Brazilian Journal of Pulmonology - Volume 38, number 4, July/August - 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

Publicação Bimestral

J Bras Pneumol. v.38, número 4, p. 417-537 July/August 2012

PUBLICAÇÃO OFICIAL DA SOCIEDADE BRASILEIRA DE PNEUMOLOGIA E TISIOLOGIA

Highlight

ASTHMA Evaluation of the efficacy and safety of a fixed-dose, single-capsule budesonide-formoterol combination in uncontrolled asthma: a randomized, double-blind, multicenter, controlled clinical trial Children and adolescents with mild intermittent or mild persistent asthma: aerobic capacity between attacks

CANCER Fiberoptic bronchoscopy findings in patients diagnosed with lung cancer

PULMONARY CIRCULATION

SEVERIDADE

Comparison of two experimental models of pulmonary hypertension

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

SURGERY An experimental rat model of ex vivo lung perfusion for the assessment of lungs regarding histopathological findings and apoptosis: low-potassium dextran vs. histidine-tryptophan-ketoglutarate

TEACHING

RISCOS

Evolution of public policies and programs for asthma control in Brazil from the perspective of consensus guidelines

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

July/August 2012 volume 38 número 4

O risco de pneumonia pneumocócica aumenta com a idade4, possivelmente devido ao declínio do sistema imunológico5, bem como ao aumento das comorbidades relacionadas com a idade.6,7

PHYSIOTHERAPY Manual hyperinflation combined with expiratory rib cage compression for reduction of length of ICU stay in critically ill patients on mechanical ventilation

INFECTION Impact of bacteremia in a cohort of patients with pneumococcal pneumonia

Clinical and pathological factors influencing the survival of breast cancer patients with malignant pleural effusion

RADIOLOGY Emphysema index in a cohort of patients with no recognizable lung disease: influence of age

TUBERCULOSIS Effectiveness of tuberculosis treatment p.417-537

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.

Anthropometric and dietary intake indicators as predictors of pulmonary function in cystic fibrosis patients

PLEURA

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

CYSTIC FIBROSIS

Tuberculosis, HIV, and poverty: temporal trends in Brazil, the Americas, and worldwide

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

Impact factor 1.391

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, número 4, p. 417-537 July/August 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, número 4, p. 417-537 July/August 2012

EDITORIAL 417 - Publication of the impact factor of the Brazilian Journal of Pulmonology: a milestone on a long and arduous journey

Divulgação do fator de impacto do Jornal Brasileiro de Pneumologia: consolidação de um longo e árduo trabalho Carlos Roberto Ribeiro Carvalho, Bruno Guedes Baldi, Carlos Viana Poyares Jardim, Pedro Caruso 419 - Understanding mortality in bacteremic pneumococcal pneumonia

Entendimento da mortalidade em pneumonia pneumocócica bacterêmica Catia Cillóniz, Antoni Torres

ORIGINAL ARTICLES / ARTIGOS ORIGINAIS 422 - Impact of bacteremia in a cohort of patients with pneumococcal pneumonia

Impacto de la bacteriemia en una cohorte de pacientes con neumonía neumocócica

Ileana Palma, Ricardo Mosquera, Carmen Demier, Carlos Vay, Angela Famiglietti, Carlos M Luna 431 - Evaluation of the efficacy and safety of a fixed-dose, single-capsule budesonideformoterol ­ combination in uncontrolled asthma: a randomized, double-blind, multicenter, controlled clinical trial

Avaliação da eficácia e segurança da associação de budesonida e formoterol em dose fixa e cápsula única no tratamento de asma não controlada: ensaio clínico randomizado, ­duplo‑cego, multicêntrico e controlado Roberto Stirbulov, Carlos Cezar Fritscher, Emilio Pizzichini, Márcia Margaret Menezes Pizzichini

438 - Children and adolescents with mild intermittent or mild persistent asthma: aerobic capacity b ­ etween attacks

Capacidade aeróbica em crianças e adolescentes com asma intermitente e persistente leve no período intercrises Eliane Zenir Corrêa de Moraes, Maria Elaine Trevisan, Sérgio de Vasconcellos Baldisserotto, Luiz Osório Cruz Portela 445 - Fiberoptic bronchoscopy findings in patients diagnosed with lung cancer

Achados de fibrobroncoscopia em pacientes com diagnóstico de neoplasia pulmonar Marcelo Fouad Rabahi, Andréia Alves Ferreira, Bruno Pereira Reciputti, Thalita de Oliveira Matos, Sebastião Alves Pinto

452 - Comparison of two experimental models of pulmonary hypertension

Comparação de dois modelos experimentais de hipertensão pulmonar

Igor Bastos Polonio, Milena Marques Pagliarelli Acencio, Rogério Pazetti, Francine Maria de Almeida, Mauro Canzian, Bárbara Soares da Silva, Karina Aparecida Bonifácio Pereira, Rogério de Souza 461 - An experimental rat model of ex vivo lung perfusion for the assessment of lungs regarding histopathological findings and apoptosis: low-potassium dextran vs. histidine-tryptophan-ketoglutarate

Modelo experimental de perfusão pulmonar ex vivo em ratos: avaliação histopatológica e de apoptose celular em pulmões preservados com solução de baixo potássio dextrana vs. solução histidina-triptofano-cetoglutarato Edson Azevedo Simões, Paulo Francisco Guerreiro Cardoso, Paulo Manuel Pêgo-Fernandes, Mauro Canzian, Rogério Pazetti, Karina Andriguetti de Oliveira Braga, Natalia Aparecida Nepomuceno, Fabio Biscegli Jatene

470 - Anthropometric and dietary intake indicators as predictors of pulmonary function in cystic fibrosis patients

Indicadores antropométricos e de ingestão alimentar como preditores da função pulmonar em pacientes com fibrose cística

Gabriele Carra Forte, Juliane Silva Pereira, Michele Drehmer, Miriam Isabel Souza dos Santos Simon

477 - Manual hyperinflation combined with expiratory rib cage compression for reduction of length of ICU stay in critically ill patients on mechanical ventilation

Hiperinsuflação manual combinada com compressão torácica expiratória para redução do período de internação em UTI em pacientes críticos sob ventilação mecânica Juliana Savini Wey Berti, Elisiane Tonon, Carlos Fernando Ronchi, Heloisa Wey Berti, Laércio Martins de Stefano, Ana Lúcia Gut, Carlos Roberto Padovani, Ana Lucia Anjos Ferreira

Published once every two months

J Bras Pneumol. v.38, número 4, p. 417-537 July/August 2012

487 - Clinical and pathological factors influencing the survival of breast cancer patients with malignant pleural effusion

Fatores clínicos e anatomopatológicos que influenciam a sobrevida de pacientes com câncer de mama e derrame pleural neoplásico Giovana Tavares dos Santos, João Carlos Prolla, Natália Dressler Camillo, Lisiane Silveira Zavalhia, Alana Durayski Ranzi, Claudia Giuliano Bica 494 - Emphysema index in a cohort of patients with no recognizable lung disease: influence of age

Índice de enfisema pulmonar em coorte de pacientes sem doença pulmonar conhecida: influência da idade Bruno Hochhegger, Giordano Rafael Tronco Alves, Klaus Loureiro Irion, José da Silva Moreira, Edson dos Santos Marchiori 503 - Effectiveness of tuberculosis treatment

Efetividade do tratamento da tuberculose

Letícia Nazareth Fernandes da Paz, Maria Deise de Oliveira Ohnishi, Camila Melo Barbagelata, Fabiana de Arruda Bastos, João Augusto Figueiredo de Oliveira III, Igor Costa Parente 511 - Tuberculosis, HIV, and poverty: temporal trends in Brazil, the Americas, and worldwide Tuberculose, HIV e pobreza: tendência temporal no Brasil, Américas e mundo Raphael Mendonça Guimarães, Andréa de Paula Lobo, Eduardo Aguiar Siqueira, Tuane Franco Farinazzo Borges, Suzane Cristina Costa Melo BRIEF COMMUNICATION / COMUNICAÇÃO BREVE 518 - Evolution of public policies and programs for asthma control in Brazil from the perspective of consensus guidelines

Evolução das políticas públicas e programas de controle da asma no Brasil sob a perspectiva dos consensos Lígia Menezes do Amaral, Pamella Valente Palma, Isabel Cristina Gonçalves Leite

CASE REPORT / RELATO DE CASO 526 - Unilateral pulmonary agenesis

Agenesia pulmonar unilateral

Maura Cavada Malcon, Claudio Mattar Malcon, Marina Neves Cavada, Paulo Eduardo Macedo Caruso, Lara Flório Real

LETTER TO THE EDITOR / CARTAS AO EDITOR 530 - Pulmonary cryptosporidiosis in AIDS patients, an underdiagnosed disease

Criptosporidiose pulmonar em pacientes com AIDS, uma doença subdiagnosticada Yvana Maria Maia de Albuquerque, Márcia Cristina Fraga Silva, Ana Luiza Magalhães de Andrade Lima, Vera Magalhães 533 - Activated charcoal bronchial aspiration

Broncoaspiração de carvão ativado

Bruna Quaranta Lobão Bairral, Makoto Saito, Nelson Morrone 535 - Lipoid pneumonia in a 40-day-old infant

Pneumonia lipoide em lactente de 40 dias de vida

Maria Cristina Ribeiro dos Santos Simões, Ivan Felizardo Contrera Toro, José Dirceu Ribeiro, Adyléia Aparecida Dalbo Contrera Toro

As válvulas endobrônquicas Zephyr (EBV) foram desenvolvidas para aliviar a dispnéia e melhorar a qualidade de vida nos pacientes com Ennsema. Com experiência de mais de 10 anos, este tratamento é realizado no Brasil e em mais de 20 países incluindo Alemanha, Inglaterra, Itália, França, Espanha, Austrália e Bélgica. Com seleção adequada é possível oferecer esta alternativa aos pacientes em um procedimento minimamente invasivo. As válvulas são implantadas sob sedação através de broncoscopia exível com mínima permanência hospitalar.

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Editorial Publication of the impact factor of the Brazilian Journal of Pulmonology: a milestone on a long and arduous journey Divulgação do fator de impacto do Jornal Brasileiro de Pneumologia: consolidação de um longo e árduo trabalho

Carlos Roberto Ribeiro Carvalho, Bruno Guedes Baldi, Carlos Viana Poyares Jardim, Pedro Caruso The Brazilian Journal of Pulmonology (BJP), originally known as Journal of Pulmonology, was founded in 1975, and its first Editor was Dr. Manoel Lopes dos Santos. Its mission was to be the official organ of a new association of specialty physicians that was being created. Since then, it has been published without interruption.

In October of 1978, the Brazilian Pulmonology Association and the Brazilian Federation of Tuberculosis and Respiratory Disease Associations merged, creating a new association. This new association was named the Brazilian Thoracic Association and adopted the founding date of the Brazilian Federation of Tuberculosis and Respiratory Disease Associations (1937) as its own.

Initially, the BJP was a quarterly publication.

From the first editorials, it was evident that it would be difficult to obtain original articles in numbers sufficient to sustain its regular publication. The hard work of many editors over these 37 years, maintaining the periodicity of our Journal, has led it to the position it occupies today. After Dr. Manoel there came Bruno Carlos Palombini; Carlos Frazzatto Junior; José Roberto B. Jardim; Miguel Bogossian (Scientific Secretary: Ana Luisa G. Fernandes); Nelson Morrone (Scientific Secretary: Eliana Sheila Mendes); Carlos Alberto C. Pereira (Scientific Secretaries: Luiz Fernando F. Pereira and Sonia Faresin); Thais A. Queluz (Scientific Secretary: Hugo Bok Yoo); Geraldo Lorenzi Filho (Scientific Secretary: Elnara Márcia Negri); and José Antonio Baddini Martinez.

Since 1998, we have had three administrative secretaries: Conceição Silva; Priscilla Bovolenta; and, currently, Luana Campos.

The BJP has gained greater international exposure since 2002, when it was indexed for SciELO, and especially since 2006, when it was indexed for MEDLINE (PubMed). The recognition received by the BJP has culminated with the debut of its first impact factor, which appeared in Journal Citation Reports at the end of last

semester. In 2009 and 2010, our Journal published 274 articles, which were cited in 381 articles published in other scientific journals indexed for MEDLINE, resulting in our newly minted impact factor: 1.391. This number is a source of pride for the entire community of researchers working in the field of respiratory diseases in Brazil, as well as being of enormous importance to the Brazilian Thoracic Association, because the BJP is its official journal. This impact factor quantifies the national and international recognition received by our Journal. The impact factor of a journal represents its relative importance within its field.

With an impact factor of 1.391, the BJP ranks fourth among the 93 Brazilian scientific journals indexed for the Thomson Reuters Journal Citation Reports database (the Science Citation Index Expanded). Within that context, our impact factor is the third highest in the medical field and the highest among the specialist journals. All this was achieved despite the fact that this is the first time our articles have been evaluated. In the graduate program evaluations conducted in the current triennium by the Brazilian Coordenação

de Aperfeiçoamento de Pessoal de Nível Superior

(CAPES, Office for the Advancement of Higher Education), the BJP was classified as category B2 in Medicine I, which allows 40 points per article published and unlimited inclusion of articles from our Journal.

Our responsibility as Editors has increased tremendously. This result is the outcome of the work of all previous Editors and especially of the researchers who submitted their articles for evaluation by the team of Associate Editors and reviewers who worked over this 37-year period, contributing in a fundamental way to the BJP achieving this recognition.

Now that the BJP has received international recognition, the great challenge that lies ahead is to persevere in our efforts to improve the quality of the articles published, not only to maintain J Bras Pneumol. 2012;38(4):417-418

418

our impact factor but also to increase it. From this point on, the number of articles submitted by national and international researchers tends to grow, and, in this context, the continuous participation of all editors and reviewers is essential for expediting the article review process, which is key for maintaining the quality of a journal on the international stage. Most importantly, we invite all researchers to submit their studies for publication in the BJP. Although we still have far to go, this has been a very good start.

Carlos Roberto Ribeiro Carvalho Editor-in-Chief of the Brazilian Journal of Pulmonology Bruno Guedes Baldi Executive Editor of the Brazilian Journal of Pulmonology Carlos Viana Poyares Jardim Executive Editor of the Brazilian Journal of Pulmonology Pedro Caruso Executive Editor of the Brazilian Journal of Pulmonology

J Bras Pneumol. 2012;38(4):417-418

Editorial Understanding mortality in bacteremic pneumococcal pneumonia Entendimento da mortalidade em pneumonia pneumocócica bacterêmica

Catia Cillóniz, Antoni Torres

Community-acquired pneumonia (CAP) caused

by Streptococcus pneumoniae is one of the major causes of morbidity and mortality in children and the elderly (adults over 60 years of age) worldwide.

(1,2) Data from community-based studies show that the estimated overall annual incidence of pneumococcal bacteremia in the United States is 15-30 cases per 100,000 population; the rate is higher for persons ≥ 65 years of age (50-83 cases per 100,000 population) and for children ≤ 2 years of age (160 cases per 100,000 population), with an overall case fatality rate ranging from 20% (in young adults) to 60% (in the elderly). Associated comorbidities also play an important role.(3) Among adults, 60-87% of all cases of pneumococcal bacteremia are attributed to pneumonia; among young children, the primary site of infection is frequently unidentified.(4,5) Bacteremic pneumococcal pneumonia is a severe form of invasive pneumonia that constitutes a subgroup with features of its own. Approximately 20% of patients with pneumococcal pneumonia develop bloodstream infection. Among adults with bacteremic pneumococcal pneumonia, mortality rates range from 10% to 30%.(6) Despite medical advances, including the wider availability of potent antimicrobial therapy, improved physician and nursing care, and even the establishment of ICUs, mortality in bacteremic pneumococcal pneumonia remains unacceptably high.(7) The current thinking is that mortality is higher among bacteremic cases than among nonbacteremic cases.(4) However, this is not borne out by data in the literature.

Since Austrian and Gold published their work in 1964,(8) a number of studies have compared CAP patients with and without pneumococcal bacteremia in terms of the clinical outcomes.

Musher et al.(4) compared 52 cases of bacteremic pneumococcal CAP with 48 cases of nonbacteremic pneumococcal CAP and found that mortality within the first 7 days of hospitalization was significantly higher among the patients with

bacteremic pneumococcal CAP. However, Marrie et al.(9) examined 56 subjects with bacteremic pneumococcal CAP and 394 subjects with nonbacteremic CAP (of any etiology). Those authors found that there were no significant differences between the two groups, in terms of overall mortality and length of hospital stay.

More recently, Bordón et al.(10) provided data from the Community-Acquired Pneumonia Organization, confirming that pneumococcal bacteremia does not increase the risk of poor outcomes in patients with CAP. In the current issue of the Brazilian Journal of Pulmonology, Palma et al.(11) present the results of a study regarding the impact that bacteremia has on outcomes among patients with CAP. The study cohort included 640 patients diagnosed with pneumococcal CAP over a 4-year period.

The authors found that, in comparison with the patients who had nonbacteremic pneumococcal CAP, those with bacteremic pneumococcal CAP were older, presented more comorbidities (primarily cardiopathy and chronic renal failure), were more critically ill (according to their Acute Physiology and Chronic Health Evaluation II and pneumonia severity index scores), and were more often admitted to the ICU. However, in agreement with the findings of Marrie et al.,(9) there was no difference between the bacteremic and nonbacteremic groups in terms of all-cause mortality. The authors also demonstrated that bacteremia does not increase the length of the hospital stay in patients with pneumococcal CAP.(11) Certain recognized factors might facilitate the understanding of mortality in bacteremic pneumococcal pneumonia: the time to the initiation of antibiotic therapy; the appropriateness of the initial therapy; and the treatment modality (monotherapy versus combination therapy). Garnacho-Montero et al.(12) evaluated 125 cases of bacteremic pneumococcal CAP and found that the most important factor related J Bras Pneumol. 2012;38(4):419-421

420

to mortality is the speed with which antibiotic therapy is initiated (ideally within the first 4 h after admission). However, this information is lacking from many studies, and it is therefore quite difficult to understand why invasive disease (bacteremia) does not influence mortality. The appropriateness of the initial antibiotic therapy is another factor associated with mortality in bacteremic pneumococcal pneumonia, as demonstrated by Lujan et al.(13) Data regarding this factor are also lacking from many studies.

In addition, there is considerable retrospective evidence that combination therapy increases survival in bacteremic pneumonia.(14) Unfortunately, the study conducted by Palma et al.(11) provides no data on any of these factors.

An additional factor associated with mortality and morbidity in bacteremic pneumococcal CAP is the causative S. pneumoniae serotype. For example, Garcia-Vidal et al.(15) found that serotype 3 is an independent risk factor for septic shock, which undoubtedly increases mortality. Again, Palma et al.(11) provided no data on this factor.

In conclusion, the results presented by Palma et al.(11) indicate that pneumococcal bacteremia is not an independent predictor of poor clinical outcomes in patients with CAP, despite the initial severity of patients with bacteremia.

However, other important factors, such as the time to the initiation of antibiotic therapy and the appropriateness of the initial therapy, as well as the pneumococcal serotype, might play a crucial role and should be taken into account.

Catia Cillóniz Department of Pulmonology, Clinical Institute for Thoracic Diseases, Hospital Clinic of Barcelona, Institut

d’investigacions Biomèdiques August Pi i Sunyer – IDIBAPS,

August Pi i Sunyer Biomedical Research Institute – University of Barcelona – UB – Ciber de Enfermedades Respiratorias – CIBERES, Network for Research in Respiratory Disease – Barcelona, Spain

J Bras Pneumol. 2012;38(4):419-421

Antoni Torres Department of Pulmonology, Clinical Institute for Thoracic Diseases, Hospital Clinic of Barcelona, Institut

d’investigacions Biomèdiques August Pi i Sunyer – IDIBAPS,

August Pi i Sunyer Biomedical Research Institute – University of Barcelona – UB – Ciber de Enfermedades Respiratorias – CIBERES, Network for Research in Respiratory Disease – Barcelona, Spain Conflict of interest statement: Dr. Torres is a member of the Advisory Board of the Pfizer Vaccine Division.

References 1. Whitney CG, Farley MM, Hadler J, Harrison LH, Bennett NM, Lynfield R, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med. 2003;348(18):1737-46.

PMid:12724479. http://dx.doi.org/10.1056/NEJMoa022823 2. Jansen AG, Rodenburg GD, van der Ende A, van Alphen L, Veenhoven RH, Spanjaard L, et al. Invasive pneumococcal disease among adults: associations among serotypes, disease characteristics, and outcome. Clin Infect Dis. 2009;49(2):e23- PMid:19522653. http:// dx.doi.org/10.1086/600045 3. Giner AM, Kuster SP, Zbinden R, Ruef C, Ledergerber B, Weber R. Initial management of and outcome in patients with pneumococcal bacteremia: a retrospective study at a Swiss university hospital, 2003-2009.

Infection. 2011;39(6):519-26. PMid:22065426. http:// dx.doi.org/10.1007/s15010-011-0218-1 4. Musher DM, Alexandraki I, Graviss EA, Yanbeiy N, Eid A, Inderias LA, et al. Bacteremic and nonbacteremic pneumococcal pneumonia. A prospective study. Medicine (Baltimore). 2000;79(4):210-21. PMid:10941350. http:// dx.doi.org/10.1097/00005792-200007000-00002 5. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1997;46(RR-8):1-24.

6. Lynch JP 3rd, Zhanel GG. Streptococcus pneumoniae: epidemiology and risk factors, evolution of antimicrobial resistance, and impact of vaccines. Curr Opin Pulm Med. 2010;16(3):217-25. PMid:20375783.

7. Feldman C, Anderson R. Bacteraemic pneumococcal pneumonia: current therapeutic options.

Drugs. 2011;71(2):131-53. PMid:21275443. http:// dx.doi.org/10.2165/11585310-000000000-00000

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8. Austrian R, Gold J. Pneumococcal Bacteremia with especial reference to bacteremic pneumococcal pneumonia. Ann Intern Med. 1964;60:759-76. PMid:14156606.

9. Marrie TJ, Low DE, De Carolis E; Canadian CommunityAcquired Pneumonia Investigators. A comparison of bacteremic pneumococcal pneumonia with nonbacteremic community-acquired pneumonia of any etiology-results from a Canadian multicentre study. Can Respir J. 2003;10(7):368-74. PMid:14571288. PMid:14571288.

10. Bordón J, Peyrani P, Brock GN, Blasi F, Rello J, File T, et al. The presence of pneumococcal bacteremia does not influence clinical outcomes in patients with community‑acquired pneumonia: results from the Community-Acquired Pneumonia Organization (CAPO) International Cohort study. Chest. 2008;133(3):618-24.

PMid:18198264. http://dx.doi.org/10.1378/chest.07-1322 11. Palma I, Mosquera R, Demier C, Vay C, Famiglietti A, Luna C. Impact of bacteremia in a cohort of patients with pneumococcal pneumonia. J Bras Pneumol. 2012;38(4):422-30.

12. Garnacho-Montero J, García-Cabrera E, Diaz-Martín A, Lepe-Jiménez JA, Iraurgi-Arcarazo P, Jiménez-Alvarez

R, et al. Determinants of outcome in patients with bacteraemic pneumococcal pneumonia: importance of early adequate treatment. Scand. J Infect Dis. 2010;42(3):185-92. PMid:20085422. http://dx.doi. org/10.3109/00365540903418522 13. Lujan M, Gallego M, Fontanals D, Mariscal D, Rello J. Prospective observational study of bacteremic pneumococcal pneumonia: Effect of discordant therapy on mortality.

Crit Care Med. 2004;32(3):625-31. PMid:15090938. http://dx.doi.org/10.1097/01.CCM.0000114817.58194.BF 14. Martinez JA, Horcajada JP, Almela M, Marco F, Soriano A, García E, et al. Addition of a macrolide to a beta-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia. Clin Infect Dis. 2003;36(4):389‑95. PMid:12567294. http://dx.doi. org/10.1086/367541 15. Garcia-Vidal C, Ardanuy C, Tubau F, Viasus D, Dorca J, Liñares J, et al. Pneumococcal pneumonia presenting with septic shock: host- and pathogen-related factors and outcomes. Thorax. 2010;65(1):77-81. PMid:19996337. http://dx.doi.org/10.1136/thx.2009.123612

J Bras Pneumol. 2012;38(4):419-421

Original Article Impact of bacteremia in a cohort of patients with pneumococcal pneumonia* Impacto de la bacteriemia en una cohorte de pacientes con neumonía neumocócica

Ileana Palma, Ricardo Mosquera, Carmen Demier, Carlos A Vay, Angela Famiglietti, Carlos M Luna

Abstract Objective: Bacteremia is the most common presentation of invasive disease in community-acquired pneumonia (CAP) due to Streptococcus pneumoniae. We investigated whether bacteremia in pneumococcal CAP worsens outcomes and whether it is related to pneumococcal vaccination (PV). Methods: Secondary analysis of a cohort of patients with pneumococcal CAP confirmed by blood culture, sputum culture, or urinary antigen testing.

Demographic, clinical, radiographic, and biochemical data were collected, as were Acute Physiology and Chronic Health Evaluation II (APACHE II) and pneumonia severity index (PSI) scores, comorbidities, and PV history. We drew comparisons between patients with bacteremic pneumococcal CAP (BPP) and those with non-bacteremic pneumococcal CAP (NBPP). Results: Forty-seven patients had BPP, and 71 had NBPP (confirmed by sputum culture in 45 and by urinary antigen testing in 26); 107 had some indication for PV. None of the BPP patients had received PV, compared with 9 of the NBPP patients (p = 0.043). Among the BPP patients, the mean age was higher (76.4 ± 11.5 vs. 67.5 ± 20.9 years), as were APACHE II and PSI scores (16.4 ± 4.6 vs. 14.1 ± 6.5 and 129.5 ± 36 vs. 105.2 ± 45, respectively), as well as the rate of ICU admission for cardiopathy or chronic renal failure (42.5% vs. 22.5%), whereas hematocrit and plasma sodium levels were lower (35.7 ± 5.8 vs.

38.6 ± 6.7% and 133.9 ± 6.0 vs. 137.1 ± 5.5 mEq/L, respectively), although mortality was similar (29.8% vs 28.2%). Conclusions: In this population at high risk for CAP due to S. pneumoniae, the PV rate was extremely low (8.4%). Although BPP patients were more severely ill, mortality was similar between the two groups. Because PV reduces the incidence of BPP, the vaccination rate in at-risk populations should be increased.

Keywords: Pneumococcal vaccines; Pneumonia, bacterial; Streptococcus pneumoniae; Pneumococcal infections; Mortality; Epidemiology.

Resumen Objetivo: Bacteriemia es la forma invasiva más común de neumonía adquirida en la comunidad (NAC) por Streptococcus pneumoniae. Investigamos si la bacteriemia en NAC neumocócica empeora los resultados y si ella guarda relación con la vacunación antineumocócica (VAN). Métodos: Análisis secundario de una cohorte de pacientes con NAC neumocócica confirmada por cultivo de sangre o esputo o antígeno urinario. Se registraron datos demográficos, clínicos, radiográficos y de laboratorio, escores Higher Acute Physiology and Chronic Health Evaluation II (APACHE II) y pneumonia severity index (PSI), comorbilidades y antecedente de VAN. Se compararon pacientes con NAC neumocócica bacteriémica (NNB) vs. no bacteriémica (NNNB). Resultados: Cuarenta y siete pacientes tenían NNB y 71 NNNB (45 por cultivo de esputo y 26 por antígeno urinario); 107 tenían alguna indicación de VAN. Ningún paciente con NNB, pero 9 con NNNB, habían recibido VAN (p = 0,043). Los pacientes con NNB eran mayores (76,4 ± 11,5 vs. 67,5 ± 20,9 años), tenían mayor APACHE II (16,4 ± 4,6 vs. 14,1 ± 6,5) y PSI (129,5 ± 36 vs. 105,2 ± 45), más frecuentemente cardiopatía e insuficiencia renal crónica e internación en UTI (42,5% vs. 22,5%) y menor hematocrito (35,7 ± 5,8 vs. 38,6 ± 6,7%) y sodio plasmático (133,9 ± 6,0 vs. 137,1 ± 5,5 mEq/L). La mortalidad fue similar (29,8% vs. 28,2%). Conclusiones: Los niveles de VAN (8,4%) en esta población con alto riesgo de NAC por S. pneumoniae fueron extremadamente bajos. Los pacientes con NNB estaban más graves, pero la mortalidad fue similar entre los dos grupos. La VAN reduce la incidencia de NNB y es razonable incrementar el nivel de vacunación de la población en riesgo.

Descriptores: Vacunas neumocócicas; Neumonía Bacteriana; Streptococcus pneumoniae; Infecciones neumocócicas; Mortalidad; Epidemiología. * Study carried out in the Department of Medicine, Pulmonology Section, University of Buenos Aires Hospital de Clínicas, Buenos Aires, Argentina.

Correspondence to: Carlos M. Luna, Arenales 25567, 1º A, CP 1425, Buenos Aires, Argentina.

Tel. 54 11 5950-8931. E-mail: cymluna@fmed.uba.ar Financial support: None.

Submitted: 26 October 2011. Accepted, after review: 22 November 2011.

J Bras Pneumol. 2012;38(4):422-430

Impact of bacteremia in a cohort of patients with pneumococcal pneumonia

Introduction Infection with Streptococcus pneumoniae is the most common cause of community-acquired pneumonia (CAP) worldwide. This pneumococcus is a common colonizer of the nasopharynx in many healthy individuals, especially children (the so-called carrier state) and, by contiguity with the upper airway, can cause diseases such as otitis, sinusitis, and pneumonia; less commonly, it can invade sterile body sites, such as the pleura, meninges, and blood, causing an invasive disease.(1) Bacteremia has been reported to occur in 10% of cases of CAP,(2-4) and there is evidence associating the presence of bacteremia with poor outcomes in patients with CAP.(5) In a study of CAP in the pre-antibiotic era, Tilghman et al. reported a high mortality rate (78%) in adults with bacteremic pneumococcal pneumonia (BPP), compared with 28% in those with non-bacteremic pneumococcal pneumonia (NBPP).(6) More recently, Austrian & Gold reported a 17% mortality rate in adults with BPP treated with penicillin.(7) The primary objective of the present study was to determine whether bacteremia in pneumococcal CAP was associated with predictors of poor outcomes (mortality, length of stay, complications, etc.) and whether it was related to vaccination history.

Methods This was a secondary analysis of a prospective cohort of patients diagnosed with CAP and treated in the Hospital de Clínicas José de San Martín emergency room, clinical medicine ward, or ICU (or any combination of the three) between June of 1997 and May of 2001. The Hospital de Clínicas is the University of Buenos Aires hospital. The hospital is a referral center and a primary care center, having approximately 400 beds. Because a significant number of patients admitted to the hospital are retired social security beneficiaries, individuals over 65 years of age are predominant.

The primary objective of the present study was to determine the association between bacteremia and predictors of poor outcomes (mortality, length of stay, complications, etc.) in patients with CAP. To that end, the primary variable was mortality, chosen mainly because of its objectivity and its obvious clinical importance. Secondary variables included the following: presence of bacteremia; hospitalization; ICU admission; mortality, as predicted by scores (pneumonia severity index

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[PSI], mental Confusion, Urea, Respiratory rate, Blood pressure, and age > 65 years [CURB-65], and Acute Physiology and Chronic Health Evaluation II [APACHE II]); being older than 65 years; being a nursing home resident; comorbidities; and biochemical data useful in screening for the presence of comorbidities and in determining clinical severity. Our secondary objective was to determine the impact of bacteremia on the severity of the manifestations of CAP in terms of demographic variables, physical examination variables, biochemical variables, and severity rates, as well as to determine the relationship of bacteremia with pneumococcal vaccination history and the presence of various comorbidities.

The inclusion criteria were as follows: being over 18 years of age; having been diagnosed with CAP in accordance with the criteria defined

by Fang et al. (i.e., presence of a new infiltrate on chest X-ray, together with one of the major criteria [fever ≥ 38.0°C, hypothermia < 35.0°C, cough, and pleuritic pain] or two of the minor criteria [dyspnea, leukocytosis > 12,000 cells/ mm3, altered level of consciousness, auscultatory signs of consolidation, and expectoration])(8); not having been hospitalized for more than 48 h prior to symptom onset; and presenting with positive blood culture for S. pneumoniae, positive sputum culture for S. pneumoniae, positive urinary antigen test results for S. pneumoniae, or any combination of the three.

The exclusion criteria were as follows: having been hospitalized in the last 30 days (or presenting with any other evidence suggestive of nosocomial pneumonia); having severe immunosuppression (e.g., having been under treatment with corticosteroids at a dose greater than 20 mg per day for more than 30 days); receiving chemotherapy for a lymphoproliferative disease or any other neoplastic disease; having neutropenia of any cause (< 1,000 cells/mm3); and being HIV-positive and having an AIDSdefining illness or a CD4+ lymphocyte count < 200 cells/mm3.

Clinical evaluation consisted of anamnesis and physical examination, the following data having been collected: demographic data (age, gender, and nursing home residence); data on flu and pneumococcal immunizations; data on clinical parameters at admission (temperature, blood pressure, HR, and RR, as well as level of consciousness, as determined by the Glasgow coma J Bras Pneumol. 2012;38(4):422-430

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scale score); data on coexisting conditions (diabetes mellitus, chronic lung diseases such as COPD and asthma, chronic heart failure, chronic liver or kidney disease, neurological disease [dementia and stroke], HIV infection, and alcoholism); biochemical data (blood workup, urea, creatinine, glucose, ionography, and acid-base status); data on pneumonia severity (hospitalization and ICU admission), including APACHE II score,(9) CURB-65 score,(10) and PSI class(11); and data on 30-day mortality (regardless of the cause) and premature death, the latter having been defined as death occurring in the first 7 days.

We defined BPP as a diagnosis of pneumonia with one or more positive blood cultures for S. pneumoniae. In contrast, we defined NBPP as a diagnosis of pneumonia with positivity for S. pneumoniae as determined by sputum culture, an immunochromatographic test (Binax Now, S. pneumoniae urinary antigen test; Binax Inc, Portland, ME, USA), or both and negativity for S. pneumoniae as determined by blood cultures.

The statistical analysis was performed with the Statistical Package for the Social Sciences, version 15.0 for Windows (SPSS Inc., Chicago, IL, USA).

We used the chi-square test or Fisher’s exact test for categorical variables and the Student’s t-test for continuous variables. In order to analyze discrete variables associated with mortality, we employed a predictive logistic regression model including the predictors that were found to be statistically significant by the chi-square test (p < 0.001). The level of statistical significance was set at p < 0.05.

Results Over a 4-year period, 798 patients diagnosed with CAP were hospitalized. Of those, 158 were excluded from the analysis because they did not meet all of the inclusion criteria or because they met one of the exclusion criteria. Of the remaining 640 patients, S. pneumoniae was found to be the etiologic agent in 118, who were therefore selected for inclusion in the study.

Forty-seven met the criteria for BPP, and 71 met the criteria for NBPP. There were 23 outpatients.

Of those, 5 were found to have bacteremia due to S. pneumoniae.

Among the BPP patients, the mean age was higher, the most common comorbidity being heart or kidney failure (Table 1). There were no differences between the two groups in terms J Bras Pneumol. 2012;38(4):422-430

of gender or any of the other comorbidities investigated. None of the BPP patients had received pneumococcal vaccination, whereas 9 (12.7%) of the NBPP patients had been vaccinated (p = 0.043). Of those 9, 7 were hospitalized (most being over 65 years of age and having severe pneumonia), and 2 (22.2%) died, whereas 32 (29.9%) of those who had not been vaccinated died (p = 0.624).

In addition to having hyponatremia, the BPP patients had significantly higher RRs and creatinine levels, as well as significantly lower hematocrit levels.

Although most of the BPP patients required hospitalization and ICU admission, there were no differences between the two groups in terms of the length of hospital stay. The BPP patients were more severely ill, as determined by APACHE II and PSI scores, the latter having shown a predominance of higher risk classes among those patients. The same was true for the CURB-65 score. However, we found no differences between the two groups in terms of mortality during hospitalization (Table 2).

Regarding the diagnostic methods, microbiological findings in sputum, urinary antigen testing, or both allowed us to identify the non-bacteremic group; it is of note that, although those methods were applied to the NBPP and BPP groups, the number of patients with microbiological findings in sputum was lower in the BPP group (Table 3).

Of the 118 patients, 34 (28.6%) died of pneumococcal pneumonia. Among those patients, being over 65 years of age, being a nursing home resident, having tachycardia and hypotension at admission, having a hematocrit level < 30%, and having a PaO2/FiO2 < 250 or oxygen saturation < 90% constituted variables that were significantly associated with higher mortality. The presence of chronic renal failure, chronic heart failure, or neurological disease was associated with higher mortality, as was the presence of more than one comorbidity. Other variables associated with a poor prognosis included ICU admission, CURB-65 ≥ 2, and PSI class IV-V. However, when analyzing those characteristics in terms of the presence or absence of bacteremia, we found no statistically significant differences between the two groups (Table 4).

Logistic regression was performed to evaluate the impact of a number of variables on mortality

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Table 1 - Demographic and clinical characteristics of the patients with pneumococcal pneumonia.

Variable Groups p BPP NBPP (n = 47) (n = 71) Demographic data 76.36 ± 11.46 67.79 ± 20.89 0.012 Age, yearsa 21/26 34/37 M/F genderb 2 (4) 11 (15.5) 0.262 Nursing home residentc 0 (0.0) 9 (12.7) 0.043 Pneumococcal vaccinationc Comorbidity, n Chronic renal failure 14 5 0.001 Chronic heart disease 26 24 0.021 Chronic lung disease 12 28 0.118 Diabetes 6 9 0.989 HIV infection 0 2 0.246 Liver disease 1 2 0.816 Alcohol consumption 1 1 0.767 Neoplastic disease 4 4 0.543 Cerebrovascular disease 9 17 0.538 Presence of more than 1 comorbidity 24 32 0.523 Physical examinationa 37.7 ± 1.1 37.6 ± 1.2 0.638 Temperature, °C 102.8 ± 16.8 100.7 ± 15.5 0.493 HR, bpm 29.7 ± 5.9 25.8 ± 6.7 0.001 RR, breaths/min 118.4 ± 23.7 117.6 ± 21.7 0.853 Systolic blood pressure, mmHg 65.8 ± 13.5 69.5 ± 13.6 0.15 Diastolic blood pressure, mmHg 13.9 ± 2.2 14.25 ± 1.9 0.503 Glasgow scale score Biochemical dataa 14268 ± 7099 12667 ± 5754 0.19 Leukocyte count, cells/mm3 35.7 ± 5.8 38.6 ± 6.7 0.021 Hematocrit, % 60.8 ± 11.8 65.1 ± 25.4 0.923 PaO2, mmHg 275.6 ± 73 273.9 ± 100 0.923 PaO2/FiO2 ratio 7.40 ± 0.07 7.40 ± 0.1 0.968 Arterial pH 136.09 ± 80.2 146.9 ± 65.33 0.448 Glucose, mg/dL 65.7 ± 39.81 59.4 ± 33.9 0.38 Urea, mg/dL 1.53 ± 0.75 1.11 ± 0.73 0.009 Creatinine, mg/dL 133.9 ± 6.06 137.1 ± 5.5 0.005 Sodium, mEq/L 3.8 ± 0.5 3.8 ± 0.6 0.977 Potassium, mEq/L 5 (10) 2 (3) 0.078 Radiological finding of pleural effusionc BPP: bacteremic pneumococcal pneumonia; NBPP: non-bacteremic pneumococcal pneumonia; M: male; and F: female. a Results expressed as mean ± SD. bResults expressed as n/n. cResults expressed as n (%).

in patients with pneumococcal pneumonia. As shown in Table 5, only three of the variables considered were found to be independently and significantly related to mortality in those patients: presence of more than one comorbidity (OR: 8.14); ICU admission (OR: 4.85); and presence of neurological disease (OR: 4.53).

Discussion Invasive pneumococcal disease causes high morbidity and mortality, especially in at-risk patients and older adults, as well as having a higher incidence in patients with lung disease, heart disease, and diabetes. The incidence of infection, especially bacteremia, empyema, and meningitis, in J Bras Pneumol. 2012;38(4):422-430

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Table 2 - Variables associated with mortality in patients with pneumococcal pneumonia.

Severity criteria Groups BPP NBPP (n = 47) (n = 71) Hospitalizationa 44 (97.8) 51 (77.4) 6.6 ± 4.5 8.12 ± 8.56 Length of hospital stay (in days)b 20 (42.5) 16 (22.5) ICU admissiona PSI, n 46 70 130 ± 36 105 ± 45 PSI (t-test)b PSI classa I 0 (0.0) 13 (18.6) II 0 (0.0) 3 (4.3) III 8 (17.4) 9 (12.9) IV 18 (39.1) 22 (31.4) V 20 (43.5) 23 (32.9) 16.38 ± 4.63 14.00 ± 6.50 APACHE IIb 2.65 ± 0.70 2.12 ± 1.20 CURB-65b 0 (0.0) 10 (14.9) 0a 2 (5.0) 9 (13.4) 1a 13 (32.5) 16 (23.9) 2a 22 (55) 27 (40.3) 3a 3 (7.5) 5 (7.5) 4a Mortality 14 (29.8) 20 (28.2) Death from any causea 12 (26.1) 13 (18.3) Premature deatha

p

0.005 0.27 0.028 0.002 0.016*

0.031 0.012 0.048

0.849 0.316

BPP: bacteremic pneumococcal pneumonia; NBPP: non-bacteremic pneumococcal pneumonia; PSI: pneumonia severity index; APACHE II: Acute Physiology and Chronic Health Evaluation II; and CURB-65: mental Confusion, Urea, Respiratory rate, Blood pressure, and age > 65 years. aResults expressed as n (%). bResults expressed as mean ± SD. *Chi-square test.

Table 3 - Diagnostic yield of the methods employed.

Diagnostic method Groups BPP NBPP (n = 47) (n = 71) BINAX - Urinary antigen testinga 11/15 (73.3) 28/41 (68.3) 7 (14.9) 45 (63.4) Microbiological findings in sputumb 4 (11.1) 6 (18.2) Resistance to pneumococcal infectionb

p

0.716 0.001 0.405

BPP: bacteremic pneumococcal pneumonia; and NBPP: non-bacteremic pneumococcal pneumonia. aResults expressed as n/N (%). bResults expressed as n (%).

sterile sites varies by geographic region and ranges from 21 to 33 cases per 100,000 population.(12) In Argentina, a study conducted in the city of Tandil reported that the incidence of BPP was 2.8 cases/1,000 admissions or 17 cases/100,000 population per year.(13) Since the introduction of the pediatric 7-valent pneumococcal conjugate vaccine (PCV7) in 2002, the rate of invasive pneumococcal disease has decreased significantly in the United States, according to the Centers for Disease Control and Prevention. This reduction occurred not only among vaccinated children but also among unvaccinated adults and individuals J Bras Pneumol. 2012;38(4):422-430

over 65 years of age, through the so-called “herd effect”.(14) In the present study, we found certain differences between the characteristics of BPP and those of NBPP. We found that BPP was more common in older individuals than was NBPP, a finding that is in disagreement with those of previous studies.(15,16) We were unable to compare the incidence of BPP and NBPP in HIV-positive patients and intravenous drugs users with the incidence of BPP and NBPP in patients who did not have those characteristics because the incidence of HIV infection and

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Table 4 - Variables associated with mortality in patients with pneumococcal pneumonia.

Variable Patients, n Mortality, % Age > 65 years 30 33.7 Male gender 14 25.5 Nursing home resident 7 54.0 Vaccination 2 22.0 Bacteremia 14 30.0 Temperature > 38°C 16 24.0 HR > 120 bpm 12 54.0 Systolic blood pressure < 90 mmHg 3 50.0 Diastolic blood pressure < 60 mmHg 10 50.0 RR > 24 breaths/min 28 33.0 Leukocytosis 20 28.0 Leukopenia 3 50.0 Hematocrit < 30% 8 61.5 16 50.0 PaO2/FiO2 ratio < 250 8 50.0 PaO2/FiO2 ratio < 200 Urea > 50 mg/dl 20 32.0 Creatinine > 1,5 mg/dl 14 35.0 Glucose > 120 mg/dl 18 34.0 Sodium < 130 mEq/l 3 33.0 22 40.7 PO2 < 60 mmHg Saturation < 90% 26 50.0 Presence of comorbidities 33 36.0 Presence of > 1 comorbidity 31 55.0 Chronic heart disease 26 52.0 Chronic renal failure 10 53.0 Neurological disease 17 65.0 Neoplastic disease 3 37.0 Chronic lung disease 15 37.0 Liver disease 1 33.0 Diabetes 5 33.3 Hospitalization 34 35.8 ICU admission 21 58.0 PSI (class IV-V) 33 97.0 CURB-65 ≥ 2 29 96.6

p 0.042 0.452 0.049 0.65 0.049 0.220 0.003 0.230 0.019 0.140 0.524 0.466 0.010 0.012 0.109 0.780 0.653 0.570 0.860 0.051 0.001 0.002 < 0.001 < 0.001 0.012 < 0.001 0.574 0.136 0.860 0.679 0.001 < 0.001 0.001 0.001

PSI: pneumonia severity index; and CURB-65: mental Confusion, Urea, Respiratory rate, Blood pressure, and age > 65 years.

Table 5 - Logistic regression predicting the likelihood of death in patients with pneumococcal pneumonia.

Variable OR 95% CI p Lower limit Upper limit ICU admission 4.85 1.57 14.92 0.006 Neurological disease 4.53 1.33 15.39 0.015 More than 1 comorbidity 8.14 1.82 36.22 0.006

intravenous drug use in our hospital population was zero. One third of our population had been diagnosed with COPD, a comorbidity that tended to be more common in NBPP patients (p = not significant). We found a predominance of BPP in patients with chronic heart disease

or chronic renal failure, as has been reported, especially in elderly individuals who present with neutrophil dysfunction, decreased production of immunoglobulins, and malnutrition.(17) Regarding clinical manifestations, the only significant difference between BPP patients J Bras Pneumol. 2012;38(4):422-430

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and NBPP patients was that the former were more tachypneic. However, the BPP group was predominantly composed of elderly individuals, in whom tachypnea is more common,(18) Tachypnea is also a well-known indicator of severity found in many patients with bacteremia.

The BPP patients were found to have lower hematocrit levels and higher creatinine levels, as well as having hyponatremia, which is in agreement with previous reports by other authors.(19-22) We found a trend toward radiological evidence of pleural effusion, a finding that has previously been described in association with BPP.(19,20) Bacteremia has traditionally been associated with poor outcomes in patients with CAP. In a study of CAP in the pre-antibiotic era, Tilghman et al. drew attention to the significant mortality in adults with BPP (78%), compared with 28% in those with NBPP.(6) More recently, Austrian & Gold reported a 17% mortality rate in adults with BPP treated with penicillin.(7) In a recent study conducted in Canada and involving 1,154 patients with invasive pneumococcal disease, Marrie et al. found that being 18-40 years of age and receiving concurrent treatment with two antibiotics were associated with lower mortality.(23) The use of two antibiotics in combination for the treatment of severe forms of BPP is in line with the observations of Baddour et al.,(24) as well as with the Infectious Diseases Society of America/ American Thoracic Society CAP management guidelines.(25) In addition, Marrie et al. observed that although premature death was not associated with comorbidities, it was associated with the presence of complications such as altered mental status, need for oxygen or mechanical ventilation, and cardiac arrest, all of which are indicators of the severity of the infection itself.(23) The mortality rate found by Marrie et al. in the aforementioned study was 14.1%, which is very similar to the 17% rate reported by Austrian & Gold in 1964, supporting the hypothesis of Austrian & Gold that, despite appropriate antibiotic therapy, invasive pneumococcal disease continues to have high mortality, which occurs during the first 3 days, in which the effect of antibiotics in reversing the fatal outcome seems to be nonexistent.(7,23) Because a proportion of patients might die in the first days despite antibiotic use, it is clear that this group of patients would benefit from prevention. In Latin American countries, J Bras Pneumol. 2012;38(4):422-430

the pneumococcal polysaccharide vaccine is indicated for individuals over 65 years of age, those aged 2-64 years with comorbidities, and those cared for in nursing homes, as well as for immunocompromised individuals, according to different guidelines.(26,27) The 23-valent pneumococcal polysaccharide vaccine (PPV23) is well tolerated when administered for the first time but is seldom administered in the region, even to patients for whom it is clinically indicated.

(28) In the present study, we confirmed the ability of PPV23 to prevent, in a significant manner, the development of BPP. However, 9 patients had NBPP despite having been vaccinated. A meta-analysis evaluating the effectiveness of PPV23 in function of patient age and risk level concluded that the vaccine is effective in preventing pneumococcal bacteremia in elderly individuals in general (65%) but less so in high-risk elderly individuals (20%), as well as showing little or no effectiveness in preventing pneumonia—the vaccine being even harmful (−16%)—in highrisk groups.(29) However, a recently published randomized controlled trial conducted in Japan and involving elderly nursing home residents (mean age > 84) demonstrated the usefulness of PPV23 in preventing NBPP.(30) Given that S. pneumoniae is the most common cause of pneumonia (25-50%), it would be very important to have a vaccine that can also protect against all forms of pneumococcal disease. Below the age of 2 years, the response to PPV23 is unsatisfactory, PCV7 being therefore indicated. It has been demonstrated that PCV7 can reduce the incidence of invasive and noninvasive pneumococcal disease, as well as reducing oropharyngeal colonization in children.(16) In this sense, there are expectations regarding the potential usefulness of conjugate vaccines that cover a larger number of serotypes and are close to being approved for use in adults.

In conclusion, BPP affects patients who are older and who are more severely ill. However, we found no significant differences between BPP patients and NBPP patients in terms of the length of hospital stay and mortality. Although it is more common in patients who are more severely ill, bacteremia does not determine severity; rather, it is an effect of disease severity. Although the pneumococcal polysaccharide vaccine prevents BPP, the levels of protection that the vaccine confers are not enough to prevent NBPP or colonization.

Impact of bacteremia in a cohort of patients with pneumococcal pneumonia

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conjugate vaccine. N Engl J Med. 2003;348(18):1737-46.

PMid:12724479. http://dx.doi.org/10.1056/NEJMoa022823 15. Marrie TJ, Low DE, De Carolis E; Canadian CommunityAcquired Pneumonia Investigators. A comparison of bacteremic pneumococcal pneumonia with nonbacteremic community-acquired pneumonia of any etiology-results from a Canadian multicentre study. Can Respir J. 2003;10(7):368-74. PMid:14571288.

16. Musher DM, Rueda-Jaimes AM, Graviss EA, RodriguezBarradas MC. Effect of pneumococcal vaccination: a comparison of vaccination rates in patients with bacteremic and nonbacteremic pneumococcal pneumonia. Clin Infect Dis. 2006;43(8):1004-8. PMid:16983612. http:// dx.doi.org/10.1086/507699 17. Lipsky BA, Boyko EJ, Inui TS, Koepsell TD. Risk factors for acquiring pneumococcal infections. Arch Intern Med. 1986;146(11):2179-85. PMid:16983612. http://dx.doi. org/10.1086/507699 18. Metlay JP, Schulz R, Li YH, Singer DE, Marrie TJ, Coley CM, et al. Influence of age on symptoms at presentation in patients with community-acquired pneumonia. Arch Intern Med. 1997;157(13):1453-9. PMid:9224224. http:// dx.doi.org/10.1001/archinte.1997.00440340089009 19. Musher DM, Alexandraki I, Graviss EA, Yanbeiy N, Eid A, Inderias LA, et al. Bacteremic and nonbacteremic pneumococcal pneumonia. A prospective study. Medicine (Baltimore). 2000;79(4):210-21. PMid:10941350. http:// dx.doi.org/10.1097/00005792-200007000-00002 20. Jover F, Cuadrado JM, Andreu L, Martínez S, Cañizares R, de la Tabla VO, et al. A comparative study of bacteremic and non-bacteremic pneumococcal pneumonia. Eur J Intern Med. 2008;19(1):15-21. PMid:18206596. http:// dx.doi.org/10.1016/j.ejim.2007.03.015 21. Brandenburg JA, Marrie TJ, Coley CM, Singer DE, Obrosky DS, Kapoor WN, et al. Clinical presentation, processes and outcomes of care for patients with pneumococcal pneumonia. J Gen Intern Med. 2000;15(9):638-46.

PMid:11029678. PMCid:1495594. http://dx.doi. org/10.1046/j.1525-1497.2000.04429.x 22. Torres JM, Cardenas O, Vasquez A, Schlossberg D. Streptococcus pneumoniae bacteremia in a community hospital. Chest. 1998;113(2):387-90. PMid:9498956. http://dx.doi.org/10.1378/chest.113.2.387 23. Marrie TJ, Tyrrell GJ, Garg S, Vanderkooi OG. Factors predicting mortality in invasive pneumococcal disease in adults in Alberta. Medicine (Baltimore).

2011;90(3):171-9. PMid:21512414. http://dx.doi. org/10.1097/MD.0b013e31821a5a76 24. Baddour LM, Yu VL, Klugman KP, Feldman C, Ortqvist A, Rello J, et al. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med. 2004;170(4):440-4. PMid:15184200. http://dx.doi. org/10.1164/rccm.200311-1578OC 25. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 Suppl 2:S27-72.

PMid:17278083. http://dx.doi.org/10.1086/511159 26. Corrêa Rde A, Lundgren FL, Pereira-Silva JL, Frare e Silva RL, Cardoso AP, Lemos AC, et al. Brazilian guidelines for community-acquired pneumonia in immunocompetent adults - 2009. J Bras Pneumol. 2009;35(6):574-601.

PMid:19618038.

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27. Luna CM, Calmaggi A, Caberloto O, Gentile J, Valentini R, Ciruzzi J, et al. Pneumonia acquired in the community.

Practical guide elaborated by a committee intersocieties [Article in Spanish]. Medicina (B Aires). 2003;63(4):319-43.

28. Donalisio MR, Rodrigues SM, Mendes ET, Krutman M. Adverse events after pneumococcal vaccination. J Bras Pneumol. 2007;33(1):51-6. PMid:17568868. http:// dx.doi.org/10.1590/S1806-37132007000100011 29. Melegaro A, Edmunds WJ. The 23-valent pneumococcal polysaccharide vaccine. Part I. Efficacy of PPV in

the elderly: a comparison of meta-analyses. Eur J Epidemiol. 2004;19(4):353-63. http://dx.doi. org/10.1023/B:EJEP.0000024701.94769.98 30. Maruyama T, Taguchi O, Niederman MS, Morser J, Kobayashi H, Kobayashi T, et al. Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents: double blind, randomised and placebo controlled trial. BMJ. 2010;340:c1004. PMid:20211953. PMCid:2834887. http://dx.doi.org/10.1136/bmj.c1004

About the authors Ileana Palma

Chief Resident in Pulmonology. Pulmonology Section, University of Buenos Aires Hospital de Clínicas, Buenos Aires, Argentina.

Ricardo Mosquera

Resident in Pulmonology. Pulmonology Section, University of Buenos Aires Hospital de Clínicas, Buenos Aires, Argentina.

Carmen Demier

Staff Member of the Bacteriology Section. Department of Biochemistry, University of Buenos Aires Hospital de Clínicas, Buenos Aires, Argentina.

Carlos A Vay

Head of the Bacteriology Section. Department of Biochemistry, University of Buenos Aires Hospital de Clínicas, Buenos Aires, Argentina.

Angela Famiglietti

Full Professor. University of Buenos Aires School of Pharmacy and Biochemistry, Buenos Aires, Argentina.

Carlos M Luna

Full Professor and Head of the Pulmonology Section. Department of Medicine, University of Buenos Aires Hospital de Clínicas, Buenos Aires, Argentina.

J Bras Pneumol. 2012;38(4):422-430

Original Article Evaluation of the efficacy and safety of a fixed-dose, single-capsule budesonide-formoterol combination in uncontrolled asthma: a randomized, double-blind, multicenter, controlled clinical trial* Avaliação da eficácia e segurança da associação de budesonida e formoterol em dose fixa e cápsula única no tratamento de asma não controlada: ensaio clínico randomizado, duplo-cego, multicêntrico e controlado

Roberto Stirbulov, Carlos Cezar Fritscher, Emilio Pizzichini, Márcia Margaret Menezes Pizzichini

Abstract Objective: To evaluate the efficacy and safety of a fixed-dose, single-capsule budesonide-formoterol combination, in comparison with budesonide alone, in patients with uncontrolled asthma. Methods: This was a randomized, double-blind, multicenter, phase III, parallel clinical trial, comparing the short-term efficacy and safety of the combination of budesonide (400 µg) and formoterol (12 µg), with those of budesonide alone (400 µg), both delivered via a dry powder inhaler, in 181 patients with uncontrolled asthma. The age of the patients ranged from 18 to 77 years. After a run-in period of 4 weeks, during which all of the patients received budesonide twice a day, they were randomized into one of the treatment groups. The treatment consisted of the administration of the medications twice a day for 12 weeks. The primary outcome measures were FEV1, FVC, and morning PEF. We performed an intention-to-treat analysis of the data. Results: In comparison with the budesonide-only group patients, those treated with the budesonide-formoterol combination showed a significant improvement in FEV1 (0.12 L vs. 0.02 L; p = 0.0129) and morning PEF (30.2 L/min vs. 6.3 L/min; p = 0.0004). These effects were accompanied by good tolerability and safety, as demonstrated by the low frequency of adverse events, only minor adverse events having occurred. Conclusions: The single-capsule combination of budesonide-formoterol appears to be efficacious and safe. Our results indicate that this formulation is a valid therapeutic option for obtaining and maintaining asthma control.

Clinical trial ANVISA no. 01392/2008.

Keywords: Asthma; Budesonide; Adrenergic beta-2 receptor agonists.

Resumo Objetivo: Avaliar a eficácia e a segurança da associação de budesonida e formoterol em dose fixa e cápsula única, em comparação ao uso de budesonida isolada em pacientes com asma não controlada. Métodos: Ensaio clínico randomizado, duplo-cego, multicêntrico, de fase III, com grupos paralelos, comparando a eficácia de curto prazo e a segurança da formulação em pó de budesonida (400 µg) e formoterol (12 µg) com a formulação em pó de budesonida (400 µg) em 181 participantes com asma não totalmente controlada. A idade dos participantes variou de 18-77 anos. Após um período de run-in de 4 semanas, durante o qual todos os participantes receberam budesonida duas vezes por dia, houve a randomização para um dos tratamentos do estudo. O tratamento foi administrado duas vezes ao dia por 12 semanas. Os principais desfechos foram VEF1, CVF e PFE matinal. Os dados foram analisados por intenção de tratar. Resultados: O grupo tratado com a associação, quando comparado ao grupo budesonida isolado, teve uma melhora significativa no VEF 1 (0,12 L vs. 0,02 L; p = 0.0129) e no PFE matinal (30,2 L/min vs. 6,3 L/min; p = 0,0004). Esses efeitos foram acompanhados por boa tolerabilidade e segurança, como demonstrado pela baixa frequência de eventos adversos menores. Conclusões: A associação em cápsula única de budesonida e formoterol mostrou ser eficaz e segura. Os resultados demonstram que essa formulação é uma opção terapêutica válida para a obtenção e manutenção do controle da asma.

Ensaio clínico ANVISA nº 01392/2008.

Descritores: Asma; Budesonida; Agonistas de receptores adrenérgicos beta 2. * Study carried out at the Santa Casa School of Medical Sciences in São Paulo, São Paulo, Brazil.

Correspondence to: Roberto Stirbulov. Rua Baronesa de Itu, 610, conjunto 93, Santa Cecília, CEP 01231-000, São Paulo, SP, Brasil.

Tel. 55 11 3663-3604. E-mail: stirbul@uol.com.br Financial support: None.

Submitted: 6 December 2011. Accepted, after review: 7 May 2012.

J Bras Pneumol. 2012;38(4):431-437

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Stirbulov R, Fritscher CC, Pizzichini E, Pizzichini MMM

Introduction The treatment of persistent asthma involves continued use of controller medications.(1-3) Current evidence shows that the use of an inhaled corticosteroid (ICS) in combination with a longacting β2 agonist (LABA), when compared with the use of an ICS alone, results in better disease control and reduces future risks.(4,5) In addition, these effects are obtained with lower ICS doses, and asthma treatment is facilitated by a reduction in the number of daily inhalations.(6) Various ICS-LABA combinations, delivered via different inhalers, have been approved and are available for the treatment of asthma in Brazil.

The budesonide-formoterol combination can be delivered via a multiple-dose dry powder inhaler (Turbuhaler) or via a single-dose inhaler with two separate capsules containing budesonide and formoterol (Aerolizer) or with a single capsule containing the budesonide-formoterol combination (Aerocaps). The medical literature has not provided sufficient evidence to support the use of a fixed-dose, single-capsule ICS-LABA combination delivered via Aerocaps. Therefore, the objective of the present study was to evaluate the efficacy and safety of a fixed-dose, singlecapsule budesonide-formoterol combination, in comparison with budesonide alone, in patients with uncontrolled persistent asthma.

Methods This was a randomized, double-blind, multicenter (four centers), phase III, parallel clinical trial conducted in Brazil and comparing the efficacy and safety of a fixed-dose, singlecapsule combination of budesonide 400 µg and formoterol 12 µg (Alenia®; Biosintética Farmacêutica Ltda., São Paulo, Brazil) with those of budesonide 400 µg alone (Busonid Caps®; Aché Lab Farm S.A., Guarulhos, Brazil) in adults with partially controlled asthma, as determined on the basis of the classifications proposed by the Global Strategy for Asthma Management and Prevention and the Fourth Brazilian Guidelines for Asthma Management.(1,3) After a run-in period of 4 weeks, during which all of the patients received 400 µg of inhaled budesonide twice daily, they were randomized into one of the treatment groups. The randomization scheme, i.e., permuted blocks of size 4 at a 1:1 ratio, J Bras Pneumol. 2012;38(4):431-437

was generated by the Statistical Analysis System, version 9.1.3 (SAS Institute, Gary, NC, USA).

Both treatments consisted of inhaled administration of the medications (identical dry powder capsules) twice daily for 12 weeks.

The primary outcome measures were changes in FEV1, FVC, and morning PEF. Secondary outcome measures included the effects of treatment on afternoon PEF, the FEV1/FVC ratio, the percentage of symptom-free days, the frequency of nocturnal awakenings due to asthma, and the frequency of use of rescue medication.

Concomitant use of other asthma treatments was not allowed, except for rescue albuterol use and oral corticosteroid use during exacerbations (courses of oral corticosteroid therapy consisting of prednisone 40 mg for 3 days, 20 mg for 3 days, and 10 mg for another 3 days).

All of the participants had been diagnosed with asthma at least one year prior, had never smoked or had stopped smoking more than one year prior (with a smoking history of fewer than 20 pack‑years), and had no other respiratory diseases or comorbidities that could affect the results of the study. None of the participants had received oral corticosteroids or had been hospitalized in the previous month. The study was approved by the human research ethics committees of each participating center, and all of the participants gave written informed consent.

The study consisted of six consecutive visits, which took place in the morning (Figure 1). At the first visit (V-2), eligible patients gave written informed consent, underwent spirometry, and received information about the study. On the following week (V-1), the participants returned to receive the run-in medication (budesonide 400 µg twice daily for 4 weeks); at the subsequent visit (V0), the patients were randomized into one of

Figure 1 - Study design. BUD: budesonide; FORM: formoterol; R: Randomization; and V: visit.

Evaluation of the efficacy and safety of a fixed-dose, single-capsule budesonide-formoterol combination in uncontrolled asthma: a randomized, double-blind, multicenter, controlled clinical trial

the treatment groups. The other visits (V1, V2, and V3) took place every 4 weeks. The spirometry results obtained at V0 were considered baseline values. The first spirometry was performed no later than 10:00 a.m., subsequent spirometry tests having been performed ± 2 h after the first spirometry, no later than 11:00 a.m. For the evaluation of safety, blood samples were collected at V-2, V0, and V3. Symptoms, use of rescue medication, and daily measurements of PEF with a Mini-Wright® meter (Clement Clarke International, Essex, England) prior to the use of the study medications were recorded by the participants in a diary.

Spirometry was performed with a computerized spirometer (Koko®; PDS Instrumentation, Louisville, CO, USA), in accordance with the Brazilian Thoracic Association guidelines.(7) The predicted normal values were those proposed by Knudson et al. in 1976(8) and 1983.(9) Adherence to treatment was measured at each visit by counting the number of capsules left. Participants with adherence below 70% were discontinued from the study.

Regarding statistical analysis, the study was designed to include 100 participants in each group, a sufficient number to detect a 20-L/min difference in morning PEF between the treatments, with a power of 80% and a level of significance of 5%, assuming a standard deviation of 50 L/min. An interim analysis was planned and was performed when 40% of the participants had completed the study. The analysis showed that the intervention had had a significant effect, and recruitment was therefore stopped. A total of 181 participants completed the study.

All of the efficacy variables were evaluated for the participants who received at least one dose of the medication and who underwent at least one post-baseline evaluation of efficacy (intention-to-treat population).

The observed values of PEF were recorded in the participant diary. The baseline measurement was represented by the mean of the last 10 values recorded in the run-in period (between V-1 and V0), whereas the final measurement was represented by the mean of the last 10 values recorded in the treatment period (between V0 and V3).

We used a covariance model to evaluate the changes in the spirometric parameters and those in PEF (i.e., the difference between final values and baseline values). In the initial adjusted model,

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treatment was considered a fixed factor, whereas baseline values, gender, age, and center were considered covariates, as were gender/type of treatment interactions and center/type of treatment interactions. Adjusted mean estimates and 95% CIs were calculated for the final adjusted model, non-significant interactions and covariates being excluded. The last-observation-carried-forward imputation method was used.

The efficacy variables representing counts were evaluated by a generalized linear model, the negative binomial distribution being used and the center being considered a covariate.

All calculations were performed with the Statistical Analysis System, version 9.1.3.

Results Between April of 2009 and June of 2010, 304 adults with asthma were recruited from among those being treated at any of four research centers in Brazil. Of those 304 patients, 181 were included in the study and were randomized into one of the intervention groups; 175 participants used at least one dose of the medication (90 in the budesonide-only group and 85 in the budesonideformoterol [BF] group), being included in the intention-to-treat analysis (Figure 2). The demographic characteristics and the baseline spirometric parameters are summarized in Table 1 and were similar between the treatment groups.

Regarding the primary outcome measures, the 12-week treatment resulted in statistically significant mean increases in FEV1 and morning PEF—of 104 mL (95% CI: 22-186 mL) and 23.93 L/min (95% CI: 10.89-36.93 L/min), respectively—in the BF group as compared with the budesonide-only group. These results represent an estimate of the difference in change (final value – baseline value) in FEV1 in the comparison of the two groups, calculated by the following formula: (final FEV1 – baseline FEV1 (BF group]) – (final FEV1 – baseline FEV1 (budesonide-only group]) In other words, these results reflect the additional effect of formoterol, when used in combination with budesonide.

There was a mean increase in FVC of 80.93 mL (95% CI: −1.28 to 163.14 mL), which was not statistically significant (Table 1 and Figure 3).

J Bras Pneumol. 2012;38(4):431-437

J Bras Pneumol. 2012;38(4):431-437

Budesonide-formoterol pd (n = 85)a Final Adjusted 95% CI pc mean mean changeb 2.40 0.12 0.05-0.18 0.0005 0.0129 80.05 3.60 1.49-5.72 0.0010 0.0017 3.33 0.11 0.05-0.18 0.0013 0.0536 93.84 2.18 0.30-4.05 0.0231 0.0039 326.61 30.19 19.59-40.80 <0.0001 0.0004 334.28 31.34 20.72-41.95 <0.0001 < 0.0001 81.62 1.29 −0.11 to 2.69 0.0711 0.2254 66.01 (52.18-83.52) 0.0673 46.63 (29.42-73.92) 0.6579 91.98 (87.67-96.51) 0.3847

a

Intention-to-treat population. bFinal value – baseline value. cEffect of change within the intervention group (baseline vs. final). dEffect of the intervention factor (budesonide-only group vs. budesonide-formoterol group). eOne participant in the budesonide-formoterol group did not record the baseline afternoon PEF in the diary. fValues expressed as % (95% CI). Adjusted mean proportion of event-free days/nights in the treatment period.

Table 1 - Treatment efficacy results in the budesonide-only and budesonide-formoterol groups.

Groups Budesonide Variable (n = 90)a Baseline Final Adjusted Baseline 95% CI pc mean mean mean changeb mean FEV1, L 2.25 2.23 0.02 −0.05 to 0.08 0.5997 2.32 75.91 74.80 −1.17 −3.23 to 0.89 0.2635 76.51 FEV1, % of predicted FVC, L 3.16 3.15 0.03 −0.03 to 0.10 0.3047 3.28 FVC, % of predicted 89.97 88.46 −1.70 −3.52 to 0.12 0.0672 91.86 Morning PEF, L/min 298.33 299.49 6.27 −3.79 to 16.32 0.2201 302.69 303.75 301.64 2.31 −7.71 to 12.33 0.6492 308.49 Afternoon PEF, L/mine 80.27 80.36 0.08 −1.27 to 1.44 0.9023 80.34 FEV1/FVC, % 49.02 (39.52-60.79) Rescue medication-free daysf 40.64 (27.27-60.56) Symptom-free daysf 89.33 (85.39-93.45) Awakening-free nightsf

434 Stirbulov R, Fritscher CC, Pizzichini E, Pizzichini MMM

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Figure 2 - Flowchart of the study population. BUD: budesonide; FORM: formoterol; and ITT: intention-to-treat.

The analysis of the secondary outcome measures revealed a statistically significant mean increase in afternoon PEF of 29.02 L/min (95% CI: 16.03-42.02 L/min) in the BF group patients. There were no statistically significant differences between the groups in terms of the remaining secondary outcome measures (Table 1 and Figure 4).

Regarding adverse events, data on all randomized patients who received at least one dose of the study medications were analyzed. The use of either treatment was well tolerated, and the proportion of patients who reported adverse events was similar in the two intervention groups.

The most common adverse events were as follows: headache, in 29.8%; influenza infection, in 13.8%; upper airway infection, in 9.4%; laryngopharyngeal pain, in 7.2%; dizziness, in 7.2%; tremors, in 5.5%; nasopharyngitis, in 5.5%; nausea, in 5.0%; and upper abdominal pain, in 5.0%.

As evaluated by the investigators, 80% of the events in the BF group and 87% of those in the budesonide-only group were considered unrelated to the study medications. Changes in the treatments given were required in only 2% of the events.

Discussion This is the first study of the efficacy and safety of the single-capsule combination of budesonide-formoterol delivered via Aerocaps to be conducted in Brazil. The effects of the budesonide-formoterol combination were found to be superior to those of budesonide alone, with the same pattern of tolerability and safety.

These results are important because they confirm the efficacy of a combination that is widely prescribed for the treatment of asthma in Brazil.

The increase in FEV1 observed in the participants who used the budesonide-formoterol combination confirms the additional controlling effect of formoterol promoted by Aerocaps, likely indicating a synergistic effect of this combination.

(10,11) The mean difference of 100 mL in FEV1 for the BF group becomes even more important when we consider that the patients included in the present study had near normal spirometric values.

Despite not being statistically significant, the trend toward improvement in FVC in the BF group can be construed as an indirect measure of deflation, possibly because of deposition and the consequent therapeutic effects on the small airways.(11,12) This suggests that the technical J Bras Pneumol. 2012;38(4):431-437

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Figure 3 - Adjusted mean change in FEV1 in liters in the groups studied. BUD: budesonide; and FORM: formoterol.

with those of previously published studies,(4,5) in which ICS-LABA combination therapy was compared with ICS treatment alone, delivered via other inhalers.

On the basis of the safety data obtained, the single-capsule combination of budesonideformoterol was well tolerated and safe, having the same rate of serious and non-serious adverse events as did budesonide alone after 12 weeks of treatment.

The lack of significance in the results of the secondary variables (nocturnal awakenings and symptom-free days) is possibly due to the fact that the sample size was calculated to achieve a statistical significance for the primary outcome measures. However, the trend toward improvement in those parameters indicates the efficacy of the budesonide-formoterol combination in obtaining asthma control. Future studies should be designed to investigate other outcome measures (including asthma control questionnaire results), as well as other combinations and concentrations currently available on the market.

The results of the present study support the use of the single-capsule combination of budesonideformoterol delivered via Aerocaps for obtaining and maintaining asthma control, given that this formulation proved to be efficacious and safe.

References

Figure 4 - Adjusted mean change in morning PEF (mPEF) in L/s. BUD: budesonide; and FORM: formoterol.

characteristics of this formulation contributed to this favorable outcome. In addition, the increase in morning PEF shows that the medication maintains its effect for the duration of the specified time period, given that this parameter was measured prior to the daily morning dose.

The scientific rigor of this study is demonstrated by its randomized, double-blind design and by the rigorous analysis of outcome measures in the intent-to-treat population. In addition, the results of the present study are in accordance J Bras Pneumol. 2012;38(4):431-437

1. Global Initiative for Asthma – GINA [homepage on the Internet]. Bethesda: Global Initiative for Asthma. [cited 2011 Apr 1]. Global Strategy for Asthma Management and Prevention 2010 [Adobe Acrobat document, 119p.].

Available from: http://www.ginasthma.org/pdf/GINA_ Report_2010.pdf 2. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, et al. Global strategy for asthma management and prevention: GINA executive summary.

Eur Respir J. 2008;31(1):143-78. PMid:18166595. http:// dx.doi.org/10.1183/09031936.00138707 3. IV Brazilian Guidelines for the management of asthma [Article in Portuguese]. J Bras Pneumol. 2006;32 Suppl 7:S447-74. PMid:17420905.

4. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group. Lancet. 1994;344(8917):219-24. http://dx.doi. org/10.1016/S0140-6736(94)92996-3 5. Pauwels RA, Löfdahl CG, Postma DS, Tattersfield AE, O’Byrne P, Barnes PJ, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med. 1997;337(20):1405-11. PMid:9358137. http:// dx.doi.org/10.1056/NEJM199711133372001

Evaluation of the efficacy and safety of a fixed-dose, single-capsule budesonide-formoterol combination in uncontrolled asthma: a randomized, double-blind, multicenter, controlled clinical trial 6. O’Byrne PM. Therapeutic strategies to reduce asthma exacerbations. J Allergy Clin Immunol. 2011;128(2):257-63; quiz 264-5. PMid:21531015. http://dx.doi.org/10.1016/j. jaci.2011.03.035 7. Sociedade Brasileira de Pneumologia e Tisiologia.

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8. Knudson RJ, Slatin RC, Lebowitz MD, Burrows B. The maximal expiratory flow-volume curve. Normal standards, variability, and effects of age. Am Rev Respir Dis. 1976;113(5):587-600. PMid:1267262.

9. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal expiratory flowvolume curve with growth and aging. Am Rev Respir Dis. 1983;127(6):725‑34. PMid:6859656.

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10. Johnson M. Interactions between corticosteroids and beta2-agonists in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2004;1(3):200-6.

PMid:16113435. http://dx.doi.org/10.1513/ pats.200402-010MS 11. Giembycz MA, Kaur M, Leigh R, Newton R. A Holy Grail of asthma management: toward understanding how long-acting beta(2)-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids. Br J Pharmacol. 2008;153(6):1090-104. PMid:18071293 PMCid:2275445. http://dx.doi.org/10.1038/sj.bjp.0707627 12. van den Berge M, ten Hacken NH, Cohen J, Douma WR, Postma DS. Small airway disease in asthma and COPD: clinical implications. Chest. 2011;139(2):412‑23. Erratum in: Chest. 2011;139(4):972. http://dx.doi.org/10.1378/ chest.10-1210

About the authors Roberto Stirbulov

Adjunct Professor. Santa Casa School of Medical Sciences in São Paulo, São Paulo, Brazil.

Carlos Cezar Fritscher

Full Professor of Pulmonology. Department of Internal Medicine, Pontifical Catholic University of Rio Grande do Sul School of Medicine, Porto Alegre, Brazil.

Emilio Pizzichini

Head of the Department of Pulmonology. Federal University of Santa Catarina, Florianópolis, Brazil.

Márcia Margaret Menezes Pizzichini

Adjunct Professor. Department of Clinical Medicine, Federal University of Santa Catarina, Florianópolis, Brazil.

J Bras Pneumol. 2012;38(4):431-437

Original Article Children and adolescents with mild intermittent or mild persistent asthma: aerobic capacity between attacks* Capacidade aeróbica em crianças e adolescentes com asma intermitente e persistente leve no período intercrises

Eliane Zenir Corrêa de Moraes, Maria Elaine Trevisan, Sérgio de Vasconcellos Baldisserotto, Luiz Osório Cruz Portela

Abstract Objective: To assess children and adolescents diagnosed with mild intermittent or mild persistent asthma, in terms of their aerobic capacity between attacks. Methods: We included 33 children and adolescents recently diagnosed with asthma (mild intermittent or mild persistent) and 36 healthy children and adolescents. Those with asthma were evaluated between attacks. All participants underwent clinical evaluation; assessment of baseline physical activity level; pre- and post-bronchodilator spirometry; and a maximal exercise test, including determination of maximal voluntary ventilation, maximal oxygen uptake, respiratory quotient, maximal minute ventilation, ventilatory equivalent, ventilatory reserve, maximal HR, SpO2, and serum lactate. Results: No significant differences were found among the groups (intermittent asthma, persistent asthma, and control) regarding anthropometric or spirometric variables. There were no significant differences among the groups regarding the variables studied during the maximal exercise test. Conclusions: A diagnosis of mild intermittent/ persistent asthma has no effect on the aerobic capacity of children and adolescents between asthma attacks.

Keywords: Asthma; Exercise; Respiratory function tests.

Resumo Objetivo: Aferir a capacidade aeróbica de crianças e adolescentes com diagnóstico de asma brônquica intermitente leve ou persistente leve no período intercrises. Métodos: Foram estudadas 33 crianças e adolescentes com diagnóstico clínico recente de asma leve intermitente e asma leve persistente, no período intercrises, e 36 crianças e adolescentes saudáveis. Foram realizadas avaliação clínica, avaliação do nível basal do nível de atividade física, espirometria antes e após o uso de broncodilatador e determinação de ventilação voluntária máxima, consumo máximo de oxigênio, quociente respiratório, ventilação minuto máxima, equivalente ventilatório, reserva ventilatória, FC máxima, SpO2 e lactato. Resultados: Não foram encontradas diferenças significativas entre os grupos asma intermitente, asma persistente e controle em relação às variáveis antropométricas e espirométricas.

Não houve diferenças significativas em relação às variáveis analisadas durante o teste de esforço máximo entre os grupos. Conclusões: O diagnóstico de asma intermitente ou persistente leve não influenciou a capacidade aeróbica em crianças e adolescentes no período intercrises.

Descritores: Asma; Exercício; Testes de função respiratória.

* Study carried out at the Federal University of Santa Maria, Santa Maria, Brazil.

Correspondence to: Eliane Zenir Corrêa de Moraes. Rua Cezar Trevisan, 1333, Tomazetti, CEP 97065-060, Santa Maria, RS, Brasil.

Tel. 55 55 3211-4135 or 55 55 9963-8143. E-mail: elianezenir@yahoo.com.br Financial support: None.

Submitted: 9 November 2011. Accepted, after review: 14 May 2012.

J Bras Pneumol. 2012;38(4):438-444

Children and adolescents with mild intermittent or mild persistent asthma: aerobic capacity between attacks

Introduction Asthma is a chronic inflammatory disease characterized by lower airway hyperresponsiveness and variable airflow limitation that can resolve spontaneously or with treatment; the clinical manifestations of asthma include recurrent episodes of wheezing, dyspnea, chest tightness, and cough, particularly at night and upon waking in the morning.(1) Exercise capacity expresses the temporal state of acute and chronic physiological adaptations in individuals. The temporal component implies that those adaptations have transitory and lasting effects. There is a consensus that, during an attack, asthma patients experience a considerable reduction in exercise capacity, which can be recovered as soon as the attack is controlled. However, because asthma symptoms lead to impaired health-related quality of life, many asthma patients choose to adopt a sedentary lifestyle.(2-4) Although it is commonly believed that children with asthma have reduced aerobic capacity, there are conflicting data in the literature.(5) Although recent studies have suggested that reduced aerobic capacity is related to greater disease severity,(6) the impact of asthma on patients with less severe disease remains unclear.

Because asthma is the most prevalent chronic disease in children and adolescents, because most asthma patients have mild intermittent or mild persistent disease,(1) and because regular physical activity has been proven to have beneficial effects,(7-9) it is essential to determine whether asthma has negative effects on exercise capacity between attacks, the approach to physical training being based on the answer to this question.

Therefore, the objective of the present study was to assess children and adolescents with mild intermittent or mild persistent asthma, in terms of their aerobic capacity between attacks.

Methods We evaluated 33 children and adolescents recently diagnosed with mild intermittent or mild persistent asthma and 36 healthy children and adolescents (control group). All participants were in the 11-14 year age bracket, those with asthma having been evaluated between attacks. None of the asthma patients were receiving inhaled corticosteroid therapy at the time of enrollment.

The asthma patients were recruited from among those being treated at the pediatric outpatient

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clinic of the Santa Maria University Hospital, located in the city of Santa Maria, Brazil. The diagnosis and severity of asthma were established in accordance with the Global Initiative for Asthma criteria.(1) Stable disease was defined as no attacks or medication changes in the last 90 days. We excluded children/adolescents with other respiratory diseases, those with symptoms of viral infection (cold and flu) in the last six weeks, and those with abnormal at-rest pulmonary function test (spirometry) results on the day of the test. We ruled out asthma and allergic rhinitis in the control group by administering the International Study of Asthma and Allergies in Childhood questionnaire,(10,11) a negative answer to question 2 and a total score < 6 indicating the absence of the two diseases. We determined the level of physical activity by administering the International Physical Activity Questionnaire (IPAQ), short version.(12,13) We used the Lohman equation to calculate the percentage of body fat.(14) The present study was approved by the Research Ethics Committee of the Federal University of Santa Maria Health Sciences Center. The parents or legal guardians of all participants gave written informed consent.

Spirometry was performed with a Vmax Series 229 spirometer (SensorMedics, Yorba Linda, CA, USA) before and after the administration of 400 µg of inhaled albuterol, having been performed in accordance with the acceptability and reproducibility criteria established by the American Thoracic Society(15) and the reference values proposed by Knudson et al.(16) In addition to measuring the spirometric values, we measured maximal voluntary ventilation (MVV), and the volumes were corrected for body temperature, ambient pressure, and saturated air.

Exercise testing was performed on a 10200 ATL treadmill (Inbramed, Porto Alegre, Brazil), in accordance with the protocol proposed by Mader et al.,(17) until maximal voluntary effort was achieved. Twenty minutes before the exercise test, we administered 400 µg of inhaled albuterol with a spacer, in order to prevent exercise-induced bronchospasm. Maximal oxygen uptake (VO2max), respiratory quotient (RQ), minute ventilation (VE), and ventilatory equivalent for oxygen (VE/VO2) were measured with the abovementioned spirometer (SensorMedics), whereas serum lactate was measured with a glucose/lactate analyzer J Bras Pneumol. 2012;38(4):438-444

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(model Biosen 5030; EKF Diagnostics, Cardiff, UK). Blood samples were collected at the end of each stage (5 min). We monitored HR with an Accurex Plus™ HR monitor (Polar Electro Ou, Kempele, Finland). All variables were measured at rest, during exercise, and during recovery.

The pulmonary function test and the exercise test were performed in a climate-controlled environment, i.e., at a temperature of 18-26°C and a relative humidity of 55-60%.

The data collected were evaluated for normality by the Shapiro-Wilk test (n < 2,000), and descriptive statistical analysis was performed.

The variables age, height, body mass, percentage of body fat, FVC, FEV1, FEV1/FVC, PEF, MVV, VO2max, ventilatory reserve, VE/VO2, RQ, and International Study of Asthma and Allergies in Childhood questionnaire score showed normal distribution, ANOVA being therefore used in order to compare the means. The variables that showed statistically significant differences, namely pre-bronchodilator FEV1 and FEV1/FVC (both in % of predicted), were analyzed by Duncan’s post hoc test. The variables that showed non-normal distribution, namely IPAQ score, running speed, exercise duration, maximal HR, and serum lactate, were analyzed by the Kruskal-Wallis test. All statistical analyses were performed with the program Statistical Analysis System, version 8.2 (SAS Institute, Cary, NC, USA).

Results The anthropometric characteristics were similar among the three groups studied (mild intermittent asthma, mild persistent asthma, and control), as were the physical activity characteristics. As shown in Table 1, ANOVA showed no statistically significant differences among the groups regarding age, body mass, height, or percentage of body fat; in addition, the Kruskal-Wallis test showed no statistically significant differences among the groups regarding the level of physical activity, as measured by the IPAQ score.

As expected, there were no significant differences among the groups regarding pulmonary function test results (Table 2). Although we found a significant difference among the groups regarding pre-bronchodilator FEV1/FVC (% of predicted), the means were above 80%, which is considered normal for the age group under study. The results showed no airway obstruction, confirming that the children and adolescents were between attacks. As J Bras Pneumol. 2012;38(4):438-444

can be seen in Table 2, there were no significant differences among the groups regarding MVV (in absolute values or in % of predicted). There were no statistically significant differences among the groups regarding the variables analyzed during the maximal cardiopulmonary exercise test, namely maximal VE (VEmax), ventilatory reserve, VE/VO2, RQ, maximal HR, VO2max, serum lactate, maximum speed attained, and exercise duration (Table 3).

Discussion The objective of the present study was to assess children and adolescents with mild asthma, in terms of their aerobic capacity between attacks.

We chose to study patients with mild intermittent or mild persistent asthma because these are the most prevalent forms of the disease.

Although different levels of baseline physical activity can influence the results of studies such as ours, we found no statistically significant differences among the groups in terms of baseline physical activity, as measured by the IPAQ score.

The three groups studied were classified as being physically active.(12) The results of the tests performed showed that the physical performance of the individuals in the control group was better than was that of those in the asthma groups.

We believe that this was due to higher routine physical activity in the control group, given that the possibility of experiencing attacks during exercise might prevent the asthma patients from engaging in physical activity more often.

However, because the IPAQ is not appropriate to determine that and because this is outside the scope of the present study, we cannot draw definitive conclusions.

Obesity is another variable that affects the physical performance of individuals with or without asthma. According to the classification proposed

by Lohman,(14) the percentage of body fat in the three groups studied was optimal. Therefore, the results of the present study should be analyzed from the perspective that the individuals studied were physically active and had an adequate percentage of body fat, which was similar among the three groups.

Group homogeneity is important when the objective is to compare individuals with asthma of varying severity and those without in terms of their aerobic capacity. Homogeneity reduces the variability in pulmonary evaluation results. As shown in Table 2, none of the patients studied

Children and adolescents with mild intermittent or mild persistent asthma: aerobic capacity between attacks

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Table 1 - Characteristics of the groups studied.a Variables Age, years Body mass, kg Height, cm Percentage of body fat IPAQ score

Mild intermittent asthma (n = 20) 12.75 ± 0.85 50.56 ± 14.00 157.71 ± 7.48 20.17 ± 8.56 4.00 ± 0.87

Groups Mild persistent asthma (n = 13) 12.69 ± 0.85 49.57 ± 12.38 156.91 ± 10.28 22.58 ± 7.27 4.00 ± 0.75

Control (n = 36) 12.94 ± 0.86 49.64 ± 8.12 158.13 ± 8.03 18.46 ± 6.84 4.00 ± 0.83

p 0.8440 0.9483 0.9021 0.2277 0.2993

IPAQ: International Physical Activity Questionnaire. aValues expressed as mean ± SD.

Table 2 - Pulmonary function variables in the groups studied.a Groups Mild intermittent Mild persistent Variables asthma asthma (n = 20) (n = 13) Pre-BD FVC, L/min 3.19 ± 0.62 3.14 ± 0.48 100.00 ± 11.54 102.23 ± 7.15 Pre-BD FVC, % of predicted 3.15 ± 0.63 3.15 ± 0.51 Post-BD FVC, L/min 98.95 ± 11.79 102.00 ± 7.38 Post-BD FVC, % of predicted 2.65 ± 0.44 2.57 ± 0.41 Pre-BD FEV1, L/min 95.15 ± 6.94 95.00 ± 10.26 Pre-BD FEV1, % of predicted 2.71 ± 0.45 2.74 ± 0.48 Post-BD FEV1, L/min 97.55 ± 8.58 100.92 ± 10.15 Post-BD FEV1, % of predicted 83.85 ± 7.40 81.85 ± 7.74 Pre-BD FEV1/FVC, % 86.65 ± 6.14 88.61 ± 7.97 Post-BD FEV1/FVC, % 5.38 ± 0.96 5.37 ± 0.93 Pre-BD PEF, L/min 88.15 ± 9.30 91.23 ± 14.13 Pre-BD PEF, % of predicted 5.29 ± 0.84 5.63 ± 1.33 Post-BD PEF, L/min 86.90 ± 11.27 95.08 ± 18.50 Post-BD PEF, % of predicted 85.20 ± 21.04 84.77 ± 19.89 Pre-BD MVV, L/min 84.35 ± 18.09 84.15 ± 14.02 Pre-BD MVV, % of predicted

Control (n = 36) 3.24 ± 0.58 102.17 ± 10.37 3.20 ± 0.58 100.39 ± 10.90 2.82 ± 0.52 101.39 ± 12.23 2.84 ± 0.54 102.11 ± 12.31 86.78 ± 5.36 88.94 ± 5.36 5.50 ± 0.86 89.47 ± 10.52 5.45 ± 1.04 88.61 ± 13.69 91.83 ± 16.74 90.14 ± 13.84

P 0.8634 0.7246 0.9423 0.7210 0.1958 0.0546 0.6062 0.3325 0.0465 0.3985 0.8626 0.7326 0.6496 0.2472 0.3238 0.2849

Pre-BD: pre-bronchodilator; Post-BD: post-bronchodilator; and MVV: maximal voluntary ventilation. aValues expressed as mean ± SD.

had airflow obstruction at the time of the evaluation (exclusion criterion), all had normal pre- and post-bronchodilator spirometry, and the possibility of exercise-induced asthma, a potential confounding variable during a maximal cardiopulmonary exercise test, was controlled by administering albuterol (400 µg) 20 min before the test. In the present study, the difference, albeit small, between the asthma patients and the controls regarding at-rest spirometry results was suggestive of reduced aerobic capacity during exercise. However, this proved not to be the case.

Defined as the maximum volume of air that an individual can inhale and exhale in 1 min

during maximal voluntary effort, MVV provides a nonspecific overview of respiratory function.

Moderate and severe obstructive pulmonary disease can result in abnormal MVV values; this is due to excessive air trapping and respiratory muscle disadvantage, which is common in patients with such breathing patterns.(18) The MVV that individuals can achieve depends on the integrity of their respiratory physiology. In all three groups, MVV values remained within the reference range, indicating that the individuals with asthma and those without had similar ventilatory capacity.

We found that MVV was higher than the maximal levels of ventilation during exercise, J Bras Pneumol. 2012;38(4):438-444

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Table 3 - Cardiorespiratory variables analyzed during maximal exercise testing in the groups studied.a Groups Mild intermittent Mild persistent Control Variables p asthma asthma (n = 20) (n = 13) (n = 36) VEmax, L/min 79.08 ± 16.65 74.07 ± 14.49 77.52 ± 17.14 0.6943 97.65 ± 24.69 82.69 ± 29.21 85.72 ± 19.47 0.1137 VR, % 39.30 ± 4.96 39.69 ± 3.99 37.58 ± 4.33 0.2215 VE/VO2 0.98 ± 0.05 0.99 ± 0.03 0.97 ± 0.41 0.2035 RQ 203.75 ± 7.77 201.69 ± 9.56 203.61 ± 10.44 0.6947 Maximal HR, bpm 41.43 ± 6.80 42.25 ± 7.58 42.06 ± 7.25 0.7374 VO2max, mL kg−1 min−1 7.23 ± 1.74 8.03 ± 2.69 7.94 ± 2.28 0.3332 Serum lactate, mmol/L 10.89 ± 1.37 10.52 ± 1.44 11.55 ± 1.63 0.0535 Speed, km/h 19.10 ± 4.09 18.15 ± 3.85 20.47 ± 4.35 0.0758 Exercise duration, min •

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VEmax: maximal minute ventilation; VR: ventilatory reserve; VE/VO2: ventilatory equivalent for oxygen; RQ: respiratory quotient; and VO2max: maximal oxygen uptake. aValues expressed as mean ± SD.

a finding that is consistent with the literature.

This is due to the fact that, during exercise, the respiratory system is not required to work to the utmost. Studies suggest that specific exercises for individuals with obstructive pulmonary disease are interesting because training can increase respiratory muscle strength, respiratory muscle endurance, and MVV.(19) If any type of organ dysfunction or adaptation is expected to occur as a result of the severity of asthma, it will necessarily be expressed by VO2max, which is a measure that includes the performance of the various systems involved in the mechanism of oxygen consumption. It reflects cardiovascular, pulmonary, and muscular components, being considered the best single index of health-related physical fitness.(20) The VO2max values obtained in the present study were similar to those reported in several studies involving children and adolescents.(20-22) In the present study, VO2max was found to be similar among the three groups, a finding that is consistent with those of a study evaluating exercise performance in 80 children with mild to moderate asthma and 80 healthy children.

The two groups were found to be similar in terms of aerobic capacity, as assessed by maximal exercise testing (40.5 ± 8.4 mL kg−1 min−1 vs.

42.6 ± 9.6 mL kg−1 min−1).(23) Garfinkel et al.

(2) reported similar findings, i.e., no significant differences between stable patients with mild to moderate asthma and controls in terms of VO2max (36.85 ± 10.80 mL kg−1 min−1 vs.

38.48 ± 5.34 mL kg−1 min−1; p = 0.32). Baraldi reported that VO2 and VE during submaximal and •

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maximal exercise testing were similar between children with asthma and those without, the two groups of children being therefore similar in terms of aerobic capacity.(24) The results of the present study are inconsistent with those of a study involving 8 children with asthma and 7 children without; VO2max was significantly lower in the former than in the latter (44 ± 5.4 mL kg−1 min−1 vs.

55.6 ± 10.3 mL kg−1 min−1), a finding that was negatively correlated with bronchial obstruction.(25) In another study,(26) a significant difference was found between boys with asthma and those without in terms of VO2max (31.6 ± 5.1 mL kg−1 min−1 vs. 35.2 ± 6.1 mL kg−1 min−1) but not between girls with asthma and those without (25.3 ± 2.8 mL kg−1 min−1 vs.

23.9 ± 4.9 mL kg−1 min−1). The variation in aerobic capacity across studies comparing individuals with asthma and those without can be explained, in part, by the differences in methods, types, intensities, duration of exercise, level of training, and, first and foremost, identification, characterization, and classification of asthma severity.

The mean VO2max values in the groups under study allow us to conclude that the severity of asthma had no impact on aerobic capacity between attacks. For instance, the mean VO2max in the mild persistent asthma group was nearly equal to that in the control group.

The fact that the three groups studied were similar in terms of VO2max indicates that the responses of the remaining VO2 components do not differ from one another or that possible •

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Children and adolescents with mild intermittent or mild persistent asthma: aerobic capacity between attacks

deficiencies are fully compensated. This answers the question regarding respiratory failure, which has been reported in other studies.(24-26) On the basis of exercise tolerance variables such as VEmax, VEmax/MVV, VE/VO2, and VO2max, we can affirm that neither asthma severity nor ventilatory limitation during exercise influenced aerobic capacity (VO2max) in any of the three groups studied.

The behavior of VEmax in the present study was similar to that reported in other studies, which found no significant differences in VEmax between individuals with asthma and those without, as well as no ventilatory limitation to the work capacity of asthma patients.(27) Ventilatory limitation to exercise capacity can occur in cases of severe asthma, in which complex mechanisms are involved in the pathophysiology of the disease, being unlikely to occur in cases of controlled, mild to moderate asthma.(28) The VEmax values found in the present study confirm the findings of Lewis et al.(28) Ventilatory reserve is the difference between the maximum ventilation rate that an individual can theoretically achieve (MVV) and the ventilation rate that is actually achieved at a given time point.

The VEmax/MVV ratio has been used as an index of ventilatory reserve, or rather of its inverse, meaning that high VEmax/MVV values indicate low ventilatory reserve. Although VEmax/MVV varies widely in males and females, values above 85% for males and above 75% for females (i.e., a ventilatory reserve of 15% and a ventilatory reserve of 25%, respectively) are uncommon in healthy sedentary individuals.(29) Some studies have reported findings that are similar to ours, i.e., no significant differences in ventilatory reserve between children with mild to moderate asthma and those without.(27) In order to assess breathing economy during exercise, we calculated VE/VO2, which is the ratio between the volume of air ventilated and the amount of oxygen consumed. A higher VE/VO2 translates to lower breathing economy. In the present study, VE/VO2max values ranged from 37 to 69, indicating breathing economy and being consistent with those reported in a study involving children and youths.(30) Finally, judging from the final result obtained, the period between attacks was clinically well characterized and well selected in the present study. This allowed group homogeneity, which

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is required to compare individuals with asthma of varying severity and those without in terms of their aerobic capacity. As a result, there were no statistically significant differences between the patients with mild intermittent asthma and those with mild persistent asthma or between the asthma patients and the controls in terms of the spirometric values. This demonstrates that the classification of asthma severity is not supported by the functional variables investigated during the period between attacks. Therefore, the limitations imposed by the criteria for determining asthma severity(3) in the period between attacks do not allow functional differentiation between patients with mild intermittent asthma and those with mild persistent asthma. It could be argued that there are no differences, given that both groups of patients are clinically equal. However, this is not supported by the literature; the results of studies on this topic refer to study groups rather than populations and are discrepant.(5) The limitations of the present study lie in the fact that our sample was a study group.

Therefore, the results reflect the characteristics of the group and those of the methods employed.

Because this was not a population-based study, the results obtained cannot be generalized. We conclude that a diagnosis of bronchial asthma (mild intermittent or mild persistent) has no effect on the aerobic capacity of children and adolescents between asthma attacks.

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About the authors Eliane Zenir Corrêa de Moraes

Professor. Federal University of Santa Maria, Santa Maria, Brazil.

Maria Elaine Trevisan

Assistant Professor, Department of Physical Therapy and Rehabilitation, Federal University of Santa Maria, Santa Maria, Brazil.

Sérgio de Vasconcellos Baldisserotto

Adjunct Professor of Clinical Medicine. Federal University of Santa Maria, Santa Maria, Brazil.

Luiz Osório Cruz Portela

Associate Professor. Federal University of Santa Maria, Santa Maria, Brazil.

J Bras Pneumol. 2012;38(4):438-444

Original Article Fiberoptic bronchoscopy findings in patients diagnosed with lung cancer* Achados de fibrobroncoscopia em pacientes com diagnóstico de neoplasia pulmonar

Marcelo Fouad Rabahi, Andréia Alves Ferreira, Bruno Pereira Reciputti, Thalita de Oliveira Matos, Sebastião Alves Pinto

Abstract Objective: To compile fiberoptic bronchoscopy findings in patients diagnosed with lung cancer and to correlate those with histopathological findings. Methods: This was a retrospective study involving 212 patients with a confirmed diagnosis of lung cancer by cytological evaluation of BAL specimens or by histopathological evaluation of endobronchial or transbronchial biopsy specimens. The data were collected at the Respiratory Endoscopy Section of Hospital São Salvador, located in the city of Goiânia, Brazil, between 2005 and 2010. The endoscopic findings were classified as endoscopically visible tumor, endoscopically invisible tumor, and mucosal injury, as well as being classified by the presence/type of secretion. The visible tumors were also classified according to their location in the tracheobronchial tree. Results: Endobronchial mass (64%) and mucosal infiltration (35%) were the main endoscopic findings. The histological type was determined in 199 cases, the most prevalent types being squamous carcinoma, in 78 (39%), adenocarcinoma, in 42 (21%), small cell carcinoma, in 24 (12%), and large cell carcinoma, in 2 (1%). More than 45% of the visible tumors were at the upper bronchi. Squamous carcinoma (n = 78) was most commonly visualized as an endobronchial mass (in 74%), mucosal infiltration (in 36%), luminal narrowing (in 10%), or external compression (in 6%). Conclusions: Our results show that an endobronchial mass is the most common bronchoscopic finding that is suggestive of malignancy. Proportionally, mucosal infiltration is the most common finding in small cell carcinoma. In adenocarcinoma, luminal narrowing, external compression, mucosal injury, and endobronchial secretion prevail.

Keywords: Lung neoplasms/diagnosis; Lung neoplasms/classification; Bronchoscopy.

Resumo Objetivo: Catalogar alterações encontradas em imagens obtidas por fibrobroncoscopia em pacientes com diagnóstico de neoplasia pulmonar e correlacionar esses achados com achados histopatológicos. Métodos: Estudo retrospectivo envolvendo 212 pacientes com diagnóstico de câncer de pulmão confirmado por citologia obtida por lavado broncoalveolar e/ou histopatologia de biópsia endobrônquica ou transbrônquica. Os dados foram obtidos no Serviço de Endoscopia Respiratória do Hospital São Salvador (Goiânia-GO), entre 2005 e 2010.

Os achados endoscópicos foram classificados como tumor endoscopicamente visível, tumor endoscopicamente não visível e lesão na mucosa, assim com quanto à presença/tipo de secreção. Os tumores visíveis também foram classificados de acordo com sua localização na árvore traqueobrônquica. Resultados: O principal achado endoscópico foi a presença de massa endobrônquica (64%), seguido por infiltração da mucosa (35%). Quanto aos tipos histológicos (n = 199), os mais prevalentes foram carcinoma escamoso (39%), adenocarcinoma (21%), carcinoma de pequenas células (12%) e carcinoma de grandes células (1%). Mais de 45% dos tumores visíveis estavam localizados nos brônquios superiores. O carcinoma escamoso (n = 78) apresentou-se mais frequentemente como massa tumoral endobrônquica (74%), infiltração da mucosa (36%), estreitamento do lúmen (10%) e compressão extrínseca (6%). Conclusões: Nossos resultados indicam que a massa tumoral endobrônquica é o achado endoscópico que mais sugere malignidade. Proporcionalmente, infiltração da mucosa é mais comumente achada em carcinoma de pequenas células. Estreitamento do lúmen, compressão extrínseca, lesão na mucosa e secreção endobrônquica prevalecem no adenocarcinoma.

Descritores: Neoplasias pulmonares/diagnóstico; Neoplasias pulmonares/classificação; Broncoscopia.

* Study carried out in the Department of Pulmonology, Hospital São Salvador, Goiás, Brazil.

Correspondence to: Marcelo Fouad Rabahi. Avenida B, 483, Setor Oeste, CEP 74110 030, Goiânia, GO, Brasil.

Tel. 55 62 3521-3333. E-mail: mfrabahi@gmail.com Financial support: None.

Submitted: 21 December 2011. Accepted, after review: 11 June 2012.

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Introduction Lung cancer is the malignancy with the highest mortality worldwide, being the only one whose incidence of death has progressively increased despite improved and more aggressive therapy in recent years. The mean five-year survival ranges from 13% to 21% and from 7% to 10% in developed and in developing countries, respectively.(1) In the state of Goiás, Brazil, in 2008, the mortality rate of lung cancer as the primary site in the male population was 13.33 per 100,000 men, lung cancer being considered the leading cause of cancer death in this group. In the female population, in that same year, the rate was 7.68 per 100,000 women, lung cancer being therefore the second leading cause of cancer death in women, second only to breast cancer.(2) Because the prognosis of lung cancer is unfavorable, early diagnosis plays an important role in increasing survival in lung cancer patients.

(3) The use of various methods can contribute to early diagnosis. Among the most commonly used methods are imaging tests (chest X-ray and CT), sputum cytology, and fiberoptic bronchoscopy.

Fiberoptic bronchoscopy is currently considered the primary method for evaluating the tracheobronchial tree in patients with suspected lung cancer.(4) In addition to allowing visualization of the lesion, the method allows the collection of cytological specimens (by bronchial lavage and bronchial brushing) and histological specimens (by endobronchial biopsy and transbronchial biopsy).

However, bronchoscopists can face difficulties in describing endobronchial lesions. Such lesions range from a devitalized area showing loss of natural luster to gross presentations of large exophytic masses obstructing the bronchial lumen.

The description of images as seen under the cold light of the endoscope is subjective, reflecting the variability to which any scientific observation is subject. Fiberoptic bronchoscopy reports show a bias in description: the same lesion can be described with different words, and the cold light of the endoscope can cause artifacts (as it often does). In addition, at best, examiners recognize endoscopic signs of malignancy, but no histopathological diagnosis can be presumed from the results of the test.(5) The objective of the present study was to compile fiberoptic bronchoscopy findings in J Bras Pneumol. 2012;38(4):445-451

patients diagnosed with lung cancer and to determine the relationship between those findings and histopathological findings.

Methods In the present retrospective study, we analyzed the findings of 376 bronchoscopic procedures (all employing fiberoptic bronchoscopy) performed between January of 2005 and December of 2010 in patients who were clinically and radiologically suspected of having lung cancer, at the Respiratory Endoscopy Section of the Pulmonology Department of Hospital São Salvador, located in the city of Goiânia, Brazil.

The patients whose tests were analyzed were guaranteed anonymity, as well as being assured that the study would not cause them any harm or injury at any stage, including treatment. In addition, the patients were assured that the researchers would provide full support in case any harm or injury was directly or indirectly caused by the study. The Directive Council of Hospital São Salvador and the Human and Animal Research Ethics Committee of the Federal University of Goiás Hospital das Clínicas approved the study.

We reviewed the medical records of the patients (including fiberoptic bronchoscopy reports and photographs) and collected data such as age, gender, indication for the test, cytological findings, and histopathological findings.

The exclusion criteria were as follows: patients with incomplete reports or repeated tests (n = 43); patients for whom cytological or histopathological findings were negative for lung cancer (n = 107); and patients submitted to any surgical procedure involving the lungs (n = 14). On the basis of these criteria, we selected 212 patients (126 males and 86 females).

Endoscopic findings were categorized according to the classification of Ikeda et al.(6) (endoscopically visible and endoscopically invisible tumors), together with some of the criteria used by the Japan Lung Cancer Society(5,7) in order to classify mucosal injury and secretion findings.

Endoscopically visible tumors were also classified according to their location in the tracheobronchial tree (trachea, left main bronchus, left upper lobe bronchus, left lower lobe bronchus, right main bronchus, intermediate bronchus, right upper lobe bronchus, middle lobe bronchus, and right lower lobe bronchus).

Fiberoptic bronchoscopy findings in patients diagnosed with lung cancer

All bronchoscopic procedures were performed by the same specialist. A Pentax VB-1830T2 fiberoptic bronchoscope (Asahi Optical Co., Tokyo, Japan) was used. Patients received sedation with midazolam and fentanyl, followed by topical anesthesia with 10% lidocaine spray and 2% lidocaine solution (maximum dose, 20 mL).

The device was inserted nasally or orally, with the patient in the supine position. During the procedure, BAL specimens were collected for cytology and endobronchial or transbronchial biopsy (without fluoroscopy) specimens were collected for histopathology. After thorough inspection of the bronchial tree, samples were taken from areas showing abnormality. In the BAL procedure, the fiberoptic bronchoscope was inserted into a bronchus as distally as possible, 120 mL of saline solution being administered and approximately 50% of the material being recovered.

Of the 212 patients, 3 did not undergo biopsy and 6 did not undergo BAL. Therefore, 203 patients underwent both procedures.

All specimens collected during the procedures were analyzed by the pathology team of the Goiás State Institute of Oncology and Hematology, located in the city of Goiânia, Brazil.

The cytological and histopathological findings were classified as being negative for, inconclusive for, suggestive of, or positive for malignancy. The findings that were classified as inconclusive were considered negative, whereas those classified as being suggestive of malignancy were considered positive. The histological and cytological classification of tumors was based on the criteria used by the World Health Organization.(8)

Results Between January of 2005 and December of 2010, we retrospectively followed 212 patients with a confirmed diagnosis of lung cancer. Of those, 59% were male. The mean age was 66 years (range, 34-88 years) for the male patients and 64 years (range, 14-89 years) for the female patients.

The endoscopic findings are presented in Table 1. The most characteristic endoscopic findings can be seen in Figure 1.

In 9 (4%) of the 212 patients diagnosed with lung cancer, the only endoscopic findings were those related to mucosal injury, with or without secretion.

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It was possible to determine the location of endoscopically visible tumors in 169 cases. In 48%, the tumor was located in the upper lobe bronchi, 28% being located in the right upper lobe bronchi and 20% being located in the left upper lobe bronchi. Regarding the main bronchi, 17% of the tests showed that the lesion was on the left side, whereas 16% showed that the lesion was on the right side. In the right and left lower lobe bronchi, respectively, tumors were visualized in 10% and 12% of the cases.

Of the 212 patients, 199 were evaluated for tumor histological type, and the results were as follows: squamous carcinoma, in 39%; adenocarcinoma, in 21%; small cell carcinoma, in 12%; and large cell carcinoma, in 1%.

We investigated the distribution of histological types in the group of patients with endoscopically visible tumors and, compiling only the test results for this group, regardless of the presence of mucosal injury or endobronchial secretion, we reviewed a total of 74 patients. Among those, the most prevalent types were squamous carcinoma, in 45%, adenocarcinoma, in 16%, and small cell carcinoma, in 16% (Table 2).

Investigating the distribution of histological types in the group of patients with endoscopically invisible tumors, we reviewed 31 patients; among those, the most prevalent types were adenocarcinoma, in 39%, squamous carcinoma, in 23%, and small cell carcinoma, in 10% (Table 2).

Considering the three main histological types found in the study, we compared the fiberoptic bronchoscopy findings specific to each type.

Of the patients with squamous carcinoma, 58 (74%) had endoscopic findings of an endobronchial mass, 28 (36%) had mucosal infiltration, 8 (10%) had lumen narrowing, and 5 (6%) had external compression (Table 3). Of the 41 patients diagnosed with adenocarcinoma, 20 (49%) had an endobronchial mass, 13 (32%) had mucosal infiltration, 9 (22%) had lumen narrowing, and 10 (24%) had external compression. Of the 25 patients diagnosed with small cell carcinoma, 16 (64%) had an endobronchial mass, 15 (60%) had mucosal infiltration, none (0%) had lumen narrowing, and 6 (24%) had external compression (Table 3).

Discussion We observed that there was a higher prevalence of lung cancer among males, with a male to female ratio of 1.46:1.00. This is in accordance J Bras Pneumol. 2012;38(4):445-451

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Table 1 - Frequency of endoscopic findings in patients with lung cancer.

Patients (n = 212)

Endoscopically visible tumor Endobronchial massa Mucosal infiltration Micronodules/macronodules in the mucosa Mucosal ulceration (with or without necrosis) Endoscopically invisible tumor Widening of the main carina External compression Luminal narrowing/constriction (concentric or otherwise) Retraction of the bronchus or carina Engorgement of submucosal blood vessels Distortion/elevation or torsion of longitudinal folds Vocal fold paralysis Rigidity of the bronchial wall or carina Mucosal injury Mucosal hyperemia (localized or generalized) Mucosal edema (localized or generalized) Mucosal friability (localized or generalized) Mucosal hypotrophy/atrophy (localized or generalized) Secretion findings Serous/seromucous Hemorrhagic/clot Purulent/mucopurulent a

n 135 74 5 0 n 40 37 28 23 18 15 7 2 n 129 48 4 3 n 45 34 4

% 64 35 2 0 % 19 18 13 11 8 7 3 1 % 61 23 2 1 % 21 16 2

Exophytic, vegetative, necrotic, lobulated, or polypoid; with or without engorgement of neoplastic blood vessels.

Figure 1 - Fiberoptic bronchoscopy findings. In A, hypervascular vegetative lesion in the right upper lobe (RUL) bronchus (squamous carcinoma). In B, infiltrative lesion in the tracheal mucosa and left main bronchus (LMB; undifferentiated carcinoma). In C, external compression (adenocarcinoma). In D, widening of the main carina. In E, engorgement of submucosal blood vessels (small cell carcinoma). In F, mucosal hyperemia and edema (adenocarcinoma). In G, abundant purulent secretion (squamous carcinoma). In H, active bleeding from the bronchi (undifferentiated carcinoma). RMB: right main bronchus; RULB: right upper lobe bronchus; LB1: lobar bronchus 1; LB2: lobar bronchus 2; and LB3: lobar bronchus 3.

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Table 2 - Incidence of histological types in patients with lung tumor classified as endoscopically visible or endoscopically invisible.

Visible tumor Invisible tumor Total Histological type (n = 74) (n = 31) (n = 105) n % n % n % Adenocarcinoma 12 16 12 38 24 23 Squamous carcinoma 33 44 7 23 40 38 Adenoid cystic carcinoma 0 0 1 3 1 1 Neuroendocrine carcinoma 0 0 1 3 1 1 Small cell carcinoma 12 16 3 10 15 14 Hemangioendothelioma 0 0 1 3 1 1 MALT lymphoma 0 0 0 0 0 0 Undifferentiated carcinoma 4 5 2 6 6 6 Carcinoid tumor 2 3 0 0 2 2 Indeterminate 11 15 4 13 15 14 MALT: mucosa-associated lymphoid tissue.

Table 3 - Histological findings compared with fiberoptic bronchoscopy findings.

Histological types SC AC Endoscopic findings (n = 78) (n = 41) n % n % Endobronchial mass 58 74 20 49 Mucosal infiltration 28 36 13 32 Widening of the main carina 17 22 8 19 Luminal widening 8 10 9 22 External compression 5 6 10 24 Mucosal hyperemia 44 56 26 63 Mucosal edema 15 19 12 29 Mucosal hypotrophy 2 26 1 2 Serous secretion 18 23 10 24 Hemorrhagic secretion 17 22 9 22 Purulent secretion 3 4 0 0

SCC (n = 25) n 16 15 6 0 6 17 6 0 7 0 0

% 64 60 24 0 24 68 24 0 28 0 0

SC: squamous carcinoma; AC: adenocarcinoma; and SCC: small cell carcinoma.

with the literature, which shows a progressive increase in incidence in females when compared with males. In the mid-20th century, the male to female ratio was 10:1.(9) In the present study, we did not investigate the prevalence of smoking among the selected patients or its role as a risk factor for lung cancer. However, this correlation has been well established by several studies. In 1950, Doll & Hill demonstrated the relationship between smoking and lung cancer. The risk of death is approximately 20-30 times as high in smokers as it is in nonsmokers. Mortality was found to be higher in patients who started smoking during adolescence and in those with higher daily cigarette consumption. Another relevant

finding is the age bracket in which the incidence of lung cancer is highest, i.e., the 50-70 year age bracket. In patients younger than 40 years of age, the incidence is lower than 5%(10,11) In the present study, the mean age at diagnosis was 65 years.

Regarding the most prevalent lung cancer location, our findings corroborate the literature: the most commonly affected sites are the upper lobes and the central sites of the right lung, in 28% of the cases analyzed.(12) According to topographic data on malignancies in patients treated at Hospital AraĂşjo Jorge, a referral center for the treatment of cancer in the state of GoiĂĄs, the most commonly affected lung sites are the upper and lower lobes, as well as the main bronchi.

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This distribution corroborates the distribution found in our study.

The value of cytological evaluation in the diagnosis of lung cancer is well established, the proportion of false-positive results being less than 1%.(3,14,15) A definitive diagnosis of cancer was established when cytological or histopathological examination showed neoplastic cells, given that the literature shows that there is a good correlation between these tests, and the cytological diagnosis is unanimously accepted.(3,16) In the literature, the yields of the two tests are approximately the same. Several studies in the literature have shown that the combination of the two tests results in a higher positivity rate, which ranges from 48% to 95%, depending on whether or not the lesion is endoscopically visible; therefore, we routinely perform lavage and biopsy.(3,17) In the sample as a whole, the most common histological type was squamous carcinoma (in 39% of the cases), followed by adenocarcinoma (in 21% of the cases), the proportions being similar to those reported in other studies. The least common histological type was large cell carcinoma, a finding that is consistent with the literature.(3,4,9,11,12) One group of authors reported an increase in adenocarcinoma incidence, which can be higher than the incidence of squamous carcinoma.(18) According to Shields,(19) 30-50% are adenocarcinomas, 20-35% are squamous carcinomas, and 15-35% are small cell carcinomas.

However, in our study, we found a predominance of squamous carcinoma, the incidence of which was similar to that of adenocarcinoma; this finding is similar to those reported in other parts of Brazil.(9,11) One group of authors analyzed three histological types (squamous carcinoma, adenocarcinoma, and large cell carcinoma) and correlated them with their location and endoscopic findings. Squamous carcinoma was most commonly located in the central region, and, on endoscopy, it was most commonly visualized as a tumor mass. Adenocarcinoma was most commonly located in peripheral areas and showed indirect findings, such as bronchial obstruction and external compression, which are endoscopically invisible, or no findings at all.(12) Analyzing the three most prevalent histological types, we demonstrated that an endobronchial (13)

J Bras Pneumol. 2012;38(4):445-451

mass is the most common bronchoscopic finding that is suggestive of malignancy. Proportionally, mucosal infiltration is the most common finding in small cell carcinoma. In adenocarcinoma, luminal narrowing, external compression, mucosal injury, and endobronchial secretion prevail.

Division of the sample into two groups (visible tumors and no direct evidence of tumor) has been used in several studies of fiberoptic bronchoscopy, given that the sensitivity of this test is different for each group in the various studies published in Brazil and worldwide.

As can be seen in Table 2, 45% of the endoscopically visible tumors were squamous carcinomas, whereas 39% of the endoscopically invisible tumors were adenocarcinomas. Small cell carcinoma predominated in the group of visible tumors. These findings are in agreement with those reported by other authors.(3) The findings of the present study, the first of its kind to be conducted in Brazil, are in agreement with those reported in the literature and underscore the importance of a standardized description of fiberoptic bronchoscopy findings as a tool in the diagnosis of lung cancer.

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Chest. 1994;105(6):1658‑62. PMid:8205857. http:// dx.doi.org/10.1378/chest.105.6.1658 6. Ikeda S, Tsuboi E, Ono R, Ishikawa S. Flexible bronchofiberscope. Jpn J Clin Oncol. 2010;40(9):e55-64.

PMid:20736215. http://dx.doi.org/10.1093/jjco/hyq114 7. The Japan Lung Cancer Society. Classification of bronchoscopic findings in lung cancer: general rule for clinical and pathological record of lung cancer. 3rd ed.

Tokyo: Kanehara shuppan; 1987. p. 61-3.

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8. Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new World Health Organization classification of lung tumours. Eur Respir J. 2001;18(6):1059-68.

PMid:11829087. http://dx.doi.org/10.1183/0903193 6.01.00275301 9. Novaes FT, Cataneo DC, Ruiz Junior RL, Defaveri J, Michelin OC, Cataneo AJ. Lung cancer: histology, staging, treatment and survival. J Bras Pneumol. 2008;34(8):595‑600.

PMid:18797744. http://dx.doi.org/10.1590/ S1806-37132008000800009 10. Jamnik S, Uehara C, da Silva VV. Location of lung carcinoma in relation to the smoking habit and gender.

J Bras Pneumol. 2006;32(6):510-4. PMid:17435901.

11. Barros JA, Valladares G, Faria AR, Fugita EM, Ruiz AP, Vianna AG, et al. Early diagnosis of lung cancer: the great challenge. Epidemiological variables, clinical variables, staging and treatment. J Bras Pneumol. 2006;32(3):221-7. PMid:17273611. http:// dx.doi.org/10.1590/S1806-37132006000300008 12. Buccheri G, Barberis P, Delfino MS. Diagnostic, morphologic, and histopathologic correlates in bronchogenic carcinoma. A review of 1,045 bronchoscopic examinations. Chest. 1991;99(4):809-14. PMid:2009779. http://dx.doi.org/10.1378/chest.99.4.809 13. Associação de Combate ao Câncer em Goiás. Distribuição das neoplasias malignas cadastradas no RCH segundo topografia (CID-0) e sexo no período de janeiro/2003

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14. Prolla JC. Citopatologia do aparelho respiratório. J Pneumol. 1986;12(3):98-206.

15. Kvale PA, Bode FR, Kini S. Diagnostic accuracy in lung cancer; comparison of techniques used in association with flexible fiberoptic bronchoscopy. Chest. 1976;69(6):752-7.

PMid:1277894. http://dx.doi.org/10.1378/chest.69.6.752 16. de Gracia J, Bravo C, Miravitlles M, Tallada N, Orriols R, Bellmunt J, et al. Diagnostic value of bronchoalveolar lavage in peripheral lung cancer. Am Rev Respir Dis. 1993;147(3):649-52. PMid:8442600.

17. Chechani V. Bronchoscopic diagnosis of solitary pulmonary nodules and lung masses in the absence of endobronchial abnormality. Chest. 1996;109(3):620-5. PMid:8617067. http://dx.doi.org/10.1378/chest.109.3.620 18. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. International association for the study of lung cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma.

J Thorac Oncol. 2011;6(2):244-85. PMid:21252716. http://dx.doi.org/10.1097/JTO.0b013e318206a221 19. Shields TW. Pathology of Carcinoma of the lung. In: Shields TW, LoCicero J, Ponn RB, editors. General Thoracic Surgery. Philadelphia: Lippincott Williams & Wilkins; 2000. p. 1249-68.

About the authors Marcelo Fouad Rabahi

Adjunct Professor. Department of Clinical Medicine, Federal University of Goiás School of Medicine, Goiás, Brazil.

Andréia Alves Ferreira

Medical Student. Federal University of Goiás School of Medicine, Goiás, Brazil.

Bruno Pereira Reciputti

Medical Student. Federal University of Goiás School of Medicine, Goiás, Brazil.

Thalita de Oliveira Matos

Medical Student. Federal University of Goiás School of Medicine, Goiás, Brazil.

Sebastião Alves Pinto

Assistant Professor. Department of Pathology, Federal University of Goiás School of Medicine, Goiás, Brazil.

J Bras Pneumol. 2012;38(4):445-451

Original Article Comparison of two experimental models of pulmonary hypertension* Comparação de dois modelos experimentais de hipertensão pulmonar

Igor Bastos Polonio, Milena Marques Pagliarelli Acencio, Rogério Pazetti, Francine Maria de Almeida, Mauro Canzian, Bárbara Soares da Silva, Karina Aparecida Bonifácio Pereira, Rogério de Souza

Abstract Objective: To compare two models of pulmonary hypertension (monocrotaline and monocrotaline+pneumonectomy) regarding hemodynamic severity, structure of pulmonary arteries, inflammatory markers (IL-1 and PDGF), and 45-day survival. Methods: We used 80 Sprague-Dawley rats in two study protocols: structural analysis; and survival analysis. The rats were divided into four groups: control; monocrotaline (M), pneumonectomy (P), and monocrotaline+pneumonectomy (M+P). In the structural analysis protocol, 40 rats (10/group) were catheterized for the determination of hemodynamic variables, followed by euthanasia for the removal of heart and lung tissue. The right ventricle (RV) was dissected from the interventricular septum (IS), and the ratio between RV weight and the weight of the left ventricle (LV) plus IS (RV/LV+IS) was taken as the index of RV hypertrophy. In lung tissues, we performed histological analyses, as well as using ELISA to determine IL-1 and PDGF levels. In the survival protocol, 40 animals (10/group) were followed for 45 days. Results: The M and M+P rats developed pulmonary hypertension, whereas the control and P rats did not. The RV/LV+IS ratio was significantly higher in M+P rats than in M rats, as well as being significantly higher in M and M+P rats than in control and P rats.

There were no significant differences between the M and M+P rats regarding the area of the medial layer of the pulmonary arteries; IL-1 and PDGF levels; or survival. Conclusions: On the basis of our results, we cannot conclude that the monocrotaline+pneumonectomy model is superior to the monocrotaline model.

Keywords: Monocrotaline; Hypertension, pulmonary; Pneumonectomy; Interleukin-1; Receptor, plateletderived growth factor beta.

Resumo Objetivo: Comparar dois modelos de hipertensão pulmonar (monocrotalina e monocrotalina+pneumonectomia) em relação à gravidade hemodinâmica, estrutura de artérias pulmonares, marcadores inflamatórios (IL-1 e PDGF) e sobrevida em 45 dias. Métodos: Foram utilizados 80 ratos Sprague-Dawley em dois protocolos de estudo: análise estrutural e de sobrevida. Os animais foram divididos em quatro grupos: controle, monocrotalina (M), pneumonectomia (P) e monocrotalina+pneumonectomia (M+P). Para a análise estrutural, 40 animais (10/grupo) foram cateterizados após 28 dias para a medição dos valores hemodinâmicos e sacrificados, obtendo-se tecidos cardíaco e pulmonar. O ventrículo direito (VD) foi dissecado do septo interventricular (SI), e a relação do peso do VD e do peso do ventrículo esquerdo (VE) com o SI foi obtida como índice de hipertrofia de VD. No tecido pulmonar, foram realizadas análises histológicas e dosados IL-1 e PDGF por ELISA. Para o estudo de sobrevida, 40 animais (10/grupo) foram observados por 45 dias. Resultados: Os grupos M e M+P apresentaram hipertensão pulmonar em relação aos demais. Houve um aumento significativo da relação VD/VE+S no grupo M+P em relação aos demais. Não houve diferenças significativas entre os grupos M e M+P quanto à área da camada média das artérias pulmonares, dosagens de IL-1 e PDGF ou sobrevida. Conclusões: Baseados nos resultados, não podemos afirmar que o modelo de monocrotalina+pneumonectomia é superior ao modelo de monocrotalina.

Descritores: Monocrotalina; Hipertensão pulmonar; Pneumonectomia; Interleucina-1; Receptor beta de fator de crescimento derivado de plaquetas.

* Study carried out at the Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo – InCor/ HC-FMUSP, Heart Institute/University of São Paulo School of Medicine Hospital das Clínicas – São Paulo, Brazil.

Correspondence to: Igor Bastos Polonio. Rua Monte Alegre, 47, Perdizes, CEP 05014-000, São Paulo, SP, Brasil.

Tel. 55 11 3862-5081. E-mail: igbpolonio@yahoo.com.br Financial support: This study received financial support from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazilian National Council for Scientific and Technological Development).

Submitted: 29 March 2012. Accepted, after review: 10 May 2012.

J Bras Pneumol. 2012;38(4):452-460

Comparison of two experimental models of pulmonary hypertension

Introduction Pulmonary arterial hypertension (PAH) comprises a group of diseases that share pathological similarities but differ in pathophysiology and prognosis.(1) Clinically, PAH is characterized by symptoms of dyspnea, chest pain, and syncope, causing progressive limitation, right heart failure, and death.(2,3) Idiopathic PAH is rare, has a peak incidence in the fourth decade of life, and mainly affects females; however, other forms of PAH, such as schistosomiasis-associated PAH, are potentially more prevalent and can become a public health problem.(1,4,5) According to the 4th World Symposium on Pulmonary Hypertension,(6) held in Dana Point, CA, USA, PAH is defined by right heart catheterization measurements. Therefore, in a patient with PAH, cardiac catheterization should show a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg and a pulmonary artery occlusion pressure ≥ 15 mmHg. The disease is the result of complex changes that lead to structural modifications in pulmonary arteries and arterioles. These changes ultimately cause the clinical manifestations of PAH. The progression of vascular changes usually occurs after one or more offending stimuli in a susceptible individual, and, despite the drugs available for treatment, PAH remains a fatal disease.(7,8) Experimental models of PAH have allowed the development of all of the therapeutic alternatives that are currently available, and the monocrotaline model remains the most widely used.(9-11) The use of seeds of Crotalaria spectabilis, the plant from which monocrotaline is derived, was described more than 40 years ago. Initially, the animals were fed the seeds, subsequently developing PAH.(12) Currently, monocrotaline is administered subcutaneously; after undergoing oxidation in the liver, monocrotaline produces its pyrrole metabolite and reaches the lung, where it causes lesions in the pulmonary circulation, the targets being various proteins and peptides of the vascular endothelium.(13) Four hours after the substance is administered, it is possible to see a relative increase in the media of intra-acinar pulmonary arteries, which is due to muscle contraction. Within 8-16 h after administration, mononuclear inflammatory infiltrates are seen in the adventitia of arteries and veins, resulting in vasculitis. After approximately 22 days, there is right ventricular hypertrophy and

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marked mononuclear vasculitis in intra-acinar arteries and veins.(14) Therefore, after monocrotaline causes an intense inflammatory reaction in the pulmonary arteries and arterioles, the process of vascular remodeling, mainly associated with medial thickening, begins.(15,16) These findings have led various authors to study the effect of monocrotaline on the rat pulmonary circulation and its association with different interventions.(9-11,17-20) Because of its simplicity, the monocrotaline model is widely used for testing new drugs; however, the list of drugs that can reverse monocrotaline-induced PAH is extensive, paradoxically including drugs that can cause PAH in humans.(21) Therefore, the problem with this model is that it does not reliably represent all of the changes that occur in human PAH, especially because there is no significant endothelial proliferation.(7) Studies conducted more recently have addressed the hypothesis that the use of a systemicpulmonary shunt or pneumonectomy—producing an increase in pulmonary blood flow—in combination with the administration of monocrotaline can lead to exacerbation of the resulting findings in the pulmonary circulation.(22-24) Although such studies have suggested that the model combining monocrotaline and increased blood flow is superior, no direct comparisons have been made in order to set the standard for use in future studies.

Therefore, the objective of the present study was to compare the monocrotaline model with the model combining monocrotaline and increased blood flow (following left pneumonectomy) in adult rats, in terms of hemodynamic severity, structural changes in the pulmonary arteries, inflammatory markers, and 45-day survival.

Methods All animals were handled humanely, in accordance with international standards for animal care.(25) The study was approved by the Research Ethics Committee of the University of São Paulo School of Medicine, located in the city of São Paulo, Brazil.

Two study protocols were performed: one for structural analysis and one for survival analysis.

Each protocol included 40 Sprague-Dawley rats (weight, 250-300 g) divided into four groups: the control group, in which the animals were given a subcutaneous injection of saline (1 mL/kg) at the study outset (D0); the monocrotaline (M) group, J Bras Pneumol. 2012;38(4):452-460

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in which the animals were given a subcutaneous injection of monocrotaline (Sigma-Aldrich, St. Louis, MO, USA; 60 mg/kg) on D0; the left pneumonectomy (P) group, in which the animals underwent left pneumonectomy 7 days prior to D0 and received a subcutaneous injection of saline (1 mL/kg) on D0; and the monocrotaline+left pneumonectomy (M+P) group, in which the animals underwent left pneumonectomy 7 days prior to D0 and received a subcutaneous injection of monocrotaline (60 mg/kg) on D0.

The pneumonectomy technique used in the present study was as follows: • The animals were anesthetized with 2.5% isoflurane in an anesthesia chamber, anesthesia being maintained throughout the surgical procedure.

• The animals were intubated with a 14-gauge Jelco® catheter (Johnson & Johnson, São José dos Campos, Brazil) and coupled to a Harvard rodent ventilator (model 683; Harvard Apparatus Co., South Natick, MA, USA), RR being maintained at 80 breaths/min and tidal volume being maintained at 10 mL/kg of body weight.

• The animals were placed in the left lateral decubitus position, the left infra-axillary region was shaved, and, subsequently, a 3-cm incision was made between the fourth and fifth intercostal spaces, running parallel to the spaces.

• The skin, subcutaneous cellular tissue, and intercostal muscle planes were sectioned until the thoracic cavity was reached, at which point the retractor was placed between the ribs.

• The left lung was freed from its ligaments and subsequently drawn out of the cavity.

• After en bloc ligation of the hilum with 2-0 cotton sutures, the left lung was sectioned.

• The muscle planes were closed with continuous 3-0 nylon sutures (Ethicon, São Paulo, Brazil), and the skin was sutured with the same suture material.

The analyses were performed 28 days after the injection of monocrotaline or saline. After deep sedation with xylazine hydrochloride (0.3 mg/kg, i.p.; Rompun®; Bayer, Leverkusen, Germany) and ketamine hydrochloride (10 mg/kg, i.p.; Ketalar®; Pfizer, New York, NY, USA), the animals were weighed. Hemodynamic measurements were performed, being followed by euthanasia J Bras Pneumol. 2012;38(4):452-460

(abdominal aortic bleeding) and removal of heart and lung tissue.

The hemodynamic measurements were performed by inserting an umbilical catheter into the external jugular vein, the catheter being connected to a pressure transducer (HP 1295C; Hewlett-Packard, Palo Alto, CA, USA) coupled to a hemodynamic monitor (Monitox Dx 2020; Hewlett-Packard), in accordance with a previously described technique.(26) The mPAP was thus measured.

The right ventricle (RV) was dissected from the left ventricle (LV), the interventricular septum (IS) having remained attached to the LV. The ratio between RV weight and LV+IS weight was taken as the index of right ventricular hypertrophy.(19) To investigate the degree of inflammation, we determined IL-1 and PDGF levels. To measure peptide levels, we used a capture ELISA with a commercial kit including anti-mouse IL-1 and PDGF (R&D System Inc., Minneapolis, MN, USA).

(27) Peptide levels were measured in frozen lung samples.

We employed 96-well plates (Costar; Corning Inc., Cambridge, MA, USA), which were sensitized with 100 µL of monoclonal antibody and incubated for 18 h at 4°C. Subsequently, in order to prevent nonspecific bindings, the plates were blocked with 300 µL of 2% BSA and incubated for 2 h at 37°C. After blocking, sample and standards diluted in PBS were added at 100 µL/well. Two wells were filled only with PBS for use as a blank.

The plates were incubated for 18 h at 4°C. After incubation, we added 100 µL of biotinylated conjugated antibody at a pre-established concentration, and the plates were incubated for 3 h at 37°C. Subsequently, we added 100 µL of streptavidin-HRP (1:250; R&D Systems, Minneapolis, MN, USA) to each well, and the plates were incubated for 30 min at 37°C. At each step, the plates were washed six times in wash buffer (PBS and Tween 20).

For color development, we added 100 µL of developer (hydrogen peroxide and tetramethylbenzidine) to each well, and the plates were incubated for 5 or 60 min, depending on the cytokine, at 37°C. The reaction was stopped by the addition of 50 µL of 30% sulfuric acid to each well, followed by gentle agitation of the plates. The plates were read by an ELISA reader (Power Wave; Bio-Tek Instruments Inc., Winooski, VT, USA) with a 450-nm filter.

Comparison of two experimental models of pulmonary hypertension

For histological quantification, five different randomly selected fields were examined (magnification, ×400) after the tissue had been stained with Miller’s stain, which allows the visualization of elastic fibers. For this quantification, we used an image analysis system (Carl Zeiss; MicroImaging GmbH, Göttingen, Germany) and AxioVision 40 version 4.7.1.0 software, 2006-2008 (Carl Zeiss Imaging Solutions GmbH, Jena, Germany), which allows quantitative geometric and quantitative densitometric measurements. Specific thresholds were established for each slide. The histological findings are expressed as area (µm2).(28) The objective of the survival protocol, with 40 rats also divided into control, P, M, and M+P rats, was to investigate differences in survival among the models. The animals were followed for 45 days, and the date of death of each rat was recorded. All of the remaining animals were sacrificed on day 45.

For the statistical analysis, ANOVA with post hoc Bonferroni correction was used in order to compare continuous variables among the groups. Proportional variables were analyzed by the chi-square test or Fisher’s exact test, as appropriate. Values of p < 0.05 were considered significant.

To estimate survival over time, we used the Kaplan-Meier method, the survival curves being compared by the log-rank test.

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The IL-1 levels were significantly higher in P, M, and M+P rats than in control rats (Figure 4A).

Although the PDGF levels were also different among the groups (p = 0.049), our post hoc analysis did not allow us to determine the significance of the differences (as it did for the IL-1 levels); nevertheless, the distribution of the data suggests that the patterns are the same (Figure 4B).

Although survival was significantly lower in M and M+P rats than in control and P rats (p < 0.05), there were no differences between M and M+P rats (Figure 5).

Discussion

Results

Our study showed that both the monocrotaline model and the model combining monocrotaline and increased blood flow produced by pneumonectomy induce PAH in rats. Analogously and consequently, we observed that RV weight and the index of RV hypertrophy were higher in M+P rats than in M rats, as well as being higher in M and M+P rats than in control and P rats.

It is of note, however, that the index of RV hypertrophy (RV/LV+IS ratio) does not represent PAH in an absolute sense, because monocrotaline can also have a direct effect on the heart.(21) Nevertheless, the finding of similar LV weights in the different groups does not suggest the presence of monocrotaline-induced cardiac abnormalities in our study.

The M and M+P rats showed no differences in medial area when compared with each other.

Invasive hemodynamic measurements revealed that M and M+P rats developed PAH, whereas control and P rats did not (Figure 1).

As can be seen in Figure 2A, the RV weight was significantly higher in the rats that developed PAH (i.e., M and M+P rats) than in those that did not (i.e., control and P rats), as well as being significantly higher in M+P rats than in M rats.

There were no differences among the groups regarding LV+IS weight (Figure 2B); this caused the index of RV hypertrophy (RV/LV+IS ratio) to be significantly higher in M+P rats than in those in the remaining groups (Figure 2C), similarly to the distribution of RV weight.

The medial area was significantly larger in M and M+P rats than that in control rats (p = 0.013; Figure 2D). There was no intimal proliferation in M or M+P rats (Figure 3).

Figure 1 - Comparison of control (C), monocrotaline (M), pneumonectomy (P), and monocrotaline+pneumonectomy (M+P) rats regarding mean pulmonary artery pressure (mPAP) in mmHg. *p < 0.001.

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Figure 2 - Comparison of control (C), monocrotaline (M), pneumonectomy (P), and monocrotaline+pneumonectomy (M+P) rats. In A, right ventricle (RV) weight in g, *p < 0.001; in B, left ventricle plus interventricular septum (LV+IS) weight in g; in C, the RV/LV+IS ratio, *p < 0.001; in D, medial area in µm2, *p = 0.013.

However, when compared with control rats, M and M+P rats showed significantly larger areas (p = 0.013), which confirmed that the two models produce pathological changes typically caused by PAH. Control and P rats showed no significant differences in medial area. One important finding is that there was no intimal proliferation in any of the groups, which is at odds with the findings of other studies.(23,29) Regarding inflammatory markers, IL-1 levels were significantly higher in P, M+P, and M rats than in control rats, and a similar pattern was found for PDGF levels. This demonstrates that surgical manipulation alone increases the levels of these inflammatory markers, which limits their use in the comparison of the models, although it has been demonstrated that these markers are increased in individuals with PAH.(17,30) However, it is of note that, in our study, the levels of these markers were measured in whole lung samples, and no microdissection technique was used in order to J Bras Pneumol. 2012;38(4):452-460

analyze isolated vascular material.(15) This means that any inflammatory phenomenon occurring in the lungs is reflected in the methodology employed, a factor that constitutes a limitation of the methodology.

The experimental models of PAH studied do not mimic human PAH closely enough. This is due to several factors, among which is the speed of disease onset, which occurs over years in humans but in weeks in rats. It is therefore logical to think that the pathophysiological mechanisms are different.(21) Consequently, other models, such as the model combining monocrotaline injection and increased pulmonary blood flow produced by systemic-pulmonary shunts or pneumonectomy, have been studied.(22-24) In 1996, Tanaka et al.(22) tested the hypothesis that, by raising pulmonary artery blood pressures to systemic levels, the effects of monocrotaline on pulmonary circulation could be increased. The authors found that the creation of a subclavian-

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Figure 3 - Sample images of histological sections of the media of acinar arterioles (magnification, ×400). C: control group; M: monocrotaline group; P: pneumonectomy group; and M+P: monocrotaline+pneumonectomy group.

Figure 4 - In A, IL-1 levels in pg/mL, *p < 0.05; in B, PDGF levels in pg/mL, *p = 0.049. C: control group; M: monocrotaline group; P: pneumonectomy group; and M+P: monocrotaline+pneumonectomy group.

pulmonary artery anastomosis in rats, with subsequent injection of monocrotaline, led to intimal lesions in large pulmonary arteries. The authors demonstrated that, in the absence of endothelial injury, there was no vascular remodeling

(at least not in large blood vessels), even when the animals were submitted to systemic pressures.

In a subsequent study,(23) left pneumonectomy was followed by injection of monocrotaline. The authors of that study found intimal lesions in distal pulmonary arteries, a finding that was J Bras Pneumol. 2012;38(4):452-460

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Figure 5 - Kaplan-Meier survival curve. There were no significant differences between monocrotaline and monocrotaline+pneumonectomy rats.

attributed to increased blood flow in the arteries of the remaining lung. The authors hypothesized that shear stress was responsible for the changes observed. The two abovementioned studies, as well as those involving other animal species, showed that, in the absence of endothelial injury, increased blood flow following pneumonectomy does not cause significant increases in pulmonary artery pressure levels.(24) In humans, histological examinations performed 1-5 years after pneumonectomy showed only medial hypertrophy, without intimal lesions in the pulmonary arteries.

(24) Therefore, the histological changes caused by these experimental models are potentially similar to the typical findings in human PAH, especially because of increased neointimal proliferation.

(18-20,22)

White et al. compared the monocrotaline+left pneumonectomy model of pulmonary hypertension in younger rats with the pathological lesions observed in autopsy studies of human PAH. The authors hypothesized that, in younger rats, the changes observed by Tanaka et al.(22) would be even more pronounced. They found complex, proliferative perivascular lesions in the rats studied.

The rats used in our study were not as young as those used by White et al.,(29) who observed complex, proliferative perivascular lesions in their rats. Tanaka et al., who pioneered this model,(22) found intimal lesions. However, their findings were different from those reported by White et al.

The difference was likely due to the younger age of the rats used, given that the methods (29)

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employed in the two studies were the same. In older rats, postpneumonectomy lung growth is less pronounced, as are the inflammatory effects of monocrotaline. Therefore, in the study by White et al., the observed phenomena might be due to compensatory lung growth following pneumonectomy.(22,29) Although we found no significant differences between M+P and M rats regarding hemodynamic changes or medial thickness, we found that RV hypertrophy was greater in M+P rats (Figure 2).

This finding alone does not allow us to conclude that the monocrotaline+pneumonectomy model is more severe than is the monocrotaline model, because survival was the same. No author had tested the difference in survival among the various models. We believe that this is the parameter that should be used for determining the actual severity of the disease produced by experimental models.

We can conclude that the results of the comparison between the monocrotaline model and the model combining monocrotaline and increased blood flow do not allow us to state that one is definitely superior to the other and therefore recommend one over the other as the standard for future studies. Because of its ease of use, the monocrotaline model is still more widely employed, despite its limitations in mimicking the pattern seen in human PAH, as was confirmed in our study. Nevertheless, studies whose primary objective is to evaluate RV hypertrophy can benefit from the combination of monocrotaline and increased blood flow.

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About the authors Igor Bastos Polonio

Graduate Student. Department of Pulmonology. Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo – InCor/HC-FMUSP, Heart Institute/University of São Paulo School of Medicine Hospital das Clínicas – São Paulo, Brazil; Attending Physician. Department of Pulmonology, Irmandade da Santa Casa de Misericórdia de São Paulo (ISCMSP, Santa Casa Sisters of Mercy Hospital of São Paulo), São Paulo, Brazil.

Milena Marques Pagliarelli Acencio

Head Biologist. Laboratory for Pleural Studies, Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo – InCor/HC-FMUSP, Heart Institute/University of São Paulo School of Medicine Hospital das Clínicas – São Paulo, Brazil.

Rogério Pazetti

Researcher specializing in Experimental Thoracic Surgery. Laboratory for Medical Research, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo – HC-FMUSP, University of São Paulo School of Medicine Hospital das Clínicas – São Paulo, Brazil.

Francine Maria de Almeida

Researcher. Laboratory for Medical Research, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo – HC-FMUSP, University of São Paulo School of Medicine Hospital das Clínicas – São Paulo, Brazil.

Mauro Canzian

Attending Physician. Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo – InCor/ HC-FMUSP, Heart Institute/University of São Paulo School of Medicine Hospital das Clínicas – São Paulo, Brazil.

Bárbara Soares da Silva

Biomedical Student. Guarulhos University, Guarulhos, Brazil; and Young Investigator. Department of Pulmonology, Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo – InCor/HC-FMUSP, Heart Institute/University of São Paulo School of Medicine Hospital das Clínicas – São Paulo, Brazil.

Karina Aparecida Bonifácio Pereira

Biomedical Student. United Metropolitan Colleges; and Young Investigator. Department of Pulmonology, Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo – InCor/HC-FMUSP, Heart Institute/University of São Paulo School of Medicine Hospital das Clínicas – São Paulo, Brazil.

Rogério de Souza

Tenured Professor. Department of Pulmonology, Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo – InCor/HC-FMUSP, Heart Institute/University of São Paulo School of Medicine Hospital das Clínicas – São Paulo, Brazil.

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Original Article An experimental rat model of ex vivo lung perfusion for the assessment of lungs regarding histopathological findings and apoptosis: low-potassium dextran vs. histidine-tryptophan-ketoglutarate* Modelo experimental de perfusão pulmonar ex vivo em ratos: avaliação histopatológica e de apoptose celular em pulmões preservados com solução de baixo potássio dextrana vs. solução histidina-triptofano-cetoglutarato

Edson Azevedo Simões, Paulo Francisco Guerreiro Cardoso, Paulo Manuel Pêgo-Fernandes, Mauro Canzian, Rogério Pazetti, Karina Andriguetti de Oliveira Braga, Natalia Aparecida Nepomuceno, Fabio Biscegli Jatene

Abstract

Objective: To compare histopathological findings and the degree of apoptosis among rat lungs preserved with low-potassium dextran (LPD) solution, histidine-tryptophan-ketoglutarate (HTK) solution, or normal saline (NS) at two ischemia periods (6 h and 12 h) using an experimental rat model of ex vivo lung perfusion. Methods: Sixty Wistar rats were anesthetized, randomized, and submitted to antegrade perfusion via pulmonary artery with one of the preservation solutions. Following en bloc extraction, the heart-lung blocks were preserved for 6 h or 12 h at 4°C and then reperfused with homologous blood for 60 min in an ex vivo lung perfusion system. At the end of the reperfusion, fragments of the middle lobe were extracted and processed for histopathological examination. The parameters evaluated were congestion, alveolar edema, alveolar hemorrhage, inflammatory infiltrate, and interstitial infiltrate. The degree of apoptosis was assessed using the TdT-mediated dUTP nick end labeling method. Results: The histopathological examination showed that all of the lungs preserved with NS presented alveolar edema after 12 h of ischemia. There were no statistically significant differences among the groups in terms of the degree of apoptosis. Conclusions: In this study, the histopathological and apoptosis findings were similar with the use of either LPD or HTK solutions, whereas the occurrence of edema was significantly more common with the use of NS. Keywords: Organ preservation; Organ preservation solutions; Lung transplantation; Reperfusion injury; Apoptosis.

Resumo

Objetivo: Comparar os achados histopatológicos e de apoptose em pulmões de ratos preservados em soluções low-potassium dextran (LPD, baixo potássio dextrana), histidine-tryptophan-ketoglutarate (HTK, histidinatriptofano-cetoglutarato) ou salina normal (SN) em 6 h e 12 h de isquemia pela utilização de um modelo experimental de perfusão pulmonar ex vivo. Métodos: Sessenta ratos Wistar foram anestesiados, randomizados e submetidos à perfusão anterógrada pela artéria pulmonar com uma das soluções preservadoras. Após a extração, os blocos cardiopulmonares foram preservados por 6 ou 12 h a 4°C, sendo então reperfundidos com sangue homólogo em um sistema de perfusão ex vivo durante 60 min. Ao final da reperfusão, fragmentos do lobo médio foram extraídos e processados para histopatologia, sendo avaliados os seguintes parâmetros: congestão, edema alveolar, hemorragia alveolar, hemorragia, infiltrado inflamatório e infiltrado intersticial. O grau de apoptose foi avaliado pelo método TdT-mediated dUTP nick end labeling. Resultados: A histopatologia demonstrou que todos os pulmões preservados com SN apresentaram edema alveolar após 12 h de isquemia. Não houve diferenças em relação ao grau de apoptose nos grupos estudados. Conclusões: No presente estudo, os achados histopatológicos e de apoptose foram semelhantes com o uso das soluções LPD e HTK, enquanto a presença de edema foi significativamente maior com o uso de SN. Descritores: Preservação de órgãos; Soluções para preservação de órgãos; Transplante de pulmão; Traumatismo por reperfusão; Apoptose. * Study carried out in the Thoracic Surgery Section of the Department of Cardiorespiratory Diseases; in Laboratório de Investigação Médica 61 (LIM-61, Laboratory for Medical Research 61), specializing in Experimental Thoracic Surgery; and at the University of São Paulo School of Medicine Hospital das Clínicas Instituto do Coração – InCor, Heart Institute – São Paulo, Brazil.

Correspondence to: Paulo Manuel Pêgo-Fernandes. Avenida Dr. Enéas de Carvalho Aguiar, 44, bloco II, 5º andar, sala 7, Cerqueira César, CEP 05403-900, São Paulo, SP, Brasil.

Tel. 55-11-26615248. E-mail: paulo.fernandes@incor.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).

Submitted: 23 February 2012. Accepted, after review: 5 June 2012.

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Introduction Lung transplantation is the only definitive treatment modality for selected patients with end-stage lung disease.

Over two decades, there has been a significant increase in the number of transplant centers, as well as in the number of transplant recipients or patients on waiting lists,(1) the mean annual number of lung transplants performed being higher than 1,500.(2) However, pulmonary transplant-related mortality remains significant. Graft dysfunction is considered the most common cause of early mortality, and its etiopathogenesis lies in ischemiareperfusion injury.(3,4) Donor lung preservation plays a key role in early graft function after transplantation.(5) The presence and severity of ischemia-reperfusion injury are influenced by factors pertaining to the donor and to the preservation techniques.

(3) Ischemia-reperfusion injury is associated with cell death in various organ systems, and there is a correlation between the degree of apoptosis and ischemia-reperfusion injury.(6) During apoptosis, a well-regulated, energy-dependent cascade of events activates specific endonucleases, such as caspases, which are cysteine proteases specifically involved in the initiation and execution phases of apoptosis.

Under the clinical lung transplant program in our hospital, low-potassium dextran (LPD) solution is used for lung preservation. However, the cost of the solution and the logistical difficulties in obtaining it led us to seek alternatives that are logistically more efficient and provide similar clinical benefits. Histidine-tryptophanketoglutarate (HTK) solution is commonly used in heart transplantation at our institution. Therefore, the exclusive use of HTK solution under both transplant programs would be desirable in order to facilitate and reduce the cost-benefit ratio of preserving both organs.

To date, there have been no experimental rat models of ex vivo lung perfusion with the use of HTK as the preservation solution, although there have been studies demonstrating the advantages of HTK use for heart, liver, kidney, and pancreas preservation.(7-9) Ex vivo lung perfusion models for the evaluation of new strategies for organ preservation have been shown to be effective and reliable in lung preservation studies.(10) We have recently demonstrated that the use of either HTK or J Bras Pneumol. 2012;38(4):461-469

LPD solutions at two ischemia periods (6 and 12 h) produced no significant differences among rat lungs in terms of physiological parameters, except for weight gain in the lungs undergoing 12 h of ischemia.(11) The objective of the present study was to compare histopathological findings and the degree of apoptosis among rat lungs preserved with HTK solution, LPD solution, or normal saline (NS, 0.9% saline solution), at two different periods of hypothermic ischemia using an experimental rat model of ex vivo lung perfusion.

Methods In the present study, 60 male Wistar (weight, 250-300 g) were used. The animals were randomized into groups (10 rats/group) according to the different periods of ischemia and the perfusion solution used: LPD-6 group (LPD, 6 h of ischemia); LPD-12 group (LPD, 12 h of ischemia); HTK-6 group (HTK, 6 h of ischemia); HTK-12 group (HTK, 12 h of ischemia); NS-6 group (NS, 6 h of ischemia); and NS-12 group (NS, 12 h of ischemia). The composition of the preservation solutions are described in Table 1.

The study was approved by the local animal research ethics committee. After having been anesthetized (pentobarbital, 50 mg/kg i.p.), the animals were tracheostomized and connected to a ventilator (IL2 - Isolated Perfused Rat or Guinea Pig Lung System; Harvard Apparatus, Holliston, MA, USA) set to a tidal volume of 10 mL/kg, a RR of 70 breaths/min, and a positive end-expiratory pressure (PEEP) of 3 cmH2O, on room air. The animals were anticoagulated (heparin, 1,500 IU, administered to the inferior vena cava). Further details on extraction and perfusion have been described elsewhere.(10,12) According to the randomization, perfusion was achieved with 20 mL of LPD solution (Perfadex®; Vitrolife, Kungsbacka, Sweden), HTK solution (Custodiol®; Franz Kohler Chemie GMBH, Bensheim, Germany), or NS, at 4°C, administered under a constant pressure of 20 cmH2O by raising the flask. At the end of the perfusion, the heart-lung block was extracted and preserved for 6 h or 12 h, according to the predetermined randomization, being prepared and connected to the ex vivo lung perfusion system (IL2 - Isolated Perfused Rat or Guinea Pig Lung System; Harvard Apparatus, Holliston, MA, USA; Hugo Sachs Elektronik, Hugstetten, Germany).

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Table 1 - Composition of the preservation solutions used in the study.

HTKa LPDb Composition Concentration Composition Concentration Sodium chloride 15 mmol/L Sodium chloride 138 mmol/L Potassium chloride 9 mmol/L Potassium chloride 6 mmol/L Potassium hydrogen 2-ketoglutarate 1 mmol/L Magnesium 0.8 mmol/L Magnesium chloride hexahydrate 4 mmol/L Phosphate 0.8 mmol/L 18 mmol/L Chloride 142 mmol/L Histidine.HCl.H2O Histidine 180 mmol/L Glucose 5 mmol/L Tryptophan 2 mmol/L Dextran 40 50 g/L Mannitol 30 mmol/L Calcium chloride 0.015 mmol/L pH 7.40-7.45 (4°C) pH (buffer solution) 7.4 (4°C) Osmolality 310 mOsmol/L Osmolality 295 mOsmol/L HTK: histidine-tryptophan-ketoglutarate; and LPD: low-potassium dextran. aCustodiol®; Franz Kohler Chemie GMBH, Bensheim, Germany. bPerfadex®; Vitrolife, Kungsbacka, Sweden.

The block was reperfused with homologous blood obtained from 3 similarly anesthetized animals, and the volume was increased by adding enough NS to achieve a hematocrit of 15-20%.

Reperfusion was performed via cannulation of the pulmonary artery/left atrium and tracheal ventilation for 60 min. The circuit was filled with blood, which was heated and recirculated through the system for 10 min with a gas mixture (90% nitrogen and 10% carbon dioxide at a flow of 200 mL/min) administered through a membrane oxygenator (D150 MediSulfone® Hemofilter; MEDICA s.r.l. Medolla, Italy). The heart-lung block was perfused (5-7 mL/min) and ventilated (tidal volume = 10 mL/kg, RR = 70 breath/min, and PEEP = 3 cmH2O). After 5-10 min, we started data collection, which was performed every 10 min for 60 min. We collected data on hemodynamics and respiratory mechanics, as well as blood gas analysis (ABL 800; Radiometer, Copenhagen, Denmark) results. At the end of the reperfusion, fragments of the middle lobe were extracted, fixed in 4% formaldehyde buffered solution, and embedded in paraffin blocks. Subsequently, 5-µm sections were cut and stained with H&E. We conducted a qualitative and semi-quantitative analysis by assessing the following: congestion; alveolar edema; alveolar hemorrhage; interstitial hemorrhage; inflammatory infiltrate; and interstitial infiltrate. For the semi-quantitative assessment of changes such as alveolar hemorrhage, interstitial hemorrhage, interstitial inflammatory infiltrate and congestion, we considered the histological compartmentalization, i.e., alveolar spaces, (axial,

septal, and peripheral) interstitium, capillary bed, and extent of changes. Each change (event) was separately semi-quantified and received a score ranging from zero to three, as follows: no event (score 0); event occurring in less than 33% of the affected compartments (score 1); event occurring in 33-66% of the affected compartments (score 2); and event occurring in more than 66% of the affected compartments (score 3).(13) Histological examination was performed by a single observer. The parameter “edema” was evaluated in two different compartments, namely the interstitial compartment and the bronchoalveolar compartment. Alveolar edema was scored with the semi-quantitative scoring system described above.

Apoptosis was assessed using the TdT-mediated dUTP nick end labeling (TUNEL) method. The fragments of the middle lobe were processed in accordance with the instructions provided in the In Situ Cell Death Detection kit (Roche Diagnostics GmbH, Mannheim, Germany) and the methods described by Gavrieli et al.(14) and Rösl.(15) After deparaffinization in xylene, slides were pretreated with proteinase K (20 mg/mL) for 30 min in a humidified chamber at room temperature, washed in PBS, and treated with a solution of 3% oxygen peroxide in methanol for 30 min at room temperature. Subsequently, the fragments were washed in PBS twice, and, after the area around the sample was dried, 50 μL of the TUNEL reaction mixture—5 μL of the enzyme solution (violet tube) and 45 μL of the labeling solution (blue tube)—were added to each lung J Bras Pneumol. 2012;38(4):461-469

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fragment, followed by incubation under Parafilm for 60 min in a humidified chamber at 37°C. The assay is employed to label DNA strand breaks (with TdT) in each fragment. The assay catalyzes the polymerization of labeled nucleotides at the 3’-OH ends of DNA independently (TUNEL reaction) per sample, therefore allowing the detection of DNA strand breaks in the early stages of lung cell apoptosis. After the incubation period (TUNEL reaction), the slides were washed in PBS three times (2 min each). The area around the fragment was dried, and the slides were mounted with glycerin solution and PBS (1:1), were coverslipped and protected from light, and were immediately analyzed under a fluorescence microscope (Carl Zeiss, Oberkochen, Germany), through which labeled apoptotic cells were quantified in five random fields (magnification, ×40). The readings were performed by two investigators, who were blinded to the TUNEL reaction quantification.

Microscopic field selection was random, the microscopic fields being always in the alveolar region. Five microscopic fields were selected, as it is done when reading H&E-stained slides. The identified cells were specific, and counts included the total number of cells in the selected region.

In the statistical analysis, we used mixed ANOVA and the Bonferroni test for parametric variables.

For non-parametric quantitative data, we used the Kruskal-Wallis test and the Mann-Whitney test.

For qualitative data, we used the chi-square test and Fisher’s exact test. The level of significance was set at 5% (p < 0.05). The statistical analyses were performed with the Statistical Package for the Social Sciences, version 13.0 (SPSS Inc., Chicago, IL, USA).

Results Histopathological examination revealed no significant differences among the LPD-6, HTK-6, and NS-6 groups or among the LPD-12, HTK-12, and NS-12 groups, as well as revealing no significant ischemia-related differences between the groups (i.e., LPD-6 vs. LPD-12, HTK-6 vs.

HTK-12, and NS-6 vs. NS-12), in terms of the following parameters: pulmonary congestion; alveolar hemorrhage; interstitial hemorrhage; and interstitial inflammatory infiltrate (Table 2).

In all groups, the occurrence of alveolar edema was significantly more common after 12 h of ischemia than after 6 h of ischemia (Figure 1).

Analysis of the frequency distribution of edema among the groups revealed that the proportion of edema was highest in the NS-12 group, and that the NS-12 group was the only group in which all of the lungs showed alveolar edema at the end of the reperfusion; in addition, the difference among the LPD-12, HTK-12, and NS-12 groups was significant (p = 0.007). The same did not occur in the comparison among the LPD-6, HTK-6, and NS-6 groups (p = 0.08).

Figure 1 - Histological sections of rat lung tissue after 6 h (in A) and 12 h (in B) of ischemia in the normal saline group. The arrows show the presence of alveolar edema in B (H&E; magnification, ×100).

Table 2 - Comparison of histopathological findings among the groups studied.

Values of p in the comparison among the groupsa LPD-6 LPD-12 Parameter LPD-6 HTK-6 vs. HTK-6 vs. HTK-12 vs. NS-6 vs. NS-12 vs. LPD-12 vs. HTK-12 Congestion 0.797 0.135 0.370 1.000 Alveolar hemorrhage 0.077 0.701 0.087 1.000 Interstitial hemorrhage 0.103 0.943 0.087 1.000 Inflammatory infiltrate 0.278 0.441 0.350 1.000 Interstitial infiltrate 0.067 0.315 0.303 0.350

NS-6 vs. NS-12 0.370 1.000 0.303 0.582 1.000

LPD: low-potassium dextran; HTK: histidine-tryptophan-ketoglutarate; and NS: normal saline. aGroups: LPD-6: LPD solution and 6 h of ischemia; LPD-12: LPD solution and 12 h of ischemia; HTK-6: HTK solution and 6 h of ischemia; HTK-12: HTK solution and 12 h of ischemia; NS-6 = NS solution and 6 h of ischemia; and NS-12: NS solution and 12 h of ischemia.

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An experimental rat model of ex vivo lung perfusion for the assessment of lungs regarding histopathological findings and apoptosis: low-potassium dextran vs. histidine-tryptophan-ketoglutarate

Nevertheless, in the HTK-6 group, the frequency of edema was 30%, whereas, in the LPD-6 group, it was 55.6%; however, the difference was not significant (p = 0.08; Figure 2).

There was no significant difference between the LPD-6 and LPD-12 groups in terms of the number of apoptotic cells (p = 0.319). The same occurred in the comparisons between the HTK-6 and HTK-12 groups (p = 0.258) and between the NS-6 and NS-12 groups (p = 0.226). In addition, no significant differences were found among the LPD-6, HTK-6, and NS-6 groups (p = 0.580) or among the LPD-12, HTK-12, and NS-12 groups regarding the number of apoptotic cells (p = 0.591; Figure 3).

Discussion The present study demonstrated that the histopathological characteristics were similar between the lungs perfused with either LPD or HTK preservation solutions. These findings are in accordance with the physiological data from the same study, which were published previously. The relative oxygenation capacity of the lungs undergoing 12 h of ischemia was found to be reduced, as were the respiratory mechanics parameters. The physiological data were recently published and demonstrated that the lungs preserved with either LPD or HTK had a similar functional performance.(11) Ischemia-reperfusion injury is a factor limiting donor organ viability, as well as being implicated as a contributing factor in the development of bronchiolitis obliterans.(16) The combination of hypothermia with preservation solutions remains the most widely used preservation method.

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The LPD solution was developed nearly two decades ago,(17,18) and its experimental results have been shown to be superior to those of most solutions.(19) The development of preservation solutions for exclusive use in lung preservation has reduced the incidence of acute graft failure from 30% to less than 15%.(3) Despite the evidence, controversy remains regarding the benefits of the LPD solution in terms of late graft performance and one-year mortality after transplantation.(20) More recently, the introduction of ex vivo lung reconditioning(21) and donation after cardiocirculatory death(4) have reignited the controversy and underscored the need to re-evaluate the preservation solutions that are currently used.

The HTK solution is used as a cardioplegic solution, as well as being used for heart preservation for transplantation. Since its development, several changes have been made to its formulation, making it more effective during longer periods of ischemia.(22) However, the use of HTK solution for lung preservation had not been tested in an ex vivo model. If the solution proved effective for this purpose, it would be possible to use a single solution for cardiopulmonary extraction.

In the present study, we used an ex vivo lung perfusion model to evaluate HTK, comparing it with an extracellular solution commonly used in lung transplantation (i.e., LPD). We used an ex vivo rat lung preparation in which the lungs were perfused with homologous venous blood obtained by exsanguination of animals of the same species.(22,23) The ex vivo perfusion system is simple and reproducible, which is why it is widely used in studies of lung preservation for

Figure 2 - Frequency of alveolar edema in lungs preserved with low-potassium dextran (LPD) solution, histidine-tryptophan-ketoglutarate (HTK) solution, or normal saline at two ischemia periods: 6 h (in A) and 12 h (in B). Note that the occurrence of alveolar edema was significantly more common in the groups undergoing 12 h of ischemia, the incidence being highest in the normal saline group.

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Figure 3 - Photomicrographs of rat lung tissue labeled by the TdT-mediated dUTP nick end labeling (TUNEL) method. In A, lung tissue undergoing 6 h of hypothermic ischemia with the use of low-potassium dextran solution and containing few apoptotic cells (arrows). In B, lung tissue undergoing 12 h of hypothermic ischemia with the use of saline and containing an increased number of apoptotic cells (TUNEL; magnification, ×40).

transplantation. We used homologous blood obtained by exsanguination of 2 or 3 rats per heart-lung block and diluted in NS. Although hemodilution affects gas exchange, we obtained reliable and consistent blood gas analysis results.

Hemodilution and its effects on reperfusion injury are well known. Puskas et al.(24) employed a similar ex vivo perfusion model, in which hemodilution was performed with a crystalloid solution, having found a reduction in ischemiareperfusion injury following ischemia. In the present model, it is possible that hemodilution was greater in the lungs in the NS-6 and NS-12 groups, given that the vascular bed of those lungs had been filled with NS before reperfusion. Therefore, in our laboratory, NS was recently replaced with Krebs solution, given that the solution was found to be more effective in producing hemodilution, especially in experiments with prolonged periods of ischemia.

In the present study, even the lungs undergoing 6 or 12 h of ischemia provided consistent data for analysis; other authors have limited the periods of ischemia to 2-4 h.(25) Although NS is not employed in clinical or experimental lung preservation, our experimental design included an NS group.

The choice to include an NS group was based on the capacity of NS to cause lung edema on reperfusion, a factor that allowed NS to be used as a parameter of edema in the comparison with the other solutions. Using the same model, we previously demonstrated that lungs preserved with NS for 12 h showed consistently worse performance than did those preserved with the other solutions for the same period of ischemia.(11) The histopathological findings of the present J Bras Pneumol. 2012;38(4):461-469

study confirmed this impression, given that all of the lungs in the NS group were edematous.

In our previous study, we found increased lung compliance in the lungs undergoing 6 h of ischemia and increased lung resistance in those undergoing 12 h of ischemia. We also found that there was no difference in relative oxygenation capacity between the lungs in the LPD-6 and LPD-12 groups or among the 12-h ischemia groups.(11) We focused the present study on histopathological examination, with the conviction that our findings of morphological changes and apoptosis would support our previous physiological findings. We chose to include morphological parameters whose changes are relevant and related to vascular endothelial injury and to changes in the lung parenchyma, all of which are representative of postischemic reperfusion injury. We found no significant differences among the groups in terms of congestion, alveolar hemorrhage, interstitial hemorrhage, inflammatory infiltrate, or interstitial infiltrate. However, we found an increase in alveolar edema in the NS-12 group.

This confirms the assumption that the use of NS solution in lung preservation causes severe edema on reperfusion, especially in prolonged periods of ischemia.

Cell death in ischemia-reperfusion-induced injury is caused by necrosis and apoptosis (programmed cell death). Apoptosis can be activated during the initial phases of reperfusion after lung ischemia.(18) Apoptosis differs from necrosis not only from a morphological standpoint but also with regard to mediators and biological mechanisms of injury. During apoptosis, there is a regulated, energy-dependent cascade of events, which activate specific endonucleases, such as caspases, which are involved in the initiation and execution phases of apoptosis.(26,27) The duration of ischemia directly influences the degree of apoptosis in the tissues. The study of the biological pathways of apoptosis in various tissues suggests that the cascade of events begins during the period of ischemia. However, signs of apoptosis appear only during reperfusion, whereas cell necrosis occurs during ischemia.(26) There is nevertheless unequivocal evidence that ischemia alone is not sufficient to trigger apoptosis.

This has been demonstrated in cardiomyocytes, in which ischemia without reperfusion led only to cell death by necrosis. Burns et al. used the

An experimental rat model of ex vivo lung perfusion for the assessment of lungs regarding histopathological findings and apoptosis: low-potassium dextran vs. histidine-tryptophan-ketoglutarate

TUNEL method to study apoptosis before and after reperfusion in kidney transplantation and found that the degree of apoptosis was lesser before reperfusion, suggesting that apoptosis occurs predominantly after reperfusion.(28) The induction of lung ischemia by pulmonary artery ligation in pigs resulted in chronic lung ischemia and overexpression of pro-apoptotic factors. The addition of reperfusion after chronic ischemia triggers massive apoptosis, leading to endothelial injury.(29) Various studies have demonstrated that the inhibition of apoptosis by caspase inhibitors results in reduced lymphocyte infiltration and cell death, which leads to improved lung function.(6,30) In the present study, the assessment of apoptosis by the TUNEL method revealed no significant differences in the number of apoptotic cells between the 6-h period of ischemia and the 12-h period of ischemia in the LPD, HTK, or NS groups after 60 min of lung reperfusion.

This finding can be interpreted in two different ways: first, the lack of differences might be due to severe ischemic injury, which was similar among the groups; second, the LPD and HTK solutions might be similar in terms of the quality of preservation (cell integrity). Therefore, the degrees of apoptosis associated with the two solutions might be similar. The lack of differences between the NS group and the other groups (LPD and HTK) in terms of the degree of apoptosis might be more closely related to ischemia itself, regardless of the protective effects of the preservation solutions.

Nevertheless, judging by the degree of edema in the NS group, we can infer that the quality of preservation was inferior, as we had anticipated.

In conclusion, the rat lungs preserved with either LPD or HTK showed comparable histopathological and apoptosis findings after 60 min of reperfusion, whereas those preserved with NS showed a greater degree of edema on reperfusion. The findings of the present study support our previously reported physiological findings in the same model and underscore the need for further studies involving models of lung transplantation to determine whether the functional performance of lungs preserved with HTK is similar to that of those preserved with LPD.

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Ann Thorac Surg. 1995;60(5):1210-4. http://dx.doi. org/10.1016/0003-4975(95)00548-Y 20. Nath DS, Walter AR, Johnson AC, Radosevich DM, Prekker ME, Herrington CS, et al. Does Perfadex affect outcomes in clinical lung transplantation? J Heart Lung Transplant. 2005;24(12):2243-8. http://dx.doi. org/10.1016/j.healun.2005.06.019 21. Steen S, Ingemansson R, Eriksson L, Pierre L, Algotsson L, Wierup P, et al. First human transplantation of a nonacceptable donor lung after reconditioning ex vivo.

Ann Thorac Surg. 2007;83(6):2191-4. http://dx.doi. org/10.1016/j.athoracsur.2007.01.033 22. Mangus RS, Tector AJ, Agarwal A, Vianna R, Murdock P, Fridell JA. Comparison of histidine-tryptophanketoglutarate solution (HTK) and University of Wisconsin solution (UW) in adult liver transplantation. Liver

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Transpl. 2006;12(2):226-30. http://dx.doi.org/10.1002/ lt.20552 23. Pêgo-Fernandes PM, Werebe E, Cardoso PF, Pazetti R, de Oliveira KA, Soares PR, et al. Experimental model of isolated lung perfusion in rats: first Brazilian experience using the IL-2 isolated perfused rat or guinea pig lung system. Transplant Proc. 2010;42(2):444-7. http://dx.doi. org/10.1016/j.transproceed.2010.01.016 24. Puskas JD, Cardoso PF, Mayer E, Shi S, Slutsky AS, Patterson GA. Equivalent eighteen-hour lung preservation with low-potassium dextran or Euro-Collins solution after prostaglandin E1 infusion. J Thorac Cardiovasc Surg. 1992;104(1):83-9.

25. Wittwer T, Wahlers T, Fehrenbach A, Cornelius JF, Elki S, Ochs M, et al. Combined use of prostacyclin and higher perfusate temperatures further enhance the superior lung preservation by Celsior solution in the isolated rat lung.

J Heart Lung Transplant. 1999;18(7):684-92. http:// dx.doi.org/10.1016/S1053-2498(98)00061-8 26. Miranda L, Viaro F, Ceneviva R, Evora P. As bases experimentais da lesão por isquemia e reperfusão do fígado. Revisão. Acta Cir Bras. 2004;19(1):3-12.

27. Hengartner MO. The biochemistry of apoptosis.

Nature. 2000;407(6805):770-6. http://dx.doi. org/10.1038/35037710 28. Burns AT, Davies DR, McLaren AJ, Cerundolo L, Morris PJ, Fuggle SV. Apoptosis in ischemia/reperfusion injury of human renal allografts. Transplantation. 1998;66(7):872-6. http://dx.doi.org/10.1097/00007890-199810150-00010 29. Sage E, Mercier O, Van den Eyden F, de Perrot M, Barlier-Mur AM, Dartevelle P, et al. Endothelial cell apoptosis in chronically obstructed and reperfused pulmonary artery. Respir Res. 2008;9:19. http://dx.doi. org/10.1186/1465-9921-9-19 30. Quadri SM, Segall L, de Perrot M, Han B, Edwards V, Jones N, et al. Caspase inhibition improves ischemiareperfusion injury after lung transplantation. Am J Transplant. 2005;5(2):292-9. http://dx.doi. org/10.1111/j.1600-6143.2004.00701.x

An experimental rat model of ex vivo lung perfusion for the assessment of lungs regarding histopathological findings and apoptosis: low-potassium dextran vs. histidine-tryptophan-ketoglutarate

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About the authors Edson Azevedo Simões

Postdoctoral Student in Cardiorespiratory Diseases. University of São Paulo School of Medicine, São Paulo, Brazil.

Paulo Francisco Guerreiro Cardoso

Professor. Thoracic Surgery Section of the Department of Cardiorespiratory Diseases, University of São Paulo School of Medicine, São Paulo, Brazil.

Paulo Manuel Pêgo-Fernandes

Tenured Professor. Department of Cardiorespiratory Diseases, University of São Paulo School of Medicine, São Paulo, Brazil.

Mauro Canzian

Pathologist. Anatomic Pathology Laboratory, University of São Paulo School of Medicine Hospital das Clínicas Instituto do Coração – InCor, Heart Institute – São Paulo, Brazil.

Rogério Pazetti

Researcher I. Laboratório de Investigação Médica 61 (LIM-61, Laboratory for Medical Research 61), specializing in Experimental Thoracic Surgery, University of São Paulo School of Medicine, São Paulo, Brazil.

Karina Andriguetti de Oliveira Braga

Laboratory Specialist. Laboratório de Investigação Médica 61 (LIM-61, Laboratory for Medical Research 61), specializing in Experimental Thoracic Surgery, University of São Paulo School of Medicine, São Paulo, Brazil.

Natalia Aparecida Nepomuceno

Biologist. Laboratório de Investigação Médica 61 (LIM-61, Laboratory for Medical Research 61), specializing in Experimental Thoracic Surgery, University of São Paulo School of Medicine, São Paulo, Brazil.

Fabio Biscegli Jatene

Full Professor. Thoracic Surgery Section of the Department of Cardiorespiratory Diseases, University of São Paulo School of Medicine, São Paulo, Brazil.

J Bras Pneumol. 2012;38(4):461-469

Original Article Anthropometric and dietary intake indicators as predictors of pulmonary function in cystic fibrosis patients* Indicadores antropométricos e de ingestão alimentar como preditores da função pulmonar em pacientes com fibrose cística

Gabriele Carra Forte, Juliane Silva Pereira, Michele Drehmer, Miriam Isabel Souza dos Santos Simon

Abstract Objective: To evaluate whether anthropometric and dietary intake indicators are predictors of pulmonary function in cystic fibrosis (CF) patients. Methods: This was a cross-sectional study involving 69 patients (age range, 5.4-16.5 years) diagnosed with CF under follow-up at the Hospital de Clínicas de Porto Alegre, located in the city of Porto Alegre, Brazil. Anthropometric assessment was based on body mass index (BMI), mid-arm muscle circumference (MAMC), and triceps skinfold thickness (TST). Dietary intake was assessed by using recall data, which were compared with the recommended dietary allowances. Pulmonary function was assessed by ventilatory capacity, expressed as FEV1. Prevalence ratios for the outcome studied (FEV1 < 80% of predicted) were calculated by indicator. Results: In patients with MAMC and TST below the 25th percentile, the prevalence of FEV1 < 80% of predicted was significantly higher than in those with higher MAMC and TST (p < 0.001 and p = 0.011, respectively). In comparison with other patients, those with a BMI below the 50th percentile showed a 4.43 times higher prevalence of FEV1 < 80% of predicted (95% CI: 1.58-12.41), and that prevalence was 2.54 times higher in those colonized with methicillin-resistant Staphylococcus aureus (MRSA) than in those not so colonized (95% CI: 1.43-4.53). The association between dietary intake and the prevalence of FEV 1 < 80% of predicted was of only borderline significance (95% CI: 0.95-3.45). Conclusions: Not being colonized with MRSA and having a BMI above the 50th percentile appear to preserve pulmonary function in CF patients.

Keywords: Cystic fibrosis; Respiratory function tests; Nutrition assessment; Energy intake.

Resumo Objetivo: Avaliar se indicadores antropométricos e de ingestão alimentar são preditores da função pulmonar em pacientes com fibrose cística (FC). Métodos: Estudo transversal com 69 pacientes (variação, 5,4-16,5 anos de idade) diagnosticados com FC e em acompanhamento no Hospital de Clínicas de Porto Alegre, em Porto Alegre (RS). A avaliação antropométrica consistiu nas medidas do índice de massa corpórea (IMC), da circunferência muscular do braço (CMB) e da dobra cutânea tricipital (DCT). A ingestão alimentar foi avaliada pelo recordatório de ingestão habitual e comparada com recommended dietary allowances. A avaliação da função pulmonar foi realizada através da capacidade ventilatória, representada pelo VEF1. Razões de prevalência foram calculadas entre os preditores e o desfecho estudado (VEF1 < 80% do previsto). Resultados: Os pacientes com CMB e DCT abaixo do percentil 25 apresentaram significativamente maior prevalência de VEF1 < 80% do previsto (p < 0,001 e p = 0,011, respectivamente). Os pacientes com IMC menor que o percentil 50 apresentaram 4,43 vezes (IC95%: 1,58 - 12,41) a prevalência de VEF1 < 80% do previsto. Os pacientes colonizados por Staphylococcus aureus resistente a meticilina apresentaram 2,54 vezes (IC95%: 1,43-4,53) a prevalência do desfecho do que os não colonizados. A associação entre consumo calórico e o desfecho estudado apresentou significância limítrofe (IC95%: 0,95-3,45). Conclusões: O IMC superior ao percentil 50 e a ausência de colonização por S. aureus resistente a meticilina apresentaram uma associação direta com função pulmonar preservada em pacientes com FC. Descritores: Fibrose cística; Testes de função respiratória; Avaliação nutricional; Ingestão de energia.

* Study carried out in the Nutrition and Dietary Department, Hospital de Clínicas de Porto Alegre, and at the Center for Food and Nutrition Studies, Porto Alegre, Brazil.

Correspondence to: Miriam Isabel Souza dos Santos Simon. Rua Ramiro Barcelos, 2350, CEP 90035-903, Porto Alegre, RS, Brasil.

Tel. 55 51 3359-8410. E-mail: misantos@hcpa.ufrgs.br Financial support: This study received financial support from the Fundo de Incentivo à Pesquisa (FIPE, Research Incentive Fund) of the Hospital de Clínicas de Porto Alegre.

Submitted: 26 March 2012. Accepted, after review: 4 June 2012.

J Bras Pneumol. 2012;38(4):470-476

Anthropometric and dietary intake indicators as predictors of pulmonary function in cystic fibrosis patients

Introduction Cystic fibrosis (CF) is an autosomal recessive genetic disease that affects various organs and systems, especially the respiratory and digestive tracts.(1) Lung disease is the major factor responsible for morbidity and mortality in CF patients.(2) The chronic malnutrition and the impaired growth observed in CF patients result from an energy deficit, which is due to increased losses, and from the energy expenditure, which exceeds the dietary intake.(3) Anorexia due to respiratory and gastrointestinal complications contributes to the worsening of this profile, leading to reduced energy intake.(4) Adequate dietary intake is essential to maintaining good nutritional status in CF patients, especially when they have pancreatic insufficiency. To that end, it is recommended that there be an intake of 120-150% of the energy requirements of healthy individuals of the same gender and age.(5,6) The nutritional status of the patient has an important relationship with the progression of lung disease, affecting quality of life and survival.(7) Maintaining adequate nutritional status is essential for the integrity of the respiratory system in CF patients.(8,9) Stallings et al.(10) found a direct association between pulmonary function and nutritional status, demonstrating that having a body mass index (BMI) above the 50th percentile is directly associated with having an FEV1 > 80%.

The objective of the present study was to evaluate whether anthropometric and dietary intake indicators are predictors of pulmonary function in CF patients under follow-up at a referral hospital.

Methods This was a cross-sectional study involving 69 children and adolescents diagnosed with CF in accordance with the Cystic Fibrosis Foundation diagnostic criteria.(11) The inclusion criteria were as follows: being ≤ 18 years of age; having a confirmed diagnosis of CF (by genetic testing, sweat testing, or both); having undergone pulmonary function tests; and being under follow-up at the Pediatric Pulmonology Outpatient Clinic of the Hospital de Clínicas de Porto Alegre (HCPA, Porto Alegre Hospital de Clínicas), located in the city of Porto Alegre, Brazil. We excluded patients with pulmonary

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exacerbation. This paper is part of a study that is aimed at validating a nutritional screening tool for CF patients (approved by the Graduate Research Group of the HCPA; Protocol nº. 09637).

Data were collected after written informed consent was obtained during a nutritional consultation, between March and October of 2010. Anthropometric measurements included weight, height, triceps skinfold thickness (TST), and mid-arm muscle circumference (MAMC). The details of the method employed for taking the anthropometric measurements and the assessment of dietary intake (recall data) are described in Pereira et al.(12) We calculated BMI and heightfor-age percentiles, in accordance with the WHO criteria,(13) as well as MAMC and TST percentiles, in accordance with the criteria established by Frisancho.(14) Data on mutation type, bacterial colonization, albumin levels, and pulmonary function—the last two items being related to the last annual checkup—were obtained from online medical records.

Pulmonary function was assessed by spirometric measurements of ventilatory capacity, expressed as FEV1, in the Pulmonology Department of the HCPA. The spirometric technique used followed the Brazilian Thoracic Association Guidelines for Pulmonary Function Testing.(15) Overall disease severity was assessed by the Shwachman-Kulczycki score, obtained by summing the scores for each of four items (general activity, physical examination, nutritional status, and radiological findings), as assessed by the attending physician and the staff nutritionist. After the scoring, the status of the patient was classified from excellent (score, 86-100) to severe (score, ≤ 40).(16) Serum albumin was measured by the bromocresol green method during the annual checkup of the patients, and the results were collected from the medical records. Regarding bacterial colonization, the data extracted from the clinical records and related to sputum samples collected over the preceding 12 months revealed the presence of the following strains: Staphylococcus aureus; methicillin-resistant S. aureus (MRSA); Pseudomonas aeruginosa; mucoid P. aeruginosa; and Burkholderia cepacia.

The outcome analyzed in this study was FEV1 < 80% of predicted, because values above this cut-off point represent preserved pulmonary function. Anthropometric and body composition variables, as well as serum albumin levels, dietary J Bras Pneumol. 2012;38(4):470-476

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intake, and bacterial colonization, were evaluated as possible predictors of this outcome.

Data were analyzed with the Statistical Package for the Social Sciences, version 18.0 for Windows (SPSS Inc., Chicago, IL, USA).

Categorical variables are expressed as absolute and relative frequencies. Sample characteristics represented by categorical variables were tested for associations by Pearson’s chi-square test.

Continuous variables are expressed as mean and standard deviation. In order to compare means, we used the Student’s t-test for independent samples. In order to build the adjusted model, we used Poisson regression with robust variance, progressively including variables showing a value of p < 0.2 in the univariate analysis. Variables with a value of p < 0.05 remained in the final model. The level of significance was set at 5% (p < 0.05).

Results We studied 69 patients (age range, 5.4-16.5 years), 35 (50.7%) of whom were female. Age at diagnosis ranged from 0 years (infants in the neonatal period) to 12 years, the median age being 6 months. Genetic testing was performed in 63 patients (91.3%), of whom 15 (21.7%) were homozygous for the ∆F508 mutation and 32 (46.4%) were heterozygous for the ∆F508 mutation.

Pancreatic insufficiency was present in 63 patients (91.3%), and CF-related diabetes mellitus was present in 2 (2.9%). Only 3 patients (4.3%) in the sample were using enteral nutritional therapy (gastrostomy). Mean Shwachman-Kulczycki scores were satisfactory (> 71.0%) in 55 patients (79.7%). Table 1 shows the characteristics of the sample by nutritional and clinical parameters, as well as by pulmonary function and bacterial colonization data.

Analysis of the sample for the outcome studied revealed that patients with an FEV1 < 80% had concomitant lower nutritional parameters (Table 2). Patients with preserved pulmonary function (FEV1 > 80%) were, on average, 2.8 years younger than were those with an FEV1 < 80%.

Patients with more severe pulmonary impairment had lower mean serum albumin levels, although their serum albumin levels were within the normal range. With regard to dietary intake, we found that, on average, patients with an FEV1 < 80% did not meet the CF dietary recommendation of J Bras Pneumol. 2012;38(4):470-476

> 120% of the recommended dietary allowance (RDA).

Analysis of body composition as a predictor of FEV1 demonstrated that, in patients with MAMC and TST below the 25th percentile, the prevalence of FEV1 < 80% was significantly higher than in those with higher MAMC and TST (p < 0.001 and p = 0.011, respectively). Analysis of bacterial colonization revealed no statistically significant differences among colonized patients in terms of FEV1 < 80%, except for those colonized with MRSA, in whom the prevalence of FEV1 < 80% was higher (p = 0.017).

Patients with a BMI below the 50th percentile showed a 4.43 times higher prevalence of FEV1 < 80% than did those with a BMI above the 50th percentile, the model being adjusted for age, %RDA < 120%, albumin, height-for-age percentile, MAMC < the 25th percentile, TST < the 25th percentile, and colonization with MRSA (Table 3). Colonization with MRSA was significantly associated with the outcome studied.

The prevalence of FEV1 < 80% was 2.54 times higher in those colonized with MRSA than in those not so colonized, the model being adjusted for the other predictor variables. The association between dietary intake and pulmonary function was of only borderline significance.

Discussion The results of the present study support the recommendations in the literature, i.e., anthropometric measurements above the 50th percentile as a protective factor against pulmonary impairment in CF patients.(10) In addition, colonization with MRSA, which is a cause for concern among CF patients in Brazil, was found to be likewise associated with pulmonary impairment.

Our sample was found to be in good nutritional and clinical status, the values for these parameters being similar to those found in CF referral centers in developed countries.(17) The mean BMI percentile found in the present study was similar to that reported by the Cystic Fibrosis Foundation, i.e., 48.7.(17) The mean FEV1 found in our sample was equivalent to that used for classifying lung disease as mild, being similar to the mean FEV1 in the USA (76.3%); the median diagnosis was also similar.(17) Analysis of the nutritional parameters, compared with the outcome studied (FEV1 < 80%

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Table 1 - Clinical, nutritional, and laboratory data for the cystic fibrosis patients included in the study.

Nutritional indicators Resultsa BMI, percentile 45.41 ± 29.36 51.37 ± 28.01 Weight-for-age, percentileb Height-for-age, percentile 47.47 ± 27.49 MAMC < p5 4 (5.8) MAMC > p25 17 (24.6) TST < p5 3 (4.3) TST > p25 23 (33.3) 4.34 ± 0.39 Serum albumin, g/dLc Dietary intake indicators RDA, % 126.45 ± 28.88 Carbohydrates, % 50.55 ± 7.19 Proteins, % 16.17 ± 3.25 Lipids, % 32.55 ± 6.10 Pulmonary function 88.23 ± 21.52 FEV1, % of predicted Pulmonary colonization Staphylococcus aureus 32 (46.4) 5 (7.2) Methicillin-resistant Staphylococcus aureus Pseudomonas aeruginosa 15 (21.7) 9 (13.0) Mucoid Pseudomonas aeruginosa Burkholderia cepacia 11 (15.9) 82.60 ± 11.47 Shwachman-Kulczycki scorec BMI: body mass index; MAMC: mid-arm muscle circumference; p5: 5th percentile; p25: 25th percentile; TST: triceps skinfold thickness. RDA: recommended dietary allowance. aValues expressed as mean ± SD or as n (%). bn = 25. cn = 68.

Table 2 - Nutritional and pulmonary function parameters for the cystic fibrosis patients included in the study.a Groups Parameter p FEV1 ≥ 80% of predicted FEV1 < 80% of predicted Age, years BMI, percentile Height-for-age, percentile Serum albumin, g/dL RDA, %

12.26 ± 3.04 26.50 ± 18.02 36.14 ± 26.74 4.11 ± 0.46 115.52 ± 22.18

9.42 ± 4.20 54.29 ± 28.96 51.84 ± 27.01 4.41 ± 0.35 138.64 ± 38.48

0.005 < 0.001 0.055 0.003 0.01

BMI: body mass index; and RDA: recommended dietary allowance. aData expressed as mean ± SD.

of predicted), demonstrated that BMI, height, and %RDA values were low in our study sample.

Patients with an FEV1 > 80% had concomitant mean BMI and height percentiles above the 50th percentile, whereas patients with an FEV1 < 80% had mean BMI percentiles close to the cut-off point for nutritional risk for CF patients (BMI < the 25th percentile). Chaves et al. found a statistically significant association of BMI and TST with the degree of pulmonary impairment (FEV1 < 70%).(18) Patients with an FEV1 < 80% had a dietary intake that was lower than that recommended for CF patients, unlike patients with better pulmonary function values, who met the nutritional

recommendations for CF patients. Simon et al.

(19) demonstrated that 51.7% of CF patients met the recommendations of 120% of the RDA and that those patients had a median BMI percentile of 56, whereas the patients whose intake was below the recommendations had a median BMI percentile of 34.9. In another study, which assessed dietary intake in a group of CF patients in the 6-9 year age bracket, the median dietary intake was 115% of the RDA, and only 39% met the dietary recommendations.(20) In the present study, patients with a lower mean age had preserved pulmonary function (FEV1 > 80%); this finding is in agreement with J Bras Pneumol. 2012;38(4):470-476

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Table 3 - Final Poisson regression model of the association of nutritional and clinical predictors with the outcome studied.a Predictor PR 95% CI BMI < the 50th percentile 4.43 1.58-12.41 RDA < 120% 1.81 0.95-3.45 Colonization with MRSA 2.54 1.43-4.53 PR: prevalence ratio; BMI: body mass index; RDA: recommended dietary allowance; and MRSA: methicillinresistant Staphylococcus aureus. aModel adjusted for age, albumin, height-for-age percentile, mid-arm muscle circumference < the 25th percentile, and triceps skinfold thickness < the 25th percentile.

the literature, which indicates that FEV1 decreases with age, especially from adolescence onward.(10,17) Döring et al.(21) reported a progressive reduction in pulmonary function in CF patients, at an estimated rate of 1-2% per year; however, it is clear that this rate can vary according to the frequency and severity of pulmonary exacerbations.

Despite being within the normal range, albumin levels were significantly different in the group of patients with an FEV1 < 80%. Albumin is a potent antioxidant that can be essential for maintaining pulmonary glutathione levels(22,23) and has been related to lung disease severity, the prognosis for CF patients being consequently poorer.(24,25) Analysis of body composition in this group revealed that patients with worse pulmonary function values had a concomitant higher prevalence of muscle mass and fat mass below the 25th percentile. Pedreira et al.(26) found a positive association between lean body mass and FEV1 in CF patients in the 7-17 year age bracket.

The indicator of nutritional status used in the final model, i.e., a BMI < the 50th percentile, was found to be a strong predictor of pulmonary function in CF patients, meaning that these patients showed a nearly five times higher prevalence of FEV1 < 80% in comparison with those with a BMI > the 50th percentile. Stallings et al.

(10) showed that having an FEV1 close to or higher than 80% was directly associated with having a BMI ≥ the 50th percentile.

The outcome analyzed in this study, however, cannot be explained solely by impaired nutritional status. Dietary intake and bacterial colonization are other factors that affect the outcome studied.

Poisson regression analysis with robust variance, adjusted for age, BMI percentile, albumin levels, J Bras Pneumol. 2012;38(4):470-476

height-for-age percentile, MAMC < the 25th percentile, TST < the 25th percentile, and colonization with MRSA, revealed that a dietary intake of less than 120% of the RDA was of borderline significance in predicting deterioration of pulmonary function. This was due to low sample power. However, colonization with MRSA was found to be strongly associated with the outcome studied. Dasenbrook et al.(27) observed an association between colonization with MRSA and poorer survival in CF patients. Among patients colonized with MRSA, the mortality rate was 27.7 deaths per 1,000 patient-years, whereas, among those not so colonized, the mortality rate was 18.3 deaths per 1,000 patient-years. The attributable risk percentage of death associated with MRSA was 34%.

The limitations of the present study are related to its cross-sectional design, which does not allow us to establish a causal relationship, meaning that the association between the factors studied and the prevalence of FEV1 < 80% of predicted might be subject to reverse causality. The association between adequacy of dietary intake and the outcome studied was not significant, because of a lack of study power. In this case, we would need a minimum of 100 patients per category of dietary adequacy (RDA) in order to detect an association with the outcome studied.

The present study sample has a power of only 28% to measure this association. However, the present study is relevant because findings in CF patients in Brazil corroborated those in CF patients worldwide and because it underscores the importance of effective nutritional care and prevention of MRSA colonization.

The present study allows us to conclude that having a BMI above the 50th percentile and not being colonized with MRSA appear to preserve pulmonary function in CF patients.

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20. Schall JI, Bentley T, Stallings VA. Meal patterns, dietary fat intake and pancreatic enzyme use in preadolescent children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2006;43(5):651-9. http://dx.doi.org/10.1097/01. mpg.0000234082.47884.d9 21. Döring G, Hoiby N; Consensus Study Group.

Early intervention and prevention of lung disease in cystic fibrosis: a European consensus. J Cyst Fibros. 2004;3(2):67‑91. http://dx.doi.org/10.1016/j. jcf.2004.03.008 22. Winklhofer-Roob BM. Cystic fibrosis: nutritional status and micronutrients. Curr Opin Clin Nutr Metab Care. 2000;3(4):293-7. http://dx.doi. org/10.1097/00075197-200007000-00009 23. Cantin AM. Bafilomycin A1, an inhibitor of vascular proton ATPase, suppresses glutathione synthesis in lung epithelial cells. Pediatr Pulmonol. 1999;19(Suppl):A307.

24. Abman SH, Reardon MC, Accurso FJ, Hammond KB, Sokol RJ. Hypoalbuminemia at diagnosis as a marker for severe respiratory course in infants with cystic fibrosis identified by newborn screening. J Pediatr. 1985;107(6):933-5. http://dx.doi.org/10.1016/S0022-3476(85)80194-3 25. Aurora P, Wade A, Whitmore P, Whitehead B. A model for predicting life expectancy of children with cystic fibrosis. Eur Respir J. 2000;16(6):1056-60. http://dx.doi. org/10.1034/j.1399-3003.2000.16f06.x 26. Pedreira CC, Robert RG, Dalton V, Oliver MR, Carlin JB, Robinson P, et al. Association of body composition and lung function in children with cystic fibrosis. Pediatr Pulmonol. 2005;39(3):276-80. http://dx.doi.org/10.1002/ ppul.20162 27. Dasenbrook EC, Checkley W, Merlo CA, Konstan MW, Lechtzin N, Boyle MP. Association between respiratory tract methicillin-resistant Staphylococcus aureus and survival in cystic fibrosis. JAMA. 2010;303(23):2386-92.

J Bras Pneumol. 2012;38(4):470-476

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Forte GC, Pereira JS, Drehmer M, Simon MISS

About the authors Gabriele Carra Forte

Graduate Student. Graduate Program in Pulmonology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.

Juliane Silva Pereira

Nutritionist. Federal University of Rio Grande do Sul, Porto Alegre, Brazil.

Michele Drehmer

Adjunct Professor. Department of Social Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.

Miriam Isabel Souza dos Santos Simon

Nutritionist. Hospital de ClĂ­nicas de Porto Alegre, Porto Alegre, Brazil.

J Bras Pneumol. 2012;38(4):470-476

Original Article Manual hyperinflation combined with expiratory rib cage compression for reduction of length of ICU stay in critically ill patients on mechanical ventilation*,** Hiperinsuflação manual combinada com compressão torácica expiratória para redução do período de internação em UTI em pacientes críticos sob ventilação mecânica

Juliana Savini Wey Berti, Elisiane Tonon, Carlos Fernando Ronchi, Heloisa Wey Berti, Laércio Martins de Stefano, Ana Lúcia Gut, Carlos Roberto Padovani, Ana Lucia Anjos Ferreira

Abstract Objective: Although manual hyperinflation (MH) is widely used for pulmonary secretion clearance, there is no evidence to support its routine use in clinical practice. Our objective was to evaluate the effect that MH combined with expiratory rib cage compression (ERCC) has on the length of ICU stay and duration of mechanical ventilation (MV). Methods: This was a prospective randomized controlled clinical trial involving ICU patients on MV at a tertiary care teaching hospital between January of 2004 and January of 2005. Among the 49 patients who met the study criteria, 24 and 25 were randomly assigned to the respiratory physiotherapy (RP) and control groups, respectively. Of those same patients, 6 and 8, respectively, were later withdrawn from the study. During the 5-day observation period, the RP patients received MH combined with ERCC, whereas the control patients received standard nursing care. Results: The two groups were similar in terms of the baseline characteristics.

The intervention had a positive effect on the duration of MV, as well as on the ICU discharge rate and Murray score. There were significant differences between the control and RP groups regarding the weaning success rate on days 2 (0.0% vs. 37.5%), 3 (0.0% vs. 37.5%), 4 (5.3% vs. 37.5%), and 5 (15.9% vs. 37.5%), as well as regarding the ICU discharge rate on days 3 (0% vs. 25%), 4 (0% vs. 31%), and 5 (0% vs. 31%). In the RP group, there was a significant improvement in the Murray score on day 5. Conclusions: Our results show that the use of MH combined with ERCC for 5 days accelerated the weaning process and ICU discharge.

Keywords: Physical therapy modalities; Ventilator weaning; Length of stay.

Resumo Objetivo: Embora a hiperinsuflação manual (HM) seja largamente usada para a remoção de secreções pulmonares, não há evidências para sua recomendação como rotina na prática clínica. O objetivo do estudo foi avaliar o efeito da HM combinada com compressão torácica expiratória (CTE) na duração de internação em UTI e no tempo de ventilação mecânica (VM) em pacientes sob VM. Métodos: Ensaio clínico prospectivo, randomizado e controlado com pacientes de UTI sob VM em um hospital acadêmico terciário entre janeiro de 2004 e janeiro de 2005. Dentre os 49 pacientes que preencheram os critérios do estudo, 24 e 25 foram randomicamente alocados nos grupos fisioterapia respiratória (FR) e controle, respectivamente, sendo que 6 e 8 foram retirados do estudo. Durante o período de observação de 5 dias, os pacientes do grupo FR receberam HM combinada com CTE, enquanto os controles receberam o tratamento padrão de enfermagem. Resultados: Os dois grupos apresentaram características basais semelhantes. A intervenção teve efeito positivo na duração de VM, alta da UTI e escore de Murray. Houve diferenças significativas entre os grupos controle e FR em relação à taxa de sucesso no desmame nos dias 2 (0,0% vs. 37,5%), 3 (0,0% vs. 37,5%), 4 (5,3 vs. 37,5%) e 5 (15,9% vs. 37,5%), assim como à taxa de alta da UTI nos dias 3 (0% vs. 25%), 4 (0% vs. 31%) e 5 (0% vs. 31%). No grupo FR, houve uma melhora significante no escore de Murray no dia 5. Conclusões: Nossos resultados mostraram que o uso combinado de HM e CTE por 5 dias acelerou o processo de desmame e de alta da UTI. Descritores: Modalidades de fisioterapia; Desmame do respirador; Tempo de internação. * Study carried out at the Botucatu Hospital das Clínicas, Botucatu School of Medicine, São Paulo State University, Botucatu, Brazil.

Correspondence to: Carlos Fernando Ronchi. Departamento de Clínica Médica, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista Júlio de Mesquita Filho, CEP 18618-970, Botucatu, SP, Brasil.

Tel. 55 14 3880-1171; Fax: 55 14 3882-2238. E-mail: fernando.ronchi@yahoo.com.br Financial support: This study received financial support from the Fundação para o Desenvolvimento da Universidade Estadual Paulista (FUNDUNESP, Foundation for the Development of the São Paulo State University, Process no. 884/03-DFP) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Office for the Advancement of Higher Education).

Submitted: 3 November 2011. Accepted, after review: 10 May 2012. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

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Introduction Mechanical ventilation (MV) and the consequent pulmonary secretion retention(1) are major risk factors associated with prolonged ICU stay and mortality in critically ill patients. Certain strategies, such as chest physiotherapy, can improve secretion clearance and prevent pulmonary complications,(2) therefore potentially reducing the length of ICU stay. Early ICU discharge is particularly relevant in public hospitals in developing countries, where there are financial restraints.

Various respiratory physiotherapy techniques, such as mobilization, manual hyperinflation (MH), percussion, and vibrations, are used in patients on MV. It has been shown that the use of respiratory physiotherapy techniques can reduce pulmonary secretion retention,(1,3) as well as improving dynamic compliance(4) and static compliance.(5,6) One of a number of respiratory physiotherapy techniques, MH is commonly used by physiotherapists in patients receiving MV.(5) Originally called “bag squeezing”, MH consists of a series of deep breaths with a three-second inspiratory pause combined with expiratory rib cage compression (ERCC) and suctioning.(7) Although MH has been shown to have a positive effect on airway secretion clearance,(2,5,8) atelectasis,(8) and alveolar recruitment,(7,9) there is moderate evidence that MH has a short-lived beneficial effect on respiratory function.(10) The absence of more convincing evidence might be due to the lack of studies evaluating the effectiveness of MH in terms of the abovementioned variables(2,11,12) or to inconsistent definitions of MH across studies.

Procedures either including or excluding the ERCC step are equally referred to as MH. In fact, some studies(5,9,13) do not clearly state whether the ERCC step was included in the MH procedure.

Although chest physiotherapy plays an important role in the multidisciplinary approach to patients in most ICUs, there is very limited or no evidence that chest physiotherapy facilitates weaning from MV, reduces the length of ICU stay, and reduces mortality.(10) There is only one study examining the effectiveness of MH (without the ERCC step) and taking those variables into consideration.(11) Because there is a lack of evidence to support the use of MH in clinical practice, we aimed to investigate whether MH, combined with ERCC after percussion and applied twice a day for five days, could shorten the length of ICU stay and the duration of MV in patients on MV. J Bras Pneumol. 2012;38(4):477-486

Other outcomes assessed included the extent of lung damage and disease severity.

Methods This was a prospective randomized controlled clinical trial conducted between January of 2004 and January of 2005 and involving patients admitted to the 9-bed ICU of the emergency room (ER) of a 450-bed tertiary care teaching hospital. The study project was approved by the local research ethics committee (Protocol no. 448/2002).

All of the patients or their legal guardians gave written informed consent, in compliance with the Helsinki Declaration. Consecutive adult patients in the ER were eligible for inclusion in the study if they had been endotracheally intubated and mechanically ventilated for 24-72 h.

Exclusion criteria were as follows: age < 18 years; length of ICU/ER stay ≤ 24 h; referral to another ICU; positive end-expiratory pressure (PEEP) > 8 cmH2O; severe asthma; ARDS; invasive bronchoscopic procedure; pneumothorax or a history of pneumothorax; chest tube drainage; chest trauma; brain swelling, raised intracranial pressure, or the potential to develop pathologically raised intracranial pressure; unstable cardiovascular status (defined as systolic blood pressure < 100 mmHg or > 180 mmHg, mean arterial pressure < 70 mmHg or > 110 mmHg, or HR < 70 bpm or > 120 bpm) on inotropic support; obesity; spinal cord injury; and do-notresuscitate status.

All of the patients were placed on a mechanical ventilator (Monterey model; Takaoka, São Paulo, Brazil) set to a tidal volume of 7 mL/kg of body weight and assist-control ventilation or synchronized intermittent mandatory ventilation.

All ventilatory parameters were routinely audited and adjusted as needed (FiO2, tidal volume, and PEEP). The patients who were successfully discharged from the ER/ICU were followed until postadmission day 30.

The patients were randomly assigned either to the usual treatment (control) group or to the respiratory physiotherapy (RP) group. The randomization process was performed daily for 13 consecutive months by means of a computer-generated random sequence. Allocation concealment was successful. The physicians who treated the patients had no influence on patient eligibility or allocation. The participants

Manual hyperinflation combined with expiratory rib cage compression for reduction of length of ICU stay in critically ill patients on mechanical ventilation

were analyzed in the groups to which they were randomly assigned.

The patients assigned to the control group received standard nursing care, which consisted of positioning (i.e., changing the body position every two hours throughout the day) and airway suctioning. Airway suctioning included disconnecting the patient from the ventilator, followed by tracheal instillation of 1 mL of saline solution,(13,14) four sets of six cycles being performed with a manual resuscitation bag (Adult Lifesaver Manual Resuscitator; Hudson RCI, Temecula, CA, USA) in order to ventilate patients with 100% oxygen (flow rate = 15 L/min) and airway suctioning being performed for 15 s in order to remove secretions. This procedure was performed six times a day. The patients assigned to the RP group received the same treatment as did those in the control group, although they did so only four times a day. They also received respiratory physiotherapy twice a day, i.e., percussion in alternate side-lying positions (10 min each), followed by MH combined with ERCC. Initially, percussion was performed manually by clapping the chest wall, the head of the bed being in a horizontal position. The patients were returned to the supine position and received 1 mL of saline solution (via the endotracheal tube), MH being subsequently performed. The first step of MH consisted of a three-second pause at the end of the inspiratory phase,(11) followed by a quick release; as soon as the expiratory phase started, ERCC was manually applied (without vibration) to both hemithoraces. This step consisted of four sets of six MH breaths combined with six ERCC maneuvers (using the palms of both hands toward the sternum).(7) The MH technique involved disconnecting the patients from the ventilator and was performed with a 2.0-L reusable manual resuscitation bag (Hudson RCI) connected to a flow of 100% oxygen at 15 L/min (calibrated with an oxygen analyzer). In order to maximize lung volume, a pressure manometer (Child Lifesaver Manual Resuscitator; Hudson RCI) was connected to the manual resuscitation bag, and each inflation was delivered to a peak airway pressure of 40 cmH2O.(5,11,15) Finally, tracheal suctioning was applied for 15 s after each set of MH breaths. Exhaled and inhaled tidal volumes were not measured. Percussion and ERCC were performed by a physiotherapist, whereas MH and suctioning were performed by a nurse. The

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same nurse and the same physiotherapist, who were not blinded to the intervention allocation, performed the maneuvers in all of the patients in the RP group.

The study was conducted during the routine treatment of other patients in the ER/ICU, where the enrolled patients were followed for 5 days. No adverse events occurred during or after each physiotherapy intervention in any of the participants. No hemodynamic, respiratory, or neurological changes were observed during the observation period. Weaning from MV was initiated after the patients had achieved general, hemodynamic, neurological, and respiratory stability (temperature < 38°C; pH < 7.6 or > 7.3; mean arterial pressure > 70 mmHg or < 110 mmHg; no hemodynamic support; HR > 70 bpm or < 130 bpm; Glasgow coma scale score > 8; PaO2/FiO2 > 200; and RR < 25 breaths/min). The weaning process involved the use of a T-piece with an FiO2 ≤ 50%. It started with 15 min/h, and the frequency was increased until patients had been completely weaned from MV on the basis of their hemodynamic, neurological, and respiratory status. The respiratory physiotherapy interventions were monitored by SpO2, HR, and electrocardiography immediately before, during, and after each intervention.

After all of the patients had been weaned from MV and disconnected from the endotracheal tube, they received respiratory physiotherapy consisting of percussion followed by airway clearance—either by coughing (if the patient was able to) or by suctioning—until the fifth day of treatment.

The patients who were excluded or withdrawn from the study received standard nursing care, which consisted of positioning (i.e., changing the body position every two hours throughout the day) and airway suctioning.

The outcome measures were assessed daily by the same physiotherapist. The patients were evaluated in the supine position, in which ventilatory parameters, SaO2, arterial blood pressure, temperature, HR, pulmonary auscultation findings, chest expansion, and chest X-ray findings were recorded.

The primary outcome measures were ICU/ER discharge and weaning success. Endpoints related to ICU/ER discharge and weaning success were assessed daily throughout the 5-day observation period. Secondary outcome measures included J Bras Pneumol. 2012;38(4):477-486

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30-day mortality, Murray score,(16) Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and Charlson comorbidity index (CCI).(18) The Murray score (weight range, 0 to > 2.5) is used in order to characterize the presence and extent of lung damage(16) and was calculated on the first and fifth days of observation. Although APACHE II is a conventional clinical model to predict mortality in ICU patients,(17) it incorporates fewer comorbid conditions than does the CCI. The APACHE II score was calculated on the first and fifth days of observation. The CCI(18) is a comorbidity index that predicts the prognosis of critically ill patients(19) and was calculated with the original method and weights (weight range, 1-6) for 18 comorbid conditions plus the age of the patient. Each decade over 40 years of age adds one point to the score.(18) A power calculation performed a priori indicated that 19 patients per group would provide a power of 80% with a type I error of 0.05 to detect a difference of 45% as the minimum significant difference between the groups in terms success rates.(20) Success was defined as weaning from MV or ICU/ER discharge over the 5-day observation period. The results are expressed as medians and interquartile ranges.

The significance of the differences between the groups regarding baseline characteristics was determined by the Mann-Whitney U test (age and CCI), the Goodman test (gender, diagnosis, and ventilatory parameters), or ANOVA (APACHE II and Murray scores). For the evaluation of the effect of the 5-day treatment on the APACHE II and Murray scores, a nonparametric repeated measures ANOVA was used in order to compare the differences between two time points (days 1 and 5) in the same group and between the two groups on the same day.(21) The discharge and weaning success rates were also analyzed every day during the observation period by means of the Goodman test. The Goodman test was also used in order to compare proportional differences between the groups regarding 30-day mortality.

(22) The normality of the data was tested with the Kolmogorov-Smirnov test. Statistical significance was set at p < 0.05.

Results Of the 472 enrolled patients, 397 (84%) were hospitalized for respiratory failure, and 235 were intubated and kept on MV. Of the 235 patients, J Bras Pneumol. 2012;38(4):477-486

186 were excluded on the basis of the study criteria. Of the 49 remaining patients, 24 and 25 were randomly assigned to the RP and control groups, respectively. During the study period, 6 and 8 patients in the RP and control groups, respectively, were withdrawn from the study for several reasons, 16 and 19 patients having therefore completed the study in their respective groups (Figure 1).

The use of MV was based on two or more indications in 15 (79%) and 12 (75%) of the patients in the control and RP groups, respectively, and pulmonary disease associated with another event (or disease) was found in 10 (53%) and 11 (69%) of the patients (Table 1).

There were no significant differences between the groups regarding age, gender, Murray score, APACHE II score, and CCI. As for MV parameters, no significant differences were found between the RP and control groups regarding the need for synchronized intermittent mandatory ventilation (21% vs. 50%) or PEEP ≤ 5 cmH2O (89% vs.

94%). However, the use of FiO2 < 50% was more common in the RP group than in the control group (88% vs. 58%; Table 2).

The duration of MV was shorter in the RP group than in the control group from day 2 on, when 37.5% of the RP patients had already been weaned and disconnected from the endotracheal tube. Statistical analyses identified differences between the groups on days 2 and 3 (p < 0.01 for both), as well as on days 4 and 5 (p < 0.05 for both). Similarly, the length of ICU stay was shorter in the RP group than in the control group from day 3 on, when 25% of the RP individuals (p < 0.05) had already been discharged from the ICU. This proportion increased to 31% on days 4 and 5 (p < 0.01). It must be emphasized that none of the patients in the control group were discharged from the ICU before day 5.

After the removal of the endotracheal tube, all of the patients were submitted to FiO2 ≤ 30% via a Venturi mask. In either group, none of the patients needed reintubation. Chest physiotherapy had no effect on the evolution of APACHE II scores. Murray scores were lower on day 5 than on day 1 in both groups, the scores on day 5 being significantly lower in the RP group than in the control group (p < 0.01; Table 3). Between days 1 and 5, there were no deaths in either group.

There was no significant difference between the

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Figure 1 - Flowchart of patient inclusion. PEEP: positive end-expiratory pressure.

control and RP groups regarding the 30-day mortality rate (26% vs. 19%).

Discussion The present randomized controlled trial showed that the use of simple techniques, performed twice a day for 5 days, improved weaning from MV, as well as reducing the duration of ICU stay and the extent of lung injury in ICU patients.

We used a combination of percussion, clearance, MH (combined with ERCC), and suctioning, the technique being performed twice a day. Few studies(4,23) have examined the effect of percussion on intubated patients, having shown improvement(4) or no significant pulmonary function changes.

(23) However, uncontrolled studies have reported that percussion is ineffective.(23) Although MH is widely used in order to remove pulmonary secretions and treat atelectasis,(24) there is no evidence to support its routine use in clinical

practice.(10) This lack of evidence is due, in part, to the scarcity of studies(2,11,12) examining the clinical relevance and efficacy of MH and to the maneuver itself. Procedures either including or excluding the ERCC step are equally referred to as MH. In addition, some studies(5,9,13) do not clearly state whether the ERCC step was included in the MH procedure. We included the ERCC step because we decided to use the maneuver as it was originally described(7) and because the ERCC step has proven effective in improving secretion clearance,(4,25) alveolar recruitment,(7) atelectasis,(25) and alveolar ventilation.(26) To our knowledge, the only study in which MH was reported to have a positive effect on weaning from MV, length of ICU stay, and mortality in patients on MV was a study by Ntoumenopoulos et al.,(11) who conducted a similar study using postural drainage, MH (without ERCC), and suctioning twice a day throughout the ICU stay of the patients. No J Bras Pneumol. 2012;38(4):477-486

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Table 1 - Characteristics of the patients included in the groups studied.

Control group RP group ID/age, years/gender Diagnosis ID/age, years/gender Diagnosis 1/53/M pp-BT 1/36/M pp-BT 2/54/M CIS 2/61/M pp-TCE; pneumonia 3/67/M Septic shock; pneumonia 3/24/M pp-TCE; pneumonia 4/19/M Head trauma 4/67/M Pneumonia 5/50/M pp-CIS 5/56/F Pesticide intoxication 6/55/M pp-SAH 6/59/F Head trauma; septic shock; pneumonia 7/66/M CIS 7/44/F pp-CAC; pneumonia 8/56/F CPE; pneumonia 8/72/M Status epilepticus; pneumonia 9/80/F Septic shock; pneumonia 9/61/M Status epilepticus; pneumonia 10/83/F Pulmonary embolism; 10/71/M Cardiac arrest; pneumonia digitalis intoxication 11/49/M pp-GI 11/63/M pp-CIS; pneumonia 12/78/F Septic shock; pneumonia 12/66/M pp-CIS; pneumonia 13/58/F Cardiogenic shock; pneumonia 13/73/M Head trauma; pneumonia 14/44/M CIS; pneumonia 14/48/F pp-GI; CPE; pneumonia 15/47/M pp-CIS; pneumonia 15/70/F Pneumonia 16/23/M pp-TCE; pneumonia 16/58/F Pneumonia 17/73/M CPE 18/46/F CPE; pneumonia 19/52/M pp-TCE RP: respiratory physiotherapy; ID: patient identification; M: male; F: female; pp: postoperative period; BT: brain tumor; CIS: cerebral ischemic stroke; TCE: traumatic cerebral edema; SAH: subarachnoid hemorrhage; CAC: cerebral aneurysm clipping; CPE: cardiogenic pulmonary edema; and GI: gastrointestinal surgery.

Table 2 - Baseline demographic characteristics of the participants in the groups studied.

Group Variables RP Control Age, yearsa 58.06 ± 13.81 55.42 ± 16.99 63/37 68/32 Gender, M/Fb 69 53 Comorbidityb a 15.81 ± 4.29 17.21 ± 7.47 APACHE II score 2.75 ± 2.57 2.32 ± 2.03 CCIa 1.04 ± 0.44 1.04 ± 0.48 Murray scorea 50 21 SIMV modeb 94 89 PEEP ≤ 5 cmH2Ob 88 58 FiO2 < 50%b

p > 0.05* > 0.05** > 0.05** > 0.05* > 0.05* > 0.05* > 0.05** > 0.05** < 0.01**

RP: respiratory physiotherapy group; M: male; F: female; Comorbidity: pulmonary disease (pneumonia, pulmonary embolism, or cardiogenic pulmonary edema) associated with another disease or event; APACHE II: Acute Physiology and Chronic Health Evaluation II; CCI: Charlson comorbidity index; SIMV: synchronized intermittent mandatory ventilation; and PEEP: positive end-expiratory pressure. aValues expressed as mean ± SD. bValues expressed as % of patients. *Student’s t-test. **Goodman test.

significant differences were found between the control and study groups regarding the length of ICU stay (6.8 days vs. 7.4 days), duration of MV (5.2 days vs. 6.1 days), or ICU mortality (0% for both) in trauma patients.(11) The replacement of MH by a vibration step did not improve those variables in a nonrandomized study involving

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patients with ventilator-associated pneumonia.

(2) Although those studies(2,11) did not compare the techniques in the same population, their results indicate that neither MH nor vibration was effective in patients on MV when individually applied. In a previous study involving patients in whom MH was used in combination with

C (n = 19) 1 (5.3)* 0 (0.0)**

5 RP C (n = 16) (n = 19) 6 (37.5) 3 (15.9)* 5 (31.0) 0 (0.0)** 0.00 [0.00-0.00] 1.00 [1.00-1.00]**** 16 [8-21] 16 [11-21]

disease severity scores.

RP: respiratory physiotherapy group; C: control group; and APACHE II: Acute Physiology and Chronic Health Evaluation II. aValues expressed as n (%) of patients. The Goodman test was used in order to compare the differences between the groups on the same day (*p < 0.05; **p < 0.01). bValues expressed as median [interquartile range]. Nonparametric repeated measures ANOVA was used in order to compare the differences between days 1 and 5 in the same group (***p = 0.01; *p < 0.05) and the differences between the groups on the same day (****p = 0.01).

Table 3 - Effect of the 5-day respiratory physiotherapy on weaning from mechanical ventilation, ICU discharge, and Day 1 2 3 4 Variable RP C RP C RP C RP (n = 16) (n = 19) (n = 16) (n = 19) (n = 16) (n = 19) (n = 16) Weaninga 0 (0.0) 0 (0.0) 6 (37.5) 0 (0.0)** 6 (37.5) 0 (0.0)** 6 (37.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 4 (25.0) 0 (0.0)* 5 (31.0) Dischargea 1.00 [0.75-1.25]*** 1.25 [1.00-1.50]* Murray scoreb 17 [14-18] 16 [12-20] APACHE II scoreb

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several respiratory physiotherapy techniques, including ERCC,(12) the length of ICU stay and the duration of MV were similar in the study and control groups. However, the proportion of smokers and that of patients with higher disease severity index scores were higher in the study group than in the control group, which might have interfered with the results. Using a different hyperinflation technique (i.e., ventilatorinduced hyperinflation), a recent study showed an improvement in secretion clearance and static compliance of the respiratory system in patients on pressure support ventilation.(27) In the RP group, the improvement in lung injury, as measured by the Murray score, was not followed by an improvement in disease severity, as measured by the APACHE II score.

Although previous studies have employed the Murray score(28) and the APACHE II(2,3,29) score, the effect of respiratory physiotherapy interventions on those indexes was not evaluated, further comparisons being therefore impossible. The present study showed that although the Murray scores improved in both groups, the proportion of patients who were successfully weaned from MV and discharged from the ICU on day 5 was higher in the RP group than in the control group (37.5% vs. 15.9% and 31% vs. 0%, respectively).

One cohort study of comorbidities in the ICU found that the mortality rate was lower in study group patients with a CCI of 2 than in control group patients with the same CCI (12.5% vs.

26.0%), although there was no difference between the two groups regarding 30-day mortality.(19) The randomization process allowed the formation of homogeneous groups regarding most of the baseline characteristics, including age,(30) gender,(1,5,25) and diagnosis.(1,25) In our study, these characteristics represent the common profile of general ICU patients. The median baseline CCI (2 in both groups) and APACHE II scores (16 and 17 in the control and RP groups, respectively) found in the present study were consistent with those reported in previous studies of critically ill patients.(2,29,30) However, the baseline Murray scores (1.25 and 1.00 in the control and RP groups, respectively) were lower in the present study than in another study of patients on MV.(28) Our study has some limitations, such as the small sample size. Although the number of patients in the present study was small, our data showed that the power of the study was 0.8, J Bras Pneumol. 2012;38(4):477-486

the effect size for ICU discharge or successful weaning from MV being greater than 0.45.

Another limitation is that the study was not blind. The interventions were performed by the only physiotherapist available. Therefore, it was impossible to conduct a blind study.

In summary, the present study demonstrated that the use of MH in combination with ERCC in patients on MV accelerates the weaning process, as well as reducing the extent of lung injury and the length of ICU stay. Further studies evaluating the effectiveness of chest physiotherapy in ICU patients on MV can provide additional evidence.

References 1. Berney S, Denehy L, Pretto J. Head-down tilt and manual hyperinflation enhance sputum clearance in patients who are intubated and ventilated. Aust J Physiother. 2004;50(1):9-14. PMid:14987187.

2. Ntoumenopoulos G, Presneill JJ, McElholum M, Cade JF. Chest physiotherapy for the prevention of ventilator-associated pneumonia. Intensive Care Med. 2002;28(7):850-6. PMid:12122521. http://dx.doi. org/10.1007/s00134-002-1342-2 3. Blattner C, Guaragna JC, Saadi E. Oxygenation and static compliance is improved immediately after early manual hyperinflation following myocardial revascularisation: a randomised controlled trial. Aust J Physiother. 2008;54(3):173-8. http://dx.doi.org/10.1016/ S0004-9514(08)70023-0 4. Jones AY, Hutchinson RC, Oh TE. Effects of bagging and percussion on total static compliance of the respiratory system. Physiotherapy. 1992;78(9):661-6. http://dx.doi. org/10.1016/S0031-9406(10)61573-8 5. Hodgson C, Denehy L, Ntoumenopoulos G, Santamaria J, Carroll S. An investigation of the early effects of manual lung hyperinflation in critically ill patients. Anaesth Intensive Care. 2000;28(3):255-61. PMid:10853205.

6. Patman S, Jenkins S, Stiller K. Manual hyperinflation-effects on respiratory parameters. Physiother Res Int. 2000;5(3):157-71. PMid:10998773. http://dx.doi. org/10.1002/pri.196 7. Clement AJ, Hübsch SK. Chest physiotherapy by the ‘bag squeezing’ method: a guide to technique.

Physiotherapy. 1968;54(10):355-9. PMid:5708074.

8. Stiller K, Jenkins S, Grant R, Geake T, Taylor R, Hall B. Acute lobar atelectasis: A comparison of five physiotherapy regimens. Physiother Theory and Pract. 1996;12(4):197‑209. http://dx.doi.org/10.3109/09593989609036437 9. Maa SH, Hung TJ, Hsu KH, Hsieh YI, Wang KY, Wang CH, et al. Manual hyperinflation improves alveolar recruitment in difficult-to-wean patients.

Chest. 2005;128(4):2714-21. PMid:16236947. http:// dx.doi.org/10.1378/chest.128.4.2714 10. Stiller K. Physiotherapy in intensive care: towards an evidence-based practice. Chest. 2000;118(6):1801-13.

PMid:11115476. http://dx.doi.org/10.1378/chest.118.6.1801 11. Ntoumenopoulos G, Gild A, Cooper DJ. The effect of manual lung hyperinflation and postural drainage on pulmonary complications in mechanically ventilated

Manual hyperinflation combined with expiratory rib cage compression for reduction of length of ICU stay in critically ill patients on mechanical ventilation

trauma patients. Anaesth Intensive Care. 1998;26(5):492-6.

PMid:9807602.

12. Templeton M, Palazzo MG. Chest physiotherapy prolongs duration of ventilation in the critically ill ventilated for more than 48 hours. Intensive Care Med. 2007;33(11):1938-45. PMid:17607561. http:// dx.doi.org/10.1007/s00134-007-0762-4 13. Choi JS, Jones AY. Effects of manual hyperinflation and suctioning in respiratory mechanics in mechanically ventilated patients with ventilator-associated pneumonia.

Aust J Physiother. 2005;51(1):25-30. http://dx.doi. org/10.1016/S0004-9514(05)70050-7 14. Dias CM, Siqueira TM, Faccio TR, Gontijo LC, Salge JA, Volpe MS. Efetividade e segurança da técnica de higiene brônquica: hiperinsuflação manual com compressão torácica. Rev Bras Ter Intensiva. 2011;23(2):190-98. http://dx.doi.org/10.1590/S0103-507X2011000200012 15. Maxwell LJ, Ellis ER. Pattern of ventilation during manual hyperinflation performed by physiotherapists.

Anaesthesia. 2007;62(1):27-33. PMid:17156224. http:// dx.doi.org/10.1111/j.1365-2044.2006.04898.x 16. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome.

Am Rev Respir Dis. 1988;138(3):720-3. Erratum in: Rev Respir Dis 1989;139(4):1065. PMid:3202424.

17. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system.

Crit Care Med. 1985;13(10):818-29. PMid:3928249. http://dx.doi.org/10.1097/00003246-198510000-00009 18. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47(11):1245-51. http://dx.doi. org/10.1016/0895-4356(94)90129-5 19. Poses RM, McClish DK, Smith WR, Bekes C, Scott WE. Prediction of survival of critically ill patients by admission comorbidity. J Clin Epidemiol. 1996;49(7):743-7. http:// dx.doi.org/10.1016/0895-4356(96)00021-2 20. Campbell MJ, Machin D. Sample size calculation. In: Campbell MJ, Machin D, editors. Medical Statistics: A Commonsense Approach. New York: Wiley; 1993. p. 156-8.

21. Norman GR, Streiner DL, editors. Biostatistics: The Bare Essentials. Saint Louis: Mosby; 1994.

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22. Goodman LA. Simultaneous confidence intervals for contrasts among multinomial population. Ann Math Stat. 1964;35:716-25. http://dx.doi.org/10.1214/ aoms/1177703569 23. Novak RA, Shumaker L, Snyder JV, Pinsky MR. Do periodic hyperinflations improve gas exchange in patients with hypoxemic respiratory failure? Crit Care Med. 1987;15(12):1081-5. PMid:3677760. http://dx.doi. org/10.1097/00003246-198712000-00001 24. Hodgson C, Carroll S, Denehy L. A survey of manual hyperinflation in Australian hospitals. Aust J Physiother. 1999;45(3):185-93. PMid:11676766.

25. Stiller K, Geake T, Taylor J, Grant R, Hall B. Acute lobar atelectasis. A comparison of two chest physiotherapy regimens. Chest. 1990;98(6):1336-40. PMid:2245671. http://dx.doi.org/10.1378/chest.98.6.1336 26. Unoki T, Mizutani T, Toyooka H. Effects of expiratory rib cage compression combined with endotracheal suctioning on gas exchange in mechanically ventilated rabbits with induced atelectasis. Respir Care. 2004;49(8):896-901.

PMid:15271228.

27. Lemes DA, Zin WA, Guimaraes FS. Hyperinflation using pressure support ventilation improves secretion clearance and respiratory mechanics in ventilated patients with pulmonary infection: a randomised crossover trial. Aust J Physiother. 2009;55(4):249-54. http://dx.doi.org/10.1016/ S0004-9514(09)70004-2 28. Clarke RC, Kelly BE, Convery PN, Fee JP. Ventilatory characteristics in mechanically ventilated patients during manual hyperventilation for chest physiotherapy.

Anaesthesia. 1999;54(10):936-40.PMid:10540056. http:// dx.doi.org/10.1046/j.1365-2044.1999.01007.x 29. Berney S, Denehy L. The effect of physiotherapy treatment on oxygen consumption and haemodynamics in patients who are critically ill. Aust J Physiother. 2003;49(2):99‑105.

PMid:12775205.

30. Yu DT, Platt R, Lanken PN, Black E, Sands KE, Schwartz JS, et al. Relationship of pulmonary artery catheter use to mortality and resource utilization in patients with severe sepsis. Crit Care Med. 2003;31(12):2734-41. http:// dx.doi.org/10.1097/01.CCM.0000098028.68323.64

J Bras Pneumol. 2012;38(4):477-486

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Berti JSW, Tonon E, Ronchi CF, Berti HW, Stefano LM, Gut AL et al.

About the authors Juliana Savini Wey Berti

Physiotherapist. Botucatu Hospital das Clínicas, Botucatu School of Medicine, São Paulo State University, Botucatu, Brazil.

Elisiane Tonon

Physiotherapist. Botucatu Hospital das Clínicas, Botucatu School of Medicine, São Paulo State University, Botucatu, Brazil.

Carlos Fernando Ronchi

Physiotherapist. Intensive Care Unit, Botucatu Hospital das Clínicas, Botucatu School of Medicine, São Paulo State University, Botucatu, Brazil.

Heloisa Wey Berti

Assistant Professor. Department of Nursing, Botucatu School of Medicine, São Paulo State University, Botucatu, Brazil.

Laércio Martins de Stefano

Assistant Professor. Department of Internal Medicine, Botucatu School of Medicine, São Paulo State University, Botucatu, Brazil.

Ana Lúcia Gut

Assistant Professor. Department of Internal Medicine, Botucatu School of Medicine, São Paulo State University, Botucatu, Brazil.

Carlos Roberto Padovani

Full Professor. Department of Biostatistics, Institute of Biosciences, São Paulo State University, Botucatu, Brazil.

Ana Lucia Anjos Ferreira

Associate Professor. Department of Internal Medicine, Botucatu School of Medicine, São Paulo State University, Botucatu, Brazil.

J Bras Pneumol. 2012;38(4):477-486

Original Article Clinical and pathological factors influencing the survival of breast cancer patients with malignant pleural effusion*,** Fatores clínicos e anatomopatológicos que influenciam a sobrevida de pacientes com câncer de mama e derrame pleural neoplásico

Giovana Tavares dos Santos, João Carlos Prolla, Natália Dressler Camillo, Lisiane Silveira Zavalhia, Alana Durayski Ranzi, Claudia Giuliano Bica

Abstract Objective: The objective of this study was to identify the clinical and pathological factors that can influence the prognosis of breast cancer patients with clinical symptoms of malignant pleural effusion. Methods: This was a clinical cohort study, in which we analyzed the medical charts of patients diagnosed with malignant pleural effusion between 2006 and 2010. By examining the charts, we identified the female patients with a history of breast cancer. For those patients, we collected pathology data related to the primary tumor and cytopathology data related to the pleural metastasis. Results: We evaluated 145 patients, 87 (60%) of whom had tested positive for malignant cells in the pleural fluid. Ductal histology was observed in 119 (82%). The triple-negative breast cancer phenotype was seen in 25 cases (17%). Those patients had the worst prognosis (with a sharp decline in the survival curve), and 20 of the 25 (80%) died during the follow-up period (through June of 2011). The mean survival after the identification of malignant pleural effusion was 6 months. Conclusions: In patients with triple-negative breast cancer who test positive for malignant cells in the pleural fluid, the prognosis is poor and survival is reduced.

Keywords: Pleural effusion, malignant/mortality; Breast neoplasms/mortality; Breast neoplasms/genetics.

Resumo Objetivo: O objetivo deste estudo foi identificar os fatores clínicos e anatomopatológicos que possam influenciar o prognóstico de pacientes com câncer de mama e sintomas clínicos de derrame pleural neoplásico. Métodos: Trata-se de um estudo clínico de coorte, no qual foram analisados os prontuários médicos de pacientes que receberam diagnóstico de derrame pleural neoplásico entre 2006 e 2010. Por meio da análise dos prontuários, identificamos as pacientes com história de câncer de mama. Para essas pacientes, coletamos dados anatomopatológicos relacionados ao tumor primário e dados citopatológicos relacionados à metástase pleural. Resultados: Das 145 pacientes avaliadas, 87 (60%) apresentaram, no exame citológico, resultado positivo para células neoplásicas no líquido pleural; além disso, 119 (82%) apresentaram tipo histológico ductal. O fenótipo triplo-negativo foi observado em 25 pacientes (17%), as quais apresentaram o pior prognóstico, com queda acentuada na curva de sobrevida. Das 25 pacientes, 20 (80%) evoluíram a óbito durante o período de seguimento (até junho de 2011).

A sobrevida média após a identificação de derrame pleural neoplásico foi de 6 meses. Conclusões: Em pacientes com câncer de mama triplo-negativo e exame citológico com resultado positivo para células neoplásicas no líquido pleural, o prognóstico é ruim e a sobrevida é menor.

Descritores: Derrame pleural maligno/mortalidade; Neoplasias da mama/mortalidade; Neoplasias da mama/ genética.

* Study conducted at the Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.

Correspondence to: Giovana Tavares dos Santos. Departamento de Patologia, Universidade Federal de Ciências da Saúde de Porto Alegre, Rua Sarmento Leite, 245, Sala 304, CEP 90050-170, Porto Alegre, RS, Brasil.

Tel. 55 51 3303-8760. E-mail: giovanat@ufcspa.edu.br Financial support: This study received financial support in the form of grants: Giovana Tavares dos Santos is the recipient of a Graduate Support Program grant from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Office for the Advancement of Higher Education); and Natália Dressler Camillo is the recipient of a Young Investigator Program grant from the Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS, Foundation for the Support of Research in the state of Rio Grande do Sul).

Submitted: 23 February 2012. Accepted, after review: 13 June 2012. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

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Introduction In recent decades, the incidence of breast cancer has increased worldwide. This is probably due to improvements in screening and diagnosis, as well as to changes in the lifestyle and habits of women, including, for instance, reproductive behavior.(1,2) In Brazil, the number of new cases breast cancer is estimated at 52,689 for 2012.

In the state of Rio Grande do Sul, the crude incidence of primary breast cancer is 81.97/100,000 population, making it the Brazilian state with the second highest incidence of breast cancer.(3) Breast cancer is considered a public health problem because of its high incidence, morbidity, and mortality, as well as the high cost of treatment.

In 2008, the total number of breast cancer deaths in Brazil was 12,098, women accounting for 11,969 of those deaths.(4) Many breast cancer patients have complications triggered by distant metastases, which primarily affect the brain, lungs, liver, and bones.(5) In this context, the lack of concrete data about breast cancer metastases is a concern.(2) However, studies have shown that 20-80% of patients with primary breast tumor will develop metastatic disease, the proportion varying depending on the biology of the tumor, the stage at diagnosis, and the subsequent treatment.(2,6) The incidence of lung metastases in breast cancer patients with a primary tumor depends on the stage at diagnosis; when the diagnosis is made at an early stage, the probability of pulmonary metastases is lower.(7) In breast cancer patients, pleural and pericardial effusions are common and, when present, occur frequently over the course of the disease.(8,9) Such pulmonary metastases have been associated with a poor prognosis.(10,11) Because the lungs are common sites of metastatic disease,(12) the identification of malignant cells in the pleural fluid, together with the results of a biopsy of the parietal pleura, can provide evidence that the primary disease has spread or progressed, and such progression has been associated with decreased life expectancy.(13) Therefore, we stress the importance of identifying organ-specific characteristics of metastatic breast cancer, because such data can further the understanding of the natural history of the disease.(5,14) The objective of this study was to identify the clinical and pathological factors that affect the survival of patients with a history of breast J Bras Pneumol. 2012;38(4):487-493

cancer who develop pleural effusion. To that end, we evaluated factors related to the diagnosis, the histological type of the primary tumor, the identification of malignant cells in the pleural fluid, the expression of immunohistochemical markers of breast cancer, and outcomes.

Methods This was a hospital-based, historical cohort study, conducted at the Santa Casa Sisters of Mercy Hospital, a referral hospital located in the city of Porto Alegre, Brazil. We analyzed the medical charts of patients diagnosed with malignant pleural effusion at the hospital between 2006 and 2010. The inclusion criteria were being female, having been diagnosed with pleural effusion, and having a history of breast cancer. Patients diagnosed with a primary tumor at a site other than the breast were excluded, as were those for whom cytology or pathology data were missing from the medical charts.

We investigated the following variables: age at diagnosis of breast cancer; age at diagnosis of malignant pleural effusion; age at death (the primary outcome measure); the histological type of the primary tumor (ductal, lobular, or other); the expression of immunohistochemical markers of breast cancer, including the estrogen receptor (ER), progesterone receptor (PR), Ki-67 protein, p53 protein, and c-erbB-2 protein; and the results of the pleural fluid cytology. All of the data were obtained from medical carts or from pathology, cytopathology, and immunohistochemistry reports issued by the hospital laboratory. The results of all laboratory tests had been evaluated by qualified professionals who were experienced in the areas of cytopathology and anatomopathology.

We conducted this study in accordance with Brazilian National Health Council Resolution 196/96, respecting the ethical and legal anonymity and confidentiality of information. The study was approved by the Research Ethics Committees of the Federal University of Health Sciences of Porto Alegre and the Santa Casa Sisters of Mercy Hospital.

Survival time is defined as the interval between the onset or diagnosis of a disease (the starting point of the follow-up period) and death. In the present study, the date on which the cytopathology report showed malignant cells in the pleural fluid was taken as the starting point of follow-up, and the occurrence of death was the primary

Clinical and pathological factors influencing the survival of breast cancer patients with malignant pleural effusion

outcome measure. Patients were followed until June of 2011. Data were censored for patients who were lost to follow-up, as well as for those who were still alive at the end of the follow-up period.

The data were processed with Microsoft Excel 2007 and analyzed with the Statistical Package for the Social Sciences, version 18.0 (SPSS Inc., Chicago, IL, USA). Survival curves were calculated using the Kaplan-Meier method, and Cox univariate analysis was applied to identify independent factors associated with survival. The log-rank test was used in order to determine whether there were any statistical differences between the distributions of the curves. We used the Student’s t-test to compare the mean values obtained for malignant pleural effusion and Ki-67 protein expression. The level of statistical significance was set at p < 0.05.

Results We identified and evaluated 145 female breast cancer patients who were referred to our hospital for investigation of malignant pleural effusion.

Table 1 shows the main demographic and clinical characteristics of the study sample.

There were some missing data. Five patients were lost to follow-up, and their survival status data was therefore unknown. For another 6 patients, the cytological analysis was unsatisfactory, because there was hemorrhagic material in the pleural fluid. In addition, the immunohistochemical panel applied to the primary tumor comprised only 3 markers in some cases, whereas it comprised 5 markers in others, and, in some cases, there were no immunohistochemical data available.

Therefore, such data were available in only 118 cases for ER and PR; 110 cases for p53 and Ki-67; 112 cases for c-erbB-2; and 105 cases for the triple-negative phenotype.

In the study sample as a whole, the age at diagnosis of the primary tumor ranged from 20 and 90 years. Of the patients with malignant pleural effusion, 21 (24%) had been diagnosed with a primary tumor before 50 years of age (Table 1).

As can be seen in Table 1, the mean age of the patients at each defining event was as follows: 55.8 ± 15.0 years at diagnosis of the primary tumor; 57.3 ± 12.0 years at identification of malignant pleural effusion; and 59.9 ± 14.0 years at death. Among the patients with malignant

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pleural effusion, the mean age at death was 57.8 ± 12.0 years. Therefore, the mean time from the diagnosis of the primary tumor to the identification of malignant pleural effusion was 20 months, and the mean survival after the identification of malignant pleural effusion was 6 months.

On the basis of the histological analysis, the primary tumor was classified as ductal in 119 patients (91%), lobular in 8 (6%), and other in 4 (3%). Of the 119 patients with a ductal tumor, 75 (63%) tested positive for malignant pleural effusion (Table 1).

In the Cox univariate analysis, mortality was not found to be significantly associated with the identification of malignant cells in the pleural fluid, with the histological type of the primary tumor, with the age at diagnosis of the primary tumor, or with Ki-67 expression.

However, the Cox univariate analysis and the Kaplan-Meier curves both revealed a statistically significant association between triple-negative breast cancer and mortality (Table 2 and Figure 1, respectively), the latter showing a strong log-rank test association (p < 0.001), with a hazard ratio of 3.12.

Of the 140 patients for whom the outcome was known, 91 (65%) died. Of the 25 patients with triple-negative breast cancer, 20 (80%) died during the follow-up period.

Figure 1 - Survival curves from pleural metastasis to death, with identification of the triple-negative phenotype.

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Table 1 - Demographic and clinical characteristics of the breast cancer patients studied.

Characteristic n = 145a Mean age, in years, at defining events, mean ± SD All patients 55.8 ± 15.0 Diagnosis of the primary tumor Diagnosis of neoplastic pleural effusion 57.3 ± 12.0 Death 59.9 ± 14.0 Patients with malignant pleural effusion Death 57.8 ± 12.0 Age at diagnosis of the primary tumor among patients with malignant pleural effusion, n (%) ≤50 years 21 (24%) >50 years 66 (76%) Total 87 (100%) Histological type of the primary tumor, n (%) Ductal 119 (91%) Lobular 8 (6%) Other 4 (3%) Total 131 (100%) Expression of tumor markers in the primary tumor, n (%) Estrogen receptor Yes 71 (60%) No 47 (40%) Total 118 (100%) Progesterone receptor Yes 69 (59%) No 49 (41%) Total 118 (100%) C-erb-B2 Yes 41 (37%) No 71 (63%) Total 112 (100%) Ki-67 Yes 96 (87%) No 14 (13%) Total 110(100%) Triple-negative, n (%) Yes 25 (24%) No 80 (76%) Total 105 (100%) Positive cytology for malignant cells in pleural fluid, n (%) Yes 87 (60%) No 51 (35%) Inconclusive 7 (5%) Total 145 (100%) Primary outcome measure (mortality), n (%) Died 91 (65%) Survived 49 (35%) Total 140 (100%) a

Because some data were missing, not all study variables were measured or evaluated in all patients.

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Table 2 - Cox univariate analysis of possible risk factors for mortality in the breast cancer patients studied.

Variables related to the primary tumor p 95% CI Hazard Ratio Histological type 0.528 0.53-3.37 1.345 Patient age at diagnosis 0.123 0.356-1.132 0.635 Ki-67 expression 0.165 0.561-29.73 4.084 Triple-negative phenotype <0.001 1.60-6.08 3.129

Data regarding the expression of Ki-67, an immunohistochemical marker of cell proliferation, were available for 103 patients, 64 (63%) of whom tested positive for Ki-67 expression. The association between Ki-67 expression and the identification of malignant cells in the pleural fluid was found to be statistically significant (p = 0.0041).

The immunohistochemical panel of the primary tumor showed that there was expression of Ki-67, ER, PR, p53, and c-erbB-2 in 87%, 60%, 59%, 38%, and 37% of the patients, respectively, comparable to the 93%, 64%, 56%, 44%, and 35%, respectively, found when we considered only the patients who were diagnosed with malignant pleural effusion. The triple-negative phenotype (characterized by the lack of expression of ER, PR, and c-erbB-2) was identified in 14 (21%) of the 66 such patients for whom data on all three markers were available.

Discussion In the present study, the prognosis was worse for patients with triple-negative breast cancer than for those with other breast cancer phenotypes. This is in agreement with data in the literature, which show that, in such patients, the tumor is more aggressive, the incidence of distant metastases, particularly in visceral organs such as the lung, is higher, and survival is lower.(5,11,15-18) We found that there was a tendency toward a worse prognosis in patients who had been diagnosed with a primary tumor before 50 years of age, perhaps suggesting that diagnosis after the age of 50 is a protective factor. The prognosis for breast cancer is relatively good if it is diagnosed in the early stages.(19) The cumulative median overall five-year survival is approximately 65% in developed countries, 56% in developing countries, and 61% worldwide.(20) Epidemiological studies conducted in Brazil have provided inconsistent data on the five-year survival of breast cancer patients, which ranges from 61% to 87.7%.(21,22)

Such variation might be attributed to the calendar year studied, the region of the country in which the patients were treated, the study methodology, or the population studied.

Fentiman et al.(8) found that the mean interval between the diagnosis of the primary tumor and the presentation of pleural effusion was 41.5 months, and that the mean survival after the presentation of pleural effusion was 15.7 months.

However, van Galen et al.(11) reported a longer mean time from the diagnosis of breast cancer to the detection of pleural effusion (63.6 months) and a shorter mean survival (9.3 months), findings that are in stark contrast with those of our study (20 months and 6 months, respectively).

Studies of the spread of breast cancer have shown that a longer interval free of pleural metastases is an indicator of a worse prognosis,(8,10,11) and this poor prognosis has been associated with factors such as the site of the metastasis and the identification of malignant cells in the pleural fluid(23); the expression of c-erbB-2(21); the triple-negative phenotype(11,15-17); and Ki-67 protein expression, which has been shown to be present in 63% of patients with malignant pleural effusion.(18,24,25) The worst breast cancer survival rates are in developing countries.(26,27) Survival in malignant pleural effusion has also been widely studied.(8,10,11) In the present study, mean survival was shorter than that reported in studies conducted in developed countries, which might be attributable to more aggressive forms of the disease, limited access to appropriate treatment,(21) or even to delayed diagnosis of the primary tumor (i.e., diagnosis at an advanced stage), which could account for the shorter interval free of pleural metastases and for the shorter survival.

According to the literature, the site of metastasis is an important prognostic factor in breast cancer. Visceral metastases, such as those affecting lungs, are predictive of a poor prognosis and shorter survival.(23,28) In addition, the clinical J Bras Pneumol. 2012;38(4):487-493

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evolution of patients with isolated pulmonary metastatic disease remains a concern.(12) Expression of Ki-67, a tumor marker closely related to the process of cell proliferation, might represent a negative prognostic factor.(24,25) The breast cancer subtypes in which there is high Ki-67 expression have been shown to respond better to the initial chemotherapy but have also been associated with a poor long-term prognosis.(18) In conclusion, we found that the triplenegative breast cancer phenotype is an unfavorable characteristic in patients with malignant pleural effusion, worsening the prognosis and reducing life expectancy. In addition, Ki-67 protein expression was found to be associated with the development of malignant pleural effusion.

The burden imposed by breast cancer calls for expanding our knowledge of its prognostic factors, not only to inform decisions regarding it treatment but also to increase our understand of its evolution. Certain prognostic factors are well established and can be safely evaluated in clinical practice. However, some are still the targets of studies attempting to provide further information about the evolution of cancer and to identify new predictors of its prognosis.

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Prognostic factors for recurrent breast cancer patients with an isolated, limited number of lung metastases and implications for pulmonary metastasectomy.

Cancer. 2010;116(12):2890-901. PMid:20564396. http:// dx.doi.org/10.1002/cncr.25054 13. Teixeira LR, Pinto JA, Marchi E. Derrame pleural neoplásico.

J Bras Pneumol. 2006;32(Suppl 4):182-9.

14. Fidler IJ. Review: biologic heterogeneity of cancer metastases. Breast Cancer Res Treat. 1987;9(1):17-26.

PMid:3297212. http://dx.doi.org/10.1007/BF01806690 15. Rakha EA, Chan S. Metastatic triple-negative breast cancer. Clin Oncol (R Coll Radiol). 2011;23(9):587‑600.

PMid:21524569. http://dx.doi.org/10.1016/j. clon.2011.03.013 16. Tischkowitz M, Brunet JS, Bégin LR, Huntsman DG, Cheang MC, Akslen LA, et al. Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer. 2007;7:134. PMid:17650314 PMCid:1948892. http://dx.doi.org/10.1186/1471-2407-7-134 17. Dent R, Hanna WM, Trudeau M, Rawlinson E, Sun P, Narod SA. Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat. 2009;115(2):423-8.

PMid:18543098. http://dx.doi.org/10.1007/ s10549-008-0086-2 18. Keam B, Im SA, Lee KH, Han SW, Oh DY, Kim JH, et al.

Ki-67 can be used for further classification of triple negative breast cancer into two subtypes with different response and prognosis. Breast Cancer Res. 2011;13(2):R22.

PMid:21366896 PMCid:3219180. http://dx.doi.org/10.1186/ bcr2834 19. Brewster AM, Do KA, Thompson PA, Hahn KM, Sahin AA, Cao Y, et al. Relationship between epidemiologic risk factors and breast cancer recurrence. J Clin Oncol. 2007;25(28):4438-44. PMid:17785707. http:// dx.doi.org/10.1200/JCO.2007.10.6815 20. Cadaval Gonçalves AT, Costa Jobim PF, Vanacor R, Nunes LN, Martins de Albuquerque I, Bozzetti MC. Increase in breast cancer mortality in Southern Brazil from 1980 to 2002 [Article in Portuguese]. Cad Saude Publica. 2007;23(8):1785-90. PMid:17653396.

21. de Moraes AB, Zanini RR, Turchiello MS, Riboldi J, de Medeiros LR. Survival study of breast cancer patients treated at the hospital of the Federal University in Santa Maria, Rio Grande do Sul, Brazil [Article in Portuguese].

Clinical and pathological factors influencing the survival of breast cancer patients with malignant pleural effusion

Cad Saude Publica. 2006;22(10):2219-28. http://dx.doi. org/10.1590/S0102-311X2006001000028 22. Guerra MR, Mendonça GA, Teixeira MT, Cintra JR, Carvalho LM, Magalhães LM. Five-year survival and prognostic factors in a cohort of breast cancer patients treated in Juiz de Fora, Minas Gerais State, Brazil [Article in Portuguese]. Cad Saude Publica. 2009;25(11):2455-66. http://dx.doi.org/10.1590/S0102-311X2009001100015 23. Largillier R, Ferrero JM, Doyen J, Barriere J, Namer M, Mari V, et al. Prognostic factors in 1,038 women with metastatic breast cancer. Ann Oncol. 2008;19(12):2012-9.

PMid:18641006 PMCid:2733115. http://dx.doi.org/10.1093/ annonc/mdn424 24. Mohsenifar J, Almassi-Aghdam M, Mohammad-Taheri Z, Zare K, Jafari B, Atri M, et al. Prognostic values of proliferative markers ki-67 and repp86 in breast cancer.

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25. de Azambuja E, Cardoso F, de Castro G Jr, Colozza M, Mano MS, Durbecq V, et al. Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer. 2007;96(10):1504‑13. PMid:17453008 PMCid:2359936. http://dx.doi.org/10.1038/sj.bjc.6603756 26. Schneider IJ, d’Orsi E. Five-year survival and prognostic factors in women with breast cancer in Santa Catarina State, Brazil [Article in Portuguese]. Cad Saude Publica. 2009;25(6):1285-96. http://dx.doi.org/10.1590/ S0102-311X2009000600011 27. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74-108. http://dx.doi.org/10.3322/canjclin.55.2.74 28. Cutler SJ, Ardyce JA, Taylor SG 3rd. Classification of patients with disseminated cancer of the breast.

Cancer. 1969;24(5):861-9. http://dx.doi.org/10.1002/10970142(196911)24:5<861::AID-CNCR2820240502>3.0.CO;2-3

About the authors Giovana Tavares dos Santos

Biologist, Graduate Program in Pathology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.

João Carlos Prolla

Cytopathologist, Laboratory of Pathology, Santa Casa Sisters of Mercy Hospital, Porto Alegre, Brazil.

Natália Dressler Camillo

Medical Student, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.

Lisiane Silveira Zavalhia

Medical Biologist, Graduate Program in Pathology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.

Alana Durayski Ranzi

Medical Biologist, Graduate Program in Pathology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.

Claudia Giuliano Bica

Researcher, Graduate Program in Pathology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.

J Bras Pneumol. 2012;38(4):487-493

Original Article Emphysema index in a cohort of patients with no recognizable lung disease: influence of age*,** Índice de enfisema pulmonar em coorte de pacientes sem doença pulmonar conhecida: influência da idade

Bruno Hochhegger, Giordano Rafael Tronco Alves, Klaus Loureiro Irion, José da Silva Moreira, Edson dos Santos Marchiori

Abstract Objective: To investigate the effects of age on pulmonary emphysema, based on the values of the emphysema index (EI) in a cohort of patients who had never smoked and who had no recognizable lung disease. Methods: We reviewed the CT scans, reported as normal, of 315 patients. Exclusion criteria were a history of smoking, cardiorespiratory disease, and exposure to drugs that could cause lung disease. From this cohort, we selected 32 patients (16 men and 16 women), matched for gender and body mass index, who were divided equally into two groups by age (< 50 years and ≥ 50 years). We quantified emphysema using a computer program specific to that task. The EI was calculated with a threshold of −950 HU. We also evaluated total lung volume (TLV) and mean lung density (MLD). Results: The overall means for TLV, MLD, and EI were 5,027 mL, −827 HU, and 2.54%, respectively. Mean values in the older and younger groups, respectively, were as follows: for TLV, 5,229 mL vs. 4,824 mL (p > 0.05); for MLD, −846 HU vs. −813 HU (p < 0.04); and for EI, 3.30% vs. 1.28% (p < 0.001). Significant correlations were found between EI and age (r = 0.66; p = 0.001), EI and TLV (r = 0.58; p = 0.001), and EI and MLD (r = −0.67; p < 0.001). The predicted EI per age was defined by the regression equation (r2 = 0.43): p50(EI) = 0.049 × age − 0.5353. Conclusions: It is important to consider the influence of age when quantifying emphysema in patients over 50 years of age. Based on the regression analysis, EI values of 2.6%, 3.5%, and 4.5% can be considered normal for patients 30, 50, and 70 years of age, respectively.

Keywords: Pulmonary emphysema; Tomography, spiral computed; Aging; Pulmonary disease, chronic obstructive.

Resumo Objetivo: Investigar os efeitos da idade no enfisema pulmonar, com base nos valores do índice de enfisema (IE) em uma coorte de pacientes que nunca fumou e que não possuía doença pulmonar conhecida. Métodos: Foram revisados exames de TC, considerados normais, de 315 pacientes. Tabagismo, doenças cardiorrespiratórias e exposição a drogas que poderiam causar doença pulmonar foram critérios de exclusão. Dessa coorte, selecionamos 32 pacientes (16 homens e 16 mulheres), igualmente divididos em dois grupos (idade < 50 anos e idade ≥ 50 anos), que foram pareados por gênero e índice de massa corpórea. Realizou-se a quantificação do enfisema utilizando um programa específico. O IE foi calculado com um limiar de −950 UH. O volume pulmonar total (VPT) e a densidade pulmonar média (DPM) também foram avaliados. Resultados: As médias gerais de VPT, DPM e IE foram 5.027 mL, −827 UH e 2,54%, respectivamente. A comparação entre os mais velhos e os mais novos mostrou as seguintes médias: VPT (5.229 mL vs. 4.824 mL; p > 0,05); DPM (−846 UH vs. −813 UH; p < 0,04) e IE (3,30% vs. 1,28%; p < 0,001). Houve correlações significativas entre IE e idade (r = 0,66; p = 0,001), IE e VPT (r = 0,58; p = 0,001) e IE e DPM (r = −0,67; p < 0,001). O IE previsto por idade foi definido através da equação de regressão (r2 = 0,43): p50(IE) = 0,049 × idade − 0,5353. Conclusões: É importante considerar a influência da idade na quantificação de enfisema em pacientes com mais de 50 anos. Baseado na análise de regressão, valores de IE de 2,6%, 3,5% e 4,5% podem ser considerados normais para pacientes com 30, 50 e 70 anos, respectivamente.

Descritores: Enfisema pulmonar; Tomografia computadorizada espiral; Envelhecimento; Doença pulmonar obstrutiva crônica.

* Study carried out at the Santa Casa Sisters of Mercy Hospital Complex in Porto Alegre, Porto Alegre, Brazil.

Correspondence to: Giordano Rafael Tronco Alves. Rua Prof. Annes Dias, 295, Centro Histórico, CEP 90020-090, Porto Alegre, RS, Brasil.

Tel. 55 55 9915-9009. E-mail: grtalves@gmail.com Financial support: None.

Submitted: 5 March 2012. Accepted, after review: 10 April 2012. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

J Bras Pneumol. 2012;38(4):494-502

Emphysema index in a cohort of patients with no recognizable lung disease: influence of age

Introduction Pulmonary emphysema is defined as an abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of the alveolar walls and without obvious fibrosis.(1) Pulmonary emphysema is a major public health problem; it is currently ranked 12th as a cause of disease burden worldwide and is projected to rank 5th by 2020 as a cause of life-years lost and lost quality of life.(2) Degeneration of elastic fibers in the respiratory bronchioles, alveolar ducts, and alveoli occurs as part of the natural aging process, usually in individuals over 50 years of age.(3,4) As a consequence, the density of lung parenchyma diminishes, because the alveolar ducts become enlarged and the alveoli become shallower.(4) These changes have been designated “senile emphysema”(3,4) and correlate with stage I COPD, which is found in approximately 35% of “healthy” elderly nonsmokers.(5) Because pulmonary emphysema is defined on an anatomical basis, CT is currently the modality of choice for an accurate and noninvasive assessment of in vivo pathological changes.(6) Additionally, HRCT and helical CT can detect and quantify pulmonary emphysema, HRCT and helical CT findings correlating well with histopathological findings.(7-14) Finally, modern CT scanners with multiple rows of detectors— multidetector CT (MDCT)—allow the acquisition of thin (< 1-mm) slices of the whole chest in a few seconds, improving spatial resolution and avoiding respiratory artifacts.

The objective of the present study was to investigate the effects of age on pulmonary emphysema, based on the values of the emphysema index (EI) in a cohort of patients who had never smoked and who had no recognizable lung disease.

Methods We retrospectively evaluated all of the patients (n = 315) referred to our institution for chest CT scans in the clinical follow-up of extrathoracic tumors (without signs of dissemination) between January of 2010 and July of 2011. Immediate exclusion criteria were smoking (current or previous), cardiorespiratory disease, occupational exposure to dust or noxious agents, and current or past use of drugs known to cause lung disease.

In addition, patients whose height was less than

495

1.6 m or more than 1.85 m and those whose weight was below 55 kg or above 90 kg were excluded, given that extreme constitutional differences might have interfered with the final outcomes. Patients in whom CT screening revealed pulmonary, pleural, or cardiac abnormalities were also excluded. The presence of significant respiratory artifacts also constituted an exclusion criterion. The medical records of all patients were reviewed for data analysis. For precise determination of height and weight, a routine questionnaire was administered to all of the patients prior to CT scanning. When available and convenient, information gathered during subsequent medical visits, as well as ancillary test results, was also reviewed. Because all CT scans were retrospectively analyzed and because the patients were to remain anonymous, no written informed consent was required, and the study was approved by the local research ethics committee.

After applying all of the exclusion criteria, we selected a cohort of 32 patients. The non-enhanced CT images of the chest of those patients (16 men and 16 women in the 23-78 year age bracket) were post-processed with the syngo InSpace 4D software (Siemens Medical Systems, Forchheim, Germany) for emphysema quantification. The cohort was divided into two groups, by age (< 50 years and ≥ 50 years). The younger group comprised 8 males and 8 females, as did the older group. The patients in the two groups were matched for gender and body mass index in order to highlight the influence of age. Total lung volume (TLV) and mean lung density (MLD) were calculated for values ranging from −1,024 HU to −400 HU, the latter being the standard threshold for the software. A threshold of −950 HU was selected for “emphysema” quantification.

Finally, two experienced thoracic radiologists reviewed the images.

The CT scans were obtained with a CT scanner with 64 rows of detectors (SOMATOM Sensation 64 Systems; Siemens Medical Systems), CT parameters being as follows: collimation, 32 × 0.6 mm (with z-flying focal spot producing 64 overlapping 0.6-mm slices per rotation); rotation time, 0.33 s; and pitch, 1.3. Radiation dose was set at 120 kV and 200 mAs (dose modulation was allowed for optimization according to patient size and anatomical shape). Images were reconstructed for contiguous 1.00-mm axial images with a medium sharp reconstruction kernel J Bras Pneumol. 2012;38(4):494-502

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Hochhegger B, Alves GRT, Irion KL, Moreira JS, Marchiori E

(B40; Siemens). The patients were scanned from cranial to caudal, holding their breath at the end of a maximal inspiratory effort. During the study period, the CT scanner was periodically calibrated in accordance with the recommendations of the manufacturer. The raw data were entered into a scale with values ranging from −1,024 HU to 3,072 HU. We chose not to use spirometry for controlling lung volumes, given that the technique can increase the radiation dose without a significant improvement in precision.(15) All examinations were performed without the injection of intravenous contrast medium. A data matrix of 512 × 512 was selected.

Pulmonary emphysema was quantified by CT densitometry and volumetry, an imaging post-processing technique for calculating the volume of an organ (or of part of an organ).

The technique uses a whole set of volumetric CT images and attenuation coefficient values (or density, expressed in HU) in order to segment the organ. In addition, the technique can measure absolute TLC (which includes air, blood, and lung tissue) and calculate the volume of a lung portion whose density is above or below a selected threshold. We used the syngo InSpace 4D software (Siemens Medical Systems), which automatically recognizes the lungs and eliminates any structures with an attenuation coefficient higher than −400 HU. After automatic segmentation, the software calculates TLV, emphysema volumes, and MLD. The operator can choose a threshold between normal lung and emphysematous lung

(in HU). Various thresholds have been suggested to differentiate between normal and abnormal lungs.(11-13) Based on the acquisition parameters used, we selected a threshold of −950 HU.(11,12) The EI was then calculated by dividing the TLV by the lung volume with densities below −950 HU. The software provides a 3D image showing the distribution of the areas of emphysema (Figure 1).

The normal distribution of the CT densitometry parameters (TLV, MLD, and EI) was tested by a normal probability plot with the MedCalc software, version 8.1.1 (MedCalc Software, Mariakerke, Belgium). We accepted a type I error of 5% for patient selection, therefore excluding those above the 95th percentile, which was based on a Student’s t-distribution with 30 degrees of freedom and calculated by the following formula: mean + 1.70 × SEyx where SEyx is the standard error of the predicted x for each y.

Correlations of TLV, MLD, and EI with age were calculated by Pearson’s correlation coefficient and tested by the Student’s t-test. The influence of age on EI and MLD was evaluated by regression analysis, and the distribution was graphically demonstrated by XY scatter plots. The 50th percentile (p50) of EI was calculated by the following equation: f(x) = bx + a where a and b were calculated on the basis of the trend line of the distribution of EI per age. The

Figure 1 - CT scans of an 83-year-old male patient with an emphysema index of 6.4%. In A, an axial CT image showing the automatic recognition of the lung margins by the software. In B, a 3D CT scan showing the volumes of emphysematous densities. The volumes with densities of emphysema are marked in blue.

Note the homogeneity of the findings in both lungs.

J Bras Pneumol. 2012;38(4):494-502

Emphysema index in a cohort of patients with no recognizable lung disease: influence of age

best adjustment of the regression equation tested was measured by determining the r2. The 75th percentile (p75) and the 95th percentile (p95) were then calculated on the basis of a Student’s t-distribution with 30 degrees of freedom, by the following equations: p75 = p50 + 0.683 × SEyx p95 = p50 + 1.70 × SEyx Finally, the normal distribution was confirmed for TLV, MLD, and EI, which were plotted as near-straight lines and tested with the KolmogorovSmirnov test.

Results The study population (n = 32) was divided into two groups, by age (< 50 years and ≥ 50 years). The mean age of the individuals in the younger group was 32.8 ± 9.0 years, whereas that of those in the older group was 63.5 ± 8.6 years. Each group comprised 8 men and 8 women, matched for age and body mass index. As shown in Table 1, the overall means for the pulmonary emphysema parameters were as follows: TLV = 5,027 mL; MLD = −827 HU; and EI = 2.54%. Mean values in the older and younger groups, respectively, were as follows: for TLV, 5,229 mL vs. 4,824 mL (p > 0.05); for MLD, −846 HU vs. −813 HU (p < 0.04); and for EI, 3.30% vs. 1.28% (p < 0.001).

After the exclusion of values above p95, the correlations between age and each of the

497

parameters were as follows: TLV (r = 0.07; p = 0.71; 95% CI, −0.29 to 0.41); MLD (r = −0.33; p = 0.07; 95% CI, −0.61 to 0.02); and EI (r = 0.66; p = 0.001; 95% CI, 0.38-0.83). Significant correlations were found between EI and TLV (r = 0.58; p = 0.001; 95% CI, 0.26-0.78) and between EI and MLD (r = −0.67; p < 0.01; 95% CI, −0.83 to −0.39).

No significant correlations were found between MLD and age or between EI and age when the younger group was analyzed separately (r = 0.14 and p = 0.6133; and r = 0.34 and p = 0.1921, respectively).

The SEs of the CT parameters for age (SEyx) were as follows: SETLV,age = 1,278 mL; SEMLD,age = 39.04 HU; and SEEI,age = 1.70%.

Therefore, the p95 values were as follows: TLV = 7,199 mL; MLD = −894 HU; EI = 5.43%; and SEyx for EI and TLV = 1.79%. The best regression equation for the predicted EI per age (r2 = 0.43) was as follows: p50 = 0.049 × age − 0.5353 The SEEI,age for p50 was 0.95%. As shown in Figure 2, p75 and p95 were calculated by the following equations: p75 = p50 + 0.683 × 0.952 p95 = p50 + 1.70 × 0.952 The best regression equation for the predicted EI per MLD (r2 = 0.63) was as follows: p50 = 5EI − 18e − 0.049 × MLD where e is the constant for EI.

Figure 2 - Percentile distribution of the emphysema index (EI) by age. Note that EI was higher in the older individuals. p50: 50th percentile; p75: 75th percentile; and p95: 95th percentile.

J Bras Pneumol. 2012;38(4):494-502

J Bras Pneumol. 2012;38(4):494-502

4,738 (2,360-8,089)

−838 (−874 to −699)

5,027 ±1,274

−827 ± 41

2.54 ± 1.96

TLV, mL

MLD, HU

EI, %

6.3

−797

7,523

p95

3.3 ± 1.9

−846 ± 24

5,229 ± 1,284

Mean ± SD

3.3 (1.4-7.2)

−846 (−874 to −798)

4,710 (3,472-8,089)

Median (range)

(n = 16)

Older group*

7.2

−800

7,228

p95

1.28 ± 0.98

−813 ± 50

4,824 ± 1,270

Mean ± SD

1.00 (0.0-2.6)

−818 (−859 to −699)

4,738 (2,360-6,861)

Median (range)

(n = 16)

Younger group*

3.2

−716

7,316

p95

TLV: total lung volume; MLD: mean lung density; p95: 95th percentile; and EI: emphysema index (measured with a threshold of −950 HU). *The older group comprised patients ≥ 50 years of age, whereas the younger group comprised patients < 50 years of age.

2.3 (0.0-7.2)

Median (range)

(n = 32)

Mean ± SD

Variable

All patients

Table 1 - Emphysema parameters in the groups studied.

498 Hochhegger B, Alves GRT, Irion KL, Moreira JS, Marchiori E

Emphysema index in a cohort of patients with no recognizable lung disease: influence of age

Based on the regression analysis, EI values of 2.6%, 3.5%, and 4.5% can be considered normal for patients 30, 50, and 70 years of age, respectively.

Discussion It has been shown that CT quantification of emphysema correlates well with histopathological findings and pulmonary function test results.

(7-15) The method has been recommended for use in longitudinal studies of emphysema and is currently considered to be better than functional tests for disease assessment.(6,16) In addition, previous studies have reported that the correlation between CT densitometry and macroscopic morphometry is higher than is that between macroscopic morphometry and subjective visual grading of emphysema.(14) Emphysema has a long and silent asymptomatic evolution, manifesting clinically only at an advanced stage.(17) Reference EI values establishing normality are required in order to distinguish between patients with no emphysema and those with mild emphysema or early disease. In order to select a reference value for comparing the EI values in a given patient, we should take into consideration the radiation dose,(18,19) the slice thickness,(18) the reconstruction algorithm,(20) the type of scanner,(21) the HU range selected for lung segmentation (usually −1,024 HU to −400 HU or −1,024 HU to −250 HU),(19,22) and the HU threshold selected in order to distinguish between normal and emphysematous lung (usually −970 HU, −950 HU, or −910 HU).(11-13,22) Various HU thresholds have been proposed in order to distinguish between normal and abnormal lungs.(10-13) The initial suggestion was a threshold of −910 HU for axial scanners, with thicker collimation (i.e., 10 mm), and for examinations performed with the administration of intravenous contrast medium.(10) For thin-slice collimation (1 mm), Gevenois et al. reported good correlations with pathology specimens when the threshold was set at −950 HU.(12,13) For examinations using individual axial images (rather than the whole lung volume) acquired with MDCT scanners, Madani et al.(11) found that the strongest correlation between CT quantification and pathology findings was obtained with thresholds between −950 HU and −970 HU. However, there is no universally accepted threshold for volumetric analysis of emphysema by MDCT scanners. Therefore, we selected a threshold

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of −950 HU as the cut-off point to distinguish between normal lungs and emphysematous lungs.

Ideally, the CT densitometry software should use the same threshold. To our knowledge, our study is the first to address the effects of age on pulmonary emphysema in nonsmokers with no recognizable lung disease using a 64-MDCT scanner and volumetric acquisition.

Studies have reported an EI > 0 in healthy individuals.(22-26) In addition, the EI has been shown to increase with age.(24,26) One group of authors(22) investigated this issue in a cohort of healthy individuals younger than 40 years of age, showing that EI values ≤ 0.35% should be considered normal for volumetric measurements performed with 10-mm collimation, 50 mAs, and a standard reconstruction algorithm; those authors found that the EI was not significantly influenced by age in that age group, a finding that is consistent with those of the present study.

However, other studies,(24,26) particularly those involving older cohorts, have found significant evidence that EI increases with age, as observed in our older group.

The cut-off point of 50 years of age was chosen on the basis of previous studies reporting that the age of 50 years marks the onset of age-related degeneration of elastic fibers in respiratory bronchioles, as well as the onset of enlargement and flattening of the alveoli.

(3,5) Interestingly, the age-related changes are remarkably homogeneous, as opposed to the irregular distribution of airspace enlargement in emphysema.(5) The EI values observed in our cohort of patients were higher than were those reported in a study involving single-slice CT(22) and lower than were those reported in a study involving HRCT.(24) Factors that might have influenced the results include the reconstruction algorithm, radiation dose, collimation, CT scan manufacturer, and HU range selected for lung segmentation.(18,20,21,27,28) The software used in the present study segments the lungs within a range of −1,024 HU to −400 HU, which results in a TLV that is lower than is that obtained with lung segmentation within a range of −1,024 HU to −250 HU.(22) Therefore, although lung volumes can be similar at densities below −950 HU, proportional differences among TLV values can be observed at higher densities.

Our study has some limitations. The main limitation was the small sample size. However, J Bras Pneumol. 2012;38(4):494-502

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Hochhegger B, Alves GRT, Irion KL, Moreira JS, Marchiori E

it should be recognized that elderly patients without signs of respiratory disease (also known as “primary” aging patients) constitute a limited group, accounting for less than 10% of the total elderly population.(29) Two other important limitations of our study were its retrospective nature and the fact that our patients had been diagnosed with extrathoracic malignancy, which means that they could not be ideally classified as healthy. However, none of the patients had been diagnosed with pulmonary emphysema or previous lung disease, as reported in their medical records or as seen on CT scans. Finally, despite our rigorous criteria for selecting and matching the patients, we should state that the equations work better for patients in the same height and weight range and for examinations performed with similar scanners and the same acquisition and software parameters.

One group of authors proposed the use of the percentile density (PD) rather than the EI in longitudinal studies of emphysema.(30) The EI is based on the assumption that voxels with densities below a chosen threshold represent emphysema, given that the proportion between lung tissue and air is reduced to a point in which the density of those lung portions is very similar to the density of air. In contrast, PD (which is usually set at 15%) is defined as the HU value below which a chosen proportion of the lungs is rated, based on a frequency distribution histogram.

A PD of 15% has been proposed as a parameter to evaluate emphysema progression.(6) However, Madani et al.(11) found that a PD of 1% correlated best with histopathological findings. We chose to use EI rather than PD because we do not agree that PD, regardless of the chosen setting, can actually quantify emphysema. For instance, if PD is applied to a completely consolidated lung, the frequency distribution histogram will always have 1% or 15% of voxels below the HU value of the selected PD (regardless of the percentile chosen), even without any air in the lungs.

In conclusion, it is important to consider the influence of age when quantifying emphysema in patients over 50 years of age. Patients who have never smoked, those who have neither clinical signs nor a history of respiratory disease, and those who have neither recognizable emphysema nor other lung abnormalities (as determined by subjective visual analysis of CT scans) can present with some degree of emphysema (as determined J Bras Pneumol. 2012;38(4):494-502

by CT quantification). Based on our regression analysis, EI values of 2.6%, 3.5%, and 4.5% can be considered normal for patients 30, 50, and 70 years of age, respectively.

Acknowledgements We would like to thank Dr. Benjamin Pinkey, Dr. Nelson Porto, and Dr. Joe Evans for their invaluable contribution to the present study.

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PMid:2298057. http://dx.doi.org/10.1378/chest.97.2.315 8. Heussel CP, Herth FJ, Kappes J, Hantusch R, Hartlieb S, Weinheimer O, et al. Fully automatic quantitative assessment of emphysema in computed tomography: comparison with pulmonary function testing and normal values. Eur Radiol. 2009;19(10):2391-402. PMid:19458953. http://dx.doi.org/10.1007/s00330-009-1437-z 9. Falaschi F, Miniati M, Battolla L, Filippi E, Sostman HD, Laiolo E, et al. Quantification of pulmonary emphysema with computerized tomography. Comparison with various methods [Article in Italian]. Radiol Med. 1995;90(1-2):16-23.

10. Müller NL, Staples CA, Miller RR, Abboud RT. “Density mask”. An objective method to quantitate emphysema using computed tomography. Chest. 1988;94(4):782-7.

PMid:3168574. http://dx.doi.org/10.1378/chest.94.4.782 11. Madani A, Zanen J, de Maertelaer V, Gevenois PA. Pulmonary emphysema: objective quantification at multidetector row CT--comparison with macroscopic and

Emphysema index in a cohort of patients with no recognizable lung disease: influence of age

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PMid:16424242. http://dx.doi.org/10.1148/ radiol.2382042196 12. Gevenois PA, de Maertelaer V, De Vuyst P, Zanen J, Yernault JC. Comparison of computed density and macroscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med. 1995;152(2):653-7. PMid:7633722.

13. Gevenois PA, De Vuyst P, de Maertelaer V, Zanen J, Jacobovitz D, Cosio MG, et al Comparison of computed density and microscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med. 1996;154(1):187‑92. PMid:8680679.

14. Bankier AA, De Maertelaer V, Keyzer C, Gevenois PA. Pulmonary emphysema: subjective visual grading versus objective quantification with macroscopic morphometry and thin-section CT densitometry.

Radiology. 1999;211(3):851-8. PMid:10352615.

15. Gierada DS, Yusen RD, Pilgram TK, Crouch L, Slone RM, Bae KT, et al. Repeatability of quantitative CT indexes of emphysema in patients evaluated for lung volume reduction surgery. Radiology. 2001;220(2):448‑54.

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16. Stolk J, Putter H, Bakker EM, Shaker SB, Parr DG, Piitulainen E, et al. Progression parameters for emphysema: a clinical investigation. Respir Med. 2007;101(9):1924‑30.

PMid:17644366. http://dx.doi.org/10.1016/j. rmed.2007.04.016 17. Litmanovich D, Boiselle PM, Bankier AA. CT of pulmonary emphysema--current status, challenges, and future directions. Eur Radiol. 2009;19(3):537-51. PMid:18825385. http://dx.doi.org/10.1007/s00330-008-1186-4 18. Madani A, De Maertelaer V, Zanen J, Gevenois PA. Pulmonary emphysema: radiation dose and section thickness at multidetector CT quantification--comparison with macroscopic and microscopic morphometry.

Radiology. 2007;243(1):250-7. PMid:17392257. http:// dx.doi.org/10.1148/radiol.2431060194 19. Zaporozhan J, Ley S, Weinheimer O, Eberhardt R, Tsakiris I, Noshi Y, et al. Multi-detector CT of the chest: influence of dose onto quantitative evaluation of severe emphysema: a simulation study. J Comput Assist Tomogr. 2006;30(3):460-8. PMid:16778622. http://dx.doi.org/10.1097/00004728-200605000-00018 20. Boedeker KL, McNitt-Gray MF, Rogers SR, Truong DA, Brown MS, Gjertson DW, et al. Emphysema: effect of reconstruction algorithm on CT imaging measures.

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Chest. 2007;132(2):617-23. PMid:17573501. http:// dx.doi.org/10.1378/chest.06-2325 22. Irion KL, Marchiori E, Hochhegger B, Porto Nda S, Moreira Jda S, Anselmi CE, et al. CT quantification of emphysema in young subjects with no recognizable chest disease. AJR Am J Roentgenol. 2009;192(3):W90-6. PMid:19234245. http://dx.doi.org/10.2214/AJR.07.3502 23. Bnà C, Zompatori M, Ormitti F, Sverzellati N, Verduri A. High resolution CT (HRCT) of the lung in adults.

Defining the limits between normal and pathologic findings. Radiol Med. 2005;109(5-6):460-71.

24. Gevenois PA, Scillia P, de Maertelaer V, Michils A, De Vuyst P, Yernault JC. The effects of age, sex, lung size, and hyperinflation on CT lung densitometry. AJR Am J Roentgenol. 1996;167(5):1169-73.PMid:8911175.

25. Vikgren J, Boijsen M, Andelid K, Ekberg-Jansson A, Larsson S, Bake B, et al. High-resolution computed tomography in healthy smokers and never-smokers: a 6-year follow-up study of men born in 1933. Acta Radiol. 2004;45(1):44-52. PMid:15164778. http://dx.doi. org/10.1080/02841850310002970 26. Horiuchi N, Fujita J, Suemitsu I, Yamasaki Y, Higa F, Tateyama M. Low-dose multislice CT and high-resolution CT assessment of pulmonary emphysema in public school teachers. Lung. 2007;185(1):25-30.PMid:17294335. http://dx.doi.org/10.1007/s00408-006-0082-4 27. Heussel CP, Kappes J, Hantusch R, Hartlieb S, Weinheimer O, Kauczor HU, et al. Contrast enhanced CT-scans are not comparable to non-enhanced scans in emphysema quantification. Eur J Radiol. 2010;74(3):473-8.

PMid:19376661. http://dx.doi.org/10.1016/j. ejrad.2009.03.023 28. Schilham AM, van Ginneken B, Gietema H, Prokop M. Local noise weighted filtering for emphysema scoring of low-dose CT images. IEEE Trans Med Imaging. 2006;25(4):451-63. PMid:16608060. http:// dx.doi.org/10.1109/TMI.2006.871545 29. Bonomo L, Larici AR, Maggi F, Schiavon F, Berletti R. Aging and the respiratory system. Radiol Clin North Am. 2008;46(4):685-702, v-vi. PMid:18922288. http:// dx.doi.org/10.1016/j.rcl.2008.04.012 30. Stoel BC, Parr DG, Bakker EM, Putter H, Stolk J, Gietema HA, et al. Can the extent of low-attenuation areas on CT scans really demonstrate changes in the severity of emphysema? Radiology. 2008;247(1):293-4; author reply 294. http://dx.doi.org/10.1148/radiol.2471071608

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Hochhegger B, Alves GRT, Irion KL, Moreira JS, Marchiori E

About the authors Bruno Hochhegger

Radiologist. Moinhos de Vento Hospital and Santa Casa Sisters of Mercy Hospital Complex in Porto Alegre, Porto Alegre, Brazil.

Giordano Rafael Tronco Alves

Medical Student. Federal University of Santa Maria, Santa Maria, Brazil.

Klaus Loureiro Irion

Radiologist. Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, United Kingdom.

JosĂŠ da Silva Moreira

Pulmonologist. Santa Casa Sisters of Mercy Hospital Complex in Porto Alegre, Porto Alegre, Brazil.

Edson dos Santos Marchiori

Radiologist. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

J Bras Pneumol. 2012;38(4):494-502

Original Article Effectiveness of tuberculosis treatment* Efetividade do tratamento da tuberculose

Letícia Nazareth Fernandes da Paz, Maria Deise de Oliveira Ohnishi, Camila Melo Barbagelata, Fabiana de Arruda Bastos, João Augusto Figueiredo de Oliveira III, Igor Costa Parente

Abstract Objective: To analyze the treatment strategies that influence the effectiveness of tuberculosis treatment at primary care clinics (PCCs) in Brazil. Methods: This was a descriptive, retrospective epidemiological survey based on the medical records of 588 tuberculosis patients enrolled in the tuberculosis control programs at two PCCs located in the city of Belém, Brazil: Centro de Saúde Escola do Marco (CSEM) and Unidade Básica de Saúde da Pedreira (UBSP). The survey was limited to patients enrolled between January of 2004 and December of 2008.

We included only patients between 18 and 59 years of age, and we excluded those who were transferred or were found to have been misdiagnosed. We collected data regarding age, gender, type of treatment (self-administered or supervised), co-infection with HIV, and treatment outcome. The health professionals involved in the tuberculosis control program at the two PCCs were interviewed regarding the strategies used for tuberculosis control and regarding routine clinical care for tuberculosis patients. Results: There were no significant differences between the CSEM and UBSP patients regarding age, gender, or co-infection with HIV. Supervised treatment was used significantly more frequently and the rate of cure was higher at the CSEM than at the UBSP, whereas the rate of treatment noncompliance was higher at the UBSP than at the CSEM. Conclusions: For patients enrolled in tuberculosis control programs at PCCs in Brazil, supervised treatment appears to be an extremely important strategy for reducing the rate of treatment noncompliance.

Keywords: Tuberculosis; Patient dropouts; Patient care planning; Treatment outcome.

Resumo Objetivo: Analisar as estratégias que influenciam a efetividade do tratamento da tuberculose em Unidades Básicas de Saúde (UBS). Métodos: Levantamento epidemiológico, descritivo, retrospectivo, envolvendo os prontuários médicos de 588 pacientes com tuberculose cadastrados no programa de controle da tuberculose, entre janeiro de 2004 e dezembro de 2008, em duas UBS — Centro de Saúde Escola do Marco (CSEM) e UBS da Pedreira (UBSP) — localizadas na cidade de Belém (PA). Os critérios de exclusão foram ter idade < 18 anos ou > 59 anos e ter alta por transferência ou mudança de diagnóstico. Os dados coletados foram idade, sexo, tipo de tratamento (autoadministrado ou supervisionado), coinfecção por HIV e desfecho do tratamento. Os profissionais de saúde envolvidos no programa da tuberculose das duas UBS foram entrevistados quanto às estratégias utilizadas no controle da doença e à rotina de atendimento. Resultados: Não houve diferenças significativas quanto a idade, sexo e coinfecção com HIV nas duas UBS. A utilização de tratamento supervisionado foi significativamente maior no CSEM que na UBSP, assim como a taxa de cura, enquanto a taxa de abandono foi maior na UBSP que no CSEM. Conclusões: Para pacientes cadastrados em programas de controle da tuberculose em UBS no Brasil, o tratamento supervisionado provavelmente é uma estratégia de extrema importância para se alcançar uma menor taxa de abandono.

Descritores: Tuberculose; Pacientes desistentes do tratamento; Planejamento de assistência ao paciente; Resultado de tratamento.

* Study carried out at the Centro de Saúde Escola do Marco and at the Unidade Básica de Saúde da Pedreira, Belém, Brazil.

Correspondence to: Letícia Paz. Passagem Dalva, 333, Marambaia, CEP 66615-080, Belém, PA, Brasil.

Tel. 55 91 8139-9259. E-mail: letpaz@hotmail.com Financial support: None.

Submitted: 19 July 2011. Accepted, after review: 5 June 2012.

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Paz LNF, Ohnishi MDO, Barbagelata CM, Bastos FA, Oliveira III JAF, Parente IC

Introduction Tuberculosis is considered the leading cause of death from infectious diseases in adults,(1) and, despite being an ancient disease, it remains a serious public health problem worldwide, primarily affecting developing countries.(2) Early diagnosis and prompt pharmacological treatment initiation are essential for effective disease control.(3) In Brazil, it is estimated that there are 50 million infected individuals and that 85,000 new cases occur each year, 6,000 tuberculosisrelated deaths occurring annually.(4) Among the 22 countries that collectively account for 80% of all cases of tuberculosis worldwide, Brazil ranks 19th.(3) In our country, the problem of tuberculosis treatment lies in the high rate of treatment noncompliance, which, in some capitals, can be as high as 25% of treated patients. The great concern about the effectiveness of treatment is due to the fact that noncompliance (or irregular treatment), in addition to not producing cure, can give rise to bacteria that are resistant to standard drugs.(5) This has been a challenge in the individual treatment of patients.(6,7) In view of this situation, the objective of the present study was to analyze the treatment strategies that influence the effectiveness of tuberculosis treatment at two primary care clinics (PCCs) in the city of Belém, Brazil, in order to identify strategies that can improve adherence to tuberculosis treatment and be used by other PCCs in an attempt to increase the effectiveness of disease control.

Methods This was a descriptive, retrospective epidemiological survey of male and female tuberculosis patients in the 18-59 year age bracket enrolled in the tuberculosis control programs at one of two PCCs: Centro de Saúde Escola do Marco (CSEM) or Unidade Básica de Saúde da Pedreira (UBSP). The survey was limited to patients who were enrolled between January of 2004 and December of 2008 and who completed the treatment (satisfactorily or not). We excluded all of the patients who did not meet the pre-established inclusion criteria, as well as those for whom there were missing data in the databases searched. In addition, we excluded those who were transferred (because J Bras Pneumol. 2012;38(4):503-510

they no longer constituted cases treated at the PCCs studied) and those who were found to have been misdiagnosed (because they no longer constituted cases of tuberculosis).

In the study period, 638 and 464 patients, respectively, were diagnosed with tuberculosis at the CSEM and at the UBSP. After applying the inclusion and exclusion criteria to the medical records, we selected a total of 588 patients. Of those, 249 were enrolled in the CSEM tuberculosis control program and 339 were enrolled in the UBSP tuberculosis control program.

The study was performed in two phases.

In the first phase, we analyzed the medical records of the CSEM and UBSP patients, as well as the tuberculosis registries of the Brazilian National Tuberculosis Control Program, together with databases containing all of the available information (including test results and the clinical course of the disease) on those patients.

In the second phase, we interviewed the health professionals (physicians, nurses, and nursing technicians) who had been working at the CSEM or UBSP since at least January of 2004 and who were involved in providing care for tuberculosis patients. The interviews were aimed at gathering information regarding the tuberculosis control strategies used at the two PCCs. In the first phase of the survey, we analyzed possible treatment outcomes (discharge after cure, treatment noncompliance, and death from tuberculosis) and the type of treatment (selfadministered or supervised). In addition, we profiled the treated patients, the profile variables including gender, age, and co-infection with HIV. In the second phase, the tuberculosis control strategies used at the PCCs were analyzed, as was routine clinical care for tuberculosis patients.

The results obtained were statistically analyzed by the chi-square test or Fisher’s exact test (depending on the type of variable) with the program BioEstat, version 5.0. The level of significance was set at p < 0.05 (5%).

All of the patients included in the present study were studied in accordance with the principles of the Declaration of Helsinki, and the study project was approved by the Research Ethics Committee of the Hospital de Clínicas Gaspar Viana (Protocol nº. 069/09).

Results Of the 588 selected patients, 249 and 339, respectively, were treated at the CSEM and

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at the UBSP. Regarding treatment outcomes (Table 1), we found a higher rate of cure among the CSEM patients than among the UBSP patients (p = 0.0016). We also found that the rate of treatment noncompliance at the CSEM was within the goal range established by the Brazilian National Ministry of Health (i.e., < 5%). In addition, selfadministered treatment prevailed at both PCCs (57.43% at the CSEM and 98.23% at the UBSP; Table 2).

There were no statistically significant differences between the CSEM and UBSP patients regarding gender, age, or co-infection with HIV (Tables 3-5). There was a predominance of males at the two PCCs (Table 3), a finding that is in agreement with the literature.(9,10) As can be seen in Table 4, most of the CSEM patients were in the 18-23 year age bracket, whereas most of the UBSP patients were in the 24-29 year age bracket, with no significant differences between the groups in terms of age. Most of the patients Table 1 - Distribution, by treatment outcome, of tuberculosis patients treated at the Centro de Saúde Escola do Marco and at the Unidade Básica de Saúde da Pedreira, both located in the city of Belém, Brazil, 2004-2008.

Place of treatment Treatment CSEM UBSPa outcome n (%) n (%) Cure 229 (91.97) 302 (89.09)* Noncompliance 11 (4.42) 27 (7.96)* Failure 2 (0.80) 0 (0.00) Death 7 (2.81) 4 (1.18) Total 249 (100.00) 333 (98.23) CSEM: Centro de Saúde Escola do Marco; and UBSP: Unidade Básica de Saúde da Pedreira. aThe 6 patients who underwent supervised treatment were excluded. *p = 0.0016.

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who underwent HIV testing were found to be HIV negative (Table 5).

Discussion Treatment noncompliance among tuberculosis patients has been seen as a major problem in tuberculosis control, because in addition to causing individual damage, it endangers public health, leading to treatment failure and the emergence of resistant strains.(5,7,8) Several factors determine or influence adherence to tuberculosis treatment. Therefore, in addition to investigating the dynamics of care and the strategies used at the PCCs studied, we evaluated some of the characteristics of the population profile. In general, there were no significant differences between the CSEM and UBSP patients regarding gender, age, or co-infection with HIV. Males and patients in the 18-29 year age bracket predominated, and there was a low rate of co-infection with HIV. Regarding the factors that are important in assessing the effectiveness of treatment, it is essential to remember that AIDS is chief among the diseases that can accompany tuberculosis.(11) We found that most of the CSEM and UBSP patients who underwent HIV testing were HIV negative, which is at odds with some studies,(12,13) in which most patients were found to have tuberculosis/ HIV co-infection. This might have been due to the difference between the location in which our study was conducted and those in which those studies were conducted in terms of the incidence of HIV. In Brazil, according to official data,(14) the incidence of HIV is much lower in the northern region than in the southeastern and southern regions, where the aforementioned studies were conducted. In addition, the rate of tuberculosis infection is higher in the northern

Table 2 - Distribution, by type of treatment, of tuberculosis patients treated at the Centro de Saúde Escola do Marco and at the Unidade Básica de Saúde da Pedreira, both located in the city of Belém, Brazil, 2004-2008.

Place of treatment Type of CSEM UBSP treatment n (%) n (%) Self-administered 143 (57.43) 333 (98.23) Supervised 106 (42.57) 6 (1.77) Total 249 (100.00) 339 (100.00)

Table 3 - Distribution, by gender, of tuberculosis patients treated at the Centro de Saúde Escola do Marco and at the Unidade Básica de Saúde da Pedreira, both located in the city of Belém, Brazil, 2004-2008.

Place of treatment Gender CSEM UBSP n (%) n (%) Male 126 (50.60) 189 (55.75)* Female 123 (49.40) 150 (44.25) Total 249 (100.00) 339 (100.00)

CSEM: Centro de Saúde Escola do Marco; and UBSP: Unidade Básica de Saúde da Pedreira.

CSEM: Centro de Saúde Escola do Marco; and UBSP: Unidade Básica de Saúde da Pedreira. *p = 0.2487.

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Table 4 - Distribution, by age bracket, of tuberculosis patients treated at the Centro de Saúde Escola do Marco and at the Unidade Básica de Saúde da Pedreira, both located in the city of Belém, Brazil, 2004-2008.

Place of treatment Age bracket, CSEM UBSP years n (%) n (%) 18-23 57 (22.89) 68 (20.06) 24-29 50 (20.08) 71 (20.94) 30-35 37 (14.86) 42 (12.39) 36-41 25 (10.04) 46 (13.57) 42-47 28 (11.24) 56 (16.52) 48-53 33 (13.25) 31 (9.14) 54-59 19 (7.63) 25 (7.37) Total 249 (100.00) 339 (100.00) CSEM: Centro de Saúde Escola do Marco; and UBSP: Unidade Básica de Saúde da Pedreira.

Table 5 - Tuberculosis/HIV co-infection in tuberculosis patients treated at the Centro de Saúde Escola do Marco and at the Unidade Básica de Saúde da Pedreira, both located in the city of Belém, Brazil, 2004-2008.

Place of treatment Tuberculosis/HIV CSEM UBSP co-infection n (%) n (%) Present 9 (5.03) 8 (5.75)* Absent 170 (94.97) 131 (94.25) Total 179 (100.00) 139 (100.00) CSEM: Centro de Saúde Escola do Marco; and UBSP: Unidade Básica de Saúde da Pedreira. *p = 0.9588.

region than in the southern and southeastern regions.(14) Regarding the type of treatment (Table 2), the CSEM is set apart by one peculiarity: the use of directly observed treatment, short-course (DOTS).

In Brazil, the DOTS strategy was implemented in 1998 and increased the rate of detection by 18%, as well as significantly increasing tuberculosis treatment success rates.(4) The DOTS strategy is recommended by the World Health Organization and is based on direct supervision of antituberculosis drug intake (at least three weekly observations in the first two months and one weekly observation for the duration of the treatment). In addition, the DOTS strategy plays an essential role in improving treatment adherence and, consequently, in increasing cure and discharge rates. The implementation of supervised treatment in countries such as Peru has been shown to J Bras Pneumol. 2012;38(4):503-510

be an effective strategy, reducing the rates of treatment noncompliance.(15) In Brazil, the DOTS strategy has been implemented at various facilities in recent years.

However, because of problems that are inherent to the current public health system, such as limited human and financial resources, there are operational difficulties in the use of DOTS for most patients undergoing tuberculosis treatment.

(16) Therefore, although DOTS was implemented at the CSEM in 2002, most patients still undergo self-administered treatment.

Unlike what occurred at the CSEM, supervised treatment was not used at the UBSP during most of the study period, having been implemented in the second half of 2008.

When analyzing the mechanisms of care delivery at the two PCCs between January of 2004 and December of 2008, we observed the differences between the use of DOTS and the use of self-administered treatment, as well as the strategies used for improving treatment success.

In this context, the CSEM provides two lines of care for the diagnosis and treatment of tuberculosis: primary health care, accounting for 80% of cases; and specialty care referral.

Primary health care is related to patients who seek medical attention on their own initiative.

Patients with symptoms of tuberculosis are first referred to the nursing ward, where they are interviewed regarding epidemiological links, risk factors, and the possible presence of another medical condition, two sputum samples being collected for sputum smear microscopy. Typically, the first sample is collected on the same day and the second sample is collected on the following day. Sputum smear microscopy is performed in the CSEM laboratory. In addition, for all patients, vulnerable contacts, such as children, are traced and notified. Therefore, as is recommended by the Brazilian National Ministry of Health,(4) the patients treated at the CSEM receive instructions regarding their treatment before starting chemotherapy. In the initial interview, they receive information, in accessible language, regarding the characteristics of the disease and the treatment regimen to be used, including drugs, treatment duration, benefits of regular medication use, consequences of treatment noncompliance, and possible adverse drug effects. However, only patients who have clinical complications during the course of the treatment or who are referred for specialist care

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consult with the CSEM physicians. This is due to the fact that the CSEM has no team providing care exclusively for tuberculosis patients. In addition, the CSEM is a referral center for tuberculosis and therefore receives a larger number of patients.

At the CSEM, in contrast to the World Health Organization recommendation, DOTS is not used in all cases of active tuberculosis, priority being given to the following cases: smear-positive cases; cases of treatment noncompliance; cases of recurrence; cases of treatment failure; and patients facing social risks (such as alcoholism, poor nutrition, and living alone).(16) According to Morrone et al.,(17) one way to overcome the difficulties in adopting supervised treatment is to restrict it to patients who really need it, preventing noncompliance with the assigned treatment.

Patients receiving DOTS are therefore selected on the basis of the aforementioned priorities and undergo two phases of treatment: the first phase, in which the patient has to report to the clinic Monday through Friday for follow-up and medication intake; and the second phase, in which the patient reports to the clinic twice a week.

Regarding the strategies employed at the CSEM, it is of note that the number of visits to the clinic for medication intake in the two treatment phases is higher than that recommended by the Brazilian National Ministry of Health.

This peculiarity of the CSEM is essential for the effectiveness of tuberculosis treatment, given that the first two to three months of treatment is when noncompliance is most likely to occur, which underscores the importance of adopting measures to reduce noncompliance as soon as the treatment begins. Therefore, the strategy of frequent follow-up visits is an intervention designed to be implemented at the beginning of treatment and has been shown to have favorable results.(18) Other strategies that have been used at the CSEM since the implementation of DOTS on September 16, 2002, in order to increase treatment effectiveness include material incentives, such as transportation passes and meals (breakfast or porridge), and non-material incentives, such as caring for patients and providing clarification to families. This caring refers to improved access to treatment—given that one of the reasons that can lead to noncompliance is the distance between the place of residence and the hospital or health

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care facility(11)—and to giving weight to patient complaints. Osterberg & Blaschke(19) found that providing little or no information regarding the possible side effects of the medication is one of the major obstacles to treatment compliance.

In contrast, reaching out to patients and family members fosters mutual understanding of views on the disease and its treatment, promotes clarification, and attempts to establish a bond that will promote trust in scientific knowledge.(1) This clarification is essential, given that families play a role in providing support to tuberculosis patients, although in some cases families are unable to provide the support required in order to achieve favorable results. Providing information to and raising awareness of families are essential so that families do not negatively affect treatment compliance.

Still on the topic of supervised treatment, a group strategy is adopted at the CSEM. Therefore, patients receive the medication at the same time of day, which facilitates rapport and stimulates the exchange of information. This strategy allows patients not to feel isolated and helpless.

Self-administered treatment, which is another form of treatment at the CSEM, is also given appropriate attention. According to the professionals interviewed, the priorities include “treating patients well and listening carefully to them” and “giving weight to their complaints”, as well as “ensuring the quality of sputum smear microscopy”. Patients undergoing self-administered treatment receive sufficient medication for 30 days of treatment during a six-month period.

In cases of failure to attend a routine visit, either for self-administered treatment or for DOTS, the CSEM immediately contacts the patient or family members. First, whenever possible, telephone contact is attempted in order to clarify the reason for the absence. Subsequently, if the first contact attempt fails, a representative of the clinic goes to the place of residence of the patient in a final attempt to bring the patient back to treatment.

Secondary care referral, which is also available at the CSEM, corresponds to scheduled demand.

This type of care allows clarification of difficult cases, such as complicated cases that do not progress as expected, as well as diagnostic elucidation of smear-negative cases suspected of treatment failure, multidrug resistance, and adverse effects.

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At the CSEM, the care provided to tuberculosis patients includes HIV serology, and, since 2008, rapid HIV testing has been performed at the clinic itself. If the test result is positive, the patient is referred to the AIDS referral center, which is prepared to treat the two infections, given that immunocompromised patients should receive twice as much attention because they are at a higher risk of developing the disease and its complications.(4) In addition, co-infection with HIV/AIDS is an important factor for the unfavorable outcome of tuberculosis treatment.(20) Therefore, early diagnosis of co-infection allows health care providers to adjust the treatment to the actual needs of the patient and reduces the weaknesses resulting from HIV infection, guaranteeing integrated health care and increasing treatment effectiveness.

A similar analysis of the mechanism of care provision for tuberculosis patients at the UBSP revealed that the organizational structure is as follows: completion of a general care form; first medical visit, in which clinical examination is performed; referral for laboratory tests (two sputum smear microscopy tests); and second medical visit or a nursing visit. Patients with a positive sputum smear are enrolled in the program, and notification, investigation, and treatment control forms are completed. At this point, patients receive counseling about the disease and the treatment, undergo a thorough history taking, are prescribed the medications, and are referred for HIV testing at the clinic itself, where rapid HIV testing began to be performed in 2008 (as it did at the CSEM).

It is of note that the rate of tuberculosis/ HIV co-infection was lower at the UBSP than at the CSEM. This is an important difference between the two PCCs, given that measures for prevention and control of HIV and tuberculosis cannot be considered separately. Tuberculosis/ HIV co-infection should be identified at the beginning of treatment so that individualized follow-up procedures can be implemented.(20) We found that most of the patients treated at the UBSP received self-administered treatment.

This type of treatment requires that patients return to the clinic once a month for a routine visit and to receive medications, the clinical and etiological status being monitored.

The UBSP team consists of a general practitioner, a nurse, and a nursing technician, and J Bras Pneumol. 2012;38(4):503-510

this team provides care exclusively for tuberculosis patients, who can also be monitored by a dentist and a psychologist as needed. In cases of failure to attend a routine visit, the health care team telephones the patient or family members in an attempt to prevent treatment noncompliance.

As occurs at the CSEM, the UBSP health care team reaches out to patients and their family members, providing information regarding the disease and the treatment to be followed, in order to establish a bond that will promote trust in the team.

It is of note that, until the second half of 2008, tuberculosis control at the UBSP was based exclusively on self-administered treatment.

However, after the implementation of DOTS, only a few special cases received supervised treatment during the study period, including patients with a low level of education and without adequate family support.

Although DOTS was officially implemented in the second half of 2008 at the UBSP, the clinic still has no structure for the program, because there is no adequate space to welcome patients and there are no financial resources for providing breakfast or other incentives, such as transportation passes.

Analysis of the types of care provided to tuberculosis patients and the strategies used at each PCC investigated in the present study revealed different values in terms of treatment outcomes. Although the cure rates at both PCCs were higher than that set by the Brazilian National Ministry of Heath,(4) i.e., 85% of the estimated number of cases of tuberculosis, the rate of cure was statistically higher at the CSEM than at the UBSP. With regard to treatment noncompliance (Table 1), only the CSEM achieved the national goal set by the Brazilian National Ministry of Health (rate of noncompliance < 5%),(4) with two or three cases of noncompliance per year.

In comparison with the literature, the rate of noncompliance observed at the CSEM was relatively lower than were those found at other health care clinics in Brazil(9,10) providing supervised treatment.

In view of this, we can infer that the use of supervised treatment with additional strategies (i.e., scheduling a higher number of visits to the clinic than that recommended by the Brazilian National Ministry of Health and administering the

Effectiveness of tuberculosis treatment

treatment in a collective fashion) contributes to a lower rate of noncompliance at the CSEM and should be adopted by other health care clinics in an attempt to improve the effectiveness of tuberculosis treatment.

On the basis of these results and considering that there were no statistically significant differences between the CSEM and UBSP patients in terms of age, gender, or co-infection with HIV, we can state that the influence of these factors, although present, as discussed earlier, does not explain the better outcome at the CSEM. In conclusion, DOTS has proven to be an effective strategy to reduce the rates of noncompliance with tuberculosis treatment,(21) reducing the risk of disease transmission in the community and resulting in major changes in the epidemiological indicators of tuberculosis. In addition, for better results in terms of treatment effectiveness, a higher number of visits to the PCCs can be scheduled in the first two to three months of treatment and the strategy of administering the medication in a collective fashion can be used.

It should be noted that the results obtained and discussed in the present study confirm the need for further studies focusing on obtaining data that are more precise and accurate for the development of strategies to improve the effectiveness of tuberculosis treatment and reduce noncompliance.

References 1. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 209 May 25]. Programa Nacional de Controle da Tuberculose. 2008. [Adobe Acrobat document, 33p.]. Available from: http://portal. saude.gov.br/portal/arquivos/pdf/2site_31_05_2011.pdf 2. Paixão LM, Gontijo ED. Perfil de casos de tuberculose notificados e fatores associados ao abandono. Rev Saude Publica. 2007;41(2):205-13. http://dx.doi.org/10.1590/ S0034-89102007000200006 3. 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 4. Brazil. Guia de vigilância epidemiológica. Brasília: Ministério da Saúde; 2005.

5. Ribeiro SA, Amado VM, Camelier AA, Fernandes MM, Schenkman S. Estudo caso-controle de indicadores de abandono em doentes com tuberculose. J Pneumol. 2000;26(6):291-6. http://dx.doi.org/10.1590/ S0102-35862000000600004

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6. Xavier MI, Barreto ML. Tuberculosis in Salvador, Bahia, Brazil, in the 1990s [Article in Portuguese]. Cad Saude Publica. 2007;23(2):445-53. http://dx.doi.org/10.1590/ S0102-311X2007000200021 7. Kritski AL. Fatores de risco para tuberculose multirresistente adquirida. J Pneumol. 2003;29(2): 55-6.

8. Rodrigues L, Barreto M, Kramer M, Barradas Barata Rde C. Brazilian response to tuberculosis: context, challenges and perspectives [Article in Portuguese]. Rev Saude Publica. 2007;41 Suppl 1:1-3. http://dx.doi.org/10.1590/ S0034-89102007000800001 9. Figueiredo TM, Villa TC, Scatena LM, Cardozo Gonzales RI, Ruffino-Netto A, Nogueira Jde A, et al. Performance of primary healthcare services in tuberculosis control.

Rev Saude Publica. 2009;43(5):825-31. http://dx.doi. org/10.1590/S0034-89102009005000054 10. Ignotti E, Oliveira BF, Hartwig S, Oliveira HC, Scatena JH. Analysis of the Tuberculosis Control Program in the city of Cáceres, Brazil, prior to and after the implementation of a Family Health Program. J Bras Pneumol. 2007;33(3):287-94. http://dx.doi.org/10.1590/ S1806-37132007000300010 11. Nogueira PA. Motivos e tempo de internação e o tipo de saída em hospitais de tuberculose do Estado de São Paulo, Brasil - 1981 a 1995. J Pneumol. 2001;27(3):123-9. http://dx.doi.org/10.1590/S0102-35862001000300001 12. Mendes AM, Fensterseifer LM. Tuberculose: porque os pacientes abandonam o tratamento? Bol Pneumol Sanit. 2004;12(1):27-38.

13. Hino P, dos Santos CB, Villa TC, Muniz JN, Monroe AA. Tuberculosis patients submitted to supervised treatment.

Ribeirão Preto-São Paulo-Brazil. 1998 and 1999. Rev Lat Am Enfermagem. 2005;13(1):27-31. http://dx.doi. org/10.1590/S0104-11692005000100005 14. Ruffino-Neto A. Carga da tuberculose: reflexões sobre o tema. J Bras Pneumol. 2004;30(4):37-9.

15. Departamento de Informatica do SUS - DATASUS [homepage on the Internet]. Brasília: Ministério da Saúde [cited 2009 Dec 4]. Indicadores de Morbidade e Fatores de Risco 2008. Available from: http://tabnet. datasus.gov.br/cgi/idb2008/matriz.htm#morb 16. Ruffino-Netto A. Recurrence of tuberculosis. J Bras Pneumol. 2007;33(5):xxvii-xxviii.

17. Morrone N, Solha MS, Cruvinel MC, Morrono Jr N, Freire JA, Barbosa ZL. Tuberculose: tratamento supervisionado “vs.” tratamento auto-administrado. Experiência ambulatorial em instituição filantrópica e revisão da literatura. J Pneumol. 1999;25(4):198-206.

18. Bergel FS, Gouveia N. Frequent return as a novel strategy for tuberculosis treatment adherence [Article in Portuguese].

Rev Saude Publica. 2005;39(6):898-905.

19. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487-97.

20. Albuquerque MF, Leitão CC, Campelo AR, de Souza WV, Salustiano A. Prognostic factors for pulmonary tuberculosis outcome in Recife, Pernambuco, Brazil [Article in Portuguese]. Rev Panam Salud Publica. 2001;9(6):368-74.

21. Programa de Controle da Tuberculose no Município de Jacareí. Tuberculosis control program and implementation of directly observed therapy: municipality of Jacareí, São Paulo, Brazil [Article in Portuguese]. Rev Saude Publica. 2004;38(6):846-7.

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About the authors Letícia Nazareth Fernandes da Paz

Medical Student. Pará State University, Belém, Brazil.

Maria Deise de Oliveira Ohnishi

Assistant Professor I. Pará State University; Adjunct Professor. Pará State University Center; and Pulmonologist. João de Barros Barreto University Hospital, Belém, Brazil.

Camila Melo Barbagelata

Medical Student. Pará State University, Belém, Brazil.

Fabiana de Arruda Bastos

Medical Student. Pará State University, Belém, Brazil.

João Augusto Figueiredo de Oliveira III

Medical Student. Pará State University, Belém, Brazil.

Igor Costa Parente

Medical Student. Pará State University, Belém, Brazil.

J Bras Pneumol. 2012;38(4):503-510

Original Article Tuberculosis, HIV, and poverty: temporal trends in Brazil, the Americas, and worldwide* Tuberculose, HIV e pobreza: tendência temporal no Brasil, Américas e mundo

Raphael Mendonça Guimarães, Andréa de Paula Lobo, Eduardo Aguiar Siqueira, Tuane Franco Farinazzo Borges, Suzane Cristina Costa Melo

Abstract Objective: To analyze the temporal trends of the incidence and prevalence of tuberculosis, with and without HIV co-infection, as well as of the associated mortality, in Brazil, the Americas, and worldwide. Methods: We collected data related to tuberculosis, with and without HIV co-infection, between 1990 and 2010, in Brazil, the Americas, and worldwide. Temporal trends were estimated by linear regression. Results: We identified a trend toward a decrease in tuberculosis prevalence and mortality, and that trend was more pronounced in Brazil and the Americas than worldwide. There was also a trend toward an increase in the incidence of tuberculosis/HIV co-infection, as well as in the rates of detection of new cases of active and latent tuberculosis. The incidence of tuberculosis was found to trend downward in Brazil, whereas it trended upward worldwide. Tuberculosis incidence rates correlated positively with poverty rates and with HIV incidence rates. Conclusions: Social inequality and the advent of AIDS are the major factors that aggravate the current situation of tuberculosis.

In this context, methodical approaches to the assessment of surveillance activities are welcome, because they will identify situations in which the reported tuberculosis data do not reflect the true incidence of this disease.

Keywords: Tuberculosis/epidemiology; HIV; Socioeconomic factors.

Resumo Objetivo: Analisar a tendência temporal das taxas de prevalência, incidência e mortalidade por tuberculose, associada ou não com HIV, no Brasil, nas Américas e no mundo. Métodos: Foram coletados os dados relacionados à tuberculose, com e sem coinfecção por HIV, entre 1990 e 2010, no Brasil, nas Américas e no mundo. As tendências foram estimadas por regressão linear. Resultados: Foi identificada uma tendência de redução nas taxas de prevalência e mortalidade de tuberculose, que foi maior no Brasil e nas Américas que no mundo.

Houve uma tendência crescente na incidência da coinfecção tuberculose/HIV e nas taxas de detecção de casos de tuberculose ativa e latente. Houve uma tendência de redução da incidência de tuberculose no Brasil, mas de aumento dessa no mundo. Houve uma correlação direta das taxas de incidência de tuberculose com as taxas de pobreza e as taxas de incidência de HIV. Conclusões: Desigualdades sociais e o advento da AIDS são os principais fatores que agravam a atual situação da tuberculose. Nesse contexto, abordagens metodológicas para a avaliação das ações de vigilância da tuberculose são bem-vindas, pois essas indicarão situações de dados de notificação da tuberculose que não reflitam a verdadeira incidência dessa doença.

Descritores: Tuberculose/epidemiologia; HIV; Fatores socioeconômicos.

* Study carried out at the Institute of Collective Health Studies, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Correspondence to: Raphael Mendonça Guimarães. Avenida Horácio Macedo, s/n, próximo a Prefeitura Universitária da UFRJ, Ilha do Fundão, Cidade Universitária, CEP 21941-598, Rio de Janeiro, RJ, Brasil.

Tel. 55 21 2598-9274. E-mail: raphael@iesc.ufrj.br Financial support: None.

Submitted: 26 March 2012. Accepted, after review: 12 June 2012.

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Introduction Tuberculosis is a public health problem worldwide, being known as “the neglected calamity”(1) and remaining unresolved in the 21st century.(2) It was estimated that 11% of all adults with tuberculosis in 2001 were co-infected with HIV or had AIDS.(3) The World Health Organization (WHO) estimated that 14% of the 72% of tuberculosis patients tested for HIV in 2009 were found to be HIV-positive.(4) In mortality surveillance systems, co-infection rates have been reported to be as high as 51% in Rio de Janeiro, Brazil.(5) The increase in the rates of tuberculosis/HIV co-infection poses challenges that prevent the reduction in the incidence of both infections, and these challenges have been well documented in recent years. The increase in the overall prevalence of HIV has serious implications for tuberculosis control programs, particularly in countries in which the prevalence of tuberculosis is high. In addition to contributing to an increase in the number of tuberculosis cases, HIV has been a major factor responsible for increased mortality among co-infected patients.(6) Since the 1980s, HIV has been a major factor contributing to the resurgence of tuberculosis in developed and developing countries alike.(7,8) The virus has altered the balance between human beings and Koch’s bacillus, as well as having a noticeable impact on the epidemiology, natural history, and clinical evolution of tuberculosis.

(9,10) Co-infection with tuberculosis/HIV results in higher mortality rates than does HIV infection alone.(5-8) Antituberculosis drug resistance and an increased risk of transmission have also emerged as problems due to noncompliance with the tuberculosis treatment.(7) Because of impaired immune response, HIV-infected patients are at increased risk of reactivation of latent tuberculosis infection, and AIDS is a strong risk factor for death in patients with tuberculosis. In co-infected patients, mortality is commonly related to delayed diagnosis, because some HIV-infected individuals postpone seeking health care in order to avoid receiving an AIDS diagnosis.(11) In addition to tuberculosis/HIV co-infection, poverty is a major reason why tuberculosis remains a public health problem. Tuberculosis and poverty have a bidirectional relationship, which means that poverty can lead to poor health status and vice versa. Individuals with poor health status J Bras Pneumol. 2012;38(4):511-517

have limited job opportunities, and this can lead to poverty, therefore creating a vicious cycle that tends to worsen. The severity and negative impact of tuberculosis are inversely proportional to the Human Development Index, and the uneven distribution of the disease is influenced by several factors, such as landmass, uncontrolled population growth, and the concentration of people living on the outskirts of cities and towns.

The last two factors have long been an unsolved problem. The relationship between poverty and tuberculosis is well documented, as are the risks related to socioeconomic indicators, such as population clusters, poverty, and unemployment.

However, no effective solution has been found.

Although many investments are being made, they focus on tuberculosis treatment rather than prevention. Although there are measures for the prevention and control of tuberculosis, innovative and effective strategies, such as the directly observed treatment, short-course (DOTS) strategy, are still unavailable to most of the population, which is due to a lack of funding and political involvement.(12) Therefore, we posed the following question: what are the trends in tuberculosis incidence, prevalence, and mortality in Brazil, the Americas, and worldwide? In an attempt to answer that question, we conducted the present study, the objective of which was to analyze the temporal trends in the incidence and prevalence of tuberculosis, as well as in the mortality of tuberculosis patients, with and without HIV co-infection, in Brazil, the Americas, and worldwide.(13)

Methods This was an ecological study examining data on the incidence of, prevalence of, and mortality from tuberculosis, with and without HIV co-infection, collected by the WHO between 1990 and 2010. The data were divided among the populations of Brazil, the Americas, and the world, and the tuberculosis incidence, prevalence, and mortality rates were calculated for each of those populations in the period.(6) Initially, scatter plots were drawn for the incidence of, prevalence of, and mortality from tuberculosis, with and without HIV co-infection, in order to visualize the relationship among them. The modeling process was then initiated.

Tuberculosis incidence, prevalence, and mortality

Tuberculosis, HIV, and poverty: temporal trends in Brazil, the Americas, and worldwide

constituted the dependent variable (y), whereas years constituted the independent variable (x). In order to study the trends, we chose to estimate regression models. The advantages of estimating trends using polynomial regression models include the great statistical power of such models, as well as the fact that they are easy to construct and interpret.(12) In order to avoid collinearity among the terms of the regression equation, we used the centered variable. The first model tested was the simple linear regression model (y = β0 + β1x). Subsequently, higher-order models were tested: a second-order or parabolic model (y = β0 + β1x + β2x2); a third-order model (y = β0 + β1x + β2x2 + β3x3); and an exponential model (y = eβ0 + β1x).

The best model was the model that showed the highest coefficient of determination (R2), together with statistical significance (lowest value of p) and unbiased residuals. When two models were statistically similar for the same location, we chose the simpler model, i.e., the lower-order model. A trend was considered significant when its estimated model showed a value of p < 0.05. For the statistical analyses, we used the Statistical Package for the Social Sciences, version 19.0 (SPSS Inc., Chicago, IL, USA). Finally, in order to calculate the average annual percent change in tuberculosis incidence, prevalence, and mortality, we used the Joinpoint Regression Program (Statistical Methodology and Applications Branch and Data Modeling Branch, Surveillance Research Program, National Cancer Institute, Rockville, MD, USA).

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Results Among tuberculosis patients without HIV co-infection, there was a trend toward a decrease in the overall incidence and prevalence of tuberculosis, as well as in the overall mortality from tuberculosis, in Brazil and the Americas.

Between 1990 and 2010, there was a reduction in tuberculosis incidence, prevalence, and mortality over the years in the three populations studied (Table 1). There was an 11.4% reduction in the incidence of tuberculosis worldwide; in Brazil and the Americas, the incidence of tuberculosis was reduced by 48.8% and 50.0%, respectively.

The prevalence of tuberculosis in Brazil, the Americas, and worldwide was reduced by 58.9%, 60.8%, and 24.6%, respectively. The mortality from tuberculosis in Brazil, the Americas, and worldwide was reduced by 70.8%, 70.7%, and 40.0%, respectively.

Table 1 shows, for the 20-year historical series, the estimated annual percent change in tuberculosis incidence, prevalence, and mortality for the populations studied. The trend toward a decrease in tuberculosis incidence, prevalence, and mortality was more pronounced in the Americas and in Brazil than worldwide.

Table 2 shows the secular trends in the estimated incidence and prevalence of tuberculosis, as well as in the estimated mortality from tuberculosis, in Brazil, the Americas, and worldwide in the 1990-2010 period. The trend toward a decrease in the overall prevalence of tuberculosis was more pronounced in the world population than in the Brazilian population, as well as being more pronounced in the Brazilian population

Table 1 - Percent change in tuberculosis incidence, prevalence, and mortality in Brazil, the Americas, and worldwide, 1990-2010. n/100,000 Cumulative Mean rate population change Rates Locations in the study AAPC 95% CI p period 1990 2010 % Incidence Americas 58 29 42.00 −50.0 −3.5 −3.5 to 3.4 < 0.001 World 144 128 139.05 −11.4 −0.4 −0.5 to 0.3 0.006 Brazil 84 43 61.48 −48.8 −3.2 −3.3 to 3.2 < 0.001 Prevalence Americas 92 36 58.67 −60.8 −4.4 −4.6 to 4.3 0.007 World 236 178 234.52 −24.6 −1.9 −2.3 to 1.5 0.04 Brazil 116 47 77.05 −59.5 −4.3 −4.5 to 4.0 < 0.001 Mortality Americas 7.5 2.2 4.22 −70.7 −5.6 −5.8 to 5.3 0.002 World 25 15 21.24 −40.0 −2.4 −2.7 to 2.0 0.03 Brazil 8.9 2.6 5.11 −70.8 −5.5 −5.8 to 5.2 0.002 AAPC: average annual percent change. Source: World Health Organization, 2011.(6)

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than in the population of the Americas; the trend toward a decrease in the estimated mortality from tuberculosis (all forms of tuberculosis, except for tuberculosis/HIV co-infection) per 100,000 population was more pronounced in the world population than in the Brazilian population, as well as being more pronounced in the Brazilian population than in the population of the Americas; the trend toward a decrease in the estimated incidence of tuberculosis (all forms) per 100,000 population was more pronounced in Brazil and the Americas, the estimated incidence of all forms of tuberculosis having slightly increased worldwide; the estimated incidence (new cases with positive sputum smears) per 100,000 population decreased in Brazil and the Americas, having increased worldwide; the upward trend in tuberculosis/ HIV co-infection was more pronounced in the world population than in the population of the Americas, as well as being more pronounced in the Americas than in Brazil; the trend toward an increase in the rates of detection of new cases (all forms) was more pronounced in the Americas than in Brazil, as well as being more pronounced in Brazil than in the world; finally, the trend toward an increase in the rates of detection of new cases (with positive sputum smears) was more pronounced in the Americas than in the world, as well as being more pronounced in the world than in Brazil.

Figures 1 and 2 show the correlation between tuberculosis/HIV co-infection and poverty for the world, as well as showing the incidence of tuberculosis in the countries. There is a direct correlation between tuberculosis/HIV co-infection and poverty, Pearson’s correlation coefficients ranging from 0.58 to 0.80, respectively, for

the proportion of the population living below the poverty line (an economic indicator that is widely used in order to assess the development of countries) and the prevalence of HIV-positive patients in the population.

Figure 1 - Correlation between the proportion of the population living in poverty and the incidence of tuberculosis (TB) worldwide, 2010. Source: World Health Organization, 2011.(6)

Figure 2 - Correlation between the prevalence of HIV infection and the incidence of tuberculosis (TB) worldwide, 2010. Source: World Health Organization, 2011.(6)

Table 2 - Secular trends in the estimated incidence of, prevalence of, and mortality from tuberculosis in Brazil, the Americas, and worldwide, 1990-2010.

Trends Brazil Americas World Linear model R2 Linear model R2 Linear model R2 abc Prevalence of TB y = −3.29x + 113.28 0.98 y = −2.64x + 87.76 0.96 y = −4.25x + 281.27 0.87 y = −0.28x + 8.27 0.95 y = −0.24x + 6.85 0.94 y = −0.49x + 26.62 0.94 Mortality from TBacd y = −2.01x + 83.50 0.99 y = −1.47x + 58.18 0.98 y = −0.55x + 145.15 0.68 Incidenceabc y = −1.16x + 47.24 0.99 y = −0.78x + 31.26 0.98 y = 0.49x + 56.33 0.90 Incidenceace 0.17 y = 43.86x + 378.25 < 0.01 y = 73.91x + 197 0.96 TB/HIV co-infection, %c y = 0.23x + 15.42 y = 1.03x + 66.27 0.56 y = 1.24x + 55.54 0.63 y = 0.53x + 44.61 0.26 Rates of detection of cases, %b y = 0.84x + 65.08 0.57 y = 3.60x + 23.04 0.57 y = 3.18x + 5.61 0.87 Rates of detection of cases, %e TB: tuberculosis. aPer 100,000 population. bAll forms. cEstimation. dAll forms, except for TB/HIV co-infection. eNew cases with positive sputum smears. Source: World Health Organization, 2011.(6)

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Tuberculosis, HIV, and poverty: temporal trends in Brazil, the Americas, and worldwide

Discussion The results shown in Table 1 reveal that there was a significant decrease in the prevalence of tuberculosis in Brazil, the Americas, and worldwide; however, the estimated incidence of the disease per 100,000 population decreased noticeably in Brazil and the Americas but not worldwide.(14) In general, the indicators of tuberculosis and tuberculosis/HIV co-infection assessment are consistent with the rates in Brazil and the Americas but not necessarily with the overall rates, highlighting the significant contribution of Brazil to the rates of the continent and the small contribution of the Americas to the overall rates, possibly influenced more strongly by pockets of poverty in Africa and in countries that are more densely populated, such as China, India, and Russia.(15) Regarding the incidence of tuberculosis without HIV co-infection, the ninth WHO report shows a decrease in the number of cases worldwide, at a rate of 1% per year; in Brazil, the rate of decline is 3% per year for smear-positive cases and for all tuberculosis cases. The exception is the African continent, where the number of HIV cases is extremely high.(1) Regarding the data presented in Table 2, in all cases, the best descriptive model was the linear model, which revealed a relatively stable and homogeneous trend, as ratified by the (mostly) high coefficients of determination (R2).

We found a downward trend in the estimated prevalence of all forms of tuberculosis, with a more significant reduction in the overall rates. The trend toward a decrease in the estimated mortality from tuberculosis (without HIV co-infection) was most pronounced in Brazil. Regarding the incidence of tuberculosis (bacillary forms and all forms of tuberculosis), we found a downward trend in Brazil and the Americas and an upward trend worldwide, other world territories, such as Africa, having been found to contribute to the global burden of disease.

We found an upward trend in the proportion of tuberculosis/HIV co-infection cases in Brazil, the Americas, and worldwide, the overall rates being particularly high. This constitutes further evidence of the contribution of other continents to the global burden of disease, as well as reflecting the impact that HIV infection and AIDS have on the occurrence of tuberculosis cases worldwide.

Finally, the trend in the indicators of health care

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quality suggests an improvement in the sensitivity of health care systems in screening for cases of tuberculosis (active or latent), reflecting an improved performance of health care facilities in establishing diagnosis for early treatment and possible cure.

Tuberculosis surveillance is aimed at identifying tuberculosis cases in the population, allowing the adoption of measures to interrupt the transmission of the disease to susceptible individuals. However, the cases that are diagnosed at and reported by health care facilities possibly represent only a proportion of the actual number of tuberculosis cases.(16) The detection of new cases has increased over time. This contributes to early treatment, which in turn contributes to downward trends in tuberculosis incidence, prevalence, and mortality.

However, other measures must be adopted in order to achieve the goals established by the WHO. The estimation of the number of tuberculosis cases in a given population has been a challenge to epidemiologists and tuberculosis control planners. Current indirect methods of estimation depend on the accuracy of other tuberculosisrelated data, such as the number of individuals infected with Mycobacterium tuberculosis and the number of deaths. Such data depend on the effective functioning of health care systems.(16) Because studies of tuberculosis prevalence are costly and methodologically complex, few such studies have been conducted. In this context, methodical approaches to the assessment of tuberculosis surveillance activities are welcome because they can identify situations in which the reported incidence of tuberculosis differs from the true incidence of the disease.(17) With regard to tuberculosis treatment, many challenges are encountered, such as improving treatment adherence, making the DOTS strategy more widely available (with quality control), decentralizing the programs, increasing access to treatment, and expanding the coverage of the program to the entire network of primary health care clinics. Therefore, the WHO has set some resolution goals: to detect 70% of the estimated cases; to cure 85% of the reported cases; and to reduce treatment noncompliance to less than 5%. In addition, one of the millennium goals set by the WHO is to reduce tuberculosis prevalence and mortality by half by 2015, by means of the Stop TB Strategy.(12) J Bras Pneumol. 2012;38(4):511-517

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The increase in the rates of tuberculosis/HIV co-infection poses challenges that prevent the reduction in the incidence of both infections.(13) Data show that immunocompetent individuals infected with M. tuberculosis have a 10% chance of developing the disease over the course of their lifetime; among HIV-infected individuals without therapeutic intervention, that chance is approximately 10% per year.(9) Annual data indicate that the mortality rates are higher in HIV-positive patients who are co-infected with tuberculosis than in those who are not. Infection with HIV is currently a major risk factor for developing tuberculosis.(15) Tuberculosis and AIDS are diseases of such magnitude that they are not confined by biological barriers, constituting a serious social problem.

Individuals become vulnerable when they assume that they are not at risk and therefore neglect self-care; in addition, limited access to health care increases patient vulnerability.(18) The epidemiological aspects of the association between tuberculosis and AIDS represent a major challenge, given the difficulties in coordinating tuberculosis and AIDS control measures. These measures are performed under separate programs, which do not coordinate efforts and which adopt control policies at different levels of health care.

Nearly all health indicators confirm the association between disease and low socioeconomic status. Respiratory and infectious diseases are two groups of diseases specifically reported as being effects of deprivation. Tuberculosis, in particular, has historically been associated with high poverty rates. The decline in the number of reported cases of tuberculosis, which began after the advent of effective chemotherapy, might have been due to the reduction in overpopulation and the improvement in nutritional and social status.(13) Tuberculosis has traditionally been a disease of the poor. However, because poverty is multifaceted, it is difficult to assess that. Moreover, poverty levels are relative to the wealth of society as a whole. The poverty and deprivation indices used range from extremely simple indices to extremely complex indices.(19) Exactly how poverty can directly cause tuberculosis remains unclear. Poverty probably results in very poor nutrition, which probably makes the immune system more vulnerable to invasion by organisms, such as M. tuberculosis.(20) J Bras Pneumol. 2012;38(4):511-517

Protein malnutrition is associated with changes in immune functions mediated by T cells, and animal studies have shown that BCG vaccination is less effective in protein-deficient animals than in normally nourished animals. Therefore, wherever there is social deprivation, particularly in areas with poor housing, high unemployment rates, and low income, there should be an increased awareness of the possibility of diagnosing tuberculosis.(21) It should be noted that the worsening of social and economic conditions results in significant degradation of living conditions, increasing the vulnerability of individuals and, consequently, the risk of tuberculosis/HIV co-infection.(22) In this sense, national planning for the restructuring of health care systems is as important as funding, leading to integrated health care systems and decentralized care in order to improve treatment adherence. The global health issues discussed in the last decade by governments, donor organizations, and national leaders should not be forgotten at this important stage of the combined pandemic (and, in particular, of the combined pandemic associated with poverty).

There is a lack of communication between AIDS programs and tuberculosis programs. More often than not, co-infected patients remain unidentified until death; this highlights a failure of the health care system to detect, diagnose, and treat these related diseases.(8) Therefore, efforts to prevent and control tuberculosis/HIV co-infection in impoverished populations, who have limited access to health care, are unlikely to succeed without an integrated approach that seeks to reduce the underlying social inequalities for which Brazil has been known.

References 1. Figueiredo TM, Villa TC, Scatena LM, Cardozo Gonzales RI, Ruffino-Netto A, Nogueira Jde A, et al. Performance of primary healthcare services in tuberculosis control.

Rev Saude Publica. 2009;43(5):825-31. http://dx.doi. org/10.1590/S0034-89102009005000054 2. Hijjar MA, Gerhardt G, Teixeira GM, Procópio MJ. Retrospect of tuberculosis control in Brazil [Article in Portuguese]. Rev Saude Publica. 2007;41 Suppl 1:50-8. http://dx.doi.org/10.1590/S0034-89102007000800008 3. Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C. Tuberculosis. Lancet. 2003;362(9387):887-99. http:// dx.doi.org/10.1016/S0140-6736(03)14333-4 4. World Health Organization [homepage on the Internet].

Geneva: World Health Organization [cited 2010 Jul 13]. Global Tuberculosis Control: Epidemiology, Strategy, Financing. WHO report 2009. [Adobe Acrobat

Tuberculosis, HIV, and poverty: temporal trends in Brazil, the Americas, and worldwide

document, 314p.]. Available from: http http://www.who. int/tb/publications/global_report/2009/pdf/full_report.pdf 5. Oliveira HB, Marín-León L, Cardoso JC. Differences in mortality profile of tuberculosis patients related to tuberculosis-AIDS co-morbidity [Article in Portuguese].

Rev Saude Publica. 2004;38(4):503-10. PMid:15311289.

6. World Health Organization [homepage on the Internet].

Geneva: World Health Organization [cited 2010 Jul 11].

Global tuberculosis control: WHO report 2011. [Adobe Acrobat document, 258p.]. Available from: http://www. who.int/tb/publications/global_report/2011/gtbr11_full.pdf 7. Muniz JN, Ruffino-Netto A, Villa TC, Yamamura M, Arcencio R, Cardozo-Gonzales RI. Epidemiological aspects of human immunodeficiency virus/tuberculosis co-infection in Ribeirão Preto, Brazil from 1998 to 2003.

J Bras Pneumol. 2006;32(6):529-34. PMid:17435903. http://dx.doi.org/10.1590/S1806-37132006000600010 8. Prado TN, Caus AL, Marques M, Maciel EL, Golub JE, Miranda AE. Epidemiological profile of adult patients with tuberculosis and AIDS in the state of Espírito Santo, Brazil: cross-referencing tuberculosis and AIDS databases.

J Bras Pneumol. 2011;37(1):93-9. PMid:21390437. http://dx.doi.org/10.1590/S1806-37132011000100014 9. Maher D, Smeeth L, Sekajugo J. Health transition in Africa: practical policy proposals for primary care. Bull World Health Organ. 2010;88(12):943-8. PMid:21124720 PMCid:2995191. http://dx.doi.org/10.2471/BLT.10.077891 10. Sester M, Giehl C, McNerney R, Kampmann B, Walzl G, Cuchí P, et al. Challenges and perspectives for improved management of HIV/ Mycobacterium tuberculosis co-infection. Eur Respir J. 2010;36(6):1242-7. PMid:21119204. http://dx.doi. org/10.1183/09031936.00040910 11. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic.

Arch Intern Med. 2003;163(9):1009-21. PMid:12742798. http://dx.doi.org/10.1001/archinte.163.9.1009 12. Vendramini SH, Villa TC, Santos Mde L, Gazetta CE. Current epidemiological aspects of tuberculosis and the impact of the DOTS strategy in disease control. Rev Lat Am Enfermagem. 2007;15(1):171-3. PMid:17375249. http://dx.doi.org/10.1590/S0104-11692007000100025 13. Jamal LF, Moherdaui F. Tuberculosis and HIV infection in Brazil: magnitude of the problem and strategies

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for control [Article in Portuguese]. Rev Saude Publica. 2007;41 Suppl 1:104-10. http://dx.doi. org/10.1590/S0034-89102007000800014 14. World Health Organization [homepage on the Internet].

Geneva: World Health Organization [cited 2010 Jul 11].

Childhood tuberculosis neglected, despite available remedies. Available from: http://www.who.int/mediacentre/ news/releases/2012/tb_20120321/en/index.html 15. Muniz JN, Ruffino-Netto A, Villa TC, Yamamura M, Arcencio R, Cardozo-Gonzales RI. Epidemiological aspects of human immunodeficiency virus/tuberculosis co-infection in Ribeirão Preto, Brazil from 1998 to 2003.

J Bras Pneumol. 2006;32(6):529-34. PMid:17435903. http://dx.doi.org/10.1590/S1806-37132006000600010 16. Assunção RM, Barreto SM, Guerra HL, Sakurai E. Maps of epidemiological rates: a Bayesian approach [Article in Portuguese]. Cad Saude Publica. 1998;14(4):713-23.

PMid:9878904.

17. Rylance J, Pai M, Lienhardt C, Garner P. Priorities for tuberculosis research: a systematic review. Lancet Infect Dis. 2010;10(12):886-92. http://dx.doi.org/10.1016/ S1473-3099(10)70201-2 18. Campion S, Cohen MS, McMichael AJ, Galvin S, Goonetilleke N. Improved detection of latent Mycobacterium tuberculosis infection in HIV-1 seropositive individuals using cultured cellular assays. Eur J Immunol. 2011;41(1):255-7.

PMid:21182097 PMCid:3119189. http://dx.doi.org/10.1002/ eji.201040296 19. Van Vooren JP, Schepers K, Wanlin M. Pulmonary tuberculosis [Article in French]. Rev Med Brux. 2010;31(4):260-6. PMid:21089402.

20. Kyeyune R, den Boon S, Cattamanchi A, Davis JL, Worodria W, Yoo SD, et al. Causes of early mortality in HIV-infected TB suspects in an East African referral hospital. J Acquir Immune Defic Syndr. 2010;55(4):446-50. http://dx.doi. org/10.1097/QAI.0b013e3181eb611a 21. Vendramini SH, Santos NS, Santos Mde L, ChiaravallotiNeto F, Ponce MA, Gazetta CE, et al. Spatial analysis of tuberculosis/HIV coinfection: its relation with socioeconomic levels in a city in south-eastern Brazil [Article in Portuguese]. Rev Soc Bras Med Trop. 2010;43(5):536-41. PMid:21085865. http://dx.doi. org/10.1590/S0037-86822010000500013 22. Girardi E. Epidemiology and control of tuberculosis in Italy [Article in Italian]. G Ital Med Lav Ergon. 2010;32(3):256-9.

About the authors Raphael Mendonça Guimarães

Adjunct Professor. Institute of Collective Health Studies, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Andréa de Paula Lobo

Epidemiologist. Brazilian National Tuberculosis Control Program, Secretaria de Vigilância em Saúde/Ministério da Saúde – SVS/ MS, Brazilian National Ministry of Health Department of Health Surveillance – Brasília, Brazil.

Eduardo Aguiar Siqueira

Undergraduate Student. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Tuane Franco Farinazzo Borges

Undergraduate Student. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Suzane Cristina Costa Melo

Undergraduate Student. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

J Bras Pneumol. 2012;38(4):511-517

Brief Communication Evolution of public policies and programs for asthma control in Brazil from the perspective of consensus guidelines* Evolução das políticas públicas e programas de controle da asma no Brasil sob a perspectiva dos consensos

Lígia Menezes do Amaral, Pamella Valente Palma, Isabel Cristina Gonçalves Leite

Abstract There is much discussion about effective public policies that allow the proper treatment of asthma, providing care that is comprehensive and centered on asthma patients within their social context. Educating health professionals and asthma patients provides better recognition of symptoms and the triggers of asthma exacerbations, as well as disseminating strategies for avoiding such triggers, thereby ensuring better treatment and quality of life for asthma patients. Asthma imposes an ever-increasing burden on society, in terms of impaired quality of life, morbidity, and health care costs, making this a very important discussion in the field of public policy.

Keywords: Health policy; Asthma; Consensus.

Resumo Percebe-se que muito se discute sobre políticas públicas eficazes que possibilitem o tratamento adequado da asma, oferecendo um atendimento integral e centrado no paciente asmático dentro do seu contexto social.

Educar profissionais de saúde e a população de asmáticos possibilita um melhor reconhecimento dos sintomas, dos fatores desencadeantes de exacerbações e das formas para evitá-los, garantindo melhor tratamento e qualidade de vida do paciente. A asma impõe crescente carga à sociedade em termos de redução da qualidade de vida, custos com cuidados de saúde e morbidade. Por isso, torna-se de suma importância sua discussão no campo das políticas públicas.

Descritores: Política de saúde; Asma; Consenso.

Asthma imposes an ever-increasing burden on society, in terms of impaired quality of life, morbidity, and health care costs. The fact that the population with a lower income and a lower level of education is more vulnerable to the morbidity caused by asthma is often attributed to issues of access to health care services and drugs, as well as to educational issues.(1-3) It is therefore imperative to discuss asthma in the field of public policy.

In 1996, the Brazilian Thoracic Association, the Brazilian Association of Allergists and Immunopathologists, and the Brazilian Society of Pediatrics published the First Brazilian

Consensus on Asthma Education,(4) drawing a plan for asthma education and control. Chart 1 summarizes the issues addressed in the Brazilian consensus guidelines for asthma.

In various Brazilian cities, programs were created in an attempt to meet the goals set by the First Brazilian Consensus on Asthma Education (Figure 1). In 1996, a program designated Criança que Chia (Wheezing Child)—a joint venture of the Belo Horizonte Municipal Department of Health and the Pediatric Pulmonology Department of the Federal University of Minas Gerais Hospital das Clínicas—was implemented. The primary objective of the program was to reduce the morbidity and

* Study carried out under the auspices of the Graduate Program in Collective Health, Department of Collective Health, Universidade Federal de Juiz de Fora – UFJF, Federal University of Juiz de Fora – School of Medicine, Juiz de Fora, Brazil.

Correspondence to: Lígia Menezes do Amaral. Hospital Universitário, Universidade Federal de Juiz de Fora, Unidade Santa Catarina, Serviço de Clínica Médica, Rua Catulo Breviglieri s/nº, Santa Catarina, CEP 36036-110, Juiz de Fora, MG, Brasil.

Tel. 55 32 2102-3830. E-mail: ligia.ma@hotmail.com Financial support: Pamella Valente Palma is the recipient of a scholarship from the Programa Institucional de Bolsas de Iniciação Científica (PIBIC, Institutional Program for Scientific Initiation Scholarships) from the Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development).

Submitted: 20 April 2012. Accepted, after review: 8 June 2012.

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Evolution of public policies and programs for asthma control in Brazil from the perspective of consensus guidelines

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Chart 1 - Brazilian consensus guidelines for asthma management.

Brazilian consensus guidelines for asthma Year Major topics discussed management First Brazilian Consensus 1996 The guidelines propose the basis for the development and implementation of on Asthma Education an asthma treatment education program adjusted to the social, economic, and cultural conditions of the target population.

Second Brazilian Consensus on Asthma Management

1998

The primary objectives of the program are as follows: • To inform the population that asthma is a chronic pulmonary disease that can be controlled if treated appropriately, appropriate treatment allowing asthma patients to lead a normal life • To educate health professionals, to guarantee an accurate diagnosis, to guarantee an appropriate therapeutic approach, and to encourage patients and family members to participate actively in the treatment • To reduce the morbidity and mortality from asthma • To educate asthma patients so that they can recognize asthma symptoms, avoid triggering factors, receive the best treatment, and improve their quality of life Definition of asthma: Chronic inflammatory disease of the airways characterized by the following: • Airflow obstruction that is reversible spontaneously or through treatment • Inflammation with involvement of various cells, particularly mast cells and eosinophils • Bronchial hyperresponsiveness • Recurrent episodes of wheezing, dyspnea, chest tightness, and cough, particularly at night and in the morning upon waking Pathology and pathogenesis: Hypertrophy and hyperactivity of the submucosal glands, which can be infiltrated by eosinophils; mucus plug formation; smooth muscle hypertrophy; basement membrane thickening; mucosal and submucosal edema; and eosinophil, neutrophil, plasma cell, macrophage, and lymphocyte infiltration Diagnosis: Clinical diagnosis is based on episodic symptoms that are consistent with the disease, on a favorable response to treatment, and on the exclusion of alternative diagnoses.

Functional diagnosis is recommended when the symptoms are atypical or when the disease onset is recent.

Quality of life assessment is described as a method for calculating the impact of asthma on patients.

Treatment: Emphasis is placed on pharmacological treatment, treatment objectives being as follows: to prevent death and long-term risks, including persistent airflow limitation; to eliminate or minimize symptoms; to allow patients to perform their regular activities at work and school; to eliminate asthma attacks and the need for emergency room visits and hospitalizations; to eliminate or reduce the need for bronchodilator use for symptom relief; and to allow normal growth in children.

Asthma medications are divided into two groups: control medications and rescue medications.

Considerations regarding education, follow-up, and action plans Treatment of acute asthma in adults

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Chart 1 - Continued...

Brazilian consensus guidelines for asthma Year management Third Brazilian 2002 Consensus on Asthma Management

Major topics discussed The introduction is immediately followed by the Carta de Salvador (Salvador Charter), which was signed by the presidents of the medical associations involved in the development of the consensus guidelines. In the Salvador Charter, which was approved by the participants of an assembly meeting that was held during the Third Brazilian Conference on Asthma, the 50,000 members of the Brazilian Thoracic Association, the Brazilian Society of Pediatrics, the Brazilian Association of Allergists and Immunopathologists, and the Brazilian Clinical Medicine Society informed the then Minister of Health José Serra of the urgency in implementing the National Asthma Control Plan.

Definition of asthma: Asthma is a chronic inflammatory disease characterized by lower airway hyperresponsiveness and variable airflow limitation that is reversible spontaneously or through treatment. The clinical manifestations of asthma include recurrent episodes of wheezing, dyspnea, chest tightness, and cough. The disease results from the interaction among genetic mechanisms, environmental exposure, and other factors that lead to the onset and maintenance of the symptoms.

Pathology and pathogenesis: Inflammation is described as the most important pathophysiological mechanism of asthma, being found in patients with recent-onset asthma, in those with mild asthma, and even in those who are asymptomatic.

Diagnosis: The diagnosis of asthma should be based on clinical and functional parameters, as well as on allergy assessment. The classification of disease severity is as follows: intermittent asthma; mild persistent asthma; moderate persistent asthma; and severe persistent asthma.

Treatment: The role of inhaled corticosteroids is highlighted, the use of inhaled corticosteroids being associated with a reduction in mortality and in the number of hospitalizations for asthma.

Fourth Brazilian Guidelines for Asthma Management

2006

Asthma education programs: The goals of asthma education programs include explaining the chronicity of asthma to patients, assisting patients in recognizing the symptoms, assisting patients in identifying aggravating factors, instructing patients on how to avoid aggravating factors, instructing patients on how to use appropriate medication correctly (i.e. using the appropriate technique), and instructing patients on how to execute an action plan.

Definition of asthma: The previous definition was maintained.

Pathology and pathogenesis: Emphasis is given to bronchial remodeling, which affects airway architecture and leads to irreversible airway obstruction in certain patients.

Diagnosis: The diagnosis should be based on clinical findings and, whenever possible, on pulmonary function test results and allergy assessment.

Treatment: The importance of asthma control is highlighted. Complete asthma control is often achieved with the currently available treatments. The objective of asthma treatment is to maintain asthma control for prolonged periods, and the following should always be taken into consideration: potential adverse effects; drug interactions; and medication costs.

The classification of the disease is based on the levels of asthma control.

Asthma prevention programs: Asthma education can be provided to the general population, health professionals, asthma patients, family members, and caregivers. Asthma education should be provided in schools, companies (public and private), and health insurance companies.

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Chart 1 - Continued...

Brazilian consensus guidelines for asthma Year management Brazilian Thoracic 2012 Association Guidelines for Asthma Management – 2012

Major topics discussed Definition of asthma: Although the previous definition was maintained, it now includes the fact that airflow obstruction is intrapulmonary and generalized.

Epidemiology: The estimated number of asthma patients in Brazil is 20 million.

Burden of disease: Expenditures on severe asthma account for approximately 25% of the family income of poorer patients.

Diagnosis: The concepts related to the clinical diagnosis of asthma were maintained, the objectives of functional diagnosis by spirometry being highlighted: to establish the diagnosis; to document the severity of airflow obstruction; and to monitor the course of the disease and consequent changes in the treatment.

Classification: The classification of the disease was based on the levels of asthma control, disease severity being determined after the exclusion of causes of uncontrolled asthma.

Treatment: Health care components • physician-patient partnership • identification and control of risk factors • asthma evaluation, treatment, and control • prevention and control of future risks • special situations in asthma management

mortality from respiratory diseases in children, particularly the morbidity and mortality from pneumonia and asthma. Before the implementation of the program, treatment was based exclusively on emergency room visits and patient follow-up was inadequate, which resulted in high hospitalization rates. The remaining objectives of the program were as follows(5,6): • to invest in the training of health care teams and in the education of patients and family members regarding asthma • to reorganize the care provided to children with asthma, involving the different levels of health care • to provide inhaled medications for exacerbation control and maintenance therapy In 1996, the Program for Integrated Health Care for Children with Asthma in Fortaleza, Brazil, was implemented, with the objectives of reducing morbidity, improving patient perception of disease progression, reducing the need for emergency room visits, and reducing the number of hospitalizations for asthma, therefore reducing the costs of the disease.(5-7) In March of 1996, the

Program for the Treatment of Asthma Patients in São Luís, Brazil, was created.(5,6) In 1998, the Brazilian National Ministry of Health issued Decree no. 3,916/GM/MS, thereby creating the National Drug Policy (as part of the process of decentralization of health care in Brazil) and facilitating access to certain medications for asthma control.(5) In 1999, the Brazilian Thoracic Association, the Brazilian Association of Allergists and Immunopathologists, and the Brazilian Society of Pediatrics, together with the Brazilian Clinical Medicine Society and the Brazilian National Ministry of Health, committed themselves to establishing guidelines for the creation of the Plano Nacional de Controle da Asma (PNCA, National Asthma Control Plan). In 2001, after extensive discussions, the Carta de Salvador (Salvador Charter) was delivered to the Brazilian National Ministry of Health, drawing attention to the urgency of implementing the PNCA in order to provide asthma treatment via the Brazilian Unified Health Care System.(8,9) In 1999, the Program for the Treatment of Asthma Patients in the Federal District of Brasília, Brazil, was created.(5,9) J Bras Pneumol. 2012;38(4):518-525

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Figure 1 - Public policies and programs for asthma control in Brazil, 1996-2012. PROAICA: Programa de Atenção Integral à Saúde da Criança Asmática (Program for Integrated Health Care for Children with Asthma); and PAPA: Programa de Assistência ao Paciente Asmático (Program for the Treatment of Asthma Patients).

Sources: Cerci Neto,(7) Brandão,(14) and Carmo et al.(20)

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Evolution of public policies and programs for asthma control in Brazil from the perspective of consensus guidelines

In 2000, the state of Paraná, Brazil, launched its own control program, designated Programa Crescendo com Saúde – Infecções e Alergias Respiratórias na Infância (Growing up Healthy – Respiratory Infections and Allergies in Children). In 2001, the city of Porto Alegre, Brazil, launched its own program, designated De Volta para Casa e Asma (Going Home and Asthma).(5) On June 23, 2002, the Brazilian National Ministry of Health issued Decree no. 1,318/ GM,(10) which was updated by Decree no. 921/ SAS/MS, issued in November of 2002,(11) whereby the Brazilian Department of Health Care was charged with taking the necessary measures to create treatment guidelines and clinical protocols for patients with severe asthma, to whom drugs such as beclomethasone, budesonide, fenoterol, formoterol, albuterol, and salmeterol were to be exclusively provided. Also in 2002, an asthma control program designated Respira Londrina (Breathe, Londrina) was implemented in the city of Londrina, Brazil, in order to prevent asthma attacks, promoting strategies for the treatment of asthma patients via the primary health care system.(5) In 2003, the Goiás State Department of Health, in partnership with the Federal University of Goiás School of Medicine, developed the Municipal Asthma Plan, which was subsequently designated Catavento – Programa de Controle da Asma de Goiânia (Pinwheel – Goiânia Asthma Control Program).(5) Another program that began to be developed in 2003 was the Plan for Asthma Control in the City of Niterói, Brazil, which was based on the Brazilian National Ministry of Health PNCA. The program consisted of two levels of health care, namely primary health care and tertiary health care, the former being provided via primary health care clinics, family health programs, and community clinics and the latter being provided via a system of referral and counter-referral.(5) In 2004, as part of what would later become the Brazilian National Policy for Integrated Respiratory Care, the Primary Health Care Guidelines for Asthma and Rhinitis were published, with the objective of broadening the scope of the health care provided to such patients, which was limited to symptomatic treatment of asthma exacerbations. Also in 2004, the Londrina asthma control program came to include all 52 family health care clinics in the city. In the same year,

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the Feira de Santana Asthma and Allergic Rhinitis Control Program was implemented in Feira de Santana—the second most populous city in the state of Bahia, Brazil—with the objectives of controlling the two diseases and reducing the numbers of emergency room visits, hospitalizations, and deaths.(11-14) In 2004, by means of a bidding process, 848,560 flasks of beclomethasone dipropionate aerosol (250 µg/dose), 864,000 flasks of beclomethasone dipropionate aerosol (50 µg/ dose), and 293,256 flasks of albuterol aerosol (100 µg) were acquired, an investment totaling R$ 32,685,232.36. The drugs were distributed in the 2004-2005 period to the cities in which the Family Health Program had been implemented. In 2004, the process of development and implementation of the Feira de Santana Asthma and Allergic Rhinitis Control Program began, with the participation of the Bahia State Asthma and Allergic Rhinitis Control Program. The program resulted in a significant reduction in mortality, in the number of emergency room visits, and in the rates of hospitalization for asthma in the following year.(5) In 2004, in the city of Rio de Janeiro, Brazil, the Health Care Plan for Asthma and Rhinitis Patients in the City of Rio de Janeiro was developed. The overall objective was to reduce the morbidity and mortality from asthma among residents of the city of Rio de Janeiro. Specific objectives included training health professionals, promoting continuing education for health professionals, improving the information system, and increasing the coverage of asthma patient follow-up by establishing new asthma referral centers. In 2006, there were 33 such facilities for children with asthma. Of those 33, 3 provided treatment to children with severe asthma and 30 provided treatment to children with mild to moderate asthma. Another 16 facilities provided treatment to adult asthma patients. The Rio de Janeiro program resulted in a reduction in hospitalizations and emergency room visits.(5) Brazilian National Ministry of Health Decree no.

2,084(13) allocated R$ 0.95/inhabitant per year for the treatment of asthma and rhinitis at the state and municipal levels, under agreements established by the Comissões Intergestores Bipartites (Bipartite Leadership Committees). At that time, the states of Minas Gerais, Amapá, Amazonas, and Pará, as well as some cities in the state of Paraíba, chose not to distribute the federal resources allocated J Bras Pneumol. 2012;38(4):518-525

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to asthma and rhinitis expenditures.(9) In 2005, the Santa Casa Sisters of Mercy Hospital Complex in Vitória, Brazil, in partnership with the Vitória City Hall, created the Asthma Referral Center for adolescents and adults in the city (with a multidisciplinary team) as part of the Santa Casa Sisters of Mercy Hospital Complex Asthma and Rhinitis Control Program.(5,13) In May of 2006, the year in which the Fourth Brazilian Guidelines for Asthma Management were published, representatives of medical associations, of the Brazilian National Ministry of Health, and of thirteen asthma programs that were currently active met in Brasília, Brazil, in order to discuss the core aspects of those programs, i.e., professional training, planning, implementation, epidemiological coverage, funding, and results. The representatives discussed the importance of developing public policies for asthma in the context of integrated health care and health surveillance, on the basis of the experience accumulated in the various programs existing in the country at that time.(15) In January of 2007, Brazilian National Ministry of Health Decree no. 204/GM regulated the allocation of federal resources to health care activities and services in the form of block funding, such allocation being monitored and controlled. Chapter II of Decree no. 204/GM deals with the purchase of drugs and materials for pharmaceutical services provided under various programs, including the asthma and rhinitis program.(12) In November of 2009, Brazilian National Ministry of Health Decree no. 2,981 approved the specialized component of pharmaceutical care, and, in December of 2010, Brazilian National Ministry of Health Decree no. 4,217(16) approved the norms for the funding and implementation of the Basic Component of Pharmaceutical Care, the asthma and rhinitis program receiving drugs on the National Drug List of the Basic Component of Pharmaceutical Care.(7) In 2012, the Brazilian Thoracic Association Guidelines for Asthma Management were published, again emphasizing the components of the health care provided to asthma patients. In May of 2012, a program designated Brasil Carinhoso (A Caring Brazil) was launched, consisting of a set of measures aimed at reducing childhood poverty; one of the measures is the free distribution of three drugs for the treatment of asthma (ipratropium bromide, beclomethasone, and albuterol) via J Bras Pneumol. 2012;38(4):518-525

the Saúde Não Tem Preço (Health Is Priceless) program.(17,18) Effective public policies that allow appropriate asthma treatment that is centered on asthma patients within their social context have long been called for. In the Fourth Brazilian Guidelines for Asthma Management,(15) Cerci Neto, Ferreira Filho, and Bueno concluded that there is a satisfactory number of health professionals involved and that the environment is favorable, given that full public funding is provided for the programs.

However, we emphasize the importance of a better use of public health strategies, such as family health programs, outreach, humanization, and community health programs, in order to offer high-quality integrated health care to the greatest possible number of asthma patients.(19,20)

References 1. Braman SS. The global burden of asthma.

Chest. 2006;130(1):4S-12S. PMid: 16840363 2. Fuhlbrigge AL, Adams RJ, Guilbert TW, Grant E, Lozano P, Janson SL, et al. The burden of asthma in the United States: level and distribution are dependent on interpretation of the national asthma education and prevention program guidelines. Am J Respir Crit Care Med. 2002;166(8):1044-9. http://dx.doi.org/10.1164/ rccm.2107057 3. Nogueira KT, Silva JR, Lopes CS. Qualidade de vida em adolescentes asmáticos: avaliação da gravidade da asma, comorbidade e estilo de vida. J Ped. 2009;85(6):523-30. http://dx.doi.org/10.1590/S0021-75572009000600009 4. Sociedade Brasileira de Pneumologia e Tisiologia.

I Consenso Brasileiro de Educação em Asma. J Pneumol. 1996;22 Suppl 1:S1-S24.

5. Cerci Neto A, Ferreira Filho OF, Bueno T. Exemplos Brasileiros de programas de controle de asma. J Bras Pneumol. 2008;34(2):103-6.

6. Vale SA. Estudo de utilização dos medicamentos inalatórios no programa “Criança que chia”, Secretaria Municipal de Belo Horizonte, MG. [master’s thesis]. [Belo Horizonte]: Universidade Federal de Minas Gerais; 2004. 118 p.

7. Cerci Neto A. Asma em saúde pública. Barueri: Manole; 2007.

8. Holanda MA, Almeida PC, Sousa CR, Araújo SHFS, Braga AD, Mindêllo MLCB. Características individuais, fatores predisponentes e desencadeantes das crises de asma em crianças do PROAICA [abstract]. J Pneumol. 2001;27 Suppl 2:S4.

9. Silva LC, Freire LM, Mendes NF, Lopes AC, Cruz A. Carta de Salvador. J Pneumol. 2002;28 Suppl 1:S2.

10. Portal de Saúde [homepage on the internet]. Brasília: Ministério da Saúde [cited 2012 Apr 20]. Portaria nº 1.318, de 23 de julho de 2002. [Adobe Acrobat document, 64p.]

Available from: http://portal.saude.gov.br/portal/arquivos/ pdf/portaria_1318.pdf 11. Portal de Saúde [homepage on the internet]. Brasília: Ministério da Saúde [cited 2012 Apr 20]. Secretaria de Atenção à Saúde. Portaria nº 921, de 16 de novembro

Evolution of public policies and programs for asthma control in Brazil from the perspective of consensus guidelines

de 2002. Available from: http://bvsms.saude.gov.br/bvs/ saudelegis/sas/2011/prt0921_16_12_2011.html 12. Brasil. Ministério da saúde. Portaria nº 204, 29 de janeiro de 2007. Diário Oficial da União, Brasília, 2007 jan 31;n. 22;Seção 1:45.

13. Portal de Saúde [homepage on the internet]. Brasília: Ministério da Saúde [cited 2012 Apr 20]. Portaria nº 2.084/GM de 26 de outubro de 2005. [Adobe Acrobat document, 13p.] Available from: http://portal.saude. gov.br/portal/arquivos/pdf/Portaria_GM_N_2084.pdf 14. Brandão, H., Silva Junior I, Neto JN, do Amaral D, Cruz C, Souza-Machado A, et al. Impacto do programa para o controle da asma e da rinite (PROAR) de Feira de Santana, Bahia. Gaz Med Bahia. 2008;78(2):64-8.

15. Sociedade Brasileira de Pneumologia e Tisiologia. IV Diretrizes Brasileiras para o Manejo da Asma. J Bras Pneumol. 2006;32(Suppl 7):S447-S474.

16. Brasil. Ministério da saúde. Portaria nº 4217, 28 de dezembro de 2010. Diário Oficial da União, Brasília. 2010 dez 29;n. 249;Seção 1:72-4.

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17. Portal de Saúde [homepage on the internet]. Brasília: Ministério da Saúde [cited 2012 Apr 20]. Brasil Carinhoso I: Farmácia Popular terá remédio de graça para asma.

Available from: http://portalsaude.saude.gov.br/ portalsaude/noticia/5034/162/farmacia-popular-tera%3Cbr%3Eremedio-de-graca-para-asma.html 18. Sociedade Brasileira de Pneumologia e Tisiologia. Diretrizes da Sociedade Brasileira de Pneumologia e Tisiologia para o manejo da asma. J Bras Pneumol. 2012;38(suppl 1):S1-S46.

19. Portal de Saúde [homepage on the internet]. Brasília: Ministério da Saúde [cited 2012 Apr 20]. Secretaria de Atenção à Saúde. Departamento de Atenção Básica.

Asma e rinite: linhas de conduta em atenção básica.

Available from http://dtr2001.saude.gov.br/editora/ produtos/livros/popup/05_0028.htm 20. Carmo TA, Andrade SM, Cerci Neto A. Avaliação de um programa de controle da asma em unidades de saúde da família. Cad Saúde Pública. 2011;27(1):162-72. http:// dx.doi.org/10.1590/S0102-311X2011000100017

About the authors Lígia Menezes do Amaral

Pulmonologist. Universidade Federal de Juiz de Fora – UFJF, Federal University of Juiz de Fora – University Hospital, Juiz de Fora, Brazil.

Pamella Valente Palma

Dental Student. Universidade Federal de Juiz de Fora – UFJF, Federal University of Juiz de Fora – School of Dentistry, Juiz de Fora, Brazil.

Isabel Cristina Gonçalves Leite

Adjunct Professor. Universidade Federal de Juiz de Fora – UFJF, Federal University of Juiz de Fora – School of Medicine, Juiz de Fora, Brazil.

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Case Report Unilateral pulmonary agenesis* Agenesia pulmonar unilateral

Maura Cavada Malcon, Claudio Mattar Malcon, Marina Neves Cavada, Paulo Eduardo Macedo Caruso, Lara Flório Real

Abstract Pulmonary agenesis is a rare congenital anomaly. We report the case of an 8-year-old boy with left lung agenesis, without any other congenital malformations. When the patient presented symptoms, including cough, wheezing, and dyspnea, with no clinical improvement after a period of 30 days, imaging studies were conducted and the diagnosis was made.

Keywords: Congenital abnormalities; Respiratory tract diseases; Bronchoscopy.

Resumo A agenesia pulmonar é uma anomalia congênita rara. Relatamos um caso de um menino de 8 anos de idade com agenesia pulmonar à esquerda sem associação com outras malformações. O diagnóstico foi realizado por achados de imagem quando o paciente apresentou sintomas como tosse, sibilância e dispneia sem melhora do quadro clínico após evolução de 30 dias.

Descritores: Anormalidades congênitas; Doenças respiratórias; Broncoscopia.

Introduction Pulmonary agenesis is a rare congenital anomaly, consisting of complete absence of the lung parenchyma, bronchi, and pulmonary vessels.(1-4) The cause is unknown. In 50% of cases, especially in cases of right lung agenesis, cardiovascular, musculoskeletal, gastrointestinal, and renal malformations are also present.(3,5-7) The prognosis is better in cases of left lung agenesis and when there are no cardiac malformations.(3) Herein, we report the clinical case of a boy with left lung agenesis, without any other congenital malformations.

Case report An 8-year-old White male patient from the city of Jaguarão, Brazil, sought medical attention.

He had been born at term, and there had been no complications during pregnancy. He had a family history of asthma. Since early 2006, when he was 7 years old, the patient had been having attacks of wheezing, having been treated at home by his family. When he sought medical attention in February of 2007, the patient

presented with a dry cough that progressed to wheezing and dyspnea for one month. He was hospitalized in his hometown. A chest X-ray performed at admission showed opacity of the left hemithorax, which was treated as bacterial pneumonia (Figure 1). Physical examination by a pulmonologist revealed that the patient was active, acyanotic, and breathing normally; pulmonary auscultation revealed retraction of the left hemithorax, dullness to percussion, and absent breath sounds on the left with wheezing on the right; cardiac auscultation revealed normal, rhythmic heart sounds without heart murmurs.

The following tests were requested: chest HRCT; bronchoscopy; Doppler echocardiography; and abdominal ultrasound. Chest HRCT showed left lung agenesis, compensatory hypertrophy of the right lung, and normal right pulmonary circulation with leftward deviation of the mediastinal structures. There were no changes in upper abdominal structures (Figure 2). Abdominal ultrasound and echocardiography showed normal findings. Bronchoscopy revealed a blind-ending

* Study carried out at the private practice of the first author, Pelotas, Brazil.

Correspondence to: Maura Malcon. Rua Félix da Cunha, 916, apto. 1001, CEP 96010-000, Pelotas, RS, Brasil.

Tel. 55 53 3222-9875 or 55 53 3222-7338. E-mail: maura.malcon@yahoo.com.br Financial support: None.

Submitted: 15 April 2010. Accepted, after review: 26 October 2010.

J Bras Pneumol. 2012;38(4):526-529

Unilateral pulmonary agenesis

left main bronchus. Two months later, the patient returned for a follow-up evaluation. He presented with clinical signs of wheezing and was treated with a β2 agonist, which provided symptom relief.

Chest X-ray findings remained consistent with left lung agenesis. Spirometry revealed moderate obstructive lung disease, with no significant variation in flow or volume after bronchodilator use. Pre-bronchodilator values were as follows: FVC = 1.19 L (106% of predicted); FEV1 = 0.60 L/s (56% of predicted); and FEV1/FVC ratio = 0.50 (55% of predicted). Post-bronchodilator values were as follows: FVC = 1.21 L (108% of predicted); FEV1 = 0.61 L/s (57% of predicted); and FEV1/FVC ratio = 0.51 (56% of predicted).

Follow-up echocardiography, performed in 2008 and 2009, revealed right ventricular enlargement (right ventricular diameter = 29 mm; reference value = 7-18 mm) with normal pulmonary flow and no communications, shunts, or intracardiac obstructions.

Discussion Unilateral pulmonary agenesis is a rare congenital anomaly, which occurs in isolation or in association with other anomalies. Its estimated incidence is 1 per 10,000-15,000 autopsies.

Although its etiology remains unknown, its pathogenesis is believed to be related to genetic factors, viral factors, or vitamin A deficits.(3,7) Its pathology has been categorized as per the classification by Schneider & Schwalbe(3,6,8):

Figure 1 - Posteroanterior chest X-ray revealing compensatory hyperinflation of the right lung due to the absence of the left lung and leftward deviation of the mediastinal structures. Note normal lung transparency on the right.

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• agenesis—complete absence of a lung and bronchi, with no blood supply to the affected side • aplasia—presence of a rudimentary bronchus with complete absence of parenchyma • hypoplasia—lobar agenesis and hypoplastic lung The clinical presentation of the disease varies among patients. In some cases, symptoms manifest at birth as respiratory distress syndrome. In others, patients remain asymptomatic until adulthood, when the defect is incidentally detected during routine examination. Patients with unilateral pulmonary agenesis can have recurrent respiratory infections,(3) as well as cardiovascular, digestive, and musculoskeletal malformations. Chief among cardiovascular malformations are patent ductus arteriosus and patent foramen ovale. Digestive tract anomalies commonly include tracheoesophageal fistula and duodenal atresia. Musculoskeletal malformations include hemivertebrae, absence of ribs, and changes in extremities (absence of the radius). Facial and renal anomalies, such as horseshoe kidney, have also been described.(7) Imaging studies are essential for the diagnosis of pulmonary agenesis. Chest X-ray and chest CT show hyperinflation of the remaining lung and displacement of the mediastinum toward the affected side.(2) Echocardiography plays a fundamental in ruling out cardiac anomalies.

Other ancillary tests, such as bronchoscopy for confirming the diagnosis and magnetic resonance imaging for detecting vascular malformations, might be indicated.(3-5) In right lung agenesis, the association with cardiovascular anomalies, malrotation of the carina, and rightward deviation of the heart and mediastinum with bronchial distortion and distortion of vascular structures results in a worse prognosis.(3,4) Asymptomatic patients do not require intervention, especially in the absence of associated anomalies. However, pulmonary infection or other lung diseases should be treated early. Pulmonary hypertension is a complication that requires attention, since it is more common in such patients because of a reduction in the pulmonary vascular bed that, if associated with congenital heart disease (left-to-right shunt), can progress to irreversible vascular disease.(4,9) At this writing, right ventricular enlargement, without changes in pulmonary flow, had been J Bras Pneumol. 2012;38(4):526-529

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Malcon MC, Malcon CM, Cavada MN, Caruso PEM, Real LF

Figure 2 - Intravenous contrast-enhanced CT scan of the chest revealing compensatory hypertrophy of the right lung and normal pulmonary circulation with leftward deviation of the mediastinal structures due to left lung agenesis.

detected, and the patient was under annual follow-up with a pediatric cardiologist.

The patient in this report remained asymptomatic for a long period of his life, which is due to his having no other congenital malformations and to his having left lung agenesis, both of which are factors that translate to a better prognosis. The clinical diagnosis was made when the child presented with respiratory infection and wheezing. Chest X-ray and intravenous contrast-enhanced CT of the chest confirmed the diagnosis.

References 1. Calvo M, Krause S, Horzella R, Sánchez A, Jiménez P. Pulmonary agenesis [Article in Spanish]. Rev Chil Pediatr. 1983;54(4):261-5. PMid:6658059.

2. Sharma S, Kumar S, Yaduvanshi D, Chauhan D. Isolated unilateral pulmonary agenesis. Indian Pediatr. 2005;42(2):170-2. PMid:15767714.

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3. Borja MB, del Río Camacho G, Orozco AL, Gil de San Vicente LP. A first event of dyspnea in an infant.

Chest. 2000;118(4):1202-4. PMid:11035697. http:// dx.doi.org/10.1378/chest.118.4.1202 4. Chou AK, Huang SC, Chen SJ, Huang PM, Wang JK, Wu MH, et al. Unilateral lung agenesis--detrimental roles of surrounding vessels. Pediatr Pulmonol. 2007;42(3):242-8.

PMid:17238192. http://dx.doi.org/10.1002/ppul.20561 5. Alvarez AJ, Vaccaro MI, Verdejo HP, Villarroel CQ, Puentes RR. Unilateral pulmonary agenesis associated with multiple malformations-a case report [Article in Spanish]. Rev Chil Pediatr. 2000;71(1):41-5.

6. Cardoso AC, Motta WA, Daré Jr S, Gonzalez CH. Agenesia Pulmonar. Pediat (Sao Paulo). 1981;3(4):362-6.

7. Mühlhausen GM, Arcil GG. Right lung agenesis in a newborn [Article in Spanish]. Rev Chil Pediatr. 1992;63(1):39-42.

8. Jimenez J, Padilla L. Agenesia pulmonar. Rev Chil Pediatr. 1974;45(2):157-9. http://dx.doi.org/10.4067/ S0370-41061974000200008 9. Clements BS. Congenital Malformations of the Lungs and Airways. In: Taussig LM, Landau LI, editors. Pediatric Respiratory Medicine. St. Louis: Mosby; 1999. p. 1106-36.

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About the authors Maura Cavada Malcon

Pulmonologist. Pelotas City Hall, Pelotas, Brazil.

Claudio Mattar Malcon

Pulmonologist. Pelotas, Brazil.

Marina Neves Cavada

Medical Student. Federal University of Pelotas, Pelotas, Brazil.

Paulo Eduardo Macedo Caruso

Medical Student. Federal University of Pelotas, Pelotas, Brazil.

Lara Flório Real

Resident in Gynecology and Obstetrics. Hospital Nossa Senhora da Conceição de Porto Alegre, Porto Alegre, Brazil.

J Bras Pneumol. 2012;38(4):526-529

Letter to the Editor Pulmonary cryptosporidiosis in AIDS patients, an underdiagnosed disease Criptosporidiose pulmonar em pacientes com AIDS, uma doença subdiagnosticada

Yvana Maria Maia de Albuquerque, Márcia Cristina Fraga Silva, Ana Luiza Magalhães de Andrade Lima, Vera Magalhães

To the Editor: Cryptosporidiosis is an infection caused by a protozoan (Cryptosporidium spp.) that infects the epithelial cells of the gastrointestinal tract of humans and animals.(1) Clinical manifestations depend on the immune status of the patient. In immunocompetent patients, cryptosporidiosis causes episodes of self-limiting diarrhea, especially in children in Latin America. In AIDS patients with advanced immunodeficiency, cryptosporidiosis is the most common parasitic cause of prolonged diarrhea, associated with pronounced weight loss, and can progress to severe dehydration and electrolyte disturbance.(1,2) In the pre-antiretroviral therapy (ART) era, intestinal cryptosporidiosis was responsible for diarrheal symptoms in 10-30% of AIDS patients in developed countries and in 30-50% of those in developing countries.(3) Currently, in developed countries in which the rates of environmental contamination are low and in which potent ART is widely available, intestinal cryptosporidiosis occurs at an incidence rate of < 1 per 100 personyears among AIDS patients.(4) Pulmonary impairment is a rare complication of intestinal cryptosporidiosis, having been reported in immunocompromised patients, most of whom have AIDS and severe immunodeficiency.(2) The prevalence of pulmonary cryptosporidiosis, however, might be underestimated, given that it is not systematically investigated.(5) In a retrospective study conducted in Spain and investigating 275 AIDS patients, 43 had enteritis caused by Cryptosporidium spp.; in 7 of those 43 patients, sputum examination identified Cryptosporidium spp. oocysts.(3) The pathogenesis of pulmonary cryptosporidiosis has yet to be fully clarified.

(2,6) The possibility that pulmonary involvement is due to inhalation of oocysts during an episode

J Bras Pneumol. 2012;38(4):530-532

of vomiting or results from hematogenous dissemination has been a point of discussion.(2) Although Cryptosporidium oocysts do not usually invade the intestinal mucosa, they have been found within macrophages, leading to reduced phagocytic ability. In addition, this parasite can multiply in macrophages in vitro, which suggests that extraintestinal parasites spread via circulating phagocytes.(7) This hypothesis is supported by the presence of Cryptosporidium spp. within the blood vessels in the intestinal and pulmonary submucosa, as revealed by autopsy studies.(2,7) The clinical manifestations of pulmonary cryptosporidiosis are nonspecific and typically include chronic cough, fever, and dyspnea as the most common symptoms, and radiological changes may or may not occur.(2) Although there have been no reports of pathognomonic radiological findings in pulmonary cryptosporidiosis, interstitial opacity has been described in some case reports.(2,3,7,8) In a survey conducted in referral hospitals for the treatment of HIV/AIDS patients with clinically suspected pulmonary tuberculosis in the city of Recife, Brazil, Cryptosporidium spp. was the only agent identified in 2 (1.5%) of the 130 sputum examinations performed during the survey period; diagnosis was based on the finding of Cryptosporidium spp. oocysts on ZiehlNeelsen-stained sputum smear (Figure 1). In both cases, the patients had evening fever, cough, weight loss, and general malaise, all of which were suggestive of pulmonary tuberculosis. In the 2 cases studied, the patients were severely immunocompromised, with very low CD4+ T-cell counts (25 and 37 cells/µL). Although the presence of Pneumocystis jirovecii was not investigated, sulfamethoxazole-trimethoprim was prescribed for prophylaxis against that agent. Both patients had recently been diagnosed with AIDS. Only one of the patients was initially suspected

Pulmonary cryptosporidiosis in AIDS patients, an underdiagnosed disease

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Figure 1 - Ziehl-Neelsen-stained sputum smear showing Cryptosporidium spp. oocysts (red arrows). Source: Image database of the researcher.

of having intestinal cryptosporidiosis (which was confirmed by stool examination for ova and parasites), whereas the other had clinical signs suggestive of pulmonary tuberculosis but no digestive complaints. Chest X-ray findings (Figure 2) were normal in the 2 patients. Sputum culture (on Löwenstein-Jensen medium and in Middlebrook 7H9 medium) yielded no bacterial growth.

The patients showed progressive clinical, immunological, and virological improvement after ART initiation. There is no specific drug with proven efficacy in the treatment of cryptosporidiosis, and clinical improvement is related to the immune status of the patient.(2) We emphasize the need for investigating this parasitosis in AIDS patients with clinically suspected pulmonary tuberculosis, especially in those with prolonged diarrhea.

Acknowledgments The authors would like to thank the Marcelo Magalhães Laboratory for the support in performing sputum examinations.

Yvana Maria Maia de Albuquerque Infectious Disease Physician, Correia Picanço Hospital, Pernambuco State Department of Health, Recife, Brazil

Figure 2 - Chest X-ray of a patient with AIDS/pulmonary cryptosporidiosis, showing normal radiological findings.

Source: Image database of the researcher.

Márcia Cristina Fraga Silva Infectious Disease Physician, Correia Picanço Hospital, Pernambuco State Department of Health, Recife, Brazil Ana Luiza Magalhães de Andrade Lima Medical Student, Pernambuco State School of Health, Recife, Brazil Vera Magalhães Full Professor of Infectious Diseases, Federal University of Pernambuco, Recife, Brazil

References 1. Vergara Castiblanco C, Santos Núñez S, Freire Santos F, Ares Mazás E. Cryptosporidiosis in the Andean region of Colombia: seroprevalence and recognition of antigens [Article in Spanish]. Rev Panam Salud Publica. 2000;8(6):373-9. http://dx.doi.org/10.1590/ S1020-49892000001100001 2. Corti M, Villafañe MF, Muzzio E, Bava J, Abuín JC, Palmieri OJ. Pulmonary cryptosporidiosis in AIDS patients [Article

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Albuquerque YMM, Silva MCF, Lima ALMA, Magalhães V

in Spanish]. Rev Argent Microbiol. 2008;40(2):106-8.

PMid:18705491.

3. López-Vélez R, Tarazona R, Garcia Camacho A, GomezMampaso E, Guerrero A, Moreira V, et al. Intestinal and extraintestinal cryptosporidiosis in AIDS patients.

Eur J Clin Microbiol Infect Dis. 1995;14(8):677-81.

PMid:6756909. http://dx.doi.org/10.1007/BF01690873 4. Bonasser Filho F. Manifestações Gastrintestinais. In: Veronesi R, editor. Tratado de infectologia. São Paulo: Atheneu; 2002. p. 208-12.

5. Meamar AR, Rezaian M, Rezaie S, Mohraz M, Kia EB, Houpt ER, et al. Cryptosporidium parvum bovine genotype oocysts in the respiratory samples of an AIDS patient: efficacy of treatment with a combination of azithromycin and paromomycin. Parasitol Res. 2006;98(6):593-5.

PMid:16416289. http://dx.doi.org/10.1007/ s00436-005-0097-4 6. Poirot JL, Deluol AM, Antoine M, Heyer F, Cadranel J, Meynard JL, et al. Broncho-pulmonary cryptosporidiosis in four HIV-infected patients. J Eukaryot Microbiol. 1996;43(5):78S-79S. PMid:8822872. http:// dx.doi.org/10.1111/j.1550-7408.1996.tb05007.x 7. Dupont C, Bougnoux ME, Turner L, Rouveix E, Dorra M. Microbiological findings about pulmonary cryptosporidiosis in two AIDS patients. J Clin Microbiol. 1996;34(1):227-9.

PMid:8748314 PMCid:228771.

8. Palmieri F, Cicalini S, Froio N, Rizzi EB, Goletti D, Festa A, et al. Pulmonary cryptosporidiosis in an AIDS patient: successful treatment with paromomycin plus azithromycin. Int J STD AIDS. 2005;16(7):515-7. http:// dx.doi.org/10.1258/0956462054308332

Submitted: 28 October 2011. Accepted, after review: 15 February 2012.

J Bras Pneumol. 2012;38(4):530-532

Letter to the Editor Activated charcoal bronchial aspiration Broncoaspiração de carvão ativado

Bruna Quaranta Lobão Bairral, Makoto Saito, Nelson Morrone

To the Editor: A 20-year-old female patient, who had attempted suicide twice, was admitted to our facility one hour after having ingested an unknown quantity of lead shot. The patient was agitated.

She was sweating and had sialorrhea. Examination revealed normal vital signs, diffuse rhonchi, and miosis. She was treated with atropine and 50 g of activated charcoal (AC) administered in 400 mL of mannitol through a gastric tube, the position of which was confirmed by auscultation. A few hours later, the patient vomited, as well as experiencing a drop in the level of consciousness and agonal respiration. She underwent bronchoscopy, and an abundant quantity of blackish material mixed with food debris was obtained. She was placed on mechanical ventilation. Chest X-ray was normal. The patient developed hypotension refractory to fluid resuscitation and was started on noradrenaline. The response was satisfactory.

On the second day, the patient became feverish.

Chest X-ray revealed bilateral alveolar opacification (Figure 1A). The PaO2/FiO2 ratio was below 200, mechanical ventilation having been set at positive end-expiratory pressure and an FiO2 of 100%.

On subsequent days, during respiratory therapy maneuvers, there was clearance of blackish material.

In order to treat pneumonias that were likely to occur over the course of her hospitalization, various antibiotic regimens were successively used. On postadmission day 12, a tracheostomy was performed. The patient developed acute kidney failure requiring hemodialysis. A chest X-ray taken on postadmission day 17 showed a pattern consistent with ARDS (Figure 1B). A chest CT scan (Figure 1C) taken on postadmission day 30 revealed a massive left pleural effusion and an interstitial pattern that was irregular and diffuse, with ground-glass areas alternating with areas of hyperinflation; there was no structural deterioration.

The patient’s condition improved slowly. A transnasal fiberoptic laryngoscopy performed when the tracheostomy tube was removed revealed no abnormalities. On postadmission day 78, the patient was discharged on diazepam and fluoxetine; chest

X-ray revealed no parenchymal changes (Figure 1D).

At the six-month follow-up evaluation, the patient had no respiratory complaints, and a chest CT scan (Figure 1E) revealed the following: thoracic asymmetry favoring the left chest; an asymmetric, diffuse pattern (of little significance) on both sides, with ground-glass areas alternating with hypertransparent areas; scar-like lines at right angles to the pleural surface in the upper and middle lobes; and only a few areas exhibiting a tree-in-bud pattern. The patient was uncooperative during the spirometry test; peak flow was normal (380 L/min).

Ingestion of lead shot is the second most commonly used method of suicide in Brazil.(1) Lead shot is illegal and usually contains carbamate.

It is used as a rodenticide, being also used in agriculture. It acts as an organophosphorus compound, inhibiting cholinesterase and acetylcholinesterase activity and, therefore, hydrolysis of acetylcholine. Lead shot poisoning is treated with atropine and single or multiple doses of AC in order to reduce lead absorption.

Acute poisoning is treated with AC. Complications resulting from AC use are rare, and it is not known whether pulmonary changes are caused by AC use, by vomiting, or by ARDS. In the present case, bacterial complications were indisputably present over the course of the condition. The initial event, one day after the normal chest X-ray, might have been determined by pulmonary edema due to an AC-elicited increase in capillary permeability,(2) by hydrochloric acid, or, remotely, by pneumonia. Bronchial obstruction by food debris can be excluded because of the extent of the opacities and the absence of lung retraction. Aspiration of AC for days confirms the slow clearance. The CT findings six months later reflected bronchiolar obstruction, which has been described in cases of aspiration of AC. An experimental animal study(3) found, at 2-4 weeks, randomly dispersed AC particles in the lumen and submucosa of bronchioles and alveolar ducts; AC-laden bronchioles showed evidence of moderate nonspecific inflammation and epithelial J Bras Pneumol. 2012;38(4):533-534

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Bairral BQL, Saito M, Morrone N

Figure 1 - In A, a chest X-ray taken on postadmission day 2, revealing alveolar opacity in the lung bases.

In B, a chest X-ray taken on postadmission day 17, showing a pattern consistent with ARDS. In C, a chest CT scan taken on postadmission day 30, revealing pleural effusion. In D, a chest X-ray taken at discharge, showing no significant changes. In E, a chest CT scan taken six months after discharge, revealing a treein-bud pattern.

injury, and there was vascular and interstitial edema. At 12-20 weeks, there was epithelial sloughing and replacement by cuboidal cells in the AC-laden bronchioles; in the submucosa, there was granulation tissue; progressive intraluminal infiltration by inflammatory cells, fibroblasts, and fibrotic tissue resulted in varying degrees of bronchiolar obstruction; there were diffuse areas of atelectasis and alveolar thickening in the parenchyma; and AC-free sites were normal.

Granulomas(4) and bronchiolitis(5) have been found years after AC administration. A profile consistent with diffuse alveolar damage was found in a female patient who died 19 days after ingestion of AC (alveolar spaces, diffuse interstitial fibrosis with AC deposition in the interstitium, and proliferation of type II pneumocytes).(6) A mass in the right lower lobe, mimicking a neoplasm, was found in a male patient after instillation of AC into the right mainstem bronchus; histopathological examination revealed a black mass of 7 × 7 × 4 cm with small satellite nodules; histology showed that the mass was infiltrated by carbonaceous material and was surrounded by granulomatous inflammation; the nodules also contained carbonaceous material.(2) We can therefore conclude that AC is not inert, because it can produce an acute pulmonary reaction, causing acute respiratory failure and histopathological lesions that increase in size over time. It is of note that these lesions occur only in AC-laden areas, AC-free areas remaining normal.

Bruna Quaranta Lobão Bairral Resident in Clinical Medicine, São Paulo Hospital for Municipal Civil Servants, São Paulo, Brazil

Makoto Saito Physician, São Paulo Hospital for Municipal Civil Servants, São Paulo, Brazil Nelson Morrone Collaborating Physician, São Paulo Hospital for Municipal Civil Servants, São Paulo, Brazil

References 1. Amaral DA. Intoxicações agudas- diagnóstico e tratamento.

In: Higa EM, Atallah AN, editors. Guia de Medicina de Urgência. São Paulo: Manole; 2004. p. 143-78.

2. Arnold TC, Willis BH, Xiao F, Conrad SA, Carden DL. Aspiration of activated charcoal elicits an increase in lung microvascular permeability. J Toxicol Clin Toxicol. 1999;37(1):9-16. PMid:10078154.

3. Lee AG, Wagner FM, Chen MF, Serrick C, Giaid A, Shennib H. A novel charcoal-induced model of obliterative bronchiolitis-like lesions: implications of chronic nonspecific airway inflammation in the development of posttransplantation obliterative bronchiolitis. J Thorac Cardiovasc Surg. 1998;115(4):822-7. PMid:9576217.

4. Seder DB, Christman RA, Quinn MO, Knauft ME. A 45-year-old man with a lung mass and history of charcoal aspiration. Respir Care. 2006;51(11):1251-4.

PMid:17067407.

5. Elliott CG, Colby TV, Kelly TM, Hicks HG. Charcoal lung.

Bronchiolitis obliterans after aspiration of activated charcoal. Chest. 1989;96(3):672-4. http://dx.doi. org/10.1378/chest.96.3.672 6. Do SI, Park S, Ha H, Kim HJ. Fatal pulmonary complications associated with activated charcoal: An autopsy case.

Basic and Applied Pathology. 2009;2(3):106-8

Submitted: 10 January 2012. Accepted, after review: 13 February 2012.

J Bras Pneumol. 2012;38(4):533-534

Letter to the Editor Lipoid pneumonia in a 40-day-old infant Pneumonia lipoide em lactente de 40 dias de vida

Maria Cristina Ribeiro dos Santos Simões, Ivan Felizardo Contrera Toro, José Dirceu Ribeiro, Adyléia Aparecida Dalbo Contrera Toro

To the Editor: Lipoid pneumonia is triggered by aspiration of endogenous or exogenous lipids.(1) Exogenous lipoid pneumonia is the most common form of lipoid pneumonia in children and is usually caused by the use of mineral oil to treat constipation.

(1,2) Lipoid pneumonia is a difficult-to-diagnose disease, whose clinical and radiological presentation is nonspecific and similar to that of various other lung diseases, being asymptomatic in some cases.(1,3) The chronic progression can trigger pulmonary sequelae, such as bronchiectasis and pulmonary fibrosis.(2) Although the scientific community has issued warnings about the dangers of using mineral oil in children, the prescription of mineral oil for the treatment of constipation is still common practice in Brazil because this medication is inexpensive and widely available.(1,2) In the case described here, a 40-day-old female patient was admitted to the emergency room of a secondary care hospital with a four-day history of moaning. On the second day of moaning while under outpatient care, the patient was prescribed mineral oil (because she had not evacuated for 2 days). Upon receiving the medication, the infant choked and, from that moment on, she had cough and breathlessness.

She was exclusively breastfed and had no history of disease or regurgitation. Physical examination revealed moaning, tachypnea (RR = 80 breaths/ min), wheezing, and hypoxemia (SpO2 = 88%).

Blood workup showed mild leukopenia with normal differential cell count, and chest X-ray revealed bilateral alveolar-interstitial opacities and lung hyperinflation (Figure 1). Blood cultures were negative. The patient received intravenous antibiotic therapy (ampicillin), oxygen therapy (via an oxygen tent), inhaled fenoterol, and respiratory therapy. On postadmission day 7, she still had clinical changes. Radiological findings remained unchanged. A CT scan of the chest was taken and showed areas of parenchymal consolidation affecting segments of upper and lower lobes with negative attenuation coefficients

(Figure 2), findings that were consistent with a presumptive diagnosis of lipoid pneumonia with multisegmental involvement.

The infant was transferred to a tertiary care hospital for bronchoscopy and BAL. She underwent three sequential procedures, performed with a rigid bronchoscope, under intravenous general anesthesia and jet ventilation. In the first procedure, anatomical changes were ruled out. Material similar to an opalescent film was found to coat the trachea and bronchi.

A BAL was performed in the right lower lobe.

Cytological examination of the BAL fluid showed cells containing inclusions suggestive of lipids.

In the second bronchoscopy, there was a small quantity of diffuse opalescent secretion. A BAL was performed in the left lower lobe, and analysis of the BAL fluid revealed numerous lipid-laden cells and few structures suggestive of fat droplets.

In the third procedure, a BAL was performed in the right upper lobe, structures suggestive of fat droplets and numerous lipid-laden cells having been found. The patient recovered well; she gained appreciable weight and became asymptomatic, radiological normalization being complete.

Mineral oil (liquid paraffin or liquid petroleum jelly) is a by-product of the petroleum distillation process that produces gasoline. It can be purified to be used for medicinal purposes as a moisturizer (cream) or as a laxative in the treatment of constipation and partial bowel obstruction caused by severe ascariasis. It is characterized as a transparent, unpleasant-tasting liquid that is not absorbed from the digestive tract. In the intestinal lumen, mineral oil reduces water absorption and acts as a lubricant.(2) It has low volatility and high viscosity, both of which produce undesirable effects, such as an inhibition of the cough reflex(1,2) when the oil is aspirated and a reduction in mucociliary transport in the lung because the oil changes the viscoelastic properties of secretions, thus impairing lung clearance.(2) Although chronic aspiration of mineral oil is

J Bras Pneumol. 2012;38(4):535-537

536

Simões MCRS, Toro IFC, Ribeiro JD, Toro AADC

Figure 1 - Chest X-ray revealing a homogeneous opacity consistent with bronchopneumonia. Image taken before treatment with BAL.

Figure 2 - HRCT scan of the chest revealing areas of parenchymal consolidation affecting segments of upper and lower lobes with negative attenuation coefficients. Image taken before treatment with BAL.

facilitated by dysphagia, esophageal diseases, and neuropathies, it can occur in patients who have no anatomic predisposition or functional abnormality,(4) as well as in those who resist taking the medication (e.g., infants).(1) When aspirated, mineral oil rapidly disseminates throughout the bronchial tree. It is not metabolized by pulmonary enzymes. When it reaches the alveolar space, it is phagocytosed by alveolar macrophages.

(1,5) Although some of these cells penetrate the interstitial tissue and reach the peribronchial lymphatic vessels and hilar lymph nodes, most of the mineral oil remains in the alveoli, either free or within macrophages, which cannot metabolize it and therefore disintegrate, returning it to J Bras Pneumol. 2012;38(4):535-537

the airspace. The activation of macrophages in the airspace promotes cytokine release and an inflammatory reaction.(1,6) Initially, there is an inflammatory foreign body reaction. Subsequently, there is chronic interstitial inflammation that progresses to pulmonary fibrosis. This vicious cycle contributes to the chronicity of the disease, even years after discontinuation of the use of the product. In anatomic pathology studies, lipoid pneumonia is characterized by the presence of giant cells, alveolar/interstitial fibrosis, and chronic inflammation. Depending on the duration of the disease, lipid-laden alveolar macrophages, as well as normal alveolar wall and septa, can be initially found. Advanced lesions show large vacuoles and inflammatory infiltrate in the alveolar walls, bronchial walls, and septa. Older lesions are characterized by fibrosis and parenchymal destruction around large, lipid-laden vacuoles.(7) Radiologically, acute lipoid pneumonia presents as bilateral pulmonary opacities, in segmental or lobar distribution, involving mainly the posterior and lower lobes. Other manifestations of lipoid pneumonia include nodules, pneumatoceles, and pleural effusion. Pneumomediastinum and pneumothorax are rare and indicate a poorer prognosis. Chest CT can reveal areas of alveolar consolidation with low attenuation and a groundglass pattern.(4,5) The diagnosis of lipoid pneumonia should be based on the following: a history of mineral oil ingestion; the risk factors described above; clinical and radiological findings; and demonstration of lipids in bronchoscopy, BAL, or lung biopsy specimens.(1,8) The presence of lipid-laden macrophages in BAL fluid is considered to be the most important finding for the diagnosis of lipoid pneumonia.(1,2,8) Although spontaneous resolution can occur after discontinuation of the use of mineral oil, complications can occur, including bacterial infection, progressive fibrosis, bronchiectasis, hemoptysis, and severe cases that progress to respiratory failure and death.(1,3,6) The best form of treatment has yet to be well established in the scientific literature. Various studies have demonstrated that treatment with multiple BALs is effective, has few risks, and leads to resolution of the clinical and radiological signs.(1,2,5,8,9) In patients with pneumonia that does not respond to treatment, the hypothesis of lipoid pneumonia should be considered in the differential diagnosis. We strongly support

Lipoid pneumonia in a 40-day-old infant

the recommendation that mineral oil be used judiciously in the treatment of chronic constipation.

This medication should not be prescribed to neonates or infants, who resist taking it, or to children with developmental delay, with or without dysphagia.

Maria Cristina Ribeiro dos Santos Simões Master’s Student in Child and Adolescent Health, State University at Campinas School of Medical Sciences, Campinas, Brazil Ivan Felizardo Contrera Toro Professor, Department of Surgery, State University at Campinas School of Medical Sciences, Campinas, Brazil José Dirceu Ribeiro Associate Professor, Department of Pediatrics, State University at Campinas School of Medical Sciences, Campinas, Brazil Adyléia Aparecida Dalbo Contrera Toro Professor, Department of Pediatrics, State University at Campinas School of Medical Sciences, Campinas, Brazil

537

References 1. Sias SM, Ferreira AS, Daltro PA, Caetano RL, Moreira Jda S, Quirico-Santos T. Evolution of exogenous lipoid pneumonia in children: clinical aspects, radiological aspects and the role of bronchoalveolar lavage. J Bras Pneumol. 2009;35(9):839-45. http://dx.doi.org/10.1590/ S1806-37132009000900004 2. Bandla HP, Davis SH, Hopkins NE. Lipoid pneumonia: a silent complication of mineral oil aspiration.

Pediatrics. 1999;103(2):E19. PMid:9925865.

3. Weinstein M. First do no harm: The dangers of mineral oil. Paediatr Child Health. 2001;6(3):129-31.

4. Betancourt SL, Martinez-Jimenez S, Rossi SE, Truong MT, Carrillo J, Erasmus JJ. Lipoid pneumonia: spectrum of clinical and radiologic manifestations. AJR Am J Roentgenol. 2010;194(1):103-9. PMid:20028911.

5. Sias SM, Daltro PA, Marchiori E, Ferreira AS, Caetano RL, Silva CS, et al. Clinic and radiological improvement of lipoid pneumonia with multiple bronchoalveolar lavages.

Pediatr Pulmonol. 2009;44(4):309-15. PMid:19283836.

6. Midulla F, Strappini PM, Ascoli V, Villa MP, Indinnimeo L, Falasca C, et al. Bronchoalveolar lavage cell analysis in a child with chronic lipid pneumonia. Eur Respir J. 1998;11(1):239-42. http://dx.doi.org/10.1183/090 31936.98.11010239 7. Simmons A, Rouf E, Whittle J. Not your typical pneumonia: a case of exogenous lipoid pneumonia. J Gen Intern Med. 2007;22(11):1613-6. http://dx.doi.org/10.1007/ s11606-007-0280-7 8. Picinin IF, Camargos PA, Marguet C. Cell profile of BAL fluid in children and adolescents with and without lung disease. J Bras Pneumol. 2010;36(3):372-85. http:// dx.doi.org/10.1590/S1806-37132010000300016 9. De Blic J, Midulla F, Barbato A, Clement A, Dab I, Eber E, et al. Bronchoalveolar lavage in children. ERS Task Force on bronchoalveolar lavage in children. European Respiratory Society. Eur Respir J. 2000;15(1):217-31.

PMid:10678650.

Submitted: 12 February 2012. Accepted, after review: 1 March 2012.

J Bras Pneumol. 2012;38(4):535-537

Errata This corrects the article “Cultural adaptation and reproducibility of the breathing problems questionnaire for use in patients with COPD in Brazil” on page 345.

In J Bras Pneumol. 2012;38(3):339-45, Silva PN, Jardim JR, Souza GM, Hyland ME, Nascimento AO, Cultural adaptation and reproducibility of the breathing problems questionnaire for use in patients with COPD in Brazil, the author Patrícia Nobre Calheiros da Silva is a professor at the Centro de Estudos Superiores de Maceió – CESMAC, Maceió Center for Higher Education – Maceió, Brazil, and not at the Alagoas State University of Health Sciences.

J Bras Pneumol. 2012;38(4)

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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.

fumarato de formoterol di-hidratado + budesonida. 12/400 mcg. Cápsulas para inalação. USO INALATÓRIO ORAL. USO ADULTO E PEDIÁTRICO (CRIANÇAS ACIMA DE 5 ANOS DE IDADE). MS - 1.1213.0308.

Indicações: ALENIA (fumarato de formoterol di-hidratado + budesonida) está indicado para a melhora e controle da falta de ar em asmáticos e em pacientes portadores da doença pulmonar obstrutiva crônica. Contraindicações: hipersensibilidade a um dos componentes da fórmula, ou em pacientes com tuberculose pulmonar ativa.

Precauções e advertências: O aumento do uso de broncodilatadores de ação rápida é indicativo de agravamento da patologia subjacente, justificando uma reavaliação da terapia. Na asma, deve-se considerar a necessidade de aumentar a terapêutica com Alenia ou adicionar corticosteroides inalatórios e/ou beta2-agonistas de longa duração ou um curso de corticosteroides orais. Em DPOC, deve-se considerar a necessidade de adicionar um curso de corticosteroides orais e/ou tratamento antibiótico se uma infecção estiver presente. Os pacientes devem ser aconselhados a terem sempre à disposição o seu broncodilatador de ação rápida. O tratamento não deve ser iniciado durante uma exacerbação grave. O crescimento de crianças e adolescentes submetidos a uma corticoterapia prolongada por qualquer via deve ser mantido sob rigoroso controle médico e devem ser pesados os benefícios da terapêutica com corticosteroides em relação ao possível risco de supressão do crescimento. Deve-se tomar cuidado especial com pacientes que precisam fazer a migração de esteroides orais para inalatórios, uma vez que podem permanecer riscos de função adrenal prejudicada durante um tempo considerável. ALENIA deve ser administrado com cautela em pacientes com graves transtornos cardiovasculares (incluindo anomalias do ritmo cardíaco), diabetes mellitus, hipocalemia não tratada ou tireotoxicose. Pacientes que tiverem tontura ou efeitos adversos similares devem ser aconselhados a evitar dirigir ou utilizar máquinas. Gravidez e lactação: categoria de risco na gestação: C. Interações medicamentosas: Os bloqueadores beta-adrenérgicos (incluindo os colírios oftálmicos) podem atenuar ou inibir o efeito do formoterol. Inibidores da CYP3A4 (uma subfamília do citocromo P450), como o cetoconazol, podem aumentar a exposição sistêmica à budesonida. Reações adversas: As reações mais frequentes são: palpitações, cefaleia e tremores. Pode ocorrer: agitação, ansiedade, nervosismo, insônia, taquicardia, edema periférico, broncoespasmo, irritação de garganta, tontura, disgeusia, cãibra muscular e mialgia. Raramente pode ocorrer: arritmias cardíacas, taquicardia e náuseas. Muito raramente pode ocorrer: hipersensibilidade, angina pectoris. Posologia: POSOLOGIA E ADMINISTRAÇÃO. A dose de ALENIA (fumarato de formoterol di-hidratado + budesonida) deve ser individualizada conforme a gravidade da doença. Quando for obtido o controle da asma, a dose deve ser ajustada para a menor dose que permita manter um controle eficaz dos sintomas. Terapia de Manutenção Regular. Doses recomendadas: Asma: Para uso inalatório em adultos e crianças acima de 5 anos de idade. Crianças (a partir de 5 anos de idade): 1 inalação uma a duas vezes ao dia num total de 12 a 24 mcg de formoterol e 400 a 800 mcg de budesonida ao dia. Adolescentes (12-17 anos de idade): 1 inalação, uma a duas vezes ao dia, num total de 12 a 24 mcg de formoterol e 400 a 800 mcg de budesonida. Durante uma piora da asma, a dose de manutenção pode ser temporariamente aumentada para um máximo de 2 inalações, duas vezes ao dia, porém se a piora clínica persistir é recomendável uma nova avaliação médica. Adultos (a partir de 18 anos de idade): 1 inalação, uma a duas vezes ao dia num total de 12 a 24 mcg de formoterol e 400 a 800 mcg de budesonida.

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, porém se a piora clínica persistir é recomendável uma nova avaliação médica. DPOC: Adultos (a partir de 18 anos de idade): 1 inalação, duas vezes ao dia, totalizando 12 a 24 mcg de formoterol e 400 a 800 mcg de budesonida. Dose máxima diária: 2 inalações. Informações Gerais: os pacientes devem ser instruídos a usar ALENIA (fumarato de formoterol di-hidratado + budesonida) mesmo quando estiverem assintomáticos para obter o benefício máximo da terapia. VENDA SOB PRESCRIÇÃO MÉDICA. Farm. Resp. : Alberto Jorge Garcia Guimarães - CRF-SP no 12.449. MB_03 SAP 4053903. Referências Bibliográficas: (1) STIRBULOV, R. et al. Evaluation of the efficacy and safety of a fixed-dose, single-capsule budesonide-formoterol, combination in uncontrolled asthma: a randomized, double-blind. Multicenter, controlled clinical Trial. BJORL – Brazilian Journal of Otorhinolaryngology. [Epub ahead of print]. (2) CUP Maio/2012 - Internal Report.

Contraindicações: Hipersensibilidade a alguns dos componentes da fórmula. Interações medicamentosas com fumarato de formoterol di-hidratado: Outros agonistas adrenérgicos – excesso da estimulação adrenérgica.

SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO.

“Material técnico-científico de distribuição exclusiva à classe médica. Produzido em junho de 2012. Código 7007425”

ALENIA.

Estudo brasileiro da associação formoterol e budesonida em cápsula única e dispositivo Aerocaps, em pacientes com asma persistente, demonstrou1: Efeito terapêutico nas pequenas vias aéreas •

Melhora significante no VEF1 e PFE matinal •

Eficácia na obtenção do controle da asma •

•

Segurança e tolerabilidade

Esses resultados confirmam a eficácia e segurança da associação mais prescrita no Brasil 1,2.

SIMPLICIDADE

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.

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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.

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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

Publicação Bimestral

J Bras Pneumol. v.38, número 4, p. 417-537 July/August 2012

PUBLICAÇÃO OFICIAL DA SOCIEDADE BRASILEIRA DE PNEUMOLOGIA E TISIOLOGIA

Destaque

ASMA Avaliação da eficácia e segurança da associação de budesonida e formoterol em dose fixa e cápsula única no tratamento de asma não controlada: ensaio clínico randomizado, duplo-cego, multicêntrico e controlado Capacidade aeróbica em crianças e adolescentes com asma intermitente e persistente leve no período intercrises

CÂNCER Achados de fibrobroncoscopia em pacientes com diagnóstico de neoplasia pulmonar

CIRCULAÇÃO

SEVERIDADE

Comparação de dois modelos experimentais de hipertensão pulmonar

CIRURGIA

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

Modelo experimental de perfusão pulmonar ex vivo em ratos: avaliação histopatológica e de apoptose celular em pulmões preservados com solução de baixo potássio dextrana vs. solução histidina-triptofano-cetoglutarato

ENSINO

RISCOS

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

July/August 2012 volume 38 número 4

O risco de pneumonia pneumocócica aumenta com a idade4, possivelmente devido ao declínio do sistema imunológico5, bem como ao aumento das comorbidades relacionadas com a idade.6,7

Indicadores antropométricos e de ingestão alimentar como preditores da função pulmonar em pacientes com fibrose cística

FISIOTERAPIA Manual hyperinflation combined with expiratory rib cage compression for reduction of length of ICU stay in critically ill patients on mechanical ventilation

INFECÇÃO PLEURA Clinical and pathological factors influencing the survival of breast cancer patients with malignant pleural effusion

RADIOLOGIA Emphysema index in a cohort of patients with no recognizable lung disease: influence of age

TUBERCULOSE p.417-537

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.

FIBROSE CÍSTICA

Impacto de la bacteriemia en una cohorte de pacientes con neumonía neumocócica

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

Evolução das políticas públicas e programas de controle da asma no Brasil sob a perspectiva dos ­consensos

Efetividade do tratamento da tuberculose Tuberculose, HIV e pobreza: tendência temporal no Brasil, Américas e mundo

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

Fator de Impacto 1.391