e-mail do autor principal, e nome do órgão financiador da pesquisa, se houver.

Resumo: Deve conter informações facilmente compreendidas, sem necessidade de recorrer-se ao texto, não excedendo 250 palavras. Deve ser feito na forma estruturada com: Objetivo, Métodos, Resultados e Conclusões. Quando tratar-se de artigos de Revisão e Relatos de Casos o Resumo não deve ser estruturado.

Para Comunicações Breves não deve ser estruturado nem exceder 100 palavras.

Abstract: Uma versão em língua inglesa, correspondente ao conteúdo do Resumo deve ser fornecida.

Descritores e Keywords: Devem ser fornecidos de três a seis termos em português e inglês, que definam o assunto do trabalho. Devem ser baseados nos DeCS (Descritores em Ciências da Saúde), publicados pela Bireme e disponíveis no endereço eletrônico: http://decs. bvs.br, enquanto os keywords em inglês devem ser baseados nos MeSH (Medical Subject Headings) da National Library of Medicine, disponíveis no endereço eletrônico http://­www.nlm.nih.gov/mesh/MBrowser.html.

Artigos originais: O texto deve ter entre 2000 e 3000 palavras, excluindo referências e tabelas. Deve conter no máximo 5 tabelas e/ou figuras. O número de referências bibliográficas não deve exceder 30. A sua estrutura deve conter as seguintes partes: Introdução, Métodos, Resultados, Discussão, Agradecimentos e Referências. A seção Métodos deverá conter menção a aprovação do estudo pelo Comitê de Ética em Pesquisa em Seres Humanos, ou pelo Comitê de Ética em Pesquisa em Animais, ligados a Instituição onde o projeto foi desenvolvido. Ainda que a inclusão de subtítulos no manuscrito seja aceitável, o seu uso não deve ser excessivo e deve ficar limitado às sessões Métodos e Resultados somente.

Revisões e Atualizações: Serão realizadas a convite do Conselho Editorial que, excepcionalmente, também poderá aceitar trabalhos que considerar de interesse. O texto não deve ultrapassar 5000 palavras, excluindo referências e tabelas. O número total de ilustrações e tabelas não deve ser superior a 8. O número de referências bibliográficas deve se limitar a 60.

Ensaios pictóricos: Serão igualmente realizados a convite, ou após consulta dos autores ao Conselho Editorial. O texto não deve ultrapassar 3000 palavras, excluídas referências e tabelas. O número total de ilustrações e tabelas não deve ser superior a 12 e as referências bibliográficas não devem exceder 30.

Relatos de Casos: O texto não deve ultrapassar 1500 palavras, excluídas as referências e figuras. Deve ser composto por Introdução, Relato do Caso, Discussão e Referências. Recomenda-se não citar as iniciais do paciente e datas, sendo mostrados apenas os exames laboratoriais relevantes para o diagnóstico e discussão.

O número total de ilustrações e/ou tabelas não deve ser superior a 3 e o limite de referências bibliográficas é 20.

Quando o número de casos exceder 3, o manuscrito será classificado como Série de Casos, e serão aplicadas as regras de um artigo original.

Comunicações Breves: O texto não deve ultrapassar 1500 palavras, excluindo as referências e tabelas. O número total de tabelas e/ou figuras não deve exceder 2 e o de referências bibliográficas 20. O texto deverá ser confeccionado de forma corrida.

Carta ao Editor: Serão consideradas para publicação contribuições originais, comentários e sugestões relacionadas à matéria anteriormente publicada, ou a algum tema médico relevante. Serão avaliados também o relato de casos incomuns. Deve ser redigida de forma sucinta, corrida e sem o item introdução. Não deve apresentar resumo/abstract e nem palavras-chave/keywords. Não deve ultrapassar 1000 palavras e ter no máximo duas figuras e/ou tabelas. Admitimos que as figuras sejam subdividas em A, B, C e D, mas que se limitem apenas duas. As referências bibliográficas devem se limitar a dez.

Tabelas e Figuras: Tabelas e gráficos devem ser apresentados em preto e branco, com legendas e respectivas numerações impressas ao pé de cada ilustração.

As tabelas e figuras devem ser enviadas no seu arquivo digital original, as tabelas preferencialmente em arquivos Microsoft Word e as figuras em arquivos Microsoft Excel, Tiff ou JPG. Legendas: Legendas deverão acompanhar as respectivas figuras (gráficos, fotografias e ilustrações) e tabelas.

Cada legenda deve ser numerada em algarismos arábicos, correspondendo a suas citações no texto. Além disso, todas as abreviaturas e siglas empregadas nas figuras e tabelas devem ser definidas por extenso abaixo das mesmas.

Referências: Devem ser indicadas apenas as referências utilizadas no texto, numeradas com algarismos arábicos e na ordem de entrada. A apresentação deve seguir o formato “Vancouver Style”, atualizado em outubro de 2004, conforme os exemplos abaixo. Os títulos dos periódicos devem ser abreviados de acordo com a List of Journal Indexed in Index Medicus, da National Library of Medicine disponibilizada no endereço: http://www.ncbi.nlm.nih.gov/entrez/journals/ loftext.noprov.html Para todas as referências, cite todos os autores até seis. Acima desse número, cite os seis primeiros autores seguidos da expressão et al.

Exemplos: Artigos regulares 1. Neder JA, Nery LE, Castelo A, Andreoni S, Lerario MC, Sachs AC et al. Prediction of metabolic and cardiopulmonary responses to maximum cyclo ergometry: a randomized study. Eur Respir J. 1999;14(6):304-13.

2. Capelozzi VL, Parras ER, Ab’Saber AM. Apresentação anatomopatológica das vasculites pulmonares. J Bras Pneumol. 2005;31 Supl 1:S9-15.

Resumos 3. Rubin AS, Hertzel JL, Souza FJFB, Moreira JS. Eficácia imediata do formoterol em DPOC com pobre reversibilidade [resumo]. J Bras Pneumol. 2006;32 Supl 5:S219.

Capítulos de livros 4. Queluz T, Andres G. Goodpasture’s syndrome. In: Roitt IM, Delves PJ, editors. Encyclopedia of immunology. London: Academic Press; 1992. p. 621-3.

Teses 5. Martinez TY. Impacto da dispnéia e parâmetros funcionais respiratórios em medidas de qualidade de vida relacionada a saúde de pacientes com fibrose pulmonar idiopática [tese]. São Paulo: Universidade Federal de São Paulo;1998.

Artigos publicados na internet 6. Abood S. Quality improvement initiative in nursing homes: the ANA acts in an advisory role. Am J Nurs [serial on the Internet]. 2002 [cited 2002 Aug 12];102(6):[about 3 p.]. Available from: http://www. nursingworld.org/AJN/2002/june/Wawatch.htm

Homepages/endereços eletrônicos 7. Cancer-Pain.org [homepage on the Internet]. New York: Association of Cancer Online Resources, Inc., c2000-01 [updated 2002 May 16; cited 2002 Jul 9].

Available from: http://www.cancer-pain.org/

Outras situações Situações não contempladas pelas Instruções aos Autores deverão seguir as recomendações contidas em

International Committee of Medical Journal Editors.

Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Updated February 2006. Disponível em http://www.icmje.org/.

Toda correspondência deve ser enviada para: Prof. Dr. Carlos Roberto Ribeiro Carvalho Editor-Chefe do Jornal Brasileiro de Pneumologia SCS - Quadra 01 - Bloco K - salas 203/204 Ed. Denasa. Asa Sul - Brasília/DF - 70398-900.

Telefones/Fax: 0xx61-3245-1030, 0xx61-3245-6218, 0800 61 62 18

Email do Jornal Brasileiro de Pneumologia: jpneumo@jornaldepneumologia.com.br (Secretária Luana Campos)

Alguns pacientes com asma

*

e DPOC não sabem como 1 a vida pode ser melhor.

Faça mais hoje 1

DAXAS.USOORAL,ADULTO.INDICAÇÕES:tratamentodemanutençãodepacientescomdoençapulmonarobstrutivacrônica(DPOC)grave(VEF1pós-broncodilatador < 50% do valor previsto) associada a bronquite crônica (tosse e expectoração crônicas) com histórico de exacerbações (crises) frequentes, em complementação ao tratamento com broncodilatadores. CONTRAINDICAÇÕES: hipersensibilidade ao roflumilaste ou a qualquer dos componentes da formulação. Este medicamento é contraindicado para pacientes com insuficiência hepática moderada e grave (classes ‘B’ e ‘C’ de Child-Pugh), pois não existem estudos sobre o uso do roflumilaste nestes pacientes. PRECAUÇÕES: DAXAS deve ser administrado apenas por via oral. DAXAS não é indicado para melhora de broncoespasmo agudo. Os comprimidos de DAXAS contêm 199 mg de lactose. Perda de peso: nos estudos de 1 ano (M-124, M-125), houve redução mais frequente do peso corporal em pacientes tratados com DAXAS versus placebo. Após a descontinuação de DAXAS, a maioria dos pacientes recuperou o peso corporal após 3 meses. Na ocorrência de perda de peso inexplicada e pronunciada, deve-se descontinuar a administração de DAXAS, se julgado necessário. Intolerância persistente: apesar das reações adversas como diarreia, náusea, dor abdominal e cefaleia serem transitórias e se resolverem espontaneamente com a manutenção do tratamento, o tratamento com DAXAS deve ser revisto em caso de intolerância persistente. Gravidez e lactação: as informações disponíveis sobre o uso de DAXAS em gestantes são limitadas, mas não indicaram eventos adversos do roflumilaste sobre a gestação ou a saúde do feto/recém-nato. Não são conhecidos outros dados epidemiológicos relevantes. Estudos em animais demonstraram toxicidade reprodutiva. O risco potencial para humanos ainda não está estabelecido. DAXAS não deve ser administrado durante a gestação. É possível que o roflumilaste e/ou seus metabólitos sejam excretados no leite materno durante a amamentação; estudos em animais (ratos) em fase de amamentação detectaram pequenas quantidades do produto e seus derivados no leite dos animais. Categoria B de risco na gravidez – este medicamento não deve ser utilizado por mulheres grávidas ou que estejam amamentando sem orientação médica ou do cirurgião dentista. Idosos: os cuidados com o uso de DAXAS por pacientes idosos devem ser os mesmos para os demais pacientes; não são recomendados ajustes na dosagem da medicação. Pacientes pediátricos (crianças e adolescentes menores de 18 anos de idade): o produto não é recomendado para este grupo de pacientes, pois não há dados disponíveis sobre a eficácia e a segurança da administração oral de DAXAS nesta faixa etária. Insuficiência hepática: não é necessário ajuste da dosagem para pacientes com insuficiência hepática leve (classe ‘A’ de Child-Pugh). No entanto, para pacientes com insuficiência hepática moderada ou grave (classes ‘B’ e ‘C’ de Child-Pugh), o uso deste medicamento não é recomendado, pois não existem estudos sobre o uso nesses pacientes.

Insuficiência renal: não é necessário ajuste da dose para pacientes com insuficiência renal crônica. Fumantes com DPOC: não é necessário ajuste da dose. Habilidade de dirigir e operar máquinas: é improvável que o uso desse medicamento cause efeitos na capacidade de dirigir veículos ou de usar máquinas. Pacientes com doenças imunológicas graves, infecciosas graves ou tratados com imunossupressores: deve-se suspender ou não iniciar o tratamento com DAXAS nesses casos. Pacientes com insuficiência cardíaca classes III e IV (NYHA): não existem estudos nessa população de pacientes, portanto não se recomenda o uso nesses pacientes. Pacientes com doenças psiquiátricas: DAXAS não é recomendado para pacientes com histórico de depressão associada com ideação ou comportamento suicida. Os pacientes devem ser orientados a comunicar seu médico caso apresentem alguma ideação suicida. INTERAÇÕES MEDICAMENTOSAS: estudos clínicos de interações medicamentosas com inibidores do CYP3A4 (eritromicina e cetoconazol) não resultaram em aumento da atividade inibitória total de PDE4 (exposição total ao roflumilaste e ao N-óxido roflumilaste); com o inibidor do CYP1A2 fluvoxamina e os inibidores duplos CYP3A4/1A2 enoxacina e cimetidina, os estudos demonstraram aumento na atividade inibitória total de PDE4. Dessa forma, deve-se esperar aumento de 20% a 60% na inibição total de PDE4 quando o roflumilaste for administrado concomitantemente com potentes inibidores do CYP1A2, como a fluvoxamina, embora não sejam esperadas interações com inibidores do CYP3A4, como cetoconazol. Não são esperadas interações medicamentosas clinicamente relevantes. A administração de rifampicina (indutor enzimático de CYP450) resultou em redução na atividade inibitória total de PDE4 de cerca de 60% e o uso de indutores potentes do citocromo P450 (como fenobarbital, carbamazepina, fenitoína) pode reduzir a eficácia terapêutica do roflumilaste.

Não se observou interações clinicamente relevantes com: salbutamol inalado, formoterol, budesonida, montelucaste, digoxina, varfarina, sildenafil, midazolam. A coadministração de antiácidos não altera a absorção nem as características farmacológicas do produto. A coadministração com teofilina aumentou em 8% a atividade inibitória sobre a fosfodiesterase 4. Quando utilizado com contraceptivo oral com gestodeno e etinilestradiol, a atividade inibitória sobre a fosfodiesterase 4 aumentou 17%.

Não há estudos clínicos que avaliaram o tratamento concomitante com xantinas, portanto não se recomenda o uso combinado a esse fármaco. REAÇÕES ADVERSAS: DAXAS foi bem avaliado em estudos clínicos e cerca de 16% dos indivíduos apresentaram reações adversas com o roflumilaste versus 5,7% com o placebo. As reações adversas mais frequentemente relatadas foram diarreia (5,9%), perda de peso (3,4%), náusea (2,9%), dor abdominal (1,9%) e cefaleia (1,7%). A maior parte dessas reações foram leves ou moderadas e desapareceram com a continuidade do tratamento. Os eventos adversos classificados por frequência foram: Reações comuns (> 1/100 e < 1/10):perda de peso, distúrbios do apetite, insônia, cefaleia, diarreia, náusea, dor abdominal. Reações incomuns (> 1/1.000 e < 1/100): hipersensibilidade, ansiedade, tremor, vertigem, tontura, palpitações, gastrite, vômitos, refluxo gastroesofágico, dispepsia, erupções cutâneas, espasmos musculares, fraqueza muscular, mal-estar, astenia, fadiga, dor muscular, lombalgia. Reações raras (> 1/10.000 e < 1/1.000): depressão e distúrbios do humor, ginecomastia, disgeusia, hematoquesia, obstipação intestinal, aumento de Gama – GT, aumento de transaminases, urticária, infecções respiratórias (exceto pneumonia), aumento de CPK. POSOLOGIA E ADMINISTRAÇÃO: a dose recomendada de DAXAS é de um comprimido uma vez ao dia. Não é necessário ajuste posológico para pacientes idosos, com insuficiência renal ou com insuficiência hepática leve (classes ‘A’ de Child-Pugh). DAXAS não deve ser administrado a pacientes com insuficiência hepática moderada ou grave (classe ‘B’ou ‘C’ de Child-Pugh). Os comprimidos de DAXAS devem ser administrados com a quantidade de água necessária para facilitar a deglutição e podem ser administrados antes, durante ou após as refeições. Recomenda-se que o medicamento seja administrado sempre no mesmo horário do dia, durante todo o tratamento. Este medicamento não deve ser partido ou mastigado. A PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. VENDA SOB PRESCRIÇÃO MÉDICA. REGISTRO MS: 1.0639.0257.

DX_0710_0211_VPS . *Marca Depositada.

Seus pacientes podem se beneficiar com uma ação anti-inflamatória e broncodilatadora por 12 horas, que é uma opção terapêutica segura, inclusive para crianças de 4

Componentes Parcerias confiáveis2

a 11 anos.

2

O Doutor pode oferecer aos seus pacientes uma dose consistente num dispositivo fácil de usar, com opção de spray com contador de doses.2,4

Dispositivo2 fácil de usar

A dosag em cert

a para c a pacient 2 da e

Um corpo extenso de evidências no qual o Doutor pode basear-se. Eficácia que definiu o padrão no tratamento da asma e da DPOC.3

Dados

es o padrõ5 definind to n e m de trata

6,7

Reduz a mortalidade e a progressão da DPOC, mesmo em pacientes moderados.

Seretide® é a terapia combinada que provou alcançar e manter o controle 3 da asma a longo prazo.

5,8

Ajude-os a sentir como a vida pode ser melhor.

O uso de Seretide® é contraindicado em pacientes com hipersensibilidade conhecida a qualquer componente da fórmula. Aconselha-se cautela ao coadministrar inibidores potentes do CYP3A4 (p. ex., cetoconazol).

Referências: 1. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease.Br J Pharmacol. 2011;163(1):53-67 Antes de prescrever DAXAS, recomendamos a leitura da Circular aos Médicos (bula) completa para informações detalhadas sobre o produto.

Contraindicações: alergia aos componentes da fórmula e pacientes com insuficiência hepática moderada ou grave. Interações Medicamentosas: a administração de indutores do citocromo

P450, como rifampicina e anticovulsivantes, pode reduzir a eficácia terapêutica do roflumilaste. Não existem estudos clínicos que avaliaram o tratamento concomitante com metilxantinas, portanto seu uso em associação não está recomendado.

Março/2012 - MC 707/11 05-2013-DAX-11-BR-707-J

Material de distribuição exclusiva para profissionais de saúde habilitados a prescrever ou dispensar medicamentos. Recomenda-se a leitura da bula e da monografia do produto, antes da prescrição de qualquer medicamento. Mais informações à disposição, sob solicitação do Serviço de Informação Médica (0800 701 2233 ou http://www.sim-gsk.com.br). Minibula do medicamento na próxima página desta edição.

REPENSE BR/SFC/0080/11 – FEV/12 Nycomed Pharma Ltda.

Rua do Estilo Barroco, 721 - CEP 04709-011 - São Paulo - SP Mais informações poderão ser obtidas diretamente com o nosso Departamento Médico ou por meio de nossos representantes.

Produto de uso sob prescrição médica.

A PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO.

A escolha de dosagem possibilita dar passos acima ou abaixo no tratamento da asma, se necessário.

No tratamento da DPOC, tem a força que o Doutor precisa para cada paciente.2,3

SERVIÇO DE INFORMAÇÃO MÉDICA 0800 701 2233 www.sim-gsk.com.br

www.gsk.com.br Estrada dos Bandeirantes, 8.464 • Jacarepaguá Rio de Janeiro • RJ • CEP 22783-110 CNPJ 33247743/0001-10

pneumocócica PREVALÊNCIA

DESAFIO A doença causada pelo S. pneumoniae é a maior causa de doença e morte em crianças e adultos no mundo.3

Jornal Brasileiro de Pneumologia

A doença pneumocócica é a causa número 1 de mortes evitáveis por vacinação, a maioria devida à pneumonia.1 O S. pneumoniae é o agente da pneumonia adquirida na comunidade em cerca de 50% dos casos em adultos2

doença

ISSN 1806-3713

Published once every two months J Bras Pneumol. v.38, number 5, p. 539-680 September/October 2012

OFFICIAL PUBLICATION OF THE BRAZILIAN THORACIC ASSOCIATION

Highlight

ASTHMA Prevalence and duration of social security benefits allowed to workers with asthma in Brazil in 2008

CANCER Analysis and validation of probabilistic models for predicting malignancy in solitary pulmonary nodules in a population in Brazil

SURGERY Electric Ventilation: indications for and technical aspects of diaphragm pacing stimulation surgical implantation

SEVERIDADE

Quantitative assessment of the intensity of palmar and plantar sweating in patients with primary ­palmoplantar hyperhidrosis

O Streptococcus pneumoniae é o agente mais encontrado em pneumonia, inclusive em casos que necessitam de internação em unidade de terapia intensiva2

COPD

RISCOS

TEACHING

IMPACTO SOCIAL No ano de 2007, ocorreram 735.298 internações por pneumonia no Brasil, conforme o Sistema de Informações Hospitalares do Sistema Único de Saúde, correspondendo à primeira causa de internação por doença pelo CID-10 8

Muscle strength as a determinant of oxygen uptake efficiency and maximal metabolic response in patients with mild-to-moderate COPD

September/October 2012 volume 38 number 5

O risco de pneumonia pneumocócica aumenta com a idade , possivelmente devido ao declínio do sistema imunológico5, bem como ao aumento das comorbidades relacionadas com a idade.6,7 4

Responsiveness of the six-minute step test to a physical training program in patients with COPD

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Referências Bibliográficas: 1. CDC. Vaccine Preventable Deaths and the Global Immunization Vision and Strategy, 2006--2015. MMWR 2006; 55(18):511-515. 2. Corrêa RA, Lundgren FLC, Pereira-Silva JL, et al. Diretrizes brasileiras para pneumonia adquirida na comunidade em adultos imunocompetentes – 2009. J Bras Pneumol. 2009;35(6):574-601. 3. WHO. 23-valent pneumococcal polysaccharide vaccine WHO position paper. WER 83(42):373-84. 4. Jokinen C, Heiskanen L, Juvonen H et al. Incidence of community-acquired pneumonia in the population of four municipalities in eastern Finland. Am J Epidemiol 1993;137:977-88 . 5. Schenkein JG, Park S, Nahm MH Pneumococcal vaccination in older adults induces antibodies with low opsonic capacity and reduced antibody potency Vaccine 26 (2008) 5521–5526. 6. Musher DM, Rueda AM, KakaAS , Mapara SMThe Association between Pneumococcal Pneumonia and Acute Cardiac Events. Clinical Infectious Diseases 2007; 45:158–65. 7. Jasti H, Mortensen EM, Obrosky DS. Causes and Risk Factors for Rehospitalization of Patients Hospitalized with Community-Acquired Pneumonia. Clinical Infectious Diseases 2008; 46:550–6. 8. Ministério da Saúde. Datasus. Tecnologia da Informação ao serviço do SUS. Morbidade Hospitalar do SUS - por local de internação - Brasil. Internações por pneumonia, 2007. Disponível em http://tabnet. datasus.gov.br/cgi/tabcgi.exe?sih/cnv/miuf.def. Acesso 22/09/2010.

EXPERIMENTAL

Factors associated with complications of community-acquired pneumonia in preschool children

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