Brazilian Journal of Pulmonology - Volume 38, number 6, November/December - 2012

pneumocócica PREVALÊNCIA

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

Jornal Brasileiro de Pneumologia

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

doença

ISSN 1806-3713

Published once every two months J Bras Pneumol. v.38, number 6, p. 681-829 November/December 2012

OFFICIAL PUBLICATION OF THE BRAZILIAN THORACIC ASSOCIATION

Highlight

ASTHMA Pharmaceutical equivalence of the combination formulation of budesonide and formoterol in a single capsule with a dry powder inhaler

BRONCHOSCOPY Evaluation of the diagnostic utility of fiberoptic bronchoscopy for smear-negative pulmonary tuberculosis in routine clinical practice

Ex vivo lung r­ econditioning Editorial: Marcelo Cypel

COPD Cross-cultural adaptation and assessment of reproducibility of the Duke Activity Status Index for COPD patients in Brazil

SEVERIDADE

Underdiagnosis of COPD at primary health care clinics in the city of Aparecida de Goiânia, Brazil

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

PULMONARY FUNCTION Reference values for sniff nasal inspiratory pressure in healthy subjects in Brazil: a multicenter study

PEDIATRICS Potential impacts of climate variability on respiratory morbidity in children, infants, and adults

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

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

November/December 2012 volume 38 number 6

RISCOS

SMOKING A new nicotine dependence score and a new scale assessing patient comfort during smoking cessation treatment Translation, cross-cultural adaptation, and reproducibility of the Brazilian Portuguese-language version of the Wisconsin Smoking Withdrawal Scale

TUBERCULOSIS Clinical and epidemiological profile and prevalence of tuberculosis/HIV co-infection in a regional health district in the state of Maranhão, Brazil Prevalence of primary drug resistance in pulmonary tuberculosis patients with no known risk factors for such Bottlenecks and recommendations for the incorporation of new technologies in the tuberculosis laboratory network in Brazil Temporal trends in tuberculosis-related morbidity and mortality in the state of Santa Catarina, Brazil, between 2002 and 2009 Primary and acquired pyrazinamide resistance in patients with pulmonary tuberculosis treated at a referral hospital in the city of Recife, Brazil

493517 PRD1139 - Material produzido em Julho/11

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.

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Wyeth Indústria Farmacêutica Ltda Rua Verbo Divino, 1.400 Chácara Santo Antonio CEP: 04719-002 - São Paulo - SP www.wyeth.com.br

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

Alguns pacientes com asma

*

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

Faça mais hoje 1

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

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

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

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

DX_0710_0211_VPS . *Marca Depositada.

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

Componentes Parcerias confiáveis2

a 11 anos.

2

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

Dispositivo2 fácil de usar

A dosag em cert

a para c a pacient 2 da e

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

Dados

es o padrõ5 definind to n e m de trata

6,7

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

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

5,8

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

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

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

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

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

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

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

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

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

Produto de uso sob prescrição médica.

A PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO.

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

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

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

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

Published once every two months J Bras Pneumol. v.38, number 6, p. 681-829 November/December 2012 Editor Chefe Carlos Roberto Ribeiro Carvalho – Universidade de São Paulo, São Paulo, SP

Editores Executivos

Associação Brasileira de Editores Científicos

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

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

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

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

SOCIEDADE BRASILEIRA DE PNEUMOLOGIA E TISIOLOGIA

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

Telefone (55) (61) 3245-1030/ 0800 616218. Site: www.sbpt.org.br. E-mail: sbpt@sbpt.org.br O Jornal Brasileiro de Pneumologia ISSN 1806-3713, é uma publicação bimestral da Sociedade Brasileira de Pneumologia e Tisiologia. Os conceitos e opiniões emitidos nos artigos são de inteira responsabilidade de seus autores. Permitida a reprodução total ou parcial dos artigos, desde que mencionada a fonte.

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

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

Published once every two months J Bras Pneumol. v.38, number 6, p. 681-829 November/December 2012

EDITORIAL

681 - A new era in lung transplantation: an individualized approach to donor lungs

Uma nova era no transplante pulmonar: medicina personalizada a pulmões doados Marcelo Cypel

ORIGINAL ARTICLES / ARTIGOS ORIGINAIS 684 - Cross-cultural adaptation and assessment of reproducibility of the Duke Activity Status Index for COPD patients in Brazil

Adaptação cultural e avaliação da reprodutibilidade do Duke Activity Status Index para pacientes com DPOC no Brasil Livia dos Anjos Tavares, José Barreto Neto, José Roberto Jardim, George Márcio da Costa e Souza, Mark A. Hlatky, Oliver Augusto Nascimento

692 - Underdiagnosis of COPD at primary health care clinics in the city of Aparecida de Goiânia, Brazil

Subdiagnóstico de DPOC na atenção primária em Aparecida de Goiânia, Goiás

Maria Conceição de Castro Antonelli Monteiro de Queiroz, Maria Auxiliadora Carmo Moreira, Marcelo Fouad Rabahi 700 - Reference values for sniff nasal inspiratory pressure in healthy subjects in Brazil: a multicenter study

Valores de referência da pressão inspiratória nasal em indivíduos saudáveis no Brasil: estudo multicêntrico Palomma Russelly Saldanha de Araújo, Vanessa Regiane Resqueti, Jasiel Nascimento Jr, Larissa de Andrade Carvalho, Ana Gabriela Leal Cavalcanti, Viviane Cerezer Silva, Ester Silva, Marlene Aparecida Moreno, Arméle de Fátima Dornelas de Andrade, Guilherme Augusto de Freitas Fregonezi

708 - Potential impacts of climate variability on respiratory morbidity in children, infants, and adults

Potenciais impactos da variabilidade climática sobre a morbidade respiratória em crianças, lactentes e adultos Amaury de Souza, Widinei Alves Fernandes, Hamilton Germano Pavão, Giancarlo Lastoria, Edilce do Amaral Albrez

716 - Translation, cross-cultural adaptation, and reproducibility of the Brazilian Portugueselanguage version of the Wisconsin Smoking Withdrawal Scale

Tradução, adaptação cultural e reprodutibilidade da Wisconsin Smoking Withdrawal Scale para o português do Brasil Boanerges Lopes de Oliveira Junior, José Roberto Jardim, Oliver Augusto Nascimento, George Márcio da Costa e Souza, Timothy B. Baker, Ilka Lopes Santoro

724 - Clinical and epidemiological profile and prevalence of tuberculosis/HIV co-infection in a regional health district in the state of Maranhão, Brazil

Perfil clínico e epidemiológico e prevalência da coinfecção tuberculose/HIV em uma regional de saúde no Maranhão

Marcelino Santos Neto, Fabiane Leita da Silva, Keyla Rodrigues de Sousa, Mellina Yamamura, Marcela Paschoal Popolin, Ricardo Alexandre Arcêncio

733 - Prevalence of primary drug resistance in pulmonary tuberculosis patients with no known risk factors for such

Prevalência de resistência primária em pacientes com tuberculose pulmonar sem fatores de risco conhecidos para resistência primária Giselle Mota Bastos, Michelle Cailleaux Cezar, Fernanda Carvalho de Queiroz Mello, Marcus Barreto Conde

740 - Primary and acquired pyrazinamide resistance in patients with pulmonary tuberculosis treated at a referral hospital in the city of Recife, Brazil

Resistência primária e adquirida à pirazinamida em pacientes com tuberculose pulmonar atendidos em um hospital de referência no Recife Liany Barros Ribeiro, Vera Magalhães, Marcelo Magalhães

Published once every two months

J Bras Pneumol. v.38, number 6, p. 681-829 November/December 2012

SPECIAL ARTICLE / ARTIGO ESPECIAL

748 - Pharmaceutical equivalence of the combination formulation of budesonide and formoterol in a single capsule with a dry powder inhaler

Equivalência farmacêutica da formulação combinada de budesonida e formoterol em cápsula única com dispositivo inalador de pó Marina Andrade-Lima, Luiz Fernando Ferreira Pereira, Ana Luisa Godoy Fernandes

COMUNICAÇÃO BREVE / BRIEF COMMUNICATION 757 - Evaluation of the diagnostic utility of fiberoptic bronchoscopy for smear-negative pulmonary tuberculosis in routine clinical practice

Avaliação da utilidade diagnóstica da fibrobroncoscopia óptica na tuberculose pulmonar BAAR negativa na prática clínica de rotina Alonso Soto, Daniela Salazar, Vilma Acurio, Patricia Segura, Patrick Van der Stuyft

761 - A new nicotine dependence score and a new scale assessing patient comfort during smoking cessation treatment

Um novo escore para dependência a nicotina e uma nova escala de conforto do paciente durante o tratamento do tabagismo Jaqueline Scholz Issa

766 - Bottlenecks and recommendations for the incorporation of new technologies in the tuberculosis laboratory network in Brazil

Gargalos e recomendações para a incorporação de novas tecnologias na rede pública laboratorial de tuberculose no Brasil Maria Alice da Silva Telles, Alexandre Menezes, Anete Trajman

771 - Temporal trends in tuberculosis-related morbidity and mortality in the state of Santa Catarina, Brazil, between 2002 and 2009

Tendência temporal da morbidade e mortalidade por tuberculose no estado de Santa Catarina, Brasil, no período entre 2002 e 2009 Jefferson Traebert, Glênio César Nunes Ferrer, Nazaré Otília Nazário, Ione Jayce Ceola Schneider, Rosemeri Maurici da Silva

REIVIEW ARTICLES / ARTIGOS DE REVISÃO

776 - Ex vivo lung reconditioning: a new era for lung transplantation

Recondicionamento pulmonar ex vivo: uma nova era para o transplante pulmonar

Alessandro Wasum Mariani, Paulo Manuel Pêgo-Fernandes, Luis Gustavo Abdalla, Fabio Biscegli Jatene 786 - Anti-inflammatory effects of macrolides in childhood lung diseases

Efeito anti-inflamatório dos macrolídeos em doenças pulmonares da infância

Fernanda Luisi, Thays Dornelles Gandolfi, Arthur Dondonis Daudt, João Pedro Zelmanowicz Sanvitto, Paulo Márcio Pitrez, Leonardo Araujo Pinto

CASE REPORT / RELATO DE CASO

797 - Pleural endometriosis: findings on magnetic resonance imaging

Endometriose pleural: achados na ressonância magnética

Edson Marchiori, Gláucia Zanetti, Rosana Souza Rodrigues, Luciana Soares Souza, Arthur Soares Souza Jr, Flávia Angélica Ferreira Francisco, Bruno Hochhegger

LETTER TO THE EDITOR / CARTAS AO EDITOR

803 - The role of academic associations in professional training

O papel das ligas acadêmicas na formação profissional

Mayara Lisboa Soares de Bastos, Anete Trajman, Eleny Guimarães Teixeira, Lia Selig, Márcia Teresa Carreira Teixeira Belo 806 - Lung transplantation without the use of cardiopulmonary bypass in a patient with Kartagener syndrome

Transplante pulmonar sem circulação extracorpórea em uma paciente com síndrome de Kartagener

Luziélio Alves Sidney Filho, Tiago Noguchi Machuca, José de Jesus Camargo, José Carlos Felicetti, Spencer Marcantonio Camargo, Fabíola Adélia Perin, Letícia Beatriz Sanchez, Sadi Marcelo Schio 810 - A successfully treated case of parainfluenza virus 3 pneumonia mimicking influenza pneumonia

Um caso de pneumonia por vírus parainfluenza 3 simulando pneumonia por influenza tratada com sucesso Nobuhiro Asai, Yoshihiro Ohkuni, Norihiro Kaneko, Yasutaka Kawamura, Masahiro Aoshima 813 - Overlap between asthma and COPD

Sobreposição de asma brônquica e DPOC

Tiago Manuel Alfaro, Sara da Silva Freitas, Carlos Robalo Cordeiro

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.

Estaduais da Sociedade Brasileira de Pneumologia e Tisiologia ASSOCIAÇÃO CATARINENSE DE PNEUMOLOGIA E TISIOLOGIA Presidente: Emílio Pizzichini Secretário: Israel Silva Maia Endereço: Hospital Universitário da UFSC - NUPAIVA - térreo.

Campus - Trindade, 88.040 - 970 - Florianópolis - SC Tel: (48) 3234-7711/ 3233-0747 E-mail: pizzichi@matrix.com.br

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74.223-040 - Goiânia - GO Tel: (62) 3087-5844 E-mail: sgpt2007@gmail.com

SOCIEDADE ALAGOANA DE PNEUMOLOGIA Presidente: Anatercia Passos Cavalcanti Secretária: Seli Almeida Endereço: Rua Walfrido Rocha 225, Jatiuca

57.036-800 - Maceió - AL Tel: (82) 33266618 Fax: (82)3235-3647 E-mail: sociedadealagoana.dt@gmail.com

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SOCIEDADE AMAZONENSE DE PNEUMOLOGIA E CIRURGIA TORÁCICA Presidente: Fernando Luiz Westphal Secretária: Maria do Socorro de Lucena Cardoso Endereço: Avenida Joaquim Nabuco, 1359

69.020-030 - Manaus - AM Tel: (92) 3234-6334 Fax: 32348346 E-mail: f.l.westphal@uol.com.br

SOCIEDADE NORTE-RIO GRANDENSE DE PNEUMOLOGIA E TISIOLOGIA Presidente: Francisco Elmano Marques Souza Endereço: Rua Mossoró, 576, sala 17, Ed. Eduardo, Tirol

59.020-090 - Natal - RN Tel: (84) 4009-2034 Fax: (84) 4009-2028 E-mail: elmano@hcnatal.com.br

SOCIEDADE BRASILIENSE DE DOENÇAS TORÁCICAS Presidente: Ricardo Brito Campos Secretário: Bianca Rodrigues Silva Endereço: Setor de Clubes Sul, Trecho 3, Conj. 6

70.200-003 - Brasília - DF Tel/fax: (61) 3245-8001 E-mail: sbdt@ambr.org.br SOCIEDADE CEARENSE DE PNEUMOLOGIA E TISIOLOGIA Presidente: Filadélfia Passos Rodrigues Martins Secretária: Micheline Aquino de Paiva Endereço: Av. Dom Luis, 300, sala 1122, Aldeota

60160-230 - Fortaleza - CE Tel: (85) 3087-6261 3092-0401 E-mail: pneumoceara@gmail.com SOCIEDADE DE PNEUMOLOGIA DA BAHIA Presidente: Tatiana Senna Galvão Nonato Alves Secretária: Margarida Célia Lima Costa Neves Endereço: Av. Oceânica, 551 - Ed. Barra Center - sala 112

40.160-010 - Barra - Salvador - BA Tel/fax: (71) 3264-2427 E-mail: spba@terra.com.br / site: www.pneumobahia.com.br SOCIEDADE DE PNEUMOLOGIA DO ESPÍRITO SANTO Presidente: Firmino Braga Neto Secretária: Cilea Aparecida Victória Martins Endereço: Rua Eurico de Aguiar, 130, Sala 514 - Ed. Blue Chip

Praia do Campo, 29.055-280 - Vitória - ES Tel: (27) 3345-0564 Fax: (27) 3345-1948 E-mail: firminobn@yahoo.com.br SOCIEDADE DE PNEUMOLOGIA E TISIOLOGIA DO MATO GROSSO Presidente: Dra Keyla Medeiros Maia da Silva Secretária: Dra Wandoircy da Silva Costa Endereço: Rua Prof Juscelino Reiners, Quadra 07, casa 04

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Bairro São José, 49010-410 - Aracaju - SE Tel: (79) 3213-7352 E-mail: j.barreto@uol.com.br

Editorial A new era in lung transplantation: an individualized approach to donor lungs Uma nova era no transplante pulmonar: medicina personalizada a pulmĂľes doados

Marcelo Cypel

Since the first successful lung transplantation (LTx), performed in Toronto in 1983, there have been many technical advances. What was initially a daring endeavor has now become a routine procedure in the treatment of patients with end-stage lung disease. Despite advances in surgical techniques and patient management, one major obstacle continues to hinder the widespread success of LTx: the supply of quality donor lungs is insufficient to meet the growing demand, an increasing number of patients being in need of this life saving procedure. Currently, most donor lungs from multi-organ donors are deemed to be â&#x20AC;&#x153;too damagedâ&#x20AC;? to be transplanted and are simply rejected.(1) Transplant surgeons and clinicians have significant concerns regarding the impact of primary graft dysfunction (PGD, an acute lung injury process occurring in the first 72 h after LTx).(2) Therefore, most transplant centers apply strict donor selection criteria.(3) However, there are two major problems with this highly selective approach(4): up to 30% of eligible recipients die before a compatible organ becomes available; and, even when such criteria are applied, 15% of all transplant recipients develop severe PGD. Two innovative approaches, both developed within the last 5 years, will have a significant impact on donor lung availability and post-transplant outcomes in the coming years(5): the use of non-heart-beating donor (NHBD) lungs; and normothermic ex vivo lung perfusion (EVLP) to reassess and recondition donor lungs that were initially rejected. The use of NHBD lungs is expected to increase the overall organ donor pool by at least 20-30%, and EVLP will significantly increase lung utilization rates (percentage of lungs from the current donor pool that are utilized for transplantation).

The controlled use of NHBD lungs is a method by which the organs can be harvested from individuals who do not meet the criteria for brain death, following elective withdrawal of life-sustaining treatments. Uncontrolled use of NHBD lungs is when the donor is either dead on arrival at the hospital or has died following unsuccessful resuscitation. The latter practice is mainly utilized in Spain.(6) The controlled use of NHBD lungs has become a more widely recognized option for increasing the number of organs available for transplantation and has, in recent years, been responsible for a large proportional increase in the lung donor pools in North America, Europe and Oceania. Although there was some skepticism when NHBD lungs began to be used, various studies have now demonstrated that the short- and long-term results achieved in patients receiving NHBD lungs are at least equivalent to those achieved in patients receiving lungs from standard (brain-dead) donors.(7,8) In fact, it is known that exposure to the inflammatory milieu after brain death is detrimental to the lungs, which could translate to an advantage of using NHBD lungs.(9) In the LTx field, the advent of normothermic EVLP is an advance that is even more exciting than is the use of NHBD lungs. Ever since the development of clinical LTx, transplant clinicians and researchers have sought to reduce injury and maximize safe preservation time during the storage and transport of donor lungs. Key advancements in lung preservation, including hypothermia, inflated storage, and low-potassium dextran solution flush, have culminated in the maturation of LTx into a standard of care for end-stage lung disease worldwide. However, hypothermic preservation is limited in its ability to rescue lungs that are deemed unusable, which, J Bras Pneumol. 2012;38(6):681-683

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unfortunately, account for 85% of potential donor lungs. Therefore, there has been a dramatic shift in the focus of lung preservation, from postponing organ death (by hypothermia) to facilitating the assessment, recovery, and regeneration of lungs prior to implantation. This has led to the emergence of normothermic EVLP as a strategy for lung preservation. The first use of the technique to reassess the function of a human NHBD lung was described by Steen et al. in 2001.(10) However, the utilization of normothermic EVLP became widespread only after the landmark prospective Toronto Lung Transplant Program study conducted in 2011.(11) Significant clinical experience has been rapidly accumulated in recent years, and three prospective clinical trials of different technologies are currently underway. Mariani et al. performed an excellent review of all experimental and clinical EVLP studies published to date.(12) The authors also described the progress of the use of the technique in Brazil, noting that the places with the greatest potential to benefit from the use of EVLP are those such as Brazil, where there is a considerable pool of multi-organ donors but quite low utilization rates of donor lungs due to significant variability in donor lung protection across intensive care units.

Although EVLP is effective for lung preservation, its true potential lies in facilitating the reassessment, recovery, and repair of donor lungs. The concept of specialized “organ repair centers”, involving the use of remote EVLP, has emerged and could have significant implications for organ utilization and allocation in the future.

(13) Finally, the development of ex vivo lung repair strategies for the broad spectrum of donor lung injury is a burgeoning and important area for research. Development of an ex vivo treatment arsenal, ranging in complexity from pharmacologic (antibiotics, thrombolytics, etc.) to gene and cellular therapies might allow practitioners to take a individualized approach to the donor organ (the “personalized” or targeted repair of injuries specific to each individual donor lung), finally allowing clinicians to utilize the full potential of the donor organ pool.

J Bras Pneumol. 2012;38(6):681-683

Marcelo Cypel Assistant Professor of Surgery, Division of Thoracic Surgery, Toronto General Hospital, Toronto Lung Transplant Program, University of Toronto, Toronto, Canada

References 1. Klein AS, Messersmith EE, Ratner LE, Kochik R, Baliga PK, Ojo AO. Organ donation and utilization in the United States, 1999-2008. Am J Transplant. 2010;10(4 Pt 2):973-86. PMid:20420647. http://dx.doi.org/10.1111/j.1600-6143.2009.03008.x 2. Lee JC, Christie JD, Keshavjee S. Primary graft dysfunction: definition, risk factors, short- and long-term outcomes.

Semin Respir Crit Care Med. 2010;31(2):161-71.

PMid:20354929. http://dx.doi.org/10.1055/s-0030-1249111 3. Van Raemdonck D, Neyrinck A, Verleden GM, Dupont L, Coosemans W, Decaluwé H, et al. Lung donor selection and management. Proc Am Thorac Soc. 2009;6(1):28‑38. PMid:19131528. http://dx.doi. org/10.1513/pats.200808-098GO 4. De Meester J, Smits JM, Persijn GG, Haverich A. Lung transplant waiting list: differential outcome of type of end-stage lung disease, one year after registration.

J Heart Lung Transplant. 1999;18(6):563-71. http:// dx.doi.org/10.1016/S1053-2498(99)00002-9 5. Cypel M, Yeung JC, Keshavjee S. Novel approaches to expanding the lung donor pool: donation after cardiac death and ex vivo conditioning. Clin Chest Med. 2011;32(2):233-44. PMid:21511086. http://dx.doi. org/10.1016/j.ccm.2011.02.003 6. Gomez-de-Antonio D, Campo-Cañaveral JL, Crowley S, Valdivia D, Cordoba M, Moradiellos J, et al.

Clinical lung transplantation from uncontrolled non-heart-beating donors revisited. J Heart Lung Transplant. 2012;31(4):349‑53. PMid:22306439. http:// dx.doi.org/10.1016/j.healun.2011.12.007 7. Wigfield CH, Love RB. Donation after cardiac death lung transplantation outcomes. Curr Opin Organ Transplant. 2011;16(5):462-8. PMid:21897244. http:// dx.doi.org/10.1097/MOT.0b013e32834a99ac 8. Levvey BJ, Harkess M, Hopkins P, Chambers D, Merry C, Glanville AR, et al. Excellent clinical outcomes from a national donation-after-determination-ofcardiac-death lung transplant collaborative. Am J Transplant. 2012;12(9):2406-13. PMid:22823062. http://dx.doi.org/10.1111/j.1600-6143.2012.04193.x 9. Kang CH, Anraku M, Cypel M, Sato M, Yeung J, Gharib SA, et al. Transcriptional signatures in donor lungs from donation after cardiac death vs after brain death: A

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functional pathway analysis. J Heart Lung Transplant. J Heart Lung Transplant. 2011;30(3):289‑98. PMid:21093300. http://dx.doi.org/10.1016/j.healun.2010.09.004 10. Steen S, Sjöberg T, Pierre L, Liao Q, Eriksson L, Algotsson L. Transplantation of lungs from a non-heart-beating donor. Lancet. 2001;357(9259):825-9. http://dx.doi. org/10.1016/S0140-6736(00)04195-7 11. Cypel M, Yeung JC, Liu M, Anraku M, Chen F, Karolak W, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med. 2011;364(15):1431‑40.

PMid:21488765. http://dx.doi.org/10.1056/ NEJMoa1014597 12. Mariani AW, Pêgo-Fernandes PM, Abdalla LG, Jatene FB. Ex vivo lung reconditioning: a new era for lung transplantation. J Bras Pneumol. 2012;38(6):776-85.

13. Wigfield CH, Cypel M, Yeung J, Waddell T, Alex C, Johnson C, et al. Successful emergent lung transplantation after remote ex vivo perfusion optimization and transportation of donor lungs. Am J Transplant. 2012;12(10):2838-44. PMid:23009140. http://dx.doi.org/10.1111/j.1600-6143.2012.04175.x

J Bras Pneumol. 2012;38(6):681-683

Original Article Cross-cultural adaptation and assessment of reproducibility of the Duke Activity Status Index for COPD patients in Brazil* Adaptação cultural e avaliação da reprodutibilidade do

Duke Activity Status Index para pacientes com DPOC no Brasil

Livia dos Anjos Tavares, José Barreto Neto, José Roberto Jardim, George Márcio da Costa e Souza, Mark A. Hlatky, Oliver Augusto Nascimento

Abstract Objective: To cross-culturally adapt the Duke Activity Status Index (DASI) for use in Brazil and evaluate the reproducibility of the new (Brazilian Portuguese-language) version. Methods: We selected stable patients with clinical and spirometric diagnosis of COPD. Initially, the DASI was translated into Brazilian Portuguese, and the cross-cultural adaptation was performed by an expert committee. Subsequently, 12 patients completed the questionnaire, so that their questions and difficulties could be identified and adjustments could be made. An independent translator back-translated the final version into English, which was then submitted to and approved by the original author. The final Brazilian Portuguese-language version of the DASI was applied to 50 patients at three distinct times. For the assessment of interobserver reproducibility, it was applied twice within a 30-min interval by two different interviewers. For the assessment of intraobserver reproducibility, it was applied again 15 days later by one of the interviewers. Results: The mean age of the patients was 62.3 ± 10.0 years, the mean FEV1 was 45.2 ± 14.7% of the predicted value, and the mean body mass index was 26.8 ± 5.8 kg/m2. The intraclass correlation coefficients for intraobserver and interobserver reproducibility were 0.95 and 0.90, respectively. The correlations between the DASI and the Saint George’s Respiratory Questionnaire (SGRQ) domains were all negative and statistically significant. The DASI correlated best with the SGRQ activity domain (r = −0.70), the total SGRQ score (r = −0.66), and the six-minute walk distance (r = 0.55). Conclusions: The Brazilian Portuguese-language version of the DASI is reproducible, fast, and simple, correlating well with the SGRQ. Keywords: Activities of daily living; Pulmonary disease, chronic obstructive; Reproducibility of results.

Resumo Objetivo: Adaptar culturalmente e avaliar a reprodutibilidade do Duke Activity Status Index (DASI) para o português do Brasil. Métodos: Foram selecionados pacientes estáveis com diagnóstico clínico e espirométrico de DPOC. Inicialmente, o DASI foi traduzido para o português, e a adaptação cultural foi realizada por uma comissão de especialistas. Em seguida, o questionário foi aplicado em 12 pacientes para saber suas dúvidas e dificuldades, sendo realizadas as devidas adaptações. Um tradutor independente fez a tradução retrógrada, que foi submetida e aprovada pelo autor original. A versão final do DASI foi aplicada em 50 pacientes em dois momentos, com intervalo de 30 minutos (reprodutibilidade interobservador) e, num terceiro momento, após 15 dias (reprodutibilidade intraobservador). Resultados: A média de idade dos pacientes foi de 62,3 ± 10,0 anos, a média do VEF1 foi de 45,2 ± 14,7% do valor previsto, e a do índice de massa corpórea foi de 26,8 ± 5,8 kg/m2. Os coeficientes de correlação intraclasse intraobservador e interobservador foram de 0,95 e 0,90, respectivamente. As correlações do DASI com todos os domínios do Saint George’s Respiratory Questionnaire (SGRQ) foram negativas e estatisticamente significantes. As melhores correlações ocorreram com o domínio atividade (r = −0,70) e a pontuação total do SGRQ (r = −0,66), assim como com a distância percorrida no teste de caminhada de seis minutos (r = 0,55). Conclusões: A versão em língua portuguesa do Brasil do DASI é reprodutível, de rápida e fácil aplicação e apresentou uma boa correlação com o SGRQ. Descritores: Atividades cotidianas; Doença pulmonar obstrutiva crônica; Reprodutibilidade dos testes.

* Study carried out at the Pulmonology Outpatient Clinic, Federal University of Sergipe University Hospital, Aracaju, Brazil, and at the Federal University of São Paulo, São Paulo, Brazil.

Correspondence to: Oliver A. Nascimento. Rua Botucatu, 740, 3º andar, Disciplina de Pneumologia, CEP 04023-062, São Paulo, SP, Brasil.

Tel. 55 11 5576-4238. E-mail: olivernascimento@yahoo.com.br Financial support: None.

Submitted: 13 March 2012. Accepted, after review: 13 September 2012.

J Bras Pneumol. 2012;38(6):684-691

Cross-cultural adaptation and assessment of reproducibility of the Duke Activity Status Index for COPD patients in Brazil

Introduction A preventable and treatable respiratory disease, COPD is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with a chronic inflammatory response of the airways and lungs to the inhalation of noxious particles or gases. Exacerbations and comorbidities individually contribute to the severity of COPD. (1) Patients with COPD present with significantly impaired functional capacity, which is usually due to airflow limitation, static and dynamic hyperinflation, peripheral muscle dysfunction, oxidative stress, poor peripheral perfusion, and physical deconditioning.(2) This leads to limitations in activities of daily living (ADL)(3) and impairs quality of life.(4) In addition to being a rapid and practical way of measuring the extent to which functional capacity is impaired, the use of a specific questionnaire to evaluate functional changes in ADL can show how patients view their ability to perform ADL, their level of independence, and their functional status.(5) The Saint George’s Respiratory Questionnaire (SGRQ) is a comprehensive, diseasespecific questionnaire consisting of 76 items assessing the following domains: symptoms; activity; and impact.(6) However, the time required to complete the SGRQ is long, and the SGRQ does not show which activities patients can perform. The Portuguese-language version of the SGRQ was validated for use in Brazil in 2000.(7) All of the abovementioned factors have motivated the development of instruments to predict cardiorespiratory fitness on the basis of the physical characteristics and lifestyle habits of individuals.(8) The Duke Activity Status Index (DASI) was developed and validated at Duke University, in Durham, NC, USA, in 1989.(9) The DASI is an easyto-administer questionnaire aimed at predicting oxygen consumption (VO2) without the need for maximal cardiopulmonary exercise testing. The DASI is a fast and simple questionnaire that can be administered to patients with physical limitation, having previously been validated with physiological measurements, such as VO2.

(9) Although it was originally designed to evaluate patients with cardiovascular disease, the DASI also proved to be valid and appropriate for assessing functional capacity in patients with moderate to severe COPD.(10) None of the instruments

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currently available for use in Brazil can assess exercise capacity in patients with COPD. However, for a given questionnaire to be administered to patients whose native language and culture are different from those of those for whom it was originally developed and validated, it needs to undergo cross-cultural adaptation, and the reproducibility of the new version needs to be evaluated. The objective of the present study was to cross-culturally adapt the DASI for use in Brazil and evaluate the reproducibility of the new (Brazilian Portuguese-language) version.

Methods The present study was approved by the Research Ethics Committee of the Federal University of Sergipe, located in the city of Aracaju, Brazil, and was conducted at the Pulmonology Outpatient Clinic of the Federal University of Sergipe University Hospital. The inclusion criteria were as follows: having been clinically and functionally diagnosed with COPD in accordance with the Brazilian Thoracic Association/Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria(1); being clinically stable (i.e., having had no episodes of exacerbation, no changes in medication, no increased cough, and no increased dyspnea in the last four weeks); being over 40 years of age; and having given written informed consent. The exclusion criteria were as follows: having been unable to answer the questionnaires; having failed to return to the outpatient clinic for the second study visit; having had exacerbations between the two stages of the study; having other lung diseases; and having severe or uncontrolled comorbidities.

The DASI is a 12-item questionnaire covering self-care, ambulation, household chores, sexual activity, and recreational activities.(9) Each item is scored proportionally to the metabolic cost of each activity (in metabolic equivalents). For each affirmative answer, points are added. The sum of the points for all affirmative answers results in a total score ranging from zero (worst result) to 58.2 (best result). In order to estimate VO2 (mL kg−1 min−1), the following multiple linear regression equation is used(9): •

•

VO2 = 0.43 × DASI + 9.6 The estimation of VO2 is based on self-reported levels of physical activity. Lower VO2 values indicate greater limitations in ADL. J Bras Pneumol. 2012;38(6):684-691

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Initially, the original (English-language) version of the DASI was translated to Brazilian Portuguese by a physiotherapist who was a native speaker of English and who was fluent in Portuguese.

Subsequently, the cross-cultural adaptation was performed by an expert committee. This initial version of the DASI was administered to and discussed with 12 COPD patients in order to analyze their questions and difficulties. The difficulties encountered by those 12 patients were discussed between the principal investigator and three experts, and a new Brazilian Portugueselanguage version of the DASI was developed. This new version was then back-translated to English by a second independent translator, who had never had any contact with the questionnaire.

The author of the original DASI analyzed the new Brazilian Portuguese-language version of the questionnaire and found that it maintained the essence of the original DASI. The final Brazilian Portuguese-language version of the DASI was thus arrived at (Appendix 1, available online at http://www.jornaldepneumologia.com.br/ english/artigo_detalhes.asp?id=1944 ). The final Brazilian Portuguese-language version of the DASI was administered to 50 COPD patients three times, in two visits. In the first visit (V1), the questionnaire was administered twice within a 30-min interval by two different interviewers in order to assess interobserver reproducibility. In the second visit (V2), 15 days after the first, the questionnaire was administered for the third time, by the same interviewer who had administered it the first time, in order to assess intraobserver reproducibility. We recorded the time required to complete the questionnaire each time it was administered. The questionnaire was administered in a standardized manner, the questions having been read to all patients because of the large proportion of illiterate individuals in the study population. The interviewers read the questions in an unbiased manner and wrote down the answers given by the patients.

In the first visit, we assessed patient weight, height, and level of education. In addition, the patients underwent spirometry (before and after bronchodilator use) and the six-minute walk test (6MWT). The body mass index (BMI) was calculated as follows: BMI = weight/height2 (in kg/m2). The Brazilian Portuguese-language version of the SGRQ, adapted and validated for use in Brazil in 2000,(7) was also administered J Bras Pneumol. 2012;38(6):684-691

to the patients. The SGRQ was also read to the patients by the investigators.

Spirometry (before and after bronchodilator use) was performed with a Koko spirometer (PDS Instrumentation Inc., Louisville, CO, USA) in accordance with the acceptability and reproducibility criteria recommended by the American Thoracic Society(11) and the Brazilian Thoracic Association Guidelines for Pulmonary Function Tests.(12) The variables analyzed were FEV1, FVC, and post-bronchodilator FEV1/FVC. The predicted values were based on the equation developed by Pereira.(13) The severity of COPD was determined in accordance with the criteria established by the GOLD(1) and the Second Brazilian Consensus on COPD.(14) The 6MWT was performed in a 30-m corridor that was straight and level, in accordance with the American Thoracic Society guidelines.(15) Two tests were performed (at least 30 min apart), the greater six-minute walk distance (6MWD) being chosen for analysis.

For the cross-cultural adaptation of the DASI, we selected 12 patients who were considered to have an appropriate cognitive level to suggest the necessary adjustments. For the assessment of reproducibility, we selected a sample of 50 patients, none of whom had participated in the cross-cultural adaptation of the DASI. Our sample size was based on the sample size in the study validating the original DASI and on that in studies cross-culturally adapting and evaluating the reproducibility of quality of life questionnaires for use in Brazil, as well as on that in the studies validating the SGRQ(7) and airways questionnaire 20(16) for use in Brazil.

In addition, we followed recommendations for achieving a smaller margin of error.(17) Those 50 patients were chosen consecutively.

Continuous variables were expressed as mean and standard deviation. Categorical variables were expressed as absolute numbers and proportions.

We used the paired t-test in order to compare the mean scores for the DASI domains and subscales between the two visits. In order to assess interobserver and intraobserver reproducibility, we used the intraclass correlation coefficient (ICC), values greater than 0.75 being considered excellent. In order to determine the correlations between the DASI and the remaining tests, we used Pearson’s correlation coefficient. We used Bland & Altman plots in order to assess the

Cross-cultural adaptation and assessment of reproducibility of the Duke Activity Status Index for COPD patients in Brazil

variability in the estimated VO2 between the two visits.(18) We used one-way ANOVA followed by the Bonferroni test in order to compare the mean DASI scores among the stages of COPD severity. The level of significance was set at 5%.

Results The original (English-language) version of the DASI was translated to Brazilian Portuguese and initially administered to 12 patients (6 males and 6 females). The mean age of the patients was 63.6 years.

Some patients reported having difficulty understanding the questions beginning with “Você consegue”, having misinterpreted them as “Você faz”. For instance, in response to question 6 (“Você consegue realizar tarefas domésticas, como tirar pó ou lavar pratos?”), some of the males stated that those activities were the responsibility of females. Therefore, we had to make clear that the objective of that question was to determine whether they were physically able to perform such activities.

Only two questions in the original DASI required cross-cultural adaptation for use in Brazil. Question 11 mentioned recreational activities such as golf, bowling, and baseball, which are not widely disseminated in Brazil. Those activities were therefore replaced by jogging and volleyball.

In question 12, skiing was replaced by cycling.

Those changes were suggested by the author of the original questionnaire because the energy expenditure in individuals performing the selected activities is similar to that in those performing the activities mentioned in the original DASI. For the assessment of reproducibility, we selected 50 patients, whose mean age was 62.3 years. Of those 50 patients, 56% were female.

Most had moderate obstructive lung disease, were normal weight, and were illiterate (Table 1).

The mean time to complete the DASI was 2 min and 19 s at V1 and 1 min and 38 s at V2.

There were no statistically significant differences between illiterate and literate individuals in terms of the time required to complete the questionnaire.

Table 2 shows the mean DASI scores and the estimated VO2 as assessed by the same investigator at V1 and V2. There were no statistically significant differences between the values. The mean DASI scores and the mean estimated VO2 were, respectively, 23.9 ± 14.9 mL kg−1 min−1 and 19.9 ± 6.4 mL kg−1 min−1, as assessed •

•

•

•

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Table 1 - Demographic data of the study participants.a Variable Result Gender Male 22 (44) Female 28 (56) BMI, kg/m2 26.8 ± 5.8 Smoking history, pack-years 47.4 ± 45.2 Level of education Illiterate 29 (58) 9 years of schooling 12 (24) High school 8 (16) College 1 (2) 45.2 ± 14.7 FEV1, % of predicted FVC, % of predicted 72.34 ± 17.30 FEV1/FVC 0.62 ± 0.13 6MWD, m 489.8 ± 105.5 GOLD stage II 19 (38) III 24 (48) IV 7 (14) BMI: body mass index; 6MWD: six-minute walk distance; and GOLD: Global Initiative for Chronic Obstructive Lung Disease. aValues expressed as n (%) or mean ± SD.

by the second investigator at V1, and were not significantly different from the values obtained by the first investigator. Table 2 shows the ICCs for intraobserver reproducibility of the DASI score and the estimated VO2, the ICCs for both variables being 0.95 (p < 0.001) and therefore indicating excellent reproducibility. The ICC for interobserver reproducibility was 0.90 (95% CI: 0.81-0.95; p < 0.001).

Figure 1 shows the Bland & Altman plots of the individual variability in DASI scores between V1 and V2.

Although VO2 (as estimated by the DASI) did not correlate significantly with age or BMI, it correlated positively with FVC (r = 0.37; p < 0.05), FEV1 (r = 0.37; p < 0.05), and the 6MWD (r = 0.55; p < 0.01).

As can be seen in Table 3, the correlations between VO2 (as estimated by the DASI) and the SGRQ domains were all negative and statistically significant. The DASI correlated best with the SGRQ activity domain and the total SGRQ score.

Table 4 shows a comparison of the GOLD stages of COPD severity with the DASI scores and the estimated VO2. Greater disease severity translated to lower DASI scores.

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Figure 1 - Bland & Altman plots. Differences between Duke Activity Status Index (DASI) scores in the first and second visits, plotted against the mean DASI score.

Table 2 - Duke Activity Status Index scores, oxygen consumption as estimated by the Duke Activity Status Index, and intraclass correlation coefficients in the two visits in which the questionnaire was administered by the same observer.

Variable V1a V2a ICC 95% CI DASI score 27.4 ± 15.8 27.7 ± 14.7 0.95 0.91-0.97 21.4 ± 6.8 21.5 ± 6.3 0.95 0.91-0.97 Estimated VO2, mL kg−1 min−1 •

•

V1: first visit; V2: second visit; ICC: intraclass correlation coefficient; DASI: Duke Activity Status Index; and VO2: oxygen consumption. aValues expressed as mean ± SD.

Table 3 - Correlations between oxygen consumption as estimated by the Duke Activity Status Index and the Saint George’s Respiratory Questionnaire domains.

SGRQ domains Correlation p Symptoms −0.44 0.004 Activity −0.70 < 0.001 Impact −0.54 < 0.001 Total −0.66 < 0.001 SGRQ: Saint George’s Respiratory Questionnaire.

Discussion The objectives of the present study were to translate the DASI to Brazilian Portuguese and cross-culturally adapt it for use in Brazil, as well as to assess the reproducibility of the new (Brazilian Portuguese-language) version and determine its correlations with other physiological variables in patients with COPD. The DASI proved to be an adaptable instrument, and the Brazilian Portuguese-language version of the questionnaire was found to be reproducible, fast, and simple.

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During the cross-cultural adaptation of the DASI, two physical activities mentioned in the original questionnaire needed to be changed in order to achieve cross-cultural equivalence. We selected 12 patients with appropriate cognitive levels, significant life experience, and a proper understanding of COPD-related limitations.

Question 11 in the original DASI mentioned activities such as golf, bowling, and baseball, and question 12 mentioned skiing. Those are not traditional Brazilian sports, being practiced by few Brazilians. For cross-cultural adaptation, the author of the original questionnaire suggested that those sports be replaced by sports that are more commonly practiced in Brazil, provided that the recreational nature and metabolic cost of such sports were similar to those of those mentioned in the original DASI. Therefore, golf and bowling (mentioned in question 11 in the original DASI) were replaced by jogging and volleyball in the Brazilian Portuguese-language version of the DASI, whereas skiing (mentioned in question 12 in the original DASI) was replaced by cycling.

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Table 4 - Duke Activity Status Index score and oxygen consumption as estimated by the Duke Activity Status Index, by Global Initiative for Chronic Obstructive Lung Disease stage of COPD severity (as determined by spirometry).

GOLD stage Variable II III IV* p (n = 19) (n = 24) (n = 7) DASI score 34.3 ± 18.4 23.4 ± 11.4 16.8 ± 7.7 0.014 24.3 ± 7.9 19.7 ± 4.9 16.8 ± 3.3 0.014 Estimated VO2, mL kg−1 min−1 •

•

GOLD: Global Initiative for Chronic Obstructive Lung Disease; DASI: Duke Activity Status Index; and VO2: oxygen consumption. *Patients with stage II COPD were significantly different from those with stage IV COPD.

This demonstrates that questionnaires originally developed in a given country should be crossculturally adapted for use in other countries, and that it is imperative that the author of the original questionnaire be involved in the process of cross-cultural adaptation. The DASI has been adapted for use in various countries in which English is not the official language, including China,(19,20) Greece,(21) and Turkey.(22) The reproducibility of the DASI was demonstrated by the absence of significant differences between the evaluations at V1 and V2 and by the high ICC values, all of which were above 0.75, a value that has been defined as being indicative of reproducibility.(23) The ICCs for interobserver and intraobserver reproducibility were 0.90 and 0.95, respectively, both of which were considered excellent. Therefore, we can state that the Brazilian Portuguese-language version of the DASI is reproducible when administered to stable patients by the same interviewer or by different interviewers. Other studies(20,21) have found ICCs of 0.78 and 0.90. These values show that cross-cultural adaptation of the DASI is easy, the questionnaire having been used in other countries with a reproducibility that is similar to or even lower than that found in our study but with values above the levels of reproducibility.

As can be seen in Figure 1, regardless of whether the DASI score was high or low, the variability in the score between the two visits was the same, meaning that the reproducibility of the DASI is good regardless of the score.

The SGRQ is a widely used quality of life questionnaire specifically developed for patients with COPD, having been cross-culturally adapted for use in Brazil in 2000.(7) We found that the DASI scores correlated significantly with all SGRQ domains. The DASI correlated best with the SGRQ activity domain (r = −0.70). This finding was not unexpected, given that the DASI estimates

VO2 on the basis of ADL, similar to the SGRQ activity domain. The total DASI score correlated well with the total SGRQ score (r = −0.66). All correlations between the DASI and the SGRQ were negative, i.e., higher VO2 values (as estimated by the DASI) translated to lower SGRQ scores, therefore indicating better quality of life. To our knowledge, this is the first study to evaluate the correlations between the DASI and the SGRQ in patients with COPD. The DASI is an instrument that assesses physical limitation and complements the assessment by the SGRQ. The DASI correlated significantly but moderately with the 6MWD (r = 0.53; p < 0.001), a finding that is consistent with those of a study validating the use of the DASI to assess functional capacity in patients with COPD.(10) The DASI was expected to correlate with the 6MWD, given that the DASI assesses the ability to perform ADL and the 6MWT assesses the ability to perform physical activities. In our study, the DASI score did not correlate significantly with age or BMI. Long-term follow-up studies of patients with cardiovascular disease have shown that age, BMI, female gender, and comorbidities (e.g., between COPD and diabetes) negatively affect the DASI score.(24-26) The DASI can be used in order to estimate VO2. In the study validating the original DASI, the DASI score was found to correlate well and significantly with objectively assessed VO2 in healthy individuals (r = 0.58)(9) but less so in COPD patients (r = 0.39).(10) Because the VO2 as predicted by the DASI correlates moderately with the actual VO2, the former should be used as an estimate and should not replace the combination of maximal exercise testing and exhaled gas measurements. However, the present study provides health professionals in Brazil with a useful and easy-to-administer instrument for the functional assessment of patients with J Bras Pneumol. 2012;38(6):684-691

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chronic diseases. By estimating VO2, we can determine whether patients can perform ADL, engage in physical activity, and even undergo surgery. According to the American College of Cardiology and the American Heart Association, patients with exercise tolerance > 4 metabolic equivalents, VO2 ≥ 14 mL kg−1 min−1, or a DASI score > 11.6 can undergo cardiac surgery without the need for further investigation or changes in perioperative management.(27) A comparison between VO2 as predicted by the DASI and the stages of COPD severity showed that greater severity translated to lower functional capacity, with statistically significant differences between stages II and IV. Had the number of patients with stage II, stage III, and stage IV COPD been higher, there might have been statistically significant differences among all stages. However, the investigation of this hypothesis was outside the scope of the present study, further studies being therefore required.

Although we obtained excellent results, our study has some limitations. First, many of the individuals in our sample were illiterate. However, the DASI can be used in various ways without losing its sensitivity(24,25,28,29): • It can be self-administered at the site where the study is conducted.

• It can be mailed to respondents.

• It can be read to respondents.

Because most of the patients in our sample had a low level of education, we chose to read the questionnaire to all (regardless of their level of education), knowing that that would not affect the results obtained. Another limitation is the fact that most of the patients were female.

However, the original version of the DASI was administered to males and females, with no differences in reproducibility. In addition, our objective was to cross-culturally adapt the DASI for use in Brazil and assess the reproducibility of the new (Brazilian Portuguese-language) version rather than to investigate possible differences between the genders.

In conclusion, the Brazilian Portugueselanguage version of the DASI is easy to understand, which demonstrates that the process of crosscultural adaptation for use in Brazil was appropriate. In addition, the Brazilian Portugueselanguage version of the DASI is reproducible, fast, and simple, correlating well with the SGRQ and the 6MWD. We therefore believe that this new •

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•

instrument will be very useful in assessing the functional capacity of COPD patients in Brazil.

Acknowledgments The authors would like to thank physiotherapists Camila Caroline Navarro Gomes, Michelle Teles Morlin, and Tássia Virgínia de Carvalho Oliveira for their invaluable assistance.

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21. Parissis JT, Nikolaou M, Birmpa D, Farmakis D, Paraskevaidis I, Bistola V, et al. Clinical and prognostic value of Duke’s Activity Status Index along with plasma B-type natriuretic peptide levels in chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J

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About the authors Livia dos Anjos Tavares

Physiotherapist. Aracaju Municipal Department of Health and Sergipe State Department of Health, Aracaju, Brazil.

José Barreto Neto

Preceptor. Department of Pulmonology, Federal University of Sergipe University Hospital, Aracaju, Brazil.

José Roberto Jardim

Tenured Professor. Department of Pulmonology, Federal University of São Paulo; and Director. Pulmonary Rehabilitation Center, Federal University of São Paulo/Associação de Assistência à Criança Deficiente – AACD, Association for Assistance to Children with Disabilities – São Paulo, Brazil.

George Márcio da Costa e Souza

Professor and Coordinator. Center for Clinical Assessment and Treatment, Alagoas State University of Health Sciences, Maceió, Brazil.

Mark A. Hlatky

Professor of Health Research and Policy and of Cardiovascular Medicine. Stanford University School of Medicine, Palo Alto, CA, USA.

Oliver Augusto Nascimento

Attending Physician. Department of Pulmonology, Federal University of São Paulo; and Vice-Director. Pulmonary Rehabilitation Center, Federal University of São Paulo/Associação de Assistência à Criança Deficiente – AACD, Association for Assistance to Children with Disabilities – São Paulo, Brazil.

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Original Article Underdiagnosis of COPD at primary health care clinics in the city of Aparecida de Goiânia, Brazil* Subdiagnóstico de DPOC na atenção primária em Aparecida de Goiânia, Goiás

Maria Conceição de Castro Antonelli Monteiro de Queiroz, Maria Auxiliadora Carmo Moreira, Marcelo Fouad Rabahi

Abstract Objective: To estimate the prevalence of undiagnosed COPD among individuals with risk factors for the disease treated at primary health care clinics (PHCCs) in the city of Aparecida de Goiânia, Brazil. Methods: Inclusion criteria were being ≥ 40 years of age, having a > 20 pack-year history of smoking or a > 80 hour-year history of exposure to biomass smoke, and seeking medical attention at one of the selected PHCCs. All subjects included in the study underwent spirometry for the diagnosis of COPD. Results: We successfully evaluated 200 individuals, mostly males. The mean age was 65.9 ± 10.5 years. The diagnosis of COPD was confirmed in 63 individuals, only 18 of whom had been previously diagnosed with COPD (underdiagnosis rate, 71.4%).

There were no significant differences between the subgroups with and without a previous diagnosis of COPD in relation to demographics and risk factors. However, there were significant differences between these subgroups for the presence of expectoration, wheezing, and dyspnea (p = 0.047; p = 0.005; and p = 0.047, respectively).

The FEV1 and FEV1/FVC ratio, expressed as percentages of the predicted values, were significantly lower in the subjects with a previous diagnosis of COPD, which was predominantly mild or moderate in both subgroups.

Conclusions: The rate of underdiagnosis of COPD was high at the PHCCs studied. One third of the patients with risk factors for COPD met the clinical and functional criteria for the disease. It seems that spirometry is underutilized at such facilities.

Keywords: Pulmonary disease, chronic obstructive/diagnosis; Primary health care; Spirometry.

Resumo Objetivo: Estimar a prevalência de DPOC não diagnosticada entre indivíduos com fatores de risco para a doença atendidos em unidades básicas de saúde (UBS) na cidade de Aparecida de Goiânia (GO). Métodos: Os critérios de inclusão foram ter idade ≥ 40 anos, ter história de tabagismo > 20 maços-ano ou de exposição à queima de biomassa > 80 horas-ano e procurar atendimento médico em uma das UBS selecionadas. Todos os indivíduos incluídos no estudo foram submetidos a espirometria para a definição diagnóstica de DPOC. Resultados: Foram avaliados com sucesso 200 indivíduos, a maioria do sexo masculino. A média de idade foi de 65,9 ± 10,5 anos.

Tiveram confirmação diagnóstica de DPOC 63 indivíduos. Desses, apenas 18 haviam sido previamente diagnosticados com DPOC (taxa de subdiagnóstico de 71,4%). Não houve diferenças significantes entre os subgrupos com e sem diagnóstico prévio de DPOC em relação a fatores demográficos e fatores de risco. Entretanto, houve diferenças significantes entre esses subgrupos em relação à presença de expectoração, chiado e dispneia (p = 0,047, p = 0,005 e p = 0,047, respectivamente). Os valores de VEF1 e VEF1/CVF, em percentual do previsto, foram significativamente menores nos indivíduos com diagnóstico prévio de DPOC. A DPOC foi predominantemente leve a moderada em ambos os subgrupos. Conclusões: A taxa de subdiagnóstico da DPOC foi alta nas UBS estudadas. Um terço dos pacientes com fatores de risco para DPOC apresentou critérios clínicos e funcionais para a doença. A espirometria foi subutilizada.

Descritores: Doença pulmonar obstrutiva crônica/diagnóstico; Atenção primária à saúde; Espirometria.

* Study carried out at the Federal University of Goiás, Goiânia, Brazil.

Correspondence to: Maria Conceição C. A. M. de Queiroz. Serviço de Pneumologia, Hospital das Clínicas da UFG, Primeira Avenida, s/n, 2º andar, Setor Leste Universitário, CEP 746005-020, Goiânia, GO, Brasil.

Tel. 55 62 3093-4744. E-mail: sissibb@ig.com.br Financial support: This study received financial support from the Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG, Goiás Research Foundation).

Submitted: 3 July 2012. Accepted, after review: 14 September 2012.

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Underdiagnosis of COPD at primary health care clinics in the city of Aparecida de Goiânia, Brazil

Introduction Chronic respiratory diseases represent a major public health problem worldwide, affecting quality of life, leading to physical disability, and having a major socioeconomic impact.(1) The mortality from COPD is expected to increase by 30% over the next 10 years unless measures are taken in order to reduce the risk factors for COPD and the underdiagnosis of the disease. It has been estimated that, by 2030, COPD will have become the third leading cause of death worldwide.(1) In the worldwide fight against COPD, underdiagnosis and the consequent lack of treatment are the primary targets. Another important facet of COPD is that it is not seen as a systemic disease and therefore is not evaluated by the system for the surveillance of chronic diseases, including cardiovascular and metabolic diseases.(1) Studies and interventions focusing on the diagnosis of COPD at primary health care clinics (PHCCs) are needed in order to detect the disease in a timely manner and control it more effectively.

The objective of the present study was to screen for COPD in patients being treated at PHCCs and having risk factors for the disease but not routinely screened for COPD at such clinics.

Methods This was an analytical, observational, crosssectional study conducted between May and September of 2011 at three PHCCs affiliated with the Family Health Program in the city of Aparecida de Goiânia, Brazil. The city is located in the metropolitan area of Goiânia and has an estimated population of 500,000 inhabitants.

The study received support from the managers of the Aparecida de Goiânia Municipal Department of Health. The selected PHCCs were chosen from among those providing treatment to the largest number of patients (in the southern, eastern, and western regions of the city). These PHCCs provide treatment to 27% of all patients being treated at PHCCs in the city of Aparecida de Goiânia (according to information from the municipal department of health). Individuals seeking the selected PHCCs for routine outpatient treatment and having no acute respiratory symptoms were invited to answer questions regarding demographics and risk factors for COPD. Inclusion criteria were

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being ≥ 40 years of age, having a ≥ 20 packyear history of smoking or a ≥ 80 hour-year history of exposure to biomass smoke (or both), and having given written informed consent. We excluded individuals with a previous diagnosis of bronchial asthma, allergic rhinitis, chronic lung diseases other than COPD, or extrapulmonary disease potentially affecting lung function, as well as those who did not meet the criteria for spirometry (Figure 1).

The individuals who met the inclusion criteria answered a modified version of the principal questionnaire used in a prevalence study.(2) We collected demographic and clinical data (respiratory symptoms, such as cough, expectoration, wheezing, and dyspnea, as well as a previous diagnosis of emphysema, chronic bronchitis, or COPD, with or without spirometry), as well as variables related to exposure to tobacco smoke and smoke from wood-burning stoves.

The quantification of exposure to smoke from wood-burning stoves was based on the exposure levels considered significant in previous studies.(2) For the assessment of lung function, we used a Spirotrac® spirometer (Vitalograph, Buckingham, UK), which was calibrated daily.

Spirometry was performed before and after bronchodilator use, in accordance with the Brazilian Thoracic Association criteria,(3) and the results were interpreted in accordance with the values predicted by Pereira et al.(4) We studied the following spirometric variables: FVC; FEV1; and FEV1/FVC. The diagnosis of COPD was based on a postbronchodilator FEV1/FVC < 0.70 (in absolute values). In order to determine the severity of COPD, we used the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria.(1) Patients with a presumptive diagnosis of COPD were defined as those who had previously been diagnosed with emphysema, chronic bronchitis, or COPD. We calculated the sample size by estimating the proportion of the population with specific absolute accuracy and by using a formula.(5) We assumed the maximum prevalence of COPD in the city population to be 25%, on the basis of the results of a study of the prevalence of COPD in five Latin American cities.(2) With a confidence level of 95% and an absolute accuracy of 6%, the minimum sample size was determined to be 200 individuals.

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Figure 1 - Flowchart of inclusions, losses, and exclusions among the study population.

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For statistical analysis, we used the Statistical Package for the Social Sciences, version 15 (SPSS Inc., Chicago, IL, USA), logistic regression analysis being performed and ORs being calculated. The level of statistical significance was set at p < 0.05.

The present study was approved by the Human Research Ethics Committee of the Federal University of Goiás Hospital das Clínicas (Protocol no. 202/2010).

wood-burning stoves was 146.0 ± 132.3 houryears (Table 1).

Cough, expectoration, wheezing, and dyspnea were more common in the COPD patients with a previous diagnosis of COPD than in those without, the two groups of patients being significantly different only in terms of expectoration, wheezing, and dyspnea. The degree of dyspnea in 44.4% of the patients with a previous diagnosis of COPD was 2, as assessed by the Medical Research Council scale (Table 2).

The FEV1 and FEV1/FVC ratio, expressed as percentages of the predicted values, were significantly lower in the individuals with a previous diagnosis of COPD. As can be seen in Table 3, COPD was predominantly mild or moderate in the group of patients without a previous diagnosis of COPD.

Results We selected 200 individuals, 63 of whom were diagnosed with COPD. The mean age of the participants was 65.0 ± 10.40 years, individuals in the 60-80 year age bracket having predominated.

Most of the participants had a low level of education, and most identified themselves as Mulattos.

Regarding risk factors (smoking history, exposure to smoke from wood-burning stoves, and type of cigarette smoked), there were no statistically significant differences between the individuals with COPD and those without.

Of the 63 individuals diagnosed with COPD, 45 reported no previous diagnosis of COPD, the rate of underdiagnosis being therefore 71.4%.

Of the 137 individuals who did not meet the diagnostic criteria for COPD, 20 reported a previous diagnosis of COPD, the rate of misdiagnosis or overdiagnosis being therefore 14.6%.

Only 5.6% of the individuals with a previous diagnosis of COPD had undergone spirometry.

The 200 individuals under study had risk factors that constituted an indication for spirometry (i.e., smoking and exposure to smoke from woodburning stoves), and the rate of use of spirometry as a diagnostic tool was 1.5%.

There were no statistically significant differences between the groups with and without a previous diagnosis of COPD in terms of gender, age, race, or level of education. In addition, there were no statistically significant differences between the groups in terms of smoking history or cumulative exposure to smoke from woodburning stoves. In the group of COPD patients without a previous diagnosis of COPD, the mean age was 65.9 ± 10.5 years, and there was a predominance of the following: males; selfreported Mulattos; and a low level of education (< 9 years of schooling). In addition, the mean smoking history was 76.3 ± 56.3 pack-years, and the mean cumulative exposure to smoke from

Discussion The rate of underdiagnosis of COPD in individuals having risk factors for the disease and being treated at PHCCs was found to be 71.4% in the present study. In the individuals with a previous diagnosis of COPD, the clinical expression of the disease was more severe and the degree of bronchial obstruction was higher.

The authors of a study aimed at documenting the extent of underdiagnosis of COPD in at-risk patients treated at PHCCs suggested that 10-20% of undiagnosed COPD cases can be detected if smokers over 40 years of age are screened.(6) They also drew attention to the probable reasons for the underdiagnosis of COPD, stating that physicians are not fully aware of the importance of risk factors for and symptoms of COPD, and that they lack knowledge of the spirometric criteria for the disease. In addition, the authors stated that patients seek medical attention only when the symptoms affect their quality of life.

In the present study, we found no differences between the subgroups of patients with and without a previous diagnosis of COPD in terms of risk factors (smoking and cumulative exposure to smoke from wood-burning stoves) or demographics.

In the present study, the mean age of the patients with COPD was higher than was that of those without. Age is often reported as a risk factor for COPD.(1,2) Several studies have shown that the proportion of COPD cases tends to increase with age.(7-9) J Bras Pneumol. 2012;38(6):692-699

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Table 1 - Demographic profile of the COPD patients with and without a previous diagnosis Aparecida de Goiânia, Brazil, 2011.a Previous diagnosis of COPD Variables No Yes (n = 45) (n = 18) Gender Male 30 (66.7) 8 (44.4) Female 15 (33.3) 10 (55.6) Age, yearsb 65.9 ± 10.5 62.6 ± 10.0 40-60 16 (35.6) 10 (55.6) 60-80 26 (57.8) 7 (38.9) > 80 3 (6.7) 1 (5.6) Self-reported race White 9 (20.0) 3 (16.7) Black 8 (17.8) 3 (16.7) Yellow 1 (2.2) 0 (0.0) Mulatto 27 (60.0) 12 (66.7) Level of education None 21 (46.7) 10 (55.6) < 9 years of schooling 22 (48.9) 8 (44.4) 9 years of schooling 2 (4.4) 0 (0.0) Smoking, pack-yearsb 76.3 ± 56.3c 72.6 ± 50.3 Exposure to smoke from wood-burning stoves, hour-yearsb,d 146.3 ± 132.3 118.6± 78.6

of COPD,

p*

0.108 0.248

0.208

0.678

0.394 0.807 0.518

Data expressed as n (%), except where otherwise indicated. bData expressed as mean ± SD. cn = 43. dn = 22 and n = 11 in the No and Yes groups, respectively. *Logistic regression analysis. a

Table 2 - Respiratory symptoms in the COPD patients with and without a previous diagnosis Aparecida de Goiânia, Brazil, 2011.a Previous diagnosis of COPD Variables No Yes OR 95% CI (n = 45) (n = 18) Chronic cough No 26 (57.8) 8 (44.4) Yes 19 (42.2) 10 (55.6) Expectoration No 30 (66.7) 7 (38.9) Yes 15 (33.3) 11 (61.1) 3.140 1.010-9.750 Wheezing No 33 (73.3) 6 (33.3) Yes 12 (26.7) 12 (66.7) 5.500 1.690-17.930 Dyspnea No 15 (33.3) 1 (5.6) Yes 30 (66.7) 17 (94.4) 8.500 1.030-70.100 MRC scale score 0 15 (33.3) 2 (11.1) 1 11 (24.4) 1 (5.6) 2 8 (17.8) 8 (44.4) 3 10 (22.2) 6 (33.3) 4 1 (2.2) 1 (5.6) 1.80 1.090-2.980 MRC: Medical Research Council. aData expressed as n (%). *Logistic regression analysis.

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of COPD,

p*

0.348

0.047

0.005

0.047

0.022

Underdiagnosis of COPD at primary health care clinics in the city of Aparecida de Goiânia, Brazil

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Table 3 - Spirometric dataa and degree of dyspnea in the COPD patients with and without diagnosis of COPD, Aparecida de Goiânia, Brazil, 2011.b Previous diagnosis of COPD Variables No Yes OR 95% CI (n = 45) (n = 18) FVC, % of predicted 95.59 ± 22.36 95.83 ± 26.17 79.08 ± 23.69 64.59 ± 22.28 0.970 0.950-1.000 FEV1, % of predicted 0.62 ± 0.09 0.53 ± 0.13 FEV1/FVC COPD stage (GOLD)c 1 22 (48.90) 5 (27.80) 2 17 (37.80) 8 (44.40) 3 6 (13.30) 5 (27.80) 0.929 0.887-0.970

a previous

p* 0.970 0.036 1.000

0.089

GOLD: Global Initiative for Chronic Obstructive Lung Disease. aData obtained after bronchodilator use.bData expressed as mean ± SD. cData expressed as n (%). *Logistic regression analysis.

Data from different studies published in various parts of the world confirm that COPD is underdiagnosed (especially in females) and that the disease is more frequently diagnosed in males than in females (especially among patients being treated at PHCCs).(10,11) In addition to smoking, exposure to biomass smoke is a risk factor for COPD in developing countries (such as Brazil), principally in rural areas, where women cook in poorly ventilated environments. In a study conducted in Brazil,(12) COPD was diagnosed in 47 of 160 females selected from among those being treated at PHCCs and showing a cumulative exposure to smoke from wood-burning stoves of 211.2 ± 98.2 hour-years.

Jain et al.(13) evaluated 702 COPD patients in terms of etiologic and risk factors for the disease, as well as investigating differences between the genders in terms of clinical presentation, radiological presentation, and comorbidities.

The authors found that, in addition to being younger and having reported more symptoms and exacerbations, females showed a higher prevalence of systemic features. Exposure to tobacco smoke predominated among males, whereas exposure to biomass smoke predominated among females.

The authors emphasized that an understanding of these differences aids in establishing an early diagnosis of COPD in females.

In the present study, the level of education was found to be lower in the individuals with COPD than in those without, a finding that is consistent with those of studies examining the relationship between COPD and smoking and between COPD and cumulative exposure to biomass smoke.(1,2,14) Those studies showed that

a low socioeconomic status and a low level of education are risk factors for COPD, and that the prevalence of COPD tends to decrease as the level of education increases.

Hamers et al.(15) conducted a study in northern and northeastern Brazil in order to determine the prevalence of chronic respiratory diseases in patients treated at PHCCs. The authors emphasized that most of the general practitioners had been trained within specialist settings and were unaware of the prevalence of COPD in the population. A bivariate analysis showed that advanced age, male gender, smoking, and presence of two respiratory symptoms were strong predictors of COPD in the initial evaluation of patients treated at PHCCs. In the present study, the prevalence of symptoms was higher in the COPD patients with a previous diagnosis of COPD than in those without, suggesting that patients with more symptoms are more easily diagnosed. This is worrisome because it suggests that the diagnosis of COPD was made in the advanced stages of the disease, in which the clinical expression of the disease is more severe. This hypothesis has been raised in another study.(16) In the present study, the presence of dyspnea in isolation was more common in the individuals with a previous diagnosis of COPD (including those who had been misdiagnosed as having COPD), suggesting that the symptom of dyspnea had been erroneously correlated with pulmonary emphysema and, consequently, COPD. The individuals with a previous diagnosis of COPD had a higher degree of obstruction, as evidenced by the FEV1 values in percentage of predicted.

This might be due to the fact that respiratory J Bras Pneumol. 2012;38(6):692-699

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symptoms are more common in the more advanced stages of the disease. Guidelines provided by the GOLD(1) underscore the role of programs for early detection of COPD and recommend that all available data be used in order to diagnose COPD when spirometry is not available.

Hill et al.(17) found that approximately one in every five adults having risk factors for COPD and seeking a PHCC (for any reason) met spirometric criteria for COPD. Although more than three quarters of the patients with COPD reported at least one respiratory symptom, two thirds were unaware of their diagnosis. The authors concluded that selecting individuals for spirometry on the basis of symptoms alone will identify less than half of the patients with moderate to severe COPD, and that spirometric data should complement the data obtained by surveillance questionnaires. Other studies have suggested that adults seeking treatment at PHCCs and presenting with risk factors for COPD and typical respiratory symptoms should be priority targets for screening and early intervention.(18-20) In the present study, the COPD patients with a previous diagnosis of COPD had a higher degree of obstruction, as evidenced by the FEV1 values in percentage of predicted. This might have been due to the fact that respiratory symptoms were more common in that subgroup. In both groups, mild to moderate obstruction predominated, a finding that is consistent with those of other studies.(18,21) In addition to an underdiagnosis rate of 71.4%, we found an overdiagnosis rate of 14.6% and a rate of use of spirometry as a diagnostic tool of 1.5%. These findings are consistent with those of other studies,(2,14,22) in which the rate of use of spirometry to diagnose COPD at PHCCs was found to be low.

The method used in the present study does not allow us to extrapolate our results to a larger population. This might have been possible had we used the methodology commonly used in prevalence studies. However, our study was conducted at PHCCs (where physicians are general practitioners), i.e., clinics that are representative of the primary health care system in the state of Goiás.

Given the high rate of underdiagnosis of COPD in individuals having risk factors for the disease and being treated at PHCCs, we believe that active surveillance for COPD and spirometry are J Bras Pneumol. 2012;38(6):692-699

measures that can play a major role in controlling the disease.

References 1. Global Initiative for Chronic Obstructive Lung Disease - GOLD [homepage on the Internet]. Bethesda: Global Initiative for Chronic Obstructive Lung Disease [cited 2011 Dec 26]. Global Strategy for the Diagnosis, Management, and Prevention of COPD - Revised 2011.

[Adobe Acrobat document, 90p.]. Available from: http:// www.goldcopd.org/uploads/users/files/GOLD_Report_2011_ Feb21.pdf 2. Menezes AM, Perez-Padilla R, Jardim JR, Muiño A, Lopez MV, Valdivia G, et al. Chronic obstructive pulmonary disease in five Latin American cities (the PLATINO study): a prevalence study. Lancet. 2005;366(9500):1875-81. http://dx.doi.org/10.1016/S0140-6736(05)67632-5 3. Sociedade Brasileira de Pneumologia e Tisiologia.

Diretrizes para testes de função pulmonar. J Pneumol. 2002;28(Suppl 3):S2-S238.

4. Pereira CA, Sato T, Rodrigues SC. New reference values for forced spirometry in white adults in Brazil. J Bras Pneumol. 2007;33(4):397-406. PMid:17982531. http:// dx.doi.org/10.1590/S1806-37132007000400008 5. Lwanga SK, Lemeshow S. Sample Size Determination in Health Studies. Geneva: World Health Organization; 1991.

6. Tinkelman DG, Price D, Nordyke RJ, Halbert RJ. COPD screening efforts in primary care: what is the yield?

Prim Care Respir J. 2007;16(1):41-8. PMid:17297526. http://dx.doi.org/10.3132/pcrj.2007.00009 7. Yamasaki A, Hashimoto K, Hasegawa Y, Okazaki R, Yamamura M, Harada T, et al. COPD is frequent in conditions of comorbidity in patients treated with various diseases in a university hospital. Int J Chron Obstruct Pulmon Dis. 2010;5:351-5. PMid:21037959 PMCid:2962301. http://dx.doi.org/10.2147/COPD.S12669 8. Lundbäck B, Gulsvik A, Albers M, Bakke P, Rönmark E, van den Boom G, et al. Epidemiological aspects and early detection of chronic obstructive airway diseases in the elderly. Eur Respir J Suppl. 2003;40:3s-9s. PMid:12762567. http://dx.doi.org/10.1183/09031936.03.00403103 9. Lindberg A, Jonsson AC, Rönmark E, Lundgren R, Larsson LG, Lundbäck B. Prevalence of chronic obstructive pulmonary disease according to BTS, ERS, GOLD and ATS criteria in relation to doctor’s diagnosis, symptoms, age, gender, and smoking habits. Respiration. 2005;72(5):471-9.

PMid:16210885. http://dx.doi.org/10.1159/000087670 10. de Torres Tajes JP, Macario CC. Chronic obstructive pulmonary disease in women [Article in Spanish]. Arch Bronconeumol. 2010;46 Suppl 3:23-7. http://dx.doi. org/10.1016/S0300-2896(10)70023-5 11. Soares S, Costa I, Neves AL, Couto L. Caracterização de uma população com risco acrescido de DPOC. Rev Port Pneumol. 2010;16(2):237-52. Pmid:20437002.

12. Moreira MA. Avaliação de aspectos pulmonares em mulheres expostas à fumaça de combustão de lenha [thesis]. Goiânia: Universidade federal de Goiás; 2011.

13. Jain NK, Thakkar MS, Jain N, Rohan KA, Sharma M. Chronic obstructive pulmonary disease: Does gender really matter? Lung India. 2011;28(4):258‑62.

PMid:22084538 PMCid:3213711. http://dx.doi. org/10.4103/0970-2113.85686 14. Peña VS, Miravitlles M, Gabriel R, Jiménez-Ruiz CA, Villasante C, Masa JF, et al. Geographic variations

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in prevalence and underdiagnosis of COPD: results of the IBERPOC multicentre epidemiological study.

Chest. 2000;118(4):981-9. PMid:11035667. http:// dx.doi.org/10.1378/chest.118.4.981 15. Hamers R, Bontemps S, van den Akker M, Souza R, Penaforte J, Chavannes N. Chronic obstructive pulmonary disease in Brazilian primary care: Diagnostic competence and case-finding. Prim Care Respir J. 2006;15(5):299‑306.

PMid:16978923. http://dx.doi.org/10.1016/j. pcrj.2006.07.008 16. Llauger Roselló MA, Pou MA, Domínguez L, Freixas M, Valverde P, Valero C, et al. Treating COPD in chronic patients in a primary-care setting [Article in Spanish].

Arch Bronconeumol. 2011;47(11):561-70. PMid:22036593. http://dx.doi.org/10.1016/j.arbres.2011.10.001 17. Hill K, Goldstein RS, Guyatt GH, Blouin M, Tan WC, Davis LL, et al. Prevalence and underdiagnosis of chronic obstructive pulmonary disease among patients at risk in primary care. CMAJ. 2010;182(7):673-8. PMid:20371646 PMCid:2855915. http://dx.doi.org/10.1503/cmaj.091784

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18. Geijer RM, Sachs AP, Hoes AW, Salomé PL, Lammers JW, Verheij TJ. Prevalence of undetected persistent airflow obstruction in male smokers 40-65 years old.

Fam Pract. 2005;22(5):485-9. PMid:15964866. http:// dx.doi.org/10.1093/fampra/cmi049 19. McIvor RA, Tashkin DP. Underdiagnosis of chronic obstructive pulmonary disease: a rationale for spirometry as a screening tool. Can Respir J. 2001;8(3):153-8.

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About the authors Maria Conceição de Castro Antonelli Monteiro de Queiroz

Attending Physician. Pulmonology Department. Federal University of Goiás School of Medicine Hospital das Clínicas, Goiânia, Brazil.

Maria Auxiliadora Carmo Moreira

Associate Professor. Federal University of Goiás School of Medicine, Goiânia, Brazil.

Marcelo Fouad Rabahi

Adjunct Professor. Federal University of Goiás School of Medicine, Goiânia, Brazil.

J Bras Pneumol. 2012;38(6):692-699

Original Article Reference values for sniff nasal inspiratory pressure in healthy subjects in Brazil: a multicenter study*,** Valores de referência da pressão inspiratória nasal em indivíduos saudáveis no Brasil: estudo multicêntrico

Palomma Russelly Saldanha de Araújo, Vanessa Regiane Resqueti, Jasiel Nascimento Jr, Larissa de Andrade Carvalho, Ana Gabriela Leal Cavalcanti, Viviane Cerezer Silva, Ester Silva, Marlene Aparecida Moreno, Arméle de Fátima Dornelas de Andrade, Guilherme Augusto de Freitas Fregonezi

Abstract Objective: The objectives of this study were to determine reference values for sniff nasal inspiratory pressure (SNIP) and to propose reference equations for the population of Brazil. Methods: We evaluated 243 healthy individuals (111 males and 132 females), between 20 and 80 years of age, with an FVC and FEV1/FVC ratio > 80% and > 85% of the predicted value, respectively. All of the subjects underwent respiratory muscle strength tests to determine MIP, MEP, and SNIP. Results: We found that SNIP values were higher in males than in females (p < 0.05) and that SNIP correlated negatively with age, for males (r = −0.29; p < 0.001) and for females (r = −0.33; p < 0.0001). Linear regression also revealed that age influenced the predicted SNIP, for males (R2 = 0.09) and females (R2 = 0.10). We obtained predicted SNIP values that were higher than those obtained for other populations. Conclusions: We have devised predictive equations for SNIP to be used in adults (20-80 years of age) in Brazil. These equations could help minimize diagnostic discrepancies among individuals.

Keywords: Respiratory Muscles; Respiratory Function Tests; Reference Values; Linear Models.

Resumo Objetivo: Os objetivos do presente estudo foram determinar equações de referência para pressão inspiratória nasal (PIN) e propor equações de referência para a população brasileira. Métodos: Foram avaliados 243 indivíduos saudáveis (111 homens e 132 mulheres), entre 20 e 80 anos, com CVF > 80% e razão VEF1/CVF > 85% do predito.

Todos os indivíduos realizaram testes de força muscular respiratória para a determinação de PIN, PImáx e PEmáx.

Resultados: Os valores da PIN foram maiores no sexo masculino que no feminino (p < 0,05), e a PIN apresentou correlação negativa com a idade para homens (r = −0,29; p < 0,001) e mulheres (r = −0,33; p < 0,0001). A análise de regressão linear múltipla também revelou que a idade permaneceu exercendo influência na predição da PIN em homens (R2 = 0,09) e mulheres (R2 = 0,10). Os valores preditos da PIN encontrados foram superiores àqueles obtidos em outras populações. Conclusões: Nesse contexto, sugerem-se equações preditivas para PIN em indivíduos brasileiros saudáveis na faixa etária entre 20 e 80 anos, com o intuito de minimizar discrepâncias diagnósticas ao comparar indivíduos.

Descritores: Músculos Respiratórios; Testes de Função Respiratória; Valores de Referência; Modelos Lineares.

* Study carried out at the Universidade Federal do Rio Grande do Norte – UFRN, Federal University of Rio Grande do Norte – Natal, Brazil; the Universidade Federal do Pernambuco – UFPE, Federal University of Pernambuco – Recife, Brazil; and the Universidade Metodista de Piracicaba – UNIMEP, Methodist University of Piracicaba – Piracicaba, Brazil.

Correspondence to: Guilherme Augusto de Freitas Fregonezi. Laboratório de Desempenho Pneumocardiovascular e Músculos Respiratórios, Universidade Federal do Rio Grande do Norte, Caixa Postal 1524, Campus Universitário Lagoa Nova, CEP 59072‑970, Natal, RN, Brasil.

Tel. 55 84 3342-2001. E-mail: fregonezi@ufrnet.br Financial support: Vanessa Regiane Resqueti is the recipient of a grant from Desenvolvimento Científico Regional (DCR, Regional Scientific Development), Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development; Grant no. 0016-4.08/11). Guilherme Augusto de Freitas Fregonezi is the recipient of a level 2 CNPq research productivity grant (PQ-2; Grant no. 301661/2009-0).

Submitted: 15 May 2012. Accepted, after review: 18 September 2012. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

J Bras Pneumol. 2012;38(6):700-707

Reference values for sniff nasal inspiratory pressure in healthy subjects in Brazil: a multicenter study

Introduction In individuals with lung, heart, or neuromuscular disease, respiratory muscle dysfunction is often associated with pulmonary complications, elevated morbidity indices, impaired quality of life, and mortality.(1) Respiratory muscle assessment is a relevant method for the early detection of such dysfunction and the quantification of its decline, providing prognostic and predictive information on the survival of these patients.(1-3) The determination of sniff nasal inspiratory pressure (SNIP) is an easily applied, noninvasive volitional technique that has been recommended as a test to complement the evaluation of inspiratory muscle strength (by determining MIP). Combining inspiratory muscle tests can significantly improve the accuracy of a diagnosis of inspiratory muscle weakness.(4-6) Normal respiratory muscle strength values are useful for establishing, interpreting, and diagnosing respiratory muscle dysfunction.(6,7) Given the specific biological characteristics of regional populations, reference values must be obtained from healthy male and female subjects within a given region, in order to avoid diagnostic discrepancies when individuals or populations are compared.(8) Although predicted values of SNIP have been established for healthy White adults,(6) Japanese adults,(9) and White children,(10) such values have yet to be established for healthy adults in Brazil.

The primary objectives of this study were to determine SNIP reference values for a population of healthy adults in Brazil; to compare maximum SNIP values between males and females and between age brackets; and to propose reference equations for the determination of SNIP in Brazil.

Methods A multicenter, observational, cross-sectional study was carried out between 2009 and 2011 at three research centers. Subjects were stratified into six age brackets (20-29 years, 30-39 years, 40-49 years, 50-59 years, 60-69 years, and 70-80 years). As in earlier studies,(6,11) subjects in each age bracket were also divided by gender, in order to determine gender-specific reference values. Individuals were assessed in terms of sociodemographic data, life habits, previous or current diseases, anthropometric parameters (weight, height, and body mass index [BMI]), and

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lung function (as assessed by spirometry). Study participants were also assessed for respiratory pressures (MIP and MEP), SNIP and habitual pattern of physical activity. At each research center, a single examiner performed the assessment on a single day. Weight and height were measured with an anthropometric scale (Filizola®, São Paulo, Brazil). We determined BMI using the following formula: BMI = weight in kilograms/ height in meters squared (kg/m2).(12) The sample was composed of individuals from the cities of Natal (in the state of Rio Grande do Norte), Recife (in the state of Pernambuco) and Piracicaba (in the state of São Paulo). The inclusion criteria were being healthy, being a non-athlete, being between 20 and 80 years of age,(6) having a BMI between 18.5 and 29.9 kg/m2, and being a non-smoker.(8) Subjects with a history of respiratory disease (asthma, chronic bronchitis, tuberculosis, COPD, or emphysema) were excluded, as were those with a history of neuromuscular disease, cerebrovascular, or cardiac disease (myocardial infarction or heart failure)(8,13,14); those with rhinitis, sinusitis, or deviated septum; those having previously undergone nasal surgery; those having had a cold or the flu in the last week(11); those regularly using medication to treat respiratory allergies; those taking oral corticosteroids, central nervous system depressants, barbiturates, or muscle relaxants(14,15); those who were pregnant(9); those with an FVC ≤ 80% of the predicted value; and those with an FEV1/FVC ratio ≤ 85% of the predicted value.(6) Individuals incapable of understanding or performing the maneuvers required for assessment were also excluded from the study. None of the participants had previously been exposed to respiratory muscle strength measuring techniques. The study was approved by the Research Ethics Committee of the Onofre Lopes University Hospital (Protocol no. 260/08), and all subjects gave written informed consent.

All procedures were conducted in accordance with the ethical standards set forth in the Declaration of Helsinki.(16) Spirometry was conducted with a DATOSPIR120C® spirometer (Sibelmed, Barcelona, Spain), properly calibrated, and all spirometric tests were conducted in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines.(17) We determined FVC, FEV1 and the FEV1/FVC ratio. Results (obtained J Bras Pneumol. 2012;38(6):700-707

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in absolute and relative values) were compared with previously published reference values.(18) Respiratory muscle strength was assessed on the basis of maximal respiratory pressures (MIP and MEP). After having been instructed in the procedure, subjects were evaluated using a MicroRPM® digital manometer (Micro Medical, Rochester, UK), and tests were conducted in accordance with ATS/ERS(4) norms and recommendations. Results were obtained in absolute values and compared with previously published reference values.(11) We measured MIP with a disposable cylindrical mouthpiece connected to the manometer. Subjects were asked to perform a maximal inspiratory maneuver from RV. To assess MEP, we instructed subjects to perform a maximal expiratory maneuver from TLC. To evaluate SNIP, the subject remained seated, with one nostril occluded by a silicon nasal plug connected to the MicroRPM® digital manometer by a polyethylene catheter (internal diameter, ≈ 1 mm). We measured SNIP from functional residual capacity (FRC). With their mouths closed, subjects performed a maximal sniff maneuver through the contralateral patent nostril at the end of a slow, normal expiration.(4,6,11) Ten maneuvers were executed.(6,19) The criteria used to select the best technically acceptable sniffs include a maneuver with a peak pressure maintained for less than 0.5 s and a 30-s rest period between maneuvers. We used the Puma computer program (The University of Manchester, Manchester, UK), which automatically identifies acceptable maneuvers, and saved the values in a database. No visual feedback was provided during the maneuvers, and the highest value obtained was used in the data analysis.

We administered the Brazilian Portugueselanguage version of Baecke’s questionnaire for the measurement of habitual physical activity (HPA), which has been cross-culturally adapted and validated for use in Brazil.(20) The questionnaire evaluates individual perceptions regarding leisuretime physical activities, as well as leisure and locomotion in the last 12 months. Responses are scored on a 0-5 point scale, and scores are expressed as a summed index.

Sample size was calculated using a t-test based on mean population and maximum standard deviation of SNIP found in a study conducted

by Uldry & Fitting,(6) and values of p < 0.05 (at a power of 99% with a confidence interval of 5%) were considered statistically significant. The J Bras Pneumol. 2012;38(6):700-707

suggested sample size was 260 individuals, with an expected interclass correlation coefficient of 7.86 cmH2O. Data were expressed as mean ± standard deviation. We applied the Kolmogorov-Smirnov test for normality in order to determine data distribution. We compared MIP, MEP and SNIP values between genders using unpaired t-tests and between age brackets with ANOVA. If a significant F ratio was obtained, post-test comparisons were conducted with the Newman-Keuls test.

Pearson’s correlation coefficient was applied in order to correlate SNIP with the study variables.

Linear regression analysis was used in order to obtain predictive equations for independent variables that correlated with SNIP. The lower limits of the regression model were calculated from the 5th percentile of the residual standard deviation, assuming a Gaussian distribution, and were estimated as follows(21):

lower limit = predicted value − 1.645 × SEE where SEE is the standard error of the estimate.

The probability of a type I error was set at 0.05 for all tests. Statistical analyses were performed with the Statistical Package for the Social Sciences, version 15 (SPSS Inc., Chicago, IL, USA).

Results The volunteers were recruited from the community and assessed in a preliminary interview, as can be seen in Figure 1. Demographic characteristics, lifestyle, anthropometric parameters, and spirometric data are detailed in Table 1.

The respiratory pressure values are presented in Table 2. Overall, the mean values of MIP, MEP, and SNIP were significantly higher in males than in females (114.3 ± 28.6 cmH2O vs. 92.6 ± 19.7 cmH2O; p < 0.05). We also found that, within each gender, there were significant differences between age brackets (p < 0.05), as demonstrated in Table 2. Correlations between SNIP and the study variables are presented in Table 3. We found that SNIP correlated negatively with age, for males (r = −0.29; p < 0.001) and females (r = −0.33; p < 0.0001). However, SNIP did not correlate significantly with weight, height, BMI or HPA, for either gender. After linear regression, the only variable that maintained its significance was age, which was found to be predictive of SNIP, for males (p < 0.001) and for females (p < 0.0001), and was therefore included in

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Figure 1 - Flow diagram of the selection of volunteers. BMI: body mass index.

Table 1 - Anthropometric and spirometric data, by age bracket within genders.a Gender/ Age Age Weight, kg Height, m BMI, kg/m2 HPA FVC, % pred FEV1,% pred bracket, years Males 20-29 22.1 ± 2.2 73.9 ± 10.6 1.75 ± 0.09 24.1 ± 2.4 5.2 ± 1.3 89.7 ± 10.4 92.1 ± 10.9 30-39 34.4 ± 3.4 76.3 ± 8.5 1.75 ± 0.04 25.0 ± 2.6 4.8 ± 1.3 94.1 ± 9.2 95.0 ± 10.2 40-49 44.2 ± 2.6 75.6 ± 9.0 1.70 ± 0.06 26.0 ± 2.6 5.0 ± 1.7 94.3 ± 9.7 95.8 ± 11.3 50-59 53.4 ± 2.8 77.1 ± 10.8 1.72 ± 0.06 26.0 ± 2.9 5.2 ± 1.2 92.7 ± 10.2 96.6 ± 12.2 60-69 63.9 ± 2.6 74.6 ± 9.0 1.65 ± 0.09 27.4 ± 1.7 5.1 ± 1.6 91.8 ± 10.7 98.6 ± 12.3 70-80 74.6 ± 4.0 71.4 ± 7.2 1.66 ± 0.08 26.0 ± 2.1 4.7 ± 1.0 90.2 ± 9.7 97.1 ± 10.9 Females 20-29 23.2 ± 3.3 61.9 ± 10.8 1.65 ± 0.06 22.8 ± 3.3 4.7 ± 0.1 92.3 ± 11.1 95.7 ± 13.6 30-39 33.5 ± 3.2 62.6 ± 7.4 1.63 ± 0.05 23.6 ± 2.2 4.4 ± 1.2 97.7 ± 14.9 98.7 ± 14.1 40-49 45.1 ± 3.4 63.6 ± 9.7 1.60 ± 0.07 24.9 ± 3.5 4.5 ± 1.5 98.4 ± 9.5 101.9 ± 10.0 50-59 54.5 ± 3.5 63.3 ± 7.3 1.58 ± 0.06 25.5 ± 2.9 4.5 ± 1.3 90.4 ± 11.0 93.2 ± 11.7 60-69 64.3 ± 3.1 65.2 ± 8.1 1.57 ± 0.07 26.5 ± 2.8 4.6 ± 1.2 96.7 ± 18.2 98.4 ± 10.3 70-80 74.8 ± 3.2 65.2 ± 9.3 1.58 ± 0.07 25.9 ± 2.7 4.6 ± 0.8 95.5 ± 15.8 107.9 ± 20.5

FEV1/FVC%

103.0 ± 9.1 101.5 ± 8.6 101.6 ± 8.2 104.5 ± 8.1 107.6 ± 6.0 108.1 ± 6.8 97.8 ± 12.2 99.4 ± 11.5 100.0 ± 9.7 99.5 ± 12.1 102.2 ± 17.2 108.4 ± 13.0

BMI: body mass index; HPA: habitual physical activity; and pred: of the predicted value. aData are presented as mean ± SD.

the model to devise the predictive equations for SNIP as a function of age (Table 4):

Females: SNIP = 110.1 − 0.36 × (age) (R 2 = 0.10; SEE = 18.6)

Males: SNIP = 135.6 − 0.47 × (age) (R 2 = 0.09; SEE = 27.4)

where R 2 is the coefficient of determination. The mean lower limits are calculated by subtracting J Bras Pneumol. 2012;38(6):700-707

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Table 2 - Respiratory pressures, by age bracket within genders.a Gender/Age Respiratory pressures n bracket, years MIP, cmH2O MEP, cmH2O Males 20-29 30-39 40-49 50-59 60-69 70-80 Females 20-29 30-39 40-49 50-59 60-69 70-80

111 27 19 19 16 16 14 132 25 20 24 24 19 20

111.0 ± 28.0 119.2 ± 33.7+ 125.3 ± 23.8+ 115.6 ± 26.3+ 107.6 ± 16.2+ 91.6 ± 17.6* 93.8 ± 25.5* 87.9 ± 17.6 96.9 ± 14.0 94.5 ± 18.3 90.2 ± 16.7 82.7 ± 17.0* 83.2 ± 19.7* 78.1 ± 13.4* +

149.6 ± 40.3 152.6 ± 47.8+ 166.2 ± 39.2+ 164.1 ± 42.7+ 150.2 ± 26.4+ 131.8 ± 30.1 117.1 ± 18.6 106.7 ± 25.2 117.0 ± 27.7 111.2 ± 19.8 115.1 ± 26.1 95.4 ± 23.7 103.3 ± 26.5 95.8 ± 17.1 +

SNIP, cmH2O 114.3 ± 28.6+ 118.6 ± 35.2 133.5 ± 25.9+ 109.4 ± 25.3 122.4 ± 17.8* + 95.3 ± 20.7* 99.3 ± 20.3* 92.6 ± 19.7 102.8 ± 26.8 94.6 ± 19.9 97.6 ± 18.7 88.0 ± 19.2 86.6 ± 9.2 82.9 ± 9.3

SNIP: sniff nasal inspiratory pressure. aData are presented as means ± SD. *Significant effect between age brackets within the same gender (p < 0.05). +Significant effect between genders within the same age bracket (p < 0.05).

Table 3 - Correlations between SNIP and independent variables, by gender.a SNIP Age, years Weight, kg Height, m BMI, kg/m2 Males −0.29* 0.12 0.13 0.02 0.02 0.08 −0.02 Females −0.33+

HPA 0.12 0.11

SNIP: sniff nasal inspiratory pressure; BMI: body mass index; and HPA: habitual physical activity. aValues are r. *p < 0.001; + p < 0.0001.

Table 4 - Linear regression analysis of SNIP in males and females between 20 and 80 years of age.

Gender Parameter Male Female Mean SNIP, cmH2O 114.3 92.6 R2 0.09 0.10 SEE 27.4 18.6 p value 0.001 0.0001 SNIP = 135.6 − 0.47 × (age) SNIP = 110.1 − 0.36 × (age) Predictive equation Mean lower limita 69.2 61.9 SNIP: sniff nasal inspiratory pressure; SEE: Standard error of the estimate. aThe mean lower limits were calculated by subtracting 1.645 times the residual SD of the mean.

1.645 times the residual standard deviation of the mean.

Discussion The objectives of the present study were to determine reference values for SNIP in a population of healthy adults in Brazil; to compare maximum SNIP values between males and females, as well as between age brackets; and to propose reference equations for SNIP in Brazilians. Our J Bras Pneumol. 2012;38(6):700-707

results show that age has a negative influence on SNIP, as well as being a predictor of SNIP, and should therefore be included in linear regression equations to determine reference values.

Several studies have mentioned the importance of SNIP as a valid, non-invasive, easy-to-apply test of inspiratory muscle strength, as well as a complement to MIP.(5,6) This is the third study in the literature to propose reference values for SNIP in healthy adults and the first to do so

Reference values for sniff nasal inspiratory pressure in healthy subjects in Brazil: a multicenter study

for the Brazilian population. The results of the present study show that SNIP was significantly lower in females than in males, a finding that is likely due to the greater muscle mass of the latter, corroborating the findings of other studies investigating respiratory muscle strength.(11,21,22) In terms of SNIP values, we found significant differences between age brackets (within each gender) and a decrease with age. This might be attributed to the reduction in inspiratory muscle strength during the aging process, resulting from sarcopenia; the loss of muscle mass(22-24); and the loss of viscoelasticity of the lungs and rib cage,(23) associated with an increase in abdominal fat, which can interfere with the biomechanics of the diaphragm.(11) Among the independent variables (age, weight, height, BMI, and HPA), only age correlated with SNIP (a weak negative correlation), which is in agreement with the findings of Uldry & Fitting(6) and, for males only, of Kamide et al.(9) Uldry & Fitting(6) also found that weight and BMI did not correlate with SNIP. Although respiratory muscle strength is directly related to the level of physical activity,(11) HPA showed no correlation with SNIP in either males or females. It should be borne in mind that Baecke’s questionnaire provides only an index, which precludes characterizing the level of physical activity, thereby making it difficult to identify sedentary lifestyles.(25) The SNIP reference values obtained in the present study differed from those reported for healthy Japanese males and females (76.8 ± 28.9 cmH2O and 60 ± 20 cmH2O, respectively). Our linear regression analysis demonstrated that predictive equations resulted from SNIP as a function of age, for both genders, which is in keeping with the findings of Uldry & Fitting(6) and Kamide et al.,(9) except that the latter group of authors found that, in females, SNIP correlated only with BMI. This is in contrast with the reported negative influence of age on respiratory muscle strength,(21-23) as well as with the positive relationship between respiratory muscle mass and lean mass, which is more evident in males.(11,21) One important aspect of our results is that the coefficient of determination for age in the linear regression model was low, for males and females (R2 = 0.09 and R2 = 0.1, respectively), although that finding is also analogous to those of Uldry & Fitting (R2 = 0.09 and R2 = 0.05, respectively) and of Kamide et al. (R2 = 0.14 for males).(6,9) According to the ATS,(21) the wide variability in reference

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values is due to methodological differences that can influence the assessment of lung function, including the measurement technique, as well as individual, biological, and population aspects.

In this context, we should highlight a number of differences between the present study and those conducted by Uldry & Fitting(6) and Kamide et al.(9) Our investigation adhered to the recommendations of the ATS(21) and was based on methodologies of earlier studies designed to obtain reference equations for lung function(14,18) and muscle function.(6,11,19) Another factor to consider is that there can be ethnic and individual differences within a given population. In comparison with the populations of European countries and of Japan, the Brazilian population is ethnically heterogeneous. Reference values should be based on recent data, and the most recent predictive equations for SNIP were published in 1995 and 2009.(6,9) Sociodemographic and environmental changes likely influence the results, which should therefore be updated periodically. As such, the differences observed might be attributed to differences in technical assessment, equipment, and population characteristics.

Although the present study has several strengths, certain limitations must be addressed.

First, SNIP values were based on unmonitored FRC. However, this was understood as being at the end of a normal expiration, as reported in other studies, and determining FRC would make the SNIP technique expensive and inaccessible.

Another potential limitation is that we did not include individuals over 80 years of age, and, consequently, the predictive equations proposed would not be valid for use in subjects who are over that age.

On the basis of the mean values obtained in our study sample, we have devised predictive equations for SNIP in the Brazilian population.

These equations can be used in the diagnostic evaluation of Brazilians between 20 and 80 years of age.

Acknowledgments We are extremely grateful to the subjects, whose contributions made this study possible.

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About the authors Palomma Russelly Saldanha de Araújo

Doctoral Student in Biotechnology. Rede Nordeste de Biotecnologia – RENORBIO, Northeastern Biotechnology Network – Natal, Brazil; and Physiotherapist. Paraíba State Department of Health, João Pessoa, Brazil.

Vanessa Regiane Resqueti

Professor of Physiotherapy. Laboratory of Respiratory Therapy, Department of Physiotherapy, Universidade Federal do Pernambuco – UFPE, Federal University of Pernambuco – Recife, Brazil.

Jasiel Nascimento Jr

Physiotherapist. Universidade Federal do Pernambuco – UFPE, Federal University of Pernambuco – Recife, Brazil.

Larissa de Andrade Carvalho

Master’s Student in Physiotherapy. Universidade Federal do Pernambuco – UFPE, Federal University of Pernambuco – Recife, Brazil.

Ana Gabriela Leal Cavalcanti

Physiotherapist. Universidade Federal do Pernambuco – UFPE, Federal University of Pernambuco – Recife, Brazil.

Viviane Cerezer Silva

Physiotherapist. Universidade Metodista de Piracicaba – UNIMEP, Methodist University of Piracicaba – Piracicaba, Brazil.

Ester Silva

Professor of Physiotherapy. Universidade Metodista de Piracicaba – UNIMEP, Methodist University of Piracicaba – Piracicaba, Brazil.

Marlene Aparecida Moreno

Professor of Physiotherapy. Universidade Metodista de Piracicaba – UNIMEP, Methodist University of Piracicaba – Piracicaba, Brazil.

Arméle de Fátima Dornelas de Andrade

Professor of Physiotherapy. Laboratory of Respiratory Therapy, Department of Physiotherapy, Health Sciences Center, Universidade Federal do Pernambuco – UFPE, Federal University of Pernambuco – Recife, Brazil.

Guilherme Augusto de Freitas Fregonezi

Professor of Physiotherapy. Laboratory of Pulmonary Function, Cardiovascular Performance, and Respiratory Muscle Function, Department of Physiotherapy, Universidade Federal do Rio Grande do Norte – UFRN, Federal University of Rio Grande do Norte – Natal, Brazil.

J Bras Pneumol. 2012;38(6):700-707

Original Article Potential impacts of climate variability on respiratory morbidity in children, infants, and adults* Potenciais impactos da variabilidade climática sobre a morbidade respiratória em crianças, lactentes e adultos

Amaury de Souza, Widinei Alves Fernandes, Hamilton Germano Pavão, Giancarlo Lastoria, Edilce do Amaral Albrez

Abstract Objective: To determine whether climate variability influences the number of hospitalizations for respiratory diseases in infants, children, and adults in the city of Campo Grande, Brazil. Methods: We used daily data on admissions for respiratory diseases, precipitation, air temperature, humidity, and wind speed for the 20042008 period. We calculated the thermal comfort index, effective temperature, and effective temperature with wind speed (wind-chill or heat index) using the meteorological data obtained. Generalized linear models, with Poisson multiple regression, were used in order to predict hospitalizations for respiratory disease. Results: The variables studied were (collectively) found to show relatively high correlation coefficients in relation to hospital admission for pneumonia in children (R2 = 68.4%), infants (R2 = 71.8%), and adults (R2 = 81.8%). Conclusions: Our results indicate a quantitative risk for an increase in the number of hospitalizations of children, infants, and adults, according to the increase or decrease in temperature, humidity, precipitation, wind speed, and thermal comfort index in the city under study.

Keywords: Meteorology; Pneumonia/epidemiology; Risk factors.

Resumo Objetivo: Estudar a relação existente entre a o número de internações por doenças do aparelho respiratório em lactentes, crianças e adultos e as variações meteorológicas na cidade de Campo Grande (MS). Métodos: Foram utilizados dados diários de internações por doenças respiratórias, precipitação, temperatura do ar, umidade e velocidade dos ventos entre 2004 e 2008. Foram calculados os índices de conforto térmico humano, temperatura efetiva e temperatura efetiva com velocidade do vento com base nas variáveis meteorológicas. Foram realizados modelos lineares generalizados utilizando o modelo múltiplo de regressão de Poisson para predizer as internações por doenças respiratórias. Resultados: Foram observados valores relativamente elevados dos coeficientes de correlação entre as variáveis estudadas e internações por pneumonia em crianças (R2 = 68,4%), lactentes (R2 = 71,8%) e adultos (R2 = 81,8%). Conclusões: Os resultados aqui apresentados indicam em termos quantitativos o risco para um aumento no número de hospitalizações de crianças, lactentes e adultos de acordo com o aumento ou a diminuição das temperaturas, umidade, precipitação, velocidade dos ventos e índice de conforto térmico na cidade de Campo Grande.

Descritores: Meteorologia; Pneumonia/epidemiologia; Fatores de risco.

Introduction The risk factors for hospitalization due to respiratory diseases include exposure to environmental pollutants (especially smoking), household crowding, deficit in nutritional status, climate seasonality, incomplete immunization schedules, low socioeconomic status and exposure

to biological agents such as pollen. These factors affect mainly individuals at the extremes of age, such as children under 5 years of age or elderly individuals over 65 years of age.(1-3) Climate seasonality has been investigated due to potential health risks, especially in relation to

* Study carried out at under the auspices of the Graduate Program in Environmental Technologies, Exact Sciences and Technology Center, Federal University of Mato Grosso do Sul, Brazil.

Correspondence to: Amaury de Souza. Centro de Ciências Exatas e Tecnologia, Universidade Federal de Mato Grosso do Sul, Programa de Pós-Graduação em Tecnologias Ambientais, Caixa Postal 549, CEP 79070-900, Campo Grande, MS, Brasil.

Tel. 55 67 3345-7990. E-mail: amaury.de@uol.com.br Financial support: None.

Submitted: 13 June 2012. Accepted, after review: 25 September 2012.

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Potential impacts of climate variability on respiratory morbidity in children, infants, and adults

the respiratory system.(4) Health risks include those directly related to climate and those that occur indirectly, due to sensitive biological systems, such as vector-borne infections, pathogens that contaminate food, production of aeroallergens and water-acquired diseases.(5,6) Although several effects of climate seasonality in public health in areas of temperate and subtropical climate have been documented,(7-9) the relationships between health and climate have yet to be understood.(10) Some studies have found a connection between temperature or humidity and the increase in the proportion of respiratory diseases, however, those studies were based on secondary data, which are subject to bias, and this causes concern about their methodological validity and reliability.(11-13) The diversity of landscape and architectural solutions has created a variety of open spaces where the thermal comfort conditions were determined. The methods employed were based on neutral outdoor temperature and in new effective temperature for the application of an adaptive model. The results showed that proper ventilation, and especially shading are absolutely necessary, adding value to these spaces and, consequently, to the architecture of the facility, which had as its starting point adaptation to the climate and the weight given to spaces. The open spaces studied showed satisfactory thermal comfort, principally due to the appropriate consideration of shading and ventilation strategies in architectural and landscaping design, as well as in the buildings.(14) Regardless of the hypotheses of global climate variations caused by human activities, it is nevertheless more evident that the ability to control or alter the climate and the weather is still very limited to local climate, principally in urban areas.(15) Therefore, the objective of this study was to investigate the relationship between the number of hospitalizations due to respiratory diseases in infants, children and adults and climate variability in Campo Grande (MS).

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with pneumonia. The period from January 1, 2004 to December 31, 2008 was analyzed.

Respiratory diseases were encoded according to the International Classification of Diseases, 9th revision (460-519). Information regarding precipitation, air temperature, humidity and wind speed were obtained from the Empresa Brasileira de Pesquisa Agropecuária, Gado de Corte (Brazilian Agency for Agricultural Research, Beef Cattle Division, Campo Grande, Brazil).

Thermal comfort can be defined as the condition of the mind which expresses satisfaction with the thermal environment. Therefore, each person will have their own thermal comfort. Thermal comfort is affected by air temperature, air movement (speed), humidity, clothing, level of activity (amount of physical work performed), mean radiant temperature (mean temperature of walls, ground, windows, etc.) and several other factors. However, the principal environmental factors which contribute to thermal comfort are air temperature, humidity and air speed, which were considered in this study. In order to analyze the thermal comfort during the study period, two indices were used in which the physiological processes of the human body are not taken into account, although the triggering processes of the physiological responses to thermal stress that causes cold or heat are considered.(16) Among the indices used in determining the availability of thermal comfort in the geographical level is the index of effective temperature, defined by the following equation: ET = T – 0.4 × (T − 10) × (1 − RH/100) (1) where ET is the effective temperature (in °C), T is the dry bulb temperature (in °C), and RH is the relative humidity (%). An index which depends on wind speed as well as on temperature and humidity was also used and is defined by the following equation:

Methods

ETW = 37 − (37 − T)/[0.68 – 0.0014 × RH + 1/(1.76 + 1.4 × v × 0.75)] – 0.29 × T × (1 − RH/100)

This study is an ecological study conducted in the city of Campo Grande (Brazil). The daily data of outpatient visits in the city health care clinics were obtained from the Municipal Department of Health and are related to the treatment of infants (1 to 4 years of age), children (5 to 14 years of age) and adults (> 14 years of age)

where ETW is the effective temperature in function of wind (in °C) and v is wind speed (m/s).

The human thermal comfort index (HTCI) is divided into nine ranges, varying from very cold to very hot: very cold (< 13°C), cold (13-16°C), moderate cold (16-19°C ), slightly cold (19-22°C) comfortable (22-25°C), slightly warm (25-28°C),

(2)

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moderately warm (28-31°C), hot (31-34°C) and very hot (> 34°C). These are known Fanger’s comfort criteria(16) and were obtained as a result of measurements of physiological responses of the human being when exposed to heat or cold. Climate variables such as temperature, humidity, wind speed and radiation affect the HTCI directly and, in general, the behavior of individuals. That is the importance of the study of biometeorological indices. In the present study, the maximum ET, minimum ET, mean ET, maximum ETW, minimum ETW and mean ETW were calculated using equations 1 and 2.

Quantitative variables were described using central tendency (mean and median) and dispersion (standard deviation and percentiles) with the calculation of coefficients of variation.

Subsequently, generalized linear models were performed using the Poisson multiple regression model.(17) In order to construct the models climate variables that showed p values < 0.25 in univariate Poisson regression model were selected, which were then used in Poisson multiple regression model by the following equation: log (E(Y)) = α + ∑βi (Xi)

(3)

where Y is the daily count of admissions, E (Y) is the expected value of count, α and β are the parameters to be estimated and Xi represents the independent variables. The relative risk, using the parameters estimated in the model, was calculated using the following equation: RR = exp(β × X)

(4)

where RR is the relative risk, X is the value of the independent variable, and β is the parameter estimated by Poisson regression.

Results During the study period, 6,630 children, 2,866 infants and 4,195 adults were treated for pneumonia. Figure 1 shows the monthly variation of morbidity for pneumonia for infants, children and adults throughout the study period.

There was an increase in morbidity during the winter months and in the month before this season (marking the transition between the two seasons), that is between May and August. This increase in the number of hospitalizations in this period is due, in part, to the entrance of masses of cold, dry air and to the fact that this is considered the most polluted period of the J Bras Pneumol. 2012;38(6):708-715

year. There was also a decrease in morbidity from pneumonia in the warmer months (January, February, November and December).

Relatively high values of correlation coefficients between hospitalizations due to pneumonia in different age groups and the studied variables were observed. In children, infants and adults, respectively, these varied from −0.77 to 0.83, −0.79 to 0.84 and −0.86 to 0.89. Negative values indicate an inverse relationship between the variables, that is, as the number of hospitalizations increases, for example, these variables tend to decrease, which can be observed in Figure 1.

The curves of the graphs of the HTCI (without speed and with speed)(18-20) have the same shape and behavior of the temperatures obtained in the present study, in the shape of a V (Figure 1).

In the analysis of the principal components, after varimax rotation, which included only the climate variables and the level of comfort, the extraction of two factors is observed, with a total explained variance in relation to hospitalizations due to pneumonia in children, infants and adults respectively, of 82.9%, 83.6% and 83.9% (Table 1).

Factor 1 presents explained variances of 68.8%, 69.0% and 68.8%, respectively, in relation to hospitalizations due to pneumonia in children, infants and adults, with high positive weights for the group of temperatures (ranging from 0.82 to 0.99). However, based on this factor, it is believed that an increase or decrease in temperature may result in a slight increase in hospitalization due to pneumonia. For factor 2, explained variance was 14.1%, 14.6% and 15.1%, respectively, in relation to hospitalizations in the same age groups, with high negative weights to the relative humidity and precipitation and less weight to wind speed (−0.994, −0.83 and −0.28, respectively), opposed to the number of hospitalizations due to pneumonia, indicating that the decrease in humidity, precipitation and wind speed (polar high winds, which are characterized by being cold and dry) favor hospitalization due to pneumonia (Table 1).

Tables 2, 3 and 4 show the relative risks and the explanatory variables for the model in relation to children, infants and adults. The b coefficients assumed negative and positive values depending on the variable, confirming that the number of hospitalizations decreases when these values rise, that is, the lower the TCI, the greater the number of people with respiratory diseases and

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Figure 1 - Temporal variation of the variables in function of the months of the year.

Table 1 - Results of analysis of the two main factors for the variables in relation to visits for pneumonia in children, infants and adults. Factor 1 was associated with a group of variables related to human energy and thermal comfort, and factor 2 was associated with the humidity component, involving precipitation and relative humidity.

Children Infants Adults Variable Factor 1 Factor 2 Factor 1 Factor 2 Factor 1 Factor 2 Precipitation 0.24 −0.83 0.57 −0.65 0.29 −0.79 Humidity 0.42 −0.90 0.01 −0.99 0.37 −0.91 Speed 0.07 −0.28 0.02 −0.26 0.06 −0.22 Tmax 0.98 −0.16 0.96 0.25 0.99 −0.12 Tmin 0.03 −0.95 0.41 −0.85 0.07 −0.94 Tmean −0.17 0.41 −0.32 0.27 −0.19 0.40 ETmax 0.95 −0.28 0.98 0.14 0.96 −0.24 ETmin 0.82 −0.55 0.97 −0.17 0.84 −0.51 ETmean 0.89 −0.43 0.99 −0.03 0.91 −0.39 ETWmax 0.97 −0.18 0.96 0.24 0.98 −0.14 ETWmin 0.90 −0.36 0.97 0.05 0.92 −0.32 ETWmean 0.92 −0.39 0.99 0.03 0.93 −0.34 Variation, % 68.8 14.1 69.0 14.6 68.8 15.1 T: temperature; max: maximum; min: minimum; ET: effective temperature; and ETW: effective temperature in function of wind.

vice versa. The highest relative risk (95% CI) was for the variable minimum temperature, followed by the biometeorological indicator which involves temperatures, relative humidity and wind speed.

Residual analysis was performed in order to evaluate the adjustment of the model. Such analysis

can be performed using the graph of residual deviations of each observation in relation to the values adjusted by the model. The graph of a well-adjusted model presents points as close as possible to zero in the interval between −2 and 2.

The adjusted model for children was as follows:

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Table 2 - Regression coefficients, standard error and 95% confidence intervals for the model to children.

Variable Standard error Lower limit Upper limit Relative risk Intercept 0.276937 2.0046 3.0902 Humidity 0.002138 −0.0001 0.0083 1.004108 ETmin 0.043991 0.0270 0.1995 1.119968 ETmax 0.029523 −0.1457 −0.0299 0.915944 ETWmin 0.053146 −0.2551 −0.0467 0.859934 ETWmax 0.020339 0.0259 0.1057 1.068013 T: temperature; max: maximum; min: minimum; ET: effective temperature; and ETW: effective temperature in function of wind.

Table 3 - Regression coefficients, standard error and 95% confidence intervals for the model to infants.

Variable Standard error Lower limit Upper limit Relative risk Intercept 0.4563 1.4025 2.3151 ETmin 0.0614 0.1097 0.2325 1.186609 ETmax 0.0695 -0.2879 −0.1489 0.803804 ET: effective temperature; min: minimum; and max: maximum.

Table 4 - Regression coefficients, standard error and 95% confidence intervals for the model to adults.

Variable Standard error Lower limit Upper limit Relative risk Intercept 0.3234 2.2593 2.9061 ETmin 0.05414 0.00076 0.10904 1.056435 ETmax 0.0223 −0.2512 −0.2066 0.795408 ETWmin 0.0351 −0.2091 −0.1389 0.840297 ETWmax 0.0204 0.0441 0.0849 1.066626 T: temperature; max: maximum; min: minimum; ET: effective temperature; and ETW: effective temperature in function of wind.

log Pchil = −2.31 – 0.00044 × P + 0.0166 × RH + 2.20 × V + 0.014 ×ETmin where Pchil is the number of children with pneumonia, P is the precipitation, S is the speed of the winds and ETmin is the minimum ET, with R2 = 68.4% and adjusted R2 = 50.3%.

The adjusted model for infants was as follows: log Pinf = −2.50 – 0.00102 × P + 0.0128 × RH + 2.03 × V + 0.045 × ETmin where Pinf is the number of infants with pneumonia, with R2 = 71.8% and adjusted R2 = 55.6%.

The adjusted model for adults was as follows: log Padul = 2.74 + 0.00221 × P – 0.0233 × RH + 1.43 × V – 0.053 × ETWmin where Padul is the number of adults with pneumonia, with R2 = 81.1% and adjusted R2 = 70.4%. The increased number of individuals J Bras Pneumol. 2012;38(6):708-715

presenting respiratory symptoms during the winter was associated with a significant reduction in humidity as a result of the low precipitation rates and low temperatures.

Discussion In this group of statistical models, the dependent variable (number of hospitalizations) is a counting process, that is, it is a discrete quantitative variable, whereas the independent variables are candidates to explain the behavior of the series over time. As independent variables, we used the climate variables (maximum mean and minimum temperatures, humidity, HTCI, wind speed and precipitation). The variables “weekday” and “holiday” were used to control the short-term seasonality. The variable “year” was used to control long-term seasonality.

Positive associations were found between climate variables and the incidence of respiratory

Potential impacts of climate variability on respiratory morbidity in children, infants, and adults

diseases (pneumonia) in Campo Grande. These effects are similar to those found in other cities of Brazil, particularly those observed in São Paulo (SP),(4) both in the diversity of climate indicators associated and in the magnitude of the estimated effects. The increased incidence of respiratory disease (pneumonia) during the colder periods of the year is due to the principal factor: the low temperatures, as shown by the relative risks for hospitalization due to respiratory diseases (pneumonia; Tables 2, 3 and 4).

Humans have an ideal temperature range. They possess the ability to adapt to environmental conditions, causing the body to function properly within a relatively wide range of temperature, according to Fanger’s comfort criteria. For the ETmin index, in which the minimum temperatures and relative humidity were used, there were 1.4% of comfortable days; for the ETmax index, in which the maximum temperatures and mean relative humidity were used, there were 11.4% of comfortable days, whereas for the ETmean index (mean temperatures and mean relative humidity), 48.8% of days were comfortable, showing that the latter is the best indicator for the distribution of days within the comfort zone of 22-25°C. Regarding ETmin (minimum temperatures, relative humidity and wind speed), ETmax (maximum temperature, relative humidity and wind speed) and ETmean (mean temperatures, relative humidity and wind speed) indices, there were respectively 5.3 %, 5.5% and 26.7% of comfortable days.

As noted, the effects caused by the increase and decrease of the temperatures are significantly different and affect children, infants and adults.

Temperature variations have caused higher risks of hospitalizations (Tables 2, 3 and 4) precisely because most people, as cities and urban construction, are neither prepared nor adapted to the changes that are occurring.

The mean height reached by precipitation throughout the year presents a distribution of 1,533 mm for the city of Campo Grande. However, these precipitations are unevenly distributed throughout the year, as more than 70% of the total precipitation accumulated during the year occurs from November to March (low hospitalization rate, Figure 1) and the November-January quarter is generally the rainiest; during this quarter, it rains on average 45-55% of the annual total.

In contrast, the winter is excessively dry (high

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hospitalization rate, Figure 1). This time of year, precipitation is very rare, with an average of only 4-5 days of rain per month. The dry season takes place in the winter quarter, that is, June to August, with low humidity, low temperatures and higher hospitalization risks (Figure 1 and Tables 2, 3 and 4).

The highest mean temperatures are observed between the months of October and March, which corresponds to summer in the domain of tropical climates in the Southern hemisphere, and the month of October presents the highest means and the highest hospitalization rates, since, during this month, the transition between the dry and rainy seasons takes place. Therefore, changes in atmospheric circulation patterns, high rates of evapotranspiration, low mean of wind speeds, incipient precipitation and low humidity favor the increase in temperatures, which indicate the beginning of summer. Another analysis that can be carried out from the temperatures is that the temperature range observed between the months with higher and lower temperatures are very low, with a mean variation of 4°C on between June (lower mean temperatures) and October (hottest month and high hospitalization rate; Figure 1).

The rainy season (October to March/ April) concentrates more than 85% of annual precipitation, and December and January contribute with more than 35% of the annual precipitation.

In contrast, the dry season, which in some years starts in April and extends to the beginning of October, is characterized by a significant decrease in precipitation, and in the driest quarter of the year (June-August), the precipitations represent on average less than 2% of the annual total.

Regarding the occurrence of daily doldrums and intensity of the winds on the surface, it appears that, between May and September, respectively, there is the occurrence the lowest and highest values. This is justified by the greater frequency of polar air masses, promoting a greater variation in pressure gradients. This fact reduces the time of permanence of particles in the atmosphere, but increases the chance of fires by the addition to the oxygen flow. The distribution of the directions of the winds at 10 m height varies greatly; winds have predominant north and northeast direction, with a mean intensity of 2.06 m/s.

The results presented here quantitatively indicate the risk for an increase in the number of hospitalizations of children, infants and J Bras Pneumol. 2012;38(6):708-715

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adults according to the increase or decrease in temperature, humidity, precipitation, wind speed and thermal comfort indices in Campo Grande. The results suggest that the minimum and maximum temperatures promote adverse effects on the health of children, infants and adults.

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About the authors Amaury de Souza

Professor. Graduate Program in Environmental Technologies, Exact Sciences and Technology Center, Federal University of Mato Grosso do Sul, Brazil.

Widinei Alves Fernandes

Professor. Graduate Program in Environmental Technologies, Exact Sciences and Technology Center, Federal University of Mato Grosso do Sul, Brazil.

Hamilton Germano Pav達o

Professor. Graduate Program in Environmental Technologies, Exact Sciences and Technology Center, Federal University of Mato Grosso do Sul, Brazil.

Giancarlo Lastoria

Professor. Graduate Program in Environmental Technologies, Exact Sciences and Technology Center, Federal University of Mato Grosso do Sul, Brazil.

Edilce do Amaral Albrez

Doctoral Student. Graduate Program in Environmental Technologies, Exact Sciences and Technology Center, Federal University of Mato Grosso do Sul, Brazil.

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Original Article Translation, cross-cultural adaptation, and reproducibility of the Brazilian Portuguese-language version of the Wisconsin Smoking Withdrawal Scale* Tradução, adaptação cultural e reprodutibilidade da

Wisconsin Smoking Withdrawal Scale para o português do Brasil*

Boanerges Lopes de Oliveira Junior, José Roberto Jardim, Oliver Augusto Nascimento, George Márcio da Costa e Souza, Timothy B. Baker, Ilka Lopes Santoro

Abstract Objective: To cross-culturally adapt the Wisconsin Smoking Withdrawal Scale (WSWS) for use in Brazil and evaluate the reproducibility of the new (Brazilian Portuguese-language) version. Methods: The original English version of the WSWS was translated into Brazilian Portuguese. For cross-cultural adaptation, the Brazilian Portuguese-language version of the WSWS was administered to eight volunteers, all of whom were smokers.

After adjustments had been made, the WSWS version was back-translated into English. The Brazilian Portugueselanguage version was thereby found to be accurate. The final Brazilian Portuguese-language version of the WSWS was applied to 75 smokers at three distinct times. For the assessment of interobserver reproducibility, it was applied twice within a 30-min interval by two different interviewers. For the assessment of intraobserver reproducibility, it was applied again 15 days later by one of the interviewers. Intraclass correlation coefficients (ICCs) were used in order to test the concordance of the answers. The significance level was set at p < 0.05.

Results: Of the 75 volunteers, 43 (57.3%) were female. The overall mean age was 46.3 years. Interobserver and intraobserver reproducibility was determined for each of the WSWS seven domains, the ICCs for which ranged from 0.87 to 0.94 and from 0.76 to 0.92, respectively. The mean time to completion of the WSWS was 6 min and 44 s, and the response time per question ranged from 4.2 to 12.6 s. Conclusions: The Brazilian Portugueselanguage version of the WSWS is reproducible, fast, and simple. It can therefore be used as a tool for assessing the severity of the symptoms of nicotine withdrawal syndrome.

Keywords: Nicotine; Tobacco use disorder; Substance withdrawal syndrome; Reproducibility of results.

Resumo Objetivo: Adaptar culturalmente e avaliar a reprodutibilidade da Wisconsin Smoking Withdrawal Scale (WSWS) para o português do Brasil. Métodos: Foi realizada a tradução da versão original em língua inglesa para o português. A versão traduzida foi aplicada em 8 voluntários fumantes para a adaptação cultural. Após ajustes, a versão da WSWS foi submetida à tradução retrógrada do português para o inglês. A versão em português do Brasil foi considerada adequada. Para a avaliação da reprodutibilidade, a escala foi aplicada em 75 fumantes em dois momentos, com intervalo de 30 minutos (reprodutibilidade interobservador) e, num terceiro momento, após 15 dias (reprodutibilidade intraobservador). Utilizou-se o coeficiente de correlação intraclasse (CCI) para testar a concordância entre as respostas. O nível de significância adotado foi p < 0,05. Resultados: Dos 75 voluntários, 43 (57,3%) eram do gênero feminino. A média geral de idade foi 46,3 anos. A reprodutibilidade interobservador e intraobservador foi determinada para cada um dos sete domínios da WSWS, com CCI variando de, respectivamente, 0,87 a 0,94 e de 0,76 a 0,92. O tempo médio de resposta da WSWS foi 6 min e 44 s, e o tempo de resposta para cada questão variou de 4,2 a 12,6 s. Conclusões: A versão da WSWS para o português do Brasil é reprodutível, de aplicação rápida e simples, podendo ser utilizada como um instrumento de avaliação da gravidade dos sintomas da síndrome da abstinência à nicotina.

Descritores: Nicotina; Transtorno por uso de tabaco; Síndrome de abstinência a substâncias; Reprodutibilidade dos testes.

* Study carried out at the Universidade Federal de São Paulo/Escola Paulista de Medicina – UNIFESP/EPM, Federal University of São Paulo/Paulista School of Medicine – São Paulo, Brazil.

Correspondence to: Ilka L. Santoro. Disciplina de Pneumologia, Rua Botucatu, 740, 3º andar, CEP 04023-062, São Paulo, SP, Brasil.

Tel. 55 11 5576-4238. Email: ilka@pneumo.epm.br Financial support: None.

Submitted: 11 April 2012. Accepted, after review: 20 September 2012.

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Translation, cross-cultural adaptation, and reproducibility of the Brazilian Portuguese-language version of the Wisconsin Smoking Withdrawal Scale

Introduction In Brazil, 900,000 deaths occur each year.

Of those deaths, 200,000 are from smoking.

According to the World Health Organization, 16% of all new cancer cases and 40% of all cancer deaths are due to smoking, as are 20% of all cases of cardiovascular disease and 75% of all cases of nonmalignant respiratory disease, 25% of all smokers dying from smoking-related diseases. Smoking is therefore the leading preventable cause of death worldwide. In Brazil, there are approximately 24 million smokers, who account for 17% of the Brazilian population.(1,2) Cigarette smoke contains more than 4,700 compounds. Of those, nicotine is the only one that is known to cause dependence, by binding to cholinergic receptors in the midbrain, rapidly leading to tolerance and addiction. The neurobiological changes caused by nicotine are intense, and the intensity of smoking can alternately trigger feelings of pleasure and depression.(3,4) In nicotine-dependent smokers, smoking cessation can lead to nicotine withdrawal syndrome, which is described in the Diagnostic and Statistical Manual of Mental Disorders (DSMIV) as an intense craving for nicotine accompanied by difficulty concentrating, mental confusion, depression, irritability, anxiety, cardiac rhythm disturbances, sleep disturbances, asthenia, and increased appetite with weight gain. These symptoms can have an early onset (60 min after smoking cessation) and last several days (10-15 days).(5-7) Among the smoking cessation strategies that are currently available, the combination of cognitive-behavioral therapy and nicotine replacement therapy with prescription-free transdermal nicotine patches has shown good results in various countries. Groups of up to 10 smokers meet with the objective of sharing their experiences and helping one another during the smoking cessation period.(8,9) There have been numerous experimental studies involving the use of specific questionnaires and scales. The main objective is to use an instrument that is useful for answering the study question by providing qualitative and quantitative information.

In addition to being noninvasive, inexpensive, and easy to use, questionnaires and scales will be adequately reproducible in specific cultures if they have good internal consistency and accuracy.(10,11)

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Various questionnaires and scales have been developed in order to assess nicotine withdrawal symptoms and improve quality of life.(10-13) In Minnesota, USA, Hughes et al. developed and validated a specific scale to evaluate the effects of smoking abstinence; the scale was designated Wisconsin Smoking Withdrawal Scale (WSWS).(11) A higher WSWS score translates to a higher level of nicotine dependence, as evidenced by the symptoms of nicotine withdrawal.(11) The hypothesis is that the WSWS can identify individuals who are prone to relapse on the basis of the symptoms of nicotine withdrawal. In Brazil, there is no scale evaluating the effects of smoking abstinence on individuals undergoing smoking cessation treatment. Therefore, it is of utmost importance to translate and culturally adapt the WSWS, given that the scale can aid therapists in predicting relapse on the basis of nicotine withdrawal symptoms. The objective of the present study was to translate and cross-culturally adapt the WSWS for use in Brazil, as well as to evaluate the reproducibility of the new (Brazilian Portugueselanguage) version.

Methods We conducted a prospective cohort study to culturally adapt the WSWS for use in Brazil and evaluate the reproducibility of the new (Brazilian Portuguese-language) version. The study project was approved by the Research Ethics Committee of the Universidade Estadual de Ciências da Saúde de Alagoas (UNCISAL, Alagoas State University of Health Sciences; Protocol no. 808), located in the city of Maceió, Brazil, where the data were collected. All of the participants gave written informed consent, and the study was conducted in accordance with Brazilian National Health Council Resolution 196/96.

The WSWS was developed by a group of researchers led by Welsch et al. and validated for use in English in 1999.(11) The WSWS is a 28-item scale divided into seven domains: anger; anxiety; concentration; craving; hunger; sadness; and sleep. The scores for each domain range from 0 to 4 (maximum total score, 112), a higher score translating to a higher prevalence of nicotine withdrawal syndrome and a greater likelihood of relapse.(11) The questions are arranged by domain rather than in numerical order. The WSWS score is progressive, i.e., a higher final score translates J Bras Pneumol. 2012;38(6):716-723

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to a higher number of nicotine withdrawal symptoms. Questions 1, 2, 4, 10, 17, 22, and 24 are reverse-scored items, i.e., a higher score translates to a less severe withdrawal syndrome.

This was relevant to the preparation of the data for statistical analysis, the scores for the abovementioned questions having been reversed before the analysis.

The original English-language version of the WSWS was translated to Brazilian Portuguese by a Brazilian translator who was proficient in English. The translated version of the scale was back-translated to English by a translator who was a native speaker of English and who was proficient in Portuguese. Neither translator knew the original WSWS. For cross-cultural adaptation, an expert committee comprising a specialist in nicotine withdrawal syndrome (proficient in English and in Portuguese), the authors of the present study, and the author of the original scale convened in order to discuss how to adapt the WSWS for use in Brazil without changing the essence of the scale.

The Brazilian Portuguese-language version of the WSWS was administered to 8 volunteers, all of whom were smokers, in order to determine whether the questions were easy to understand and whether there were any questions regarding the text. The final version of the Brazilian Portuguese-language WSWS was arrived at after its cross-cultural adaptation and submission to the author of the original scale.

In order to evaluate the reproducibility of the Brazilian-Portuguese language version of the WSWS, the scale was administered to a convenience sample of 75 volunteers, all of whom were smokers, in accordance with a study by Hopkins.(12) The volunteers were selected from among patients being treated at the UNCISAL Núcleo de Apoio à Prevenção e Cessação do Tabagismo (PREVFUMO, Center for Support on Smoking Prevention and Cessation) Outpatient Clinic, where they were evaluated. Our sample size was adequate, given that previous studies cross-culturally adapting and evaluating the reproducibility of respiratory disease questionnaires for use in Brazil, including the Saint George’s Respiratory Questionnaire(13) and Airway Questionnaire 20,(14) evaluated 30 patients each.

The inclusion criteria were as follows: being over 18 years of age; having decided to quit J Bras Pneumol. 2012;38(6):716-723

smoking; and showing an appropriate cognitive level, as assessed by the Mini-Mental State Examination (MMSE).(15) The exclusion criteria were as follows: having had acute myocardial infarction or stroke in the three months preceding the evaluation; having uncontrolled chronic disease; having malignant disease; having disabling disease; being pregnant; having an MMSE score < 21; and showing exhaled carbon monoxide (eCO) levels ≤ 6 ppm.(8) Initially, we administered the MMSE questionnaire to the volunteers in order to evaluate their mental state (cognitive level). Subsequently, we collected demographic data and administered the Brazilian Economic Classification Criterion questionnaire.

On evaluation day 1 (T0) at the PREVFUMO Outpatient Clinic, the volunteers completed the following: the Brazilian Portuguese-language version of the WSWS; the Fagerström Test for Nicotine Dependence (FTND), previously adapted for use in Brazil(16); and the hospital anxiety and depression scale (HADS), previously validated for use in Brazil.(17) In addition, eCO levels were measured.(18,19) On the same day, the WSWS was administered to the volunteers for the second time, 30 min after T0 (T1), by a different investigator, in order to assess interobserver reproducibility. Fifteen days after T0, before the initiation of smoking cessation treatment, the Brazilian-Portuguese language version of the WSWS was administered to the volunteers for the third time (T2), by the same investigator who had administered it at T0, in order to assess intraobserver reproducibility.

In order to minimize symptoms of anxiety and depression, we did not tell the volunteers when their smoking cessation treatment was going to start.

Prior to each evaluation, we measured eCO levels using an eCO monitor (SmokeCheck®; MicroDirect Inc., Lewiston, ME, USA) in order to determine whether the volunteers were indeed smokers (eCO levels > 6 ppm)(8) and whether they were light smokers (eCO levels = 7-10 ppm), moderate smokers (eCO levels = 11-20 ppm), or heavy smokers (eCO levels > 20 ppm).(17) In order to measure eCO levels, we asked the volunteers to hold their breath for 20 s. This allowed a better balance between blood carbon monoxide levels and alveolar carbon monoxide levels, therefore improving measurement accuracy.

After the inspiratory pause, the volunteers were

Translation, cross-cultural adaptation, and reproducibility of the Brazilian Portuguese-language version of the Wisconsin Smoking Withdrawal Scale

instructed to exhale slowly and completely with their lips around the mouthpiece of the device in order to prevent air leakage.(19) In the statistical analysis, categorical variables were expressed as absolute and relative frequencies (proportions), whereas continuous variables were expressed as means, standard deviations, medians, and overall range (minimum and maximum). We used the chi-square test in order to determine the correlation between two variables with normal distribution. We used the Student’s t-test in order to compare two independent variables with normal distribution. We used the Mann-Whitney test in order to compare two independent variables with non-normal distribution.(20) We used the intraclass correlation coefficient (ICC) in order to assess the reproducibility of the WSWS. The ICC ranges from 0 to 1, ICC values closer to 1 translating to a greater reproducibility of the variable. In order to measure the level of agreement between two assessments sorted into categories (WSWS questions), we used the kappa reliability coefficient. Finally, we used nonparametric Spearman’s correlation coefficient in order to determine the correlation between two minimally ordinal variables, taking into consideration the distributions of the variables studied or the variability of the measurements taken.(21) For all statistical tests, the level of significance was set at a type I error < 0.05 or 5%. The statistical analysis was performed with the Statistical Package for the Social Sciences, version 13.0 (SPSS Inc., Chicago, IL, USA).

Results After the WSWS was first translated to Brazilian Portuguese, we evaluated 8 volunteers, 6 of whom were male. The mean age was 38.0 ± 11.2 years.

The Brazilian Portuguese-language version of the WSWS was well understood, no questions having arisen. The only modification was that all items beginning with “sinto-me” were changed to “eu tenho sentido.” This change was tested in another 30 volunteers, and “eu tenho sentido” was chosen over “sinto-me”. The time to complete the WSWS remained unchanged, as did patient understanding of the scale. The items beginning with “sinto-me” were changed to “eu tenho sentido” because the latter was found to be more in keeping with Brazilian Portuguese than was the former. The time to complete the WSWS was

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recorded by two investigators and was found to be 6 min and 44 s. The response time per question ranged from 4.2 s to 12.6 s (SD = 4.18 s).

In order to assess the reproducibility of the Brazilian Portuguese-language version of the WSWS, we selected 76 volunteers (smokers only) from among those being treated at the PREVFUMO Outpatient Clinic. Of the 76 smokers, only 1 had an MMSE score < 21 and was therefore excluded from the evaluation. Of the 75 volunteers evaluated, most were female, had completed at least high school, and belonged to socioeconomic class A or B (Table 1).

The mean age of the volunteers was 46.3 ± 10.5 years. Although the body mass index characterized the study population as overweight, the values were very close to the normal range. The mean smoking history was 28.5 ± 18.5 pack-years, nicotine dependence being low (Table 2).

There were no statistically significant differences between the genders in terms of the level of education (p = 0.17) or the socioeconomic class (p = 0.79), as assessed by the chi-square test. On the basis of the levels of eCO, 65.3% of the volunteers were classified as heavy smokers (eCO levels > 20 ppm).

There were no significant differences between the genders in terms of the level of nicotine Table 1 - Characteristics of the 75 volunteers.

Characteristics n % Female gender 43 57.3 Level of education Illiterate 1 1.3 < 9 years of schooling 12 16.0 9 years of schooling/high school 21 28.0 (incomplete) High school (complete)/college 30 40.0 (incomplete) College (complete) 11 14.7 Socioeconomic class A 16 21.3 B 38 50.6 C 20 26.6 D 1 1.5 eCO, ppm 0-6 3 4.0 7-10 2 2.7 11-20 21 28.0 > 20 49 65.3 Anxiety (HADS) 67 89.3 Depression (HADS) 50 66.7 eCO: exhaled carbon monoxide; and HADS: hospital anxiety and depression scale.

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dependence (p = 0.60) or the smoking history (p = 0.57), as assessed by the Mann-Whitney test. Likewise, the HADS scores (for anxiety and depression) did not correlate with the FTND scores, as assessed by Spearman’s correlation coefficient.

Table 3 shows the means and standard deviations, as well as the overall range (minimum and maximum), for each WSWS domain at T0 and T1, the scale having been administered by different investigators (interobserver reproducibility). The ICC values were higher than 0.75, and the 95% CI ranged from 0.80 to 0.93, intraclass correlation being therefore excellent.

Table 4 shows the means, ICCs, and 95% CIs for each WSWS domain at T0 and T2, the scale having been administered by the same investigator (intraobserver reproducibility). All ICC values were higher than 0.75, intraobserver reproducibility being therefore excellent. However, the lower limits of the 95% CI were lower than 0.75 for the anger, anxiety, concentration, and sadness domains.

The kappa reliability coefficient was used in order to assess the reproducibility of each WSWS question. Most questions showed moderate to high reproducibility, questions 18 and 27 being

Table 2 - Age, body mass index, smoking history, and Fagerström Test for Nicotine Dependence scores for the 75 volunteers.

Variable Mean ± SD Median (min-max) Age, years 46.3 ± 10.5 47.0 (19.0-75.0) BMI, kg/m2 25.1 ± 4.6 24.9 (14.8-37.1) Smoking history, pack-years 28.5 ± 18.5 26.3 (1.9-127) FTND score 5.4 ± 2.0 6 (1-10) BMI: body mass index; and FTND: Fagerström Test for Nicotine Dependence.

Table 3 - Results for each of the domains of the Brazilian Portuguese-language version of the Wisconsin Smoking Withdrawal Scale administered at T0 (first administration) and at T1 (second administration, 30 min after the first) by two different investigators in order to assess interobserver reproducibility (intraclass correlation coefficient and 95% CI).

T1 T0 Domains ICC 95 CI% Mean ± SD Mean ± SD Raiva 1.97 ± 1.05 2.00 ± 1.18 0.92 0.87-0.94 Ansiedade 2.68 ± 0.98 2.63 ± 0.92 0.91 0.86-0.94 Concentração 2.18 ± 0.98 2.18 ± 0.85 0.89 0.83-0.93 Desejo 3.04 ± 0.93 2.93 ± 0.92 0.89 0.83-0.93 Fome 1.97 ± 0.85 2.00 ± 0.89 0.89 0.83-0.93 Tristeza 2.09 ± 0.90 2.14 ± 0.74 0.87 0.80-0.92 Sono 2.16 ± 1.11 2.09 ± 0.99 0.94 0.90-0.96 ICC: intraclass correlation coefficient.

Table 4 - Results for each of the domains of the Brazilian Portuguese-language version of the Wisconsin Smoking Withdrawal Scale administered at T0 (first administration) and at T2 (third administration, 15 days after the first) by the same investigator in order to assess intraobserver reproducibility (intraclass correlation coefficient and 95% CI).

T2 T0 Domains ICC 95% CI Mean ± SD Mean ± SD Raiva 1.97 ± 1.05 1.79 ± 1.09 0.763 0.625-0.850 Ansiedade 2.68 ± 0.98 2.45 ± 1.05 0.773 0.635-0.758 Concentração 2.18 ± 0.98 2.08 ± 0.92 0.768 0.634-0.853 Desejo 3.04 ± 0.93 2.87 ± 0.95 0.882 0.807-0.926 Fome 1.97 ± 0.85 2.02 ± 0.87 0.865 0.787-0.915 Tristeza 2.09 ± 0.90 2.14 ± 0.90 0.799 0.681-0.873 Sono 2.16 ± 1.11 2.08 ± 1.08 0.926 0.884-0.953 ICC: intraclass correlation coefficient.

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the only questions showing a kappa reliability coefficient of less than 0.4 (Table 5).

Discussion The Brazilian Portuguese-language version of the WSWS showed excellent reproducibility, with ICC values greater than 0.76 for all domains, demonstrating excellent agreement between the answers. The different observers had no influence on the answers given by the volunteers, as evidenced by the similar scores obtained at T0, T1, and T2. In addition, the kappa reliability coefficient showed excellent results, with values above 0.4 for 92.9% of the WSWS questions.(21) The WSWS can be self-administered, and the volunteers had no difficulty understanding or answering the questions. The volunteers had MMSE scores higher than 21, and most belonged to socioeconomic class A or B. This possibly had

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a direct influence on their understanding of the questions. We analyzed the reproducibility of the WSWS before the initiation of smoking cessation treatment in order to prevent withdrawal-related factors from affecting the reproducibility of the scale.(22) The investigators read and partly explained the questionnaire to those volunteers who had difficulty reading.

We found no correlation between the smoking history and the FTND scores. This finding is consistent with those of other studies in the literature, in which the correlation between smoking history and FTND scores was found to be poor, a finding that shows that there is no direct association between the number of cigarettes smoked per year and the level of nicotine dependence.(21) Other studies, however, have shown a strong correlation between the abovementioned variables; this shows that, despite being controversial, such findings are relevant

Table 5 - Kappa reliability coefficient values for each of the questions in the Brazilian Portuguese-language version of the Wisconsin Smoking Withdrawal Scale in the first two evaluations.* Domain Question kappa Raiva 13 (irritado, com raiva) 0.488 0.442 15 (sentimentos negativos) 0.384 18 (me sentido frustrado) Ansiedade 3 (tenso ou ansioso) 0.424 0.449 6 (impaciente) 0.450 8 (preocupado com problemas) 0.502 10 (calmo ultimamente) Concentração 4 (concentração excelente) 0.417 0.537 23 (prestar atenção às coisas) 0.395 27 (difícil pensar de forma clara) Desejo 9 (frequência ânsia para fumar) 0.416 0.579 11 (desejo de fumar um cigarro) 0.600 20 (pensado muito em fumar) 0.566 26 (dificuldade de tirar o cigarro da mente) Fome 1 (comida não me atrai) 0.405 0.401 14 (beliscar doces ou lanches) 0.511 16 (tenho comido muito) 0.523 21 (tenho sentido fome) 0.505 28 (penso muito em comida) Tristeza 7 (me sentido empolgado e otimista) 0.578 0.488 12 (me sentido triste ou deprimido) 0.460 19 (sem esperança ou desanimado) 0.444 24 (me sentido feliz e contente) Sono 2 (tenho dormido tranquilamente) 0.519 0.453 5 (acordo frequentemente durante a noite) 0.596 17 (estou satisfeito com meu sono) 0.556 22 (tenho dormido o suficiente) 0.621 25 (dormir tem sido um problema) *p < 0.001 for all questions.

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for future studies.(5,16) It should be taken into consideration that self-reported smoking history might not be reliable, given that many smokers underestimate the number of cigarettes smoked, such underestimation being deliberate or due to a recall bias.(23) We found a poor correlation between the levels of eCO and the FTND scores. Although the study participants showed, on average, a low level of nicotine dependence, most showed eCO levels that were consistent with heavy smoking.

These findings are consistent with those of various studies in which volunteers were found to have a low level of nicotine dependence (median, 5) and high (> 20 ppm) eCO levels, a finding indicating a weak correlation between those variables and underscoring the difficulty in quantifying nicotine dependence.(23-25) We believe that the anxiety generated by the imminent entry into the smoking cessation program led the volunteers to smoke more than usual in the hours preceding the interview, and this raised the levels of eCO. Studies in the literature have shown an increase in negative affects in smokers,(26,27) as well as high levels of anxiety and depression in those who are about to enter a smoking cessation program.

(28,29) The fact that our facility is a referral center for smoking cessation might have influenced the smokers evaluated in the present study to seek treatment there, those individuals having high levels of anxiety and depression, which were primarily due to failed attempts to quit smoking.

We found no significant correlation between the HADS scores and the level of nicotine dependence. This finding is consistent with those of studies showing no correlation between a trend toward depression (as evidenced by HADS scores) and nicotine dependence (as assessed by FTND scores).(28,29) However, studies have shown a significant positive correlation of anxiety and depression with nicotine dependence, a finding that is consistent with the DSM-IV.(5,30) The conflicting results might be due to the different instruments employed, as shown in a study that found poor agreement between FTND scores and the DSM-IV. The authors of that study stated that the DSM-IV defines nicotine dependence in terms of psychiatric symptoms, whereas the FTND gives greater weight to the pleasure of smoking. Therefore, the measurement of nicotine dependence should be multifactorial, meaning that nicotine dependence cannot be measured by a single instrument.(30) J Bras Pneumol. 2012;38(6):716-723

In conclusion, the present study showed that it is possible to translate and culturally adapt an instrument originally developed in a foreign language, the translated version showing excellent reproducibility. All of the domains of the Brazilian Portuguese-language version of the WSWS showed excellent intraobserver and interobserver reproducibility. The Brazilian Portuguese-language version of the WSWS is reproducible and easy to use. It can therefore be used as a tool for assessing the severity of the symptoms of nicotine withdrawal in the Brazilian population.

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22. West R, Ussher M, Evans M, Rashid M. Assessing DSM-IV nicotine withdrawal symptoms: a comparison and evaluation of five different scales. Psychopharmacology (Berl). 2006;184(3-4):619-27. PMid:16308727. http:// dx.doi.org/10.1007/s00213-005-0216-z 23. Burling AS, Burling TA. A comparison of selfreport measures of nicotine dependence among male drug/alcohol-dependent cigarette smokers.

Nicotine Tob Res. 2003;5(5):625-33. http://dx.doi. org/10.1080/1462220031000158708 24. Meneses-Gaya IC, Zuardi AW, Loureiro SR, Crippa JA. Psychometric properties of the Fagerström Test for Nicotine Dependence. J Bras Pneumol. 2009;35(1):73‑82.

PMid:19219334. http://dx.doi.org/10.1590/ S1806-37132009000100011 25. Brown C, Madden PA, Palenchar DR, Cooper-Patrick L. The association between depressive symptoms and cigarette smoking in an urban primary care sample. Int J Psychiatry Med. 2000;30(1):15-26. PMid:10900558. http://dx.doi.org/10.2190/NY79-CJ0H-VBAY-5M1U 26. Karp I, O’Loughlin J, Hanley J, Tyndale RF, Paradis G. Risk factors for tobacco dependence in adolescent smokers. Tob Control. 2006;15(3):199-204. PMid:16728750 PMCid:2564659. http://dx.doi.org/10.1136/tc.2005.014118 27. Cosci F, Schruers KR, Pistelli F, Griez EJ. Negative affectivity in smokers applying to smoking cessation clinics: a case-control study. Depress Anxiety. 2009;26(9):824-30.

PMid:19105219. http://dx.doi.org/10.1002/da.20473 28. Breslau N, Johnson EO. Predicting smoking cessation and major depression in nicotine-dependent smokers.

Am J Public Health. 2000;90(7):1122-7. http://dx.doi. org/10.2105/AJPH.90.7.1122 29. Psujek JK, Martz DM, Curtin L, Michael KD, Aeschleman SR. Gender differences in the association among nicotine dependence, body image, depression, and anxiety within a college population. Addict Behav. 2004;29(2):375‑80.

PMid:14732426. http://dx.doi.org/10.1016/j. addbeh.2003.08.031 30. Spada MM, Nikcević AV, Moneta GB, Wells A. Metacognition as a mediator of the relationship between emotion and smoking dependence. Addict Behav. 2007;32(10):2120-9. PMid:17307299. http:// dx.doi.org/10.1016/j.addbeh.2007.01.012

About the authors Boanerges Lopes de Oliveira Junior

Attending Physiotherapist. Universidade Estadual de Ciências da Saúde de Alagoas – UNCISAL, Alagoas State University of Health Sciences – Maceió, Brazil.

José Roberto Jardim

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

Oliver Augusto Nascimento

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

George Márcio da Costa e Souza

Assistant Professor. Department of Physical Therapy, Universidade Estadual de Ciências da Saúde de Alagoas – UNCISAL, Alagoas State University of Health Sciences – Maceió, Brazil.

Timothy B. Baker

Director of Research. Center for Tobacco Research and Intervention, University of Wisconsin, Madison, WI, USA.

Ilka Lopes Santoro

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

J Bras Pneumol. 2012;38(6):716-723

Original Article Clinical and epidemiological profile and prevalence of tuberculosis/HIV co-infection in a regional health district in the state of Maranhão, Brazil* Perfil clínico e epidemiológico e prevalência da coinfecção tuberculose/HIV em uma regional de saúde no Maranhão

Marcelino Santos Neto, Fabiane Leita da Silva, Keyla Rodrigues de Sousa, Mellina Yamamura, Marcela Paschoal Popolin, Ricardo Alexandre Arcêncio

Abstract Objective: To describe the clinical and epidemiological profile, as well as the prevalence, of tuberculosis/HIV co-infection in the Regional Health District of Tocantins, which serves 14 cities in the state of Maranhão, Brazil. Methods: This was a descriptive epidemiological study based on secondary data obtained from individual tuberculosis reporting forms in the Brazilian Case Registry Database. We included all reported cases of tuberculosis/ HIV co-infection, by city, between January of 2001 and December of 2010. Results: In the district, 1,746 cases of tuberculosis were reported. Of those tested for HIV, 100 had positive results, which corresponded to a tuberculosis/HIV co-infection prevalence of 39%. Of the co-infected patients, 79% were male, 42% were Mulatto, and 64% were in the 20- to 40-year age bracket, 31% had had ≤ 4 years of schooling, and 88% resided in the city of Imperatriz. Cases of pulmonary tuberculosis and new cases of tuberculosis predominated (in 87% and 73%, respectively). Of the co-infected patients, 27% had positive sputum smear microscopy results, and 89% had chest X-ray findings suggestive of tuberculosis. Sputum culture was performed in only 7% of the cases. Conclusions: Our results show that, because of its clinical and epidemiological profile, tuberculosis/HIV co-infection is still a major public health problem in the southwestern region of Maranhão. This situation calls for better coordination between tuberculosis and sexually transmitted disease/AIDS control programs, as well as a political commitment and greater involvement on the part of administrators and health care professionals in the planning of interventions and the functioning of health care facilities.

Keywords: Tuberculosis/epidemiology; HIV infections/epidemiology; Comorbidity.

Resumo Objetivo: Descrever o perfil clínico e epidemiológico e a prevalência da coinfecção tuberculose/HIV na Unidade Regional de Saúde do Tocantins, que envolve 14 municípios no estado do Maranhão. Métodos: Estudo epidemiológico descritivo baseado em dados secundários das fichas individuais de tuberculose do Sistema Nacional de Informação de Agravos de Notificação. Foram incluídos todos os casos notificados de coinfecção tuberculose/HIV, por município de residência, no período entre janeiro de 2001 e dezembro de 2010. Resultados: Foram notificados 1.746 casos de tuberculose no distrito. Dos pacientes testados para HIV, 100 eram coinfectados. equivalendo a uma prevalência de 39%. Dos coinfectados, 79% eram do sexo masculino, 42% eram de cor parda, 64% tinham idade entre 20 e 40 anos, 31% tinham até quatro anos de estudo, e 88% residiam em Imperatriz. A forma clínica predominante foi a pulmonar (87%), e 73% eram casos novos. Dos coinfectados, 27% apresentaram resultados positivos na baciloscopia de escarro e 89% tinham imagem sugestiva de tuberculose na radiografia do tórax.

A cultura de escarro foi realizada em apenas 7% dos casos. Conclusões: Evidenciou-se que a situação clínica e epidemiológica da coinfecção tuberculose/HIV ainda é um grande problema de saúde pública no sudoeste do Maranhão e impõe uma maior articulação entre os programas de controle de tuberculose e de doenças sexualmente transmissíveis/AIDS. Além disso, são necessários o compromisso e o envolvimento político dos gestores e profissionais de saúde no planejamento de ações e serviços de saúde.

Descritores: Tuberculose/epidemiologia; Infecções por HIV/epidemiologia; Comorbidade.

* Study carried out at the Center for the Social Sciences, Health and Technology, Universidade Federal do Maranhão – UFMA, Federal University of Maranhão – Imperatriz, Brazil.

Correspondence to: Marcelino Santos Neto. Rua Urbano Santos, s/n, CEP 65900-410, Imperatriz, MA, Brasil.

Tel. 55 99 3221-7600. E-mail: marcelinosn@gmail.com Financial support: None.

Submitted: 2 April 2012. Accepted, after review: 31 August 2012.

J Bras Pneumol. 2012;38(6):724-732

Clinical and epidemiological profile and prevalence of tuberculosis/HIV co-infection in a regional health district in the state of Maranhão, Brazil

Introduction Tuberculosis continues to occupy a prominent place among the major infectious diseases in underdeveloped countries. The increase in tuberculosis cases has mostly been due to the emergence of AIDS in the 1980s, together with factors of impoverishment, social disorder, and lack of investment in effective disease control programs.(1) Among the 22 countries that, together, account for 80% of all tuberculosis cases worldwide, Brazil ranks 19th in number of cases and 108th in incidence. In more explicit terms, in 2010 alone, there were approximately 71,000 reported cases of tuberculosis, 4,800 of which died, making tuberculosis the third leading cause of death from infectious diseases and the first leading cause of death among AIDS patients.(2) Mortality from tuberculosis is 2.4 to 19 times higher in individuals who are co-infected with HIV than in those who are not co-infected with HIV; therefore, one in every four deaths caused by tuberculosis is related to HIV.(3) In addition, for this specific population, the risk of developing active tuberculosis is 10% per year, whereas, for HIV-negative individuals, this risk is approximately 10% over the course of their lifetime.(4) The rate of tuberculosis detection in advanced stages of AIDS is relatively low, given that only a few patients will present the typical-clinical radiological findings of tuberculosis. Furthermore, test positivity rates are unfortunately low in these patients, leading to late diagnosis in a significant number of patients, which prevents early treatment initiation and contributes to bacillary dissemination in the community.(5) Also in the clinical sphere, it is important to mention that HIV infection changes the clinical presentation of tuberculosis, treatment duration, tolerance to antituberculosis drugs, resistance to the available drugs, and, possibly, contact susceptibility.(6,7) Undoubtedly, a diagnosis of HIV seropositivity in tuberculosis patients is a potent weapon in disease control.(2) However, in Brazil, the demand for HIV testing is still low,(8) despite the recommendation of the Brazilian National Ministry of Health (all tuberculosis patients should undergo HIV testing).(2) In this context, it is of note that a lower proportion of patients tested for HIV translates to greater uncertainty

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regarding the true magnitude of the prevalence of co-infection.(9) In addition to the entire clinical trajectory that hinders tuberculosis control, it is also necessary to consider social aspects. Studies have demonstrated that the emotional and economic impact of tuberculosis/HIV co-infection is greater than that of tuberculosis or HIV infection alone.

This perpetuates a poor quality of life, possibly associated with the stigma or social ills of the combined diseases.(10) In addition, the prevalence of tuberculosis/HIV co-infection, as well as of tuberculosis alone, is unevenly distributed and mainly affects the most marginalized and poorest segments of society, i.e., those that are the most receptive and vulnerable to the disease.(11) Given the complexity of the situation of tuberculosis/HIV co-infection, as well as the need for specific strategies and interventions that prioritize resources for the most vulnerable groups, and especially because of the lack of studies conducted in the region referred to below and examining the profile and prevalence of tuberculosis/HIV co-infection, it is essential to understand the epidemiological profile of this comorbidity in the various areas in Brazil, as well as in the 14 cities in the southwestern region of the state of Maranhão that are served by the Unidade Regional de Saúde do Tocantins (URST, Regional Health District of Tocantins).

In view of these facts, tuberculosis/HIV co-infection is an important indicator of the quality of the health care facilities, and this opens up possibilities for reflection on health care practices in the region and on the challenges faced by the country in devising a control policy that is socially relevant. Therefore, the objective of the present study was to determine the prevalence of tuberculosis/HIV co-infection in the URST and to describe the clinical and epidemiological profile of the co-infected cases.

Methods This was a descriptive epidemiological study based on secondary data collected at the URST Epidemiological Surveillance Center, using tuberculosis reporting forms in the Brazilian Ministry of Health Sistema Nacional de Informação de Agravos de Notificação (SINAN, National Case Registry Database).

The state of Maranhão is currently one of the federal units with the highest social inequality, J Bras Pneumol. 2012;38(6):724-732

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and the region investigated in the present study provides low levels of human opportunity, with cities having an index of social exclusion of approximately 0.31 and a Human Development Index of 0.58 in 2010. These figures are close to those reported in sub-Saharan African countries.

The URST is located in southwestern Maranhão and serves 14 cities: Amarante; Buritirana; Campestre; Davinópolis; Estreito; Governador Edson Lobão; Imperatriz; João Lisboa; Lajeado Novo; Montes Altos; Porto Franco; Ribamar Fiquene; São João do Paraíso; and Senador La Rocque. Together, the cities served by this regional health district cover a geographical area of 22,773.853 km2, have a population of 478.220 people, and have a life expectancy at birth of 61.5 years or less.(12) We included all reported cases of tuberculosis between January of 2001 and December of 2010.

The sociodemographic variables assessed were gender, age bracket, race, level of education, city of residence, and area of residence. The epidemiological data analyzed here were clinical presentation; status at admission; results of sputum smear microscopy, tuberculin skin testing (TST), culture, and HIV testing; provision of supervised treatment; and treatment outcome.

Data collection was carried out in September of 2011, after authorization was obtained from the Epidemiological Surveillance Center Coordination Board. To that end, we used a pre-coded form

containing the variables under consideration. To prepare the form, we used exclusively the official data input document for SINAN, i.e., the individual tuberculosis reporting form. Subsequently, the information was entered into a second database and analyzed using the Epi Info program, version 6.5.3. Finally, to present the information, we created tables showing the absolute and relative values found in the study.

The study was submitted to the Research Ethics Committee of the Federal University of Maranhão University Hospital (Process no. 005712/2011-80), and a waiver of approval was granted (Protocol no. 36/12), given that the study does not meet the evaluation criteria requirements established in Brazilian National Health Council Resolution no. 196/96 and its complementary regulations.

Results The study reference population consisted of 1,746 reported cases of tuberculosis in the URST, by city, between 2001 and 2010. Table 1 shows the HIV serostatus of the reported cases: 1,414 (81.0%) of the total number of reported cases did not undergo HIV testing; and, of the 332 (19.0%) that underwent testing, 100 (30.1%) tested positive, 156 (47.0%) tested negative, and 76 (22.9%) were still waiting for the results at this writing. In the city of Imperatriz, there

Table 1 - HIV serostatus of the reported cases of tuberculosis in the Regional Health District of Tocantins, Maranhão, 2001-2010, by city.a HIV testing HIV testing result Tuberculosis City cases Not performed Performed Positive Negative Pending Amarante 166 (9.51) 159 (95.78) 7 (4.22) 1 (14.29) 4 (57.13) 2 (28.58) Buritirana 12 (0.69) 12 (100.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) Campestre 14 (0.80) 8 (57.14) 6 (42.86) 1 (16.70) 3 (50.00) 2 (33.30) Davinópolis 53 (3.04) 43 (81.13) 10 (18.87) 4 (40.00) 5 (50.00) 1 (10.00) Estreito 35 (2.00) 30 (85.71) 5 (14.29) 0 (0.00) 3 (60.00) 2 (40.00) Governador Ed. Lobão 42 (2.41) 40 (95.24) 2 (4.76) 0 (0.00) 1 (50.00) 1 (50.00) Imperatriz 1.207 (69.13) 940 (77.88) 267 (22.12) 88 (32.96) 115 (43.07) 64 (23.97) João Lisboa 72 (4.12) 66 (91.67) 6 (8.33) 2 (33.33) 4 (66.67) 0 (0.00) Lajeado Novo 3 (0.17) 3 (100.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) Montes Altos 34 (1.95) 27 (79.41) 7 (20.59) 0 (0.00) 7 (100.00) 0 (0.00) Porto Franco 25 (1.43) 15 (60.00) 10 (40.00) 1 (10.00) 6 (60.00) 3 (30.00) Ribamar Fiquene 10 (0.57) 7 (70.00) 3 (30.00) 1 (33.33) 2 (66.67) 0 (0.00) São João do Paraíso 6 (0.34) 5 (83.33) 1 (16.67) 0 (0.00) 1 (100.00) 0 (0.00) Senador La Rocque 67 (3.84) 59 (88.07) 8 (11.94) 2 (25.00) 5 (62.50) 1 (12.50) Total 1,746 (100.00) 1,414 (81.00) 332 (19.00) 100 (30.10) 156 (47.00) 76 (22.90) Values expressed as n (%). Source: SINAN-net, Epidemiological Surveillance Center-Regional Health District of Tocantins (2011). a

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Clinical and epidemiological profile and prevalence of tuberculosis/HIV co-infection in a regional health district in the state of Maranhão, Brazil

were 88 cases (88%) of co-infection, and HIV testing coverage of tuberculosis patients was 22.12%. In the cities of Buritirana and Lajeado Novo, none of the reported cases underwent serologic testing.

The prevalence of tuberculosis/HIV co-infection in the study population was 39%, on the basis of HIV testing results, except for testing that was in progress. The sociodemographic characteristics of these cases are shown in Table 2. Most of the co-infected patients resided in the urban area (92%) and were male (79%). In addition, a large number of the co-infected patients were in the 20- to 40-year age bracket (64%), were Mulatto (42%), and had had ≤ 4 years of schooling (31%).

According to Table 3, which shows the epidemiological data, cases of pulmonary tuberculosis and new cases of tuberculosis

Table 2 - Sociodemographic characteristics of the 100 cases of tuberculosis/HIV co-infection in the Regional Health District of Tocantins, Maranhão, 2001-2010.a Variable Result Gender Male 79 (79) Female 21 (21) Age bracket, years < 20 10 (10) 64 (64) 20 ‫ ׀–׀‬40 18 (18) 40 ‫ ׀–׀‬60 ≥ 60 8 (8) Race White 32 (32) Black 10 (10) Asian 4 (4) Mulatto 42 (42) Indigenous 2 (2) No data 9 (9) Area Urban 92 (92) Rural 7 (7) No data 1 (1) Level of education No schooling 9 (9) ≤ 4 years 31 (31) 5 to 8 years 23 (23) > 8 years 26 (26) No data 7 (7) Not applicable 4 (4) Values expressed as n (%). Source: SINAN-net, Epidemiological Surveillance Center-Regional Health District of Tocantins (2011). a

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predominated (in 87% and 73%, respectively).

Of the co-infected patients, 27% had positive sputum smear microscopy results (1st sample), and 89% had chest X-ray findings suggestive of tuberculosis. Sputum culture and TST were performed in only 12% of the cases. It can also be seen that 57% of the co-infected patients underwent supervised treatment and that the cure rate was 62%. In addition, in 54% of the cases, no data were available on the microscopy results from the second sputum sample.

Discussion According to the World Health Organization 2011 report on tuberculosis control, 23% of tuberculosis patients diagnosed in Brazil in 2010 were infected with HIV.(13) Of the reported cases of tuberculosis in the URST between 2001 and 2010 that underwent HIV testing, 39% were found to be infected with HIV. Studies conducted in Brazil showed that the prevalence of tuberculosis/HIV co-infection was 42.4% in the city of Taubaté, located in the state of São Paulo,(3) 33.3% in the city of Recife, located in the state of Pernambuco,(14) 31.2% in the city of Ribeirão Preto, located in the state of São Paulo,(8) 29.2% in the city of Porto Alegre, located in the state of Rio Grande do Sul,(15) 14.9% in the city of Londrina, located in the state of Paraná,(10) 3.6% in Fortaleza, located in the state of Ceará(16), and 0.8% in the city of Bagé, located in the state of Rio Grande do Sul.(17) It is of note that these differences might be related to variations associated with the type of study or to true differences in the prevalence of HIV infection in tuberculosis patients.

It is possible that the prevalence of co-infection in the area under study is below the national average, and this might be associated with the low demand for HIV testing in the area, given that most patients (81.0%) did not undergo HIV testing, as shown in Table 1.

The Programa Nacional de Controle da Tuberculose (PNCT, Brazilian National Tuberculosis Control Program) aims to make HIV testing available to 100% of individuals with tuberculosis.

(4) In each of the 14 cities under study, less than 50% of the cases underwent HIV testing. Therefore, it is clearly necessary that the proposal that all patients diagnosed with tuberculosis should undergo HIV testing be effectively implemented, given that reliable reporting of tuberculosis/HIV

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Table 3 - Clinical and epidemiological characteristics of the 100 cases of tuberculosis/HIV co-infection in the Regional Health District of Tocantins, Maranhão, 2001-2010.a Variable Result Status at admission New case 73 (73) Recurrence 19 (19) Readmission following dropout 4 (4) Transfer 4 (4) Clinical presentation Pulmonary 87 (87) Extrapulmonary 11 (11) Pulmonary + extrapulmonary 2 (2) Sputum smear microscopy, 1st/2nd sample Positive 27 (27)/12 (12) Negative 27(27)/18(18) Not performed 46(46)/15(15) No data 0 (0)/54 (54) Tuberculin skin testing Negative 6 (6) Weakly positive 1 (1) Strongly positive 2 (2) Not performed 88 (88) No data 3 (3) Sputum culture Positive 4 (4) Negative 5 (5) Pending 3 (3) Not performed 88 (88) Chest X-ray Suspicious 89 (89) Normal 1 (1) Other pathologies 2 (2) Not performed 6 (6) No data 2 (2) Supervised treatment Yes 57 (57) No 34 (34) No response 1 (1) No data 8 (8) Outcome Cure 62 (62) Dropout 8 (8) Death from tuberculosis 1 (1) Death from other causes 22 (22) Transfer 6 (6) Change in diagnosis 1 (1) Values expressed as n (%). Source: SINAN-net, Epidemiological Surveillance Center-Regional Health District of Tocantins (2011). a

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co-infection is essential for appropriate planning of control measures and for the holistic care of the patient.

The data on HIV serostatus in tuberculosis patients revealed that there were a considerable number of reported cases of tuberculosis (22.9%) for which there were no definitive HIV testing results, i.e., the database contained cases for which testing was in progress. These figures regarding the URST might be the result of failures in the health care structure, such as difficult access to laboratory facilities, delay in receiving the results from the laboratory, mislaid specimens or results, or lack of regular updating of the database system. Therefore, significant losses associated with delayed diagnosis occur as a function of an inadequate infrastructure and deficient information flow within the health care network.(18) Considering the reported cases of tuberculosis/ HIV co-infection in the URST by city, we found that the city of Imperatriz, which is one of the 19 priority cities for tuberculosis control in the state of Maranhão, is noteworthy in that it had the highest number of cases (88.00%). This might be due to the existence of the Municipal Sexually Transmitted Disease/HIV/AIDS Control Program, which was implemented in 1998. The other cities in this health district do not have an implemented AIDS control program. However, they have had qualified professionals to perform rapid HIV testing since 2007. Although the city of Imperatriz has a functioning control program and the other cities have professionals trained to diagnose HIV/AIDS, HIV testing coverage still falls far short of the recommendation by the PNCT. Consequently, it is necessary to implement changes to the health care structure to ensure that all tuberculosis patients undergo HIV testing.

The reporting and analysis of cases of tuberculosis/HIV co-infection are relevant components of an epidemiological assessment system, which is minimally satisfactory when it makes it possible to estimate the situation of diseases in a specific population or area, as well as to assess the potential impact of control measures.(4) The sociodemographic characteristics of the co-infected patients are similar to the patient characteristics described in various studies conducted in Brazil, where tuberculosis/HIV co-infection predominantly affects males.(3,8,10,15,19,20)

Clinical and epidemiological profile and prevalence of tuberculosis/HIV co-infection in a regional health district in the state of MaranhĂŁo, Brazil

However, it is not yet clear whether, in fact, there is a gender disparity in the prevalence of co-infection or whether confounding factors, such as differences in access to treatment or stigmatization, are involved.(20) The fact that the highest occurrence was found in the 20- to 40-year age group suggests that the patients are young adults in the most productive phase of their life, which causes economic losses and subsequently has social repercussions for patients, families, and society.

These data are in agreement with those reported in the literature,(3,9,10,14,15,19-22) which confirm that this age group is the target of the tuberculosis and AIDS epidemics, and this might be related the lifestyle of young adults, who engage in risky behaviors, such as not using condoms, and deny any possibility of infection because of their feeling of protection or emancipation, resulting in greater exposure to HIV and Mycobacterium tuberculosis.

Another observed trend was that there were patients in the 40- to 60-year age bracket, as well as cases of tuberculosis in patients over 60 years of age, raising the age bar for those affected by tuberculosis and HIV/AIDS. This finding is in agreement with what is stated in PNCT documents,(2) which indicate a trend toward an increase in co-infection rates among men over 40 years of age.

In our sample, there was a predominance of Mulatto patients (42%), which is in contrast to the findings of other studies conducted in Brazil.(21,23) In addition, in the literature, the risk for this co-infection has been reported to be higher in Black subjects,(24) whereas, in the present study, this was not confirmed, since the prevalence of tuberculosis was lower in Blacks than in Whites. Although increased risk seems to have a more significant relationship with socioeconomic conditions than with ethnicity, studies conducted in the USA and involving socially disadvantaged populations have also shown a higher prevalence of tuberculosis in Black subjects.(25,26) The magnitude of tuberculosis/HIV co-infection goes beyond biological barriers and is a serious social problem. The vulnerability of individuals is evidenced by their lack of awareness of the imminent risks they face, which hinders the practice of self-care and results in significant difficulties for health care providers.(21) The predominance of co-infection in individuals with a low level of

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education (i.e., individuals who have had â&#x2030;¤ 4 years of schooling), found in the present study, reflects the educational situation in Brazil, a situation characterized by functional illiteracy, which results from high dropout rates throughout the school system.(22) In addition, 54% of the co-infected patients had had only up to 8 years of schooling (without considering the 9% who had had no schooling). The professional chances of this group are a cause for concern, since they are restricted to unfavorable living and working conditions, which maintain the state of impoverishment. It is exactly in this population that the incidence of HIV infection is high, promoting the maintenance of unfavorable social conditions and fostering an environment that is conducive to increasing the prevalence of tuberculosis. Therefore, this comorbidity is significantly associated with social factors (level of education) and collective factors (social deprivation and marginality).(3,21) Pulmonary tuberculosis was found to be the most common clinical presentation of the disease in the co-infected patients (in 87%). Similar results were found in other studies.(3,10,19,22) Tuberculosis can become active at any stage of the progression of HIV infection, but, in patients with severe immunological impairment who are treated at tertiary care facilities, extrapulmonary tuberculosis is the most common clinical condition,(3) which is in contrast to the situation found in the present study.

Early diagnosis of tuberculosis in HIV-infected patients and treatment initiation interrupt disease progression, which causes improvement in clinical status, with positive effects on prognosis.(27) Studies have highlighted that, although sputum smear microscopy is the primary diagnostic test for tuberculosis because of its low cost and simplicity, the limitations of smear microscopy require that culture be performed.(28) In the present study, we found that few patients underwent sputum smear microscopy, TST, and culture, which, to some extent, hinders early diagnosis and, consequently, appropriate patient care. The situation is a cause for even greater concern given that chest X-ray was prioritized in the detection of suggestive cases of tuberculosis (in 89%). In this sense, there is an urgent need that the challenging situations be improved by administrators and health care professionals, especially in health care, so that early diagnosis can in fact be established.

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Supervised treatment is a strategy that, in addition to its therapeutic focus, allows welcoming, bonding, and responsibility, increasing the capacity of professionals and patients to interact with one another, with the prospect of ensuring better quality of care and patient adherence to treatment.

(4) According to the data collected, supervised treatment reached 57% of the co-infected patients, i.e., it exceeded the 48% rate found in the city of Ribeirão Preto, located in the state of São Paulo,(8) and was below the 65% rate reported in the city of São José do Rio Preto, also located in the state of São Paulo.(29) The epidemiological trend of tuberculosis in immunocompromised individuals is different from that in immunocompetent individuals, since the former are more likely to develop resistance to antituberculosis drugs. In addition, infection with M. tuberculosis accelerates HIV replication, which can make cure difficult and result in increased mortality for co-infected patients.(3) Analysis of treatment outcomes revealed that the cure rate was 62%, which is below the rate recommended by the Brazilian National Ministry of Health (85%).(2) This finding suggests that local public health care facilities should reevaluate their strategies for patient monitoring during tuberculosis treatment and for discharge, which should occur after confirmation of cure. The proportion of treatment dropout (8%) exceeds the 5% rate recommended by the Brazilian National Ministry of Health,(2) whereas the rate of death from tuberculosis (1%) is below the 9% rate reported in other studies.(29,30) It is also important to mention that there were failures related to data entry into the database system. There were a considerable number of fields which read “no data” for some variables, such as sputum smear microscopy (2nd sample), TST, chest X-ray, and supervised treatment.

These failures can be attributed to health care professionals or to data entry clerks. The lack of information on reporting forms can ultimately lead to case underreporting and can generate a misleading picture of the health status of the population, thereby resulting in interventions that fall short of meeting their real needs. This changes, especially, the quality of care that will be provided.

The failures identified in the present study underscore the importance of developing human resources and of monitoring data recording and J Bras Pneumol. 2012;38(6):724-732

the database system. In this sense, it is essential that the database system be effectively monitored and that there be communication between those responsible for managing the database system and the health care professionals working in the public health care system.

Improving the quality of data recording in terms of the completeness of forms and the updating of data is fundamental to the reliability of epidemiological analyses. From this perspective, the present study demonstrated that periodic review of the SINAN database, as well as of registries, is an essential activity for case reporting and outcome data completeness. Finally, we highlight the need to share the analyses of the SINAN data with the health care professionals who monitor the cases and fill out the reporting forms so that they understand the importance of appropriate data recording and feel motivated to ensure the quality of the data collected.

Our results show that, because of its clinical and epidemiological profile, tuberculosis/HIV co-infection is a major public health problem in the southwestern region of Maranhão. This situation calls for better coordination between tuberculosis and sexually transmitted disease/ AIDS control programs, as well as a political commitment and greater involvement on the part of administrators and health care professionals in the planning of interventions and the functioning of health care facilities.

Knowledge of the clinical and epidemiological aspects of tuberculosis/HIV co-infection is a key element in devising strategies aimed at reducing the damage caused by the association of tuberculosis and HIV/AIDS, thereby increasing survival and improving patient quality of life.

Resolving these situational aspects of the health care systems is essential for care that is holistic, results in a greater resolution, and has a chance of reducing the burden of tuberculosis in the different contexts.

Acknowledgments We would like to thank the Regional Health District of Tocantins Management Board and the Epidemiological Surveillance Center Coordination Board for the authorization to conduct the study and for granting access to the data.

Clinical and epidemiological profile and prevalence of tuberculosis/HIV co-infection in a regional health district in the state of Maranhão, Brazil

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Lancet. 2006;368(9547):1575-80. http://dx.doi. org/10.1016/S0140-6736(06)69573-1 7. Daftary A. HIV and tuberculosis: the construction and management of double stigma. Soc Sci Med. 2012;74(10):1512-9. PMid:22444460. http:// dx.doi.org/10.1016/j.socscimed.2012.01.027 8. Brunello ME, Chiaravalloti Neto F, Arcêncio RA, Andrade RL, Magnabosco GT, Villa TC. Areas of vulnerability to HIV/TB co-infection in Southeastern Brazil. Rev Saude Publica. 2011;45(3):556-63. PMid:21484011. http:// dx.doi.org/10.1590/S0034-89102011005000018 9. Zenteno-Cuevas R, Montes-Villaseñor E, Morales-Romero J, Coronel-Martín del Campo G, Cuevas B. Co-infection and risk factors of tuberculosis in a Mexican HIV+ population.

Rev Soc Bras Med Trop. 2011;44(3):282-5. PMid:21901871. http://dx.doi.org/10.1590/S0037-86822011005000034 10. Morimoto AA, Bonametti AM, Morimoto HK, Matsuo T. Human immunodeficiency virus seroprevalence in patients with tuberculosis in the city of Londrina, in the state of Paraná, Brazil. J Bras Pneumol. 2005;31(4):325-31.

11. Escombe AR, Moore DA, Gilman RH, Pan W, Navincopa M, Ticona E, et al. The infectiousness of tuberculosis patients coinfected with HIV. PLoS Med. 2008;5(9):e188.

PMid:18798687 PMCid:2535657. http://dx.doi. org/10.1371/journal.pmed.0050188 12. Instituto Brasileiro de Geografia e Estatística [homepage on the Internet]. Brasília: Instituto Brasileiro de Geografia e Estatística [cited 2012 Apr 1]. Censo 2010. Available from: http://censo2010.ibge.gov.br/ 13. World Health Organization. Global tuberculosis control: WHO report 2011. Geneva: WHO; 2011.

14. Liberato IR, de Albuquerque Mde F, Campelo AR, de Melo HR. Characteristics of pulmonary tuberculosis in HIV seropositive and seronegative patients in a Northeastern region of Brazil. Rev Soc Bras Med Trop. 2004;37(1):46‑50. PMid:15042183. http://dx.doi. org/10.1590/S0037-86822004000100012 15. Rodrigues JLC, Fiegenbaum M, Martins AF. Prevalência de coinfecção tuberculose/HIV em pacientes do Centro

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17. Silveira MP, de Adorno RF, Fontana T. Profile of patients with tuberculosis: evaluation of the Brazilian national tuberculosis control program in Bagé, Brazil. J Bras Pneumol. 2007;33(2):199-205. PMid:17724540. http:// dx.doi.org/10.1590/S1806-37132007000200015 18. Silva HO, Gonçalves MLC. Coinfecção Tuberculose e HIV nas Capitais Brasileiras: observações a partir dos dados do Sistema de Informação de Agravos de Notificação. RBPS. 2009;22(3):172-8. http://dx.doi. org/10.5020/18061230.2009.p172 19. 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 20. Garcia GF, Correa PC, Melo MG, Souza MB. Prevalência da infecção pelo HIV em pacientes internados por tuberculose. J Pneumol. 2000;26(4):189-93. http:// dx.doi.org/10.1590/S0102-35862000000400006 21. Silveira JM, Sassi RA, de Oliveira Netto IC, Hetzel JL. Prevalence of and factors related to tuberculosis in seropositive human immunodeficiency virus patients at a reference center for treatment of human immunodeficiency virus in the southern region of the state of Rio Grande do Sul, Brazil. J Bras Pneumol. 2006;32(1):48‑55.

PMid:17273569. http://dx.doi.org/10.1590/ S1806-37132006000100011 22. Santos Mde L, Ponce MA, Vendramini SH, Villa TC, Santos NS, Wysocki AD, et al. The epidemiological dimension of TB/HIV co-infection. Rev Lat Am Enfermagem. 2009;17(5):683-8. PMid:19967218. http://dx.doi.org/10.1590/S0104-11692009000500014 23. Batista LE. Masculinidade, raça/cor e saúde. Ciênc Saúde Coletiva. 2005;10(1):71-80. http://dx.doi.org/10.1590/ S1413-81232005000100013 24. Centers for Disease Control and Prevention (CDC).

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morbidity and mortality rates (1985 - 2003) J Bras Pneumol. 2005;31(3):237-43. http://dx.doi.org/10.1590/ S1806-37132005000300010 30. Hijjar MA, Oliveira MJ, Teixeira GM. A tuberculose no Brasil e no mundo. Bol Pneumol Sanit. 2001;9(2):9-16.

About the authors Marcelino Santos Neto

Doctoral Student in Public Health. University of São Paulo at Ribeirão Preto School of Nursing, Ribeirão Preto, Brazil; and Assistant Professor II, Department of Nursing, Universidade Federal do Maranhão – UFMA, Federal University of Maranhão – Imperatriz, Brazil.

Fabiane Leita da Silva

Nursing Student. Universidade Federal do Maranhão – UFMA, Federal University of Maranhão – Imperatriz, Brazil.

Keyla Rodrigues de Sousa

Nursing Student. Universidade Federal do Maranhão – UFMA, Federal University of Maranhão – Imperatriz, Brazil.

Mellina Yamamura

Doctoral Student in Public Health. University of São Paulo at Ribeirão Preto School of Nursing, Ribeirão Preto, Brazil.

Marcela Paschoal Popolin

Master’s Student in Public Health. University of São Paulo at Ribeirão Preto School of Nursing, Ribeirão Preto, Brazil.

Ricardo Alexandre Arcêncio

Professor. Department of Maternal-Infant Care and Public Health, University of São Paulo at Ribeirão Preto School of Nursing, Ribeirão Preto, Brazil.

J Bras Pneumol. 2012;38(6):724-732

Original Article Prevalence of primary drug resistance in pulmonary tuberculosis patients with no known risk factors for such* Prevalência de resistência primária em pacientes com tuberculose pulmonar sem fatores de risco conhecidos para resistência primária

Giselle Mota Bastos, Michelle Cailleaux Cezar, Fernanda Carvalho de Queiroz Mello, Marcus Barreto Conde

Abstract Objective: To estimate the prevalence of primary resistance to the drugs in the basic treatment regimen for tuberculosis in treatment-naïve patients with pulmonary tuberculosis and no known risk factors for such resistance, as well as to identify factors potentially associated with drug resistance. Methods: This was an exploratory cross-sectional study. We analyzed the medical records of the subjects enrolled in two clinical trials of treatments for drug-susceptible tuberculosis between November 1, 2004 and March 31, 2011 at the Prof.

Newton Bethlem Outpatient Clinic of the Federal University of Rio de Janeiro Thoracic Diseases Institute, located in the city of Rio de Janeiro, Brazil. The inclusion criteria were being ≥ 18 years of age, testing positive for AFB in the first sputum sample, having a positive culture for Mycobacterium tuberculosis, having undergone drug susceptibility testing, and being treatment-naïve. Patients with a history of imprisonment or hospitalization were excluded, as were those who had been in contact with drug-resistant tuberculosis patients. Results: We included 209 patients. The overall prevalence of primary drug resistance was 16.3%. The overall prevalence of resistance to isoniazid and streptomycin was, respectively, 9.6% and 9.1%, compared with 5.8% and 6.8% for single-drug resistance to isoniazid and streptomycin, respectively. The prevalence of resistance to two or more drugs was 3.8%, and the prevalence of multidrug resistance was 0.5%. No statistically significant associations were found between the variables studied and drug susceptibility testing results. Conclusions: In this sample, the prevalence of primary drug resistance was high despite the absence of known risk factors.

Keywords: Tuberculosis, pulmonary; Tuberculosis, multidrug-resistant; Risk factors.

Resumo Objetivo: Estimar a prevalência de resistência primária aos medicamentos do esquema básico de tratamento antituberculose em pacientes com tuberculose pulmonar virgens de tratamento sem fatores de risco conhecidos para resistência primária, e identificar os possíveis fatores associados à resistência medicamentosa. Métodos: Estudo transversal exploratório com a análise de prontuários de pacientes que participaram de dois ensaios clínicos de tuberculose sensível entre 1° de novembro de 2004 e 31 de março de 2011 no Ambulatório Prof. Newton Bethlem do Instituto de Doenças do Tórax da Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ). Os critérios de inclusão foram ter idade ≥ 18 anos, ter pesquisa direta de BAAR positiva na primeira amostra de escarro, ter cultura positiva para Mycobacterium tuberculosis, ter realizado testes de sensibilidade aos fármacos, ser virgem de tratamento para tuberculose e não ter história de prisão, hospitalização ou contato com caso de tuberculose resistente. Resultados: Foram incluídos 209 pacientes. A prevalência de resistência primária geral foi de 16,3%. A prevalência geral de resistência à isoniazida e à estreptomicina foi, respectivamente, 9,6% e 9,1%, enquanto a prevalência de monorresistência à isoniazida e à estreptomicina foi de, respectivamente, 5,8% e 6,8%. A prevalência de resistência a dois ou mais fármacos foi de 3,8%, e a prevalência de tuberculose multirresistente foi de 0,5%. Não foram observadas associações estatisticamente significativas entre as variáveis estudadas e resultados do teste de sensibilidade aos fármacos. Conclusões: Na amostra estudada, a prevalência de resistência primária foi elevada apesar da ausência de fatores de risco conhecidos.

Descritores: Tuberculose pulmonar; Tuberculose resistente a múltiplos medicamentos; Fatores de Risco. * Study carried out at the Federal University of Rio de Janeiro Thoracic Diseases Institute, Rio de Janeiro, Brazil.

Correspondence to: Marcus Barreto Conde. Rua Professor Rodolpho Paulo Rocco, 255, Cidade Universitária, Ilha do Fundão, CEP 21941-913, Rio de Janeiro, RJ, Brasil.

Tel. 55 21 2562-2432 or 55 21 2562-6247. E-mail: marcusconde@hucff.ufrj.br Financial support: Giselle M. Bastos has been the recipient of a fellowship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Office for the Advancement of Higher Education). Marcus B. Conde is the recipient of a research fellowship from the Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development; 300414/2010-2) and a Young Scientist Fellowship from the Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ, Rio de Janeiro Research Foundation; E26/101491/2010).

Submitted: 2 June 2012. Accepted, after review: 3 September 2012.

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Bastos GM, Cailleaux-Cesar M, Mello FCQ, Conde MB

Introduction In Brazil, the basic treatment regimen for all cases of adult and adolescent (over 10 years of age) tuberculosis, except for the meningoencephalitic form, consists of two months of treatment with rifampin, isoniazid, pyrazinamide, and ethambutol followed by four months of treatment with rifampin and isoniazid.(1) Culture for Mycobacterium tuberculosis and drug susceptibility testing at the outset of treatment are indicated only in patients considered to be at increased risk for primary drug resistance (those with recurrent tuberculosis, those with a history of hospitalization or imprisonment, homeless individuals, and those with comorbidities, such as HIV infection) or for acquired drug resistance (particularly those with a history of poor treatment adherence).(1) The theoretical substratum for not performing culture for M. tuberculosis or drug susceptibility testing in treatment-naïve patients is provided by drug resistance survey data published in a technical note by the Brazilian National Ministry of Health (NMH), as well as by the premise that the risk of primary drug resistance is not significant in patients who do not belong to the aforementioned groups.(2) However, the limited cure rate associated with the high rate of treatment dropout and the consequent poor treatment efficacy in many regions in Brazil, as shown by data from the Sistema Nacional de Informação de Agravos de Notificação (SINAN, National Case Registry Database), suggest that cases of primary drug resistance might not be restricted to the defined risk groups.(3) The objective of the present study was to estimate the prevalence of primary resistance to the drugs in the basic treatment regimen for tuberculosis in the first sputum sample from patients with pulmonary tuberculosis and no known history of tuberculosis, imprisonment, hospitalization for any reason, or contact with patients with known drug-resistant tuberculosis.

Methods This was an exploratory cross-sectional study in which we analyzed the medical records of the subjects enrolled in either of two clinical trials of treatments for drug-susceptible tuberculosis, one of which has been completed and one of which is ongoing.(4,5) Those trials were/are being conducted at the Laboratory for Clinical Research J Bras Pneumol. 2012;38(6):733-739

on Tuberculosis of the Prof. Newton Bethlem Outpatient Clinic of the Instituto de Doenças de

Tórax da Universidade Federal do Rio de Janeiro

(IDT/UFRJ, Federal University of Rio de Janeiro Thoracic Diseases Institute), which is located in the city of Rio de Janeiro, Brazil, and proactively treats patients referred there from primary health care facilities. The inclusion criteria for the present study were being ≥ 18 years of age, testing positive for AFB in the first sputum sample, having a positive culture for M. tuberculosis, having undergone drug susceptibility testing, and being treatment-naïve. The exclusion criteria were having an incomplete medical record, or having a history of imprisonment, hospitalization, or contact with patients with known drug-resistant tuberculosis.

The routine of care for the aforementioned trials included history taking, physical examination, and posteroanterior and lateral chest X-rays, as well as AFB smear testing, culture for M. tuberculosis, and drug susceptibility testing of all (spontaneous or induced) sputum samples collected during the initial evaluation.(6) All sputum samples were sent to the Mycobacteriology Laboratory of the IDT/UFRJ for testing. The results of AFB smear were available after 24 h. The culture results were available within 60 days, whereas the drug susceptibility testing results were available within 90 days. The sputum smear microscopy method employed was the Ziehl-Neelsen method, and culture was performed on Löwenstein-Jensen medium in accordance with a standardized protocol.(7) All samples with a positive culture for M. tuberculosis underwent biochemical testing in order to differentiate the M. tuberculosis complex from other nontuberculous mycobacteria.

Drug susceptibility testing was performed by the proportion method, on the basis of indirect tests, as described by Canetti et al.(8) We tested susceptibility to isoniazid, rifampin, ethambutol, streptomycin, and ethionamide, the final concentrations of which on LöwensteinJensen were 0.2 mg/mL, 40.0 mg/mL, 2.0 mg/mL, 4.0 mg/mL, and 20 mg/mL, respectively. All antibiotics were obtained in pure powder form (Sigma-Aldrich Chemie BV, Zwijndrecht, The Netherlands). All techniques were carried out in accordance with the guidelines of the Brazilian NMH.(9) A data collection instrument was developed specifically for the present study, as well as being

Prevalence of primary drug resistance in pulmonary tuberculosis patients with no known risk factors for such

pilot tested and adjusted by using data from 15 medical records (which were not included in the study). One single person, who had been trained for this purpose, reviewed the medical records and completed the instrument. Variables that have been described in the literature as potentially associated with drug resistance in tuberculosis (radiological extent of tuberculosis, alcoholism, residence in a low-income area, unemployment, diabetes mellitus, smoking, previous use of antibiotics, and illicit drug use) were recorded on the data collection instrument. An extensive radiological lesion was defined as that for which the total affected area exceeded that of one lobe or as that in which there was cavitation of 1 cm or more in diameter. Alcoholism was defined by means of the CAGE questionnaire, the name being an acronym for key terms in the instrument’s four questions,(6) whereas current smokers with any smoking history or former smokers with a smoking history of 15 pack-years or more were considered smokers. These data were imported into a Microsoft Office Excel spreadsheet for subsequent analysis.

Results were analyzed with the Statistical Package for the Social Sciences, version 11.0 (SPSS Inc., Chicago, IL, USA). The chi-square test was used for analysis of dichotomous variables. The OR for the outcome resistance was calculated, as was the respective 95% CI. Results were considered

735

significant when p < 0.05. The study protocol was approved by the Research Ethics Committee of the Federal University of Rio de Janeiro Clementino Fraga Filho University Hospital on August 22, 2008 (Process no. 596/08).

Results The study included 211 patient medical records, 2 of which were excluded because they were incomplete. Therefore, 209 medical records of patients with pulmonary tuberculosis were considered eligible for data analysis. Of those patients, 34 (16%) showed primary resistance to at least one of the five drugs tested in the first sputum sample. Table 1 shows the gender and age of the 209 patients with pulmonary tuberculosis by patient group stratified by drug susceptibility testing result. There were no significant differences regarding these variables.

Table 2 shows the profile of drug resistance in the 34 patients. The overall prevalence of resistance to isoniazid (alone or in combination with other drugs) was 9.6%. The prevalence of resistance to streptomycin (alone or in combination with other drugs) was 9.1%.

Table 3 shows an analysis of the variables potentially associated with drug resistance in the study sample. None of the variables studied were found to be statistically associated with drug resistance.

Table 1 - Demographic data on the 209 patients with pulmonary tuberculosis.

Antibiotic drug susceptibility testing results (n = 209) Demographic Susceptible to all of the drugs testeda Resistant to 1 or more of the drugs tested data (n = 175) (n = 34) Gender Male, n (%) 113 (64.6) 18 (52.9) Female, n (%) 62 (35.4) 16 (47.1) 35 ± 13 [32 (25-45)] 39 ± 14 [37 (25-50)] Age, yearsb

p

0.1 0.07

Isoniazid, rifampin, ethambutol, streptomycin, and ethionamide. bValues expressed as mean ± SD [median (interquartile range)]. a

Table 2 - Prevalence of drug resistance in the study sample by drug, either alone or in combination.

Resistance to Prevalence, % Isoniazid (single-drug resistance) 5.8 Isoniazid + rifampin 0.5 Isoniazid + ethionamide 0.9 Isoniazid + streptomycin 0.9 Isoniazid + streptomycin + ethambutol 0.9 Isoniazid + streptomycin + ethionamide 0.5 Streptomycin (single-drug resistance) 6.8

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Table 3 - Measures of association between resistance to at least one drug and the variables Susceptible to Resistant to 1 or all of the drugs more of the drugs Variable p tested tested (n = 175) (n = 34) Presence of an extensive radiological lesion, yes/no 122/53 27/7 0.2 Residence in a low-income area, yes/no 127/48 24/10 0.8 Employment status, employed/unemployed 89/86 23/11 0.07 22/153 6/28 0.4 Presence of comorbidities,a yes/no Smoking, yes/no 46/129 11/23 0.4 Alcoholism, yes/no 45/130 8/26 0.7 21/154 4/30 0.9 Previous use of antibiotics,b yes/no

tested.

OR (95% CI) 1.6 (0.6-4.0) 0.9 (0.4-2.0) 2.0 (0.9-4.3) 1.4 (0.5-4.0) 1.3 (0.6-2.9) 0.8 (0.3-2.1) 0.9 (0.3-3.0)

Comorbidity (N of patients): leukemia (n = 3) and diabetes mellitus (n = 26). bPrevious use of antibiotics (N of patients): amoxicillin (n = 13), amoxicillin + clavulanate (n = 6), levofloxacin (n = 1), amoxicillin + clavulanate + cephalexin (n = 2), amoxicillin + clavulanate + clarithromycin (n = 1), amoxicillin + clavulanate + ciprofloxacin (n = 1), and amoxicillin + clavulanate + azithromycin (n = 1). a

No statistically significant associations were found between the variables studied and drug susceptibility testing results. None of the patients reported using immunosuppressants.

Discussion The rate of resistance to isoniazid in the study sample (9.6%) was more than 40% higher than that reported by the Brazilian NMH as having been found in the Second National Survey on Anti-Tuberculosis Drug Resistance (6%), whereas the rate of resistance to rifampin alone (0% vs. 0.5%) and the rate of multidrug resistance (0.5% vs. 1.4%) were lower.(2) The technical note published by the Brazilian NMH does not describe the methodology employed in conducting the Second National Survey, nor does it cite the survey in its reference list.(2) A search of the SciELO and PubMed databases for Portugueselanguage and English-language articles published from 2008 onward also did not identify this reference, which prevented us from discussing potential differences or similarities between the samples or methodologies. The surprisingly high rate of resistance to streptomycin (9.1%) found in the present study sample suggests that, in Brazil, there has been endogenous reactivation of strains that emerged before the 1980s, since streptomycin is not used in new cases, except in cases of multidrug-resistant tuberculosis or in cases of intolerance to isoniazid or rifampin.(1,10) The absence of resistance to rifampin, however, is in contrast to the data reported in the technical note published by the Brazilian NMH and to what has been observed worldwide, since rifampin ranks J Bras Pneumol. 2012;38(6):733-739

third among drugs that cause resistance.(11) In fact, even in Central and Western Europe, where the rate of drug resistance is lower, resistance to rifampin is 1.1%.(11) In a study conducted in the state of Mato Grosso do Sul, Brazil, and involving 645 samples collected from new cases between 2000 and 2006, the rates of primary drug resistance were 3.4% for streptomycin, 2.9% for isoniazid, and 1.7% for ethambutol,(12) i.e., the prevalence of primary drug resistance was approximately half of that found in our sample. As in our study, no resistance to rifampin was found. It is of note that the rate of resistance to ethambutol (which has recently been included in the basic treatment regimen because of the increasing rate of resistance to isoniazid) was 1.7%, whereas, in our sample, the rate of resistance to ethambutol, which was used in combination with isoniazid and streptomycin, was 0.9% (Table 2). Because that study was based on a review of data from SINAM, potential risk factors for drug resistance were not assessed, nor were there detailed information on the sample characteristics.

In a prospective study conducted in the city of Cabo de Santo Agostinho, located in northeastern Brazil, from 2000 to 2003 and involving 174 samples, the prevalence of primary resistance to at least one drug was 14%, whereas the prevalence of multidrug resistance was 8.3%.

(13) However, in that study sample, previous tuberculosis treatment and treatment dropout were identified as variables associated with risk of drug resistance. The prevalence of primary multidrug resistance was higher than that reported

Prevalence of primary drug resistance in pulmonary tuberculosis patients with no known risk factors for such

in the technical note published by the Brazilian NMH(2) and that found in our sample. In fact, the rate was comparable to that found in countries where the prevalence of multidrug resistance is high, such as Mozambique, Colombia, Lithuania, and Uzbekistan.(11) It is of note that the rate of treatment dropout in the region was higher than 10%, i.e., slightly above the national average.(3) Two studies conducted in Brazil(14,15) and involving samples from patients admitted to either a referral hospital for tuberculosis and AIDS in Rio de Janeiro (samples collected between 2001 and 2005) or to a tertiary care hospital in Rio Grande do Sul (samples collected between 1997 and 2003) found prevalences of 16% and 18%, respectively, for primary resistance to at least one drug and prevalences of 4.3% and 2.0%, respectively, for multidrug resistance, i.e., the prevalence of resistance to at least one drug in the samples from those groups (which consisted of individuals with known risk factors for drug resistance) was the same as that found in our sample, which consisted of individuals with no known or perceived risk factors for drug resistance.

Between 2000 and 2002, a study conducted in the city of Rio de Janeiro and involving a group of 75 patients diagnosed with pulmonary tuberculosis who lived in the Complexo de Manguinhos found resistance to at least one drug in 10.6% of the new cases of tuberculosis.(16) The prevalence of single-drug resistance to isoniazid was 2.6%, and the prevalence of single-drug resistance to streptomycin was 4%. No rifampin-resistant or ethionamide-resistant strains were detected.

Although the samples are not comparable, the fact that the Complexo de Manguinhos is located near the IDT/UFRJ Tuberculosis Outpatient Clinic and that the recorded prevalence of drug resistance was nearly half of that seen in our sample one decade later should be a cause for reflection.

In our study, we identified no association between the variable “cavitation on baseline chest X-ray” and the rate of drug resistance.

However, a study conducted at a referral center for infectious diseases in the state of Minas Gerais, Brazil, between September of 2000 and January of 2004, found that the risk of multidrug resistance was higher in patients with cavitation of more than 4 cm in diameter and in those who had received previous tuberculosis treatment.(17) A population-based, case-control study (134 cases and 185 controls) that was conducted

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in the state of Ceará, Brazil, between 1990 and 1999 and that also evaluated only cases of multidrug-resistant tuberculosis found that five variables (no home sewage treatment system, alcoholism + smoking, number of previous treatments, irregular treatment, and lung cavities) were associated with drug resistance.(18) In our sample, we evaluated only cases of primary drug resistance and we did not identify alcoholism or smoking as risk factors. Although the association between tuberculosis and smoking, as well as the increase in infectivity, morbidity, and mortality in active or passive smokers, has been demonstrated, the association between smoking and drug resistance has yet to be described.(19) The high rate of primary drug resistance in patients with no known risk factors or in patients from areas where the rates of tuberculosis incidence and treatment dropout are high should be a cause for reflection by authorities in Brazil. The current practice of considering culture and drug susceptibility testing necessary only in patients with known risk factors is not justified, either from a medical or an economic standpoint. Despite the fact that, in 2009, the Brazilian NMH took a correct step in adding a fourth drug (ethambutol) to the then employed triple treatment regimen, reducing the risk of disease recurrence in patients with resistance to isoniazid, the possibility of emergence of resistance to ethambutol itself was not considered.

(2) In addition, the high prevalence of resistance to streptomycin causes its use in patients with intolerance or single-drug resistance (to one of the drugs in the basic treatment regimen) to be a risk factor for disease recurrence or even for treatment failure.

The present study has some limitations. The sample studied was not random, is small, and included patients mostly from a health program area in the city of Rio de Janeiro, and, therefore, there might have been no statistical power to detect significant associations and it might not have been representative of other regions. This was a retrospective study that was based on data obtained from medical records, which may introduce information bias. However, this can be minimized by the systematic data collection, which was performed in an outpatient clinic with a strict routine of care for clinical research purposes.

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Despite its limitations, the present study showed that there was a high prevalence of primary drug resistance in treatment-naïve patients with pulmonary tuberculosis and no known risk factors. This finding demonstrates the importance of performing culture for M. tuberculosis and drug susceptibility testing in the study sample and emphasizes the need to perform these tests in all patients with pulmonary tuberculosis in Brazil. Although there are only a small number of facilities performing solid medium culture for M. tuberculosis and even fewer facilities performing drug susceptibility testing, these methods are affordable and could be universally implemented, whereas more modern, rapid, and expensive methods, such as automated methods, would be reserved for patients with known risk factors.

Acknowledgments We would like to thank the staff of the IDT/UFRJ Laboratory for Clinical Research on Tuberculosis and Professor José Roberto Lapa e Silva.

References 1. Conde MB, Melo FA, Marques AM, Cardoso NC, Pinheiro VG, Dalcin Pde T, et al. III Brazilian Thoracic Association Guidelines on tuberculosis. J Bras Pneumol. 2009;35(10):1018-48. PMid:19918635.

2. Portal da Saúde [homepage on the Internet]. Brasília: Mistério da Saúde [cited 2012 May 10]. Nota técnica sobre as mudanças no tratamento da tuberculose no Brasil para adultos e adolescentes. [Adobe Acrobat document, 6p.].

Available from: http://portal.saude.gov.br/portal/arquivos/ pdf/nota_tecnica_versao_28_de_agosto_v_5.pdf 3. Portal da Saúde [homepage on the Internet].

Brasília: Mistério da Saúde [cited 2011 Nov 21].

TUBERCULOSE - Casos confirmados notificados no Sistema de Informação de Agravos de Notificação - SINAN Net. Available from: http://dtr2004.saude.gov.br/sinanweb/ tabnet/dh?sinannet/tuberculose/bases/tubercbrnet.def 4. Conde MB, Efron A, Loredo C, De Souza GR, Graça NP, Cezar MC, et al. Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial. Lancet. 2009;373(9670):1183-9. http://dx.doi.org/10.1016/S0140-6736(09)60333-0 5. ClinicalTrials.gov [homepage on the Internet]. Bethesda: National Institutes of Health [cited 2012 May 10].

Rifapentine Plus Moxifloxacin for Treatment of Pulmonary Tuberculosis. Available from: http://clinicaltrials.gov/ ct2/show/NCT00728507?term=tuberculosis&cntry1= SA%3ABR&rank=2 6. Masur J, Monteiro MG. Validation of the “CAGE” alcoholism screening test in a Brazilian psychiatric inpatient hospital setting. Braz J Med Biol Res. 1983;16(3):215-8.

PMid:6652293.

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7. Kent PT, Kubica GP; Centers for Disease Control (U.S.).

Public Health Mycobacteriology. A Guide for the level III Laboratory. Atlanta: U.S. Dept. of Health and Human Services, Public Health Service, Centers for Disease Control; 1985.

8. Canetti G, Froman S, Grosset J, Hauduroy P, Langerova M, Mahler HT, et al. Mycobacteria: Laboratory Methods For Testing Drug Sensitivity And Resistance. Bull World Health Organ. 1963;29:565-78. PMid:14102034 PMCid:2555065.

9. Centro de Referência Professor Helio Fraga. Manual de Bacteriologia da Tuberculose. Rio de Janeiro: Fundação Nacional de Saúde; 1994.

10. Fiúza FA, Afiune J, Ribeiro L, Felice E, Castelo A. Resistência primária do M. tuberculosis num serviço ambulatorial de referência em São Paulo: evolução por três décadas e comparação com outros estudos nacionais.

J Pneumol. 1996;22(1):3-8.

11. World Health Organization [homepage on the Internet].

Geneva: World Health Organization [cited 2012 Jan 5].

MDR-TB and XDR-TB Response Plan 2007-2008. [Adobe Acrobat document, 52p.]. Available from: http://www.who. int/tb/publications/2007/mdr_xdr_global_response_plan.pdf 12. Marques M, Cunha EA, Ruffino-Netto A, Andrade SM. Drug resistance profile of Mycobacterium tuberculosis in the state of Mato Grosso do Sul, Brazil, 2000-2006.

J Bras Pneumol. 2010;36(2):224-31. PMid:20485944.

13. Baliza M, Bach AH, Queiroz GL, Melo IC, Carneiro MM, Albuquerque Mde F, et al. High frequency of resistance to the drugs isoniazid and rifampicin among tuberculosis cases in the city of Cabo de Santo Agostinho, an urban area in Northeastern Brazil. Rev Soc Bras Med Trop. 2008;41(1):11-6. PMid:18368264. http://dx.doi. org/10.1590/S0037-86822008000100003 14. Aguiar F, Vieira MA, Staviack A, Buarque C, Marsico A, Fonseca L, et al. Prevalence of anti-tuberculosis drug resistance in an HIV/AIDS reference hospital in Rio de Janeiro, Brazil. Int J Tuberc Lung Dis. 2009;13(1):54‑61.

PMid:19105879.

15. Wolfart M, Barth AL, Willers D, Zavascki AP. Mycobacterium tuberculosis resistance in HIV-infected patients from a tertiary care teaching hospital in Porto Alegre, southern Brazil. Trans R Soc Trop Med Hyg. 2008;102(5):421-5.

PMid:18394664. http://dx.doi.org/10.1016/j. trstmh.2008.02.017 16. Mendes JM, Lourenço MC, Ferreira RM, Fonseca Lde S, Saad MH. Drug resistance in Mycobacterium tuberculosis strains isolated from sputum samples from symptomatic outpatients: Complexo de Manguinhos, Rio de Janeiro, Brazil. J Bras Pneumol. 2007;33(5):579‑82.

PMid:18026657. http://dx.doi.org/10.1590/ S1806-37132007000500014 17. de Souza MB, Antunes CM, Garcia GF. Multidrugresistant Mycobacterium tuberculosis at a referral center for infectious diseases in the state of Minas Gerais, Brazil: sensitivity profile and related risk factors. J Bras Pneumol. 2006;32(5):430-7. PMid:17268747.

18. Barroso EC, Mota RM, Santos RA, Souza AL, Barroso JB, Rodrigues JL. Fatores de risco para tuberculose multirresistente adquirida. J Pneumol. 2003;29(2):89-97. http://dx.doi.org/10.1590/S0102-35862003000200008 19. Lin HH, Ezzati M, Murray M. Tobacco smoke, indoor air pollution and tuberculosis: a systematic review and meta-analysis. PLoS Med. 2007;4(1):e20. PMid:17227135 PMCid:1769410. http://dx.doi.org/10.1371/journal. pmed.0040020

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About the authors Giselle Mota Bastos

Masterâ&#x20AC;&#x2122;s Student. Federal University of Rio de Janeiro School of Medicine, Rio de Janeiro, Brazil.

Michelle Cailleaux Cezar

Doctoral Student. Federal University of Rio de Janeiro School of Medicine, Rio de Janeiro, Brazil.

Fernanda Carvalho de Queiroz Mello

Associate Professor. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Marcus Barreto Conde

Associate Professor. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

J Bras Pneumol. 2012;38(6):733-739

Original Article Primary and acquired pyrazinamide resistance in patients with pulmonary tuberculosis treated at a referral hospital in the city of Recife, Brazil* Resistência primária e adquirida à pirazinamida em pacientes com tuberculose pulmonar atendidos em um hospital de referência no Recife

Liany Barros Ribeiro, Vera Magalhães, Marcelo Magalhães

Abstract Objective: To determine primary and acquired resistance to pyrazinamide in Mycobacterium tuberculosis strains isolated in sputum samples from patients with pulmonary tuberculosis. Methods: This was a prospective, descriptive study conducted between April and November of 2011 at a referral hospital for tuberculosis in the city of Recife, Brazil. Cultures, drug sensitivity tests, and tests of pyrazinamidase activity were conducted in a private laboratory in Recife. Results: Of the 71 patients included in the study, 37 were treatment-naïve and 34 represented cases of retreatment. Pyrazinamide-resistant strains were isolated in 14 (41.2%) of the 34 patients who had previously been treated for tuberculosis and in none of the 37 treatment-naïve patients.

Of the 14 isolates, 10 (90.9%) tested negative for pyrazinamidase activity. A total of 60 isolates tested positive for pyrazinamidase activity. Of those, 56 (93.3%) were found to be sensitive to pyrazinamide. Conclusions: The high frequency of pyrazinamide-resistant strains (41.2%) in patients previously treated for tuberculosis highlights the need for drug susceptibility testing prior to the adoption of a new treatment regimen.

Keywords: Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis, multidrug-resistant.

Resumo Objetivo: Verificar a resistência primária e adquirida à pirazinamida em cepas de Mycobacterium tuberculosis provenientes de amostras de escarro de pacientes com tuberculose pulmonar. Métodos: Estudo prospectivo e descritivo realizado no período entre abril e novembro de 2011 em um hospital de referência para o tratamento de tuberculose em Recife (PE). Culturas, testes de sensibilidade a fármacos e testes da pirazinamidase foram realizados em um laboratório particular na mesma cidade. Resultados: Dos 71 pacientes incluídos no estudo, 37 eram virgens de tratamento e 34 eram casos de retratamento. Desses, 0 (0,0%) e 14 (41,2%), respectivamente, apresentaram cepas resistentes à pirazinamida. Desses 14 isolados, 10 (90,9%) apresentaram resultados negativos no teste da pirazinamidase. Dos 60 isolados que apresentaram resultados positivos para o teste da pirazinamidase, 56 (93,3%) eram sensíveis à pirazinamida. Conclusões: A elevada frequência de cepas resistentes à pirazinamida em pacientes em retratamento da tuberculose destaca a necessidade da realização de testes de sensibilidade à pirazinamida antes de se escolher um novo esquema de tratamento.

Descritores: Mycobacterium tuberculosis; Pirazinamida; Tuberculose resistente a múltiplos medicamentos.

Introduction Multidrug-resistant Mycobacterium tuberculosis strains have emerged worldwide, and there is a need for rapid methods for diagnosis and determination of antituberculosis drug susceptibility.(1) There are few data on multidrug-resistant (MDR) tuberculosis and extensively drug resistant (XDR) tuberculosis

in the 22 countries that, together, account for 80% of all tuberculosis cases worldwide, among which Brazil ranks 19th.(2) In 2010 in Brazil, only 32% of the patients at risk of harboring drug-resistant M. tuberculosis strains (i.e., those who had regimen failure, had

* Study carrried out at the Otávio de Freitas Hospital, Recife, Brazil.

Correspondence to: Liany Barros Ribeiro. Rua Madre Rosa, 174, Jardim São Paulo, CEP 50781-730, Recife, PE, Brasil.

Tel. 55 81 3455-5313. E-mail: lianyribeiro@gmail.com or lianyribeiro@hotmail.com Financial support: None.

Submitted: 7 May 2012. Accepted, after review: 26 September 2012.

J Bras Pneumol. 2012;38(6):740-747

Primary and acquired pyrazinamide resistance in patients with pulmonary tuberculosis treated at a referral hospital in the city of Recife, Brazil

recurrence, or dropped out of treatment and then returned) underwent drug susceptibility testing, and the northeastern region showed the lowest rate of testing (15.2%). In that year, 611 cases of MDR tuberculosis were reported, compared with 334 in 2001, i.e., there was an 82% increase between the years analyzed.(3) Pyrazinamide is a first-line drug used for the treatment of tuberculosis in recently diagnosed patients and in patients with MDR tuberculosis.(4) Nevertheless, pyrazinamide susceptibility testing is not routinely performed in many laboratories, because of technical difficulties. Given that pyrazinamide requires an acid pH for being converted to its active form, i.e. pyrazinoic acid,

by M. tuberculosis pyrazinamidase, there is a direct correlation between pH and the minimum inhibitory concentration of the drug. Therefore, a conflict occurs, especially because, at a lower pH, many mycobacterial strains are inhibited. Consequently, the variation in antibiogram methods affects the data on overall pyrazinamide resistance rates.(5,6) In Brazil, most studies of antituberculosis drug resistance do not report any data on pyrazinamide susceptibility testing.(7,8) In addition, in the state of Pernambuco, for instance, there have not even been recent studies of antituberculosis drug resistance in general. The present study aims to fill this gap by reporting the rates of primary and acquired resistance to antituberculosis drugs, including pyrazinamide, in M. tuberculosis strains isolated in sputum samples from patients with pulmonary tuberculosis treated at a referral hospital in the state of Pernambuco.

Methods This was a prospective, descriptive study conducted between April and November of 2011 at a referral hospital for tuberculosis in the state of Pernambuco, Brazil. Patients aged 18 years or older who had a positive sputum culture for M. tuberculosis were included. The study was approved by the research ethics committee of the hospital (Protocol no. 0.33.06.11).

A specific form was used to collect data on the following variables: age; gender; alcoholism; smoking; illicit drug use; cancer; diabetes; HIV serology; previous treatment with pyrazinamide; treatment dropout or irregular medication use; discharge as cured; and appropriate medication use.

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The participants were divided into two groups.

The first group, designated treatment-naïve (TN) group, consisted of recently diagnosed treatment-naïve patients treated at the hospital.

The second group, designated retreatment (RT) group, included patients previously treated with first-line antituberculosis drugs, some of whom had received more than one course of treatment and some of whom had been hospitalized and treated with salvage drug regimens.

After sputum samples were collected and delivered to the laboratory, the specimens were processed with N-acetylcysteine-sodiumhydroxide.(9) Examination for AFB was performed by use of Ziehl-Neelsen staining. Culture for mycobacteria was performed on LöwensteinJensen solid medium and in Middlebrook 7H9 liquid medium enriched with oleic acid-albumindextrose-catalase (OADC; Becton Dickinson Co. Sparks, MD, USA). The improved medium was made selective by the addition of a mixture of antibiotics: polymyxin B; amphotericin B; nalidixic acid; trimethoprim; and azlocillin (PANTA; Becton Dickinson). After inoculation, the culture media were incubated at 37°C for 7 days, after which they were assessed for the presence of bacterial growth in order to detect any rapidly growing mycobacteria. Subsequently, they were reincubated and reassessed at 30 and 60 days, before the samples were classified as negative.

Cultures were screened by real-time polymerase chain reaction (in-house method). The TaqMan platform was used, and the design of primers and probes was based on a previously validated protocol.(10) All positive cultures underwent drug susceptibility testing. An indirect proportion method was used, as recommended by Canetti et al.(11) The drugs were added to the Löwenstein-Jensen medium at the following concentrations: streptomycin, 4 µg/mL; isoniazid, 0.2 µg/mL; rifampin, 40 µg/mL; and ethambutol, 4 µg/mL. The Löwenstein-Jensen media containing and not containing drugs were solidified by coagulation at 80°C for 45 minutes.

Regarding pyrazinamide susceptibility testing, a previous study(6) proposed 300 µg/mL pyrazinamide in 7H9-OADC liquid medium as the cut-off point for defining pyrazinamide resistance. Given that pyrazinamide is totally converted to pyrazinoic acid, pyrazinamide was theoretically estimated at 156 µg/mL, in accordance with the HendersonJ Bras Pneumol. 2012;38(6):740-747

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Hasselbalch equation. Therefore, in the present study, pyrazinamide susceptibility testing was performed in 7H9-OADC medium containing 200 µg/mL pyrazinamide, with pH being adjusted to 5.9, as recommended in that study.(6) The pyrazinamidase activity assay was performed by the method of Singh et al.(1) For each case, two tubes were inoculated and incubated at 37°C. Four days later, 500 µg of a 1% ammonium ferrous sulfate solution, prepared immediately before use, were added to one of the tubes. Any color change from white to pinkish or brown was considered a positive reaction. If that tube tested negative, its duplicate was reincubated and reassessed at 10 days. Each culture testing negative for pyrazinamidase activity underwent a real-time polymerase chain reaction(12) for the purpose of potentially detecting a strain of M. Bovis, a species that is intrinsically resistant to pyrazinamide and, therefore, does not produce pyrazinamidase.

For data analysis, absolute and percentage distributions, as well as univariate and bivariate values, were obtained for categorical variables, and the statistical measures mean, median, and standard deviation were obtained for the variable “age” (descriptive statistical techniques). We used the Student’s t-test with equal variances and either Pearson’s chi-square test or Fisher’s exact test when appropriate (inferential statistical techniques). To test the hypothesis of equality of means, we used Levene’s F-test.

The margin of error used in deciding what statistical tests to use was 5.0%. Data were entered into an Excel spreadsheet, and statistical calculations were performed with the Statistical Package for the Social Sciences, version 17.0 (SPSS Inc., Chicago, IL, USA).

Results We included 93 patients with suspected tuberculosis. Subsequently, 21 patients were excluded because they had negative sputum culture for M. tuberculosis, and 1 patient was excluded because he was infected with M. bovis, a strain that is intrinsically resistant to pyrazinamide.

Therefore, the study population consisted of 71 patients.

The TN and RT groups comprised 37 (52.1%) and 34 (47.9%) patients, respectively.

Patient age in the TN group ranged from 21 to 76 years, with a mean of 41.0 years, a J Bras Pneumol. 2012;38(6):740-747

median of 40.0 years, and a standard deviation of 13.90 years. In the RT group, patient age ranged from 25 to 76 years, with a mean, a median, and a standard deviation of 40.00, 37.50, and 10.73 years, respectively. According to the Student’s t-test with equal variances, there was no significant difference in mean age between the two groups (p = 0.738).

Table 1 shows the characteristics of the participants by group, with the following highlights: in the sample as a whole, most patients (67.6%) were male, slightly more than half (52.1%) were between 18 and 39 years of age, and alcohol and smoking were the most common comorbidities (in 71.8% and 59.2%, respectively), bearing in mind that the same patient could simultaneously have more than one comorbidity. In the RT group, all patients (100%) reported having previously been treated with pyrazinamide, 55.9% declared having dropped out of treatment, 20.6% reported having used the medication correctly, 14.7% reported having been discharged as cured, and the remaining 8.8% admitted having used the medication irregularly.

For the chosen margin of error, alcoholism was the only variable for which there was a significant difference between the RT and TN groups (85.3% vs. 59.5%; p = 0.016).

Table 2 shows the susceptibility testing results of each of the five drugs tested. We can see that, in the TN group, there was one case of isoniazid resistance and one case of streptomycin resistance, whereas all of the other cases were classified as drug-susceptible. In contrast, in the RT group, the rates of drug-resistant cases ranged from 41.2% (pyrazinamide) to 85.3% (isoniazid), indicating significant differences between the two groups in the susceptibility testing results of all of the drugs tested (p < 0.05 for all).

Analysis of the association between the pyrazinamidase activity assay results and the pyrazinamide susceptibility testing results (Table 3) shows that the rate of pyrazinamide-resistant cases was higher in the absence than in the presence of pyrazinamidase (90.9% vs. 6.7%).

This difference indicates a significant association between the presence of pyrazinamidase and pyrazinamide susceptibility (p < 0.001).

Discussion This sample showed a predominance of male patients (67.6%), a result that is similar to those

Primary and acquired pyrazinamide resistance in patients with pulmonary tuberculosis treated at a referral hospital in the city of Recife, Brazil

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Table 1 - Characteristics of the treatment-naïve and retreatment patients diagnosed with pulmonary tuberculosis who were treated at a referral hospital for tuberculosis in the city of Recife, Brazil, between April and November of 2011.

Group Total TN RT p Variable n % n % n % Gender Male 23 62.2 25 73.5 48 67.6 0.307* Female 14 37.8 9 26.5 23 32.4 Age, years 18-39 17 45.9 20 58.8 37 52.1 0.519** 40-59 16 43.2 12 35.3 28 39.4 60 or older 4 10.8 2 5.9 6 8.5 Comorbidity Diabetes 6 16.2 1 2.9 7 9.9 0.109** HIV 3 8.1 3 8.8 6 8.5 1.000** No comorbidity 7 18.9 5 14.7 12 16.9 0.636* Alcoholism 22 59.5 29 85.3 51 71.8 0.016* Smoking 21 56.8 21 61.8 42 59.2 0.668* Illicit drug use 8 21.6 7 20.6 15 21.1 0.915* Tuberculosis retreatment 34 100.0 N/A Previous treatment with pyrazinamide Dropout 19 55.9 N/A Irregular medication use 3 8.8 N/A Discharged as cured 5 14.7 N/A Appropriate medication use 7 20.6 N/A Total 37 100.0 34 100.0 71 100.0 TN: treatment-naïve; and RT: retreatment. *Pearson’s chi-square test. **Fisher’s exact test.

Table 2 - Drug susceptibility testing results for the M. tuberculosis strains isolated from treatment-naïve and retreatment patients with pulmonary tuberculosis who were treated at a referral hospital for tuberculosis in the city of Recife, Brazil, between April and November of 2011.

Group Total TN RT p* Drug susceptibility testing n % n % n % Pyrazinamide Resistant 14 41.2 14 19.7 < 0.001 Susceptible 37 100.0 20 58.8 57 80.3 Rifampin Resistant 22 64.7 22 31.0 < 0.001 Susceptible 37 100.0 12 35.3 49 69.0 Isoniazid Resistant 1 2.7 29 85.3 30 42.3 < 0.001 Susceptible 36 97.3 5 14.7 41 57.7 Ethambutol Resistant 19 55.9 19 26.8 < 0.001 Susceptible 37 100.0 15 44.1 52 73.2 Streptomycin Resistant 1 2.7 17 50.0 18 25.4 < 0.001 Susceptible 36 97.3 17 50.0 53 74.6 100.0 34 100.0 71 100.0 Total 37 TN: treatment-naïve; and RT: retreatment. *Pearson’s chi-square test.

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Table 3 - Pyrazinamidase activity assay results and pyrazinamide susceptibility testing results for the M. tuberculosis strains isolated from patients treated at a referral hospital for tuberculosis in the city of Recife, Brazil, between April and November of 2011.

Pyrazinamide susceptibility testing Total Resistant Susceptible p* Pyrazinamidase activity assay n % n % n % Positive 4 6.7 56 93.3 60 100.0 < 0.001 Negative 10 90.9 1 9.1 11 100.0 Total 14 19.7 57 80.3 71 100.0 *Fisher’s exact test.

reported in other studies.(13-17) With regard to age, the literature provides mixed findings. In this sample, tuberculosis primarily affected those between 18 and 39 years of age, a finding that was also reported in a survey conducted in Rio de Janeiro, Brazil.(14) Comorbidities are risk factors for the occurrence of clinical presentations that are more severe and difficult to diagnose or that are responsible for affecting tuberculosis treatment success.

Alcoholism and smoking are clearly related to MDR tuberculosis.(15,16) Other studies have revealed that alcoholism(18) and HIV/AIDS are factors associated with dropping out of pulmonary tuberculosis treatment.(19) In the present study, we found high rates of alcoholism (71.8%) and smoking (59.1%). This occurred similarly in the TN and RT groups, and it might be related to disease susceptibility. However, alcoholism was the only variable for which there was a significant difference between the TN and RT groups, and it might be associated with a higher rate of treatment dropout.

Tuberculosis/HIV co-infection was present at an equal rate in the TN and RT groups, demonstrating the close relationship between the two diseases.

In fact, in developing countries, such as Brazil, tuberculosis is often the first opportunistic infection in HIV-infected individuals.(20,21) In a study conducted in the city of Belo Horizonte, Brazil, positive HIV serology was found in 12.5% of the tuberculosis cases.(22) In South Africa, where there is a high rate of HIV infection in the general population (over 20%) and low rates of cure with tuberculosis treatment, there has been an increase in the number of cases of MDR tuberculosis and numerous outbreaks of XDR tuberculosis, especially in hospitals and prisons where the tuberculosis infection control measures J Bras Pneumol. 2012;38(6):740-747

proposed by the World Health Organization in 1999 have not been adopted.(23) In Brazil, most cases of MDR tuberculosis are cases of post-primary or acquired disease unrelated to HIV co-infection or institutional outbreaks and resulting from irregular medication use and treatment dropout. Among new tuberculosis cases, the rate of new cases of MDR tuberculosis is 0.9%.(21) In the present study, primary isoniazid resistance and primary streptomycin resistance, respectively, were found in 1 (2.7%) and 1 (2.7%) patient in the TN group. These rates are higher than the national average. However, the study was conducted at a referral hospital for tuberculosis, which might result in overestimation of rates.

Nevertheless, there was no primary pyrazinamide resistance.

Pyrazinamide resistance was found in 14/71 strains. Of the patients from whom these strains were isolated, all (14/14) reported having previously been treated with this drug and 6/14 stated that they had dropped out of treatment.

A study evaluating the drug resistance profile in a public referral center for tuberculosis in the city of João Pessoa, Brazil, showed that, of 22 patients, 12 (55%) were resistant to pyrazinamide, a rate that was higher than that found in our study, whereas 21 (95%) had previously been treated for tuberculosis.(15) Studies conducted in the states of Ceará and Minas Gerais, Brazil, found pyrazinamide resistance in 3.9% (59/1,500) and 6.38% (20/313), respectively.(17,24) A survey conducted in South Africa reported that, of 127 drug-resistant M. tuberculosis strains isolated from previously treated patients, 68 (53.5%) were also resistant to pyrazinamide, and that only 1 of 47 M. tuberculosis strains (2.1%) were resistant to pyrazinamide alone, suggesting single-drug resistance.(5) In that same study, it was observed that, of the 68 pyrazinamide-

Primary and acquired pyrazinamide resistance in patients with pulmonary tuberculosis treated at a referral hospital in the city of Recife, Brazil

resistant strains, 62 (91%) were also resistant to isoniazid and rifampin.(5) In the present study, of the 14 pyrazinamide-resistant strains, 12 (85.7%) were also resistant to isoniazid and rifampin. Therefore, we can suggest that, in our hospital, pyrazinamide resistance is associated with resistance to other drugs, emphasizing the need for pyrazinamide susceptibility testing prior to treatment initiation, especially in patients previously treated for tuberculosis.

In a study conducted in Japan, pyrazinamide resistance was found in 53% of the MDR M. tuberculosis strains. All isolates testing positive for pyrazinamidase activity were found to be susceptible to pyrazinamide, whereas all isolates testing negative for pyrazinamidase activity were found to be resistant to pyrazinamide.(25) These data are consistent with those reported in a previous study.(26) In contrast, in a study conducted in Thailand,(27) pyrazinamide resistance was found in 6% (3/50) of the susceptible strains and in 49% (49/100) of the MDR tuberculosis strains. Pyrazinamidase activity was detected in 98 pyrazinamide-susceptible M. tuberculosis strains and in 18 of the pyrazinamideresistant M. tuberculosis strains. Therefore, the pyrazinamidase activity assay had a sensitivity of 65.4% and a specificity of 100%. In that study conducted in Thailand, the sensitivity of the pyrazinamidase assay was low compared with those of the other methods used. Various factors, such as medium pH, inoculum size, growth stage, and the metabolic state of the bacillus, might have contributed to false resistance in the pyrazinamidase activity assay.(28) In the present study, 4 (28.6%) of the pyrazinamideresistant strains were positive for pyrazinamidase activity, and 1 strain (1.7%) was negative for pyrazinamidase activity, although it was susceptible to pyrazinamide. This suggests that other genomic regions, different from the pncA gene, govern pyrazinamide resistance with the support of alternative mechanisms of resistance, such as insufficient drug uptake or the presence of an active efflux pump, which would limit the usefulness of the pyrazinamidase activity assay.

Previous studies have also reported that pyrazinamide-resistant M. tuberculosis strains were positive for pyrazinamidase activity.(1,28) Singh et al. found that, of 35 pyrazinamideresistant strains, 6 were positive for pyrazinamidase activity. It should be highlighted that all strains

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were isolated from patients who had previously been treated for tuberculosis,(1) similarly to those used in the present study. The pyrazinamidase activity assay, because of its simplicity and low cost, might be important as a screening method for evaluation of pyrazinamide resistance, especially in developing countries, although its sensitivity and specificity must be considered in the analysis of results.

The rate of pyrazinamide-resistant strains (41.2%) found in the tuberculosis patients in the RT group in the present study highlights the need for pyrazinamide susceptibility testing in the follow-up of these patients.

Acknowledgments We would like to thank the multidisciplinary team of the Otávio de Freitas Hospital Tuberculosis Outpatient Clinic. Our special thanks to the Marcelo Magalhões Laboratory staff, who performed cultures and drug susceptibility testing.

References 1. Singh P, Wesley C, Jadaun GP, Malonia SK, Das R, Upadhyay P, et al. Comparative evaluation of LöwensteinJensen proportion method, BacT/ALERT 3D system, and enzymatic pyrazinamidase assay for pyrazinamide susceptibility testing of Mycobacterium tuberculosis.

J Clin Microbiol. 2007;45(1):76-80. PMid:17093022 PMCid:1828947. http://dx.doi.org/10.1128/JCM.00951-06 2. Kritski AL. Multidrug-resistant tuberculosis emergence: a renewed challenge. J Bras Pneumol. 2010;36(2):157-8.

PMid:20485934. http://dx.doi.org/10.1590/ S1806-37132010000200001 3. Secretaria de Vigilância em Saúde do Ministério da Saúde.

Boletim Epidemiológico nº 43. - Especial Tuberculose.

Brasília: Ministério da Saúde; 2012.

4. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica.

Manual de recomendações para o controle da tuberculose no Brasil. Brasília: Ministério da Saúde; 2011.

5. Louw GE, Warren RM, Donald PR, Murray MB, Bosman M, Van Helden PD, et al. Frequency and implications of pyrazinamide resistance in managing previously treated tuberculosis patients. Int J Tuberc Lung Dis. 2006;10(7):802-7. PMid:16848344.

6. Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis. 2003;7(1):6‑21. PMid:12701830.

7. Marques M, Cunha EA, Ruffino-Netto A, Andrade SM. Drug resistance profile of Mycobacterium tuberculosis in the state of Mato Grosso do Sul, Brazil, 2000-2006.

J Bras Pneumol. 2010;36(2):224-31. PMid:20485944.

8. Brito RC, Mello FC, Andrade MK, Oliveira H, Costa W, Matos HJ, et al. Drug-resistant tuberculosis in six hospitals in Rio de Janeiro, Brazil. Int J Tuberc Lung Dis. 2010;14(1):24-33. PMid:20003691.

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9. Pfeyffer GE. Mycobacterium: General characteristics, laboratory detection and staining procedures. In: Murray PR, Baron EJ, Jorgensen JH, Landry ML, Pfaller MA, editors. 9th ed. Manual of Clinical Microbiology.

Washington DC: American Society for Microbiology; 2007. p. 543-72.

10. Lemaître N, Armand S, Vachée A, Capilliez O, Dumoulin C, Courcol RJ. Comparison of the real-time PCR method and the Gen-Probe amplified Mycobacterium tuberculosis direct test for detection of Mycobacterium tuberculosis in pulmonary and nonpulmonary specimens. J Clin Microbiol. 2004;42(9):4307-9.

PMid:15365029 PMCid:516309. http://dx.doi.org/10.1128/ JCM.42.9.4307-4309.2004 11. Canetti G, Rist N, Grosset J. Measurement of sensitivity of the tuberculous bacillus to antibacillary drugs by the method of proportions. Methodology, resistance criteria, results and interpretation [Article in French]. Rev Tuberc Pneumol (Paris). 1963;27:217-72.

12. Pinsky BA, Banaei N. Multiplex real-time PCR assay for rapid identification of Mycobacterium tuberculosis complex members to the species level. J Clin Microbiol. 2008;46(7):2241-6. PMid:18508937 PMCid:2446918. http://dx.doi.org/10.1128/JCM.00347-08 13. Gonçalves BD, Cavalini LT, Valente JG. Epidemiological monitoring of tuberculosis in a general teaching hospital.

J Bras Pneumol. 2010;36(3):347-55. PMid:20625673. http://dx.doi.org/10.1590/S1806-37132010000300013 14. Oliveira HM, Brito RC, Kritski AL, Ruffino-Netto A. Epidemiological profile of hospitalized patients with TB at a referral hospital in the city of Rio de Janeiro, Brazil.

J Bras Pneumol. 2009;35(8):780-7. PMid:19750331. http://dx.doi.org/10.1590/S1806-37132009000800010 15. Nogueira JA, Marques RR, Silva TR, França UM, Villa TC, Palha PF. Caracterização clínico-epidemiológica dos pacientes com diagnóstico de tuberculose resistente às drogas em João Pessoa, PB. Rev Eletr Enf. 2008;10(4):979-89.

16. 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 17. Barroso EC, Rodrigues JL, Pinheiro VG, Campelo CL. Prevalência da tuberculose multirresistente no Estado do Ceará, 1990-1999. J Pneumol. 2001;27(6):310-14. http://dx.doi.org/10.1590/S0102-35862001000600004 18. Vieira AA, Ribeiro SA. Noncompliance with tuberculosis treatment involving self administration of treatment or the directly observed therapy, short-course strategy in a tuberculosis control program in the city of Carapicuíba, Brazil. J Bras Pneumol. 2008;34(3):159‑66.

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PMid:18392464. http://dx.doi.org/10.1590/ S1806-37132008000300006 19. Campani ST, Moreira Jda S, Tietbohel CN. Pulmonary tuberculosis treatment regimen recommended by the Brazilian National Ministry of Health: predictors of treatment noncompliance in the city of Porto Alegre, Brazil. J Bras Pneumol. 2011;37(6):776-82. PMid:22241035. http://dx.doi.org/10.1590/S1806-37132011000600011 20. DeRiemer K, Soares EC, Dias SM, Cavalcante SC. HIV testing among tuberculosis patients in the era of antiretroviral therapy: a population-based study in Brazil. Int J Tuberc Lung Dis. 2000;4(6):519-27. PMid:10864182.

21. World Health Organization. Towards Universal Access to Diagnosis and Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis by 2015--WHO Progress Report 2011. Geneva: World Health Organization; 2011.

22. Lima SS, Clemente WT, Palaci M, Rosa RV, Antunes CM, Serufo JC. Conventional and molecular techniques in the diagnosis of pulmonary tuberculosis: a comparative study.

J Bras Pneumol. 2008;34(12):1056-62. PMid:19180341. http://dx.doi.org/10.1590/S1806-37132008001200011 23. Gandhi NR, Shah NS, Andrews JR, Vella V, Moll AP, Scott M, et al. HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality. Am J Respir Crit Care Med. 2010;181(1):80-6.

PMid:19833824. http://dx.doi.org/10.1164/ rccm.200907-0989OC 24. de Souza MB, Antunes CM, Garcia GF. Multidrugresistant Mycobacterium tuberculosis at a referral center for infectious diseases in the state of Minas Gerais, Brazil: sensitivity profile and related risk factors. J Bras Pneumol. 2006;32(5):430-7. PMid:17268747.

25. Ando H, Mitarai S, Kondo Y, Suetake T, Sekiguchi JI, Kato S, et al. Pyrazinamide resistance in multidrugresistant Mycobacterium tuberculosis isolates in Japan.

Clin Microbiol Infect. 2010;16(8):1164-8. PMid:19832709. http://dx.doi.org/10.1111/j.1469-0691.2009.03078.x 26. Sekiguchi J, Miyoshi-Akiyama T, Augustynowicz-Kopeć E, Zwolska Z, Kirikae F, Toyota E, et al. Detection of multidrug resistance in Mycobacterium tuberculosis.

J Clin Microbiol. 2007;45(1):179-92. PMid:17108078 PMCid:1828975. http://dx.doi.org/10.1128/JCM.00750-06 27. Jonmalung J, Prammananan T, Leechawengwongs M, Chaiprasert A. Surveillance of pyrazinamide susceptibility among multidrug-resistant Mycobacterium tuberculosis isolates from Siriraj Hospital, Thailand. BMC Microbiol. 2010;10:223.

Erratum in: BMC Microbiol. 2010;10:278. http://dx.doi. org/10.1186/1471-2180-10-278 28. Shenai S, Rodrigues C, Sadani M, Sukhadia N, Mehta A. Comparison of phenotypic and genotypic methods for pyrazinamide susceptibility testing. Indian J Tuberc. 2009;56(2):82-90. PMid:19810590.

Primary and acquired pyrazinamide resistance in patients with pulmonary tuberculosis treated at a referral hospital in the city of Recife, Brazil

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About the authors Liany Barros Ribeiro

Pulmonologist and Preceptor in the Clinical Medicine Residency Program, Getúlio Vargas Hospital; and Pulmonologist and Preceptor in the Pulmonology Residency Program, Otávio de Freitas Hospital, Recife, Brazil.

Vera Magalhães

Full Professor of Infectious Diseases. Department of Tropical Medicine, Federal University of Pernambuco, Recife, Brazil.

Marcelo Magalhães

Full Professor of Microbioloby. Department of Tropical Medicine, Federal University of Pernambuco, Recife, Brazil.

J Bras Pneumol. 2012;38(6):740-747

Special Article Pharmaceutical equivalence of the combination formulation of budesonide and formoterol in a single capsule with a dry powder inhaler* Equivalência farmacêutica da formulação combinada de budesonida e formoterol em cápsula única com dispositivo inalador de pó

Marina Andrade-Lima, Luiz Fernando Ferreira Pereira, Ana Luisa Godoy Fernandes

Abstract Objective: To evaluate the pharmaceutical equivalence of a test formulation (fixed-dose combination of budesonide and formoterol fumarate in a single capsule dispensed in an Aerocaps® inhaler) in relation to a reference formulation (budesonide and formoterol fumarate in two separate capsules dispensed in an Aerolizer® inhaler). Methods: This was an in vitro study in which we performed the identification/quantification of the active ingredients by HPLC and determined dose uniformity and aerodynamic particle size distribution in the test and reference formulations. Results: In the test formulation, the content of budesonide and formoterol was 111.0% and 103.8%, respectively, compared with 110.5% and 104.5%, respectively, in the reference formulation. In the test formulation, dose uniformity regarding budesonide and formoterol was 293.2 µg and 10.2 µg, respectively, whereas it was 353.0 µg and 11.1 µg in the reference formulation. These values are within the recommended range for this type of formulation (75-125% of the labeled dose). The fine particle fraction (< 5 µm) for budesonide and formoterol was 45% and 56%, respectively, in the test formulation and 54% and 52%, respectively, in the reference formulation. Conclusions: For both of the formulations tested, the levels of active ingredients, dose uniformity, and aerodynamic diameters were suitable for use with the respective dry powder inhalers.

Keywords: Asthma; Budesonide; Bronchodilator agents; Drug therapy, combination.

Resumo Objetivo: Avaliar a equivalência farmacêutica da formulação teste (associação fixa de budesonida e fumarato de formoterol em cápsula única dispensada com o dispositivo Aerocaps®) em relação a uma formulação referência (budesonida e fumarato de formoterol em duas cápsulas distintas dispensadas com o dispositivo Aerolizer®).

Métodos: Estudo in vitro no qual foram realizadas identificação/quantificação dos ingredientes ativos por HPCL e determinação da uniformidade da dose liberada e da distribuição aerodinâmica das partículas das formulações teste e referência. Resultados: Na formulação teste, o teor de budesonida e de formoterol foi de 111,0% e 103,8%, respectivamente, enquanto esse foi de 110,5% e 104,5% na formulação referência. Na formulação teste, a uniformidade das doses de budesonida e de formoterol foi de 293,2 µg e 10,2 µg, respectivamente, enquanto essa foi de 353,0 µg e 11,1 µg na formulação referência. Esses resultados estão dentro da faixa recomendada para esse tipo de formulação (75-125% da dose rotulada). A fração de partículas finas (< 5 µm) para budesonida e formoterol foi de, respectivamente, 45% e 56% na formulação teste e de 54% e 52% na formulação referência.

Conclusões: As formulações teste e referência apresentaram níveis de ingredientes ativos, uniformidade de doses e diâmetros aerodinâmicos apropriados ao uso com seus respectivos dispositivos inalatórios de pó.

Descritores: Asma; Budesonida; Broncodilatadores; Terapia combinada.

* Study carried out in the Laboratório T&E Analítica - Centro Analítico e Científico Ltda, Campinas, Brazil.

Correspondence to: Marina Andrade Lima. Hospital Pró-Cardíaco, Setor Assistência Ventilatória, Rua General Polidoro, 192, Botafogo, CEP 22280-010, Rio de Janeiro, RJ, Brasil.

Tel. 55 21 2528-1411. E-mail: marina.lima@procardiaco.com.br Financial support: This study received financial support from Aché Laboratórios Farmacêuticos S.A. Submitted: 18 June 2012. Accepted, after review: 21 August 2012.

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Pharmaceutical equivalence of the combination formulation of budesonide and formoterol in a single capsule with a dry powder inhaler

Introduction Inhalation is the preferred method for administration of drugs for the treatment of obstructive respiratory diseases, in accordance with national and international guidelines.(1-4) Inhaled drug therapy is much more complex than is oral drug therapy. To be effective, it requires an inhaler containing the proposed drug, in the amount specified for each dose, and producing appropriately sized particles that will reach the lower airways. Aerodynamic size diameter is usually the most important particlerelated factor, affecting aerosol deposition, which is determined by impaction, sedimentation, and Brownian motion. Particles more than 5 µm in diameter deposit by impaction onto the oropharynx and are swallowed. The percentage of particles less than 5 µm in diameter in an aerosol is designated the fine particle fraction (or fine particle dose, which is expressed as the absolute mass of such particles). Particles of 4-5 µm deposit primarily in the bronchi and large airways, whereas smaller particles remain in the air stream and are carried into the peripheral airways and the alveolar region, where the airflow rate is reduced and particles deposit by sedimentation.

In contrast, particles between 0.1 µm and 1.0 µm diffuse by Brownian motion and deposit when they collide with the airway wall. A longer residence time in the smaller airways translates to greater deposition from sedimentation and Brownian motion.(5) There are three basic systems for administration by inhalation: metered dose inhalers; dry powder inhalers; and nebulizers. The treatment of persistent asthma implies continuous use of controller medications. Current evidence shows that the use of the combination of an inhaled corticosteroid and a long-acting β2 agonist bronchodilator, when compared with the use of an inhaled corticosteroid alone, improves current control and reduces future risk.(2) Various combinations of inhaled corticosteroids and long-acting β2 agonists, administered via different inhalers, have been approved and are available for use in the treatment of asthma and COPD in Brazil. The combination of budesonide and formoterol for dry powder inhalation can be dispensed in a multiple-dose inhaler (Turbuhaler®), in a single-dose inhaler with separate capsules containing budesonide and formoterol (Aerolizer®), or in an inhaler with a single capsule containing

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a fixed-dose combination (Aerocaps®). There is not sufficient evidence in the medical literature to support the use of this fixed-dose combination dispensed in an inhaler manufactured in Brazil.

For this reason, we designed the present in vitro study.

The objective of the present study was to evaluate the pharmaceutical equivalence of a test formulation (fixed-dose combination of budesonide and formoterol fumarate in a single capsule dispensed in an Aerocaps® inhaler) in relation to a reference formulation. The test formulation used was the drug commercially known as Alenia® (Aché Laboratórios Farmacêuticos S.A., São Paulo, Brazil), whereas the reference formulation was that containing budesonide and formoterol fumarate in separate capsules dispensed in a dry powder inhaler (Aerolizer®); in the latter case, the drug commercially known as Foraseq® (Novartis Biociências S.A., São Paulo, Brazil) was used. The batch numbers used in the present study, as well as their manufacture date and expiration date, are as follows: Alenia®, batch number 0702213, manufactured in May of 2007 and good through November of 2008; and Foraseq®, batch number U0173, manufactured in October of 2006 and good through September of 2008.

Methods The present study was conducted in 2007, when there was no specific legislation on regulatory issues related to dry powder inhalers by the Agência Nacional de Vigilância Sanitária (ANVISA, Brazilian National Health Oversight Agency). However, the ANVISA required that the following procedures be performed: drug identification; determination of the average capsule content weight; determination of the active ingredient content (dosing); determination of content uniformity; determination of delivered dose uniformity; determination of aerodynamic particle size distribution; microbiology testing; determination of the water content; and determination of volume variability; all of which were performed in accordance with the specifications of the U.S. and Brazilian pharmacopeias.(6,7) Throughout the process, two ANVISA technicians directly supervised the procedures, which were performed in an accredited laboratory (T&E Analítica; Campinas, Brazil).

Chart 1 shows the definitions of the main technical terms and norms used in the J Bras Pneumol. 2012;38(6):748-756

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present study. The details of each method are available in the online appendix (http://www. jornaldepneumologia.com.br/english/artigo_ detalhes.asp?id=1943).

In summary, the methods used were as follows: drug identification was performed by HPLC column elution; dosing was performed by HPLC with UV detection (HPLC-UV); content uniformity determination, the aim of which is to investigate variability in the concentrations of active ingredients in a pharmaceutical formulation, was also performed by HPLC-UV(7); delivered dose uniformity was determined with a dosage unit sampling apparatus for dry powder inhalers (DUSA-DPIs; Westech Scientific Instruments, Bedfordshire, UK; Figure 1)(6); aerodynamic particle size distribution was determined with an Andersen cascade impactor (ACI; model 830160; Copley Scientific Ltd., Nottingham, UK),(8) by means of which the ingredient content in the discharged spray from the inhaler is drawn by vacuum at a controlled flow rate through a set of filters that mimic in vitro the airways up to the pulmonary alveoli (Figure 2); the water content was determined by the Karl Fischer method; microbiology testing included bacterial and fungal counts and detection of total and fecal coliforms; and variability in the volumes of the

test formulation with low inspiratory volumes (simulating a patient with breathlessness) was determined by testing of aerodynamic particle size distribution with a multistage liquid impinger (Astra Draco MSLI; Erweka, Heusenstamm, Germany), which assesses in vitro the effect of inhalation on particle size distribution.

Results The results of the in vitro analyses, which were performed using HPLC, a DUSA, and an ACI, are shown in Table 1. In accordance with

Figure 1 - Dosage unit sampling apparatus, used for determining dose uniformity of samples.

Chart 1 - Terms, definitions, and norms used in the study.a Term Definition/norm Aerosol Suspension of solid particles and liquid droplets in air Labeled dose or nominal dose The mass of drug that is available within the device per actuation Delivered dose The mass of drug delivered per actuation that is actually available for inhalation at the mouth Fine particle dose The mass of particles < 5 µm in size within the total delivered dose Fine particle fraction The fine particle dose divided by the total delivered dose.

Mass median aerodynamic diameter The diameter at which 50% of the particles of an aerosol by mass are larger and 50% are smaller Tests for delivered dose uniformity They are used to assess delivered dose uniformity of inhaled medications containing the active ingredient or active ingredient formulations, packaged in reservoirs or in premetered dosage units where these containers are labeled for use with a named inhalation device. For dry powder inhalers, the specified target-delivered dose is usually less than the label claim. Its value reflects the expected mean active ingredient content for a large number of delivered doses collected from the product, using the specified method.

Acceptance criteria The test results are considered satisfactory if not less than 9 of the 10 doses tested are within the range of 75% to 125% of the specified targetdelivered dose and none is outside the range of 65% to135% of the specified target-delivered dose. If the content of a maximum of 3 doses is outside the range of 75% to 125% of the specified target-delivered dose, but is within the range of 65% to135%, another 20 capsules are selected and one minimum dose from each is analyzed as described elsewhere.(6) a

In accordance with the U.S. Pharmacopeial Convention(6) and the Brazilian Pharmacopeia.(7)

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Figure 2 - In A, image of the Andersen cascade impactor, which simulates the aerodynamic particle size distribution in the human respiratory system. In B, the assembled device and the correspondence between its stages and the different parts of the human respiratory system.

the parameters laid down by the pharmacopeias, there were no differences between the test and reference formulations regarding drug identification (Figure 3), active ingredient content, content uniformity, delivered dose, or aerodynamic particle size distribution. Figure 4 shows that the portion of active ingredient collected on each ACI stage, corresponding to the estimated median mass diameter, was very similar for the two formulations.

For the test formulation (Aerocaps® inhaler), the delivered doses of budesonide and formoterol were, respectively, 73% and 85% of the labeled doses, compared with 88% and 92%, respectively, for the reference formulation (Aerolizer® inhaler),

The results of the microbiological analyses for the test and reference formulations were < 10 CFU/g for bacteria and fungi (recommended specification, < 100 CFU/g) and absence of pathogens and fecal coliforms. The water content of the test formulation was 4.76%, as determined by the Karl Fischer method, whereas the water content of the capsules of formoterol and budesonide of the reference formulation was 5.00% and 5.12%, respectively.

The comparative profile of the aerodynamic particle size distribution of budesonide and formoterol, with inspiratory volumes of 1 L and 4 L, was similar, demonstrating the good J Bras Pneumol. 2012;38(6):748-756

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Table 1 - Capsule weight, active ingredient content, content uniformity, delivered dose uniformity, and fine particle distribution in the test and reference formulations.a Formulation Variable Test Reference Budesonide Formoterol Budesonide Formoterol Capsule 25.56 ± 0.79 25.35 ± 1.08 25.19 ± 0.70 weightb, mg [25.3 (24.2-27.1)] [25.5 (23.0-27.3)] [25.3 (23.8-26.3)] Active 111.41 103.80 110.59 104.51 ingredient content, % 293.24 ± 12.91 10.23 ± 0.47 353.04 ± 11.48 11.07 ± 0.60 Delivered dose uniformityc, µg [292.32 (271.80-320.39)] [10.33 (9.20-11.05)] [352.98 (322.40-378.24)] [11.06 (10.10-12.38)] 92.69-109.25 89.63-108.01 91.31-107.14 91.32-111.83 Delivered dose uniformity, %d 103.68 ± 1.68 97.93 ± 1.98 107.20 ± 5.83 100.00 ± 3.23 Content uniformitye, % [103.68 (101.40-106.59)] [98.38 (95.00-100.77)] [107.16 (97.20-117.76)] [99.80 (95.80-105.33)] 140.67 (44.71) 6.18 (56.13) 181.53 (53.56) 5.46 (52.05) Fine particle dosef, µg (%) Values expressed as mean ± SD [median (min-max)], except where otherwise indicated. bOn the basis of 20 capsules.

On the basis of 30 capsules. dIn mean percent variation. The recommended specification is 75-125% in at least 9 of the 10 samples tested. eOn the basis of 10 capsules.fOn the basis of 10 capsules. a c

Figure 3 - Chromatography for identification of the drugs contained in the capsules of the test and reference formulations.

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Figure 4 - Comparison of the reference and test formulations regarding aerodynamic particle size distribution of formoterol and budesonide on the different stages of the Andersen cascade impactor.

performance of the test formulation even with low volumes (Figure 5).

Discussion The use of regular doses of maintenance medication is a key element in asthma management.

Current guidelines recommend continuous medication use for achieving asthma control and minimizing future risks,(3,9) and, therefore, it is important that tests be conducted to validate the active ingredient content of commercial formulations of the drugs prescribed in Brazil.

The tests for determination of the active ingredient content by HPLC demonstrated that the capsules of the test and reference formulations contained budesonide and formoterol. The present in vitro study is of relevance because it allows the determination and validation of the drug content of a formulation, as well as allowing sequential weighing of capsules, all of which ensure formulation homogeneity during production. It was also demonstrated that the test formulation was equivalent to the reference formulation in terms of fine particle fraction.

The results obtained regarding the doses of active ingredients delivered by the inhalers of the test and reference formulations indicate that both were in compliance with the guidelines for the acceptance of such devices by the ANVISA, which are based on the recommendations of the U.S. and Brazilian pharmacopeias.(6,7) Although the absolute values were lower for the delivered doses of the ingredients of the test formulation than for those of the reference formulation, caution should be exercised in this analysis.

First, because both formulations, as previously mentioned, are within the accepted range for this type of test by the pharmacopeias and are therefore equivalent from a pharmaceutical standpoint. Second, because these tests, when repeated, usually show significantly different results: another dosage with other capsules could invert the situation, with the values for the reference formulation being lower than those for the test formulation. For this reason, there is the equivalence acceptance range. Finally, this was an in vitro study: we do not know what the consequences are under in vivo conditions.

To answer this question, we would need clinical trials. A study that was recently published in the J Bras Pneumol. 2012;38(6):748-756

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Figure 5 - Aerodynamic particle size distribution of formoterol and budesonide in the test formulation with inspiratory volumes (IVs) of 1 L and 4 L.

Brazilian Journal of Pulmonology(10) showed the clinical efficacy of budesonide alone and of the budesonide/formoterol combination contained in a test formulation. To date, there have been no clinical studies directly comparing the ingredients of a test formulation with those of a reference formulation.

The delivered dose is the dose that is actually available for inhalation at the mouth, and, for the test formulation, the mean delivered dose was obtained after 30 analyses, collected from many inhalers of the chosen product. These procedures ensure device regularity and reproducibility in delivering a certain amount of drug for inhalation.

The effectiveness of the inhaled medication also depends on the size of the particles produced following actuation of the device.

The results of the in vitro tests, which, in the present study, were performed with an ACI, showed that the fine particle (diameter < 5 µm) fraction was similar in the test and reference formulations (Figure 4). The use of an ACI for this purpose is validated and recommended by the U.S. and Brazilian pharmacopeias for quality control of medications dispensed in dry powder inhalers.(6,7) The device used in the test is the most comprehensive, because it is applied to dry powder J Bras Pneumol. 2012;38(6):748-756

inhalers and metered dose inhalers, allowing an evaluation equivalent to that performed in the respiratory tract. It is considered the only technique for measuring particle size that can differentiate the active ingredient from the other components of the formulation, measuring the mass median aerodynamic diameter, a parameter that is particularly relevant to understanding the behavior of the particles during inhalation.

Recommendations for validation of particulate quality control advocate the use of a standard flow rate of 90 L/min. However, it should be borne in mind that inspiratory flow, when the patient is using the device, varies depending on disease state, age, postural position, and patient-device interaction.(11) In a study of the Turbuhaler® inhaler, at flow rates of 30 L/min, 60 L/min, and 90 L/min, the mean delivered dose was 37.5%, 64.4%, and 107.4%, respectively. The authors emphasized the importance of flow rate in drug discharge from the inhaler.(12) In the present study, the delivered fine particle fraction of budesonide and formoterol was 45% and 56%, respectively, when using the Aerocaps® inhaler at a standard flow rate of 90 L/min, compared with 54% and 52%,

Pharmaceutical equivalence of the combination formulation of budesonide and formoterol in a single capsule with a dry powder inhaler

respectively, when using the Aerolizer® inhaler.

In the study of the Turbuhaler® inhaler, the fine particle fraction was found to be 11.9% and 28.6% of the labeled dose at flow rates of 28.3 L/m and 60 L/m, respectively, confirming that the emitted dose from the inhaler is dependent on patient inhalation flow rates.(12) Radiolabeling has also been employed to study the regional deposition of inhaled particles. A study of mannitol labeled with 99mtechnetiumdiethylenetriamine pentaacetic acid was conducted in which the Aerolizer® inhaler was used. The deposited lung dose of mannitol particles decreased with increasing particle diameter.

For particles measuring 2.7 µm, 3.6 µm, and 5.4 µm in diameter, the mean (standard error) lung deposition was 44.8 ± 2.4%, 38.9 ± 0.9%, and 20.6 ± 1.6%, respectively; p < 0.0001).

The sites of deposition of particles measuring 2.7 µm and 3.6 µm were similar.(13) These studies demonstrate the importance of knowing the mean particle diameter of the drugs to be prescribed.

Under in vivo conditions, aerosol particle deposition can be limited by collision with a solid wall or by the aerodynamic characteristics of the particles, which are affected by laminar and turbulent flows, typical of the anatomical features of the airways.(14,15) To simulate flow variations, the inhalers were tested with a flow volume simulator with inspiratory volumes of 1 L and 4 L, and were shown to perform similarly.

The regional deposition of aerosols is also dependent on temperature and humidity, as well as on the presence of secretions in the airways. All these limitations mean that validation studies of drug formulations must be conducted in clinical research settings in order to prove the therapeutic effectiveness of such formulations.

A study comparing patient handling of various types of inhalers demonstrated that 76% of the patients who used metered dose inhalers made at least one error when using it, whereas the same was true for 49% and 55% of those who used breath-actuated inhalers. Errors compromising treatment efficacy were made by 11.5% of the patients using Aerolizer®, Autohaler®, or Diskus® inhalers, by 28% of those using metered dose inhalers, and by 32% of those using Turbuhaler® inhalers.(16) It is also important to emphasize that the inhalation technique must be reviewed at all visits and that systematic training on the correct

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use of the medication contributes to asthma control.(17) In summary, the present in vitro study confirmed that the test and reference formulations were quite similar in terms of active ingredient content and that the delivered dose uniformity of both formulations was within the range recommended by ANVISA. The fine particle fraction at a standard flow rate was approximately half of the delivered dose, which is similar to that of other inhalers commonly used in the treatment of obstructive lung diseases.

References 1. Sociedade Brasileira de Pneumologia e Tisiologia.

II Consenso Brasileiro sobre Doença Pulmonar Obstrutiva Crônica - DPOC - 2004. J Bras Pneumol. 2004;30(Suppl 5):S1-S42.

2. Global Initiative for Asthma. Bethesda: Global Initiative for Asthma. [cited 2012 Jun 18]. Global Strategy for Asthma Management and Prevention 2011. [Adobe Acrobat document, 124p.]. Available from: http://www.ginasthma. org/uploads/users/files/GINA_Report2011_May4.pdf 3. Sociedade Brasileira de Pneumologia e Tisiologia.

Diretrizes da Sociedade Brasileira de Pneumologia e Tisiologia para o Manejo da Asma - 2012. J Bras Pneumol. 2012;38(Suppl 1):S1-S46.

4. Global Initiative for Chronic Obstructive Lung Disease.

Bethesda: Global Initiative for Chronic Obstructive Lung Disease. [cited 2012 Jun 18]. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease. Revised 2011. [Adobe Acrobat document, 90p.]. Available from: http://www.goldcopd. org/uploads/users/files/GOLD_Report_2011_Feb21.pdf 5. Laube BL, Janssens HM, de Jongh FH, Devadason SG, Dhand R, Diot P, et al. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J. 2011;37(6):1308-31. PMid:21310878. http:// dx.doi.org/10.1183/09031936.00166410 6. U.S. Pharmacopeial Convention. Rockville: The United States Pharmacopeial Convention. [cited 2012 Jun 18].

Available from: http://www.usp.org 7. Agência Nacional de Vigilância Sanitária. FarmacopÉia brasileira, 4ª edição, São Paulo: Atheneu; 1988.

8. Wong W, Crapper J, Chan HK, Traini D, Young PM. Pharmacopeial methodologies for determining aerodynamic mass distributions of ultra-high dose inhaler medicines. J Pharm Biomed Anal. 2010;51(4):853-7. PMid:19932579. http://dx.doi.org/10.1016/j.jpba.2009.10.011 9. 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 10. Stirbulov R, Fritscher CC, Pizzichini E, Pizzichini MM. Evaluation of the efficacy and safety of a fixed-dose, single-capsule budesonide-formoterol combination in uncontrolled asthma: a randomized, doubleblind, multicenter, controlled clinical trial. J Bras Pneumol. 2012;38(4):431-7. PMid:22964926. http:// dx.doi.org/10.1590/S1806-37132012000400004

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11. Byron PR, Hindle M, Lange CF, Longest PW, McRobbie D, Oldham MJ, et al. In vivo-in vitro correlations: predicting pulmonary drug deposition from pharmaceutical aerosols.

J Aerosol Med Pulm Drug Deliv. 2010;23 Suppl 2:S59-69.

PMid:21133801. http://dx.doi.org/10.1089/jamp.2010.0846 12. Tarsin W, Assi KH, Chrystyn H. In-vitro intra- and interinhaler flow rate-dependent dosage emission from a combination of budesonide and eformoterol in a dry powder inhaler. J Aerosol Med. 2004;17(1):25-32, PMid:15120010. http://dx.doi.org/10.1089/089426804322994433 13. Glover W, Chan HK, Eberl S, Daviskas E, Verschuer J. Effect of particle size of dry powder mannitol on the lung deposition in healthy volunteers. Int J Pharm. 2008;349(1‑2):314-22. PMid:17904774. http:// dx.doi.org/10.1016/j.ijpharm.2007.08.013

14. Sociedade Brasileira de Pneumologia e Tisiologia.

Diretrizes para teste de função pulmonar. J Pneumol. 2002;28(3):S2-S238.

15. Sameshima K. Relação fluxo-resistência no sistema respiratório: aspectos teóricos.

J Pneumol. 1987;13(Suppl 1):S10-S20.

16. Molimard M, Raherison C, Lignot S, Depont F, Abouelfath A, Moore N. Assessment of handling of inhaler devices in real life: an observational study in 3811 patients in primary care. J Aerosol Med. 2003;16(3):249-54. PMid:14572322. http://dx.doi.org/10.1089/089426803769017613 17. Costa Mdo R, Oliveira MA, Santoro IL, Juliano Y, Pinto JR, Fernandes AL. Educational camp for children with asthma. J Bras Pneumol. 2008;34(4):191-5.

About the authors Marina Andrade-Lima

Coordinator for Pulmonology Clinical Research. Hospital Pró-Cardíaco, Rio de Janeiro, Brazil.

Luiz Fernando Ferreira Pereira

Coordinator. Outpatient Smoking Cessation Clinic, Pulmonology Residency Program, Federal University of Minas Gerais Hospital das Clínicas, Belo Horizonte, Brazil.

Ana Luisa Godoy Fernandes

Tenured Associate Professor. Federal University of São Paulo/Paulista School of Medicine, São Paulo, Brazil.

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Brief Communication Evaluation of the diagnostic utility of fiberoptic bronchoscopy for smear-negative pulmonary tuberculosis in routine clinical practice*,** Avaliação da utilidade diagnóstica da fibrobroncoscopia óptica na tuberculose pulmonar BAAR negativa na prática clínica de rotina

Alonso Soto, Daniela Salazar, Vilma Acurio, Patricia Segura, Patrick Van der Stuyft

Abstract We evaluated the diagnostic yield of fiberoptic bronchoscopy for the diagnosis of smear-negative pulmonary tuberculosis in patients treated at a referral hospital in Lima, Peru. Of the 611 patients who underwent the procedure, 140 (23%) were diagnosed with tuberculosis based on the analysis of BAL samples. Being young and being male were significantly associated with positive cultures. In addition, 287 patients underwent postbronchoscopic sputum smear testing for AFB, the results of which increased the diagnostic yield by 22% over that obtained through the analysis of BAL samples alone. We conclude that the analysis of BAL samples and post-bronchoscopic sputum samples provides a high diagnostic yield in smear-negative patients suspected of having pulmonary tuberculosis.

Keywords: Tuberculosis, pulmonary/diagnosis; Bronchoscopy; Sputum.

Resumo Avaliamos o rendimento diagnóstico da fibrobroncoscopia óptica no diagnóstico de tuberculose pulmonar BAAR negativa em pacientes atendidos em um hospital de referência em Lima, Peru. Dos 611 pacientes submetidos ao procedimento, 140 (23%) foram diagnosticados com tuberculose com base nas amostras de LBA. Ser mais jovem e do sexo masculino foi associado a culturas positivas. Além disso, 287 pacientes tiveram baciloscopia de escarro após a broncoscopia, e os resultados aumentaram o rendimento diagnóstico em 22% em relação às amostras de lavado. Concluímos que amostras de lavado brônquico e de escarro pós-broncoscopia tiveram um bom rendimento diagnóstico nos pacientes com suspeita de tuberculose pulmonar BAAR negativa.

Descritores: Tuberculose pulmonar/diagnóstico; Broncoscopia; Escarro.

In low- and middle-income countries, fiberoptic bronchoscopy (FBO) is typically indicated as a means of identifying infectious conditions.(1) However, access to the procedure is limited in resource-constrained settings, and it implies some risks; therefore, patient selection should be quite accurate in order to avoid unnecessary risk for the patients and the overburdening of medical staff and laboratories. One common indication for FBO has been the diagnosis of smear-negative pulmonary tuberculosis (SNPT). The decision to perform FBO is usually based on the premise that the bacillary load is higher in samples taken directly

from bronchial secretions than in sputum samples.

Nevertheless, the evaluation of this particular application of FBO has been limited, and few studies have been conducted in Latin America.

In addition, according to guidelines established by the Peruvian National Tuberculosis Control Program,(2) the use of bronchoscopy is not to be included in the diagnostic workup of patients with clinical suspicion of SNPT; the suggested course of action is to wait for sputum culture results before a consultation with an expert, who will decide whether treatment should be initiated or not. The pragmatic evaluation of the

* Study carried out at the Department of General Epidemiology and Disease Control, Institute of Tropical Medicine, Antwerp, Belgium, and at the Hospital Nacional Hipólito Unanue, Lima, Peru.

Correspondence to: Alonso Soto. Institute of Tropical Medicine, Nationalstraat 155 B-2000. Antwerp, Belgium.

Tel. 32 3 247 62 55. E-mail: sotosolari@gmail.com Financial support: This study received financial support from Damian Foundation.

Submitted: 13 August 2012. Accepted, after review: 24 September 2012. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

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diagnostic yield of bronchoscopy is therefore a key element of generating evidence-based recommendations for the use of the procedure in cases of SNPT. The objective of our study was to evaluate the diagnostic value of FBO in patients with two negative sputum smears and clinical suspicion of pulmonary tuberculosis in routine clinical practice.

The study was carried out at the Hospital Nacional Hipólito Unanue, a referral hospital in Lima, Peru. Within the districts served by the hospital the incidence of tuberculosis is high, being up to 300/100,000 population in some areas.(3) The study was approved by the Research Ethics Committee of Hospital Nacional Hipólito Unanue.

We reviewed the results of AFB smears and mycobacterial cultures from bronchial aspirates of adult patients who underwent FBO between January of 2008 and December of 2009 due to clinical suspicion of tuberculosis and who had at least two negative AFB smears. The procedures were performed by trained pulmonologists.

Samples obtained by BAL were decontaminated, stained with Ziehl-Neelsen, and cultured in Ogawa medium in accordance with national guidelines.(2) Pulmonary tuberculosis was defined as a positive AFB smear or a positive culture for M. tuberculosis in the BAL or sputum samples obtained within two weeks before or after the procedure. A secondary analysis was carried out in order to compare the BAL results with the results of the pre-procedure sputum culture (if available) and the post-bronchoscopic sputum sample analysis.

The incremental diagnostic yield was defined as the number of additional diagnoses divided by the number of cases diagnosed times 100, and it was calculated for all three procedures.

During the study period, 632 patients underwent FBO. Of those, 21 patients were excluded: 6 because their sputum smears tested positive prior to the procedure, 6 because the samples were contaminated, and 9 because data were missing. Therefore, 611 patients were included in the analysis. The mean age of the patients was 41.98 ± 17.09 years. Most of the patients were male (56.5%). Pulmonary tuberculosis was diagnosed in 140 patients (22.9%). In comparison with the other patients, those diagnosed with tuberculosis were younger (31.8 vs. 45.2 years; p < 0.001) and more often male (65% vs. 54%; p = 0.02).

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The AFB smears of BAL samples were positive in 68 (49%) of the tuberculosis patients (Table 1).

Positive cultures provided the diagnosis in 72 additional cases, giving an incremental diagnostic yield over AFB smears of BAL samples of 106%.

The results of post-bronchoscopic sputum AFB smears were available for 278 patients.

The comparison between AFB smears of postbronchoscopic sputum samples and those of BAL samples is shown in Table 2. The incremental diagnostic yield of AFB testing of post-bronchoscopic sputum smears over that of BAL smears was 19%. Cultures of postbronchoscopic samples were obtained for 30 patients. Of those 30 cultures, 11 were positive in both post-bronchoscopy sputum and BAL samples, 3 were positive only in post-bronchoscopy sputum samples, and 2 were positive only in BAL samples.

Sputum cultures performed before the procedure were available for comparison in 56 patients. Of those 56 patients, 14 were diagnosed with pulmonary tuberculosis, the diagnosis being based only on positive BAL samples in 8 and only on pre-procedure sputum cultures in 3. In the 3 remaining patients, BAL and pre-procedure sputum cultures were both positive.

Our results show that, in patients suspected of having SNPT, the diagnostic yield of AFB Table 1 - Comparison between the diagnostic yield of AFB and that of culture in BAL samples in patients suspected of having smear-negative pulmonary tuberculosis. Lima, Peru, 2008-2009.

Method Culture Method Positive Negative Total AFB Positive 61 7 68 Negative 72 471 543 Total 133 478 611

Table 2 - Comparison of the diagnostic yield of direct testing for AFB in BAL samples and in postbronchoscopic sputum samples in patients suspected of having smear-negative pulmonary tuberculosis.

Lima, Peru, 2008-2009.

Post-bronchoscopy Sample type sputum Sample type Positive Negative Total BAL Positive 15 16 31 Negative 6 241 247 Total 21 257 278

Evaluation of the diagnostic utility of fiberoptic bronchoscopy for smear-negative pulmonary tuberculosis in routine clinical practice

smears and cultures from BAL samples is high, having the potential to diagnose tuberculosis in 1 out of 4 patients undergoing FBO. This might even be an underestimation, considering that we used only solid culture media, which have low sensitivity in comparison with other media.(4,5) Another Latin American study in an HIV-prevalent setting also reported a good diagnostic yield from the procedure.(6) Nevertheless, the procedure is not included in the diagnostic workup of SNPT by the Peruvian Tuberculosis Control Program(2) or by the World Health Organization.(4) One remarkable finding of the present study was the high frequency of tuberculosis among young male patients. This probably does not mean that the procedure is better for this age group but might rather reflect the higher prevalence of tuberculosis among such individuals.

Another interesting result was the high positivity of post-bronchoscopic sputum samples, which increased the diagnostic yield by approximately 20%. Although the analysis of post-bronchoscopy sputum samples has already been shown to have a good diagnostic yield in settings other than Latin America, the increase in diagnostic yield in previous studies was found to be close to 7%.(7) It is also of note that post-bronchoscopy sputum samples are currently sent for AFB smears but not for culture. In the few patients for whom cultures were performed in post-bronchoscopy samples, the cultures appeared to increase the diagnostic yield. However, because of the small size of our study sample, we could not explore this hypothesis further. Other limitations of our study are the retrospective nature of data collection, which might generate bias due to missing data, and the relatively short follow-up period (which might preclude the diagnosis of additional SNPT cases among those with negative AFB and culture results from BAL samples). In addition, we were not able to perform transbronchial biopsies, which have been shown to increase the sensitivity of the procedure from 25% to 40%.(8,9) Unless contraindicated, we believe that transbronchial biopsies should be performed in all patients who undergo FBO for the diagnosis of tuberculosis.

It is worrisome that, in routine clinical practiceâ&#x20AC;&#x201D;despite the recommendations of the Peruvian National Tuberculosis Control Program, which stipulate that, after two negative sputum samples, a culture should be performedâ&#x20AC;&#x201D;a very low

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proportion of patients undergo sputum culture before undergoing FBO. This could be due to the lack of rapid sputum sample testing methods and the belief that BAL samples are superior to sputum samples. In addition, other methods for optimizing the yield of smear microscopy are not currently performed in routine clinical practice in Peru. In particular, sputum induction has been shown to be an effective method for the diagnosis of tuberculosis, with a high rate of agreement with bronchoscopy,(6) and this can avoid a significant number of procedures. However, this method has not been yet implemented.

Given the very low proportion of patients for whom sputum cultures were performed, either prior to or immediately after FBO, we cannot draw definitive conclusions regarding their utility. However, our results suggest that both types of cultures add value to BAL testing.

We believe that pre-bronchoscopy sputum, BAL, and post-bronchoscopy sputum samples should all be cultured, although the utility of this approach has not been formally validated, and, from an operational point of view, this could overburden laboratories. In fact, laboratory facilities typically do not perform more than one culture per patient. However, considering that few patients undergo FBO and that the diagnostic yield of such an invasive procedure should be maximized, we believe that it is worthwhile to culture those samples. Further research on the value of these types of samples should be done under operational conditions in order to evaluate their true contribution. In addition, the use of liquid media and molecular methods, which can improve the sensitivity of bronchoscopic sample analysis, should also be investigated.(10) In summary, FBO is a procedure with a good diagnostic yield in patients suspected of having SNPT in a high incidence setting, such as ours. It is reasonable to perform at least one post-bronchoscopy sputum smear test in addition to BAL testing. The routine culture of pre-bronchoscopy sputum samples (including induced sputum samples) and post-bronchoscopy sputum samples seems to be useful and should be the object of future studies.

Acknowledgments We would like to thank Lely Solari for reviewing and advising us in the drafting of the manuscript.

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References 1. Sawy MS, Jayakrishnan B, Behbehani N, Abal AT, El-Shamy A, Nair MG. Flexible fiberoptic bronchoscopy. Diagnostic yield. Saudi Med J. 2004;25(10):1459-63. PMid:15494822.

2. Dirección General de Salud de las Personas. Estrategia Sanitaria Nacional de Prevención y Control de la Tuberculosis. Norma técnica de salud para el control de la tuberculosis. Lima: Ministerio de Salud; 2006.

3. Estrategia Sanitaria de Prevención y Control de la Tuberculosis. Situación de la tuberculosis en el Perú.

Informe de gestión. Lima: Ministerio de Salud; 2008.

4. World Health Organization. Improving the Diagnosis and Treatment of Smear-Negative Pulmonary and Extrapulmonary Tuberculosis Among Adults and Adolescents: Recommendations for HIV-Prevalent and Resource-Constrained Settings. Geneva: Stop TB Department; 2007.

5. Soto A, Agapito J, Acuña-Villaorduña C, Solari L, Samalvides F, Gotuzzo E. Evaluation of the performance of two liquid-phase culture media for the diagnosis of pulmonary tuberculosis in a national hospital in Lima, Peru. Int J Infect Dis. 2009;13(1):40-5. PMid:18555721. http:// dx.doi.org/10.1016/j.ijid.2008.03.023

6. Conde MB, Soares SL, Mello FC, Rezende VM, Almeida LL, Reingold AL, et al. Comparison of sputum induction with fiberoptic bronchoscopy in the diagnosis of tuberculosis: experience at an acquired immune deficiency syndrome reference center in Rio de Janeiro, Brazil. Am J Respir Crit Care Med. 2000;162(6):2238-40. PMid:11112145.

7. George PM, Mehta M, Dhariwal J, Singanayagam A, Raphael CE, Salmasi M, et al. Post-bronchoscopy sputum: improving the diagnostic yield in smear negative pulmonary TB. Respir Med. 2011;105(11):1726-31. PMid:21840695. http://dx.doi.org/10.1016/j.rmed.2011.07.014 8. Jacomelli M, Silva PR, Rodrigues AJ, Demarzo SE, Seicento M, Figueiredo VR. Bronchoscopy for the diagnosis of pulmonary tuberculosis in patients with negative sputum smear microscopy results. J Bras Pneumol. 2012;38(2):167‑73. PMid:22576423.

9. Bammann RH, Fernandez A, Vásquez CM, Araújo MR, Leite KR. Broncoscopia no diagnóstico de tuberculose: papel da biópsia transbrônquica em imunocompetentes e em HIV-positivos. J Pneumol. 1999;25(4):207-12.

10. Min JW, Yoon HI, Park KU, Song JH, Lee CT, Lee JH. Realtime polymerase chain reaction in bronchial aspirate for rapid detection of sputum smear-negative tuberculosis.

Int J Tuberc Lung Dis. 2010;14(7):852-8. PMid:20550768.

About the authors Alonso Soto

Predoctoral Research Assistant. Department of General Epidemiology and Disease Control, Institute of Tropical Medicine, Antwerp, Belgium; and Internist. Department of Medicine, Hospital Nacional Hipólito Unanue, Lima, Peru.

Daniela Salazar

Resident in Pulmonology. Universidad Peruana Cayetano Heredia, Lima, Peru.

Vilma Acurio

Physician. Hospital Nacional Hipólito Unanue, Lima, Peru.

Patricia Segura

Pulmonologist. Hospital Nacional Hipólito Unanue, Lima, Peru.

Patrick Van der Stuyft

Professor. General Epidemiology and Disease Control, Institute of Tropical Medicine, Antwerp, Belgium; and Professor. Public Health Department, Ghent University, Ghent, Belgium.

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Brief Communication A new nicotine dependence score and a new scale assessing patient comfort during smoking cessation treatment* Um novo escore para dependência a nicotina e uma nova escala de conforto do paciente durante o tratamento do tabagismo

Jaqueline Scholz Issa

Abstract Smoking is considered the leading preventable cause of morbidity and mortality. The pharmacological management of nicotine withdrawal syndrome enables better cessation rates. In our smoking cessation program, we have developed a data collection system, which includes two new instruments: a score that assesses nicotine dependence in smokers of ≤ 10 cigarettes/day; and a patient comfort scale to be used during smoking cessation treatment.

Here, we describe the two instruments, both of which are still undergoing validation.

Keywords: Smoking cessation; Nicotine; Treatment outcome; Substance withdrawal syndrome; Tobacco use disorder.

Resumo O tabagismo é considerado a maior causa evitável de morbidade e mortalidade. O manuseio farmacológico da síndrome de abstinência de nicotina possibilita melhores taxas de cessação. Desenvolvemos um sistema de coleta de dados em nosso programa de assistência ao fumante, que inclui dois instrumentos novos: um escore para dependência de nicotina em fumantes de ≤ 10 cigarros/dia e uma escala de conforto do paciente durante o tratamento do tabagismo. Descrevemos aqui os dois instrumentos, que estão em processo de validação.

Descritores: Abandono do hábito de fumar; Nicotina; Resultado de tratamento; Síndrome de abstinência a substâncias; Transtorno por uso de tabaco.

The Smoking Cessation Treatment Outpatient Clinic of the Department of Prevention and Rehabilitation, Heart Institute, University of São Paulo School of Medicine Hospital das Clínicas, located in the city of São Paulo, Brazil, started its health care activities in November of 1996.

Since the creation of the Smoking Cessation Treatment Outpatient Clinic, the proposed treatment has been based on the doctor-patient relationship and on the prescription of drugs to treat nicotine withdrawal symptoms. Initially, the therapeutic armamentarium was limited to nicotine replacement therapy with transdermal patches.

In 2001, we initiated the use of bupropion and noticed that it contributed to therapeutic success.

At that time, there was no instrument (scale or questionnaire) to assess patient comfort during smoking cessation treatment, as all existing scales

focused exclusively on withdrawal symptoms.

Therefore, we created a questionnaire to assess patient comfort during treatment. In 2007, we developed our own smoking cessation program, the Program to Aid Smokers (PAS), which was registered with the Brazilian National Institute for Industrial Property in 2008 and updated to an online version in 2011. By 2007, over 3,000 smokers had been treated under our program.

The PAS is a consolidated system to collect medical information on smoking cessation treatment and make the information available in a systematic and organized manner. The PAS system has questionnaires for brief assessment of clinical history; current and previous psychiatric disorders; medications being used and their total quantities; demographic variables, such as age, gender, level of education, socioeconomic status,

* Study carried out at the Heart Institute, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Correspondence to: Jaqueline Scholz Issa. Rua Dr. Enéas de Carvalho Aguiar, 44, 1º andar, Bloco 2, CEP 05403-000, São Paulo, SP, Brasil.

Tel. 55 11 2661-5592. E-mail: jaquelineissa@yahoo.com.br Financial support: None.

Submitted: 10 May 2012. Accepted, after review: 23 July 2012.

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race, sexual orientation, number of diagnoses, smoking history, number of previous attempts to quit smoking, and previous experience with smoking cessation medications; and other data, such as weight, HR, blood pressure, and exhaled carbon monoxide levels. All of this information can be made available through database-generated reports, patient anonymity being guaranteed.

During the medical visit, patients are asked whether data regarding their smoking cessation treatment can be made available for research purposes, and only the information on those who give consent is made available for the reports.

Nicotine dependence is assessed with the Fagerström test.(1) However, the PAS has an additional assessment score to be used in smokers of ≤ 10 cigarettes/day, a score known as the Issa Situational Smoking Score (Table 1). The development of this instrument was necessary because current guidelines on smoking cessation treatment(2) recommend the use of smoking cessation medications only for smokers of > 10 cigarettes/day. However, the behavior of smokers has changed because of the measures to prevent passive smoking, i.e., measures that restrict smoking in social settings.

Therefore, it has become increasingly common to find smokers who smoke < 10 cigarettes/day.

(3) However, this does not necessarily indicate low nicotine dependence. The existence of an instrument that can identify smokers with low consumption but possibly with a moderate or high degree of nicotine dependence allows us to consider prescribing smoking cessation drugs to facilitate the smoking cessation process in this subgroup of patients.

The Issa Situational Smoking Score (named after its author) comprises four questions, and the score ranges from 0 to 4 (Table 1). The questions were developed based on the description of the mechanism of action of nicotine on the central nervous system, a mechanism that involves effects on neurotransmitter receptors related to cognition, attention, concentration, mood, well-being, and

pleasure. The neurotransmitters known to act on these receptors are acetylcholine, dopamine, noradrenaline, and serotonin.(4) As a consequence of the psychoactive effects of nicotine, smokers develop behaviors that can indicate the level of dependence as the urge to smoke is triggered by situations related to improved performance, discomfort relief, or increased feelings of pleasure.

We consider that a higher perception of the urge to smoke in these situations translates to a higher dependence, and we deem it appropriate to use smoking cessation medications when the score is ≥ 2. This approach is limited to the population treated at our facility. After nicotine dependence is assessed, the physician can determine the therapeutic strategy to be used, taking into consideration other patient data. At present, the PAS methodology introduces the concept of using a scale to assess patient comfort during the proposed treatment.

There are many instruments for diagnosing nicotine withdrawal syndrome,(5,6) as well as scales that assess the presence and severity of withdrawal symptoms in patients who quit smoking.(7) However, no scale has been developed to assess the performance of smoking cessation drugs during the treatment of nicotine withdrawal syndrome. In this context, the PAS Comfort Scale was designed to assess patient comfort during treatment on the basis of the answers to 10 items, with scores ranging from 0 (greatest discomfort) to 38 (greatest comfort; Table 2). The rationale for using the PAS Comfort Scale is that the use of smoking cessation medications can relieve and change the severity of nicotine withdrawal symptoms and produce adverse effects that can have a direct influence on the smoking cessation treatment. None of the currently available scales assess the effect of smoking cessation drugs on nicotine withdrawal symptoms. The PAS scale, which is used during treatment, compares patient status before and after quitting smoking, allowing continuous assessment of the level of adaptation to abstinence and of the impact of the approaches

Table 1 - The Issa Situational Smoking Score to assess nicotine dependence in smokers of ≤ 10 cigarettes/day.

1. Do you need to smoke to improve your attention, concentration, and production?

Yes No 2. Do you need to smoke when you are anxious, tense, or worried?

Yes No 3. Do you need to smoke when you are sad or upset?

Yes No 4. Do you need to smoke while drinking alcoholic beverages, after a meal, or on festive occasions?

Yes No One point is assigned for each affirmative response: ≤ 1 point, low dependence; 2-3 points, moderate dependence; and 4 points, high dependence.

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Table 2 - The Program to Aid Smokers Comfort Scale.

1. How often do you have cravings?

Never Not every day A few times a day Many times a day 2. In comparison with your levels of anger and irritability as a smoker, your current levels are Lower The same or I do not experience that Slightly higher Moderately higher Much higher 3. In comparison with your levels of anxiety and tension as a smoker, your current levels are Lower The same or I do not experience that Slightly higher Moderately higher Much higher 4. In comparison with your levels of impatience and restlessness as a smoker, your current levels are Lower The same or I do not experience that Slightly higher Moderately higher Much higher 5. In comparison with the frequency of depressive mood as a smoker, the current frequency is Lower The same or I do not experience that Slightly higher Moderately higher Much higher 6. In comparison with your level of difficulty concentrating as a smoker, your current level of difficulty is Lower The same or I do not experience that Slightly higher Moderately higher Much higher 7. In comparison with your appetite as a smoker, your appetite is currently as follows: The same Slightly increased Moderately increased Strongly increased I have no appetite 8. In comparison with your level of insomnia as a smoker, your current level of insomnia is Lower The same or I do not experience that Slightly higher Moderately higher Much higher

Score 3 2 1 0 Score 4 3 2 1 0 Score 4 3 2 1 0 Score 4 3 2 1 0 Score 4 3 2 1 0 Score 4 3 2 1 0 Score 3 2 1 0 0 Score 4 3 2 1 0

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Table 2 - Continued...

9. In comparison with your level of daytime sleepiness as a smoker, your current level of daytime sleepiness is Lower The same or I do not experience that Slightly higher Moderately higher Much higher 10. In comparison with your level of headache as a smoker, your current level of headache is Lower The same or I do not experience that Slightly higher Moderately higher Much higher

adopted, with the purpose of increasing patient comfort during treatment. The clinical use of the PAS scale revealed the need to revise the therapeutic approach to patients with a score below 20. A PAS scale score below 20 reveals mild discomfort, i.e., discomfort that is neither limiting (moderate) nor disabling (severe). Therefore, the use of the PAS scale has allowed us to determine the level of comfort during treatment, and this can directly affect the outcomes.

The PAS system was designed on the basis of outpatient clinical experience in the treatment of smokers over a 16-year period of specialized care.

Before the creation of the system, over 3,000 had been treated and approximately 18,000 medical consultations had been held. In the ambulatory care setting, the PAS system has been used as a tool in the smoking cessation treatment of more than 2,000 patients in its desktop version and in the treatment of approximately 800 patients in its online version, being also a tool for the implementation of the Framework Convention on Tobacco Control,(8) which is a global treaty on smoking control. Article 14 of that convention aims at encouraging the treatment of smokers as a strategy for achieving a rapid decrease of the consequences of this global pandemic.(9) The PAS system makes it possible to conduct objective, careful medical consultations, as well as providing systematic information that allows a rational and well-thought-out use of the therapeutic strategies available. Examples of its use in clinical practice were found by searching the PAS system database in the 2007-2009 period.

In one analysis, the use of varenicline alone or in combination with other drugs was found to J Bras Pneumol. 2012;38(6):761-765

Score 4 3 2 1 0 Score 4 3 2 1 0

be effective.(10) In another analysis, the time and reason of smoking relapse were studied.(11) In addition, analysis of the PAS system database made it possible to evaluate the influence of smoking cessation drugs on blood pressure, HR, and exhaled carbon monoxide levels.(12) All of those analyses allowed a better understanding of the population treated and the therapeutic strategies adopted.

The use of the PAS methodology has allowed a better understanding of nicotine dependence and a better quality of care for patients during the smoking cessation process, as well as allowing a critical analysis of the effectiveness of the therapeutic approaches to smoking cessation, which is a dynamic process, with the use of the PAS Comfort Scale during treatment and follow-up.

The PAS system was developed in order to organize and standardize the routine care for smokers, thus improving cessation rates in the population treated.

Finally, we would like to emphasize that the Issa Situational Smoking Score and the PAS Comfort Scale are currently undergoing psychometric validation. The principal objective of this communication was to allow other researchers to conduct validation tests in order to validate and endorse the use of these instruments in clinical practice.

References 1. Fagerstrom KO, Schneider NG. Measuring nicotine dependence: a review of the Fagerstrom Tolerance Questionnaire. J Behav Med. 1989;12(2):159-82.

PMid:2668531. http://dx.doi.org/10.1007/BF00846549

A new nicotine dependence score and a new scale assessing patient comfort during smoking cessation treatment

2. 2008 PHS Guideline Update Panel, Liaisons, and Staff.

Treating tobacco use and dependence: 2008 update U.S. Public Health Service Clinical Practice Guideline executive summary. Respir Care. 2008;53(9):1217-22.

PMid:18807274.

3. Pierce JP, White MM, Messer K. Changing age-specific patterns of cigarette consumption in the United States, 1992-2002: association with smoke-free homes and state-level tobacco control activity. Nicotine Tob Res. 2009;11(2):171-7. http://dx.doi.org/10.1093/ntr/ ntp014 4. Koob GF, Volkow ND. Neurocircuitry of addiction.

Neuropsychopharmacology. 2010;35(1):217-38. Erratum in: Neuropsychopharmacology. 2010;35(4):1051.

PMid:19710631 PMCid:2805560. http://dx.doi.org/10.1038/ npp.2009.110 5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000.

6. Organização Mundial da Saúde. CID - 10 - Classificação estatística internacional de doenças e problemas relacionados a saúde. São Paulo: Editora da Universidade de São Paulo; 1997.

7. Shiffman S, West R, Gilbert D; SRNT Work Group on the Assessment of Craving and Withdrawal in Clinical Trials. Recommendation for the assessment of tobacco craving and withdrawal in smoking cessation trials.

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Nicotine Tob Res. 2004;6(4):599-614. http://dx.doi. org/10.1080/14622200410001734067 8. World Health Organization. WHO Framework Convention on Tobacco Control. Geneva: World Health Organization; 2005.

9. World Health Organization. WHO Report on the Global Tobacco Epidemic 2008: The Mpower Package.

Geneva: World Health Organization; 2008.

10. Issa JS, Abe TO, Pereira AC, Moura SS. Effectiveness of varenicline combination therapy in real life setting: PAF database study. Proceedings and On-Site Program of the Joint Conference of the Society for Research on Nicotine and Tobacco; 2011 Feb 16-19; Toronto, Canada. Madison: Society for Research on Nicotine and Tobacco; 2011.

11. Issa. JS, Moura SS, Abe TO. Time and reason of smoking relapse in outpatients smoking cessation service in a cardiology hospital. Proceedings and On-Site Program of the Joint Conference of the Society for Research on Nicotine and Tobacco; 2012 Mar 15-17; Houston, Texas. Madison: Society for Research on Nicotine and Tobacco; 2012.

12. Issa JS, Moura SS, Abe TO. Influence of anti-tobacco drugs in blood pressure and heart rate in patients with high risk for cardiovascular disease. Proceedings and On-Site Program of the Joint Conference of the Society for Research on Nicotine and Tobacco; 2012 Mar 15-17; Houston, Texas. Madison: Society for Research on Nicotine and Tobacco; 2012.

About the authors Jaqueline Scholz Issa

Director. Smoking Cessation Program, Area of Cardiology, Heart Institute, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

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Brief Communication Bottlenecks and recommendations for the incorporation of new technologies in the tuberculosis laboratory network in Brazil* Gargalos e recomendações para a incorporação de novas tecnologias na rede pública laboratorial de tuberculose no Brasil

Maria Alice da Silva Telles, Alexandre Menezes, Anete Trajman

Abstract The World Health Organization (WHO) has recently recommended new technologies for the diagnosis of tuberculosis. The WHO recommendations include the development of a strategic plan for bringing the network up to grade; investment in supervision and quality control; and implementation of a system of laboratory environmental management. Without those measures having been taken, no new technology can be effectively incorporated. We surveyed the tuberculosis laboratory network in Brazil in order to identify possible bottlenecks for the incorporation of new technologies. We identified a lack of resources allocated to supervision and quality control; a low number of requests for cultures; a lack of effective laboratory information systems; and a lack of awareness regarding the future infrastructure needs of the laboratory network at the municipal level.

Keywords: Quality control; Tuberculosis; Laboratories; Clinical laboratory information systems; Technology.

Resumo Novas tecnologias para o diagnóstico da tuberculose foram recentemente recomendadas pela Organização Mundial da Saúde (OMS). Algumas recomendações da OMS incluem a elaboração de um plano estratégico para a adequação da rede, investimentos em supervisão e controle de qualidade, implementação de um sistema de gerenciamento de ambiente laboratorial, sem o que nenhuma nova tecnologia poderá ser eficazmente incorporada.

Realizamos um levantamento da rede laboratorial de tuberculose no Brasil para identificar possíveis gargalos para a incorporação dessas tecnologias. Identificamos escassez de recursos para supervisão e controle de qualidade, baixa solicitação de culturas, ausência de sistemas eficazes de informação laboratorial e o desconhecimento da rede periférica municipal quanto às necessidades futuras na infraestrutura.

Descritores: Controle de qualidade; Tuberculose/diagnóstico; Laboratórios; Sistemas de informação em laboratório clínico; Tecnologia.

The diagnosis of tuberculosis remains a challenge. After more than half a century using sputum smear microscopy as the principal diagnostic tool, new, molecular biology-based techniques have become commercially available.

Some of these techniques, such as the Xpert® MTB/ RIF assay, which allows rapid and simultaneous detection of Mycobacterium tuberculosis and rifampin resistance with great accuracy, are being recommended by the World Health Organization (WHO) and international partners.(1,2)

The Brazilian National Ministry of Health (NMH) has recently announced the incorporation of this technology in the laboratory network operated by the Brazilian Unified Health Care System.(3) In order to inform the Programa Nacional de Controle da Tuberculose (PNCT, Brazilian National Tuberculosis Control Program) on the incorporation of the Cepheid Xpert® MTB/RIF assay, a study of the implementation, cost-effectiveness, and acceptability of the method is being conducted at two cities. The adoption of other new tests, the so-called line probe assays, which include

* Study carried out at the Adolfo Lutz Institute, São Paulo, and at the Gama Filho University, Rio de Janeiro, Brazil.

Correspondence to: Maria Alice da Silva Telles. Rua Cristiano Viana, 505, apto. 11, CEP 05411-001, São Paulo, SP, Brasil.

Tel. 55 11 3068-2895. E-mail: atelles.msh@gmail.com Financial support: This study received financial support in the context of the project known as Inovações para o Controle da Tuberculose (InCo-TB, Innovations in Tuberculosis Control), which is the result of a partnership between the Programa Nacional de Controle da Tuberculose (PNCT, Brazilian National Tuberculosis Control Program) and the Fundação Ataulpho de Paiva (FAP, Ataulpho de Paiva Foundation), with support from the Bill & Melinda Gates Foundation (#GH5254).

Submitted: 2 July 2012. Accepted, after review: 17 September 2012.

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Bottlenecks and recommendations for the incorporation of new technologies in the tuberculosis laboratory network in Brazil

Hain Lifescience’s DNA strip technology,(1,2) is also under study in the country.

We discuss here the potential that is currently available at the various hierarchical levels of the Sistema Nacional de Laboratórios de Saúde Pública (SISLAB, Brazilian National Public Health Laboratory System), as well as its major weaknesses in meeting the PNCT recommendations, in order to identify potential bottlenecks for the incorporation of new diagnostic technologies in the country and to propose measures to strengthen the laboratory network. Our opinions and conclusions are based on the annual self-assessment undertaken by the Laboratórios Centrais de Saúde Pública (LACENs, Central Public Health Laboratories), on technical visits performed by the Laboratório Nacional de Referência (LRN, National Referral Laboratory) between 2009 and 2010, on published interviews with actors in the field of tuberculosis, and on a review of official documents (directives, guidelines, norms, and recommendations by the PNCT and the WHO).(1,4-7) In Brazil, diagnostic tests for tuberculosis are performed mostly in the SISLAB,(7) which is composed of the LRN, 27 LACENs, and another 3,000 local laboratories. The local laboratories perform sputum smear microscopy, and few of them also perform culture and drug susceptibility testing (DST).

Despite the major challenge of coordinating a network of continental proportions, the LRN adequately carries out many of its duties, which are defined in Directive no. 2,031(6): standardization of techniques; human resource development; technical coordination of the laboratory network; and performance of highly complex laboratory procedures, such as genetic sequencing, genotyping, and second-line DST. However, the LRN needs to increase recent scientific partnerships and exchanges and improve the supervision of the LACENs, which is negatively affected by the inadequate information system and by the deficiencies in the team of supervisors. Between 2009 and 2010, the LRN directly supervised the 27 LACENs. However, with the current team, it will be impossible to perform this activity with the desired frequency. In 2011, the LRN joined the team that had been established by the PNCT and the Coordenação Geral de Laboratórios de Saúde Pública (CGLAB, General Coordination of Public Health Laboratories) to assess and monitor state and municipal tuberculosis control

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programs annually. This experience showed that the coordination of the different actors involved in this task can be a history of success.

Of all LACENs, only 8 consider themselves to meet 20 or more of the 25 quality criteria used in the self-assessment. The most frequently cited strengths are decentralization of sputum smear microscopy, use of standard operational procedures, computerized laboratories, organized teams of professionals, good work organization, quality control (QC) of reagents and media, qualified professionals, suitable size, and quality practices for sputum smear microscopy. The universally acknowledged weakness is the poor QC of the peripheral network. Re-reading of slides and technical visits are insufficient in nearly all of the Brazilian states, the average coverage being 22% (Chart 1). The LACENs with poorer performance in terms of QC are those with a greater number of laboratories in their network, which means that the most populous metropolitan areas receive less QC coverage. This difficulty is due to the excessive workload, since there is no team exclusively involved in performing this activity, and to the lack of resources for transportation and expenses. This weakness is a cause for specific concern, given that any other test that may replace or complement sputum smear microscopy will also require QC. Sputum smear microscopy reaches 86% of the expected target, and bottlenecks occur only in more remote cities. Culture coverage, however, is insufficient (Chart 2): the number of tests does not reach that expected for situations in which culture and DST are recommended.(5,8) The laboratories do not establish quotas, and all cultures and DST requested by patient care professionals are performed. Therefore, for now, it is not a matter of supply but of reduced demand for tests by physicians and nurses, who do not believe in the ability and promptness of the laboratories. This credibility depends on the ability of the laboratories to meet the demand and report results promptly. Decentralization of culture to the network of municipal laboratories might be a solution that will make it possible to streamline the reporting of results and expand the installed capacity if there is an increase in the demand for culture in the country, which is in accordance with the recent recommendations by the PNCT.(5) There is a consensus among the various sectors of the Brazilian NMH that the J Bras Pneumol. 2012;38(6):766-770

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Chart 1 - Tests performed by the Central Public Health Laboratories, classified by state, 2009.

Sputum smear Drug susceptibility Identification Identification State Culture Incidencea microscopy testing of NTM of MTB Acre 7,941 252 34 3 34 322 Amazonas 1,511 1,246 78 8 70 2,254 Amapá 342 300 5 1 21 218 Roraima 1,200 1,110 72 2 7 132 Rondônia 1,555 625 53 23 132 566 Pará 2,185 1,208 87 2 87 3,539 Tocantins 118 70 0 0 0 196 Maranhão 2,136 Ceará 6,604 6,805 978 58 606 3,837 Piauí 830 Bahia 1,225 1,673 629 129 1,090 5,740 Rio Grande do Norte 45 978 Paraíba 1,943 1,943 141 2 139 1,061 Pernambuco 2,014 1,306 289 17 292 4,167 Alagoas 3,285 445 50 34 411 1,176 Sergipe 757 445 42 5 37 565 Mato Grosso 780 780 39 49 66 972 Mato Grosso do Sul 6,119 6,097 181 94 480 883 Distrito Federal 2,367 2,922 131 5 124 286 Goiás 1,926 44 41 91 875 Minas Gerais 1,505 274 56 343 4,239 São Paulo 23,392 28,688 3,209 1,164 4,373 15,783 Espírito Santo 1,849 1,849 186 18 161 1,263 Rio de Janeiro 4,894 4,894 726 105 1,335 11,634 Paraná 1,270 1,517 289 7 289 2,409 Santa Catarina 3,344 3,344 690 23 667 1,641 Rio Grande do Sul 3,666 4,512 409 74 692 5,032 TOTAL 78,361 75,462 8,681 1,920 11,547 72,790 NTM: nontuberculous mycobacteria; and MTB: Mycobacterium tuberculosis. Source: General Coordination of Public Health Laboratories, 2009. aNew cases per federal state of residence.

financial investment needed to meet any increase in demand for culture is low relative to the health care budget in the country.

Another serious weakness that might impact the incorporation of technologies is the staff of human resources. Although the professionals working at the LACENs are regularly trained and have a good technical level, the vast majority is close to retirement age, which requires training programs for urgent staff replacement. In order to overcome this and other weaknesses of the laboratory network, a technical group, composed of managers of the PCT and the LACENs, should develop a strategic plan on the basis of a careful analysis of the network, including assessment of needs in terms of infrastructure, biosafety, and human resources, as well as of the number of tests performed, definition of targets for each laboratory, and establishment of algorithms and J Bras Pneumol. 2012;38(6):766-770

needs in the case of the incorporation of new technologies. In the case of the adoption of the Xpert® MTB/RIF assay, for example, it is necessary that the electricity supply be stable, the materials be stored in refrigerated space, and the logistics involved in the purchase and distribution of the materials be refined, given that the cartridges are imported and have a 12-month expiry period.

(9,10) Likewise, the PNCT could establish, at the federal level, a permanent group to foster links with the state network and develop a plan for network coordination, clearly establishing the duties of the CGLAB, the LRN, and the PNCT, which currently overlap.

One of the major bottlenecks in the SISLAB, however, is not found at the laboratory benches.

The information system is weak. The various component sectors of the program have difficulty in obtaining information. Case reporting forms

Bottlenecks and recommendations for the incorporation of new technologies in the tuberculosis laboratory network in Brazil

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Chart 2 - Composition of the laboratory network operating under the direction of the Central Public Health Laboratory of each state and proportion of laboratories for which the Central Public Health Laboratory conducted supervision and external quality control in 2009.

Laboratories with Laboratories Laboratories Laboratories Supervised external QC of sputum performing State performing performing laboratories smear microscopy sputum smear culture DST microscopy n (%) n (%) Acre 38 3 1 12 (32) 26 (68) Amazonas 58 7 2 0 (0) 58 (100) Amapá 17 1 1 8 (47) 4 (23) Roraima 51 2 1 26 (51) 48 (100) Rondônia 27 2 0 1 (4) 4 (15) Pará 261 7 2 77 (29) 146 (56) Tocantins 89 1 0 29 (33) 59 (66) Maranhão 197 1 1 18 (9) 32 (16) Ceará 147 5 2 107 (73) 122 (83) Piauí 1 1 Bahia 345 20 2 56 (16) 94 (27) Rio Grande do Norte 99 1 1 70 (87) 48 (61) Paraíba 198 1 1 28 (14) 49 (25) Pernambuco 126 2 1 25 (20) 66 (54) Alagoas 80 1 1 9 (11) 15 (19) Sergipe 92 1 1 16 (17 20 (22) Mato Grosso 133 1 1 34 (26) 87 (65) Mato Grosso do Sul 68 3 1 0 (0) 56 (82) Distrito Federal 16 1 1 8 (50) 12 (75) 23 (35) 42 (64) Goiás 66 1 1 Minas Gerais 597 15 1 49 (8) 51 (9) São Paulo 214 70 5 92 (43) 50 (23) Espírito Santo 80 6 2 68 (85) 59 (74) Rio de Janeiro 220 26 6 60 (27) 60 (27) Paraná 263 29 1 1 (0) 88 (33) Santa Catarina 394 5 1 8 (2) 200 (51) Rio Grande do Sul 290 14 1 51 (18) 113 (39) TOTAL 3,969 221 35 876 (22) 1,609 (40) DST: drug susceptibility testing; and QC: quality control. Source: General Coordination of Public Health Laboratories, 2009.

are completed and updated with a delay. More importantly, the information flow is inadequate at the bottom. Collection of samples from the health care facilities depends on a regular transportation service, which causes delays in the delivery of test results to the requesting facility and, consequently, in treatment. In order to overcome this bottleneck, the Brazilian NMH has developed a computerized system called Gerenciamento de Ambiente Laboratorial (GAL, Laboratory Environmental Management). For local managers, GAL represents the possibility of real-time identification of cases by health care facility’s coverage region and the consequent

referral control of such cases. For patient care professionals, GAL enables early case detection.

The major obstacles to the implementation of GAL have been the team responsible for its implementation, which is considered too small for the size of the country, and the lack of Internet access. Two years after GAL began to be implemented, it is still not used by 5 LACENs and it has been implemented in the whole network by only 5 LACENs. This system will only be universal if there is a significant investment in the recruitment of a team of multipliers to cover the entire Brazilian territory. Access of health care facilities to GAL will require, in addition to training, investment in Internet access. The J Bras Pneumol. 2012;38(6):766-770

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implementation of this computerized system should include the creation of a national identification number for health care purposes that would allow the correlation of all health-related information about a citizen.

In conclusion, organizing and strengthening the Brazilian national laboratory network is a key step for tuberculosis control. The incorporation of new technologies will be effective only if other technological advances, such as GAL and Internet access for health care facilities, are incorporated and the logistics of the laboratory network is reviewed. While there is not a firm political decision, on the part of the Brazilian NMH, for effective implementation of GAL, the problem of rapid diagnosis of tuberculosis will remain unresolved. This is a bottleneck that will jeopardize the success of any new technology that may be adopted. Soft technologies, such as the training of health professionals working in laboratories or in patient care, should be incorporated simultaneously. In addition, new technologies also required supervision and QC, which means investment in human and financial resources and strengthening of the LACENs. Finally, if the new technologies are proven to be accurate and feasible, the classic tests should be maintained, for the purpose of treatment control and confirmation of drug resistance. It should also be borne in mind that better and earlier detection of drug-resistant tuberculosis will result in an increased demand on referral centers, which should be prepared to accommodate the patient.

The gearing should work as a whole, and, to that end, the integration between clinical practice and laboratories, as well as between managers and professionals, must improve at the federal, state, and municipal levels.

The present article was written as part of the activities of the project known as “Innovations in Tuberculosis Control”. The authors alone are responsible for the views expressed in the present article.

References 1. World Health Organization. Policy Framework for Implementing New Tuberculosis Diagnostics. Geneva: WHO; 2010.

2. Migliori GB, Matteelli A, Cirillo D, Pai M. Diagnosis of multidrug-resistant tuberculosis and extensively drugresistant tuberculosis: Current standards and challenges.

Can J Infect Dis Med Microbiol. 2008;19(2):169-72.

PMid:19352448. PMCid:2605858.

3. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2012 Jul 2]. Clipping SVS-27 de março de 2012. [Adobe Acrobat document, 9p.]

Available from: http://portal.saude.gov.br/portal/arquivos/ pdf/27032012.pdf 4. Stop TB Partnership (World Health Organization), Global Fund to Fight AIDS, Tuberculosis, and Malaria, and World Health Organization. Priorities in Operational Research to Improve Tuberculosis Care and Control.

Geneva: World Health Organization; 2011.

5. Ministério da Saúde. Secretaria de Vigilância em Saúde.

Programa Nacional de Controle da Tuberculose. Manual de Recomendações para o Controle da Tuberculose no Brasil. Brasília: Ministério da Saúde; 2010.

6. Conde MB, Melo FA, Marques AM, Cardoso NC, Pinheiro VG, Dalcin Pde T, et al. III Brazilian Thoracic Association Guidelines on tuberculosis. J Bras Pneumol. 2009;35(10):1018-48. PMid:19918635.

7. Fundação Oswaldo Cruz - Fiocruz [homepage on the Internet]. Rio de Janeiro: Fundação Oswaldo Cruz [cited 2012 Jul 2]. Portaria GM/MS no 2031, de 23 de setembro de 2004. [Adobe Acrobat document, 6p.].

Available from: http://www.castelo.fiocruz.br/vpplr/ laboratorio_referencia/portarias/PORTARIA_2031.pdf 8. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde. Brasília: Ministério da Saúde [cited 2012 May 10]. Situação da Tuberculose no Brasil.

[Adobe Acrobat document, 34p.]. Available from: http:// portal.saude.gov.br/portal/arquivos/pdf/apresentacao_ dia_mundial_tb_26_03_12.pdf 9. World Health Organization [homepage on the Internet].

Geneva: World Health Organization [cited 2012 Jul 2]. WHO policy statement: Automated realtime nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF. [Adobe Acrobat document, 36p.]. Available from: http://whqlibdoc. who.int/publications/2011/9789241501545_eng.pdf 10. World Health Organization [homepage on the Internet]. Geneva: World Health Organization [cited 2012 Jul 2]. Rapid implementation of the Xpert MTB/RIF diagnostic test: technical and operational “How-to”; practical considerations. [Adobe Acrobat document, 36p.]. Available from: http://whqlibdoc. who.int/publications/2011/9789241501569_eng.pdf

About the authors Maria Alice da Silva Telles

Senior Researcher. Adolfo Lutz Institute, São Paulo, Brazil.

Alexandre Menezes

Vice President. Global Health Strategies, Rio de Janeiro, Brazil.

Anete Trajman

Coordinator. Professional Master’s Program in Health Education, Gama Filho University, Rio de Janeiro, Brazil.

J Bras Pneumol. 2012;38(6):766-770

Brief Communication Temporal trends in tuberculosis-related morbidity and mortality in the state of Santa Catarina, Brazil, between 2002 and 2009* Tendência temporal da morbidade e mortalidade por tuberculose no estado de Santa Catarina, Brasil, no período entre 2002 e 2009

Jefferson Traebert, Glênio César Nunes Ferrer, Nazaré Otília Nazário, Ione Jayce Ceola Schneider, Rosemeri Maurici da Silva

Abstract The objective of this study was to describe temporal trends in tuberculosis morbidity and mortality in the state of Santa Catarina, Brazil, between 2002 and 2009. Data regarding mortality and incidence were obtained from the Brazilian Mortality Database and National Case Registry Database, respectively. Crude rates were calculated and standardized by age using the direct method. We estimated annual variation by joinpoint regression, identifying the points at which there were changes in the trends. There was a significant (3.7%) annual decrease in the mortality rate. In the study period, two distinct temporal trends were identified: one between 2002 and 2007, showing a significant (5.9%) annual decrease in the mortality rate; and one between 2007 and 2009, showing an insignificant (2.0%) annual increase. There was also a significant (0.9%) annual reduction in tuberculosis incidence.

Keywords: Tuberculosis/epidemiology; Tuberculosis/mortality; Brazil.

Resumo O objetivo deste estudo foi descrever a tendência temporal da morbidade e mortalidade por tuberculose no estado de Santa Catarina no período entre 2002 e 2009. Os dados de mortalidade e incidência foram obtidos, respectivamente, do Sistema de Informação de Mortalidade e do Sistema Nacional de Informação de Agravos de Notificação. As taxas brutas foram calculadas e padronizadas por idade pelo método direto. Estimou-se a variação anual por intermédio de regressão linear segmentada e identificaram-se pontos em que houve modificação da tendência. Observou-se uma redução significativa na taxa de mortalidade de 3,7% ao ano. No período estudado, houve duas tendências distintas: a primeira, entre 2002 e 2007, com redução significativa na taxa de mortalidade de 5,9% ao ano; a segunda, com incremento não significativo dessa taxa de 2,0% ao ano entre 2007 e 2009. Em relação à incidência, observou-se uma redução significativa de 0,9% ao ano.

Descritores: Tuberculose/epidemiologia; Tuberculose/mortalidade; Tuberculose/estatística e dados numéricos.

Tuberculosis remains one of the most significant causes of mortality in developing countries, notably in male patients and in the 45-59 age group, which makes Koch’s bacillus the single leading agent of death among infectious diseases.(1) Despite being an ancient disease and having been vulnerable to drug treatment for more than half a century, tuberculosis remains one of the major adverse health events worldwide.(2) A recently published study(3) reported that the incidence of tuberculosis worldwide, in the

Americas, and in Brazil decreased by 11.4%, 50.0%, and 48.8%, respectively, in a 20-year historical time series. whereas the mortality rates decreased by 40.0%, 70.7%, and 70.8%, respectively.

Specifically, in Brazil, the incidence rate of tuberculosis has shown a decline of 26% since 1990, with a mean of 1.4% per year. In 2009, there were 71,700 new cases of the disease and the incidence rate was 37/100,000 population. The highest incidence rates are in the states of Rio de

* Study carried out at the University of Southern Santa Catarina, Tubarão, Brazil.

Correspondence to: Jefferson Traebert. Programa de Pós-Graduação em Ciências da Saúde, Avenida José Acácio Moreira, 787, CEP 88704-900, Tubarão, SC, Brasil.

Tel/fax: 55 48 3621-3363. Email: jefferson.traebert@unisul.br Financial support: None.

Submitted: 21 July 2012. Accepted, after review: 24 September 2012.

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Traebert J, Ferrer GCN, Nazário NO, Schneider IJC, Silva RM

Janeiro, Amazonas, and Pará. The lowest rates are reported in the Federal District of Brasília and in the states of Goiás and Tocantins. The mortality rate from tuberculosis in Brazil had a 16.7% reduction between 2002 and 2008, decreasing from 3 to 2.5 deaths/100,000 population.(4) The objective of the present study was to analyze temporal trends in tuberculosis incidence and mortality in the state of Santa Catarina, Brazil, between 2002 and 2009. Data regarding mortality and incidence were obtained from the Brazilian National Ministry of Health Mortality Database and National Case Registry Database, respectively. All tuberculosis-related deaths and reported tuberculosis cases occurring between 2001 and 2010 in residents of the state of Santa Catarina were selected. For the purpose of smoothing the time series of point-to-point fluctuations caused by the small number of cases in specific strata, the moving average was calculated on the basis of three terms. In this process, the smoothed annual coefficient corresponded to the arithmetic average of the previous, current, and following years’ coefficients. This resulted in the data presentation from years 2002 to 2009.

The databases used the tenth revision of the International Classification of Diseases in the recording of occurrences. The census and intercensus estimates of the resident population of the state by age, which are used as denominators to calculate mortality rates, were obtained from the Information Technology Department of the Unified Health Care System of the Brazilian National Ministry of Health.

Initially, crude incidence and mortality rates, which are expressed per 100,000 population, were calculated by the ratio between the number of reported cases or deaths and the estimated population on July 1 of each year in the series.

Subsequently, the crude rates were standardized by age using the direct method, with the population of Santa Catarina in 2010 being used as the standard.

The obtained rates were used in the analysis of the temporal trends estimated by regression models. For the purpose of model formation, the standardized rates were considered the dependent variable (y), whereas the years of the study period were considered the independent variable (x).

The Joinpoint Regression Program, version 3.5.1 (Statistical Research and Applications Branch, National Cancer Institute, Rockville, MD, USA), J Bras Pneumol. 2012;38(6):771-775

was used to calculate annual change in mortality and in the number of reported cases between 2002 and 2009. This program uses joinpoint regression analysis to estimate annual percent change and to identify the points at which there are changes in the trends. We tested successively adjusted models, in which we assumed a different number of “points” of trend change, ranging from zero (a case in which the trend is represented by a single line segment) to a maximum of two, because of the quantity of observations. The model chosen was the one that had the largest number of points and that maintained statistical significance (p < 0.05). On the basis of the estimated slope of each line segment (regression coefficient), we calculated annual percent change and assessed its statistical significance, which was estimated by the generalized linear least squares method, assuming that the rates follow a Poisson distribution and that rate change is not constant over the period. We calculated the upper and lower limits of the 95% CI for the estimated slope of each line segment.

The present study was conducted in accordance with Brazilian National Health Council Resolution 196/96, which outlines the ethical principles for human research in the country. However, all data used were obtained from official public domain health information systems, in which there is no identification of individuals, and therefore there could be no ethical principle violations.

In the study period, there was a significant 3.7% annual decrease in the mortality rate in the state of Santa Catarina (95% CI: −6.6 to −0.7). However, as can be seen in Figure 1 and in Table 1, two distinct temporal trends were identified: one between 2002 and 2007, showing a significant 5.9% annual decrease in the mortality rate (95% CI: −8.9 to −2.8); and one between 2007 and 2009, showing an insignificant 2.0% annual increase (95% CI −12.6 to 19.2). There was also a significant 0.9% annual reduction in tuberculosis incidence (95% CI: −1.5 to −0.3).

The fall in tuberculosis mortality is a global trend. According to the World Health Organization, the absolute number of cases has decreased since 2006 and the incidence of the disease has decreased since 2002. Likewise, there was an 8.6% annual decrease in mortality between 1990 and 2010.(5) This trend has also been reported in Brazil.(6-8) Between 1980 and 2004, there was an irregular decrease in the mortality rate from

Temporal trends in tuberculosis-related morbidity and mortality in the state of Santa Catarina, Brazil, between 2002 and 2009

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Table 1 - Observed and fitted tuberculosis mortality and morbidity/incidence rates per 100,000 population, as well as annual percent change. Santa Catarina, 2002-2009.

Mortality Morbidity/incidence Year Observed Fitted APC (95% CI) Observed Fitted APC (95% CI) 2002 1.28 1.31 −5.9 (−8.9 to −2.8) 35.34 35.66 −0.9 (−1.5 to −0.3) 2003 1.25 1.24 36.09 35.34 2004 1.19 1.16 35.31 35.02 2005 1.13 1.10 34.53 34.71 2006 1.00 1.03 33.55 34.39 2007 0.97 0.97 33.75 34.09 2007 0.97 0.97 2.0 (−12.6 to 19.2) 2008 0.97 0.99 33.83 33.78 2009 1.02 1.01 34.03 33.48 APC: Annual percent change.

Figure 1 - Trends in tuberculosis mortality (in A) and morbidity/incidence (in B) rates (per 100,000 population).

Santa Catarina, 2002-2009. APC: annual percent change. *p < 0.05.

tuberculosis, which ranged from 5.8/100,000 population in 1980 to 2.8/100,000 population in 2004. In 2004, 4,981 deaths where tuberculosis

was the underlying cause of death were reported in Brazil. However, this value would increase by 50% if deaths where tuberculosis was an associated J Bras Pneumol. 2012;38(6):771-775

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cause of death, as well as deaths where sequelae of tuberculosis were the underlying cause of death, were included. In that same year, the highest standardized rates were found in the states of Pernambuco (5.4/100,000 population) and Rio de Janeiro (5.0/100,000 population), as well as in the capital cities of the states of Pernambuco (namely, Recife; 7.7/100,000 population) and Pará (namely, Belém; 5.8/100,000 population).

The AIDS epidemics has an indirect effect on the trends in tuberculosis mortality in Brazil.(8) One of the factors that might have positively affected incidence and mortality was the implementation of the directly observed treatment strategy in Brazil in 1999, which, by 2007, had resulted in a 32% decline in mortality.(1,9) The directly observed treatment strategy produces a 1% annual increase in the cure rate and drastically reduces treatment dropout, which is directly related to worse disease outcomes.(10,11) Likewise, investments in health might have had a highly positive effect on the epidemiological situation of infectious diseases. Of the 22 countries with the highest prevalence of tuberculosis, 5 (Brazil, Russia, India, China, and South Africa) collectively invested 2.1 billion dollars in tuberculosis control in 2010, 95% of which was from domestic sources. Tuberculosis indicators were markedly better in the countries with higher expenditures, such as Brazil.(5) The decline in tuberculosis morbidity and mortality could also be attributed to free, universal access to treatment, as well as to the growth of the network of primary health care facilities. However, resistance to first-line drugs is an emerging problem worldwide, although it still occurs infrequently in Brazil, which might have contributed to the favorable rates reported here.(5,9) Despite the low prevalence of multidrugresistant tuberculosis in Brazil, according to global indicators, the results for the 2007-2009 period, which showed a slight, insignificant increase, could be related to the increase in primary isoniazid resistance (from 4.4% to 6.0%) and in primary isoniazid and rifampin resistance (from 1.1% to 1.4%). Given these increases, the Brazilian National Tuberculosis Control Program introduced ethambutol in the intensive treatment phase of the basic regimen in 2009, which can contribute to keeping the rates within the ranges described here.(9,11) J Bras Pneumol. 2012;38(6):771-775

Therefore, factors related to health care facilities, whether in terms of improved access or quality of care, might have had a significant influence on the tuberculosis indicators in the study period. Interventions aimed at early diagnosis and appropriate treatment could have an extremely positive impact on tuberculosis incidence and mortality rates, especially if they are universal in scope and egalitarian in concept, with special attention being given to the lower classes.

It must be emphasized that the results of this descriptive study should be interpreted with caution, because the study design does not allow a cause and effect relationship to be established, but rather describes morbidity and mortality during a limited observation period.

In the light of the findings of the present study, we can conclude that, in the state of Santa Catarina, there was a significant 3.7% annual decrease in the mortality rate from tuberculosis, with two distinct temporal trends being identified.

There was also a significant 0.9% annual decrease in the number of reported cases.

References 1. Conde MB, Melo FA, Marques AM, Cardoso NC, Pinheiro VG, Dalcin Pde T, et al. III Brazilian Thoracic Association Guidelines on tuberculosis. J Bras Pneumol. 2009;35(10):1018-48. PMid:19918635.

2. Barreira D, Grangeiro A. Evaluation of tuberculosis control strategies in Brazil. Foreword [Article in Portuguese]. Rev Saude Publica. 2007;41 Suppl 1:4-8. PMid:18038085. http://dx.doi.org/10.1590/S0034-89102007000800002 3. Guimarães RM, Lobo AD, Siqueira EA, Borges TF, Melo SC. Tuberculosis, HIV, and poverty: temporal trends in Brazil, the Americas, and worldwide. J Bras Pneumol. 2012;38(4):511-7. PMid:22964936. http:// dx.doi.org/10.1590/S1806-37132012000400014 4. Hijjar MA. Tuberculose: desafio permanente. Cad Saúde Pública. 2005;21(2):348-9. http://dx.doi.org/10.1590/ S0102-311X2005000200001 5. World Health Organization. Global Tuberculosis Control: WHO report 2011. Geneva: World Health Organization; 2011.

6. Espíndola LC. Estudo da mortalidade por tuberculose em Campo Grande – MS, 2001 a 2008 [dissertation].

Campo Grande: Escola Nacional de Saúde Pública Sérgio Arouca; 2010.

7. Hino P, da Costa-Júnior ML, Sassaki CM, Oliveira MF, Villa TC, dos Santos CB. Time series of tuberculosis mortality in Brazil (1980-2001). Rev Lat Am Enfermagem. 2007;15(5):936-41. PMid:18157445. http://dx.doi.org/10.1590/S0104-11692007000500009 8. Bierrenbach AL, Duarte EC, Gomes AB, Souza Mde F. Mortality trends due to tuberculosis in Brazil, 1980-2004 [Article in Portuguese]. Rev Saude Publica. 2007;41 Suppl 1:15-23. PMid:18038087. http://dx.doi.org/10.1590/ S0034-89102007000800004

Temporal trends in tuberculosis-related morbidity and mortality in the state of Santa Catarina, Brazil, between 2002 and 2009

9. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica.

Programa Nacional de Controle da Tuberculose. Manual de recomendações para o controle da tuberculose no Brasil. Brasília: Ministério da Saúde; 2010.

10. Nogueira JA, Ruffino-Netto A, Villa TCS, Monroe AA, Lucca MES. Implantação da estratégia DOTS no controle

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da tuberculose em Ribeirão Preto, São Paulo (1998‑2004).

Bol Pneumol Sanit. 2006;14(3):141-4.

11. Domingos MP, Caiaffa WT, Colosimo EA. Mortality, TB/ HIV co-infection, and treatment dropout: predictors of tuberculosis prognosis in Recife, Pernambuco State, Brazil.

Cad Saude Publica. 2008;24(4):887-96. PMid:18392367. http://dx.doi.org/10.1590/S0102-311X2008000400020

About the authors Jefferson Traebert

Professor. Graduate Program in Health Sciences, University of Southern Santa Catarina, Tubarão, Brazil.

Glênio César Nunes Ferrer

Master’s Student. Graduate Program in Health Sciences, University of Southern Santa Catarina, Tubarão, Brazil.

Nazaré Otília Nazário

Professor of Medicine. University of Southern Santa Catarina, Palhoça, Brazil.

Ione Jayce Ceola Schneider

Professor of Medicine. University of Southern Santa Catarina, Palhoça, Brazil.

Rosemeri Maurici da Silva

Professor. Graduate Program in Health Sciences, University of Southern Santa Catarina, Tubarão, Brazil.

J Bras Pneumol. 2012;38(6):771-775

Review Article Ex vivo lung reconditioning: a new era for lung transplantation* Recondicionamento pulmonar ex vivo: uma nova era para o transplante pulmonar

Alessandro Wasum Mariani, Paulo Manuel Pêgo-Fernandes, Luis Gustavo Abdalla, Fabio Biscegli Jatene

Abstract Lung transplantation has come to be viewed as the best treatment option for various end-stage lung diseases.

The low number of viable donors continues to be a major obstacle to increasing the number of lung transplants, resulting in high mortality among patients on the waiting list. Unlike transplantation of other solid organs, lung transplantation is primarily limited not by the absolute number of donors but by the viability of the donor lungs, which can be damaged by brain death and by treatments given in the ICU. There are various proposals of ways to increase the number of lung donors: intensification of donation campaigns, use of non-heart-beating donors, living lobar lung transplantation, and adoption of more flexible criteria for donors. However, the proposal that has attracted the most attention from lung transplant groups is ex vivo lung perfusion, especially due to the prospect of reconditioning previously discarded lungs. This system consists of perfusion and ventilation of the isolated heart-lung block using a modified cardiopulmonary bypass circuit. Various authors have been studying this technique due to the satisfactory results obtained and the prospect of an increase in the number of organs suitable for transplantation. Researchers in Sweden, Canada, Austria, England, Spain, and Brazil have extensive experience with the method and have introduced modifications to it. The objective of this article was to review the development of, state of the art in, and future prospects for the ex vivo model of lung perfusion and reconditioning.

Keywords: Lung transplantation; Transplantation conditioning; Perfusion; Organ preservation.

Resumo O transplante pulmonar consolidou-se como a melhor opção terapêutica para diversas pneumopatias terminais.

O baixo número de doadores viáveis ainda persiste como uma grande limitação ao aumento do número de transplantes de pulmão, causando alta mortalidade na lista de espera. Diferentemente do transplante de outros órgãos sólidos, a maior limitação do transplante pulmonar não é o número absoluto de doadores e sim a viabilidade desses órgãos, que é reduzida devido às agressões ao pulmão ocasionadas pela morte encefálica e aos cuidados na UTI. Diversas são as propostas para o aumento do número de doadores: intensificação das campanhas de doação, o uso de doadores com coração parado, transplante pulmonar lobar intervivos e maior flexibilidade dos critérios para aceitação de doadores de pulmão. Todavia, a proposta que atrai a atenção de diversos grupos de transplante pulmonar é a perfusão pulmonar ex vivo, principalmente pela perspectiva de recuperação de pulmões inicialmente descartados. Esse sistema consiste na reperfusão e ventilação do bloco pulmonar isolado em um circuito de circulação extracorpórea modificado. Devido aos bons resultados apresentados e à perspectiva de aumento no número de órgãos aptos a transplante, diversos grupos têm estudado a técnica.

Pesquisadores na Suécia, Canadá, Áustria, Inglaterra, Espanha e Brasil já possuem experiência sólida com o método e introduziram algumas variações. O objetivo deste artigo foi revisar o desenvolvimento, o estado da arte e as perspectivas futuras do modelo ex vivo de perfusão e recondicionamento pulmonar.

Descritores: Transplante de pulmão; Condicionamento pré-transplante; Perfusão; Preservação de órgãos.

* 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: Paulo Manuel Pêgo Fernandes. Avenida Dr. Enéas de Carvalho Aguiar, 44, 2º andar, bloco II, sala 9, Cerqueira César, CEP 05403-900, São Paulo, SP, Brasil.

Tel. 55 11 2661-5248. E-mail: paulo.fernandes@incor.usp.br Financial support: None.

Submitted: 31 January 2012. Accepted, after review: 13 September 2012.

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Ex vivo lung reconditioning: a new era for lung transplantation

Introduction Lung transplantation has come to be viewed as the best treatment option for various end-stage lung diseases. This heterogeneous group comprises diseases that are highly disabling and that have high mortality rates, despite considerable advances in the pharmacological treatment options that are currently available.

The low number of viable donors is currently the major obstacle to increasing the number of lung transplants, resulting in a long waiting time for transplantation and high mortality among lung transplant candidates on waiting lists.(1) Unlike transplantation of other solid organs, such as the liver and the kidneys, lung transplantation is primarily limited not by the absolute number of donors but by the viability of the donor lungs. Factors that can damage the donor lung and therefore make it unsuitable for transplantation include those related to brain death (including bronchial aspiration, pulmonary edema, and chest trauma) and those related to ICU treatment (including hypervolemia, barotrauma, and ventilator-associated pneumonia). The reported rates of donor lung use are low, i.e., approximately 15% (6.1-27.1%).(2) In Brazil, these rates are even lower. A study conducted in 2006 and analyzing data from the São Paulo State Department of Health Transplant Center showed that only 4.9% of all donor lungs were effectively transplanted.(3) There have been various proposals of ways to increase the number of actual lung donors, including intensification of donation campaigns, living donor transplantation,(4) use of non-heartbeating donors,(5) and adoption of donor criteria that are more flexible.(6) However, the proposal that has attracted the most attention from lung transplant groups is ex vivo lung perfusion (EVLP), especially due to the prospect of reconditioning previously discarded lungs.

The objective of the present article was to review the development of, state of the art in, and future prospects for the ex vivo model of lung perfusion and reconditioning.

Development of the EVLP system The EVLP system began to be developed in the late 1990s, when a group of researchers at Lund University, in Lund, Sweden, began to study non-heart-beating donor lungs with the objective

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of increasing the number of organs suitable for transplantation.(7) Steen et al. proposed a circuit that allowed an objective assessment of lung function in those patients.

Lung perfusion in mechanical circuits is not a new concept, being widely used in studies of pulmonary physiology in small- and mediumsized animals.(8,9) However, one major technical limitation to ex vivo perfusion of human lungs was the impossibility of maintaining the integrity of the alveolar-capillary membrane, leading to increased vascular resistance and edema formation, which inevitably led to loss of lung function.(7) By studying pigs, that group of researchers developed a perfusion solution that prevented edema formation and loss of lung function. The solution was designated Steen Solution® (Vitrolife; Gothenburg, Sweden). The Steen Solution is an extracellular solution for lung preservation, being composed of electrolytes, dextran, and albumin. A noteworthy feature of the solution is its high oncotic pressure.(10) The first clinical use of EVLP was for the evaluation of the lungs from a non-heart-beating donor. The results of the ex vivo evaluation were satisfactory, the lungs being therefore transplanted into the recipient, who had been on the Lund University waiting list.(11) The donor was a 54-year-old man who had suffered cardiac arrest due to acute myocardial infarction. The transplantation was successful, the recipient being a patient with pulmonary emphysema.

The EVLP system originally described by Steen et al. consists of a rigid, transparent rectangular box (Figure 1) to support the heart-lung block (with inlets for connecting the cardiopulmonary bypass circuit tubes), a centrifugal pump, a heat exchanger, and a membrane oxygenator, as well as a pressure transducer, a flow meter, and a thermometer (and their respective monitors) for EVLP monitoring.

The perfusate consists of 1,500 mL of Steen Solution and a variable amount of packed red blood cells, the hematocrit level of the perfusate being approximately 15%. A gas mixture (of nitrogen, oxygen, and carbon dioxide) is used in order to “deoxygenate” the perfusate through the gas exchange membrane, gas flow being adjusted so that the gas concentration in the perfusate is similar to that in the venous blood. According to the Lund University EVLP protocol, flow and temperature should be gradually increased.

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Figure 1 - Ex vivo lung perfusion model used by the lung transplant group at Lund University, Lund, Sweden. In A, empty containment box. In B, a lung being perfused and ventilated inside the containment box. Note the perfusion cannula (arrow 1) and the ventilation tube (arrow 2).

Ventilation is initiated when the temperature reaches 32°C, and the maximum flow should never exceed values that will cause pulmonary artery pressure to be greater than 20 mmHg. The most important evaluation is blood gas analysis of the perfusate collected from the pulmonary veins when the temperature reaches 37°C.(11) After having established the EVLP model, Steen et al. hypothesized that it had uses other than the evaluation of non-heart-beating donor lungs. On the basis of the hypothesis that many of the lungs deemed unsuitable for transplantation could be used if additional evaluation guaranteed their viability, the authors proposed the use of EVLP for evaluating “marginal donors”. In a study published in 2006, that group of authors evaluated six initially rejected donor lungs and found that EVLP increased the oxygenation capacity of the lungs.(12) In another study, also published in 2006, one group of researchers at the University of North Carolina at Chapel Hill, in Chapel Hill, NC, obtained satisfactory results using a similar methodology.(13) However, during the evaluation of those marginal donor lungs, the major finding was that EVLP apparently “improved” lung function. This was attributed to the following characteristics of the EVLP system: • The EVLP system allows the use of alveolar recruitment maneuvers.

• The EVLP system allows more effective clearance of bronchial secretions.

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• The EVLP system allows the removal of clots in the pulmonary circulation.

• The high oncotic pressure of the perfusate reduces pulmonary edema.

• The EVLP system allows the removal of inflammatory cells, dextran reducing the degree of lung inflammation and improving the microvasculature.

This gave rise to what is currently known as ex vivo lung reconditioning, whereby donor lungs initially deemed unsuitable for transplantation can be “reconditioned” by EVLP.(12) In 2005, after the good results of the experimental studies in pigs, the Lund University lung transplant group performed the first transplantation of an initially rejected lung submitted to ex vivo lung reconditioning.(14) The donor lung had been considered unsuitable for transplantation because of bilateral lung contusion (as seen on chest X-ray) and low pre-harvesting PaO2 (as revealed by arterial blood gas analysis; last measurement, 67 mmHg, with an FiO2 of 0.7).

The researchers then harvested the organ for ex vivo evaluation rather than for transplantation.

The organ underwent EVLP for approximately 1 h, when a new arterial blood gas analysis was performed. The analysis revealed a PaO2 of 391.5 mmHg and an FiO2 of 100%. Macroscopic evaluation revealed an apparently good compliance, despite the presence of hemorrhagic stippling on the lung surface. The organ was then deemed

Ex vivo lung reconditioning: a new era for lung transplantation

suitable for transplantation, and the recipient was summoned.

At the end of EVLP, in order to preserve the organ, the Lund University lung transplant group opted to place the lung on topical extracorporeal membrane oxygenation, which was achieved by reducing the temperature of the perfusate to 25°C and by stopping ventilation and perfusion.

The semi-inflated organ was immersed in the same solution that was used for perfusion, which was oxygenated and kept in recirculation at a controlled temperature of 8°C for approximately 10 h until the arrival of the recipient and the performance of the transplantation. The patient underwent single (left) lung transplantation.

There were no intraoperative or immediate postoperative complications, and there were no late postoperative complications. At postoperative month 11, the patient died from septic shock unrelated to EVLP.

The Canadian EVLP model Encouraged by the good results obtained by the Lund University lung transplant group, the lung transplant group at the University of Toronto, in Toronto, Canada, conducted EVLP studies with the objective of reconditioning previously discarded lungs. A distinguishing characteristic of those studies was the concern

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with prolonging the duration of perfusion. To that end, the Canadian group modified the Swedish EVLP protocol, as follows: • use of an acellular perfusate, the perfusate consisting only of Steen Solution (i.e., no red blood cells) • use of a maximum perfusion flow of approximately 40% of the estimated cardiac output • use of a pulmonary artery pressure of 10-15 mmHg The use of an acellular perfusate facilitates the logistics of EVLP by reducing the costs and preventing ethical conflicts arising from the use of blood products in studies of organs that may or may not be used clinically. The disadvantages of using blood in the perfusate include hemolysis caused by mechanical trauma to red blood cells and the proinflammatory response typically elicited by the transfusion. The modifications were successful in prolonging the duration of EVLP (to up to 12 h).(15) The absence of red blood cells did not affect the assessment of lung function. The degree of oxygen diffusion in the Steen Solution perfusate is high and therefore allows reliable blood gas analysis. The Canadian group also developed a new (round) containment box (Figure 2) and specific cannulae (Figure 3) that allow a better connection of the pulmonary artery and left

Figure 2 - Ex vivo lung perfusion model developed by the lung transplant group at the University of Toronto, Toronto, Canada. In A, empty containment box. Note the inlets for perfusion cannulae (arrow 1) and for the ventilation tube (arrow 2). Note also the accessory cannula for venous return (arrow 3). In B, a lung being ventilated and perfused inside the containment box. Note the pulmonary artery cannula (arrow 4) and the orotracheal tube (arrow 5).

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Figure 3 - Cannulae for connecting the lung to the ex vivo lung perfusion circuit (Canadian model). In A, cannula for pulmonary venous return. Note lateral outlet for air removal and sample collection (arrow 1).

Note also probes for pressure measurement (arrow 2) and the tip to be attached to the main pulmonary artery (arrow 3). In B, pulmonary artery cannula. Note the silicone cone to be sutured to the edge of the left atrium (arrow 4).

atrial stump (pulmonary venous connection) to the circuit. In addition, the cannulae have built-in pressure catheters. The atrial cannula allows closed perfusion (Figure 4) and the atrial pressure to be maintained at 3-5 mmHg. Although the Swedish EVLP protocol recommends 1 h of normothermic perfusion, the Canadian EVLP protocol recommends at least 4 h of normothermic perfusion with stable parameters for the organ to be considered suitable for transplantation.

Chart 1 shows a comparison between the Lund University EVLP protocol and the University of Toronto EVLP protocol.

The experience in Brazil In Brazil, Pêgo-Fernandes et al. began to study EVLP in 2008. In a study published in the Brazilian Journal of Pulmonology in 2009, the authors described a modification of the EVLP circuit aimed at reducing the amount of solution needed for EVLP.(16) The authors J Bras Pneumol. 2012;38(6):776-785

Figure 4 - Venous cannula being sutured to the atrial cuff (closed venous return), as recommended by the University of Toronto lung transplant group. In A, venous cannula with a silicone cone for suture; in B, right pulmonary vein; in C, left pulmonary vein; and in D, detail of the suture line between the atrial cuff and the venous return cannula.

Ex vivo lung reconditioning: a new era for lung transplantation

described an EVLP system comprising a set of pediatric tubes, a pediatric venous reservoir, and a pediatric membrane oxygenator (Figure 5).

The system also comprised a heat exchanger and a centrifugal pump (Braile Biomédica, São José do Rio Preto, Brazil). The heart-lung block remained in a rigid, transparent box (Vitrolife), an orotracheal tube being inserted into the trachea and a perfusion cannula (Vitrolife) being inserted into the main pulmonary artery. The solution returning through the pulmonary veins flowed directly into the containment box, being drained into the venous reservoir by the force of gravity. For lung reconditioning and clinical use, the protocol included closed cannulation of the atrium with special cannulae, as described by the University of Toronto lung transplant group.(15) The system was filled with 1,500 mL of Steen Solution (Vitrolife). In that protocol, EVLP was initiated with the solution at 20°C and an initial flow of 10% of the calculated value, the

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Figure 5 - Ex vivo lung perfusion system used at the University of São Paulo School of Medicine Hospital das Clínicas Heart Institute, São Paulo, Brazil. In A, centrifugal pump; in B, pediatric membrane oxygenator; in C, pediatric reservoir; and in D, heart-lung block inside the containment box.

Chart 1 - Comparison between the Lund University ex vivo lung perfusion protocol and the University of Toronto ex vivo lung perfusion protocol. CO: cardiac output; PAP: pulmonary artery pressure; and LAP: left atrial pressure.

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temperature and flow being gradually increased.

When the temperature reached 32°C (20 min after EVLP initiation), ventilation was initiated and a gas (7% CO2 + 93% N2) was released into the system through the membrane oxygenator in order to “deoxygenate” the perfusate coming from the pulmonary veins so that the solution that enters the pulmonary artery has the same gas concentrations as those of the venous blood. The ventilator was set at a tidal volume of 6-8 mL/kg, an RR of 7 breaths/min, an FiO2 of 100%, and a positive end-expiratory pressure of 5 cmH2O. The flow and temperature were increased until a flow of 40% of the estimated cardiac output and a temperature of 37°C were reached (i.e., within approximately 40-60 min). If the pulmonary artery pressure was as high as 20 mmHg before the estimated maximum flow was reached, the maximum flow was kept at a lower value. Within 60 min after the initiation of EVLP, perfusate samples were collected from the pulmonary veins for blood gas analysis. The following parameters were analyzed: PaO2; PaCO2; pulmonary vascular resistance; and lung compliance. The first studies conducted by that group of authors focused on establishing an EVLP model suitable for use in Brazil(17) and on reconditioning lungs deemed unsuitable for transplantation.(18,19)

Clinical use The first cases of clinical use of EVLP were published in 2009 and involved the monitoring of six lung transplant recipients who received initially rejected lungs submitted to EVLP. The results showed a three-month survival of 100% and a one-year survival of 67%, the deaths being apparently unrelated to EVLP.(20) In 2010, the University of Toronto lung transplant group published a study of 16 lung transplant recipients who received lungs submitted to ex vivo evaluation and reconditioning; there was no 30-day mortality, and the incidence of primary graft dysfunction was similar to that in lung transplant recipients receiving, in the same period, lungs that had not undergone EVLP.(21) In 2011, that group published another study, in which 23 lungs that had been deemed unsuitable for transplantation underwent ex vivo reconditioning for 4 h. Of the total of organs, 20 remained stable in the EVLP system and were therefore transplanted, with good results.(22) J Bras Pneumol. 2012;38(6):776-785

Other transplant groups have published studies reporting their experience with the clinical use of EVLP. Of those studies, the most recent is a study conducted by an Austrian group and published in 2012. The authors reported that 9 of 13 lungs submitted to ex vivo evaluation showed improvement in PaO2 and were therefore transplanted. According to the authors, the postoperative outcome was similar to that in patients receiving standard lung transplants during the observation period.(23) In England, Zych et al. evaluated 13 heartlung blocks; of those, 6 had good parameters and were therefore transplanted, short-term (three-month) survival being excellent (100%).(24) Moradiellos et al. evaluated 8 non-heartbeating donor lungs submitted to EVLP; of those, 4 showed good lung function and were therefore transplanted. Although two patients died before the end of post-transplantation year 1, the causes of death were unrelated to EVLP.(25)

Experimental studies of EVLP Because EVLP has uses other than clinical use, various groups have used EVLP in experimental studies. Frank et al. used EVLP in order to investigate pathophysiological mechanisms of lung function, including edema formation.(26) Sakuma et al. studied drugs having an effect on lung function and demonstrated the role of endotracheal adrenaline and the use of betaadrenergic stimulation in reducing pulmonary edema.(27) Inci et al. studied the addition of urokinase to the EVLP perfusate and found that it improved lung function and reduced pulmonary vascular resistance.(28) The same group of authors used an EVLP model in order to study the effect of surfactant lavage on lungs injured by gastric acid aspiration.(29) Mariani et al. used human donor lungs deemed unacceptable for transplantation in order to develop a variation of the ex vivo model of lung evaluation. The technique consisted of separating the lung block into right and left blocks and subsequently reconnecting those two blocks, being designated the split lung block technique.(30)

Ex vivo animal model A variation of the EVLP model can also be used for experimental studies in small animals, facilitating the logistics of such studies. Several

Ex vivo lung reconditioning: a new era for lung transplantation

questions regarding lung transplantation can be answered that way. Pierre et al. studied rat lungs and demonstrated that slow (i.e., gradual) reperfusion is less harmful than rapid reperfusion.(31) Silva et al. studied rat lungs submitted to EVLP and confirmed that lung preservation techniques disarrange lung architecture and lead to ischemia-reperfusion injury.(32) Pêgo-Fernandes et al. have conducted studies using a system that is marketed under the name IL2 - Isolated Perfused Rat or Guinea Pig Lung System (Harvard Apparatus, Holliston, MA, USA; Hugo Sachs Elektronik, Hugstetten, Germany). This system allows ventilation and perfusion of the heart-lung block, as well as being capable of measuring respiratory mechanics and hemodynamic parameters.(33) There have been studies evaluating the system itself(34) and lung preservation, either by comparing preservation solutions(35,36) or by investigating the effect of additives in the solutions.(37)

Future prospects All lung transplant groups believe that ex vivo lung reconditioning will lead to an increase in the number of lung transplants; nevertheless, studies have proposed new, ingenious uses for EVLP, including the treatment of certain conditions that prevent transplantation, such as pneumonia and acute lung injury.(38) Another prospect is the optimization of donor lung conditioning by reducing inflammatory activity. Some researchers foresee the possibility of using EVLP to “condition” all donor lungs, including those initially deemed suitable for transplantation, in an attempt to improve posttransplant outcomes.(39) The EVLP model including activation of lung metabolism at normothermia seems to be ideal for lung reconditioning and for monitoring the effectiveness of lung reconditioning before transplantation. In addition, side effects are minimized because the drugs used are not systemically absorbed by the recipient. Furthermore, there is the prospect of prolonging EVLP for several days, which would allow prolonged treatment of infected lungs.(40) Studies have investigated anti-inflammatory agents, some of which seem promising: activated protein C(41); alpha-1 antitrypsin(42); and IL-10.(43) The University of Toronto lung transplant group conducted a study in which gene therapy with

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an adenoviral vector encoding human IL-10 was used during EVLP in order to increase IL-10 levels and therefore produce potent anti-inflammatory activity in the donor lungs.(44)

Final considerations Currently, EVLP represents a promising tool for use in the field of lung transplantation. In addition to having the potential to increase the number of donor lungs that are suitable for transplantation, EVLP can be used in studies aimed at developing new techniques to improve lung conditioning in the immediate pre-transplant period, therefore improving post-transplant outcomes.

Although the clinical use of EVLP is becoming increasingly more common in various countries, long-term studies are needed in order to understand the real impact of EVLP on posttransplant outcomes.

Acknowledgments We would like to thank Dr. Marcos Naoyuki Samano for kindly contributing to the study by helping us with the figures and providing invaluable suggestions.

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Transplant Proc. 2009;41(3):927-31. PMid:19376390. http://dx.doi.org/10.1016/j.transproceed.2009.01.048 2. Punch JD, Hayes DH, LaPorte FB, McBride V, Seely MS. Organ donation and utilization in the United States, 1996-2005.

Am J Transplant. 2007;7(5 Pt 2):1327‑38. PMid:17428283. http://dx.doi.org/10.1111/j.1600-6143.2007.01779.x 3. Fernandes PM, Samano MN, Junqueira JJ, Waisberg DR, Noleto GS, Jatene FB. Lung donor profile in the State of São Paulo, Brazil, in 2006. J Bras Pneumol. 2008;34(7):497‑505. PMid:18695795. http:// dx.doi.org/10.1590/S1806-37132008000700010 4. Camargo SM, Camargo Jde J, Schio SM, Sánchez LB, Felicetti JC, Moreira Jda S, et al. Complications related to lobectomy in living lobar lung transplant donors. J Bras Pneumol. 2008;34(5):256-63. PMid:18545820.

5. Gomez-de-Antonio D, Campo-Cañaveral JL, Crowley S, Valdivia D, Cordoba M, Moradiellos J, et al.

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Ann Thorac Surg. 1997;63(2):345-51. http://dx.doi. org/10.1016/S0003-4975(96)01101-0 8. Wang LS, Yoshikawa K, Miyoshi S, Nakamoto K, Hsieh CM, Yamazaki F, et al. The effect of ischemic time and temperature on lung preservation in a simple ex vivo rabbit model used for functional assessment. J Thorac Cardiovasc Surg. 1989;98(3):333-42. PMid:2770316.

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10. Steen S, Liao Q, Wierup PN, Bolys R, Pierre L, Sjöberg T. Transplantation of lungs from non-heart-beating donors after functional assessment ex vivo. Ann Thorac Surg. 2003;76(1):244-52; discussion 252. http://dx.doi. org/10.1016/S0003-4975(03)00191-7 11. Steen S, Sjöberg T, Pierre L, Liao Q, Eriksson L, Algotsson L. Transplantation of lungs from a non-heart-beating donor. Lancet. 2001;357(9259):825-9. http://dx.doi. org/10.1016/S0140-6736(00)04195-7 12. Wierup P, Haraldsson A, Nilsson F, Pierre L, Scherstén H, Silverborn M, et al. Ex vivo evaluation of nonacceptable donor lungs. Ann Thorac Surg. 2006;81(2):460-6. PMid:16427831. http://dx.doi. org/10.1016/j.athoracsur.2005.08.015 13. Egan TM, Haithcock JA, Nicotra WA, Koukoulis G, Inokawa H, Sevala M, et al. Ex vivo evaluation of human lungs for transplant suitability. Ann Thorac Surg. 2006;81(4):1205-13. PMid:16564244. http:// dx.doi.org/10.1016/j.athoracsur.2005.09.034 14. 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. PMid:17532422. http://dx.doi.org/10.1016/j.athoracsur.2007.01.033 15. Cypel M, Yeung JC, Hirayama S, Rubacha M, Fischer S, Anraku M, et al. Technique for prolonged normothermic ex vivo lung perfusion. J Heart Lung Transplant. 2008;27(12):1319-25. PMid:19059112. http:// dx.doi.org/10.1016/j.healun.2008.09.003 16. Pêgo-Fernandes PM, Medeiros IL, Mariani AW, Fernandes FG, Unterpertinger Fdo V, Samano MN, et al. Ex vivo lung perfusion: initial Brazilian experience. J Bras Pneumol. 2009;35(11):1107-11. PMid:20011846.

17. Pêgo-Fernandes PM, de Medeiros IL, Mariani AW, Fernandes FG, Unterpertinger FD, Samano MN, et al. Ex vivo lung perfusion: early report of Brazilian experience. Transplant Proc. 2010;42(2):440-3. PMid:20304159. http://dx.doi. org/10.1016/j.transproceed.2010.01.015 18. Pêgo-Fernandes PM, Mariani AW, Medeiros IL, Pereira AE, Fernandes FG, Valle Unterpertinger F, et al. Ex vivo lung evaluation and reconditioning. Rev Bras Cir Cardiovasc. 2010;25(4):441-6. PMid:21340372. http:// dx.doi.org/10.1590/S0102-76382010000400006 19. Medeiros IL, Pêgo-Fernandes PM, Mariani AW, Fernandes FG, do Vale Unterpertinger F, Canzian M, et al. Histologic and functional evaluation of lungs reconditioned by ex vivo lung perfusion. J Heart Lung Transplant. 2012;31(3):305-9. PMid:22133788. http:// dx.doi.org/10.1016/j.healun.2011.10.005 20. Ingemansson R, Eyjolfsson A, Mared L, Pierre L, Algotsson L, Ekmehag B, et al. Clinical transplantation of initially

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rejected donor lungs after reconditioning ex vivo. Ann Thorac Surg. 2009;87(1):255-60. PMid:19101308. http:// dx.doi.org/10.1016/j.athoracsur.2008.09.049 21. Cypel M, Yeung JC, de Perrot M, Karolak W, Chen F, Sato M, et al. Ex vivo lung perfusion in clinical lung transplantation – the HELP trial. J Heart Lung Transplant. 2010;29(2S):S88. http://dx.doi.org/10.1016/j. healun.2009.11.270 22. Cypel M, Yeung JC, Liu M, Anraku M, Chen F, Karolak W, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med. 2011;364(15):1431‑40.

PMid:21488765. http://dx.doi.org/10.1056/ NEJMoa1014597 23. Aigner C, Slama A, Hötzenecker K, Scheed A, Urbanek B, Schmid W, et al. Clinical ex vivo lung perfusion--pushing the limits. Am J Transplant. 2012;12(7):1839-47. PMid:22458511. http:// dx.doi.org/10.1111/j.1600-6143.2012.04027.x 24. Zych B, Popov AF, Stavri G, Bashford A, Bahrami T, Amrani M, et al. Early outcomes of bilateral sequential single lung transplantation after ex-vivo lung evaluation and reconditioning. J Heart Lung Transplant. 2012;31(3):274‑81. PMid:22088786. http:// dx.doi.org/10.1016/j.healun.2011.10.008 25. Moradiellos FJ, Naranjo JM, Córdoba C, Salas MC, Gómez D, Campo-Cañaveral JL, et al. Clinical lung transplantation after ex vivo evaluation of uncontrolled non heartbeating donors lungs: initial experience [abstract 90].

J Heart Lung Transplant. 2011;30(Suppl 4):S38. http:// dx.doi.org/10.1016/j.healun.2011.01.097 26. Frank JA, Briot R, Lee JW, Ishizaka A, Uchida T, Matthay MA. Physiological and biochemical markers of alveolar epithelial barrier dysfunction in perfused human lungs.

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PMid:17351061 PMCid:2764531. http://dx.doi.org/10.1152/ ajplung.00256.2006 27. Sakuma T, Gu X, Wang Z, Maeda S, Sugita M, Sagawa M, et al. Stimulation of alveolar epithelial fluid clearance in human lungs by exogenous epinephrine. Crit Care Med. 2006;34(3):676-81. PMid:16505652 PMCid:2765117. http://dx.doi.org/10.1097/01.CCM.0000201403.70636.0F 28. Inci I, Zhai W, Arni S, Inci D, Hillinger S, Lardinois D, et al. Fibrinolytic treatment improves the quality of lungs retrieved from non-heart-beating donors. J Heart Lung Transplant. 2007;26(10):1054-60. PMid:17919627. http://dx.doi.org/10.1016/j.healun.2007.07.033 29. Inci I, Ampollini L, Arni S, Jungraithmayr W, Inci D, Hillinger S, et al. Ex vivo reconditioning of marginal donor lungs injured by acid aspiration. J Heart Lung Transplant. 2008;27(11):1229-36. PMid:18971096. http:// dx.doi.org/10.1016/j.healun.2008.07.027 30. Mariani AW, Medeiros IL, Pêgo-Fernandes PM, Fernandes FG, Unterpertinger Fdo V, Fernandes LM, et al. Ex vivo experimental model: split lung block technique. J Bras Pneumol. 2011;37(6):791-5. PMid:22241037. http:// dx.doi.org/10.1590/S1806-37132011000600013 31. Pierre AF, DeCampos KN, Liu M, Edwards V, Cutz E, Slutsky AS, et al. Rapid reperfusion causes stress failure in ischemic rat lungs. J Thorac Cardiovasc Surg. 1998;116(6):932‑42. http://dx.doi.org/10.1016/S0022-5223(98)70043-1 32. Silva CA, Carvalho RS, Cagido VR, Zin WA, Tavares P, DeCampos KN. Influence of lung mechanical properties and alveolar architecture on the pathogenesis of ischemia-reperfusion injury. Interact Cardiovasc Thorac

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Surg. 2010;11(1):46-51. PMid:20378696. http://dx.doi. org/10.1510/icvts.2009.222018 33. 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. PMid:20304160. http://dx.doi.org/10.1016/j.transproceed.2010.01.016 34. Pêgo-Fernandes PM, Werebe Ede C, Cardoso PF, Pazetti R, Oliveira KA, Soares PR, et al. Experimental model of isolated lung perfusion in rats: technique and application in lung preservation studies. J Bras Pneumol. 2010;36(4):490-3. PMid:20835597. http:// dx.doi.org/10.1590/S1806-37132010000400015 35. Soares PR, Braga KA, Nepomuceno NA, Pazetti R, Correia AT, Cardoso PF, et al. Comparison between Perfadex and locally manufactured low-potassium dextran solution for pulmonary preservation in an ex vivo isolated lung perfusion model. Transplant Proc. 2011;43(1):84-8. PMid:21335161. http://dx.doi. org/10.1016/j.transproceed.2010.12.005 36. Simões EA, Pêgo-Fernandes PM, Cardoso PF, Pazetti R, Werebe E, de Oliveira Braga KA, et al. Comparing the performance of rat lungs preserved for 6 or 12 hours after perfusion with low-potassium dextran or histidine-tryptophan-ketoglutarate.

Transplant Proc. 2011;43(5):1520-4. PMid:21693228. http://dx.doi. org/10.1016/j.transproceed.2010.12.001 37. Cardoso PF, Pazetti R, Moriya HT, Pêgo-Fernandes PM, Almeida FM, Correia AT, et al. An experimental rat model of ex vivo lung perfusion for the assessment of lungs after prostacyclin administration: inhaled versus parenteral routes. J Bras Pneumol. 2011;37(5):589‑97.

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38. Lee JW, Fang X, Gupta N, Serikov V, Matthay MA. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci U S A. 2009;106(38):16357-62. PMid:19721001 PMCid:2735560. http://dx.doi.org/10.1073/ pnas.0907996106 39. Sanchez PG, Bittle GJ, Burdorf L, Pierson RN 3rd, Griffith BP. State of art: clinical ex vivo lung perfusion: rationale, current status, and future directions. J Heart Lung Transplant. 2012;31(4):339-48. PMid:22423980. http://dx.doi.org/10.1016/j.healun.2012.01.866 40. Karamanou DM, Perry J, Walden HR, Simpson AJ, Corris P, Gould K, et al. The effect of ex-vivo perfusion on the microbiological profile of the donor lung [abstract 279].

J Heart Lung Transplant. 2010;29(2):S94. http://dx.doi. org/10.1016/j.healun.2009.11.291 41. Hirayama S, Cypel M, Sato M, Anraku M, Liaw PC, Liu M, et al. Activated protein C in ischemia-reperfusion injury after experimental lung transplantation. J Heart Lung Transplant. 2009;28(11):1180-4. PMid:19782612. http://dx.doi.org/10.1016/j.healun.2009.06.026 42. Nita I, Hollander C, Westin U, Janciauskiene SM. Prolastin, a pharmaceutical preparation of purified human alpha1antitrypsin, blocks endotoxin-mediated cytokine release.

Respir Res. 2005;6:12. PMid:15683545 PMCid:549028. http://dx.doi.org/10.1186/1465-9921-6-12 43. Martins S, de Perrot M, Imai Y, Yamane M, Quadri SM, Segall L, et al. Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model. Gene Ther. 2004;11(24):1786-96. PMid:15470481. http:// dx.doi.org/10.1038/sj.gt.3302357 44. Cypel M, Liu M, Rubacha M, Yeung JC, Hirayama S, Anraku M, et al. Functional repair of human donor lungs

by IL-10 gene therapy. Sci Transl Med. 2009;1(4):4ra9.

About the authors Alessandro Wasum Mariani

Attending Physician. Department of Thoracic Surgery, 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.

Paulo Manuel Pêgo-Fernandes

Associate Professor. Department of Cardiorespiratory Diseases, Faculdade de Medicina da Universidade de São Paulo – FMUSP, University of São Paulo School of Medicine – São Paulo, Brazil.

Luis Gustavo Abdalla

Attending Physician. Lung Transplant Group, 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.

Fabio Biscegli Jatene

Full Professor. Department of Thoracic Surgery, Faculdade de Medicina da Universidade de São Paulo – FMUSP, University of São Paulo School of Medicine – São Paulo, Brazil.

J Bras Pneumol. 2012;38(6):776-785

Review Article Anti-inflammatory effects of macrolides in childhood lung diseases* Efeito anti-inflamatório dos macrolídeos em doenças pulmonares da infância

Fernanda Luisi, Thays Dorneles Gandolfi, Arthur Dondonis Daudt, João Pedro Zelmanowicz Sanvitto, Paulo Márcio Pitrez, Leonardo Araujo Pinto

Abstract Macrolides are drugs that have antimicrobial effects, especially against intracellular pathogens. Various studies have shown that macrolides might also have anti-inflammatory effects. Macrolides inhibit the production of interleukins and can reduce pulmonary neutrophilic inflammation. Clinical trials have demonstrated beneficial effects of macrolides in various chronic lung diseases. The objective of this study was to review recent data in the medical literature on the anti-inflammatory effects of macrolides in childhood lung diseases by searching the Medline (PubMed) database. We used the following search terms: “macrolide and cystic fibrosis”; “macrolide and asthma”; “macrolide and bronchiolitis obliterans”; and “macrolide and acute bronchiolitis”. We selected articles published in international scientific journals between 2001 and 2012. Clinical studies and in vitro evidence have confirmed the anti-inflammatory effect of macrolides in respiratory diseases. Some clinical trials have shown the benefits of the administration of macrolides in patients with cystic fibrosis, although the risk of bacterial resistance should be considered in the analysis of those benefits. Such benefits are controversial in other respiratory diseases, and the routine use of macrolides is not recommended. Further controlled clinical trials are required in order to assess the efficacy of macrolides as anti-inflammatory drugs, so that the benefits in the treatment of each specific clinical condition can be better established.

Keywords: Macrolides; Asthma; Cystic Fibrosis; Bronchiolitis.

Resumo Os macrolídeos são fármacos com efeitos antimicrobianos especialmente contra patógenos intracelulares. Vários estudos têm demonstrado possíveis efeitos anti-inflamatórios dos macrolídeos. Esses medicamentos inibem a produção de algumas interleucinas e podem reduzir a inflamação neutrofílica pulmonar. Ensaios clínicos têm demonstrado efeitos benéficos dos macrolídeos em diversas doenças pulmonares crônicas. O objetivo deste estudo foi revisar os dados recentes da literatura médica sobre os efeitos anti-inflamatórios dos macrolídeos nas doenças respiratórias da infância, através da pesquisa da base de dados Medline (PubMed) dos seguintes termos em inglês: “macrolide and cystic fibrosis”; “macrolide and asthma”; “macrolide and bronchiolitis obliterans”; e “macrolide and acute bronchiolitis” Foram selecionados artigos publicados em revistas científicas internacionais entre 2001 e 2012. Estudos clínicos e evidências in vitro comprovam o efeito anti-inflamatório dos macrolídeos em doenças respiratórias. Alguns ensaios clínicos demonstram benefícios na administração de macrolídeos em pacientes com fibrose cística; porém, o risco de resistência bacteriana deve ser considerado na análise desses benefícios. Tais benefícios são controversos em outras doenças respiratórias, e seu uso rotineiro não está indicado. Mais estudos clínicos controlados são necessários para avaliar a eficácia desses medicamentos como anti-inflamatórios. Dessa forma, poderemos definir melhor os benefícios dos macrolídeos no tratamento de cada uma das situações clínicas especificadas.

Descritores: Macrolídeos; Asma; Fibrose Cística; Bronquiolite.

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

Correspondence to: Leonardo A. Pinto. Avenida Ipiranga, 6690, 2º andar, Instituto de Pesquisas Biomédicas, CEP 90610-000, Porto Alegre, RS, Brasil.

Tel. 55 51 651-1919. E-mail: leonardo.pinto@pucrs.br Financial support: Thays D. Gandolfi is the recipient of a Young Investigator 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). Arthur D. Daudt is the recipient of a Young Investigator Grant from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development).

Submitted: 26 March 2012. Accepted, after review: 18 September 2012.

J Bras Pneumol. 2012;38(6):786-796

Anti-inflammatory effects of macrolides in childhood lung diseases

Introduction Macrolides are a group of drugs that are widely used in the treatment of various infectious diseases. These drugs act by inhibiting protein synthesis and bacterial growth, precluding the synthesis of vital proteins and causing the death of the pathogen. Some studies have reported that, in addition to their antimicrobial activity, macrolides have anti-inflammatory and anti-viral properties.(1,2) More recent studies have assessed this class of medications as immunomodulatory drugs in several respiratory diseases, although the recommendation of their use in these conditions remains relatively controversial.(1,3,4) The antiinflammatory mechanism of macrolides was originally discovered in Japan in the 1980s, when treatment with macrolides significantly increased survival in patients with diffuse panbronchiolitis (DPB), a severe chronic lung disease with intense neutrophilic inflammation.(5) Among the most important effects of macrolides are the inhibition of pro-inflammatory cytokine synthesis and secretion and the increase in antiinflammatory cytokine secretion, as well as effects on neutrophil activity via inhibition of neutrophil migration to sites of inflammation.(6,7) Macrolides can also inhibit leukocyte degranulation, reduce eosinophilic inflammation, activate macrophage phagocytic activity,(7) and increase mucociliary transport, reducing mucus production in vivo(8,9) and in vitro.(6) In addition, these drugs can have an effect on adaptive immunity via regulation of T-cells and of antigen presentation. Studies have demonstrated a reduction in the number of lymphocytes in bronchoalveolar lavage samples, increased apoptosis of activated lymphocytes, and suppression of pro-inflammatory cytokine production by T-cells.(7) Other reported effects include reduced goblet cell secretion, reduced

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bronchoconstriction induced by a decreased release of endothelin-1, and inhibition of the cholinergic response in the airway smooth muscle.(2,8) A summary of the anti-inflammatory mechanisms is provided in Chart 1.

In a number of childhood lung diseases (acute bronchiolitis, cystic fibrosis, asthma, etc.), neutrophils play either a central or a supporting role in the onset and maintenance of inflammation, and recent studies have investigated the antiinflammatory effects of macrolides in such diseases.(10,11) In the present article, we describe the anti-inflammatory effects of macrolides, as well as evaluating and discussing the indications for their use in various childhood respiratory diseases, on the basis of the most current data in the medical literature.

Methods We chose four respiratory diseases that are relevant to pediatric practice and on which there are sufficient data to justify this review. We searched the Medline/PubMed database by using the following search strings: “macrolide” AND “cystic fibrosis”; “macrolide” AND “asthma”; “macrolide” AND “bronchiolitis obliterans”; and “macrolide” AND “acute bronchiolitis”. All searches were conducted between December of 2011 and August of 2012, and we limited our searches to articles published in 2001 or later. We performed additional searches in which we replaced the term “macrolide” with the three major representatives of the macrolide class: “erythromycin”, “azithromycin”, and “clarithromycin”. We used the following filters: clinical studies in humans; meta-analyses; guidelines; and published in English. We also included some experimental studies in order to flesh out the discussion of the anti-inflammatory mechanisms of this class of medications.

Chart 1 - Major immunomodulatory effects of macrolides.

Inhibition of cytokines or inhibition of inflammatory pathways ↓ activation of transcription factors in the bronchial epithelium ↓ TNF-α secretion in bronchial epithelial cells ↓ TNF- α, IL-1, IL-4, and IL-8 expression in various cells Inhibition of innate immunity components ↓ phagocytic capacity of polymorphonuclear cells ↑ apoptosis of neutrophils, lymphocytes, and eosinophils ↓ neutrophil chemotaxis ↓ mucus secretion in the airways

Reference Desaki et al.(54) Cigana et al.(55) Reato et al.(56) Theron et al.(57) Kadota et al.(58) Tsai et al.(59) Shimizu et al.(60)

J Bras Pneumol. 2012;38(6):786-796

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Luisi F, Gandolfi TD, Daudt AD, Sanvitto JPZ, Pitrez PM, Pinto LA

Results The criteria described above were applied to all searches. Using the search string “macrolide” AND “cystic fibrosis”, we identified 34 articles, of which 26, 25, and 6 were related to erythromycin, azithromycin, and clarithromycin, respectively.

Using the search string “macrolide” AND “asthma”, we identified 25 articles, of which 16, 9, and 7 were related to erythromycin, azithromycin, and clarithromycin, respectively. Using the search string “macrolide” AND “bronchiolitis obliterans”, we identified 24 articles, 8 of which were related to erythromycin, 8 of which were related to azithromycin, and none of which were related to clarithromycin. Using the search string “macrolide” AND “acute bronchiolitis”, we identified 14 articles, of which 3, 3, and 1 were related to erythromycin, azithromycin, and clarithromycin, respectively.

These articles were reviewed again in order to exclude overlapping studies and those that were irrelevant for the theme of the review (evidence on the anti-inflammatory activity of these drugs).

The remaining articles are listed in the references section of the present study and are discussed separately, considering in vitro/in vivo evidence of anti-inflammatory efficacy or clinical efficacy in each of the diseases studied. When only clinical trials of cystic fibrosis were looked at, we identified 4 involving only children, 5 involving children and adults, and 1 involving only adults.

We identified 4 clinical trials of bronchiolitis obliterans all involved adults. For asthma, we identified 1 clinical trial involving children and 1 involving adults. For acute bronchiolitis, we identified 3 clinical trials, all involving infants less than 1 year of age.

Discussion Cystic fibrosis Cystic fibrosis is a systemic autosomal recessive hereditary disease that causes significant pulmonary impairment. A defect in the cystic fibrosis transmembrane conductance regulator gene results in abnormal epithelial ion transport, which causes increased mucus viscosity and consequent stasis of secretion in the lungs, contributing to an increased propensity for recurrent respiratory infections, especially with Staphylococcus aureus, Haemophilus influenza, and Pseudomonas J Bras Pneumol. 2012;38(6):786-796

aeruginosa. The infection and the inflammation lead to lung tissue damage, bronchiectasis, and progressive respiratory failure. Cystic fibrosis is similar to DPB in many ways.(12) Both are characterized by chronic sinusitis, neutrophilic airway inflammation, susceptibility to chronic bronchial infection with specific pathogens, and progressive deterioration of pulmonary function.

The improvement in outcome for DPB patients treated with macrolides and the recognition that these drugs have various anti-inflammatory and immunomodulatory effects resulted in the hypothesis that the use of this class of antibiotics would be beneficial in the treatment of cystic fibrosis.(9,13) Macrolides have been shown to have positive effects on pulmonary function in cystic fibrosis, in addition to reducing secretion viscosity and airway adhesion of P. aeruginosa. They have also been shown to reduce the frequency of pulmonary exacerbations and to stabilize or improve respiratory capacity.(14) In a randomized double-blind, placebocontrolled crossover trial,(15) the effects of azithromycin were evaluated in 41 children with cystic fibrosis over a 15-month period. Patients received either azithromycin or placebo for 6 months. Subsequently, there was a 2-month washout period, after which the treatments were crossed over. The primary outcome measure was change in FEV1, and drug dose was adjusted for body weight (body weight ≤ 40 kg: 250 mg/day; body weight > 40 kg: 500 mg/day). Pulmonary function improved in both groups when patients were on azithromycin. In comparison with controls, patients given azithromycin had an improvement in FEV1 of 5.4% (95% CI: 0.8-10.5), an improvement in FVC of 3.9% (95% CI: 2.5-9.2), and an improvement in FEF25-75% of 11.4% (95% CI: 1.19-23.7%). Patients required fewer courses of other antibiotics when on azithromycin. No significant differences were found in sputum bacterial densities, exercise tolerance, or qualityof-life. The therapy was well tolerated, with no evidence of significant adverse events.(15) Another study evaluated 60 clinically stable cystic fibrosis patients who received either azithromycin or placebo (250 mg/day) for 3 months. Pulmonary function levels were maintained in patients receiving azithromycin, whereas, in patients receiving placebo, there was a decline in FEV1 and FVC of 3.62% and 5.73%, respectively. In addition, patients receiving

Anti-inflammatory effects of macrolides in childhood lung diseases

azithromycin had significantly fewer total days of i.v. antibiotic treatment, fewer days at home receiving i.v. antibiotics (p = 0.04), and fewer courses of i.v. antibiotics (p = 0.02).(16) A major concern regarding the chronic use of macrolides in cystic fibrosis is related to the emergence of bacterial resistance to this class of antibiotics. One study evaluated the frequency of resistance to macrolides in S. aureus and H. influenzae isolates from cystic fibrosis patients, cultured between 1999 and 2004, a period in which there was a significant increase in the use of azithromycin in cystic fibrosis patients.

Erythromycin resistance in isolated S. aureus strains increased from 6.9% to 53.8% in the period, and clarithromycin resistance in H. influenzae strains increased from 3.7% to 37.5%. Cultures from patients who received azithromycin yielded fewer positive results for both agents than did cultures from patients who did not receive azithromycin.(17) Many unanswered questions can be raised as to how azithromycin should be used, including dose, dose interval, duration of effect, and impact of long-term treatment on disease progression and on the microbiological environment of the lung.

In one clinical trial, children were randomized to receive either one of two doses of azithromycin (5 or 15 mg/kg/day) for 6 months in order to compare the effects of these doses. No differences in FEV1, clinical scores, Pseudomonas colonization rates, pulmonary exacerbations, or need for antibiotics were found between the groups. The significant increase in the number of exacerbations and the decline in FEV1 after azithromycin was discontinued in both groups suggest that the anti-inflammatory effect is a function of duration of use.(18) Another study analyzed azithromycin administered daily (250 mg/day) vs. azithromycin administered weekly (1,200 mg/week). The two groups showed equivalent improvement in pulmonary function. The once-weekly high dose regimen was associated with a moderate increase in gastrointestinal adverse effects.(19) A recent systematic review analyzed clinical status and adverse effects in cystic fibrosis patients treated with macrolides vs. placebo.(20) Ten studies were included (959 patients). Eight of those studies compared azithromycin with placebo, and 2 studies compared the administration of different doses of azithromycin. Four clinical trials (549 patients) demonstrated that there were significant improvements in pulmonary

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function after treatment with azithromycin, when compared with placebo, at 6 months, the mean difference at 6 months being 3.97% (95% CI: 1.74-6.19). Data beyond six months were less clear, although reduction in the number of respiratory exacerbations was sustained. Patients treated with azithromycin were approximately twice as likely to be free of pulmonary exacerbations (OR = 1.96; 95% CI: 1.15-3.33), had a reduced need for oral antibiotics, and experienced a greater weight gain. In addition, treatment with azithromycin was associated with reduced identification of S. aureus in airway sample cultures. Adverse effects were uncommon and were not associated with azithromycin, although an increase in macrolide resistance was observed. Six studies were assessed as having a low potential for bias, whereas four had potentially significant risks for bias, although they had no major impact on the conclusion of the results or outcomes. The authors concluded that azithromycin has a small but consistent beneficial effect on the treatment of cystic fibrosis, the safety of use being satisfactory over a 6-month period, with a thrice-weekly dose regimen. However, considering the few longterm data available and the concern over the emergence of bacterial macrolide resistance, the evidence that is currently available is not strong enough to support the recommendation that all CF patients should receive azithromycin.(20) The long-term effects of azithromycin were assessed in a follow-on study(21) involving cystic fibrosis patients who had participated in a randomized placebo-controlled clinical trial.

Although at 6 months azithromycin did not acutely improve pulmonary function, it reduced the number of pulmonary exacerbations, decreased the initiation of new oral antibiotics, and increased the rate of weight gain. At 12 months, durability of response to azithromycin was observed, as measured by pulmonary exacerbations and weight gain.

Clarithromycin has been studied to a lesser degree as long-term treatment in cystic fibrosis patients. In a small pilot study conducted in the United States, 10 cystic fibrosis patients (19-26 years of age) infected with P. aeruginosa were treated with placebo for 3 weeks, followed by clarithromycin (500 mg, twice a day); there were no significant differences in neutrophil counts, nor in IL-8, elastase, or myeloperoxidase levels in sputum. According to the authors, these J Bras Pneumol. 2012;38(6):786-796

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findings might be due to the small number of patients or to the short duration of treatment.(22) However, one study involving 27 children showed a significant reduction in TNF-α, IL-8, IL-4, and IFN-γ levels in sputum and plasma, as well as an increase in the IFN- γ/IL-4 ratio and in peripheral lymphocyte response to phytohemagglutinin, after treatment with clarithromycin (250 mg/day) for 12 months.(23) In contrast, an in vitro study demonstrated that azithromycin decreased IL-8 secretion only in non-cystic fibrosis cells and had no antiinflammatory effects on cystic fibrosis epithelial or glandular cells.(24) A more recent double-blind study of clarithromycin vs. placebo found that, relative to placebo, treatment with slow-release clarithromycin for 5 months was not associated with significantly improved pulmonary function, weight gain, frequency of pulmonary exacerbations, or quality of life.(25) Macrolides have been shown to slow the decline in pulmonary function in cystic fibrosis.

The potential mechanisms of action include direct effects on the pathogen and on the host. A decrease in bacterial virulence, especially in P. aeruginosa virulence, and a late bactericidal effect, as well as a decrease in airway adherence of, motility of, and biofilm production by Pseudomonas, are the potential effects on the agent. The immunomodulatory effects on the host include suppression of the enhanced immune response and of the inflammation, inhibition of inflammatory cytokine production by alveolar macrophages, and decreased mucus hypersecretion.

(11,23,26,27)

Various studies have shown positive results regarding the reduction in the number of exacerbations and regarding stabilization of or increase in respiratory capacity, whereas others have failed to demonstrate these effects (Chart 2).

Treatment with azithromycin can have beneficial effects in cystic fibrosis, although the optimal dosage and duration of administration have yet to be well defined.(28) Two studies seem to synthesize the recommendations of and the controversies over the use of azithromycin in cystic fibrosis: while one study demonstrated significant benefits of treatment with azithromycin in children colonized with P. aeruginosa, another study undertaken by the same group of authors found no benefits of treatment with azithromycin in patients uninfected with P. aeruginosa.(29,30) In addition, it is essential J Bras Pneumol. 2012;38(6):786-796

to bear in mind the possibility that resistance to macrolides and other antibiotics will increase, as well as the clinical impact of colonization with more resistant pathogens.(18-20)

Bronchiolitis obliterans Bronchiolitis obliterans is an inflammatory disease that affects the end of the airways, leading to obliteration of the bronchiole lumen. Bronchiolitis obliterans is the leading cause of death in the postoperative period after lung transplantation. It is one of the most common complications of allogeneic bone marrow transplantation (BMT) and, although its pathogenesis is still not completely understood, it is believed to be part of the graft-versus-host reaction. In contrast, bronchiolitis obliterans can occur in pediatric non-transplanted patients, following an infectious process.(27,31) The clinical manifestations characteristic of bronchiolitis obliterans include tachypnea, increase in the anteroposterior diameter of the chest, crackles, wheezing, and hypoxemia for at least 30 days after exposure to the triggering factor. The most common infectious agent responsible for the initial insult in post-infectious bronchiolitis obliterans is adenovirus, which occurs primarily in children.(32) Approximately 10% of patients with graftversus-host disease develop bronchiolitis obliterans, and prognosis is very poor (3-year mortality of 65%). Macrolides have been shown to decrease the progression of post-BMT bronchiolitis obliterans.(31) One group of authors(33) conducted an observational study involving 8 patients who underwent BMT and developed bronchiolitis obliterans. Treatment with azithromycin had positive effects, such as a 21% improvement in FVC and a 20% improvement in FEV1. Another case study(34) also reported positive effects, although a randomized clinical trial found no differences in the results between the placebo and azithromycin groups.(35) Post-lung transplant bronchiolitis obliterans is the most common form of the disease in developed countries and in adults, because of the larger number of procedures. Its pathogenesis and clinical findings are very similar to those of post-BMT bronchiolitis obliterans. The use of macrolides apparently prevents progression to bronchiolitis obliterans after lung transplantation, showing positive effects in the neutrophilic type

Anti-inflammatory effects of macrolides in childhood lung diseases

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Chart 2 - Major studies contributing to the evaluation of the anti-inflammatory effects of macrolides in cystic fibrosis patients.

Authors Design Principal findings Saint-Criq et al.(24) Experimental Azithromycin had no anti-inflammatory effect on epithelial or glandular cells of CF patients in vitro.

Zarogoulidis et al.(27) SR Macrolides reduce airway hyperresponsiveness and improve pulmonary function.

Southern et al.(20) SR The evidence that is currently available is not strong enough to support the recommendation that all CF patients should receive azithromycin, considering the concern over the emergence of bacterial resistance.

Saiman et al.(30) RCT Patients without chronic infection with PA showed no significant clinical benefit from treatment with azithromycin.

Kabra et al.(18) RCT No differences in FEV1, pulmonary exacerbations, or need for antibiotics were found between the groups.

McArdle et al.(26) Review Long-term administration of macrolides leads to clinical benefits in CF patients.

McCormack et al.(19) RCT Equivalence was demonstrated between the two groups (daily vs. weekly use) with respect to improvements in pulmonary function.

Phaff et al.(17) RCT Erythromycin resistance in S. aureus isolates increased, as did clarithromycin resistance in H. influenzae isolates. Cultures from patients who received azithromycin yielded fewer positive results for both agents.

Rubin et al.(28) Review In vitro and in vivo studies suggest that macrolides inhibit the pulmonary influx of neutrophils, inhibit the release of cytokines, and improve the transportability of secretions Pukhalsky et al.(23) RCT Treatment with clarithromycin significantly reduced TNF-α, IL-8, IL-4, and IFN-γ levels in sputum and plasma.

Saiman et al.(29) RCT Patients with chronic infection with PA showed significant benefit from treatment with azithromycin.

Equi et al.(15) RCT There was a significant improvement in pulmonary function associated with the use of azithromycin.

Wolter et al.(16) RCT Pulmonary function levels were maintained in patients receiving azithromycin, whereas, in patients receiving placebo, there was a decline in FEV1 and FVC. SR: systematic review; RCT: randomized clinical trial; CF: cystic fibrosis; and PA: Pseudomonas aeruginosa.

of the disease but not in the fibroproliferative type.(14,31) The efficacy of treating bronchiolitis obliterans with macrolides in transplant recipients has been tested in adults, outcome measures varying across studies. Two studies that used similar but not identical measures reported conflicting results.(36,37) One study, involving 146 lung transplant recipients with a survival of more than 180 days (102 of whom were treated with clarithromycin and 44 of whom received standard postoperative care), demonstrated that clarithromycin did not reduce the incidence of bronchiolitis obliterans (76 patients treated with clarithromycin developed bronchiolitis obliterans, whereas 7 receiving standard care developed the disease) or the incidence of respiratory complications (35 patients treated with clarithromycin vs. 18 receiving

standard care).(36) One study,(37) assessing forced expiratory volume in 11 patients over 10 months of unblinded treatment with azithromycin (250 mg, 3 times a week), demonstrated that there was no improvement in pulmonary function. Those authors, however, reported that there was a change in the natural history of bronchiolitis obliterans, since the disease did not progress during the assessment period.(37) This result is in contrast with the findings of another group of authors,(36) whose patients developed bronchiolitis obliterans regardless of treatment with a macrolide (clarithromycin), there being no change in the natural history of the disease. Therefore, the role of the use of macrolides in patients with post-transplant bronchiolitis obliterans has yet to be well defined.

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The major risk factors for post-infectious bronchiolitis obliterans in children are adenovirus infection and the use of mechanical ventilation; many cases have been reported in South America.(32) This disease has a major clinical impact, as demonstrated in a study conducted in a hospital in Buenos Aires, Argentina, in which bronchiolitis obliterans was found to account for 14% of all hospital days in a 10-year period.(38) There have been no studies testing the efficacy of treatment with macrolides in patients with post-infectious bronchiolitis obliterans, and the determination of this efficacy is essential, given the major impact of this disease in developing countries.(39)

Asthma Asthma is a chronic inflammatory disease whose main characteristics are bronchial hyperresponsiveness and chronic lower airway inflammation. These characteristics are responsible for variable airflow limitation, causing episodes of wheezing, dyspnea, chest tightness, and cough, which are often associated with respiratory infections during exacerbations. Worldwide, asthma results in high hospitalization rates and significant impairment of patient quality of life. Bronchial inflammation is the main pathophysiological characteristic of asthma and can be present even in asymptomatic patients. In addition to the inflammatory process, causing mucosal edema and mucus production, there is bronchospasm, further contributing to the decrease in airway caliber.(1) Macrolides are known not only for their bacteriostatic effect but also for having an anti-inflammatory effect (reducing neutrophil counts).(5) Although the pathogenesis of asthma is complex, the importance of inflammatory cells and pro-inflammatory cytokine secretion is recognized, the major cells being Th2, eosinophils, and mast cells.(40) The positive effect of macrolides is controversial in various studies of asthma patients. However, the reduction in neutrophilic airway inflammation, in edema, and in bronchial hyperresponsiveness, as well as the inhibition of mucus production and the improvement in pulmonary function in asthma patients, are benefits associated with the potential immunomodulatory capacity of macrolides.(1,27,40) Asthma exacerbations are related to allergens and infections, and rhinovirus seems to be one of the most common triggers of viral exacerbations.

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Although it has not been demonstrated that asthma patients experience viral infections more often than do healthy subjects, their symptoms seem to be more persistent and severe. A defect in IFN production seems to be related to the difficulty in eliminating the virus via apoptosis.(7,14) According to one study,(41) the airway epithelium of asthma patients produces more inflammation mediators than does the normal epithelium when infected with a virus.

It is certain that 40-80% of asthma exacerbations are triggered by viral infections, which induce a response, with an influx of neutrophils, eosinophils, mast cells, CD4 cells, and CD8 cells into the airways, together with the production of pro-inflammatory cytokines.

(7,14,42) Similarly to viruses, atypical bacteria can cause bronchial inflammation, also leading to asthma exacerbations, as well as causing chronic airway infection and hindering disease control efforts.(7,43) With regard to bacterial infections, one study showed that when organisms such as Chlamydophila pneumoniae and Mycoplasma pneumoniae are responsible for asthma exacerbation, the use of macrolides improves disease control.(43) A recent review(7) concluded that the routine use of macrolides in patients with uncontrolled asthma did not reduce symptoms or improve pulmonary function. However, a specific phenotype of asthma, determined by PCR testing of bronchoscopy samples for the presence and diversity of pathogens, can benefit from the use of macrolides.

The beneficial effects of macrolides have also been tested in the treatment of asthma that is not associated with infectious exacerbations.

Clarithromycin and azithromycin have been shown to be efficient in reducing airway inflammation, the former having been associated with decreased airway edema and decreased TNF-α, IL-1, and IL-10 concentrations in nasal aspirates.(8,44,45) One group of authors demonstrated that azithromycin decreased IL-5 production in lymphocytes of children with atopic asthma, without affecting IFN‑ γ production, thereby showing that azithromycin has a beneficial effect on the pathogenesis of asthma.(40) Even with all of these theoretical justifications based on experimental or mechanistic studies,(46) the positive effects of macrolides has not been consistent in the published clinical trials in

Anti-inflammatory effects of macrolides in childhood lung diseases

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Chart 3 - Major studies contributing to the evaluation of the anti-inflammatory effects of macrolides in asthma patients.

Authors Design Principal findings Good et al.(7) Review The documentation of the presence and diversity of infection in bronchoalveolar lavage samples can identify an asthma phenotype that responds favorably to therapy with macrolides.

Gao et al.(46) Experimental Macrolides were effective in improving chemotaxis, reducing the injury caused by airway inflammation.

Simpson et al.(44) RCT Clarithromycin was found to reduce airway inflammation, particularly neutrophilic inflammation.

Kraft et al.(43) RCT Asthma patients colonized with Chlamydophila pneumoniae and Mycoplasma pneumoniae who were treated with clarithromycin showed improvement in FEV1 when compared with patients in the placebo group.

RCT: Randomized clinical trial.

asthma (Chart 3). Further studies investigating the effects of macrolides in asthma management are required. This research should focus not only on confirming that the use of macrolides has an anti-inflammatory effect in asthma but also on the impact of the benefits that these medications can bring to clinical practice.

Acute bronchiolitis Acute bronchiolitis is the leading cause of hospitalization in infants. It is characterized by extensive lower airway inflammation, accompanied by increased mucus production and epithelial cell necrosis.(47) A clinical diagnosis of acute bronchiolitis is characterized by tachypnea, wheezing, and upper airway infection. The primary cause of acute bronchiolitis is infection with respiratory virus, especially respiratory syncytial virus, with widespread neutrophilic airway inflammation.(10,48) Antibiotics are not routinely recommended in the management of acute bronchiolitis, but some researchers have proposed the use of macrolides in the treatment of this disease.(47) In one study,(49) 21 hospitalized children with moderate acute bronchiolitis received oral clarithromycin for 3 weeks and showed a significant reduction in duration of oxygen therapy, length of hospital stay, and 6-month post-discharge hospital readmission, which indicates a beneficial effect on disease severity. In contrast, in another study,(50) 71 children received azithromycin for 3 days and no significant result was found.

Although the findings of those two studies are conflicting, a review(51) points out serious biases in them, such as the blinding, the randomization, the power of the sample, and even the data

analysis. Therefore, the effects of the use of macrolides in acute bronchiolitis remain unclear, and clinical trials involving an adequate number of participants are therefore warranted.

Our group has recently demonstrated, in a large sample of hospitalized infants with acute bronchiolitis, that the use of azithromycin did not affect clinical outcomes, even when we stratified the analysis by viral identification. These findings suggest that azithromycin should not be used in infants presenting with their first episode of wheezing, and they could contribute to reducing the use of antibiotics in infants with acute bronchiolitis.(52)

Final considerations One group of authors(53) demonstrated that the anti-inflammatory and antimicrobial activities of macrolides are independent and can be separated, which would make it possible to create new anti-inflammatory agents, particularly bearing in mind the potential risk of increasing bacterial resistance with the indiscriminate use of macrolides worldwide. Many studies have confirmed the anti-inflammatory effects of macrolides in respiratory diseases. Some clinical trials have demonstrated the benefits of the administration of macrolides in patients with cystic fibrosis. In other respiratory diseases, such benefits remain controversial, and the routine use of macrolides is not recommended. In the management of respiratory diseases, physicians should evaluate the prescribed treatments carefully and individually, as well as analyzing their capacity to reduce symptoms, length of hospital stays, and sequelae.

In addition, obviously, physicians should monitor abuse of antimicrobial agents and devise new J Bras Pneumol. 2012;38(6):786-796

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strategies to change current medical practice.

Finally, additional randomized controlled clinical trials involving a large number of patients are needed in order to assess the effects of macrolides in each clinical condition, so that the benefits of these drugs in the treatment of respiratory diseases can be established.

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PMid:20442386. http://dx.doi.org/10.1001/jama.2010.563 31. Maimon N, Lipton JH, Chan CK, Marras TK. Macrolides in the treatment of bronchiolitis obliterans in allograft recipients. Bone Marrow Transplant. 2009;44(2):69-73.

PMid:19430505. http://dx.doi.org/10.1038/bmt.2009.106 32. Fischer GB, Sarria EE, Mattiello R, Mocelin HT, CastroRodriguez JA. Post infectious bronchiolitis obliterans in children. Paediatr Respir Rev. 2010;11(4):233-9.

PMid:21109182. http://dx.doi.org/10.1016/j. prrv.2010.07.005 33. Khalid M, Al Saghir A, Saleemi S, Al Dammas S, Zeitouni M, Al Mobeireek A, et al. Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study. Eur Respir J. 2005;25(3):490-3.

PMid:15738293. http://dx.doi.org/10.1183/0903193 6.05.00020804 34. Norman BC, Jacobsohn DA, Williams KM, Au BK, Au MA, Lee SJ, et al. Fluticasone, azithromycin and montelukast therapy in reducing corticosteroid exposure in bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: a case series of eight patients. Bone Marrow Transplant. 2011;46(10):1369-73. PMid:21132024. http://dx.doi.org/10.1038/bmt.2010.311 35. Lam DC, Lam B, Wong MK, Lu C, Au WY, Tse EW, et al.

Effects of azithromycin in bronchiolitis obliterans syndrome after hematopoietic SCT--a randomized double-blinded placebo-controlled study. Bone Marrow Transplant. 2011;46(12):1551-6. PMid:21317934. http:// dx.doi.org/10.1038/bmt.2011.1 36. Dhillon GS, Valentine VG, Levitt J, Patel P, Gupta MR, Duncan SR, et al. Clarithromycin for prevention of bronchiolitis obliterans syndrome in lung allograft recipients.

Clin Transplant. 2012;26(1):105-10. PMid:21352378. http://dx.doi.org/10.1111/j.1399-0012.2011.01420.x 37. Shitrit D, Bendayan D, Gidon S, Saute M, Bakal I, Kramer MR. Long-term azithromycin use for treatment of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant. 2005;24(9):1440-3.

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PMid:16517579 PMCid:2111218. http://dx.doi.org/10.1136/ thx.2005.044909 39. Colom AJ, Teper AM. Postinfectious bronchiolitis obliterans [Article in Spanish]. Arch Argent Pediatr. 2009;107(2):160-7.

PMid:19452089.

40. Lin SJ, Lee WJ, Liang YW, Yan DC, Cheng PJ, Kuo ML. Azithromycin inhibits IL-5 production of T helper type 2 cells from asthmatic children. Int Arch Allergy Immunol. 2011;156(2):179-86. PMid:21597298. http:// dx.doi.org/10.1159/000322872 41. Holgate ST. The sentinel role of the airway epithelium in asthma pathogenesis. Immunol Rev. 2011;242(1):205-19. PMid:21682747. http://dx.doi. org/10.1111/j.1600-065X.2011.01030.x 42. Papadopoulos NG, Christodoulou I, Rohde G, Agache I, Almqvist C, Bruno A, et al. Viruses and bacteria in acute asthma exacerbations--a GA² LEN-DARE systematic review. Allergy. 2011;66(4):458-68. PMid:21087215. http://dx.doi.org/10.1111/j.1398-9995.2010.02505.x 43. Kraft M, Cassell GH, Pak J, Martin RJ. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest. 2002;121(6):1782-8.

PMid:12065339. http://dx.doi.org/10.1378/ chest.121.6.1782 44. Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med. 2008;177(2):148-55. PMid:17947611. http:// dx.doi.org/10.1164/rccm.200707-1134OC 45. Fonseca-Aten M, Okada PJ, Bowlware KL, Chavez-Bueno S, Mejias A, Rios AM, et al. Effect of clarithromycin on cytokines and chemokines in children with an acute exacerbation of recurrent wheezing: a double-blind, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2006;97(4):457-63. http://dx.doi.org/10.1016/ S1081-1206(10)60935-0 46. Gao X, Ray R, Xiao Y, Ishida K, Ray P. Macrolide antibiotics improve chemotactic and phagocytic capacity as well as reduce inflammation in sulfur mustard-exposed monocytes.

Pulm Pharmacol Ther. 2010;23(2):97-106. PMid:19895898. http://dx.doi.org/10.1016/j.pupt.2009.10.010 47. Smyth RL, Openshaw PJ. Bronchiolitis.

Lancet. 2006;368(9532):312-22. http://dx.doi.org/10.1016/ S0140-6736(06)69077-6 48. Everard ML, Swarbrick A, Wrightham M, McIntyre J, Dunkley C, James PD, et al. Analysis of cells obtained by bronchial lavage of infants with respiratory syncytial virus infection. Arch Dis Child. 1994;71(5):428-32. PMid:7826113 PMCid:1030058. http://dx.doi.org/10.1136/adc.71.5.428 49. Tahan F, Ozcan A, Koc N. Clarithromycin in the treatment of RSV bronchiolitis: a double-blind, randomised, placebo-controlled trial. Eur Respir J. 2007;29(1):91-7. PMid:17050564. http://dx.doi. org/10.1183/09031936.00029206 50. Kneyber MC, van Woensel JB, Uijtendaal E, Uiterwaal CS, Kimpen JL; Dutch Antibiotics in RSV Trial (DART) Research Group. Azithromycin does not improve disease course in hospitalized infants with respiratory syncytial virus (RSV) lower respiratory tract disease: a randomized equivalence trial. Pediatr Pulmonol. 2008;43(2):142-9.

PMid:18085694. http://dx.doi.org/10.1002/ppul.20748

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51. Spurling GK, Doust J, Del Mar CB, Eriksson L. Antibiotics for bronchiolitis in children. Cochrane Database Syst Rev. 2011;(6):CD005189. PMid:21678346.

52. Pinto LA, Pitrez PM, Luisi F, de Mello PP, Gerhardt M, Ferlini R, et al. Azithromycin Therapy in Hospitalized Infants with Acute Bronchiolitis is Not Associated with Better Clinical Outcomes: A Randomized, Double-Blinded, and Placebo-Controlled Clinical Trial. J Pediatr. 2012.

[Epub ahead of print] http://dx.doi.org/10.1016/j. jpeds.2012.05.053 53. Bosnar M, Kragol G, Koštrun S, Vujasinović I, Bošnjak B, Bencetić Mihaljević V, et al. N’-substituted-2’-O,3’-Ncarbonimidoyl bridged macrolides: novel anti-inflammatory macrolides without antimicrobial activity. J Med Chem. 2012;55(13):6111-23. PMid:22697905. http:// dx.doi.org/10.1021/jm300356u 54. Desaki M, Takizawa H, Ohtoshi T, Kasama T, Kobayashi K, Sunazuka T, et al. Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun. 2000;267(1):124-8. PMid:10623585. http:// dx.doi.org/10.1006/bbrc.1999.1917 55. Cigana C, Assael BM, Melotti P. Azithromycin selectively reduces tumor necrosis factor alpha levels in cystic fibrosis airway epithelial cells. Antimicrob Agents

Chemother. 2007;51(3):975-81. PMid:17210769 PMCid:1803122. http://dx.doi.org/10.1128/AAC.01142-06 56. Reato G, Cuffini AM, Tullio V, Mandras N, Roana J, Banche G, et al. Immunomodulating effect of antimicrobial agents on cytokine production by human polymorphonuclear neutrophils. Int J Antimicrob Agents. 2004;23(2):150-4. PMid:15013040. http:// dx.doi.org/10.1016/j.ijantimicag.2003.07.006 57. Theron AJ, Feldman C, Anderson R. Investigation of the anti-inflammatory and membrane-stabilizing potential of spiramycin in vitro. J Antimicrob Chemother. 2000;46(2):269-71. PMid:10933651. http:// dx.doi.org/10.1093/jac/46.2.269 58. Kadota J, Mizunoe S, Kishi K, Tokimatsu I, Nagai H, Nasu M. Antibiotic-induced apoptosis in human activated peripheral lymphocytes. Int J Antimicrob Agents. 2005;25(3):216-20. PMid:15737515. http:// dx.doi.org/10.1016/j.ijantimicag.2004.10.009 59. Tsai WC, Standiford TJ. Immunomodulatory effects of macrolides in the lung: lessons from in-vitro and in-vivo models. Curr Pharm Des. 2004;10(25):3081-93. http:// dx.doi.org/10.2174/1381612043383430 60. Shimizu T, Shimizu S, Hattori R, Gabazza EC, Majima Y. In vivo and in vitro effects of macrolide antibiotics on mucus secretion in airway epithelial cells. Am J Respir Crit Care Med. 2003;168(5):581-7. PMid:12829454. http://dx.doi.org/10.1164/rccm.200212-1437OC

About the authors Fernanda Luisi

Physical Therapist specializing in Child Health, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS, Pontifical Catholic University of Rio Grande do Sul – Porto Alegre, Brazil.

Thays Dorneles Gandolfi

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

Arthur Dondonis Daudt

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

João Pedro Zelmanowicz Sanvitto

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

Paulo Márcio Pitrez

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

Leonardo Araujo Pinto

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

J Bras Pneumol. 2012;38(6):786-796

Case Report Pleural endometriosis: findings on magnetic resonance imaging*,** Endometriose pleural: achados na ressonância magnética

Edson Marchiori, Gláucia Zanetti, Rosana Souza Rodrigues, Luciana Soares Souza, Arthur Soares Souza Jr, Flávia Angélica Ferreira Francisco, Bruno Hochhegger

Abstract Endometriosis is a benign gynecological disorder associated with pelvic pain and infertility, primarily affecting women of reproductive age. Thoracic endometriosis affects the pulmonary parenchyma or pleura. We report the cases of two patients with pleural endometriosis who presented with recurrent pneumothorax. In both cases, magnetic resonance imaging (MRI) of the chest showed right hydropneumothorax and well-defined, rounded nodules on the pleural surface in the right hemithorax. We conclude that MRI is a good option for the characterization of pleural endometriotic nodules and hemorrhagic pleural effusion.

Keywords: Endometriosis; Magnetic resonance imaging; Pneumothorax.

Resumo A endometriose é uma doença ginecológica benigna associada à dor pélvica e infertilidade que afeta principalmente mulheres em idade reprodutiva. A endometriose torácica afeta o parênquima pulmonar ou a pleura. Relatamos os casos de duas pacientes com endometriose pleural que apresentaram pneumotórax recorrente. Em ambos os casos, a ressonância magnética de tórax mostrou hidropneumotórax à direita e nódulos redondos, bem definidos, na superfície pleural à direita. A ressonância magnética é uma boa opção para a caracterização dos nódulos de endometriose pleural e de derrame pleural hemorrágico.

Descritores: Endometriose; Imagem por ressonância magnética; Pneumotórax.

Introduction Endometriosis is a benign gynecological disorder associated with pelvic pain and infertility, primarily affecting women of reproductive age. The disease is defined as the presence of functional endometrial glands and stroma outside the uterine cavity.(1,2) These tissues typically grow within the pelvic cavity. However, in extrapelvic endometriosis, they grow in other locations, such as the pericardium, intestinal tract, and even the brain. Thoracic endometriosis is a form of extrapelvic endometriosis found in the pulmonary parenchymal tissues or pleura(2); it manifests most frequently as catamenial pneumothorax (CP), thus named in order to reflect its temporal relationship with menses and is defined as pneumothorax occurring between 24 h before and 72 h after the onset of menstruation.(3-5) In the present article,

we report the magnetic resonance imaging (MRI) findings of two patients with pleural endometriosis who presented with recurrent pneumothorax.

Case reports Case 1 A 33-year-old woman presented with significant pelvic pain, dyspnea, moderate right-sided pleuritic pain, and dry cough 5 years prior; those symptoms showed cyclic changes in severity in accordance with the menstrual cycle. A chest X-ray showed massive right hydropneumothorax, and thoracocentesis revealed hemorrhagic fluid.

The cytology was negative for malignancy. A transvaginal ultrasound revealed, in the right

* Study carried out in the Department of Radiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Correspondence to: Edson Marchiori. Rua Thomaz Cameron, 438, Valparaíso, CEP 25685-120, Petrópolis, RJ, Brasil.

Tel. 55 24 2249-2777. Fax: 55 21 2629-9017. E-mail: edmarchiori@gmail.com Financial support: None.

Submitted: 7 July 2012. Accepted, after review: 31 August 2012. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

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adnexa, a multiloculated cystic mass suggestive of endometrioma, ipsilateral hematosalpinx, and hemoperitoneum.

The patient was referred to our institution and hospitalized for diagnostic thoracoscopy. Dark lesions were observed throughout the pleura. The lesions were biopsied, and the histopathological analysis indicated pleural endometriosis.

Subsequently, two pleurodeses with tetracycline were performed and the menstruation of the patient was suppressed (with oral contraceptives) for six months. These measures resulted in significant symptomatic improvement, although a small hydropneumothorax persisted.

The patient remained asymptomatic for 4 years.

Approximately six months prior to this writing, the patient presented with cyclic dyspnea, dry cough, and mild pelvic pain, despite her use of oral contraceptives. A chest X-ray and a CT scan of the chest revealed mild right hydropneumothorax.

The lung parenchyma was normal. On T1- and T2-weighted MRI sequences of the chest, performed with and without fat suppression, we observed right hydropneumothorax, and T1-weighted MRI sequences with fat suppression showed hyperintense nodular lesions in the pleura; some of those lesions showed restricted diffusion (Figure 1), which is suggestive of endometriomas.

The patient underwent video-assisted thoracic surgery (VATS). All dark lesions in the pleura were resected. The surgery caused significant symptomatic improvement, and the patient remained asymptomatic at 1 year after the surgery.

Case 2 A 41-year-old woman presented with a 6-year history of pain in her right shoulder during menstruation. She had reported chest pain and pleural effusion 1 year prior. During clinical examination, right hydropneumothorax was identified. Two months prior, another episode of chest pain was followed by spontaneous pneumothorax and pleural effusion. The patient was referred to our institution and hospitalized for diagnostic examination. The results of laboratory tests were normal. A chest X-ray showed right hydropneumothorax.

The patient underwent CT, which revealed right hydropneumothorax without focal lesions.

On MRI scans of the chest, T1- and T2-weighted sequences showed right hydropneumothorax with J Bras Pneumol. 2012;38(6):797-802

hyperintense small nodular lesions (Figure 2), which are suggestive of endometriomas.

Thoracocentesis revealed hemorrhagic fluid.

The examination was negative for mycobacteria, fungi, and malignancy. The patient underwent VATS, which revealed dark lesions throughout the pleura. The lesions were biopsied, and the histopathological analysis indicated pleural endometriosis. Pleurodesis with tetracycline was performed, and the menstruation of the patient was suppressed with oral contraceptives.

At this writing, the patient was under outpatient follow-up treatment and remained asymptomatic.

Discussion The diagnosis of thoracic endometriosis is usually based on clinical data and is confirmed by the histopathological examination of resected specimens.(2) Thoracic endometriosis, manifesting most frequently as CP,(4) is more common in the third and fourth decades of life. In almost all cases, CP is unilateral and right-sided, although it can also affect the left lung or be bilateral.(4,6) Most patients experience chest pain and dyspnea, and many have a known history of pelvic endometriosis or infertility. The diagnosis of CP should be suspected when the recurrence of pneumothorax coincides with the menstrual period.(6) Other less common findings include hemoptysis and hemothorax.(4,6) Pathologically, thoracic endometriosis is defined by the presence of morphologically normal endometrial tissue within the thoracic cavity.

Regardless of the site, endometriotic foci consist of stroma and glands in variable proportions; the glands are often dilated and are lined with epithelium, the form of which typically ranges from pseudostratified cuboidal to cylindrical.(4) In recent years, MRI of the chest has progressed markedly. Because of improvements in speed and image quality, MRI is now ready for routine clinical use.(7-9) In both of the cases presented here, chest MRI revealed hydropneumothorax and well-defined, rounded nodules on the pleural surface in the right hemithorax. In Case 1, the pleural effusion had intermediate signal intensity on T1-weighted images, suggesting high protein content, probably related to hemorrhagic products. In Case 2, the pleural effusion had high signal intensity, suggesting recent hemothorax. The pleural nodules observed in Case 1 showed homogeneously high signal

Pleural endometriosis: findings on magnetic resonance imaging

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Figure 1 - Magnetic resonance imaging (MRI). In A, axial, T1-weighted, out-phase MRI sequence showing right hydropneumothorax. The pleural effusion has signal intensity similar to that of muscle, suggesting a high protein content related to hemorrhagic products. In B, unenhanced, fat-suppressed T1-weighted MRI sequence showing a well-defined, rounded lesion with homogeneous high signal intensity in the right hemithorax, abutting the pleura (arrows). In C, diffusion-weighted MRI sequence showing diffusion restriction in the pleural lesion (arrows). Endometrioma was confirmed by thoracoscopy.

intensity on fat-suppressed T1-weighted images and restricted diffusion on diffusion-weighted imaging (DWI). In Case 2, the nodules showed heterogeneous signal intensity on T1- and

T2-weighted images, without diffusion restriction.

As in pelvic endometriosis,(1,10) pleural nodules of thoracic endometriosis might show different signal intensity on T1- and T2-weighted images, J Bras Pneumol. 2012;38(6):797-802

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Figure 2 - Magnetic resonance imaging (MRI). In A, axial, T2-weighted MRI sequence of the lower third of the hemithorax showing right hydropneumothorax. In B and C, respectively, unenhanced T1-weighted and fat-suppressed T1-weighted MRI sequences showing high signal intensity of the pleural effusion, suggesting recent hemothorax. Note the nodules on the visceral pleural surface in the right hemithorax that show heterogeneous signal intensity in the T1-weighted image (arrowheads). Endometriotic nodules and pleural hemorrhage were confirmed by thoracoscopy.

as well as variable diffusion restriction, depending on the age of the lesion.

Some previous reports have compared MRI findings with CT findings in cases of CP.(6,11) Our data corroborate the results of those studies by J Bras Pneumol. 2012;38(6):797-802

demonstrating that MRI is more accurate than is CT in the detection of CP. However, to our knowledge, there have been no reports discussing the MRI signal characteristics of hemorrhage in the pleural spaces. The MRI signal intensity of

Pleural endometriosis: findings on magnetic resonance imaging

hemorrhage was first described in brain tissues; however, we can extrapolate some physical aspects of the interaction between hemoglobin and magnetic field from brain tissue to pleural tissue.(12) The MRI signal of hemorrhagic tissues depends on the chemical state of iron atoms in the hemoglobin molecules and on the integrity of erythrocyte membranes.(10) Iron can be diamagnetic or paramagnetic, depending on the state of its outer electron orbitals. Paramagnetic iron alters T1 and T2 relaxation times of water protons through magnetic dipole-dipole interactions and susceptibility effects.(12,13) Dipole-dipole interactions shorten both T1 and T2 relaxation times, but have a greater effect on those of T1-weighted sequences.

(13) Our data suggest that pleural lesions exhibiting hyperintensity on T1-weighted sequences represent these hemorrhagic interactions. These findings might be useful for the diagnosis and differential diagnosis of CP. A susceptibility effect is present when iron atoms are compartmentalized within the erythrocyte membrane, causing magnetic field heterogeneity with a resulting loss of phase coherence and selective shortening of the T2 relaxation time.(12,13) Iron becomes more homogenously distributed after the degradation of erythrocyte membranes, and this effect is nullified.(12,13) Our findings probably represent that phase of hemoglobin degradation.

One of the most rapidly evolving techniques in the MRI field is DWI. This method explores the random diffusional motion of water molecules, which has intriguing properties depending on the physiological and anatomical environment of the organism studied. Although DWI has been applied in the study of pelvic endometriosis, there have as yet been no significant results.(1,10) However, our findings demonstrate that DWI might be useful for the detection of small endometriomas in pleural endometriosis.

In conclusion, pleural endometriosis usually presents with hydropneumothorax on chest X-rays or CT scans. In addition to the identification of hydropneumothorax, T1- and T2-weighted MRI sequences can be used in order to identify endometriomas presenting as hyperintense nodules.

In some cases, the restriction of diffusion visible on DWI could also be useful for the detection of small endometriomas. Pleural effusion might also show signal hyperintensity on T1-weighted MRI sequences. These findings are probably due to the blood component of the lesions. Therefore,

801

MRI is a good option for the characterization of pleural endometriotic nodules and hemorrhagic pleural effusion.

References 1. Coutinho A Jr, Bittencourt LK, Pires CE, Junqueira F, Lima CM, Coutinho E, et al. MR imaging in deep pelvic endometriosis: a pictorial essay.

Radiographics. 2011;31(2):549-67. PMid:21415196. http://dx.doi.org/10.1148/rg.312105144 2. Haruki T, Fujioka S, Adachi Y, Miwa K, Taniguchi Y, Nakamura H. Successful video-assisted thoracic surgery for pulmonary endometriosis: Report of a case. Surg Today. 2007;37(2):141-4. PMid:17243034. http://dx.doi. org/10.1007/s00595-006-3360-0 3. Alifano M, Legras A, Rousset-Jablonski C, Bobbio A, Magdeleinat P, Damotte D, et al. Pneumothorax recurrence after surgery in women: clinicopathologic characteristics and management. Ann Thorac Surg. 2011(1);92:322-6 PMid:21718864. http://dx.doi.org/10.1016/j. athoracsur.2011.03.083 4. Alifano M. Catamenial pneumothorax. Curr Opin Pulm Med. 2010;16(4):381-6. PMid:20473170. http://dx.doi. org/10.1097/MCP.0b013e32833a9fc2 5. Makhija Z, Marrinan M. A case of catamenial pneumothorax with diaphragmatic fenestrations. J Emerg Med. 2012;43(1):e1-3. PMid:19682826. http://dx.doi. org/10.1016/j.jemermed.2009.05.023 6. Ciudad MJ, Santamaría N, Bustos A, Ferreirós J, Cabeza B, Gómez A. Imaging findings in catamenial pneumothorax [Article in Spanish]. Radiologia. 2007;49(4):263-7. http:// dx.doi.org/10.1016/S0033-8338(07)73768-2 7. Hochhegger B, Irion K, Marchiori E. Whole-body magnetic resonance imaging: a viable alternative to positron emission tomography/CT in the evaluation of neoplastic diseases. J Bras Pneumol 2010;36(3):396. PMid:20625681. http://dx.doi.org/10.1590/S1806-37132010000300021 8. Santos MK, Elias J Jr, Mauad FM, Muglia VF, Trad CS. Magnetic resonance imaging of the chest: current and new applications, with an emphasis on pulmonology.

J Bras Pneumol. 2011;37(2):242-58. PMid:21537662. http://dx.doi.org/10.1590/S1806-37132011000200016 9. Hochhegger B, Marchiori E, Irion K, Souza AS Jr, Volkart J, Rubin AS. Magnetic resonance of the lung: a step forward in the study of lung disease. J Bras Pneumol. 2012;38(1):105-15. PMid:22407047. http:// dx.doi.org/10.1590/S1806-37132012000100015 10. Busard MP, Mijatovic V, van Kuijk C, Pieters-van den Bos IC, Hompes PG, van Waesberghe JH. Magnetic resonance imaging in the evaluation of (deep infiltrating) endometriosis: the value of diffusion-weighted imaging. J Magn Reson Imaging. 2010;32(4):1003-9. PMid:20882634. http://dx.doi.org/10.1002/jmri.22310 11. Picozzi G, Beccani D, Innocenti F, Grazzini M, Mascalchi M. MRI features of pleural endometriosis after catamenial haemothorax. Thorax. 2007;62(8):744. PMid:17687105 PMCid:2117275. http://dx.doi.org/10.1136/thx.2006.071415 12. Atlas SW, Thulborn KR. Intracranial hemorrhage. In: Atlas SW, editor. Magnetic resonance imaging of the brain and spine. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2002: p.773-832.

13. Gomori JM, Grossman RI, Goldberg HI, Zimmerman RA, Bilaniuk LT. Intracranial hematomas: imaging by highfield MR. Radiology 1985;157(1):87-93. PMid:4034983.

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About the authors Edson Marchiori

Associate Professor. Department of Radiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Gláucia Zanetti

Professor of Clinical Medicine. Petrópolis School of Medicine, Petrópolis, Brazil.

Rosana Souza Rodrigues

Radiologist. Federal University of Rio de Janeiro and D’Or Research and Education Institute, Rio de Janeiro, Brazil.

Luciana Soares Souza

Radiologist. Clínica Ultra X, São José do Rio Preto, Brazil.

Arthur Soares Souza Jr

Professor. São José do Rio Preto School of Medicine; and Radiologist. Clínica Ultra X, São José do Rio Preto, Brazil.

Flávia Angélica Ferreira Francisco

Resident in Radiology. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Bruno Hochhegger

Thoracic Radiologist. Santa Casa Hospital Complex in Porto Alegre, Porto Alegre, Brazil.

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Letter to the Editor The role of academic associations in professional training O papel das ligas acadêmicas na formação profissional

Mayara Lisboa Soares de Bastos, Anete Trajman, Eleny Guimarães Teixeira, Lia Selig, Márcia Teresa Carreira Teixeira Belo

To the Editor: The training of future health professionals should be aimed at the acquisition of knowledge, attitudes, and practices that will enable them to promote health, prevent diseases, and address the most prevalent conditions in their country.

The Brazilian National Curriculum Guidelines for healthcare courses, published in late 2001, recommend that “the most common health care needs be at the core of the curriculum development” and suggest that methodologies that favor the integration of teaching, research, outreach, and health care be used in order to foster attitudes toward citizenship.(1,2) In order to achieve these goals, the curricula should provide different teaching-learning scenarios, facilitate active interaction with users and health professionals at the outset of the training program, and integrate the social needs of health care into academic training, with an emphasis on the Sistema Único de Saúde (SUS, Brazilian Unified Health Care System). Teaching activities that stimulate creativity, as well as initiative for selflearning and critical thinking, prepare future professionals for the constant changes and advances in knowledge in the modern world, which require critical analysis in decision-making regarding whether or not to implement everincreasing technological innovations into their practices. The classical professor-centered model no longer meets the needs of the new society.

In this scenario, there have been an increasing number of alternative ways of stimulating and sharing professional experiences even during the training program. Academic associations represent one such alternative. They are student organizations whose activities are undertaken in conjunction with professors, researchers, and professionals working within the SUS, at the initiative of students themselves, who are interested in exploring or increasing their knowledge of a given theme.

Academic associations can have different formats and statutes. However, in 2006, the

Executive Board of the Brazilian National Medical Student Association released a booklet containing guidelines for establishing medical academic associations and for developing statutes for such associations.(3) Although the booklet can be used as a guide in the process of founding academic associations, the guidelines provided are not aimed at standardizing such associations.

The Executive Board of the Brazilian National Medical Student Association understands that each school of medicine has its own particularities.

Academic association activities are based on the triad of teaching, research, and outreach.

Teaching activities include lectures, clinical case discussion, seminars, mini-courses, and practical activities, including the follow-up of outpatients and of patients being treated at other facilities.

Health promotion activities, which are usually neglected in the curricula, are one of the most important academic association activities. Health campaigns can be developed in conjunction with nongovernmental organizations and community centers. This interaction, together with day-to-day practice, can aid students in choosing their future specialty. The reported experiences are quite diverse.

In some medical schools, academic association councils have emerged; these are organizations that are often linked to academic centers and that aim at organizing and coordinating the various academic association activities, as well as at evaluating proposals for new associations.(3) In the past decade, the number of academic associations in the medical schools in Brazil has increased, as has the impact of such associations.

The Brazilian Society of Medical Academic Associations was created during the VIII Brazilian Clinical Medicine Conference, held in the city of Gramado, Brazil, in 2005.(4) More recently, various medical specialty societies have provided support for the development of academic associations, making room for the dissemination of information on such associations on their homepages. In April of 2012, the Rio de Janeiro Regional Council J Bras Pneumol. 2012;38(6):803-805

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Bastos MLS, Trajman A, Teixeira EG, Selig L, Belo MTCT

of Medicine organized a meeting of academic associations in the state in order to increase their visibility and to stimulate the creation of new academic associations.

On the Internet, there are records of academic associations for various medical specialties or diseases. Among those of interest to the readers of the Brazilian Journal of Pulmonology are the Academic Associations of Pulmonology, Infectious Diseases, and Pediatrics, as well as the Liga Científica de Tuberculose do Rio de Janeiro (LCTRJ, Rio de Janeiro Tuberculosis Scientific League).

Such associations are generally linked to a single institution, although some are inter-institutional; some are linked to a single department (nearly always a medical department), whereas others, such as the LCT-RJ, are multidisciplinary.

Our experience began in March of 2001,(5) when the LCT-RJ was founded by students and faculty members of the Gama Filho University School of Medicine with the objectives of contributing to tuberculosis control through activities aimed at increasing the visibility of the disease; increasing medical student knowledge; doing research, under the guidance of faculty members, on issues affecting the state; and raising the awareness of health administrators, faculty members, health professionals, and civil society to the serious problem of tuberculosis.

Students from other departments and educational institutions soon joined the LCT-RJ, approximately 300 undergraduate students having joined the LCT-RJ since its creation.

For recruiting new members, the LCT-RJ holds a biennial awareness-raising symposium, during which health administrators, professionals working within the SUS, and researchers address the importance of the LCT-RJ and senior students present their papers and share their experiences.

Since 2001, six symposia have been held, and there has been an increasing participation of students from different institutions: the 2010 symposium had 250 participants. After selection during the symposia, students attend lectures on epidemiological, clinical, and operational aspects of the disease. In one decade, 82 students have received young investigator grants; 98 abstracts have been presented at 22 national events and at 16 international events; and 15 articles have been published in indexed journals. As a means of disseminating information, a blog was created (lctrj.multiply.com/).

In addition to contributing to the civic education of health professionals, the J Bras Pneumol. 2012;38(6):803-805

multiplication of such initiatives can promote interdisciplinarity and stimulate interest in research and specialization, as well as contributing to continuing education, as recommended in the Brazilian National Curriculum Guidelines.

Mayara Lisboa Soares de Bastos Medical Student at the Gama Filho University and Student Coordinator for the Rio de Janeiro Tuberculosis Scientific League, Rio de Janeiro, Brazil Anete Trajman Coordinator of the Professional Master’s Program in Health Education, Gama Filho University, and Professor Coordinator for the Rio de Janeiro Tuberculosis Scientific League, Rio de Janeiro, Brazil Adjunct Professor. McGill University, Montreal, Canada Eleny Guimarães Teixeira Assistant Professor at the Souza Marques Technical Educational Foundation and Professor for the Rio de Janeiro Tuberculosis Scientific League, Rio de Janeiro, Brazil Lia Selig Full Professor at the Serra dos Órgãos University Center School of Medicine and Professor for the Rio de Janeiro Tuberculosis Scientific League, Rio de Janeiro, Brazil Márcia Teresa Carreira Teixeira Belo Assistant Professor at the Souza Marques Technical Educational Foundation and Professor for the Rio de Janeiro Tuberculosis Scientific League, Rio de Janeiro, Brazil

References 1. Brasil. Resolução CNE/CES nº 4, de 7 de novembro de 2001. Institui Diretrizes Curriculares Nacionais do Curso de Graduação em Medicina. Diário Oficial da União.

09 Nov 2001;Seção 1:38.

The role of academic associations in professional training

2. Brasil. Resolução nº 3, de 7 de novembro de 2001.

Institui Diretrizes Curriculares Nacionais do Curso de Graduação em Enfermagem. Diário Oficial da União.

09 Nov 2001;Seção 1:37.

3. Torres AR, Oliveira GM, Yamamoto FM, Lima MC. Ligas Acadêmicas e formação médica: contribuições e desafios.

Interface (Botucatu). 2008;12(27):713-20. http://dx.doi. org/10.1590%2FS1414-32832008000400003

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4. Associação Brasileira de Ligas Acadêmicas de Medicina - ABLAM. São Paulo: Associação Brasileira de Ligas Acadêmicas de Medicina [cited 2012 Feb 26].

Available from: http://www.ablam.org.br/institucional.html 5. Trajman A, Selig L, Teixeira Belo MT, Teixeira EG, Brito R, Kritski A. The Tuberculosis Scientific League: enrolling medical students in the battle against the disease. Int J Tuberc Lung Dis. 2001;5(12):1165-6. PMid:11769780.

Submitted: 26 February 2012. Accepted, after review: 02 April 2012.

J Bras Pneumol. 2012;38(6):803-805

Letter to the Editor Lung transplantation without the use of cardiopulmonary bypass in a patient with Kartagener syndrome Transplante pulmonar sem circulação extracorpórea em uma paciente com síndrome de Kartagener

Luziélio Alves Sidney Filho, Tiago Noguchi Machuca, José de Jesus Camargo, José Carlos Felicetti, Spencer Marcantonio Camargo, Fabíola Adélia Perin, Letícia Beatriz Sanchez, Sadi Marcelo Schio

To the Editor: We read with great interest the article by Athanazio et al. addressing the issue of whether the bronchiectasis treatment given to cystic fibrosis patients should be extrapolated to those with bronchiectasis from other causes.(1) Primary ciliary dyskinesia is a rare condition that results in the formation of bronchiectasis, and surgical treatment is invariably indicated. Some of the patients with this condition develop advanced lung disease refractory to clinical treatment and surgical resection, therefore becoming candidates for lung transplantation. When associated with dextrocardia, bronchiectasis, and chronic sinus disease, primary ciliary dyskinesia is designated Kartagener syndrome and is considered a contraindication to lung transplantation in many centers.(2,3) Thirteen years ago, we treated a 26-year-old female patient who had Kartagener syndrome and a history of recurrent pneumonia, together with localized bronchiectasis refractory to clinical treatment. Left middle lobectomy and right lingulectomy were indicated. The patient remained asymptomatic for 10 years, at which point the pneumonia recurred because of new foci of bronchiectasis (Figure 1), the patient showing significant lung function impairment requiring continuous oxygen therapy at 7 L/min.

The patient was evaluated for lung transplantation and was included on a waiting list. She had an FEV1 of 0.52 L (18.6% of predicted) and an FVC of 0.63 L (18.5% of predicted).

Her six-minute walk distance was 197 m with desaturation of 19% (SpO2 having decreased from 94% to 75%). Her pulmonary artery systolic pressure was 32 mmHg, and she presented with 79% perfusion in the right lung.

J Bras Pneumol. 2012;38(6):806-809

While on the waiting list, the patient experienced severe deterioration in lung function due to infection with resistant organisms (Acinetobacter baumannii), and mechanical ventilation was therefore required. She underwent tracheostomy on the seventh day of mechanical ventilation and was successfully treated with a prolonged course of linezolid. The patient was still in the ICU when a compatible organ became available. She underwent bilateral lung transplantation.

The procedure was performed through bilateral transverse thoracosternotomy (clamshell incision), and, because of the dextrocardia, the superior and inferior vena cava were on the left side (Figure 2).

First, lysis of adhesions was performed, followed by dissection of the left pulmonary hilum and pneumonectomy (21% perfusion). There was no hemodynamic instability or desaturation after clamping of the left pulmonary artery, and singlelung ventilation was well tolerated. Therefore, cardiopulmonary bypass (CPB) was not used.

The left bronchus (which was shorter than the right) was sectioned juxta-proximal to the branching to the upper lobe, and pneumonectomy was completed. End-to-end bronchial anastomosis was performed with continuous 4-0 polydioxanone suture, end-to-end arterial anastomosis was performed with continuous 6-0 polypropylene suture, and end-to-end atrial anastomosis was performed with continuous 5-0 polypropylene suture.

After reperfusion, we proceeded similarly for the right side. The pleural cavities were drained with 32F and 36F chest tubes, and surgical time was 330 min.

Lung transplantation without the use of cardiopulmonary bypass in a patient with Kartagener syndrome

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Figure 1 - In A, preoperative chest CT scans showing areas of bronchiectasis. In B, chest CT scans taken two months after transplantation and revealing healthy lungs and no bronchiectasis.

The postoperative period was uneventful.

The patient received antibiotic prophylaxis with linezolid and piperacillin-tazobactam until the culture results were known. The tracheostomy tube was removed on postoperative day 2. The patient was discharged from the ICU on postoperative day 15 and was discharged from the hospital on postoperative day 30. The patient had no acute rejection or infection with cytomegalovirus during hospitalization.

At postoperative month 2, the patient had an FEV1 of 2.05 L (74.3% of predicted) and an FVC of 2.45 L (75.4% of predicted). At postoperative month 6, her FEV1 was 2.27 L (81% of predicted).

At this writing (postoperative month 12), the patient had an FEV1 of 2.47 L (85% of predicted) and an FVC of 2.37 L (82.4% of predicted).

Lung transplantation is indicated for patients with clinically unmanageable advanced bronchiectasis and significantly impaired lung function. This group includes patients with cystic fibrosis and those with other types of bronchiectasis, although it rarely includes those with Kartagener syndrome. Although the

presence of Kartagener syndrome is considered a contraindication for lung transplantation in some centers, lung transplantation is the procedure of choice, provided that the usual technique is modified.(3) In situs inversus, lung anatomy is reversed, and finding a donor with situs inversus is extremely unlikely. Therefore, techniques were developed for lung transplantation in such cases. It is a challenging procedure, being indicated for patients without cardiac involvement.(4-6) Miralles et al. were the first to describe heatlung transplantation in this situation, proposing the creation of a large single atrium that, through CPB, was anastomosed to the donor atrium.(5) In 1996, Rábago et al. modified that technique, rotating the cardiac apex in order to restore normal anatomy.(6) In 2009, Deuse & Reitz anastomosed a portion of the superior vena cava to the donor atrial appendage without the use of vascular prostheses.(4) In all of the cases described above, there was heart-lung transplantation and use of CPB. J Bras Pneumol. 2012;38(6):806-809

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Sidney Filho LA, Machuca TN, Camargo JJ, Felicetti JC, Camargo SM, Perin FA et al.

Figure 2 - View of the left hemithorax showing the vena cava on the left side and ligation of the vessels for pneumonectomy.

Patients with situs inversus rarely present with cardiac function impairment requiring heart transplantation, and, because of the embolic complications caused by the creation of large atria, alternative techniques were developed for bilateral lung transplantation without heart transplantation.

In 1994, Macchiarini et al. reported three cases in which only bilateral lung transplantation was performed.(7) The technique employed by those authors is similar to the technique that we employed in our patient, except for the use of a median sternotomy rather than a clamshell incision in two of the three patients. Unlike other authors, Macchiarini et al. anastomosed the bronchi rather that the trachea; nevertheless, the three patients were placed on CPB.(7) In 2000, the procedure was performed without the use of CPB for the first time, having been performed through sequential bilateral thoracotomies in a 15-year-old female patient; a technical modification was needed in order to adjust bronchial size, and ischemia time was 460 min, which is a long period of ischemia.(8) In the case reported here, the clamshell incision J Bras Pneumol. 2012;38(6):806-809

was used, and surgical time was 330 min, which reduced ischemia time.

Recently, Date et al. performed living donor transplantation for primary ciliary dyskinesia in a 24-year-old female patient on mechanical ventilation, and CPB was used.(9) Referral centers will inevitably have to face these challenges. Because it is difficult to perform studies that are more comprehensive, cases like the one presented here should be reported in order to add to the experience and discussion.

We demonstrated the good results obtained in a high-risk patient (with multidrug-resistant organism colonization and on mechanical ventilation) and reviewed alternative techniques that can be useful in other centers.

Luziélio Alves Sidney Filho Thoracic Surgeon of the Lung Transplant Group at the Santa Casa Hospital Complex in Porto Alegre, Porto Alegre, Brazil

Lung transplantation without the use of cardiopulmonary bypass in a patient with Kartagener syndrome

Tiago Noguchi Machuca Thoracic Surgeon of the Lung Transplant Group at the Santa Casa Hospital Complex in Porto Alegre, Porto Alegre, Brazil Fellow in Thoracic Surgery, Toronto General Hospital, Toronto, ON, Canada José de Jesus Camargo Head of the Department of Thoracic Surgery and Coordinator for the Lung Transplant Group at the Santa Casa Hospital Complex in Porto Alegre, Porto Alegre, Brazil José Carlos Felicetti Thoracic Surgeon of the Lung Transplant Group at the Santa Casa Hospital Complex in Porto Alegre, Porto Alegre, Brazil Spencer Marcantonio Camargo Thoracic Surgeon of the Lung Transplant Group at the Santa Casa Hospital Complex in Porto Alegre, Porto Alegre, Brazil Fabíola Adélia Perin Thoracic Surgeon of the Lung Transplant Group at the Santa Casa Hospital Complex in Porto Alegre, Porto Alegre, Brazil Letícia Beatriz Sanchez Pulmonologist of the Lung Transplant Group at the Santa Casa Hospital Complex in Porto Alegre, Porto Alegre, Brazil

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Sadi Marcelo Schio Clinical Coordinator for the Lung Transplant Group at the Santa Casa Hospital Complex in Porto Alegre, Porto Alegre, Brazil

References 1. Athanazio RA, Rached SZ, Rohde C, Pinto RC, Fernandes FL, Stelmach R. Should the bronchiectasis treatment given to cystic fibrosis patients be extrapolated to those with bronchiectasis from other causes? J Bras Pneumol. 2010;36(4):425-31. PMid:20835588. http:// dx.doi.org/10.1590/S1806-37132010000400006 2. Ortega HA, Vega Nde A, Santos BQ, Maia GT. Primary ciliary dyskinesia: considerations regarding six cases of Kartagener syndrome. J Bras Pneumol. 2007;33(5):602-8.

PMid:18026660. http://dx.doi.org/10.1590/ S1806-37132007000500017 3. Camargo Jde J, Camargo SM, Machuca TN, Perin FA, Schio SM, Felicetti JC. Surgical maneuvers for the management of bronchial complications in lung transplantation. Eur J Cardiothorac Surg. 2008;34(6):1206-9. PMid:18715795. http://dx.doi.org/10.1016/j.ejcts.2008.06.027 4. Deuse T, Reitz BA. Heart-lung transplantation in situs inversus totalis. Ann Thorac Surg. 2009;88(3):1002-3.

PMid:19699943. http://dx.doi.org/10.1016/j. athoracsur.2009.01.060 5. Miralles A, Muneretto C, Gandjbakhch I, Lecompte Y, Pavie A, Rabago G, et al. Heart-lung transplantation in situs inversus. A case report in a patient with Kartagener’s syndrome. J Thorac Cardiovasc Surg. 1992;103(2):307‑13.

PMid:1735997.

6. Rábago G, Copeland JG 3rd, Rosapepe F, Tsen AC, Arzouman DA, Arabia FA, et al. Heart-lung transplantation in situs inversus. Ann Thorac Surg. 1996;62(1):296-8. http://dx.doi.org/10.1016/0003-4975(96)00203-2 7. Macchiarini P, Chapelier A, Vouhé P, Cerrina J, Ladurie FL, Parquin F, et al. Double lung transplantation in situs inversus with Kartagener’s syndrome. Paris-Sud University Lung Transplant Group. J Thorac Cardiovasc Surg. 1994;108(1):86-91. PMid:8028384.

8. Lama Martínez R, Santos Luna F, Salvatierra Velázquez A, Cerezo Madueño F, Algar Algar J, Alvarez Kindelán A. Sequential double lung transplant in Kartagener’s syndrome [Article in Spanish]. Arch Bronconeumol. 2000;36(2):106-8.

PMid:10726200.

9. Date H, Yamashita M, Nagahiro I, Aoe M, Andou A, Shimizu N. Living-donor lobar lung transplantation for primary ciliary dyskinesia. Ann Thorac Surg. 2001;71(6):2008-9. http://dx.doi.org/10.1016/S0003-4975(00)02276-1

Submitted: 01 March 2012. Accepted, after review: 26 March 2012.

J Bras Pneumol. 2012;38(6):806-809

Letter to the Editor A successfully treated case of parainfluenza virus 3 pneumonia mimicking influenza pneumonia Um caso de pneumonia por vírus parainfluenza 3 simulando pneumonia por influenza tratada com sucesso

Nobuhiro Asai, Yoshihiro Ohkuni, Norihiro Kaneko, Yasutaka Kawamura, Masahiro Aoshima

To the Editor: Influenza infection is the most common viral infection causing respiratory illness. Influenza pneumonia is the most severe complication of influenza virus infection, resulting in high mortality.(1) Although seasonal influenza viruses are commonly detected by rapid antigen testing of nasopharyngeal swabs, a swine flu virus (H1N1) is rarely isolated.(1) Therefore, anti-influenza therapy should be started empirically if influenza pneumonia is suspected.

It is known that parainfluenza virus (PIV) caused influenza-like illness during the swine influenza pandemics.(2) It has been reported that PIV type 3 (PIV3) can cause pneumonia in immunosuppressed patients, such as adult transplant recipients.(3) We report a successfully treated case of PIV3 pneumonia mimicking influenza pneumonia in a 31-year-old female patient with asthma. The patient had high fever (39.5°C), general fatigue, systemic joint pain, and anorexia for two days before being referred to our medical center. She was a current smoker and had a history of smoking (20 pack-years) and of bronchial asthma (no current use of medication). The patient also had poorly controlled diabetes mellitus and a body mass index of 30 kg/m2. A chest X-ray revealed diffuse ground-glass opacities in both lungs (Figure 1).

Laboratory tests showed severe inflammatory reaction (C-reactive protein = 19.2 mg/dL and ESR = 83 mm/h). She had severe respiratory failure and an SpO2 of 80% on room air at the first visit, and oxygen therapy was started with noninvasive positive pressure ventilation. Because of the severe respiratory failure, bronchoalveolar lavage was not performed. Although the result of a rapid influenza antigen detection test was negative, she was diagnosed with influenza pneumonia J Bras Pneumol. 2012;38(6):810-812

on the basis of influenza-like symptoms and radiological findings, such as diffuse groundglass opacities (Figure 2).

The patient was started on empirical treatment with peramivir (600 mg/day) for 5 days (for the influenza infection) combined with a steroid pulse and i.v. erythromycin (1,000 mg/day) for 5 days (for the acute respiratory failure). Her respiratory function gradually improved, and noninvasive positive pressure ventilation was discontinued on day 5. Oral prednisolone was then started (at 80 mg/day), and the dose was tapered, being modified once every three days, as follows: to 40 mg/day on day 6; to 30 mg/day on day 9; to 15 mg/day on day 12; and discontinuation on day 15. The patient was discharged on day 18. Although she tested negative for influenza A and influenza B antibodies, the patient tested

Figure 1 - Chest X-ray showing bilateral shadows predominantly in the hilar region.

A successfully treated case of parainfluenza virus 3 pneumonia mimicking influenza pneumonia

Figure 2 - CT scan of the chest showing bilateral diffuse ground-glass opacities.

positive for PIV3 antibody. A final diagnosis of PIV3 pneumonia was made.

The most common mimics of swine influenza (H1N1) pneumonia are Legionnaires’ disease and human PIV3 (HPIV3) pneumonia in adults and pneumonia caused by respiratory syncytial virus or human metapneumovirus in children.(4) It is known that HPIV types 1-3 are primarily pediatric respiratory pathogens and a common cause of laryngotracheobronchitis (croup) in young children.(4) In adults, HPIV3 is a recognized cause of community-acquired pneumonia (CAP) in immunosuppressed patients or transplant recipients.

However, HPIV3 can also present as a viral CAP in normal hosts.(5) During an influenza pandemic, clinicians should consider the diagnosis of PIV3 pneumonia if patients present with influenza-like symptoms and negative rapid influenza antigen detection test results.

Although some successfully treated cases have previously been reported,(2) the standard treatment for PIV3 pneumonia has yet to be established. We administered a combination of steroid pulse therapy (i.v. erythromycin) and anti-flu medication. As a result, the respiratory function of the patient rapidly improved. It has been reported that macrolides can be effective for severe inflammation, since it is evident that they decrease neutrophil chemotaxis and infiltration into the respiratory epithelium, downregulating adhesion molecule expression and enhancing neutrophil apoptosis.(6,7) In addition, animal studies have shown that high doses of steroids

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are effective in reducing pulmonary lesions and suppressing cytokines, leading to a shutdown in macrophage activation.(6-8) It is reasonable to assume that, in the present case, erythromycin had an immunomodulatory effect rather than an antimicrobial effect when combined with a high dose of prednisolone.

The plasma level of cytokines such as IL-6 and IL-10 was found to be higher in influenza A (H1N1)-infected patients who died or who had acute respiratory distress syndrome than in patients with less severe disease.(9) The mechanism of severe pulmonary inflammation is still unclear. Adipokines released by adipocytes could cause an allergic reaction. In addition, a cytokine storm could easily occur in patients with allergic conditions such as bronchial asthma and rheumatic disease.(10) Because she was obese and had a history of bronchial asthma, our patient was at risk of severe pulmonary inflammation.

One limitation of our report is that the plasma levels of cytokines were not determined. Given that inflammatory markers such as C-reactive protein and ESR were very high, we speculate that a cytokine storm occurred in our patient.

In conclusion, physicians should be aware that other pathogens can cause viral CAP mimicking influenza pneumonia during an influenza pandemic. More cases should be investigated in order to establish the standard treatment for viral pneumonia.

Acknowledgments We are grateful for the diligent and thorough critical reading of our manuscript by Mr. John Wocher, Executive Vice President and Director, International Affairs/International Patient Services, Kameda Medical Center, Kamogawa, Japan.

Nobuhiro Asai Resident, Kameda Medical Center, Kamogawa, Japan Yoshihiro Ohkuni Chief, Kameda Medical Center, Kamogawa, Japan Norihiro Kaneko Chief, Kameda Medical Center, Kamogawa, Japan J Bras Pneumol. 2012;38(6):810-812

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Asai N, Ohkuni Y, Kaneko N, Kawamura Y, Aoshima M

Yasutaka Kawamura Head of the Radiology Department, Kameda Medical Center, Kamogawa, Japan Masahiro Aoshima Head of the Pulmonology Department, Kameda Medical Center, Kamogawa, Japan

References 1. Itoh Y, Shinya K, Kiso M, Watanabe T, Sakoda Y, Hatta M, et al. In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses.

Nature. 2009;460(7258):1021-5. PMid:19672242 PMCid:2748827.

2. Cunha BA, Corbett M, Mickail N. Human parainfluenza virus type 3 (HPIV 3) viral community-acquired pneumonia (CAP) mimicking swine influenza (H1N1) during the swine flu pandemic. Heart Lung. 2011;40(1):76-80. PMid:20888645. http://dx.doi.org/10.1016/j.hrtlng.2010.05.060 3. Whimbey E, Vartivarian SE, Champlin RE, Elting LS, Luna M, Bodey GP. Parainfluenza virus infection in adult bone marrow transplant recipients. Eur J Clin Microbiol Infect Dis. 1993;12(9):699-701. PMid:8243487. http:// dx.doi.org/10.1007/BF02009383 4. Cunha BA, Pherez FM, Strollo S. Swine influenza (H1N1): diagnostic dilemmas early in the pandemic. Scand J

Submitted: 06 April 2012. Accepted, after review: 07 May 2012.

J Bras Pneumol. 2012;38(6):810-812

Infect Dis. 2009;41(11-12):900-2. PMid:19922079. http://dx.doi.org/10.3109/00365540903222465 5. Marx A, Gary HE Jr, Marston BJ, Erdman DD, Breiman RF, Török TJ, et al. Parainfluenza virus infection among adults hospitalized for lower respiratory tract infection.

Clin Infect Dis. 1999;29(1):134-40. PMid:10433576. http://dx.doi.org/10.1086/520142 6. Amsden GW, Baird IM, Simon S, Treadway G. Efficacy and safety of azithromycin vs levofloxacin in the outpatient treatment of acute bacterial exacerbations of chronic bronchitis. Chest. 2003;123(3):772-7. PMid:12628877. http://dx.doi.org/10.1378/chest.123.3.772 7. Asai N, Ohkuni Y, Matsunuma R, Iwama K, Otsuka Y, Kawamura Y, et al. A case of novel swine influenza A (H1N1) pneumonia complicated with virus-associated hemophagocytic syndrome. J Infect Chemother. 2012.

[Epub ahead of print]. http://dx.doi.org/10.1007/ s10156-011-0366-3 8. Ottolini M, Blanco J, Porter D, Peterson L, Curtis S, Prince G. Combination anti-inflammatory and antiviral therapy of influenza in a cotton rat model. Pediatr Pulmonol. 2003;36(4):290-4. PMid:12950040. http:// dx.doi.org/10.1002/ppul.10320 9. Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza, Bautista E, Chotpitayasunondh T, Gao Z, Harper SA, Shaw M, et al.

Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med. 2010;362(18):1708-19. Erratum in: N Engl J Med. 2010;362(21):2039. PMid:20445182. http://dx.doi.org/10.1056/NEJMra1000449 10. Shore SA, Terry RD, Flynt L, Xu A, Hug C. Adiponectin attenuates allergen-induced airway inflammation and hyperresponsiveness in mice. J Allergy Clin Immunol. 2006;118(2):389-95. PMid:16890763. http:// dx.doi.org/10.1016/j.jaci.2006.04.021

Letter to the Editor Overlap between asthma and COPD Sobreposição de asma brônquica e DPOC

Tiago Manuel Alfaro, Sara da Silva Freitas, Carlos Robalo Cordeiro

To the Editor: We have recently treated a 60-year-old female patient who was a college professor. She reported having bronchial asthma since childhood, having been treated by a pulmonologist until age 40 years.

The patient had remained asymptomatic until 7 years prior, when she began to have episodes of dyspnea, wheezing, and productive cough, which prompted repeated emergency room visits.

More recently, she had been hospitalized for community-acquired pneumonia and exacerbation of bronchial asthma. The patient responded well to treatment and was therefore discharged. However, she still complained of dyspnea on moderate exertion and occasional nocturnal wheezing.

The patient also complained of hypopharyngeal pain when using inhalers, as well as experiencing retrosternal burning after meals. She had no other complaints. The patient had been a smoker since she was 16 years old (smoking history, 30 pack-years). She had a history of bronchial asthma since childhood and of allergy to dust mites, as well as having pulmonary emphysema (diagnosed at age 49 years) and hiatal hernia.

Since her hospitalization, the patient had been receiving the salmeterol-fluticasone combination, tiotropium, aminophylline, and rescue albuterol.

She reported no occupational or domestic exposure to inhaled pollutants. In addition, she reported no contact with animals or recent trips abroad.

She also reported no contact with individuals with communicable diseases. Her family history was unremarkable. Physical examination revealed good general health and normal vital signs, with no signs of breathlessness. Pulmonary auscultation revealed diminished breath sounds at both lung bases and increased expiratory time. Examination of the abdomen and limbs revealed no abnormalities.

An HRCT scan showed centrilobular and paraseptal emphysema, cylindrical bronchiectasis (predominantly central and upper lobe bronchiectasis), and two micronodules of 3 mm and 4 mm in diameter, respectively, in the right lower lobe and in the left lower lobe (Figure 1).

Immunoglobulin quantification showed an increase in total IgE levels (671 IU/mL), with no other abnormalities. Alpha-1 antitrypsin levels were normal. Respiratory function test results revealed moderately severe obstructive lung disease accompanied by inflation, moderately reduced alveolar-capillary diffusion, and mild type I respiratory failure. The patient had a negative bronchodilator response (Table 1). Her electrocardiogram was normal, and the results of the microbiological study of sputum were negative.

The final diagnosis was uncontrolled bronchial asthma, pulmonary emphysema, diffuse bronchiectasis, and gastroesophageal reflux disease (GERD). The patient attributed her hypopharyngeal pain to the use of inhaled corticosteroids and therefore decided to discontinue the medication, having consequently shown improvement. She was started on esomeprazole, and salmeterol was replaced by indacaterol. Although this improved her pharyngeal and epigastric pain, she still had

Table 1 - Respiratory function parameters and arterial blood gas analysis results on room air.

Variation after Parameters Results bronchodilation, % FVC, % of predicted 99.6 0,0 FEV1, % of predicted 54.5 −0.17 FEV1/FVC, % 46.1 −0.17 TLC, % of predicted 110 10.2 RV, % of predicted 146 16.7 DLCO, % of predicted 51.3 pH 7.43 PaO2, mmHg 67 PaCO2, mmHg 44 HCO3, mEq/L 29 SaO2, % 93 HCO3: bicarbonate.

J Bras Pneumol. 2012;38(6):813-816

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Alfaro TM, Freitas S, Robalo Cordeiro C

Figure 1 - HRCT scan showing centrilobular and paraseptal emphysema, cylindrical bronchiectasis, and two micronodules (one in the left lower lobe and the other in the right lower lobe).

mild respiratory complaints. Treatment with inhaled budesonide was initiated, having been well tolerated by the patient. At this writing, the patient was under treatment with budesonide, indacaterol, tiotropium, esomeprazole, and aminophylline and had no respiratory or digestive complaints. In addition, she had been enrolled in a smoking cessation program and was currently receiving nicotine replacement therapy.

In asthma patients, smoking is a common problem that is difficult to manage. The incidence of active smoking in asthma patients can be as high as 35%.(1) Active smoking is associated with an increased risk of developing asthma in adults, such a risk being higher in females. Passive smoking is also associated with an increased risk of developing asthma, especially when it occurs in the uterus.(2) In asthma patients, smoking is associated with poorly controlled disease, the J Bras Pneumol. 2012;38(6):813-816

manifestations of which include a higher frequency of exacerbations and nocturnal complaints. This has been reported in studies including smokers and individuals (children and adults) exposed to passive smoking, although it is more difficult to determine the degree of exposure in the latter.(3,4) Another manifestation is corticosteroid resistance, which is seen in smokers with asthma. Smoking seems to make such patients resistant to the effects of low- or medium-dose inhaled corticosteroids, such patients therefore responding exclusively to high-dose inhaled corticosteroids.(5) Resistance to short-term oral corticosteroid therapy (even at high doses) has also been demonstrated.(6) Therefore, it is imperative to identify smokers with asthma and to make additional efforts in order to aid such patients in quitting smoking. In the clinical case described herein, despite having been repeatedly advised to quit smoking, the patient

Overlap between asthma and COPD

did not, having therefore been enrolled in the smoking cessation program available at our center.

Another noteworthy aspect is the association of bronchial asthma with pulmonary emphysema.

Our diagnosis of bronchial asthma with COPD was based on the lifestyle habits of our patient, the radiological findings, and the respiratory function test results. The overlap syndrome of asthma and COPD has been increasingly recognized, although its clinical features have yet to be well defined. Classically, uncontrolled bronchial asthma is recognized as a risk factor for COPD; however, such patients are often excluded from clinical trials.(7) Recent studies including patients with COPD and a history of asthma or investigating this specific population have shown that patients with the overlap syndrome of asthma and COPD are generally younger than those with COPD alone and have a shorter history of exposure to smoking, exacerbations being more frequent and quality of life being worse in the former group of patients.(8,9) In one study,(10) patients with the overlap syndrome of asthma and COPD were found to account for health care expenditures that were five times as high as were those that patients with either asthma or COPD accounted for.(10) Therefore, it is important to identify this subgroup of patients, for whom intensified therapy aiming at reducing the number of exacerbations is probably warranted. Our patient also presented with bronchiectasis and two pulmonary micronodules. Bronchiectasis has been reported in association with COPD and asthma.(11,12) The micronodules should be treated within 12 months after having been detected, given that the patient was a smoker.(13) Although the incidence of GERD is higher in patients with asthma (as is the incidence of asthma in patients with GERD), there is no evidence for a causal relationship. Hypotheses regarding how GERD can affect asthma include microaspiration (acid reflux having direct effects on the tracheobronchial mucosa) and vagal stimulation caused by the presence of acid in the esophagus.(14) A common comorbidity in patients with COPD, GERD appears to be associated with an increased risk of exacerbations. Although GERD treatment is not associated with a clear improvement in asthma control, the presence of symptoms in our patient led us to prescribe proton pump inhibitors, with good results. Finally, our patient presented with one of the local oropharyngeal

815

side effects of inhaled corticosteroids,(15) the symptoms having resolved after her medication was changed. The description and discussion of the present case allows us to conclude that special attention should be given to the smoking habits of patients with asthma, as well as to the association of asthma with COPD.

Tiago Manuel Alfaro Intern in Pulmonology, Coimbra Hospital and University Center, EPE, Coimbra, Portugal Sara da Silva Freitas Pulmonologist, Coimbra Hospital and University Center, EPE, Coimbra, Portugal Carlos Robalo Cordeiro Pulmonologist, Coimbra Hospital and University Center, EPE, and Professor of Pulmonology, University of Coimbra, Coimbra, Portugal

References 1. Stapleton M, Howard-Thompson A, George C, Hoover RM, Self TH. Smoking and asthma. J Am Board Fam Med. 2011;24(3):313-22. PMid:21551404. http://dx.doi. org/10.3122/jabfm.2011.03.100180 2. Gilliland FD, Berhane K, McConnell R, Gauderman WJ, Vora H, Rappaport EB, et al. Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function. Thorax. 2000;55(4):271-6.

PMid:10722765 PMCid:1745733. http://dx.doi. org/10.1136/thorax.55.4.271 3. Chaudhuri R, McSharry C, McCoard A, Livingston E, Hothersall E, Spears M, et al. Role of symptoms and lung function in determining asthma control in smokers with asthma. Allergy. 2008;63(1):132-5. PMid:18053022. http://dx.doi.org/10.1111/j.1398-9995.2007.01538.x 4. Jindal SK, Gupta D, Singh A. Indices of morbidity and control of asthma in adult patients exposed to environmental tobacco smoke. Chest. 1994;106(3):746-9.

PMid:8082352. http://dx.doi.org/10.1378/chest.106.3.746 5. Tomlinson JE, McMahon AD, Chaudhuri R, Thompson JM, Wood SF, Thomson NC. Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax. 2005;60(4):282-7.

PMid:15790982 PMCid:1747368. http://dx.doi. org/10.1136/thx.2004.033688 6. Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med. 2003;168(11):1308‑11.

J Bras Pneumol. 2012;38(6):813-816

816

Alfaro TM, Freitas S, Robalo Cordeiro C

PMid:12893649. http://dx.doi.org/10.1164/ rccm.200304-503OC 7. Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax. 2009;64(8):728-35. PMid:19638566. http:// dx.doi.org/10.1136/thx.2008.108027 8. Hardin M, Silverman EK, Barr RG, Hansel NN, Schroeder JD, Make BJ, et al. The clinical features of the overlap between COPD and asthma. Respir Res. 2011;12:127.

PMid:21951550 PMCid:3204243. http://dx.doi. org/10.1186/1465-9921-12-127 9. Kauppi P, Kupiainen H, Lindqvist A, Tammilehto L, Kilpelainen M, Kinnula VL, et al. Overlap syndrome of asthma and COPD predicts low quality of life. J Asthma. 2011;48(3):279-85. PMid:21323613. http:// dx.doi.org/10.3109/02770903.2011.555576 10. Soriano JB, Visick GT, Muellerova H, Payvandi N, Hansell AL. Patterns of comorbidities in newly diagnosed COPD and asthma in primary care. Chest. 2005;128(4):2099‑107.

PMid:16236861. http://dx.doi.org/10.1378/ chest.128.4.2099

Submitted: 02 April 2012. Accepted, after review: 04 June 2012.

J Bras Pneumol. 2012;38(6):813-816

11. Oguzulgen IK, Kervan F, Ozis T, Turktas H. The impact of bronchiectasis in clinical presentation of asthma. South Med J. 2007;100(5):468-71. PMid:17534081. http:// dx.doi.org/10.1097/SMJ.0b013e31802fa16f 12. Garcia MA, Cataluna JJ. Chronic obstructive pulmonary disease and bronchiectasias [Article in Spanish]. Arch Bronconeumol. 2010;46 Suppl 3:11-7. PMid:20620687.

13. MacMahon H, Austin JH, Gamsu G, Herold CJ, Jett JR, Naidich DP, et al. Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology. 2005;237(2):395‑400.

PMid:16244247. http://dx.doi.org/10.1148/ radiol.2372041887 14. Ratier JC, Pizzichini E, Pizzichini M. Gastroesophageal reflux disease and airway hyperresponsiveness: concomitance beyond the realm of chance? J Bras Pneumol. 2011;37(5):680-8. PMid:22042402. http:// dx.doi.org/10.1590/S1806-37132011000500017 15. Buhl R. Local oropharyngeal side effects of inhaled corticosteroids in patients with asthma.

Allergy. 2006;61(5):518-26. PMid:16629778. http:// dx.doi.org/10.1111/j.1398-9995.2006.01090.x

Índice Remissivo Índice remissivo de assunto do volume 38 (1-6), 2012 A

Abandono do hábito de fumar......................... 72, 761 Adenocarcinoma bronquíolo-alveolar.................... 218 Adenosina desaminase..............................................181 Adesão à medicação...................................................88 Agonistas de receptores adrenérgicos beta 2.........431 Alergia e imunologia................................................ 158 Análise de sobrevida................................................ 372 Anormalidades congênitas...................................... 526 Antibióticos antituberculose................................... 630 Apoptose....................................................................461 Aromatizantes.......................................................... 395 Asma.............................. 158, 116, 299, 308, 431, 438, 518, 550, 595, 643, 748, 786 Asma induzida por exercício................................... 292 Asma/diagnóstico........................................................24 Asma/prevenção & controle.......................................24 Aspergillus fumigatus.............................................. 125 Atenção primária à saúde................................382, 692 Atividades cotidianas............................................... 684 Atletas....................................................................... 292 Audiometria.................................................................81 Avaliação nutricional............................................... 470

B

Biópsia por agulha fina..............................................33 Biópsia...................................................................... 167 Brasil......................................................................... 282 Broncodilatadores.................................................... 748 Broncoscopia...........33, 167, 174, 315, 445, 526, 757 Bronquiectasia.......................................................... 346 Bronquiolite......................................................395, 786 Budesonida....................................................... 431, 748

C

Calibragem................................................................ 194 Camundongos.................................................... 98, 595 Capacidade inspiratória..............................................13 Carcinoma de pequenas células do pulmão.......... 372 Carcinoma pulmonar de células não pequenas.......................................105, 559 Circulação Extracorpórea com Oxigenador de Membrana...................................7 Coelhos..................................................................... 214 Comorbidade............................................................ 724 Condicionamento pré-transplante.......................... 776 Consenso....................................................................518 Consumo de oxigênio...............................................541 Controle de qualidade............................................. 766 Corpos estranhos.......................................................315 Cuidados intensivos................................................. 246

D

Dermatologia/instrumentação................................ 573 Derrame pleural...................... 125, 181, 226, 400, 614 Derrame pleural maligno/mortalidade................... 487 Desmame do respirador...................................364, 477 Desnutrição............................................................... 588 Diacetil...................................................................... 395 Diafragma................................................................. 566 Diagnóstico diferencial.............................................181 Diagnóstico por imagem......................................... 656 Diagnóstico tardio................................................... 202 Doença granulomatosa crônica.............................. 321 Doença pulmonar obstrutiva crônica...... 33, 116, 257, 331, 339, 494, 541, 579, 643, 684 Doença pulmonar obstrutiva crônica/diagnóstico.692 Doenças pulmonares intersticiais....................105, 282 Doenças respiratórias............................................... 526

E

Empiema pleural..............................................125, 226 Endometriose........................................................... 797 Enfermedades pulmonares fúngicas....................... 264 Enfisema pulmonar.................................................. 494 Ensaio clínico controlado como tópico................. 237 Envelhecimento................................................494, 656 Epidemiología.......................................................... 422 Escarro..............................................................167, 757 Espirometria......................................................188, 692 Esportes.......................................................................24 Estadiamento de neoplasias.......................................33 Estenose traqueal..................................................... 214 Estresse oxidativo........................................................98 Exercício.................................................... 13, 438, 579 Exposição ocupacional............................................ 550

F

Fatores de risco................. 57, 88, 559, 622, 708, 733 Fatores socioeconômicos.......................................... 511 Ferritinas................................................................... 666 Fertilização in vitro.................................................. 400 Fibrose cística..................... 41, 50, 116, 188, 470, 786 Fibrose pulmonar idiopática....................................116 Fidelidade a diretrizes.............................................. 148 Força muscular................................................. 541, 605

G

Glutationa transferase................................................50 Gordura abdominal.................................................. 356 Gravidez.................................................................... 643 Guias como assunto................................................ 282

J Bras Pneumol. 2012;38(6):817-819

818

H

Hemorragia............................................................... 133 Hiperidrose................................................................ 573 Hipertensão pulmonar............................................. 452 Histoplasmosis.......................................................... 264 HIV.......................................................................88, 511 Hospitalização.....................................57, 72, 148, 386

I

Imagem por ressonância magnética...............105, 797 Implante de prótese................................................. 214 Imunofenotipagem.................................................. 321 Infecciones neumocócicas....................................... 422 Infecções comunitárias adquiridas..........................614 Infecções pneumocócicas...........................................66 Infecções por HIV/epidemiologia............................ 724 Infecções respiratórias.......................................66, 643 Infectologia.............................................................. 634 Inflamação...................................................................98 Ingestão de energia................................................. 470 Insuficiência Respiratória.................................... 7, 386 Interleucina-1........................................................... 452

L

Laboratórios.............................................................. 766 Lavagem broncoalveolar.......................................... 167 Lesão pulmonar induzida por ventilação mecânica....................................................98 Linfohistiocitose hemofagocítica............................ 666 Linfoma......................................................................181

M

Macrolídeos.............................................................. 786 Manuseio das vias aéreas.........................................315 Marca-passo artificial.............................................. 566 Matriz extracelular...........................................321, 588 Mecânica respiratória............................................... 194 Meteorologia............................................................ 708 Microscopia.............................................................. 174 Modalidades de fisioterapia.................................... 477 Modelos Lineares..................................................... 700 Monocrotalina.......................................................... 452 Mortalidad................................................................ 422 Músculos respiratórios............................ 257, 308, 700 Mycobacterium tuberculosis.................. 210, 622, 740 Mycoplasma pneumoniae........................................ 226

N

Neoplasias da mama/genética................................ 487 Neoplasias da mama/mortalidade........................... 487 Neoplasias pulmonares......................................33, 218 Neoplasias pulmonares/classificação...................... 445 Neoplasias pulmonares/diagnóstico....................... 445 Neumonía Bacteriana.............................................. 422 Nicotina............................................................ 716, 761 Nitrato redutase....................................................... 210 Nódulo pulmonar solitário...................................... 559

J Bras Pneumol. 2012;38(6):817-819

O Obesidade................................................................. 356 Obstrução das vias respiratórias...............................315 Oncologia.................................................................. 634 Oseltamivir...................................................................57 Ovalbumina.............................................................. 595 Oxigenoterapia..........................................................331

P Pacientes desistentes do tratamento...................... 503 Paracoccidioidomicosis............................................ 264 Penicilina G.................................................................66 Perda auditiva.............................................................81 Perfusão.................................................................... 776 Pesquisa.................................................................... 634 Pirazinamida............................................................. 740 Planejamento de assistência ao paciente............... 503 Pletismografia........................................................... 194 Pneumologia............................................................ 634 Pneumonectomia..................................................... 452 Pneumonia.............................................. 105, 226, 614 Pneumonia/epidemiologia...................................... 708 Pneumonia/mortalidade.......................................... 148 Pneumonia/terapia................................................... 148 Pneumopatias........................................................... 105 Pneumotórax............................................................ 797 Política de saúde.......................................................518 Poluição do ar.......................................................... 643 Postura...................................................................... 194 Preservação de órgãos..................................... 461, 776 Prevalência................................................................ 550 Previdência social..................................................... 550 Pseudomonas aeruginosa...........................................41 Pulmão..................................................... 105, 246, 656

Q Quadriplegia............................................................. 566 Qualidade de vida................................... 331, 339, 346 Questionários............................................................ 299

R Radioterapia............................................................. 372 Receptor beta de fator de crescimento derivado de plaquetas........................ 452 Regulador de condutância transmembrana em fibrose cística.............................50 Remodelação das vias aéreas.................................. 588 Reprodutibilidade dos testes.................. 339, 684, 716 Resistência a medicamentos.......................................66 Resistência das vias respiratórias............................ 188 Respiração artificial................................... 98, 386, 566 Resultado de tratamento................................. 503, 761 Rifampicina..................................................................88

819

S

Sarcoidose................................................................. 321 Sarcoidose pulmonar............................................... 666 Saúde do trabalhador.............................................. 550 Sequestro broncopulmonar..................................... 133 Serviços de Saúde.................................................... 299 Síndrome de abstinência a substâncias......... 716, 761 Síndrome de ativação macrofágica........................ 666 Síndrome de hiperestimulação ovariana................ 400 Sistema respiratório.........................................605, 643 Sistemas de informação em laboratório clínico.... 766 Soluções para preservação de órgãos......................461 Soroprevalência de HIV........................................... 382 Staphylococcus aureus................................................41 Stents........................................................................ 214 Streptococcus pneumoniae...............................66, 422 Suor........................................................................... 573

T

Tabagismo................................................................ 356 Tabagismo/epidemiologia..........................................72 Técnicas de diagnóstico do sistema respiratório... 174 Tecnologia................................................................ 766 Tempo de internação............................................... 477 Terapia combinada.................................................. 748 Teste de esforço................................13, 116, 292, 579 Testes de função respiratória........158, 188, 257, 308, 321, 346, 438, 470, 541, 605, 700 Testes de sensibilidade microbiana......................... 210 Tolerância ao exercício.................................... 116, 346 Tomografia..................................................................41 Tomografia computadorizada espiral..................... 494 Tomografia computadorizada por raios X............. 218 Tomografia de coerência óptica............................. 174 Tórax......................................................................... 656 Toxicidade de drogas........................................... 81, 88 Transplante de pulmão.............................................461

Transplante de pulmão............................................ 776 Transtorno por uso de tabaco........................ 716, 761 Traqueia.................................................................... 174 Traqueia/anatomia e histologia.............................. 588 Traqueia/crescimento e desenvolvimento.............. 588 Traumatismo por reperfusão....................................461 Traumatismos da medula espinal........................... 566 Tuberculose............... 81, 88, 125, 181, 382, 386, 503 Tuberculose pulmonar.....................................167, 733 Tuberculose pulmonar/diagnóstico;....................... 757 Tuberculose pulmonar/epidemiologia.................... 622 Tuberculose resistente a múltiplos medicamentos........................ 210, 733, 740 Tuberculose/diagnóstico........................ 202, 237, 766 Tuberculose/epidemiologia.....................511, 724, 771 Tuberculose/estatística e dados numéricos............771 Tuberculose/microbiologia...................................... 630 Tuberculose/mortalidade..........................................771 Tuberculose/prevenção e controle.......................... 237 Tuberculose/quimioterapia...................................... 630 Tuberculose/terapia................................................. 202 Tumor Carcinoide.................................................... 133

U Ultrassonografia....................................................... 246 Ultrassonografia de intervenção................................33 Unidades de Terapia Intensiva............................ 7, 246

V Vacunas neumocócicas............................................ 422 Valores de Referência............................................... 700 Ventilação................................................................. 364 Ventiladores mecânicos........................................... 364 Vírus da influenza A subtipo H1N1..........................57

J Bras Pneumol. 2012;38(6):817-819

Índice Remissivo Índice remissivo de autores do volume 38(1-6), 2012 A

Abdalla LG................................................................ 776 Acencio MMP........................................................... 452 Acurio V.................................................................... 757 Adame ML................................................................ 672 Aidé MA.................................................................... 282 Albrez EA.................................................................. 708 Albuquerque ALP................................................... 1, 24 Albuquerque Filho APL............................................ 395 Albuquerque YMM................................................... 530 Alcântara CCS........................................................... 622 Alfaro TM...................................................................813 Algranti E.................................................................. 282 Almeida FM.............................................................. 452 Almeida PCA............................................................. 299 Alves GRT..........................................................404, 494 Amaral LM.................................................................518 Amato MBP...................................................................7 Amorim PG................................................................614 Andrade AFD............................................................ 700 Andrade CHS.............................................................116 Andrade FM.............................................................. 588 Andrade-Lima M...................................................... 748 Andreazzi D.................................................................66 Antonangelo L...........................................................181 Antonio CA............................................................... 674 Aoshima M.................................................................810 Arakaki JSO............................................................... 282 Araújo PRS................................................................ 700 Arbex MA.................................................................. 643 Arcêncio RA.............................................................. 724 Arteta Z..................................................................... 264 Asai N.........................................................................810 Ávila DV.................................................................... 188 Azevedo LCP..................................................................7

B

Babinski MA............................................................. 588 Bairral BQL............................................................... 533 Baker TB....................................................................716 Baldi BG........................................................1, 282, 417 Baldisserotto SV....................................................... 438 Balleste R.................................................................. 264 Ballester G................................................................ 566 Bammann RH........................................................... 400 Baracat ECE...............................................................614 Barbagelata CM........................................................ 503 Barbosa RCC............................................................. 194 Barreto Neto J.......................................................... 684 Barreto RB...................................................................72 Bártholo TP.............................................................. 666 Bastos FA.................................................................. 503 Bastos GM................................................................ 733 Bastos MLS............................................................... 803

J Bras Pneumol. 2012;38(6):820-825

Belasco AGS...............................................................331 Belo MTCT................................................................ 803 Beltrami FG............................................................... 246 Berti HW................................................................... 477 Berti JSW.................................................................. 477 Berton DC....................................................................13 Bertuzzo CS.................................................................50 Bethlem EP............................................................... 282 Bettencourt ARC.......................................................331 Bica CG..................................................................... 487 Boechat MCB...............................................................41 Boin AC..................................................................... 372 Borges LG................................................................. 364 Borges TFF................................................................. 511 Botelho C.................................................................. 356 Bottoni FA................................................................ 275 Braga ALF................................................................. 643 Braga KAO.................................................................461 Braile DM.................................................................. 214 Branco ABA.............................................................. 550 Brasil PEA....................................................................88 Brotto MWI............................................................... 566 Brunetto AF (in memoriam).................................... 257 Buffon VR..................................................................415

C

Cailleaux-Cezar M.................................................... 202 Calderan TRA............................................................ 677 Callefe F.................................................................... 364 Camargo JJ.......................................................125, 806 Camargo SM............................................................. 806 Camillo ND............................................................... 487 Campos JRM............................................................. 573 Cancian T...................................................................412 Canzian M........................................................ 452, 461 Cao RG...................................................................... 595 Capelozzi VL............................................................. 321 Capobianco J............................................................ 218 Caramori ML............................................................. 282 Cardoso GP............................................................... 588 Cardoso MSL............................................................ 133 Cardoso PFG..............................................................461 Cardoso SR............................................................... 138 Caruso P.....................................................................417 Caruso PEM.............................................................. 526 Carvalho CRF............................................. 24, 194, 292 Carvalho CRR................................ 7, 24, 282, 321, 417 Carvalho JF............................................................... 282 Carvalho LA.............................................................. 700 Carvalho RM............................................................. 605 Carvalho WS............................................................. 210 Casquilho NV...............................................................98 Castro ACP................................................................ 400 Castro JDV................................................................ 269 Castro LAM............................................................... 299

821

Cavada MN............................................................... 526 Cavalcanti AGL......................................................... 700 Cavalcanti ZR............................................................ 395 Cedano S....................................................................331 Cereda DCR............................................................... 138 Cezar MC.................................................................. 733 Cezimbra HM............................................................ 404 Cianci RG...................................................................116 Cillóniz C...................................................................419 Cisne R...................................................................... 588 Coelho AAC............................................................... 299 Coelho CM................................................................ 605 Cohen RWF..................................................................41 Coletta ENAM...................................................282, 395 Colpo CM.................................................................. 404 Conde MB.........................................................202, 733 Cordeiro CR...............................................................813 Cordoni PK..................................................................13 Corrêa JRM............................................................... 404 Corrêa RA..........................................................148, 275 Coscia AP.................................................................. 408 Costa AN................................................................... 282 Costa ASM................................................................ 275 Costa CH................................................................... 666 Costa ELV......................................................................7 Costa JB.................................................................... 275 Costa Júnior AS........................................................ 559 Costa LAR................................................................. 292 Costa Neto JM.......................................................... 214 Costa-Carvalho BT................................................... 674 Cremonese RV.......................................................... 364 Cruz AA 299....................................................................

Cruz CS..................................................................... 299 Cunha HFR............................................................... 408 Cury JL...................................................................... 257 Cury PM.................................................................... 214 Cypel M......................................................................681

D

Dal Corso S................................................................116 Dalcin PTR............................................... 246, 346, 386 Dalcolmo M.................................................................88 Daltro P........................................................................41 Daud DF.................................................................... 559 Daudt AD.................................................................. 786 De Capitani EM........................................................ 282 Demarzo SE.............................................................. 167 Demier C................................................................... 422 Demir M.................................................................... 679 Der Stuyft PV........................................................... 757 Dexheimer Neto FL.................................................. 246 Di Lorenzo VAP........................................................ 579 Dias L...........................................................................24 Donadio MVF........................................................... 188 Drehmer M................................................................ 470 Duarte RS.................................................................. 630

E

Esteche VT................................................................ 264

F

Façanha MC.............................................................. 622 Fagundes AL..............................................................412 Famiglietti A............................................................. 422 Faria CMNM............................................................. 214 Faria CS..................................................................... 356 Felicetti JC................................................................ 806 Fernandes ALG......................................................... 748 Fernandes Junior LA................................................ 210 Fernandes WA.......................................................... 708 Fernandez A............................................................. 400 Ferreira AA................................................................ 445 Ferreira ALA.............................................................. 477 Ferreira CS................................................................ 148 Ferreira EVM............................................................. 539 Ferreira MG............................................................... 356 Ferreira RG................................................................ 282 Ferreira VG................................................................ 622 Ferrer GCN.................................................................771 Figueiredo VR....................................33, 167, 174, 315 Fiks IN..........................................................................24 Fiss E............................................................................13 Folescu TW..................................................................41 Fonseca LS................................................................ 630 Forte GC.................................................................... 470 Fracasso J..................................................................415 Fraga GP..........................................................672, 677 Fraga AMA.................................................................614 Francisco FAF........................................................... 797 Franco MRG.................................................................66 Fregonezi G.............................................................. 257 Fregonezi GAF.......................................................... 700 Freitas SS...................................................................813 Fritscher CC...............................................................431 Frota S.........................................................................81

G

Gandolfi TD.............................................................. 786 Garcia E..................................................................... 656 Garcia JHP................................................................ 269 Gazzana MB.....................................................346, 386 Gehm F..................................................................... 364 Genofre EH................................................................181 Gezuele E.................................................................. 264 Godoy ACF........................................................672, 677 Golub JE................................................................... 202 Gomes AM................................................................ 634 Gomes NP................................................................. 140 Gonçalves MEP......................................................... 138 Gonçalves MLC......................................................... 382 Gouvêa DSA.............................................................. 605 Gregório MG..............................................................315 Grochocki MHC...........................................................57 Gualdi LP.................................................................. 595

J Bras Pneumol. 2012;38(6):820-825

822

Guazzelli LS.............................................................. 125 Guerra RL.................................................................. 202 Guimarães RM........................................................... 511 Gut AL....................................................................... 477

H

Haygert CJP.............................................................. 404 Higa DA..................................................................... 634 Higa LYS......................................................................41 Hirota A.........................................................................7 Hlatky MA................................................................. 684 Hochhegger B................................. 105, 494, 656, 797 Hoff LS...................................................................... 125 Holanda MA.....................................................140, 269 Hommerding PX....................................................... 188 Huf G........................................................................ 237 Hyland ME................................................................ 339

I

Ikeda VY.................................................................... 372 Ildefonso SAG........................................................... 550 Irion KL.................................................... 105, 494, 656 Ishy A................................................................400, 573 Issa JS........................................................................761

J

Jacomelli M...................................................... 167, 315 Jacques PS................................................................ 346 Jamami M................................................................. 579 Japiassu AM............................................................. 408 Jardim CVP................................................................417 Jardim JR................................................. 339, 684, 716 Jatene FB...........................................33, 461, 566, 776 Jezler S...................................................................... 282 Jones MH.................................................................. 158 Judice LF.................................................................. 588 Junqueira JJM.......................................................... 400

K

Kairalla RA........................................................282, 321 Kaneko N...................................................................810 Karadeniz G.............................................................. 679 Kauffman P.............................................................. 573 Kawamura Y..............................................................810 Kritski AL................................................... 81, 237, 622

L

Lage SG..................................................................... 566 Lanza FC................................................................... 308 Lanzetti M...................................................................98 Lastoria G................................................................. 708 Leão LEV................................................................... 559 Leitão TMJS.............................................................. 622 Leite ICG....................................................................518 Leite MS.................................................................... 299 Lemos Neto PA......................................................... 174

J Bras Pneumol. 2012;38(6):820-825

Lenzi L.........................................................................57 Lima ALMA............................................................... 530 Lima CSP......................................................................50 Lima ILQ................................................................... 272 Lima LC.............................................................133, 272 Lima MAMT.................................................................81 Lima MS.................................................................... 282 Lima Netto JC..................................................133, 272 Lobo AP..................................................................... 511 Longo AG.................................................................. 408 Luisi F................................................................158, 786 Luna CM................................................................... 422 M......................................................................................

Maccari JG................................................................ 364 Machado AS............................................................. 364 Machado MCLO.........................................................331 Machuca TN............................................................. 806 Mafort TT................................................................. 666 Magalhães M............................................................ 740 Magalhães V.....................................................530, 740 Maior ML.................................................................. 202 Malaguti C.................................................................116 Malcon CM............................................................... 526 Malcon MC............................................................... 526 Manes J........................................................................72 Mansur MFFO........................................................... 210 Marchiori E..................................... 105, 494, 656, 797 Marchiori RC..............................................................412 Mariani AW............................................................... 776 Marino DM............................................................... 579 Marostica L............................................................... 158 Marostica PJC........................................................... 188 Marques EA.................................................................41 Marrara KT................................................................ 579 Marsico AG............................................................... 630 Marson FAL.................................................................50 Martinez JAB........................................... 143, 279, 282 Martins EGS.............................................................. 408 Martins LC................................................................ 643 Martins MA............................................................... 292 Matos TO.................................................................. 445 Meireles GP............................................................... 656 Meirelles GSP............................................................ 218 Mello AM.....................................................................57 Mello FCQ.........................................................630, 733 Mello Neto AB ..........................................................412 Melo AC.......................................................................98 Melo CBC.................................................................. 559 Melo SCC................................................................... 511 Mendes MS............................................................... 269 Menegotto M............................................................415 Menescal ZLC........................................................... 140 Menezes A................................................................ 766 Menna Barreto SS.................................................... 346 Michel GT..................................................................412 Mickleborough TDM................................................ 292 Minamoto H....................................................... 33, 214 Miranda SS............................................................... 210

823

Montandon Júnior ME............................................ 218 Monteiro TV............................................................. 573 Moraes EZC.............................................................. 438 Morcillo AM...............................................................614 Moreira J................................................................... 656 Moreira JS................................................................. 494 Moreira MAC............................................................ 692 Moreno MA.............................................................. 700 Moriya HT................................................................. 194 Morris AH.......................................................................4 Morrone N........................................................533, 674 Mosquera R.............................................................. 422 Mota RS.................................................................... 622 Moura MDG.............................................................. 672 Müller PTG................................................................541

N

Narde I...................................................................... 321 Nascimento Júnior J................................................ 700 Nascimento OA........................................ 339, 684, 716 Nazário NO................................................................771 Neder JA......................................................................13 Nepomuceno NA.......................................................461 Novo Júnior JM....................................................... 605 Nunes MCP............................................................... 275 Nuñez NK................................................................. 595

O

Ohkuni Y....................................................................810 Ohnishi MDO............................................................ 503 Okumura EM............................................................ 566 Oliveira CMG............................................................. 308 Oliveira CMN.............................................................181 Oliveira EQ.................................................................315 Oliveira ES................................................................. 364 Oliveira III JAF.......................................................... 503 Oliveira Junior AD.................................................... 579 Oliveira Junior BL......................................................716 Oliveira RKF.............................................................. 282 Oliveira RP................................................................ 364 Oliveira TL................................................................. 275 Onders RP................................................................. 566 Orofino RL...................................................................88 Ortega MM..................................................................50

P

Padovani CR............................................................. 477 Pádua AI................................................................... 143 Palma I...................................................................... 422 Palma PV...................................................................518 Palombini DV........................................................... 346 Parente IC................................................................. 503 Park M............................................................................7 Parra ER.................................................................... 321 Patusco LAP...............................................................541 Paulin E.................................................................... 257 Pavão HG.................................................................. 708

Paz LNF..................................................................... 503 Pazetti R........................................................... 452, 461 Pêgo-Fernandes PM........................................ 461, 776 Pereira AC................................................................. 595 Pereira CAC.......................................................282, 395 Pereira JS.................................................................. 470 Pereira KAB............................................................... 452 Pereira LAA............................................................... 643 Pereira LFF................................................................ 748 Pereira RM.................................................................614 Pereira-Silva JL......................................................... 145 Perfeito JAJ.............................................................. 559 Perin FA.................................................................... 806 Pezzi T.......................................................................415 Pimenta SP............................................................... 282 Pincelli MP...................................................................72 Pinto GLF.................................................................. 125 Pinto KB.................................................................... 364 Pinto LA............................................................158, 786 Pinto SA.................................................................... 445 Pires KMP....................................................................98 Pitrez PMC............................................... 158, 595, 786 Pizzichini E................................................................431 Pizzichini MMM........................................................431 Polonio IB................................................................. 452 Pontarolo R.................................................................57 Pontes RS.................................................................. 622 Popolin MP............................................................... 724 Portela FX................................................................. 269 Portela LOC............................................................... 438 Porto LC.......................................................................98 Prata TA.................................................................... 275 Preta RGC................................................................. 210 Prolla JC.................................................................... 487 Pugliese JG............................................................... 666

Q

Queiroz MCCAM....................................................... 692

R

Rabahi MF........................................................445, 692 Ramos CF.................................................................. 588 Ranzi AD................................................................... 487 Real LF...................................................................... 526 Reciputti BP.............................................................. 445 Reis RC...................................................................... 269 Resqueti VR......................................................257, 700 Ribeiro AF....................................................................50 Ribeiro JD.........................................................226, 535 Ribeiro LB................................................................. 740 Rocha A..................................................................... 188 Rocha MJJ................................................................ 282 Rodrigues AJ...................................138, 167, 174, 315 Rodrigues AM........................................................... 595 Rodrigues D.............................................................. 674 Rodrigues F............................................................... 321 Rodrigues HMP...........................................................66

J Bras Pneumol. 2012;38(6):820-825

824

Rodrigues OR............................................................ 214 Rodrigues RS............................................................ 797 Rodrigues SCS.......................................................... 282 Rolla VC.......................................................................88 Ronchi CF................................................................. 477 Rossi F..........................................................................66 Rubin AS...........................................................105, 282 Ruffino Netto A...........................................................81 Rufino R.................................................................... 666

S

Saad MHF................................................................. 630 Saddy F..................................................................... 408 Saito M..................................................................... 533 Sakiyama BYP........................................................... 573 Salazar D................................................................... 757 Saldiva PHN.............................................................. 643 Sales RKB...................................................................181 Sanchez LB............................................................... 806 Santana ANC 282..........................................................

Santanella F.............................................................. 372 Santilli C................................................................... 674 Santoro IL......................................................... 559, 716 Santos EV......................................................................7 Santos GT................................................................. 487 Santos JWA................................................................412 Santos Neto M......................................................... 724 Santos UP................................................................. 643 Sanvitto JPZ............................................................. 786 Savi A........................................................................ 364 Schettino GPP...............................................................7 Schio SM................................................................... 806 Schleich AP............................................................... 595 Schmaltz CAS..............................................................88 Schmidt CZP............................................................. 595 Schneider IJC.............................................................771 Scordamaglio PR.......................................................315 Scuarcialupi MEA........................................................13 Segura P.................................................................... 757 Seicento M................................................................ 167 Selig L....................................................................... 803 Severo CB.................................................................. 125 Severo LC.................................................................. 125 Sidney Filho LA........................................................ 806 Silva AP........................................................................72 Silva BS..................................................................... 452 Silva DR..................................................................... 386 Silva E....................................................................... 700 Silva FL...................................................................... 724 Silva HO.................................................................... 382 Silva LR........................................................................57 Silva MCF.................................................................. 530 Silva MS............................................................133, 272 Silva PHRQ................................................................ 321 Silva PNC.................................................................. 339 Silva PRAA................................................................ 167 Silva RB..................................................................... 210 Silva RM.....................................................................771

J Bras Pneumol. 2012;38(6):820-825

Silva RMVG............................................................... 356 Silva RVA................................................................... 404 Silva TS..................................................................... 372 Silva VC..................................................................... 700 Silva VL..................................................................... 666 Silveira CD................................................................. 148 Simões EA..................................................................461 Simões MCRS............................................................ 535 Simon MISS.............................................................. 470 Siqueira EA................................................................ 511 Soares MR................................................................. 282 Solé D........................................................................ 308 Soto A....................................................................... 757 Sousa KR................................................................... 724 Souza A..................................................................... 708 Souza GMC.............................................. 339, 684, 716 Souza Junior AS...............................................105, 797 Souza LS................................................................... 797 Souza R..................................................................... 452 Souza RG.................................................................. 595 Souza-Machado A.................................................... 299 Squassoni SD...............................................................13 Stefano LM............................................................... 477 Steidle LJM......................................................... 72, 282 Stein RT.................................................................... 158 Steinwandter R............................................................72 Stirbulov R.................................................................431

T

Tagliari LGM..............................................................412 Takimura CK............................................................. 174 Taniguchi LU.................................................................7 Tavares LA................................................................ 684 Tedde ML............................................................ 33, 566 Teixeira C..........................................................246, 364 Teixeira EG................................................................ 803 Teixeira LR........................................................ 181, 292 Teixeira MJ............................................................... 566 Teixeira RN............................................................... 292 Telles MAS................................................................ 766 Terra RM............................................................. 33, 400 Tironi Junior M........................................................ 226 Tonietto TF............................................................... 364 Tonon E.................................................................... 477 Toro AADC................................................................ 535 Toro IFC.................................................................... 535 Torres A......................................................................419 Torres G.................................................................... 264 Torres PPTS.............................................................. 218 Traebert J...................................................................771 Trajman A.................................................. 88, 766, 803 Traldi F.......................................................................331 Tresoldi AT.................................................................614 Trevisan ME.............................................................. 438

U

Uzto E....................................................................... 679

825

V

Valenรงa SS...................................................................98 Vargas FS...................................................................181 Vasconcelos KA...........................................................81 Vaucher A................................................................. 264 Vay C......................................................................... 422 Vervloet LA............................................................... 226 Vervloet VEC............................................................. 226 Viani GA.................................................................... 372 Vianna BS................................................................. 372 Viegas CAA................................................................541 Vieira CM.................................................................. 275 Vieira GBO................................................................ 630 Vieira LMRN..............................................................415 Vieira SRR................................................................. 364 Volkart J................................................................... 105

W

Westphal DC.....................................................133, 272 Westphal FL......................................................133, 272 Wickert R.................................................................. 364 Wolosker N............................................................... 573

Y

Yamamura M............................................................ 724

Z

Zanetti G...........................................................656, 797 Zavalhia LS............................................................... 487 Zin WA.........................................................................98 Zocolaro WS............................................................. 321 Zulli R...........................................................................50

J Bras Pneumol. 2012;38(6):820-825

Relação de Revisores - 2012 Ada Clarice Gastaldi - Universidade de São Paulo - Ribeirão Preto - SP Adalberto Rezende Santos - Fundação Oswaldo Cruz - Rio de Janeiro - RJ Adalberto Sperb Rubin - Universidade Federal de Ciências da Saúde de Porto Alegre - Porto Alegre - RS Adriana Claudia Lunardi - Universidade de São Paulo - São Paulo - SP Afrânio Lineu Kritski - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Alberto Cukier - Universidade de São Paulo - São Paulo - SP Alberto José de Araújo - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Alcindo Cerci Neto - Universidade Estadual de Londrina - Londrina - PR Alfredo Nicodemos Cruz Santana - HRAN da Faculdade de Medicina da ESCS - Brasília - DF Álvaro A. Cruz - Universidade Federal da Bahia - Salvador - BA Amarilio Vieira de Macedo Neto - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Ana Cristina Burigo Grumann - Hospital Nereu Ramos - Florianópolis - SC Ana Luisa Godoy Fernandes - Universidade Federal de São Paulo - São Paulo - SP Ana Maria Baptista Menezes - Universidade Federal de Pelotas - Pelotas - RS Ana Paula Ochoa Santos - Universidade Federal de Pernambuco - Recife - PE Ana Thereza Cavalcanti Rocha - Universidade Federal da Bahia - Salvador - BA Andre Luis Pereira de Albuquerque - Universidade de São Paulo - São Paulo - SP André Luiz Dresler Hovnanian - Universidade de São Paulo - São Paulo - SP André Nathan Costa - Universidade de São Paulo - São Paulo - SP Anete Trajman - Universidade Gama Filho - Rio de Janeiro - RJ Antonio José Maria Cataneo - Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu - SP Antonio Ruffino Netto - Universidade de São Paulo - Ribeirão Preto - SP Arthur Oswaldo de Abreu Vianna - Clínica São Vicente - Rio de Janeiro - RJ Ascedio Jose Rodrigues - Universidade de São Paulo - São Paulo - SP Audrey Borghi Silva - Universidade Federal de São Carlos - São Carlos - SP Benedito Aparecido Caiel - Faculdade de Ciências Médicas da Santa Casa de São Paulo - São Paulo - SP Bruno do Valle Pinheiro - Universidade Federal de Juiz de Fora - Juiz de Fora - MG Bruno Guedes Baldi - Universidade de São Paulo - São Paulo - SP Caio Júlio Cesar dos Santos Fernandes - Universidade de São Paulo - São Paulo - SP Carlos Alberto de Assis Viegas - Universidade de Brasília - Brasília - DF Carlos Alberto Guimarães - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Carlos Antônio Riedi - Universidade Federal do Paraná - Curitiba - PR Carlos Viana Poyares Jardim - Universidade de São Paulo - São Paulo - SP Carmen Sílvia Valente Barbas - Universidade de São Paulo - São Paulo - SP Carolina Fu - Universidade de São Paulo - São Paulo - SP Cássio da Cunha Ibiapina - Universidade Federal de Minas Gerais - Belo Horizonte - MG Celso Ricardo Fernandes de Carvalho - Universidade de São Paulo - São Paulo - SP César Uehara - Universidade Federal de São Paulo - São Paulo - SP Clemax Couto Sant`Anna - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Clovis Botelho - Universidade Federal de Mato Grosso - Cuiabá - MT Clystenes Odyr Soares Silva - Universidade Federal de São Paulo - São Paulo - SP Cristiano Feijó Andrade - Hospital das Clínicas de Porto Alegre - Porto Alegre - RS Danielle Soares Rocha Vieira - Universidade Federal de Minas Gerais - Belo Horizonte - MG Danilo Cortozi Berton - Santa Casa de Porto Alegre - Porto Alegre - RS Dany Jasinowodolinski - Universidade de São Paulo - São Paulo - SP David Hsia - Harbor-UCLA Medical Center - Torrance - CA Denis Martinez - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Denise Carnieli Cazati - Universidade de São Paulo - São Paulo - SP Denise Duprat Neves - Universidade Federal do Estado do Rio de Janeiro - Rio de Janeiro - RJ Eanes Delgado Barros Pereira - Universidade Federal do Ceará - Fortaleza - CE Edgar E. Sarria - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS Edson Marchiori - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Eduardo Leite Vieira Costa - Hospital Sírio-Libanês - São Paulo - SP

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827

Eduardo Mello De Capitani - Universidade Estadual de Campinas - Campinas - SP Eduardo Pamplona Bethlem - Universidade Federal do Estado do Rio de Janeiro - Rio de Janeiro - RJ Eduardo Rosa Borges - Hospital Sírio-Libanês - São Paulo - SP Élcio dos Santos Oliveira Vianna - Universidade de São Paulo - Ribeirão Preto - SP Elie Fiss - Faculdade de Medicina do ABC - Santo André - SP Eloara Vieira Machado Ferreira - Universidade Federal de São Paulo - São Paulo - SP Emanuel Sarinho - Universidade Federal de Pernambuco - Recife - PE Érica Ortiz - Universidade Estadual de Campinas - Campinas - SP Ethel Leonor Noia Maciel - Universidade Federal do Espírito Santo - Vitória - ES Fábio Biscegli Jatene - Universidade de São Paulo - São Paulo - SP Fabio Luiz Teixeira Gonçalves - Universidade de São Paulo - São Paulo - SP Fabiola Villac Adde - Universidade de São Paulo - São Paulo - SP Fernanda Carvalho de Queiroz Mello - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Fernando José Pinho Queiroga Júnior - Hospital Miguel Arraes - Recife -PE Fernando Uliana Kay - Universidade de São Paulo - São Paulo - SP Fernando Luiz Cavalcanti Lundgren - Hospital Geral Otávio de Freitas - Recife - PE Fernando Sergio Studart Leitão Filho - Universidade Federal de São Paulo - São Paulo - SP Francisco José Caldeira Reis - Universidade Federal de Minas Gerais - Belo Horizonte - MG Francisco José F. da Silveira - Faculdade de Ciências Médicas de Minas Gerais - Belo Horizonte - MG Frederico Leon Arrabal Fernandes - Universidade de São Paulo - São Paulo - SP Gabriel Ferreira Rozin - Universidade de São Paulo - São Paulo - SP George Jerre Vieira Sarmento - Hospital Nossa Senhora de Lourdes - São Paulo - SP Geraldo Lorenzi-Filho - Universidade de São Paulo - São Paulo - SP Geruza Alves da Silva - Universidade de São Paulo - Ribeirão Preto - SP Gilberto Bueno Fisher - Universidade Federal de Ciências da Saúde de Porto Alegre - Porto Alegre - RS Gustavo Faibischew Prado - Universidade de São Paulo - São Paulo - SP Hélio Minamoto - Universidade de São Paulo - São Paulo - SP Heloisa de Andrade Carvalho - Universidade de São Paulo - São Paulo - SP Hugo Hyung Bok Yoo - Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu - SP Igor Bastos Polonio - Faculdade de Ciências Médicas da Santa Casa de São Paulo - São Paulo - SP Ilda de Godoy - Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu - SP Ilka Lopes Santoro - Universidade Federal de São Paulo - São Paulo - SP Ilma Aparecida Paschoal - Universidade Estadual de Campinas - Campinas - SP Iolanda Calvo Tibério - Universidade de São Paulo - São Paulo - SP Irma de Godoy - Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu - SP Israel Lopes de Medeiros - Hospital de Messejana - Fortaleza - CE Israel Silva Maia - Hospital Nereu Ramos - Florianópolis - SC Jamocyr Moura Marinho - Escola Bahiana de Medicina e Saúde Pública - Salvador - BA Jaquelina Sonoe Ota Arakaki - Universidade Federal de São Paulo - São Paulo - SP Jaqueline Scholz Issa - Universidade de São Paulo - São Paulo - SP Jefferson Luiz Gross - Fundação Antônio Prudente - São Paulo -SP João Carlos Thomson - Universidade Estadual de Londrina - Londrina - PR Jonatas Reichert - Universidade Federal do Paraná - Curitiba - PR Jorge Lima Hetzel - Santa Casa de Porto Alegre - Porto Alegre - RS Jorge Montessi - Faculdade de Ciências Médicas e da Saúde de Juiz de Fora - SUPREMA - Juiz de Fora - MG José Alberto Neder - Universidade Federal de São Paulo - São Paulo - SP José Antônio Baddini Martinez - Universidade de São Paulo - Ribeirão Preto - SP José Dirceu Ribeiro - Universidade Estadual de Campinas - Campinas - SP José Eduardo Delfini Cançado - Faculdade de Ciências Médicas da Santa Casa de São Paulo - São Paulo - SP José Miguel Chatkin - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS José Ueleres Braga - Universidade do Estado do Rio de Janeiro - Rio de Janeiro - RJ José Wellington Alves dos Santos - Hospital Universitário de Santa Maria - Santa Maria - RS Julia Ignez Salem - Universidade Federal do Amazonas - Manaus - AM

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828

Leila John Marques Steidle - Universidade Federal de Santa Catarina - Florianópolis - SC Leila Souza Fonseca - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Leonardo Araújo Pinto - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS Lídia Alice Gomes M. M. Torres - Universidade de São Paulo - Ribeirão Preto - SP Lisete Ribeiro Teixeira - Universidade de São Paulo - São Paulo - SP Luciana Chiavegato - Universidade Cidade de São Paulo - São Paulo - SP Luiz Carlos Severo - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Luiz Eduardo Villaça Leão - Universidade Federal de São Paulo - São Paulo - SP Luiz Hirotoshi Ota - Universidade Federal de São Paulo - São Paulo - SP Luiz Vicente Ribeiro Ferreira da Silva Filho - Universidade de São Paulo - São Paulo - SP Mara Rúbia Fernandes de Figueiredo - Hospital de Messejana - Fortaleza - CE Marcelo Alcântara Holanda - Universidade Federal do Ceará - Fortaleza - CE Marcelo Bicalho de Fuccio - Fundação Hospitalar do Estado de Minas Gerais - Belo Horizonte - MG Marcelo Cypel - University of Toronto - Toronto - CA Marcelo Fouad Rabahi - Universidade Federal de Goiás - Goiânia - GO Marcelo Park - Universidade de São Paulo - São Paulo - SP Marcelo Velloso - Universidade Federal de Minas Gerais - Belo Horizonte - MG Márcia Pizzichini - Universidade Federal de Santa Catarina - Florianópolis - SC Marcia Seiscento - Universidade de São Paulo - São Paulo - SP Márcio Vinícius Fagundes Donadio - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS Marcos Abdo Arbex - Universidade Federal de São Paulo - São Paulo - SP Marcos Naoyuki Samano - Universidade de São Paulo - São Paulo - SP Marcus Barreto Conde - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Maria Alenita de Oliveira - Hospital Beneficência Portuguesa de São Paulo - São Paulo - SP Maria Auxiliadora Carmo Moreira - Universidade Federal de Goiás - Goiânia - GO Maria de Fátima B. Pombo March - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Maria Helena Feres Saad - Fundação Oswaldo Cruz - Rio de Janeiro - RJ Maria Ignêz Zanetti Feltrim - Universidade de São Paulo - São Paulo - SP Maria José Carvalho Carmona - Universidade de São Paulo - São Paulo - SP Maria Penha Uchoa Sales - Hospital de Messejana - Fortaleza - CE Maria Raquel Soares - Hospital do Servidor Público Estadual - São Paulo - SP Maria Vera Cruz de Oliveira - Hospital do Servidor Público Estadual - São Paulo - SP Mariana Silva Lima - Hospital do Servidor Público Estadual - São Paulo - SP Marília Montenegro Cabral - Universidade Estadual de Pernambuco - Recife - PE Marina Andrade Lima - Hospital Pró-Cardíaco, Rio de Janeiro (RJ) Brasil Mário Terra Filho - Universidade de São Paulo - São Paulo - SP Marli Maria Knorst - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Marlos de Souza Coelho - Pontifícia Universidade Católica do Paraná - Curitiba - PR Mauro Musa Zamboni - Instituto Nacional do Câncer - Rio de Janeiro - RJ Mauro Roberto Tucci - Universidade de São Paulo - São Paulo - SP Meyer Izbicki - Universidade Federal de São Paulo - São Paulo - SP Miguel Abidon Aidê - Universidade Federal Fluminense - Niterói - RJ Miguel Lia Tedde - Universidade de São Paulo - São Paulo - SP Milton de Arruda Martins - Universidade de São Paulo - São Paulo - SP Mônica Corso Pereira - Pontifícia Universidade Católica de Campinas - Campinas - SP Neio Boechat - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Nise Hitomi Yamaguchi - Universidade de São Paulo - São Paulo - SP Olavo Henrique Munhoz Leite - Universidade de São Paulo - São Paulo - SP Olavo Ribeiro Rodrigues - Universidade de Mogi das Cruzes - Mogi das Cruzes - SP Oliver Augusto Nascimento - Universidade Federal de São Paulo - São Paulo - SP Paulo Augusto Moreira Camargos - Universidade Federal de São João del-Rei - São João del-Rei - MG Paulo de Tarso Roth Dalcin - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Paulo Francisco Guerreiro Cardoso - Universidade de São Paulo - São Paulo - SP

J Bras Pneumol. 2012;38(6):826-830

829

Paulo Márcio Pitrez - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS Pedro Caruso - Universidade de São Paulo - São Paulo - SP Pedro Luís Reis Crotti - Universidade Federal de Mato Grosso - Cuiabá - MT Pedro Rodrigues Genta - Universidade de São Paulo - São Paulo - SP Pérsio Roxo Júnior - Universidade de São Paulo - Ribeirão Preto - SP Philip Suffys - Fundação Oswaldo Cruz - Rio de Janeiro - RJ Rafael Stelmach - Universidade de São Paulo - São Paulo - SP Regina de Cássia Rondina - Universidade Estadual Paulista “Julio de Mesquita Filho” - Marília - SP Renato Tetelbom Stein - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS Ricardo Beyruti - Universidade de São Paulo - São Paulo - SP Ricardo de Amorim Corrêa - Universidade Federal de Minas Gerais - Belo Horizonte - MG Ricardo Mingarini Terra - Universidade de São Paulo - São Paulo - SP Rita Mattiello - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS Roberta Karla Barbosa de Sales - Universidade de São Paulo - São Paulo - SP Roberto de Menezes Lyra - Hospital do Servidor Público Estadual - São Paulo - SP Roberto Martinez - Universidade de São Paulo - Ribeirão Preto - SP Roberto Rodrigues Júnior - Faculdade de Medicina do ABC - São Paulo - SP Roberto Stirbulov - Faculdade de Ciências Médicas da Santa Casa de São Paulo - São Paulo - SP Rodrigo Abensur Athanazio - Universidade de São Paulo - São Paulo - SP Rodrigo Afonso da Silva Sardenberg - Hospital Sírio-Libanês - São Paulo - SP Rodrigo Caruso Chate - Universidade de São Paulo - São Paulo - SP Rosane Goldwasser - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Rui Haddad - Pontifícia Universidade Católica do Rio de Janeiro - Rio de Janeiro - RJ Saeid Khansarinia - Piedmont Heart Institute - Atlanta - GA Samia Zahi Rached - Universidade de São Paulo - São Paulo - SP Sergio Eduardo Demarzo - Fundação Antônio Prudente - São Paulo -SP Sérgio Fernandes de Oliveira Jezler - Universidade Federal da Bahia - Salvador, BA Sérgio Jamnik - Universidade Federal de São Paulo - São Paulo - SP Sidney Bombarda - Universidade de São Paulo - São Paulo - SP Silvana Spíndola de Miranda - Universidade Federal de Minas Gerais - Belo Horizonte - MG Silvia Elaine Cardozo Macedo - Universidade Federal de Pelotas - Pelotas - RS Silvia Maria de Toledo Piza Soares - Pontifícia Universidade Católica de Campinas - Campinas - SP Simone Dal Corso - Universidade Nove de Julho - São Paulo - SP Sonia Maria Faresin - Universidade Federal de São Paulo - São Paulo - SP Sônia Perez Cendon Filha - Universidade Federal de São Paulo - São Paulo - SP Sonia Regina Lambert Passos - Fundação Oswaldo Cruz - Rio de Janeiro - RJ Suelene Aires Franca - Universidade Federal de Goiás - Goiânia - GO Suzana Erico Tanni - Universidade Estadual Paulista “Julio de Mesquita Filho” - Botucatu - SP Sylvia Luisa Pincherle Cardoso Leão - Universidade Federal de São Paulo - São Paulo - SP Teresa Yae Takagaki - Universidade de São Paulo - São Paulo - SP Thais Helena Abrahão Thomaz Queluz - Universidade Estadual Paulista “Julio de Mesquita Filho” - Botucatu - SP Ubiratan de Paula Santos - Universidade de São Paulo - São Paulo - SP Verônica Franco Parreira - Universidade Federal de Minas Gerais - Belo Horizonte - MG Veronica Moreira Amado - Universidade de Brasília - Brasília - DF Victor Zuniga Dourado - Universidade Federal de São Paulo - Santos - SP Viviane Rossi Figueiredo - Universidade de São Paulo - São Paulo - SP Walter Villela de Andrade Vicente - Universidade de São Paulo - Ribeirão Preto - SP Wilson Leite Pedreira Júnior - Universidade de São Paulo - São Paulo - SP

J Bras Pneumol. 2012;38(6):826-830

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.

Eventos 2013 NACIONAIS IX Curso Nacional de Doenças Intersticiais

Data: 22 e 23 de março de 2013 Local: Hotel Novotel Jaraguá - São Paulo – SP Informações: SBPT 080061 6218 Email: sbpt@sbpt.org.br

XIV Curso Nacional de Atualização em Pneumologia Data: 11 a 13 de abril de 2013 Local: Hotel Renaissance – São Paulo - SP Informações: SBPT 0800616218 Email: sbpt@sbpt.org.br

XVII Congresso da Sociedade Brasileira de Cirurgia Torácica Data: 17 a 20 de abril de 2013 Local: Centro de Convenções de Vitória - ES Organização: Sociedade Brasileira de Cirurgia Torácica e Comissão Organizadora Regional Informações: BM Eventos: (27) 3229-8176/ 3229-7641 Email: bruno@bmeventos-es.com.br

IX Congresso Brasileiro de Asma e V Congresso Brasileiro de DPOC e Tabagismo

Data: 21 a 24 de agosto de 2013 Local: Centro de Convenções de Vitória, Vitória - ES Informações: SBPT 0800616218 Email: sbpt@sbpt.org.br

Pneumo in Rio - XIV Congresso de Pneumologia e Tisiologia do Estado do Rio de Janeiro

Data: 27 a 29 de setembro de 2013 Local: Hotel Atlântico Búzios - Armação de Búzios - RJ Informações: Método Eventos – (21)2548-5141 Email: pneumo2013@metodorio.com.br

15º Congresso Paulista de Pneumologia e Tisiologia

Congresso Gaúcho de Pneumologia

Data: 14 a 17 de novembro de 2013 Local: Centro Fecomércio de Eventos Rua Dr. Plínio Barreto, 285 – Bela Vista – São Paulo - SP Informações: SPPT - 0800171618 Email: sppt@sppt.org.

XV Congresso Norte Nordeste de Pneumologia e Tisiologia

INTERNACIONAIS

Data: 06 a 08 de junho de 2013 Local: Porto Alegre - RS Informações: (51)3384-2889 (manhã) Email: sptrs@terra.com.br Data: 12 a 15 de junho de 2013 Local: Hotel Praia Centro – Fábrica de Negócios Endereço: Av. Monsenhor Tabosa nº 740 Praia de Iracema – Fortaleza – CE Informações: Site: www.scpt.org.br

IV Curso Nacional de Circulação Pulmonar

Data: 28 e 29 de junho de 2013 Local: Hotel Novotel Jaraguá - São Paulo - SP Informações: SBPT 080061 6218 Email: sbpt@sbpt.org.br

XIII Congresso Mineiro de Pneumologia e Cirurgia do Tórax DATA: 8 a 10 de agosto de 2013 LOCAL: Associação Médica de Minas Gerais Informações: SMPCT (31) 3213-3197 Email: smpct@smpct.org.br Site: www.smpct.org.br

ATS 2013

Data: 17 a 22 de maio de 2013 Local: Filadélfia/USA Informações: www.thoracic.org

ERS 2013

Data: 7 a 11 de setembro de 2013 Local: Barcelona/Espanha Informações: www.ersnet.org

CHEST 2013

Data: 26 a 31 de outubro de 2013 Local: Chicago/EUA Informações: www.chestnet.org

A eficácia do antileucotrieno 1 A eficácia do antileucotrieno para o tratamento das vias aéreas combinadas 1

para crianças de 6 meses a 5 anos de idade.2

Contribui para a redução de: Uso de corticóides 1 Crises de Asma 1 Número de hospitalizações 1

montelucaste de sódio 4 mg/granulado 3, 4

Contraindicações: Hipersensibilidade a qualquer componente do produto. Interações medicamentosas: MONTELAIR pode ser administrado com outros medicamentos na profilaxia e tratamento crônico da asma e tratamento de rinite alérgica. Em estudos de interações medicamentosas, a dose terapêutica recomendada não teve efeitos clinicamente importantes na farmacocinética dos medicamentos: teofilina, prednisona, prednisolona, contraceptivos orais (etinilestradiol/noretindrona 35 µg/1 mg), terfenadina, digoxina e varfarina. Embora não tenham sido realizados outros estudos específicos de interação, o montelucaste de sódio foi usado em estudos clínicos concomitantemente à ampla variedade de medicamentos comumente prescritos (hormônios tireoidianos, sedativos hipnóticos, agentes anti-inflamatórios não esteróides, benzodiazepínicos e descongestionantes),sem evidência de interações. Não é recomendado ajuste posológico.

Referências bibliográficas: 1. BORDERIAS, Luis et al. Asthma control in patients with asthma and allergic rhinitis receiving add-on montelukast therapy for 12 months: a retrospective observational study. Current medical research and options. v. 23, n. 4, p. 721-730, 2007. 2. Bula do produto MONTELAIR® GRANULADO 4MG. Responsável técnico: Wilson R. Farias. Aché Laboratórios Farmacêuticos SA. Guarulhos, SP. 3. Comparação feita com base no produto Singulair Baby®, marca registrada do laboratório Merck Sharp & Dohme. 4. Revista KAIROS. Junho 2012 - PMC ICMS 18%.

MONTELAIR (montelucaste de sódio - comprimidos revestidos 10 mg - Uso adulto. Granulado 4mg - Uso pediátrico acima de 6 meses de idade). Uso oral. Indicações: MONTELAIR é indicado para a profilaxia e o tratamento crônico da asma, incluindo a prevenção de sintomas diurnos e noturnos, broncoconstrição induzida pelo exercício e pacientes asmáticos sensíveis a aspirina. Pode ser utilizado concomitantemente a corticosteróides inalatórios com efeitos aditivos no controle da asma e para reduzir a dose deste corticosteróide inalatório num quadro clínico estável. MONTELAIR é indicado para o alivio dos sintomas da rinite alérgica; lacrimejamento e hiperemia ocular. Precauções e Advertências: MONTELAIR não deve ser usado para o tratamento das crises agudas de asma. Os pacientes devem ser aconselhados a ter disponível medicamento de resgate.

MONTELAIR não deve substituir abruptamente os corticosteróides inalatórios ou orais.Gravidez e lactação: Categoria de risco na gravidez: B. Este medicamento não deve ser utilizado por mulheres grávidas sem orientação médica ou do cirurgião-dentista. O montelucaste de sódio não foi estudado em gestantes, portanto, deve ser usado durante a gravidez somente se claramente necessário. Não há informações sobre a excreção de montelucaste no leite humano. Como muitos medicamentos são excretados no leite humano, deve-se ter cautela quando administrado a nutrizes. Reações adversas: O montelucaste de sódio tem sido bem tolerado. As reações adversas, usualmente leves, geralmente não requereram descontinuação da terapia. A incidência global das reações adversas foi comparável à do placebo. Posologia: MONTELAIR deve ser administrado uma vez ao dia. Para asma, a dose deve ser administrada à noite. Para rinite alérgica, o horário da administração pode ser individualizado para atender às necessidades do paciente. Montelair 4mg granulado: Pacientes pediátricos de 6 meses a 2 anos de idade com asma e pacientes de 2 a 5 anos com asma e/ou rinite alérgica: a posologia é de um sachê de grânulos orais de 4 mg diariamente. Administração dos grânulos orais: os grânulos orais de MONTELAIR podem ser administrados diretamente na boca ou misturados com uma colher cheia de alimentação leve (por exemplo, papinha de maçã) à temperatura ambiente ou fria. A embalagem deve ser mantida fechada até o uso e, depois de aberta, toda a dose deve ser administrada imediatamente (no período de 15 minutos). Se misturado com algum alimento, MONTELAIR não deve ser armazenado para uso posterior. Os grânulos orais de MONTELAIR não foram desenvolvidos para serem dissolvidos em líquidos, mas podem ser administrados após o uso do medicamento. Montelair 10mg comprimido revestido: Adultos e adolescentes a partir de 15 anos de idade com asma e/ou rinite alérgica: a posologia é de 1 comprimido de 10 mg diariamente. “SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO.” VENDA SOB PRESCRIÇÃO MÉDICA. MS - 1.0573.0405 – Montelair granulado MB_03 e comrev MB_02. Para informações completas, consultar a bula na íntegra através da Central de Atendimento ao Cliente.

Material técnico-científico de distribuição exclusiva a profissionais de saúde habilitados à prescrição e/ou dispensação de medicamentos.

Out/2012

ALENIA. fumarato de formoterol di-hidratado + budesonida 6/100 e 6/200 mcg. Cápsulas para inalação. USO INALATÓRIO ORAL. USO ADULTO E PEDIÁTRICO (CRIANÇAS ACIMA DE 4 ANOS DE IDADE). MS - 1.1213.0399. Indicações: ALENIA (fumarato de formoterol di-hidratado + budesonida) está indicado no tratamento regular da asma nos casos em que o uso de uma associação (corticosteroide inalatório com um agonista beta2 de ação prolongada) é apropriada. ALENIA 6/200 está indicado também no tratamento regular de pacientes com doença obstrutiva crônica (DPOC) de moderada a grave, com sintomas frequentes e histórias de exacerbações. Contraindicações: hipersensibilidade a algum dos componentes da fórmula. Precauções e advertências: Deve-se ter cautela durante o manuseio em pacientes com: história de hipersensibilidade ou de efeitos indesejados com o uso de beta-bloqueadores ou outros corticoides. Mulheres pós-menopausadas não recebendo estrógeno, tuberculose pulmonar aguda ou recente, arritmias, coronariopatias e hipertensão, diabetes, herpes simples ocular ou outra infecção local/sistêmica (bacteriana, viral ou fúngica), hipertireoidismo e suspeita ou confirmação de feocromocitoma. Gravidez e lactação: Corticoides/beta2-agonistas inalatórios são geralmente continuados em gestantes bem controladas. A budesonida é classificada como categoria de risco “B” e o formoterol di-hidratado como categoria de risco “C” na gestação, pelo FDA. No entanto, evita-se o uso da combinação formoterol di-hidratado/budesonida durante a gestação. Interações medicamentosas: Formoterol di-hidratado: Outros agonistas adrenérgicos: excesso da estimulação adrenérgica.

Antidepressivos tricíclicos, inibidores da MAO: pode resultar em aumento dos efeitos cardiovasculares. Budesonida: O metabolismo da budesonida é mediado principalmente pela CYP3A4, uma subfamília do citocromo P450. Portanto, inibidores desta enzima, como o cetoconazol, podem aumentar a exposição sistêmica a budesonida. Esta possibilidade tem importância clínica limitada para o tratamento a curto prazo (1-2 semanas) com cetoconazol, mas deve ser levada em consideração durante tratamento a longo prazo. Reações adversas: Dado que ALENIA (fumarato de formoterol di-hidratado + budesonida) contém budesonida e formoterol di-hidratado, deve ocorrer o mesmo padrão de efeitos não desejáveis observados com estes fármacos, quando administrados isoladamente. Não se observou qualquer aumento da incidência de reações adversas após a administração concomitante dos dois fármacos. As reações adversas mais frequentes relacionadas com o fármaco consistem em efeitos secundários, farmacologicamente previsíveis, da terapêutica agonista-beta2. Estes tendem a ser leves e a desaparecer após alguns dias de tratamento. Formoterol di-hidratado: em doses terapêuticas e usado isoladamente foi observado aumento mínimo da frequência cardíaca, tremor, vertigens, agitação, cefaleia, hipocalemia (dose-dependente), aumento da glicemia, náuseas e boca seca, quando da utilização isolada e em doses terapêuticas de formoterol di-hidratado. Budesonida: seu uso isolado pode ser associado à cefaleia, insônia, dispepsia, boca seca, dor abdominal, vômitos, candidíase oral, infecção respiratória, sinusite, faringite, alterações da voz. Raramente podem ocorrer: supressão da função hipotalâmica-pituitária-adrenal, reação de hipersensibilidade, incluindo urticária, angioedema, rash cutâneo e broncoespasmo imediato em pacientes hipersensíveis, que deverá ser tratada administrando-se um beta2-adrenérgico de curta duração por inalação. Posologia: 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. ALENIA (fumarato de formoterol di-hidratado + budesonida ) 6/100 mcg. Adultos e adolescentes (a partir de 12 anos de idade): inalar de 1 cápsula totalizando 6 mcg de formoterol e 100 mcg de budesonida, a 2 cápsulas, totalizando 12 mcg de formoterol e 200 mcg de budesonida, duas vezes ao dia, com dose diária máxima de manutenção de 4 cápsulas inaladas totalizando 24 mcg de formoterol e 400 mcg de budesonida. Durante uma piora da asma, a dose, em adultos, pode ser temporariamente aumentada para um máximo de 4 cápsulas inaladas duas vezes ao dia, totalizando 48 mcg de formoterol e 800 mcg de budesonida. Crianças (a partir de 4 anos de idade): inalar de 1 cápsula totalizando 6 mcg de formoterol e 100 mcg de budesonida, uma vez ao dia, a 1 cápsula, duas vezes ao dia, totalizando 12 mcg de formoterol e 200 mcg de budesonida, com dose máxima de manutenção diária de 4 cápsulas, totalizando 24 mcg de formoterol e 400 mcg de budesonida. ALENIA (fumarato de formoterol di-hidratado + budesonida) 6/200 mcg Asma brônquica: doses recomendadas para uma terapia de manutenção regular. Adultos e adolescentes (a partir de 12 anos de idade): inalar de 1 cápsula totalizando 6 mcg de formoterol e 200 mcg de budesonida, a 2 cápsulas totalizando 12 mcg de formoterol e 400 mcg de budesonida, duas vezes ao dia, com dose diária máxima de manutenção de 4 cápsulas inaladas totalizando 24 mcg de formoterol e 800mcg de budesonida. Durante uma piora da asma, a dose, em adultos, pode ser temporariamente aumentada para um máximo de 4 cápsulas inaladas duas vezes ao dia, totalizando 48 mcg de formoterol e 1600 mcg de budesonida. Crianças (a partir de 4 anos de idade): inalar de 1 cápsula totalizando 6 mcg de formoterol e 200 mcg de budesonida uma vez ao dia a 1 cápsula, duas vezes ao dia, totalizando 12 mcg de formoterol e 400 mcg de budesonida, com dose máxima de manutenção diária de 4 cápsulas, totalizando 24 mcg de formoterol e 800 mcg de budesonida. DPOC: doses recomendadas para uma terapia de manutenção regular. Adultos a partir de 18 anos de idade: 2 inalações duas vezes ao dia. Dose máxima diária de 4 inalações. Os pacientes devem ser instruídos a usar o medicamento mesmo quando estiverem assintomáticos, para obter o benefício máximo da terapia. Não é necessário efetuar qualquer ajuste da dose em pacientes idosos. Não existem dados disponíveis sobre o uso de ALENIA (fumarato de formoterol di-hidratado + budesonida) em pacientes com insuficiência hepática ou renal. Uma vez que a budesonida e o formoterol di-hidratado são essencialmente eliminados por metabolismo hepático, é previsível que se verifique um aumento da exposição em pacientes com cirrose hepática grave. ALENIA. 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 (fumarato de formoterol di-hidratado + budesonida) 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 (fumarato de formoterol di-hidratado + budesonida) 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) ANDRADE-LIMA, M.; PEREIRA, L. F. F.; FERNANDES, A.L.G. Equivalência farmacêutica da formulação combinada de budesonida e formoterol em cápsula única com dispositivo inalador de pó. In press 2012. (2) Bula do Produto.

“Material técnico-científico de distribuição exclusiva à classe médica. Produzido em novembro de 2012. Código BIO 7007995”

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.

Estudo brasileiro In Vitro da equivalência farmacêutica da associação fixa de formoterol e budesonida em cápsula única com dispositivo Aerocaps, demonstrou1: As características aerodinâmicas das partículas são adequadas ao tipo de dispositivo Uniformidade na dose liberada Aerocaps tem boa performance, mesmo em baixos volumes

SIMPLICIDADE

no Tratamento da Asma e DPOC

6 | 100mcg2 6 | 200mcg2 12 | 400mcg2

Instruções aos Autores O Jornal Brasileiro de Pneumologia (J Bras Pneumol) ISSN-1806-3713, publicado bimestralmente, é órgão oficial da Sociedade Brasileira de Pneumologia e Tisiologia destinado à publicação de trabalhos científicos referentes à Pneumologia e áreas correlatas.

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O Jornal Brasileiro de Pneumologia apóia as políticas para registro de ensaios clínicos da Organização Mundial da Saúde (OMS) e do International Committee of Medical Journal Editors (ICMJE), reconhecendo a importância dessas iniciativas para o registro e divulgação internacional de informações sobre estudos clínicos em acesso aberto. Sendo assim, somente serão aceitos para publicação ensaios clínicos que tenham recebido um número de identificação em um dos Registros de Ensaios Clínicos validados pelos critérios estabelecidos pela OMS e ICMJE. O número de identificação deverá ser registrado ao final do resumo.

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o nome do estado ou província também deverá ser citado; por exemplo: “ . . . tTG de fígado de porco da Guiné (T5398; Sigma, St. Louis, MO, EUA) . . .” A não observância das instruções redatoriais implicará na devolução do manuscrito pela Secretaria da revista para que os autores façam as correções pertinentes antes de submetê-lo aos revisores. Os conceitos contidos nos manuscritos são de responsabilidade exclusiva dos autores. Instruções especiais se aplicam para confecção de Suplementos Especiais e Diretrizes, e devem ser consultadas pelos autores antes da confecção desses documentos na homepage do jornal.

A revista reserva o direito de efetuar nos artigos aceitos adaptações de estilo, gramaticais e outras.

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Para Comunicações Breves não deve ser estruturado nem exceder 100 palavras.

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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.

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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.

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

Produto de uso sob prescrição médica.

A PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO.

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

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

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

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

pneumocócica PREVALÊNCIA

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

Jornal Brasileiro de Pneumologia

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

doença

ISSN 1806-3713

Published once every two months J Bras Pneumol. v.38, number 6, p. 681-829 November/December 2012

OFFICIAL PUBLICATION OF THE BRAZILIAN THORACIC ASSOCIATION

Highlight

ASTHMA Pharmaceutical equivalence of the combination formulation of budesonide and formoterol in a single capsule with a dry powder inhaler

BRONCHOSCOPY Evaluation of the diagnostic utility of fiberoptic bronchoscopy for smear-negative pulmonary tuberculosis in routine clinical practice

Ex vivo lung r­ econditioning Editorial: Marcelo Cypel

COPD Cross-cultural adaptation and assessment of reproducibility of the Duke Activity Status Index for COPD patients in Brazil

SEVERIDADE

Underdiagnosis of COPD at primary health care clinics in the city of Aparecida de Goiânia, Brazil

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

PULMONARY FUNCTION Reference values for sniff nasal inspiratory pressure in healthy subjects in Brazil: a multicenter study

PEDIATRICS Potential impacts of climate variability on respiratory morbidity in children, infants, and adults

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

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

November/December 2012 volume 38 number 6

RISCOS

SMOKING A new nicotine dependence score and a new scale assessing patient comfort during smoking cessation treatment Translation, cross-cultural adaptation, and reproducibility of the Brazilian Portuguese-language version of the Wisconsin Smoking Withdrawal Scale

TUBERCULOSIS Clinical and epidemiological profile and prevalence of tuberculosis/HIV co-infection in a regional health district in the state of Maranhão, Brazil Prevalence of primary drug resistance in pulmonary tuberculosis patients with no known risk factors for such Bottlenecks and recommendations for the incorporation of new technologies in the tuberculosis laboratory network in Brazil Temporal trends in tuberculosis-related morbidity and mortality in the state of Santa Catarina, Brazil, between 2002 and 2009 Primary and acquired pyrazinamide resistance in patients with pulmonary tuberculosis treated at a referral hospital in the city of Recife, Brazil

493517 PRD1139 - Material produzido em Julho/11

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.

p.680-829

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