Brazilian Journal of Pulmonology - Vol.37, number 5 (september/october) 2011.

Material Produzido em maio/2011

Jornal Brasileiro de Pneumologia

Disponível nas doses de 150 mg e 300 mg

O único Ultra-LABA com rápido início de ação em 5 minutos com 24 horas de Broncodilatação

J Bras Pneumol. v.37, number 5, p. 571-702 September/October 2011

PUBLICAÇÃO OFICIAL DA SOCIEDADE BRASILEIRA DE PNEUMOLOGIA E TISIOLOGIA

Highlight

ASTHMA Acute asthma management in children: knowledge of the topic among health professionals at teaching hospitals in the city of Recife, Brazil

Weaning from MV Editorial Martin J. Tobin

EXPERIMENTAL An experimental rat model of ex vivo lung perfusion for the assessment of lungs after prostacyclin administration: inhaled versus parenteral routes

PULMONARY FUNCTION

Hematopoietic stem cell transplantation: pulmonary function tests and post-transplant mortality Reference equations for the performance of healthy adults on field walking tests Spirometric reference values for healthy adults in the Mazandaran province of Iran

INFECTION

Robotic Thymectomy

Occurrence of influenza among patients hospitalized for suspicion of influenza A (H1N1) infection in 2010 at a sentinel hospital in São Paulo, Brazil September/October 2011 volume 37 number 5

Pneumonia associada a influenza A (H1N1)

SLEEP Negative expiratory pressure test: a new, simple method to identify patients at risk for obstructive sleep apnea

TUBERCULOSIS Restriction enzyme analysis of the hsp65 gene in clinical isolates from patients suspected of having pulmonary tuberculosis in Teresina, Brazil Active tuberculosis among health care workers in Portugal Tuberculin skin test: operational research in the state of Mato Grosso do Sul, Brazil Identification of Mycobacterium bovis among mycobacterial isolates from human clinical specimens at a university hospital in Rio de Janeiro, Brazil

REVIEW Weaning from mechanical ventilation Gastroesophageal reflux disease and the airways

p.571-702

ONBRIZETM 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: ONBRIZETM 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% do valor normal previsto e um VEF1/CVF pós-broncodilatador inferior a 70%. Posologia: Adultos – A dose recomendada de ONBRIZETM é uma inalação uma vez ao dia do conteúdo de uma cápsula de ONBRIZETM 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. Método de administração: As cápsulas de ONBRIZETM devem ser administradas apenas por via inalatória oral e apenas usando o inalador. As cápsulas de ONBRIZE™ não devem ser engolidas. ONBRIZETM 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 armazenadas no blíster, e apenas removidas imediatamente antes do uso. Contraindicações: Hipersensibilidade ao princípio ativo ou a qualquer um dos excipientes. ONBRIZETM é contraindicado para pacientes asmáticos. Precauções e Advertências: Asma – ONBRIZETM 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, ONBRIZETM 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 ONBRIZETM 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 fertilidade com 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 ONBRIZETM. Lactação – o uso de ONBRIZETM 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 beta2-adrenérgicos. 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. • Referência bibliográfica: (1) Battram C, Charlton SJ et al. In vitroan in Vivo Pharmacological Characterization of 5-[(5,6-Diethyl-indan-2ylamino)-1-hydroxy-ethyl]-8-hydroxy-1Hquinolin-2-one(Indacaterol), a Novel Inhaled Beta 2 Adrenoceptor Agonist with a 24 h Duration of Action.

The Journal of Pharamacology and Experimental Therapeutics 2006; Vol 317:762-770. Material destinado exclusivamente à classe médica. A figura do leão é meramente ilustrativa, não refletindo o mecanismo de ação do medicamento. www.portal.novartis.com.br/onbrize.

Publicação Bimestral

Six-minute walk test: reference values for healthy adults in Brazil

1

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 hipocalemicos.

ISSN 1806-3713

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

Six-minute walk test Editorial Celso R. F. de Carvalho

VAN.11.C.122 - Produzido em Julho/2011.

Escolha alcançar e manter o controle 1

Spray HFA com contador DOSE A DOSE2

• Controle rápido e sustentado da asma em pacientes não controlados.2,4,5 • Utiliza HFA como propelente. 3

6/200 mcg

6/100 mcg

Referências bibliográficas: 1. Kairos: publicação dirigida aos médicos, farmacêuticos, odontólogos, e outros profissionais de saúde. 2011; Jan/Março,266: pag 187. 2. Hampel FC, Martin P, Mezzanotte WS. Early bronchodilatory effects of budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI and albuterol pMDI: 2 randomized controlled trials in adults with persistent asthma previously treated with inhaled corticosteroids. J Asthma. 2008 May;45(4):265-72. 3. Bula do produto. 4.Kaiser H, Parasuraman B, Boggs R, Miller CJ, Leidy NK, O’Dowd L. Onset of effect of budesonide and formoterol administered via one pressurized metered-dose inhaler in patients with asthma previously treated with inhaled corticosteroids. Ann Allergy Asthma Immunol. 2008;101(3):295-303. 5. Kaiser H, Miller CJ, O´Dowd L. Measured onset of bronchodilation with budesonide and formoterol administered via one pressurized metered-dose inhaler (pMDI) in patients with asthma previously receiving inhaled corticosteroids (Abstract no. 974). J Allergy Clin Immunol 2007;119:S249.

• Reduz em 57% as exacerbações em comparação

Vannair® 6/100 mcg/inalação e Vannair® 6/200 mcg/inalação (fumarato de formoterol diidratado/budesonida) é composto por substâncias que possuem diferentes modos de ação e que apresentam efeitos aditivos em termos de redução da asma do que outros produtos isoladamente. A budesonida é um glicocorticosteroide que tem uma rápida (dentro de horas) e dose-dependente ação anti-inflamatória nas vias aéreas e o formoterol é um agonista beta-2-adrenérgico seletivo de início de ação rápido (1-3 minutos) e de longa duração (pelo menos 12 horas). Contraindicações: hipersensibilidade a budesonida, ao formoterol ou a outros componentes da fórmula.Interações medicamentosas: o metabolismo da budesonida é mediado principalmente pela CYP3A4, uma subfamília do citocromo P450. Portanto, inibidores desta enzima, como o cetoconazol ou suco de grapefruit (pomelo), podem aumentar a exposição sistêmica à budesonida. A cimetidina apresenta um leve efeito inibidor sobre o metabolismo hepático da budesonida. Fármacos como a procainamida, fenotiazina, agentes anti-histamínicos (terfenadina), inibidor da monoaminooxidase (MAO) e antidepressivos tricíclicos foram relacionados com um intervalo QTc prolongado e um aumento do risco de arritmia ventricular. Os bloqueadores beta-adrenérgicos (incluindo os colírios oftálmicos) podem atenuar ou inibir o efeito do formoterol (para maiores informações vide bula completa do produto). Indicações: Vannair® está indicado no tratamento da asma nos casos em que o uso de uma associação (corticosteroide inalatório com um beta-2 agonista de ação prolongada) é apropriado. Cuidados e Advertências: é recomendado que a dose seja titulada quando o tratamento de longo prazo é descontinuado e este não deve ser interrompido abruptamente. Para minimizar o risco de candidíase orofaríngea, o paciente deve ser instruído a lavar a boca com água após administrar as inalações de Vannair®. Uma deterioração súbita e progressiva do controle da asma é um risco potencial e o paciente deve procurar suporte médico. Pacientes que necessitaram de terapia corticosteroide de alta dose emergencial ou tratamento prolongado de altas doses recomendadas de corticosteroides inalatórios podem exibir sinais e sintomas de insuficiência adrenal quando expostos a situações de estresse grave. Administração de corticosteroide sistêmico adicional deve ser considerada durante situações de estresse ou cirurgia eletiva. Vannair® deve ser administrado com cautela em pacientes com graves alterações cardiovasculares (incluindo anomalias do ritmo cardíaco), diabetes mellitus, hipocalemia não tratada ou tireotoxicose. Pacientes com prolongamento do intervalo QTc devem ser cuidadosamente observados (para maiores informações vide bula completa do produto). Uso durante a gravidez e a lactação: categoria C de risco de gravidez. Este medicamento não deve ser utilizado por mulheres grávidas sem orientação médica ou do cirurgião dentista. A administração de Vannair® em mulheres lactantes deve ser apenas considerada se os benefícios esperados para a mãe superarem qualquer possível risco para a criança (para maiores informações vide bula completa do produto). Reações adversas: as reações adversas que foram associadas à budesonida ou ao formoterol são apresentadas a seguir. Comum: palpitações, candidíase na orofaringe, cefaleia, tremor, leve irritação na garganta, tosse, rouquidão. Incomum: taquicardia, náusea, cãibras musculares, tontura, agitação, ansiedade, nervosismo e perturbações do sono (para outras reações adversas, vide bula completa do produto). Posologia: a dose de Vannair® deve ser individualizada conforme a gravidade da doença. Quando for obtido o controle da asma, a dose deve ser titulada para a menor dose que permita manter um controle eficaz dos sintomas. Vannair® 6/100 mcg/ inalação: Adultos (a partir de 18 anos de idade): 2 inalações uma ou duas vezes ao dia. Em alguns casos, uma dose máxima de 4 inalações duas vezes ao dia pode ser requerida como dose temporária de manutenção durante a piora da asma. Adolescentes (12-17 anos): 2 inalações uma ou duas vezes ao dia. Durante a piora da asma a dose pode temporariamente ser aumentada para o máximo de 4 inalações duas vezes ao dia.

Crianças (6-11 anos): 2 inalações duas vezes ao dia. Dose máxima diária: 4 inalações. Vannair® 6/200 mcg/inalação: Adultos (a partir de 18 anos de idade): 2 inalações uma ou duas vezes ao dia. Em alguns casos, uma dose máxima de 4 inalações duas vezes ao dia pode ser requerida como dose temporária de manutenção durante a piora da asma. Adolescentes (12-17 anos): 2 inalações uma ou duas vezes ao dia.

Durante a piora da asma a dose pode temporariamente ser aumentada para o máximo de 4 inalações duas vezes ao dia. Instruções de Uso: vide bula completa do produto. Superdose: a superdosagem de formoterol irá provavelmente provocar efeitos típicos dos agonistas beta-2-adrenérgicos: tremor, cefaleia, palpitações e taquicardia. Poderá igualmente ocorrer hipotensão, acidose metabólica, hipocalemia e hiperglicemia. Pode ser indicado um tratamento de suporte e sintomático. A administração de uma dose de 90 mcg durante três horas em pacientes com obstrução brônquica aguda e quando administrada três vezes ao dia como um total de 54 mcg/dia por 3 dias para a estabilidade asmática não suscitou quaisquer problemas de segurança. Não é esperado que uma superdosagem aguda da budesonida, mesmo em doses excessivas, constitua um problema clínico. Quando utilizado cronicamente em doses excessivas, podem ocorrer efeitos glicocorticosteroides sistêmicos (para informações de superdosagem grave vide bula completa do produto). Apresentações: Vannair® 6/100 mcg/inalação: Aerossol bucal 6/100 mcg/inalação em embalagem com 1 tubo contendo 120 doses. USO ADULTO E PEDIÁTRICO. Vannair® 6/200 mcg/inalação: Aerossol bucal 6/200 mcg/inalação em embalagem com 1 tubo contendo 120 doses. USO ADULTO. USO POR INALAÇÃO ORAL. VENDA SOB PRESCRIÇÃO MÉDICA. Para maiores informações, consulte a bula completa do produto. (VAN6_100_002a / VAN6_200_002a). AstraZeneca do Brasil Ltda., Rod. Raposo Tavares, Km 26,9 - Cotia - SP - CEP 06707-000 Tel.: 0800-0145578. www.astrazeneca.com.br. Vannair®. MS – 1.1618.0234.

• A opção terapêutica segura, inclusive para crianças

CONTRAINDICAÇÃO: HIPERSENSIBILIDADE A BUDESONIDA E/OU AO FORMOTEROL E AOS OUTROS COMPONENTES DA FORMULAÇÃO. INTERAÇÃO MEDICAMENTOSA: DA BUDESONIDA COM O CETOCONAZOL. A PERSISTIREM OS SINTOMAS O MÉDICO DEVERÁ SER CONSULTADO. Material destinado à classe médica.

com formoterol+budesonida4

Spray:2 25/50 mcg 25/125 mcg 25/250 mcg

Diskus:3 50/100 mcg 50/250 mcg 50/500 mcg

de 4 a 11 anos5 • É a terapia combinada que provou alcançar e manter o controle da asma definido pelo GINA1

Com Seretide, a asma não detém seu paciente.

Referências bibliográficas: 1 - BATEMAN, ED. et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med, 170(8): 836-44, 2004. 2 - Seretide® Spray (xinafoato de salmeterol/propionato de fluticasona). Bula do produto. 3 - Seretide® Diskus (xinafoato de salmeterol/propionato de fluticasona).

Bula do produto. 4 - DAHL, R. et al. EXCEL: A randomised trial comparing salmeterol/fluticasone propionate and formoterol/budesonide combinations in adults with persistent asthma.

Respir Med, 100(7): 1152-62, 2006. 5 - KRAMER, JM. Balancing the benefits and risks of inhaled long-acting beta-agonists — the influence of values. N Engl J Med, 360(16): 1592-5, 2009.

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).

A minibula encontra-se no interior desta edição.

Material de divulgação 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 ao Serviço de Informação Médica (DDG 0800 701 22 33 ou http://www.sim-gsk.com.br).

REPENSE SER182009 – JAN/10 www.gsk.com.br Estrada dos Bandeirantes, 8.464 • Jacarepaguá Rio de Janeiro • RJ • CEp 22783-110 CNpJ 33247 743/0001-10

Publicação Bimestral

J Bras Pneumol. v.37, número 5, p. 571-702 September/October 2011

Editor Chefe Carlos Roberto Ribeiro de 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

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Publicação Bimestral

J Bras Pneumol. v.37, número 5, p. 571-702 September/October 2011

EDITORIAL 571 - The new irrationalism in weaning

A nova irracionalidade no desmame Martin J. Tobin

574 - Reference values: necessary in order to understand patient limitations

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ORIGINAL ARTICLES / ARTIGOS ORIGINAIS 576 - Six-minute walk test: reference values for healthy adults in Brazil

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598 - Hematopoietic stem cell transplantation: pulmonary function tests and post-transplant mortality

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Equações de referência para os testes de caminhada de campo em adultos saudáveis Victor Zuniga Dourado, Milena Carlos Vidotto, Ricardo Luís Fernandes Guerra

615 - Spirometric reference values for healthy adults in the Mazandaran province of Iran

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Pneumonia associada a influenza A (H1N1)

Antonello Nicolini, Simonassi Claudio, Fabrizio Rao, Lorenzo Ferrera, Michele Isetta, Monica Bonfiglio 628 - Restriction enzyme analysis of the hsp65 gene in clinical isolates from patients suspected of having pulmonary tuberculosis in Teresina, Brazil

Análise de restrição enzimática do gene hsp65 de isolados clínicos de pacientes com suspeita de tuberculose pulmonar em Teresina, Piauí Maria das Graças Motta e Bona, Maria José Soares Leal, Liline Maria Soares Martins, Raimundo Nonato da Silva, José Adail Fonseca de Castro, Semiramis Jamil Hadad do Monte 636 - Active tuberculosis among health care workers in Portugal

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José Castela Torres da Costa, Rui Silva, José Ferreira, Albert Nienhaus 646 - Tuberculin skin test: operational research in the state of Mato Grosso do Sul, Brazil

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Sandra Maria do Valle Leone de Oliveira, Antônio Ruffino-Netto, Anamaria Mello Miranda Paniago, Olcinei Alves de Oliveira, Marli Marques, Rivaldo Venâncio da Cunha, Renato Andreotti

Publicação Bimestral

J Bras Pneumol. v.37, número 5, p. 571-702 September/October 2011

BRIEF COMMUNICATION / COMUNICAÇÃO BREVE 655 - Occurrence of influenza among patients hospitalized for suspicion of influenza A (H1N1) infection in 2010 at a sentinel hospital in São Paulo, Brazil

Ocorrência de influenza em pacientes hospitalizados com suspeita de infecção por influenza A (H1N1) em 2010 em um hospital sentinela na cidade de São Paulo Thaís Boim Melchior, Sandra Baltazar Guatura, Clarice Neves Camargo, Aripuanã Sakurada Aranha Watanabe, Celso Granato, Nancy Bellei

659 - Negative expiratory pressure test: a new, simple method to identify patients at risk for obstructive sleep apnea

Teste de pressão negativa expiratória: um novo método simples para identificar pacientes com risco para apneia obstrutiva do sono Luis Vicente Franco de Oliveira, Salvatore Romano, Raquel Pastréllo Hirata, Newton Santos de Faria Júnior, Lílian Chrystiane Giannasi, Sergio Roberto Nacif, Fernando Sergio Studart Leitão Filho, Giuseppe Insalaco

664 - Identification of Mycobacterium bovis among mycobacterial isolates from human clinical specimens at a university hospital in Rio de Janeiro, Brazil

Identificação de Mycobacterium bovis em cepas micobacterianas isoladas de espécimes clínicos ­humanos em um complexo hospitalar na cidade do Rio de Janeiro Luciana Fonseca Sobral, Rafael Silva Duarte, Gisele Betzler de Oliveira Vieira, Marlei Gomes da Silva, Neio Boechat, Leila de Souza Fonseca

REVIEW ARTICLES / ARTIGOS DE REVISÃO 669 - Predictive parameters for weaning from mechanical ventilation

Parâmetros preditivos para o desmame da ventilação mecânica Sérgio Nogueira Nemer, Carmen Sílvia Valente Barbas

680 - Gastroesophageal reflux disease and airway hyperresponsiveness: concomitance beyond the realm of chance?

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Jaqueline Cavalcanti de Albuquerque Ratier, Emilio Pizzichini, Marcia Pizzichini

CASE REPORT / RELATO DE CASO 689- Pulmonary actinomycosis as a pseudotumor: a rare presentation

Actinomicose pulmonar na forma pseudotumoral: uma apresentação rara Hylas Paiva da Costa Ferreira, Carlos Alberto Almeida de Araújo, Jeancarlo Fernandes Cavalcanti, Roberta Lacerda Almeida de Miranda, Rachel de Alcântara Oliveira Ramalho

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Rodrigo Afonso da Silva Sardenberg, Ricardo Zugaib Abadalla, Igor Renato Louro Bruno Abreu, Eli Faria Evaristo, Riad Naim Younes 697 - Diaphragmatic pacing: unusual indication with successful application

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Editorial The new irrationalism in weaning A nova irracionalidade no desmame

Martin J. Tobin To be a good doctor is quite challenging.

The challenge is to spot clues that unveil an unsuspected diagnosis and then decide on the right therapy. Sometimes, however, when medical matters are not especially difficult, problems arise because irrational recommendations have been promulgated which often prove more persuasive to clinicians than do scientifically corroborated findings.(1) Having watched the approach to ventilator weaning for more than 30 years, I believe that this field has now become a prototype of this irrationality.

The discontinuation of mechanical ventilation involves three diagnostic steps: measurement of weaning predictors; a trial of unassisted breathing (T-tube trial); and a trial of extubation.

Because a spontaneous breathing trial always precedes an extubation trial, one might argue that one could skip predictor tests and start the weaning process with a spontaneous breathing trial. Indeed, this is the recommendation of the Evidence-Based Medicine (EBM) Task Force on weaning.(2,3) The recommendation, however, misses the very purpose of weaning predictors.

The sole purpose of weaning predictors is to act as a screening test: to prompt a doctor to consider doing a T-tube trial sooner than is his or her custom—for the trial to occur earlier than would otherwise happen. A positive result on a weaning-predictor test acts as a “physician alert” and aids in the cognitive process known as diagnostic triggering.(4) In every subspecialty of medicine, the approach to diagnosis is identical(5): to first screen for a suspected condition and then try to confirm it. The approach is the same for endocrinologists, gynecologists, orthopedic surgeons, and every subspecialist. Examples abound: a dipstick is used to screen for diabetes, followed by a glucose-tolerance test to confirm or exclude the diagnosis; a chest X-ray is used to screen for lung cancer, followed by bronchoscopy to confirm the suspicion; an electrocardiogram is used to screen for myocardial infarction, followed by angiography to confirm it—the list is endless. In weaning, however, the EBM

Task Force proposes the opposite direction.

They recommend that clinicians start with a spontaneous breathing trial (a confirmatory test) and use the initial few minutes of the trial as a screening test.(2) This is analogous to saying that when you suspect diabetes, start with a glucose-tolerance test and then, as the test gets underway, ask the patient for a urine sample in order to do a dipstick.

The initial randomized trials on weaning techniques revealed that 60-80% of patients who had been ventilated for a week had the ventilator removed on the first day they were evaluated for weaning.(6,7) If weaning-predictor tests had been performed sooner in these patients, it is likely that many could have had the ventilator removed a day, or several days, earlier.

A recent trial on computerized weaning provided further evidence that physicians are too slow in screening patients for weanability.(8) A computer system automatically screened patients for weanability at a point when physicians were not measuring weaning predictors (because their pre-test probability was too low). Compared with usual care, the computerized system decreased weaning duration from 5 to 3 days.

But physicians do not need a computer to expedite weaning: they can achieve the same by performing a screening test when their pre-test probability of weanability is low (20-40%).

The recommendation to skip screening tests and begin with a spontaneous breathing trial fosters the delays observed in the justdiscussed studies. The recommendation also ignores extensive research in cognitive psychology that has revealed the causes of faulty decision making. Psychologists have repeatedly demonstrated that people make wrong decisions because they are more confident in their judgments (such as deciding that a patient is not ready for a T-tube trial) than is validly justified by the data on which the decisions are based.(9) In particular, psychologists have shown that insufficient attention to prior probability leads to major errors in decision making.(10) By alerting an unsuspecting physician to a patient’s J Bras Pneumol. 2011;37(5):571-573

572

readiness to tolerate unassisted ventilation hours or days before he or she would otherwise order a spontaneous breathing trial, weaning-predictor tests circumvent the cognitive errors inherent in clinical decision-making. The whole purpose of diagnostic screening is to perform a simple test at a time when a physician’s pre-test probability is low (less than 50%).(5) A screening test should be inexpensive, easy to perform, pose minimal risk to patients, and provide a quick answer.

A spontaneous breathing trial that involves 30-120 minutes of monitored performance is the antithesis of a screening test.

The EBM Task Force’s recommendation to skip predictors would be understandable if the tests performed poorly. The predictor test most widely employed is the frequency-to-tidal volume ratio (f/VT).(11) Since the original report on f/VT, its accuracy has been evaluated by at least 27 groups of investigators, making it perhaps the most re-investigated phenomenon in critical care.(12) Some investigators concluded that f/VT was reliable, others found it unreliable.

When all the data were compared against the test characteristics in the original 1991 report and Bayesian pretest probability was taken into account, the weighted Pearson correlation coefficient was 0.82 or higher (p < 0.0001), providing de facto confirmation of the sensitivity and specificity of f/VT in the original study.(12) The essential ingredients of a good screening test are a low number of false-negative results together with a high number of true-positive results (high sensitivity).(12) In the 27 studies that have evaluated f/VT, the average sensitivity was 0.87—higher than that of most tests in critical care medicine.

The evaluation of diagnostic tests is fraught with difficulties: it is a perilous zone for the uneducated. Naïve investigators entering this minefield end up with mangled limbs in the form of erroneous inferences and invalid claims.

Based on a meta-analysis, the EBM Task Force concluded that f/VT was not a reliable predictor of weaning outcome.(2,3) Throughout all branches of medicine, every diagnostic test is based on Bayes’ theorem. Likewise, analysis of research studies on the performance of diagnostic tests must be founded on Bayesian principles. The main hazard for the unwary researcher is to turn a blind eye on pre-test probability and ignore spectrum bias and test-referral bias; such J Bras Pneumol. 2011;37(5):571-573

carelessness completely mangles the calculations of sensitivity, specificity, and likelihood ratio.

(13) In their meta-analysis, the EBM Task Force committed at least 15 major errors, any one of which was sufficient to scupper their conclusions.(14) The Task Force does not contend against even one of these errors but instead views them as side issues that do not detract from their recommendations.(15) To ignore testreferral bias in the evaluation of a diagnostic test is analogous to a physiologist who claims that a PaO2 of 80 mmHg is always better than a PaO2 of 60 mmHg, and the fact that the measurements were made at inspired oxygen concentrations of 50% and 21%, respectively, is an academic distraction best ignored.

Having watched the field of weaning for more than 30 years, I find this new irrationalism difficult to fathom. For the first 15 years, there was considerable progress, largely derived from a better understanding of the pathophysiologic mechanisms of weaning failure.(16) Over the past 15 years, the field has regressed, largely through disregard for basic scientific principles: failure to comprehend the different goals of screening tests and confirmatory tests, blindness to the Bayesian foundation of all diagnostic testing, a cavalier approach to test-referral bias, and other irrationalities. It is time for thoughtful physicians to reclaim the field and apply logic to achieve better care for their patients.

Martin J. Tobin Physician, Division of Pulmonary and Critical Care Medicine Edward Hines Jr. Veterans Affairs Hospital and Loyola University of Chicago Stritch School of Medicine, Hines, Illinois

References 1. Wheen F. How mumbo-jumbo conquered the world: a short history of modern delusions. London: Harper Perennial; 2004.

2. MacIntyre NR, Cook DJ, Ely EW Jr, Epstein SK, Fink JB, Heffner JE, et al. Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine.

Chest. 2001;120(6 Suppl):375S-95S.

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3. Meade M, Guyatt G, Cook D, Griffith L, Sinuff T, Kergl C, et al. Predicting success in weaning from mechanical ventilation. Chest. 2001;120(6 Suppl):400S-24S. 4. Kassirer JP. Diagnostic reasoning, Ann Intern Med. 1989;110(11):893-900.

5. Feinstein AR. Clinical Epidemiology: The Architecture of Clinical Research. 2nd ed. Philadelphia: WB Saunders; 1985. p. 597-631.

6. Brochard L, Rauss A, Benito S, Conti G, Mancebo J, Rekik N, et al. Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation. Am J Respir Crit Care Med. 1994;150(4):896-903.

7. Esteban A, Frutos F, Tobin MJ, Alía I, Solsona JF, Valverdú I, et al. A comparison of four methods of weaning patients from mechanical ventilation. Spanish Lung Failure Collaborative Group. N Engl J Med. 1995;332(6):345-50.

8. Lellouche F, Mancebo J, Jolliet P, Roeseler J, Schortgen F, Dojat M, et al. A multicenter randomized trial of computer-driven protocolized weaning from mechanical ventilation. Am J Respir Crit Care Med. 2006;174(8):894-900

9. Slovic P, Fischhoff B, Lichtenstein S. Behavioral decision theory. Ann Rev Psychol. 1977; 28:1-39.

10. Tversky A, Kahneman D. Judgment under Uncertainty: Heuristics and Biases. Science. 1974;185(4157):1124-31.

11. Yang KL, Tobin MJ: A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. N Engl J Med. 1991;324(21):1445-50.

12. Tobin MJ, Jubran A. Variable performance of weaning-predictor tests: role of Bayes’ theorem and spectrum and test-referral bias. Intensive Care Med. 2006;32(12):2002-12 13. Tobin MJ, Jubran A. Meta-analysis under the spotlight: focused on a meta-analysis of ventilator weaning. Crit Care Med. 2008;36(1):1-7.

14. Tobin MJ, Jubran A. Four questions for Dr. MacIntyre on his editorial. Crit Care Med. 2008;36(9):2709.

15. MacIntyre N. Four questions for Dr. MacIntyre on his editorial. Crit Care Med. 2008;36(9):2709-10.

16. Tobin MJ. Remembrance of weaning past: the seminal papers. Intensive Care Med. 2006;32(10):1485-93.

J Bras Pneumol. 2011;37(5):571-573

Editorial Six-minute walk test: necessary in order to understand patient limitations Valores de referência: uma necessidade para compreendermos a limitação dos nossos pacientes

Celso Ricardo Fernandes Carvalho Most activities of daily living involve walking. On the basis of this concept, field tests have been devised in order to evaluate exercise tolerance in patients with lung disease.

McGavin et al.(1) developed a proposal to use walk tests for the assessment of exercise tolerance in such patients, and, only a few years later, Butland et al.(2) showed that one such test—the six-minute walk test (6MWT)—could be used for assessing exercise tolerance in patients with moderate or severe COPD. As the 6MWT came to be widely used, the American Thoracic Society(3) published a consensus statement on how to perform the test, which promoted its systematic use in patients with cardiopulmonary disease. The 6MWT is currently considered an important test, not only because of its capacity to document changes resulting from physical exercise programs but also because of its association with major patient-related variables, such as activities of daily living, exacerbations, and the risk of death in patients with COPD.(4,5) However, other tests, such as the incremental shuttle walk test, have also been widely used.(6) In view of the systematic use of the 6MWT, the first reference values for healthy American adults were published in 1998.(7) Iwama et al.(8) were the first to establish an equation for the prediction of the six-minute walk distance (6MWD) in healthy Brazilians. However, in that study, the age of the subjects was not representative of that of patients with COPD and the age distribution was not uniform. Recognizing the need for reference values that are more appropriate, the Brazilian Journal of Pulmonology has published, in the current issue, two studies proposing predictive equations for the 6MWD in Brazilians.

Soares & Pereira(9) evaluated 132 employees of a large hospital in the city of São Paulo, and Dourado et al.(10) evaluated 98 employees of a university in the city of Santos. In both of those studies, height, age, and body weight seemed to be the principal predictive factors. However, each group of authors arrived at a different equation. To improve clinical practice and to J Bras Pneumol. 2011;37(5):574-575

increase our understanding of this topic, it would be desirable to have a single equation. My suggestion would be that, at some future date, those two groups of authors combine their data in order to produce such an equation.

Despite the discrepancies between the two studies cited above, we congratulate both groups of authors for taking the initiative to research a topic of great interest to pulmonologists: country-specific 6MWD reference values.

Dourado was involved in developing the first reference equation related to the use of the 6MWT in Brazil,(8) and Pereira was among those responsible for establishing spirometric reference values for adults in our country.(11) To our pleasant surprise, Etemadinezhad & Alizadeh,(12) in this same issue, have published spirometric reference values for Iran.

It is now imperative that we employ the 6MWD predictive equations proposed here,(9,10) not only for expressing the distance covered by our patients but also for determining the physical limitation of those patients in values relative to those of the general population of Brazil.

Celso Ricardo Fernandes Carvalho Tenured Professor, Department of Respiratory Therapy, University of São Paulo School of Medicine, São Paulo, Brazil

References 1. McGavin CR, Gupta SP, McHardy GJ. Twelve-minute walking test for assessing disability in chronic bronchitis.

Br Med J. 1976;1(6013):822-3.

2. Butland RJ, Pang J, Gross ER, Woodcock AA, Geddes DM. Two-, six- and 12-minute walking tests in respiratory disease. Br Med J (Clin Res Ed). 1982;284(6329):1607-8.

3. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111-7.

4. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in

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chronic obstructive pulmonary disease. N Engl J Med. 2004;350(10):1005-12.

5. Garcia-Aymerich J, Farrero E, Félez MA, Izquierdo J, Marrades RM, Antó JM, et al. Risk factors of readmission to hospital for a COPD exacerbation: a prospective study. Thorax. 2003;58(2):100-5.

6. Singh SJ, Morgan MD, Scott S, Walters D, Hardman AE. Development of a shuttle walking test of disability in patients with chronic airways obstruction. Thorax.

1992;47(12):1019-24.

7. Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am J Respir Crit Care Med. 1998;158(5 Pt 1):1384-7 8. Iwama AM, Andrade GN, Shima P, Tanni SE, Godoy I, Dourado VZ. The six-minute walk test and body weight-

walk distance product in healthy Brazilian subjects. Braz J Med Biol Res. 2009;42(11):1080-5.

9. Soares MR, Pereira CA. Six-minute walk test: reference values for healthy adults in Brazil. J Bras Pneumol.

2011;37(5):576-83.

10. Dourado VZ, Vidotto MC, Guerra RL. Reference equations for the performance of healthy adults on field walking tests. J Bras Pneumol. 2011;37(5):607-14.

11. 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.

12. Etemadinezhad S, Alizadeh A. Spirometric reference values for healthy adults in the Mazandaran province of Iran. J Bras Pneumol. 2011;37(5):615-20.

J Bras Pneumol. 2011;37(5):574-575

Original Article Six-minute walk test: reference values for healthy adults in Brazil* Teste de caminhada de seis minutos: valores de referência para adultos saudáveis no Brasil

Maria Raquel Soares, Carlos Alberto de Castro Pereira

Abstract Objective: To develop regression equations for six-minute walk distance (6MWD) in healthy adults (20-80 years of age) in Brazil. Methods: We included 132 volunteers (66 males) without respiratory disease, cardiac disease, or comorbidities that affect ambulation. The volunteers completed three six-minute walk tests. Prior to and at the end of each test, we obtained SpO2 and maximal HR, as well as the Borg scale scores for sensation of dyspnea and lower limb fatigue. The data included in the final analysis were derived from the test with the greatest 6MWD. Results: The mean 6MWD values were 566 ± 87 m and 538 ± 95 m in males and females, respectively (p = 0.08). The 6MWD was greater in taller individuals and decreased in parallel with increases in age or body index mass (BMI).

The best adjusted model was the quadratic model. We derived the following equation (valid for both genders): 6MWD = 511 + stature2 (cm) × 0.0066 − age2 × 0.030 − BMI2 × 0.068. This equation explained 55% of the variance in 6MWD. Conclusions: Reference values explaining a high proportion of the variance were derived by a quadratic regression model in healthy adults (of a wide range of ages) in Brazil.

Keywords: Reference values; Exercise test; Walking.

Resumo Objetivo: Desenvolver equações de regressão para a distância caminhada no teste de caminhada de seis minutos (DTC6) em adultos saudáveis (20-80 anos de idade) no Brasil. Métodos: Foram incluídos 132 voluntários (66 homens) sem doenças respiratórias ou cardíacas, assim como sem comorbidades que afetassem a deambulação. Os voluntários completaram três testes de caminhada de seis minutos. Foram obtidos antes e ao final de cada teste: SpO2, FC máxima e escores da escala de Borg para dispneia e fadiga de pernas. Os dados incluídos na análise final foram os derivados do teste com a maior DTC6. Resultados: Os valores médios de DTC6 foram de 566 ± 87 m e 538 ± 95 m em homens e mulheres, respectivamente (p = 0,08). A DTC6 aumentou com a estatura e diminuiu com a idade e com o índice de massa corpórea (IMC). O melhor modelo ajustado foi o quadrático. A equação derivada para ambos os sexos foi: DTC6 = 511 + altura2 (cm) × 0,0066 − idade2 × 0,030 − IMC2 × 0,068. Esta equação explicou 55% da variação na DTC6. Conclusões: Valores de referência com uma elevada variância explicada foram derivados por um modelo quadrático de regressão em adultos saudáveis com ampla variação de idade no Brasil.

Descritores: Valores de referência; Teste de esforço; Caminhada.

Introduction Reference values for diagnostic tests are important in order to characterize a variety of diseases and determine their severity. The reference values for pulmonary function tests vary considerably from population to population.

(1,2) Walk tests have been used in clinical practice since the 1960s.(3) The distance covered on the six-minute walk test (6MWT), commonly referred to as the six-minute walk distance (6MWD), adequately reflects the physical capacity of

patients to perform routine tasks.(4) The 6MWT is simple, well-tolerated, and reproducible. In addition, the equipment required to perform the test is affordable. The importance of the 6MWT for the evaluation of the functional status of patients for comparing the effects of therapeutic interventions, as well as for predicting the morbidity and mortality associated with various cardiopulmonary diseases, has been extensively described in the literature.(5-8)

* Study carried out in the Pulmonary Function Laboratory of the Respiratory Diseases Department, São Paulo Hospital for State Civil Servants, São Paulo, Brazil.

Correspondence to: Maria Raquel Soares. Rua Carneiro da Cunha, 675, apto. 126, Saúde, CEP 04144 001, São Paulo, SP, Brasil.

Tel. 55 11 5574-6603. E-mail: mrsoares2010@gmail.com Financial support: None.

Submitted: 22 December 2010. Accepted, after review: 6 June 2011.

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Six-minute walk test: reference values for healthy adults in Brazil

The primary objective of the 6MWT is to determine the greatest 6MWD on a level course.

The results obtained should be compared with appropriate reference values. Since 1998, a number of equations have been devised in order to calculate predicted values. Various studies have employed a variety of methods and investigated small patient samples.(9-13) In other studies, the methods and sample size have been appropriate.(14-17) In a study recently conducted in Brazil and involving 134 individuals, the predicted 6MWD was determined considering only age and gender.(18) However, in most studies, stature is also considered a relevant variable for determining the predicted 6MWD.(9,10,12-17) Other authors have devised equations indicating that body weight or the body mass index (BMI) significantly influence the predicted 6MWD. (9,10,12,13,15,17) A multicenter study, involving 10 centers in seven countries, determined 6MWD reference values for individuals over 40 years of age.(19) In that study, the 6MWD reference values were found to vary in function of the geographic location; therefore, different countries require specific equations. The objective of the present study was to determine reference values for the 6MWD in healthy adults of a wide range of ages (20-80 years) in Brazil.

Methods We evaluated 132 individuals (66 males and 66 females) between 20 and 80 years of age. The individuals included in the present study were recruited from among those working at the São Paulo Hospital for State Civil Servants, located in the city of São Paulo, Brazil. All of the participants volunteered for the study, in response to a verbal invitation or to advertisements posted on the walls of the hospital (either on bulletin boards or near the clock-in points). Patients who were in the hospital for a medical appointment or for outpatient tests because of conditions other than those that constituted the exclusion criteria were also invited to participate in the study, as were their companions.

All of the participants were evaluated with a standardized respiratory epidemiology questionnaire,(20) as well as with a questionnaire developed by Baecke et al. in order to quantify habitual physical activity,(21) which translated to Portuguese and validated for use in Brazil.(22,23) The questionnaire developed by Baecke et al.

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is designed to be administered exclusively to individuals who are fully ambulatory.

The study was approved by the São Paulo Hospital for State Civil Servants Research Ethics Committee (Ruling no. 087/07). All of the participants gave written informed consent.

The exclusion criteria were as follows: • having any difficulty in walking • presenting with diseases that could affect ambulation, including stroke, neuromuscular diseases, peripheral vascular disease, musculoskeletal disorders, claudication, cognitive deficit, and arthritis • having had respiratory symptoms, the flu, or any other lung disease in the last seven days • having had any respiratory disease, with the exception of pneumonia, that could result in dysfunction, including tuberculosis and asthma (the latter characterized as a lifetime history of two or more wheezing attacks, which improved with the use of a bronchodilator) • having undergone thoracic surgery • having a history of physician-diagnosed heart disease • presenting with uncontrolled hypertension • presenting with a pre-test (at-rest) systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg • having worked, for one year or more, in environments in which the concentration of dust was high and there was a risk of developing respiratory disease • having a history of smoking • having a history of exposure to cigarette smoke in sleeping quarters • Having a history of exposure to smoke from wood-burning stoves • Being considered an athlete, as determined by a score ≥ 8 on the questionnaire employed(19) • having diabetes • being underweight (BMI < 18 kg/m2) or presenting with class III obesity (BMI > 40 kg/m2) • presenting with self-reported blood diseases, metabolic diseases, or both • being under treatment with drugs that can affect muscle function (e.g., statins) Prior to the 6MWT, we determined the weight, height, and blood pressure of all of (21)

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the individuals under study. The 6MWT was performed three times on the same day, in accordance with the American Thoracic Society (ATS) guidelines.(5) The test was repeated after the HR had returned to baseline levels (to within ± 10 bpm of the at-rest HR before the initial test). Before and after each test, we measured SpO2 (by pulse oximetry) and HR, as well as calculating the Borg scale scores(24) for sensation of dyspnea and leg fatigue. We measured SpO2 at the beginning of and immediately after the 6MWT. The pulse oximeter (Fingertip Pulse Oximeter model CMS50DL; Contec Medical Systems Co., Ltd, Qinhuangdao, China) was previously tested by comparing SpO2 values as measured by the equipment with those of SaO2 obtained by ten arterial blood gas measurements taken at the emergency room of the hospital (SpO2 − SaO2 = 0.45 ± 1%). Before administering the Borg scale to the individuals, the examiner explained the meaning of the score. The data included in the final analysis were derived from the test with the greatest 6MWD. The tests were performed in a 30-m outdoor corridor that was level and free of any other foot traffic.

The corridor surface was marked at every 3 m.

The course was delineated with traffic cones.

Immediately before the beginning of the tests, the participants received instructions in accordance with the Brazilian Portuguese-language version of the ATS guidelines for the 6MWT.(5) The individuals were instructed to remain in place after the completion of the 6MWT until the abovementioned measurements had been taken.

The measurements were taken immediately after the completion of the test. The examiner did not walk alongside the participants. At the end of every minute, the examiner informed the participants of how many minutes remained and provided standard phrases of encouragement (“You’re doing well!”, Good job, keep it up!”, and “You’re doing well, keep it up!”). Fifteen seconds before the end of the test, the examiner informed the participants that the test was about to end, and, at the end of the sixth minute, the examiner clearly informed the participants that the test was over by saying “Stop!”

To calculate the minimum sample size needed in order to give the study sufficient statistical power, we used the following formula:

N > 50 + 8m J Bras Pneumol. 2011;37(5):576-583

where m is the number of variables.(25) Given that there should be a separate equation for each gender and that stature and age were dependent variables, we included 50 + 16 males and 50 + 16 females (i.e., a total of 132 individuals).

In order to analyze the results, we used the Statistical Package for the Social Sciences, version 17 (SPSS Inc., Chicago, IL, USA).

After data collection, the steps were as follows: We determined the distribution of functional and anthropometric variables, as well as determining discrepant values. We performed univariate regression analysis, in which the 6MWD correlation coefficients were tested with the anthropometric variables and their transformations. Variables with a value of p < 0.10 were selected for inclusion in the multivariate analysis. We calculated the regression equations and determined discrepant values, which were detected by standardized residuals above 3.3 standard deviations and by analyzing the Mahalanobis distance.(26) In order to evaluate the influence that the conflicting results had on the results of the regression models, we analyzed Cook’s distance(26) for the residuals. Cases with values above 1 were excluded. We determined the multiple regression equation, and, subsequently, we evaluated the residuals. Their adherence to the normal curve was confirmed graphically. The residuals were plotted against each of the independent variables, as well as against the expected values, as determined by the regression equation. The lower regression limit was calculated by the 5th percentile of the residuals. We determined the influence of habitual physical activity on the 6MWD by analysis of covariance, taking the gender into account. Finally, we identified the test with the greatest 6MWD. The level of significance was set at p < 0.05.

Results The tests were well tolerated by all of the participants, and none of the tests were interrupted before the 6-min mark. A total of 132 individuals (66 males and 66 females) were included in the final analysis. Of those 132, 113 were White, and 19 were Black. Table 1 shows the distribution of individuals by gender and anthropometric data.

The determination of discrepant values led to the exclusion of 3 individuals: 2 because

Six-minute walk test: reference values for healthy adults in Brazil

Table 1 - Distribution of the reference population by gender, age bracket, stature, and body mass index.a Variable Males Females n = 66 n = 66 Age, years 20-29 9 (13.6) 11 (16.7) 30-39 10 (15.2) 7 (10.6) 40-49 10 (15.2) 17 (25.7) 50-59 12 (18.2) 12 (18.2) 60-69 12 (18.2) 6 (9.1) ≥ 70 13 (19.7) 13 (19.7) Stature, cm 135-144 0 (0.0) 2 (3.03) 145-154 2 (3.03) 23 (34.8) 155-164 16 (24.2) 29 (43.9) 165-174 31 (46.9) 9 (13.6) 175-184 17 (25.8) 3 (4.5) ≥ 185 0 (0.0) 0 (0.0) BMI, kg/m² 18-24 19 (28.7) 28 (42.4) 25-29 28 (42.4) 22 (33.3) 30-38 19 (27.2) 16 (24.2) BMI: body mass index. aValues expressed in n (%).

their statures were at either end of the spectrum (1.95 m and 1.33 m, respectively); and 1 for walking only 240 m during the 6MWT. The latter individual was subsequently contacted by telephone and reported having been, during the week of the 6MWT, under clinical suspicion of angina (which was subsequently confirmed).

The individual also reported having omitted that information because of a strong desire to participate in the study. Subsequently, the determination of discrepant values when calculating the regression equations led to the

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exclusion of 3 additional individuals. Of those, 2 were excluded on the basis of the Mahalanobis distance, and 1 was excluded for not achieving a value that was within the accepted range for the residuals (3.3 standard deviations).

The anthropometric variables that significantly correlated with the 6MWD in the univariate analysis were age (r = −0.66; p < 0.01), stature (r = 0.42; p < 0.01), and BMI (r = −0.37; p < 0.01). Weight in isolation was not significantly correlated with the 6MWD. Although the 6MWD was greater in males than in females, the difference was not statistically significant (p = 0.08; Table 2). Although habitual physical activity showed a borderline significant correlation with the 6MWD in the univariate analysis (r = 0.23; p = 0.07), that correlation did not remain significant in the multivariate analysis.

Various regression models were tested in order to determine the best adjustment of the anthropometric data to the 6MWD (Table 3).

The quadratic model was the best adjusted model, showing the highest coefficient of determination and the lowest values for the 5th percentile for the residuals. The model explained 55% of the total variance in the 6MWD (r2 = 0.55). In order to predict the 6MWD, we derived the following equation (valid for both genders):

6MWD = 511 + stature2 × 0.0066 – age2 × 0.030 − BMI2 × 0.068 where stature is expressed in cm, age is expressed in years, and BMI is expressed in kg/m2. When the residuals were plotted against the 6MWD, we found that the dispersion decreased in parallel with decreases in the 6MWD (Figure 1). On the

Table 2 - General data regarding the six-minute walk test, by gender.

Variable Male gender n = 66 Initial Final HR, bpma 77 ± 11 109 ± 18 Predicted HRmax, bpma,b 168 ± 17 HRmax, %a 65 ± 11 SpO2, %a 97 ± 1 96 ± 1 −1.0 (−2.0 to 1.0) ΔSpO2, %c Borg scale score for sensation of dyspneac 0 (0-0) 2 (0-4) Borg scale score for leg fatiguec 0.0 (0.0-0.5) 0 (0-3) Greatest 6MWD, ma 566 ± 87 HPA questionnaire scorea 7.38 ± 1.23

Female gender n = 66 Initial Final 80 ± 11 115 ± 16 171 ± 17 68 ± 10 97 ± 1 96 ± 1 −0.5 (−2.0 to 1.0) 0 (0-0) 2 (0-4) 0 (0-3) 1 (0-5) 538 ± 95* 7.2 ± 1.26**

HRmax: maximal HR; 6MWD: six-minute walk distance; HPA: habitual physical activity. aValues expressed as mean ± SD. b Predicted HRmax = 220 − age. cValues expressed as median (range). *t = 1.76; p = 0.08. **t = 0.79; p = 0.43.

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28 (21%) were considered physically active but not physically fit.

The mean 6MWD on the first, second, and third attempts was 525 m, 534 m, and 534 m, respectively (repeated measures ANOVA; F = 3.21; p = 0.044). Regarding the three sequential 6MWD measurements, 35 (27.7%) of the individuals achieved the greatest 6MWD on the first test, compared with 51 (40.4%) on the second test and 40 (31.7%) on the third test.

For 6 individuals, the 6MWD was the same on all three tests.

Figure 1 - Calculation of the lower limit, expressed as percentage of predicted, of the regression equation derived for the six-minute walk distance in both genders. Note the difference between the cases with values above the median and those with values below the median regarding the mean dispersion of residuals.

basis of that finding, the 5th percentile for the 6MWD was calculated separately for values above and below the median. The lower limit, transformed into a proportion, was found to be 81% of the value predicted for both groups.

Table 3 shows the equations for both genders.

Nine individuals were using beta blockers as antihypertensive agents. In those individuals, the maximal HR (HRmax) was 91 ± 20 bpm, compared with 114 ± 17 bpm in the remaining 123 individuals, who were not using beta blockers (t = 3.97; p < 0.001).

The maximum drop in SpO2 was 2% (Table 2).

The Borg scale score for sensation of dyspnea increased to a maximum of 4, and the Borg scale score for leg fatigue increased to a maximum of 5. Of the total of individuals under study, 104 (79%) were considered sedentary (total habitual physical activity questionnaire score < 8.0) and

Discussion In the present study, we derived an equation for the 6MWD in a sample composed of 20- to 80-year-olds in Brazil. The model that best fit the data was the quadratic model. In that model, stature, age, and BMI explained 55% of the total variance. Although there were no significant differences between the genders, the 6MWD was slightly greater in males. In addition to deriving an equation that is valid for both genders, we derived separate equations for each gender, because of the borderline significant difference (p = 0.08). The establishment of 6MWD equations considers, a priori, that the 6MWD is greater in males, which is why equations are derived separately for each gender. However, not all studies have found differences between the genders when calculating the 6MWD on the basis of stature and weight. In one study, for instance, the findings were clearly similar for both genders.(14) In the present study, habitual physical activity showed a borderline significant correlation with the 6MWD only in the univariate analysis. However, it should be borne in mind that physically fit individuals were excluded.

Habitual physical activity has been evaluated in seven studies of 6MWT reference values,(10-12,16-19)

Table 3 - Models tested for the six-minute walk distance and the anthropometric variables selected.

Model Constant Stature Age BMI r2 5th percentile cm years kg/m2 Quadratic, general Quadratic, males Quadratic, females Linear, general Linear, males Linear, females

511 504 636 417 390 683

0.0066 0.0059 0.0025 2.31 2.14 0.91

BMI: body mass index; r2: coefficient of determination.

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−0.030 −0.025 −0.039 −2.95 −2.37 −3.94

−0.068 −0.044 −0.074 −3.49 −2.34 −3.57

0.55 0.37 0.74 0.52 0.33 0.71

107 118 84 114 121 97

Six-minute walk test: reference values for healthy adults in Brazil

in which it was shown to correlate, albeit poorly, with the 6MWD. Ideal samples are those that consist of people who are randomly chosen from among the general population. In the present study, we included volunteers (convenience sample), which might have introduced a selection bias. Although the individuals included were selected primarily by age, they had a variety of occupations and were in different socioeconomic strata.

Various conditions that can affect ambulation and cardiorespiratory function constituted the exclusion criteria. Therefore, the volunteers that were included met the criteria for a sample to be used in the establishment of reference values.(2) Because our sample comprised only individuals who had never smoked and who had no signs or symptoms of respiratory disease (as determined with a validated respiratory epidemiology questionnaire), spirometry was not performed. The exercise capacity of individuals without respiratory disease is limited by the cardiovascular and peripheral muscle systems rather than by pulmonary function.(27) Because of the well-established role of the 6MWT in the follow-up of patients with diseases that affect various age groups, it is important to consider not only a significant sample but also a wide range of ages in order to derive reference values. Of the studies investigating reference values for the 6MWT, only seven have evaluated samples comprising more than 100 individuals.

(13-19) Of those seven studies, four included only individuals over 40 years of age(14,15,17,19) and two included individuals between 18 and 50 years of age.(13,16) A study conducted by Iwama et al.

(18) included 134 individuals between 13 and 84 years of age. However, only 5 of the volunteers were older than 65 years of age, and only 10 were younger than 20 years of age. In the present study, the 132 individuals included were well distributed by gender and age bracket.

The 6MWD is influenced by the learning effect. One group of authors(28) suggested that three tests were required in order to determine the greatest 6MWD more accurately. Studies of the 6MWD in normal individuals confirmed that at least three tests are required.(8-10,17) In studies in which only two tests were performed,(9,13,15,17,18) as well as in those in which only one test was performed,(14,16) it is likely that the 6MWD was underestimated. Although Iwama et al.(18)

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performed only two tests, the authors used the 6MWD achieved on the second test, even if the 6MWD was greater on the first test.

Stature was a relevant anthropometric variable for the prediction of the 6MWD in the present study, as it was in all such studies involving significant samples.(13-17,19) In the study conducted by Iwama et al.,(18) only age and gender were taken into consideration when the regression equation was being derived. However, in the univariate analysis, the authors found that stature had the highest correlation coefficient, and its inclusion in the multivariate equation was therefore obligatory. In three studies,(14,15,19) weight was included in the prediction equation.

This was not the case in the present study, in which, unlike BMI, weight in isolation had no significant influence on the 6MWD. In all studies investigating 6MWD reference values, age has been shown to be relevant.

The 6MWD coefficient of determination (r2) provided by anthropometric variables varies from 0.25 to 0.42 across most studies, with the exception of one study, in which a surprising value of 0.77 was found.(15) In the present study, the r2 was 0.55, a high value that can be explained, at least in part, by the evaluation of the best regression model, which was not performed in any other study. In other studies, the r2 was increased by the inclusion of HRmax in the prediction equation.(11,17) In the present study, SpO2 at the end of the 6MWT dropped no more than 2 points, a result that is in agreement with those of other studies involving normal individuals.(13-16,18) Many consider oxygen desaturation during exercise to be significant when there is a drop ≥ 4% in baseline saturation. However, that cut-off value was derived from studies involving maximal cardiopulmonary exercise testing in athletes.(29) In the present study, we found that the Borg scale scores for sensation of dyspnea and leg fatigue were no higher than 4 and 5, respectively.

One group of authors(30) used the Borg scale scores for sensation of dyspnea and leg fatigue in order to evaluate 460 normal individuals who underwent incremental cycle ergometer exercise.

At 60% of the maximum workload, a value that is similar to the workload estimated by the HR found in the present study, the highest scores for sensation of dyspnea and leg fatigue were 5 and 6, respectively, for both genders.

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Reference values should be established in specific populations.(19) The values obtained in the present study are different from those derived from another sample of the Brazilian population,(18) which can be explained by the aforementioned factors. No comparisons were drawn with other equations, because the age range was limited in those studies.(14,19) In the present study, reference values for the 6MWT were derived from a sample of male and female adults of a wide range of ages in Brazil.

A quadratic equation was the model that best adjusted to the data, with a high r2. The values found in the present study are different from the predicted values previously reported.

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9. Troosters T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur Respir J. 1999;14(2):270-4.

10. Gibbons WJ, Fruchter N, Sloan S, Levy RD. Reference values for a multiple repetition 6-minute walk test in healthy adults older than 20 years. J Cardiopulm Rehabil. 2001;21(2):87-93.

11. Poh H, Eastwood PR, Cecins NM, Ho KT, Jenkins SC. Six-minute walk distance in healthy Singaporean adults cannot be predicted using reference equations derived from Caucasian populations. Respirology.

2006;11(2):211-6.

12. Camarri B, Eastwood PR, Cecins NM, Thompson PJ, Jenkins S. Six minute walk distance in healthy subjects aged 55-75 years. Respir Med. 2006;100(4):658-65.

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13. Chetta A, Zanini A, Pisi G, Aiello M, Tzani P, Neri M, et al. Reference values for the 6-min walk test in healthy subjects 20-50 years old. Respir Med. 2006;100(9):1573-8.

14. Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am J Respir Crit Care Med. 1998;158(5 Pt 1):1384-7.

15. Ben Saad H, Prefaut C, Tabka Z, Mtir AH, Chemit M, Hassaoune R, et al. 6-minute walk distance in healthy North Africans older than 40 years: influence of parity.

Respir Med. 2009;103(1):74-84.

16. Alameri H, Al-Majed S, Al-Howaikan A. Six-min walk test in a healthy adult Arab population. Respir Med. 2009;103(7):1041-6.

17. Jenkins S, Cecins N, Camarri B, Williams C, Thompson P, Eastwood P. Regression equations to predict 6-minute walk distance in middle-aged and elderly adults.

Physiother Theory Pract. 2009;25(7):516-22.

18. Iwama AM, Andrade GN, Shima P, Tanni SE, Godoy I, Dourado VZ. The six-minute walk test and body weightwalk distance product in healthy Brazilian subjects. Braz J Med Biol Res. 2009;42(11):1080-5.

19. Casanova C, Celli BR, Barria P, Casas A, Cote C, de Torres JP, et al. The 6-min walk distance in healthy subjects: reference standards from seven countries. Eur Respir J. 2011;37(1):150-6.

20. Aguiar VA, Beppu OS, Romaldini H, Ratto OR, Nakatani J. Validade de um questionário respiratório modificado (ATS-DLD-78) como instrumento de um estudo epidemiológico em nosso meio. J Pneumol.

1988;14(3):111-6.

21. Baecke JA, Burema J, Frijters JE. A short questionnaire for the measurement of habitual physical activity in epidemiological studies. Am J Clin Nutr.

1982;36(5):936-42.

22. Florindo AA, Latorre Mdo R, Jaime PC, Tanaka T, Zerbini CA. Methodology to evaluation the habitual physical activity in men aged 50 years or more [Article in Portuguese]. Rev Saude Publica. 2004;38(2):307-14.

23. Florindo AA, Latorre MR. Validação e reprodutibilidade do questionário de Baecke de avaliação da atividade física habitual em homens adultos. Rev Bras Med Esporte. 2003;9(3):121-8.

24. Borg GA. Psychophysical bases of perceived exertion.

Med Sci Sports Exerc. 1982;14(5):377-81.

25. Tabachnick BG, Fidell LS. Multiple regression. In: Tabachnick BG, Fidell LS, editors. Using multivariate statistics. Boston: Allyn and Bacon; 2001. p. 71.

26. Field A. Regressão. In: Field A, editor. Descobrindo a estatística usando o SPSS. São Paulo: Artmed; 2009. p. 156-220.

27. Jones NL, Killian KJ. Exercise limitation in health and disease. N Engl J Med. 2000;343(9):632-41.

28. Guyatt GH, Pugsley SO, Sullivan MJ, Thompson PJ, Berman L, Jones NL, et al. Effect of encouragement on walking test performance. Thorax. 1984;39(11):818-22.

29. Prefaut C, Durand F, Mucci P, Caillaud C. Exerciseinduced arterial hypoxaemia in athletes: a review. Sports Med. 2000;30(1):47-61.

30. Killian KJ, Summers E, Jones NL, Campbell EJ. Dyspnea and leg effort during incremental cycle ergometry. Am Rev Respir Dis. 1992;145(6):1339-45.

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About the authors Maria Raquel Soares

Attending Physician. Department of Respiratory Diseases, S達o Paulo Hospital for State Civil Servants, S達o Paulo, Brazil.

Carlos Alberto de Castro Pereira

Director. Department of Respiratory Diseases, S達o Paulo Hospital for State Civil Servants, S達o Paulo, Brazil.

J Bras Pneumol. 2011;37(5):576-583

Original Article Acute asthma management in children: knowledge of the topic among health professionals at teaching hospitals in the city of Recife, Brazil* Manejo de crises asmáticas em crianças: conhecimento de profissionais de saúde quanto ao tópico em hospitais-escola do Recife (PE)

Giovanna Menezes de Medeiros Lustosa, Murilo Carlos Amorim de Britto, Patrícia Gomes de Matos Bezerra

Abstract Objective: Knowledge of acute asthma management in children is a subject that has rarely been explored. The objective of this study was to assess the level of such knowledge among health professionals in the city of Recife, Brazil. Methods: This was a cross-sectional survey involving 27 pediatricians and 7 nurses, all with at least two years of professional experience, at two large pediatric teaching hospitals in Recife. The participants completed a self-administered multiple-choice questionnaire. Results: The pediatricians and nurses all possessed insufficient knowledge regarding the use of metered dose inhalers, nebulization, and types/doses of medications, as well as techniques for decontamination and disinfection of the equipment. Conclusions: Insufficient knowledge of acute asthma management in children can lead to less effective treatment in hospitals such as those evaluated here.

Educational programs should be developed in order to minimize this problem.

Keywords: Asthma; Health knowledge, attitudes, practice; Nebulizers and vaporizers.

Resumo Objetivo: O conhecimento sobre o manejo da asma aguda em crianças é um tema pouco explorado. O objetivo deste estudo foi avaliar o conhecimento de profissionais de saúde do Recife (PE) sobre o assunto. Métodos: Estudo transversal de tipo inquérito com 27 médicos e 7 enfermeiros, com mais de 2 anos de trabalho, de dois grandes hospitais-escola de pediatria do Recife, avaliados através de questionários autoaplicáveis com questões fechadas.

Resultados: Tanto os pediatras quanto os enfermeiros apresentaram conhecimento inadequado sobre o uso de inaladores dosimetrados, nebulização, tipo e dosagem dos medicamentos, assim como técnicas de descontaminação e desinfecção do material. Conclusões: O conhecimento inadequado do manejo da asma aguda em crianças pode refletir em um tratamento menos efetivo nesses hospitais. Medidas educativas são necessárias para minimizar o problema.

Descritores: Asma; Conhecimentos, atitudes e prática em saúde; Nebulizadores e vaporizadores.

Introduction Acute asthma accounts for a large number of emergency room visits and hospitalizations, as well as leading to school absenteeism, restriction of physical activity, and parents having to take time off from work.(1,2) In 2010, asthma accounted for 192,601 hospital admissions in Brazil, and

expenditures—in Brazilian reals (R$)—amounted to R$ 100,537,934.90. In that same year, asthma accounted for approximately 6% of all hospital admissions in children under 14 years of age in the Brazilian state of Pernambuco, being the third leading cause of such admissions.(3) Although acute asthma management might seem simple at first glance, it requires that

* Study carried out at the Instituto de Medicina Integral Prof. Fernando Figueira – IMIP, Professor Fernando Figueira Institute of Comprehensive Medicine – Recife, Brazil.

Correspondence to: Murilo Carlos Amorim de Britto. IMIP - Ambulatório de Pneumologia Pediátrica, Rua dos Coelhos, 300, Boa Vista, CEP 50070-550, Recife, PE, Brasil.

Tel. 55 81 2122-4100. E-mail: murilobritto@ig.com.br; Webpage: www.imip.org.br Financial support: None.

Submitted: 1 June 2011. Accepted, after review: 11 July 2011.

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Acute asthma management in children: knowledge of the topic among health professionals at teaching hospitals in the city of Recife, Brazil

health professionals know the basics so that they can act effectively, reducing the risk of hospitalization and minimizing side effects, as well as maximizing cost-effectiveness. Two wellestablished principles to be considered in asthma management, for patients of all ages, are that inhalation is the most effective way of delivering medication and that short-acting β2 agonists are the first-line drugs. Inhaled medications are most often delivered via nebulizers or metered dose inhalers (MDIs).(1,2,4,5) The most common way of delivering β2 agonists is by nebulization.

However, a systematic review of the literature, involving 2,295 children and 614 adults, showed that MDIs are as efficient as are nebulizers and provoke fewer side effects.(6) In children, MDIs should be used with a spacer.(1,2,4,5) Various studies have shown that the use of MDIs attached to a spacer, be it conventional or homemade, is as effective as is that of conventional nebulization.

(7-10) In choosing between using MDIs and nebulization, another important aspect to be considered is the cost. Studies conducted in the United States(11) and in Brazil(12) have shown that MDIs are more economical than are nebulizers.

There are no guidelines specifying the preferred type of device for managing acute asthma in children. However, how to choose the type of inhalation device in the longterm management of asthma, by age group, is described in the National Institutes of Health/ World Health Organization Global Initiative for Asthma guidelines on asthma management in children up to five years of age.(13) Those recommendations can inform decisions regarding the devices to be used in acute asthma, except for dry powder inhalers, which, in Brazil, are available only for long-acting β2 agonists, medications that are not indicated for children with asthma.(1,2) The effective disinfection of semi-critical items, which include spacers and nebulizers, requires adequate knowledge, such as knowledge of methods of decontamination/disinfection and knowledge of proper storage of solutions.

The Brazilian National Health Oversight Agency has established guidelines for these procedures.

(14)

Although acute asthma is a common cause of emergency room visits, the level of knowledge of its management among health professionals is a subject that has rarely been explored. A

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search of the Biblioteca Regional de Medicina (Bireme, Regional Library of Medicine), SciELO, and PubMed databases revealed only one study on this topic. In that study, conducted in Rio de Janeiro, 50 of the 72 physicians interviewed did not know how to prescribe an MDI with a spacer as the device of choice for treating acute asthma and rarely classified asthma on the basis of the symptoms of the attack.(4) The objective of the present study was to assess the level of knowledge of acute asthma management among health professionals— pediatricians and nurses working in pediatric emergency rooms at teaching hospitals.

Methods This was a cross-sectional study involving pediatricians and nurses working in the emergency rooms of pediatric teaching hospitals affiliated with the Brazilian Unified Health Care System in the city of Recife, Brazil, between January and April of 2010. We enrolled a convenience sample of attending pediatricians and nurses at the Instituto de Medicina Integral Prof.

Fernando Figueira (IMIP, Professor Fernando Figueira Institute of Comprehensive Medicine) and at the Barão de Lucena Hospital, since these are two important teaching centers for pediatric emergency care in the state of Pernambuco.

We included all health professionals with at least two years of work experience at either of the two hospitals. We used self-administered multiple-choice questionnaires, one for physicians and one for nurses (Appendices 1 and 2). The research project was approved by the IMIP Research Ethics Committee (Protocol no.

1594-09). All participants gave written informed consent.

Results Of the 45 health professionals at the two hospitals, 10 were excluded because they had less than two years of work experience. One nurse declined to participate in the study, without providing a reason for doing so. Of the remaining 34 health professionals, 27 were physicians and 7 were nurses. The median age of the pediatricians and nurses was 37 years (range, 28-61 years) and 29 years (range, 26-42 years), respectively. The median time since graduation was 13 and 6 years, respectively, and the median

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length of professional experience was 12 and 6 years, respectively. Table 1 shows other sociodemographic characteristics of the sample.

All of the nurses reported that MDIs were not available in the emergency rooms in which they worked. Sixteen (59%) of the 27 physicians and 3 (43%) of the 7 nurses opined that MDIs are easier to use than are nebulizers. Only 10 of the physicians (37%) and 1 of the nurses (14%) responded that MDIs are as efficient as are nebulizers.

Of the 27 physicians, 20 (74%) stated that a dose of 2.5 mg of nebulized fenoterol is too high for a child weighing 20 kg. Twenty-two of the physicians (81%) reported that they did not use the ipratropium bromide-β2 agonist combination in moderate or severe asthma.

In addition, 22 (81%) stated that they do not approve of the use of the ipratropium bromide-β2 agonist combination in a mild asthma.

Only 13 of the 27 physicians (48%) responded that oxygen is the optimal nebulizer gas. Regarding the gas flow rate, 17 physicians (63%) recommended the use of 6-8 L/min. All stated that saline is the recommended nebulizer solution.

Regarding the types of nasal/oral adapter (masks and mouthpieces), 13 (48%) of the 27 physicians and 6 (86%) of the 7 nurses responded that five-year-old children do not need a mouthpiece for nebulization. When questioned about the MDI technique, 21 (78%) of the physicians responded correctly (slow and deep inhalation), compared with only 3 (43%) of the nurses, 4 (57%) of the nurses responding that inhalation should be rapid and deep. Regarding how the MDI should be attached to the spacer (with the canister upward or downward), 18 of the physicians (67%) and 4 of the nurses (57%) checked the option stating that the position does not interfere with the delivery of the drug to the respiratory tract. Only the nurses were questioned about the age group in which MDIs can be used: 4 (57%) did not know; and 1 (14%) stated that MDIs are suitable for all ages. Of the 7 nurses, 4 (57%) stated that the nebulizer circuit and the spacer should be cleaned and disinfected once a week (Table 1).

Discussion Acute asthma is a common problem, and knowledge of acute asthma management is

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a subject that has rarely been explored in the literature. In light of the current knowledge, the present study raises an important question: Do health professionals in Brazil have sufficient knowledge of acute asthma management in children?

Currently, there is not enough scientific evidence to make the use of MDIs more common in the treatment of acute asthma. A systematic review of randomized trials(6) confirmed that aerosol β2 agonists are as efficient as are nebulized β2 agonists, as well as being safer.

In addition, delivering β2 agonists via an MDI is known to be less costly than is doing it by nebulization.(11,12) This raises the question of why a cheaper and more efficient technology is less commonly used, as has been observed here. The present study was not designed to address this question. However, we can speculate on two factors. The first is related to paradigm shifts.

According to Kuhn, an obsolete scientific theory is replaced not merely because it has been scientifically refuted, but because its former advocates cease to act.(15) Although the problem in question does not involve a scientific theory but rather an evidence-based technology, the argument can be applied to the case in question.

The second factor is related to the lack of sufficient knowledge of the subject among health professionals directly involved in the treatment of patients and among health care managers.

In the topics addressed in the questionnaires of the present study, it is evident that physicians and nurses do not have sufficient knowledge of the use of MDIs. These data are in accordance with those obtained in a study conducted in São Paulo, Brazil.(16) The lack of availability of MDIs and spacers in the facilities studied can explain, in part, the insufficient knowledge of the subject among health professionals.

However, knowledge of the low cost and effectiveness of the method, per se, is sufficient for health professionals to argue that health care managers should make such devices available in pediatric emergency rooms. In contrast, it was expected that, since nebulization is the available method of treatment with β2 agonists, health professionals would have sufficient knowledge of this procedure. However, this was also not observed. Parameters for nebulized medication doses, types of nebulizer gas, and nebulizer gas flow rates, as well as for types of nasal/oral

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Table 1 - Sociodemographic characteristics of physicians and nurses working in pediatric emergency rooms at teaching hospitals in the city of Recife, Brazil, between January and April/2010.

Characteristic Type of professional Physician Nurse Total (n = 27) (n = 7) (n = 34) n (%) n (%) n (%) Workplace IMIP 22 (82) 6 (85) 28 (82) HBL 5 (18) 1 (15) 6 (18) Gender Female 25 (92) 6 (85) 31 (91) Male 2 (8) 1 (15) 3 (9) Level of education Bachelor’s degree 2 (8) 2 (8) 4 (11) Specialization 2 (8) 3 (42) 5 ( 14) Residency 20 (74) 1 (15) 21 (64) Master’s degree 3 (11) 1 (15) 4 (11) Continuing education Attendance of conferences in the previous year 4 (14) 4 (57) 8 (24) Reading of articles in the previous week 19 (70) 3 (42) 22 (65) Reading of articles online in the previous month 4 (14) 0 (0) 4 (11) IMIP: Instituto de Medicina Integral Prof. Fernando Figueira (Professor Fernando Figueira Institute of Comprehensive Medicine); and HBL: Hospital Barão de Lucena (Barão de Lucena Hospital).

adapter, have previously been established—in the Brazilian Guidelines for Asthma Management(1) and in an international consensus guideline.

(2) These documents are available online and have been widely disseminated in the pediatric community. Therefore, a lack of valid scientific evidence cannot be the reason for the results obtained. A systematic review showed that administration of multiple doses of ipratropium bromide, especially during attacks that are more severe, reduces the risk of hospitalization.(17) The respondents evaluated in the present study showed a lack of knowledge of that aspect as well.

We can presume that the lack of sufficient knowledge for treating children with acute asthma in emergency rooms leads to a greater chance of hospitalization, more emergency room visits, more time spent in the emergency room, and an increased risk of treatment side effects.

This also increases health care expenditures, because the direct costs associated with the use of nebulizers are higher than are those associated with that of MDIs,(11,12) as well as because the numbers of hospital admissions and emergency room visits are increased.

The present study has certain limitations.

First, the choice of the hospitals in the sample

was non-probabilistic, which might have biased the results. However, the inclusion of the IMIP, which is the center with the greatest number of pediatric visits in the state of Pernambuco, as well as having the greatest number of residents and graduate students in pediatrics, makes the sample significant in terms of teaching hospitals.

The Barão de Lucena Hospital is also a major center for pediatric education in the state. We can suppose that the potential sample selection bias would have the effect of minimizing the problem, that is, in emergency rooms used exclusively for patient care, the level of knowledge on acute asthma management would be even less sufficient. Another limitation is the fact that we used an unvalidated questionnaire.

However, the questions asked were based on Brazilian and international consensus guidelines on asthma management,(1,2,18) on systematic reviews of the literature,(6,17) and on other studies of good methodological quality, making it possible to establish a reliable profile of the health professionals in Brazilian Unified Health Care System emergency rooms in capital cities in northeastern Brazil, in terms of their level of knowledge regarding the treatment of children with acute asthma. In addition, this study did not include facilities located in the interior the J Bras Pneumol. 2011;37(5):584-588

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state or in other northeastern states. However, it seems unlikely that the level of knowledge of such health professionals is better than is that of those in Recife.

In summary, pediatricians and nurses working in two large emergency rooms in northeastern Brazil have insufficient knowledge of acute asthma management. In view of the large number of children with asthma who seek emergency room treatment, federal, state, or even institutional educational programs should be developed in order to make asthma management more efficient and less costly.

References 1. Sociedade Brasileira de Pneumologia e Tisiologia. IV Diretrizes Brasileiras para o Manejo da Asma. J Bras Pneumol. 2006;32(Suppl 17):S447-S474.

2. Global Initiative for Asthma. National Heart, Lung, and Blood Institute. World Health Organization. Global strategy for asthma management and prevention.

Bethesda: National Institutes of Health, National Heart, Lung, and Blood Institute; 2009.

3. DATASUS [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2011 Mar 3]. Morbidade Hospitalar do SUS - por local de internação - Brasil.

Available from: http://tabnet.datasus.gov.br/cgi/ deftohtm.exe?sih/cnv/niuf.def 4. Amantéa SL, Sánchez I, Piva JP, Garcia PC. Controversies in the pharmacological management of acute asthma in children [Article in Portuguese]. J Pediatr (Rio J).

2002;78 Suppl 2:S151-60.

5. Piva JP, Canani SF, Pitrez PM, Stein RT. Severe acute asthma in the child [Article in Portuguese]. J Pediatr (Rio J). 1998;74 Suppl 1:S59-68.

6. Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2006;(2):CD000052.

7. Teo J, Kwang LW, Yip WC. An inexpensive spacer for use with metered-dose bronchodilators in young asthmatic children. Pediatr Pulmonol. 1988;5(4):244-6.

8. Schuh S, Johnson DW, Stephens D, Callahan S, Winders P, Canny GJ. Comparison of albuterol delivered by a metered dose inhaler with spacer versus a nebulizer in children with mild acute asthma. J Pediatr.

1999;135(1):22-7.

9. Singhal T, Garg H, Arora HS, Lodha R, Pandey RM, Kabra SK. Efficacy of a home-made spacer with acute exacerbation of bronchial asthma: a randomized controlled trial. Indian J Pediatr. 2001;68(1):37-40.

10. Zar HJ, Brown G, Donson H, Brathwaite N, Mann MD, Weinberg EG. Home-made spacers for bronchodilator therapy in children with acute asthma: a randomised trial. Lancet. 1999;354(9183):979-82.

11. Closa RM, Ceballos JM, Gómez-Papí A, Galiana AS, Gutiérrez C, Martí-Henneber C. Efficacy of bronchodilators administered by nebulizers versus spacer devices in infants with acute wheezing. Pediatr Pulmonol. 1998;26(5):344-8.

12. Chong Neto HJ, Chong-Silva DC, Marani DM, Kuroda F, Olandosky M, Noronha L. Different inhaler devices in acute asthma attacks: a randomized, double-blind, placebo-controlled study [Article in Portuguese]. J Pediatr (Rio J). 2005;81(4):298-304.

13. Global Initiative for Asthma. Global Strategy for the Diagnosis and Management of Asthma in Children 5 Years and Younger. Bethesda: Global Initiative for Asthma; 2009.

14. ANVISA. Curso Básico de Controle de Infecção Hospitalar - Caderno C Métodos de Proteção Anti-Infecciosa.

Brasília: Ministério da Saúde; 2000.

15. Villani A. Filosofia da ciência e o ensino da ciência: uma analogia. C&E. 2001;7(2):169-81.

16. Muchão FP, Perín SL, Rodrigues JC, Leone C, Silva Filho LV. Evaluation of the knowledge of health professionals at a pediatric hospital regarding the use of metereddose inhalers. J Bras Pneumol. 2008;34(1):4-12.

17. Plotnick LH, Ducharme FM. Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children. Cochrane Database Syst Rev. 2000;(4):CD000060.

18. Sociedade Brasileira de Pneumologia e Tisiologia. I Consenso Brasileiro de Educação em Asma. J Pneumol.

1996;22(Suppl 1):1-24.

About the authors Giovanna Menezes de Medeiros Lustosa

Nurse. Instituto de Medicina Integral Prof. Fernando Figueira – IMIP, Professor Fernando Figueira Institute of Comprehensive Medicine – Recife, Brazil.

Murilo Carlos Amorim de Britto

Pediatric Pulmonologist. Instituto de Medicina Integral Prof. Fernando Figueira – IMIP, Professor Fernando Figueira Institute of Comprehensive Medicine – Recife, Brazil.

Patrícia Gomes de Matos Bezerra

Pediatric Pulmonologist. Instituto de Medicina Integral Prof. Fernando Figueira – IMIP, Professor Fernando Figueira Institute of Comprehensive Medicine – Recife, Brazil.

J Bras Pneumol. 2011;37(5):584-588

Artigo Original An experimental rat model of ex vivo lung perfusion for the assessment of lungs after prostacyclin administration: inhaled versus parenteral routes* Modelo experimental de perfusão pulmonar ex vivo em ratos: avaliação de desempenho de pulmões submetidos à administração de prostaciclina inalada versus parenteral Paulo Francisco Guerreiro Cardoso, Rogério Pazetti, Henrique Takachi Moriya, Paulo Manuel Pêgo-Fernandes, Francine Maria de Almeida, Aristides Tadeu Correia, Karina Fechini, Fabio Biscegli Jatene

Abstract Objective: To present a model of prostaglandin I2 (PGI2) administration (inhaled vs. parenteral) and to assess the functional performance of the lungs in an ex vivo lung perfusion system. Methods: Forty Wistar rats were anesthetized and placed on mechanical ventilation followed by median sterno-laparotomy and anticoagulation.

The main pulmonary artery was cannulated. All animals were maintained on mechanical ventilation and were randomized into four groups (10 rats/group): inhaled saline (IS); parenteral saline (PS); inhaled PGI2 (IPGI2); and parenteral PGI2 (PPGI2). The dose of PGI2 used in the IPGI2 and PPGI2 groups was 20 and 10 µg/kg, respectively.

The heart-lung blocks were submitted to antegrade perfusion with a low potassium and dextran solution via the pulmonary artery, followed by en bloc extraction and storage at 4°C for 6 h. The heart-lung blocks were then ventilated and perfused in an ex vivo lung perfusion system for 50 min. Respiratory mechanics, hemodynamics, and gas exchange were assessed. Results: Mean pulmonary artery pressure following nebulization decreased in all groups (p < 0.001), with no significant differences among the groups. During the ex vivo perfusion, respiratory mechanics did not differ among the groups, although relative oxygenation capacity decreased significantly in the IS and PS groups (p = 0.04), whereas mean pulmonary artery pressure increased significantly in the IS group.

Conclusions: The experimental model of inhaled PGI2 administration during lung extraction is feasible and reliable.

During reperfusion, hemodynamics and gas exchange trended toward better performance with the use of PGI2 than that with the use of saline.

Keywords: Prostaglandins; Lung transplantation; Reperfusion; Models, animal; Rats.

Resumo Objetivo: Apresentar um modelo experimental de administração de prostaglandina I2 (PGI2) por via inalatória vs. parenteral e avaliar o desempenho funcional dos pulmões em um sistema de perfusão pulmonar ex vivo.

Métodos: Quarenta ratos Wistar foram anestesiados, ventilados, submetidos a laparotomia com ressecção do esterno e anticoagulados. O tronco da artéria pulmonar foi canulado. Todos os animais foram submetidos a ventilação mecânica. Os animais foram randomizados em quatro grupos (10 ratos/grupo): salina nebulizada (SN); salina parenteral (SP); PGI2 nebulizada (PGI2N); e PGI2 parenteral (PGI2P). A dose de PGI2 nos grupos PGI2N e PGI2P foi de 20 e 10 µg/kg, respectivamente. Os blocos cardiopulmonares foram submetidos in situ a perfusão anterógrada com solução de baixo potássio e dextrana a 4°C via artéria pulmonar, extraídos em bloco e armazenados a 4°C por 6 h. Os blocos foram ventilados e perfundidos em um sistema ex vivo por 50 min, sendo obtidas medidas de mecânica ventilatória, hemodinâmica e trocas gasosas. Resultados: Houve redução da pressão arterial pulmonar média após a nebulização em todos os grupos (p < 0,001), sem diferença entre os grupos. Na perfusão ex vivo, a mecânica ventilatória não diferiu entre os grupos. Houve redução da capacidade relativa de oxigenação ao longo da perfusão nos grupos SN e SP (p = 0,04), e houve aumento significativo da pressão arterial pulmonar no grupo SN. Conclusões: O modelo experimental de administração de PGI2 na extração pulmonar é exequível e confiável. Na reperfusão, os resultados de hemodinâmica e de trocas gasosas demonstraram tendência a um melhor desempenho com o uso de PGI2 do que com solução salina.

Descritores: Prostaglandinas; Transplante de pulmão; Reperfusão; Modelos animais; Ratos. * Study carried out in the Department of Cardiorespiratory Diseases, Thoracic Surgery Section; in Laboratório de Investigação Médica 61 (LIM-61, Laboratory for Medical Research 61), specializing in Experimental Thoracic Surgery; in Laboratório de Investigação Médica 20 (LIM-20, Laboratory for Medical Research 20), specializing in Experimental Therapy; at the Heart Institute of the University of São Paulo School of Medicine Hospital das Clínicas; and in the Biomedical Engineering Laboratory, University of São Paulo Polytechnic Institute, São Paulo, Brazil.

Correspondence to: Paulo Manuel Pêgo-Fernandes. InCor/Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Rua Dr. Enéas de Carvalho Aguiar, 44, Bloco 2, 2º andar, Sala 9, Cerqueira Cesar, CEP 05403-000, São Paulo, SP, Brasil.

Tel. 55 11 3069-5248. E-mail: paulo.fernandes@incor.usp.br Financial support: This study received financial support from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, São Paulo Research Foundation). Karina Fechini is the recipient of a Young Investigator Grant from FAPESP. Submitted: 24 May 2011. Accepted, after review: 29 July 2011.

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Cardoso PFG, Pazetti R, Moriya HT, Pêgo-Fernandes PM, Almeida FM, Correia AT et al.

Introduction Lung transplantation is a well-established therapeutic alternative for selected patients with end-stage lung disease. Lung function immediately after transplantation is affected by how well the donor lung was preserved, as is the subsequent performance of the organ.

(1) Since the early days of lung preservation, prostanoids have been used in order to enhance preservation. Prostanoids have beneficial effects on graft function after reperfusion and are therefore added to intracellular solutions for preservation, such as the Euro-Collins and University of Wisconsin solutions. Because experimental animal studies have shown that prostaglandin E1 (PGE1) changes the cytokine profile from pro-inflammatory to antiinflammatory,(2) it has been incorporated into lung preservation protocols as an adjuvant to extracellular solutions. However, the addition of prostanoids directly to the pulmonary circulation causes severe systemic hypotension, and prolonged hypotension can cause lung graft dysfunction, which is why prostanoids can only be used immediately before lung extraction.(3) Inhaled prostacyclin—prostaglandin I2 (PGI2)— has been used as a pulmonary vasodilator in the treatment of pulmonary hypertension and has the advantage of not causing systemic hypotension.(4) Therefore, prostacyclin can be administered to donors for prolonged periods, which increases the beneficial effects on the lung to be transplanted. There is still no consensus regarding the efficacy of inhaled prostanoids in preserving the lung for transplantation. This merits investigation, given that other inhaled agents, such as drugs and perfluorocarbons, have also been shown to be beneficial for the transplanted lung.(5,6) The objective of the present study was to present a model of PGI2 administration (inhaled vs. parenteral) and to assess the functional performance of the lungs in an ex vivo lung perfusion system in rats.

Methods Adult male Wistar rats (n = 40), weighing 300-350 g, were obtained from the animal J Bras Pneumol. 2011;37(5):589-597

facility of the University of São Paulo School of Medicine, in the city of São Paulo, Brazil.

The animals were maintained under controlled temperature and humidity on a 12/12-h light/ dark cycle. The animals had ad libitum access to water and Nuvilab CR-1 chow (Nuvital Nutrientes Ltda., Colombo, Brazil).

The study was approved by the local animal research ethics committee. The animals were anesthetized via inhalation of 5% isoflurane in a bell jar. They subsequently underwent tracheostomy and were mechanically ventilated with a flexiVent® ventilator (SCIREQ, Montreal, Canada). The animals were maintained under the following conditions: RR, 90 breaths/min; tidal volume (VT), 10 mL/kg; FiO2, 1.0; and 3% isoflurane. A median sterno-laparotomy was performed, and the animals received heparin (1,500 IU) through the inferior vena cava. The diaphragm was opened radially, and the inferior pulmonary ligament was sectioned. A 23-G scalp vein needle was inserted into the main pulmonary artery and was fixed into position.

Mean pulmonary artery pressure (mPAP) was measured at baseline. The animals were ventilated for 2 min and were subsequently randomized into four groups (10 rats/group): • inhaled saline (IS) group—mechanical ventilation (2 min) + first nebulization with saline (1 min) + interval (30 s) + second nebulization with saline (1 min), mPAP being measured before and after nebulization • parenteral saline (PS) group—mechanical ventilation (2 min) + nebulization with saline (1 min) + interval (30 s) + second nebulization with saline (1 min) + administration of saline (0.1 mL) via the pulmonary artery, mPAP being measured before nebulization and after the administration of saline via the pulmonary artery • inhaled PGI2 (IPGI2) group—mechanical ventilation (2 min) + nebulization with PGI2 (Ilomedin; Schering, Traiskirchen, Austria) at 20 µg/kg (1 min) + interval (30 s) + second nebulization with PGI2 (1 min), mPAP being measured before and after nebulization • parenteral PGI2 (PPGI2) group—mechanical ventilation (2 min) + nebulization with saline (1 min) + interval (30 s) + second

An experimental rat model of ex vivo lung perfusion for the assessment of lungs after prostacyclin administration: inhaled versus parenteral routes

nebulization with saline (1 min) + administration of PGI2 (10 µg/kg) via the pulmonary artery, mPAP being measured before nebulization and after the administration of PGI2 via the pulmonary artery Nebulization was performed with an ultrasonic nebulizer (Aeroneb®; Aerogen, Galway, Ireland) connected directly to the tracheostomy tube. In order to analyze total respiratory system resistance (Rrs) and compliance (Crs), we used the one-compartment model(7):

P = Rrs × VY + Crs × V + P0 where P is the airway opening pressure, Y is the flow, V is the volume, and P0 is the value of P when both Y and V are equal to zero, assuming a practical use in the absorption of errors in situations in which functional residual capacity is calculated on the basis of an integrated flow signal. The model was adjusted to a 1-s sine wave volume perturbation, with a VT of 10 mL/kg.

Basal values were recorded before sternotomy, after sternotomy, and after nebulization.

After the second nebulization and the measurement of mPAP, the inferior vena cava was sectioned, the main pulmonary artery was cannulated, and a longitudinal left ventriculotomy was performed. The heartlung blocks were submitted to perfusion with 20 mL of a low potassium and dextran solution (Perfadex®; Vitrolife, Kungsbacka, Sweden) at 4°C, the pressure being maintained at 10 cmH2O by raising the reservoir, and drainage of effluent through the left ventriculotomy, as previously described.(8,9) During perfusion with the preservation solution, the lungs were hyperventilated. After perfusion, the trachea was ligated to the partially inflated lungs, lung extraction was performed, and the heart-lung blocks were stored in saline for 6 h at 4-7°C. We used an ex vivo perfusion circuit (IL2 - Isolated Perfused Rat or Guinea Pig Lung System; Harvard Apparatus, Holliston, MA, USA; Hugo Sachs Elektronik, Hugstetten, Germany) capable of measuring respiratory mechanics and hemodynamic parameters. The heart-lung blocks were perfused with a mixture of homologous blood and saline solution at a ratio of 1:1, in a total volume of approximately 80 mL, with a hematocrit of 15-20%. Pulmonary venous blood was deoxygenated with a membrane oxygenator

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(D150 MediSulfone® Hemofilter; MEDICA s.r.l.

Medolla, Italy) containing a gas mixture (N2/ CO2 at a ratio of 9:1) administered continuously (flow rate, 100 mL/min).

After a heart-lung block had been positioned in the ex vivo lung perfusion system, ventilation (RR, 60 breaths/min; inhalation/exhalation ratio, 60%; breath/min rate, 50% over the VT; and positive end-expiratory pressure, 1 cmH2O) was started with 50% of the VT, which was increased until it reached 10 mL/kg of body weight. The heart-lung block was initially perfused at a low flow rate (2 mL/min), which was progressively increased over the course of 5-10 min until it reached 5-7 mL/min.

After the heart-lung block had become stable, we collected data related to hemodynamics, respiratory mechanics, pulmonary arterial blood gases, and pulmonary venous blood gases—every 10 min for 50 min. Blood samples were collected through the pulmonary arterial cannula and left atrial cannula for blood gas analysis (ABL 800; Radiometer, Copenhagen, Denmark). The relative oxygenation capacity of the lungs(10) was calculated by the following formula:

ROC = [(PvO2 − PaO2) × 100]/PaO2 where ROC is the relative oxygenation capacity, PaO2 is the deoxygenated blood collected through the pulmonary arterial cannula, and PvO2 is the oxygenated blood collected through the left atrial cannula. We corrected blood perfusate pH by adding sodium bicarbonate to the system (0.3 mEq • L−1 • dose−1) in order to maintain arterial pH within the 7.1-7.4 range.

(11) After perfusion, the heart-lung block was removed, and the left lung was weighed and stored at 70°C for 72 h, after which it was weighed again in order to determine the wet/dry lung weight ratio.

We used descriptive statistics. Quantitative data with normal distribution are expressed as means and the respective standard errors.

Quantitative data without normal distribution are expressed as medians. The assumptions of normal distribution in each group and homogeneity of variances among the groups were evaluated by the Shapiro-Wilk test and the Levene test, respectively. For quantitative dependent variables, we used repeated measures ANOVA. The Bonferroni test was used for multiple comparisons of the means. In the J Bras Pneumol. 2011;37(5):589-597

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Table 1 - Difference between mean pulmonary artery pressure before and after nebulization in the groups under study.

Groups p 95% CI ΔmPAP mmHga IS 3.36 ± 0.64 0.0001 2.04-4.67 PS 2.77 ± 0.64 0.0001 1.46-4.09 IPGI2 2.77 ± 0.64 0.0001 1.46-4.09 PPGI2 4.45 ± 0.64 0.0001 3.14-5.77 ΔmPAP: difference between mean pulmonary artery pressure before and after nebulization; IS: inhaled saline; PS: parenteral saline; IPGI2: inhaled prostaglandin I2; and PPGI2: parenteral prostaglandin I2. aValues expressed as mean ± SE.

absence of normal distribution and homogeneity of variance, we used nonparametric tests (the Kruskal-Wallis test for the variable “type of solution” and the Mann-Whitney test for the variable “position”). The level of significance was set at p < 0.05. The analyses were performed with the Statistical Package for the Social Sciences, version 13.0 (SPSS Inc., Chicago, IL, USA).

Results There were no significant differences among the four groups in terms of the mean weight of the animals (p > 0.05), which was 312 g in the IS group, 319 g in the PS group, 317 g in the IPGI2 group, and 317 g in the PPGI2 group.

For the sample as a whole, the mPAP was 11.4 ± 0.7 mmHg before nebulization and 8.1 ± 0.8 mmHg after (p < 0.001). The analysis of the difference between the pre- and postnebulization mPAP revealed that nebulization significantly reduced mPAP in all of the groups (Table 1). Although the reduction in mPAP was more pronounced in the PPGI2 group than in the remaining groups, the difference was not statistically significant (p = 0.63). The evaluation of respiratory mechanics during mechanical ventilation showed that the four groups behaved similarly in terms of Rrs and Crs (Table 2).

All of the lungs were perfused for 50 min in the ex vivo lung perfusion system, with the exception of two PS group lungs, which became unviable because of edema at 30 min and 40 min, respectively. There were no significant differences among the four groups regarding mean VT (p = 0.53), which was 1.45 mL in the IS group, 1.84 mL in the PS group, 1.93 mL in the IPGI2 group, and 1.66 mL in the PPGI2 group.

Among the PS, IPGI2, and PPGI2 groups, Rrs was similar. Although Rrs was higher in the IS group than in the remaining groups, the difference was not significant (p = 0.08).

Among the IS, PS, and PPGI2 groups, Crs was similar. In the latter half of the perfusion phase, Crs was slightly higher in the IPGI2 group, although the difference was not significant (p = 0.43).

There were no significant differences among the four groups under study regarding the relative oxygenation capacity of the lungs (p = 0.29). In the IS group, there was a significant decrease in the relative oxygenation capacity of the lungs measured at 50 min of perfusion when compared with that measured at the other perfusion time points (p = 0.01). The same occurred in the PS group, in which the relative oxygenation capacity of the lungs measured at

Table 2 - Respiratory system resistance and compliance, at baseline (before sternotomy), before nebulization, and after nebulization.

Groups Resistance Compliance cmH2O • mL−1 • s−1 cmH2O/mL Baseline IS PS IPGI2 PPGI2

0.15 ± 0.06 0.13 ± 0.03 0.16 ± 0.03 0.13 ± 0.04

Prenebulization 0.11 ± 0.05 0.13 ± 0.10 0.11 ± 0.03 0.11 ± 0.05

Postnebulization 0.21 ± 0.05 0.21 ± 0.04 0.19 ± 0.06 0.22 ± 0.07

Baseline 1.78 ± 0.18 1.65 ± 0.23 1.77 ± 0.28 1.72 ± 0.19

Prenebulization 0.99 ± 0.20 0.74 ± 0.29 0.91 ± 0.21 0.92 ± 0.13

Postnebulization 1.07 ± 0.31 0.87 ± 0.27 1.03 ± 0.41 0.93 ± 0.34

IS: inhaled saline; PS: parenteral saline; IPGI2: inhaled prostaglandin I2; and PPGI2: parenteral prostaglandin I2.

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Over the course of the ex vivo perfusion, there was a gradual and significant increase in the weight of the heart-lung blocks (p = 0.001), the increase being more evident in the IS and PS groups at 40 min of perfusion. The differences among the groups were not significant (p = 0.59). Although the nominal values of the wet/ dry lung weight ratio were higher in the IS and PS groups, there were no significant differences among the four groups regarding that aspect (p = 0.63; Figure 3).

Figure 1 - Relative oxygenation capacity in function of the duration of perfusion in the groups under study. There was a significant reduction in the relative oxygenation capacity measured at 50 min of perfusion in comparison with that measured at the remaining perfusion time points in the IS and PS groups (p = 0.01 and p = 0.04, respectively). No significant decrease in relative oxygenation capacity was observed in the IPGI2 or PPGI2 group. IS: inhaled saline; PS: parenteral saline; IPGI2: inhaled prostaglandin I2; and PPGI2: parenteral prostaglandin I2.

50 min of perfusion was lower than was that measured at 10 min (p = 0.04; Figure 1).

There were no significant differences among the four groups regarding mPAP (p = 0.11), which was 9.5 ± 1.1 mmHg in the IS group, 7.4 ± 1.3 mmHg in the PS group, 7.2 ± 1.1 mmHg in the IPGI2 group, and 5.3 ± 1.2 mmHg in the PPGI2 group. Although there was a progressive increase in mPAP over the course of the ex vivo lung perfusion in all of the groups, the increase was significant only in the IS group (p = 0.01; Figure 2).

Figure 2 - Progressive increase in mean pulmonary artery pressure over the course of perfusion in all of the groups under study. Note that the increase was significant in only one group. IS: inhaled saline; PS: parenteral saline; IPGI2: inhaled prostaglandin I2; and PPGI2: parenteral prostaglandin I2.

Discussion Primary graft dysfunction (PGD) is a form of acute lung injury that results from a sequence of events occurring between the brain death of the donor and the reperfusion of the graft.(12) In addition to increasing morbidity and mortality, PGD increases the risk of acute rejection, impairing the long-term function of the transplanted lung. In deceased donors, increased IL-8 concentration in the BAL fluid and lung tissue correlates with the incidence of PGD.(13) Hypothermia and the administration of an intracellular or extracellular solution play a fundamental role in lung preservation because they reduce the metabolic activity and degradation of cellular components and are implicated in the activation of inflammatory mediators.(14,15) Prostaglandins, such as PGE1 and PGI2, are potent vasodilators that are generally administered directly to the pulmonary circulation at the time of graft perfusion and are added to the hypothermic preservation solution.

The beneficial effect of prostaglandins on lung transplantation is related to the preservation of the endothelial barrier of the pulmonary vasculature(16) and to vasodilation, which facilitates the distribution of the preservation solution through the lung parenchyma at extraction. Intracellular solutions, such as the Euro-Collins and University of Wisconsin solutions, have a high potassium content, which causes pulmonary vasoconstriction, vasodilators being therefore required during the administrations of such solutions. However, even after the introduction of low potassium extracellular solutions, prostaglandins continued to be used because their benefits go beyond vasodilation.(17) The fact that other vasodilators are not as efficient in preventing PGD supports the idea that the effects of prostaglandins J Bras Pneumol. 2011;37(5):589-597

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Figure 3 - Higher wet/dry lung weight ratio values in the IS and PS groups. Note that there were no significant differences among the groups (p = 0.63).

IS: inhaled saline; PS: parenteral saline; IPGI2: inhaled prostaglandin I2; and PPGI2: parenteral prostaglandin I2.

are not limited to vasodilation.(2) Prostanoids are also able to ameliorate reperfusion injury through direct cytoprotection, effected by mediating the balance between pro- and antiinflammatory cytokines. In rat models of lung transplantation, the administration of PGE1 during reperfusion increases IL-10 in lung tissue, whereas it decreases TNF-α, IL-12, and IFN-γ.(18) However, prostanoids have not been found to be as effective in dog lungs harvested 3 h after cardiac arrest.(19) In the setting of extreme injury, the addition of PGE1 appears to have no beneficial effects.(19) Therefore, adding prostanoids to the pulmonary circulation might not be sufficient in that setting.

Clinically, the addition of high doses of prostanoids is limited to the moment of lung extraction, in order to minimize the notoriously deleterious effects of systemic arterial hypotension on the transplanted lung.(3) Inhalation has been proposed as an alternative method of selective pulmonary vasodilation without systemic effects. It has been demonstrated that inhaled PGI2 reduces mPAP and redistributes pulmonary flow without causing significant systemic hypotension.

(20,21) The use of inhaled PGI2 in patients with ARDS has been reported to reduce pulmonary vascular resistance by 30%, improving gas exchange (by redistributing the perfusion to areas that were previously less perfused) without causing systemic hypotension.(22) Experimental studies have shown that the vasodilator properties of IPGI2 are as effective as are those of nitric oxide.(23) The use of inhaled PGI2 is J Bras Pneumol. 2011;37(5):589-597

currently recommended in cases of pulmonary hypertension, right ventricular failure, and ARDS, as well as in the treatment of congenital heart diseases associated with pulmonary hypertension.(22,24) A natural prostaglandin with a half-life of 6 min, PGI2 has antithrombotic properties and inhibits platelet aggregation, as well as having effects that are similar to those of nitric oxide. The use of inhaled PGI2 in patients with ARDS reduces pulmonary shunt fraction, improving oxygenation while reducing mPAP.(25) On the basis of the abovementioned evidence, we can suggest that the administration of prostanoids through inhalation minimizes the systemic effects (therefore allowing prostanoids to be used for prolonged periods) and, at the same time, maximizes the beneficial effects on the donor lung. We used an ex vivo rat lung perfusion model in order to evaluate preservation methods. The ex vivo lung perfusion system has the advantage of serving as a screening method for new lung preservation strategies and has an excellent cost-benefit ratio.(8,9,11) Another group of authors used the same system in order to test preservation solutions and administer PGI2 parenterally.(10) The same authors recently demonstrated that the functional performance of transplanted lungs in pigs was better in the animals receiving PGI2 by inhalation than in those receiving PGI2 parenterally.(26) Those authors also demonstrated that PGI2 delivered via an ultrasonic nebulizer before lung extraction resulted in less edema, better gas exchange, and increased lung compliance.(27) Our choice of a 6-h ischemia period was based on a previous study, in which we demonstrated that this duration of ischemia results in a larger number of viable lungs during perfusion.(11) Our decision to use a dose of 10 µg/kg when administering PGI2 parenterally was based on the dose used in another study (a mean of 10 µg every 3 min).(26) Because we found no reports of the dose of inhaled PGI2 to be used in models similar to ours, we empirically determined that the dose of inhaled PGI2 should be twice that of parenteral PGI2, in order to increase airway exposure to the drug and evaluate its systemic effects. In the study sample as a whole, there was a 29% reduction in mPAP after nebulization. Hypotension was more evident in the PPGI2 group, a finding that is in agreement with those reported for models

An experimental rat model of ex vivo lung perfusion for the assessment of lungs after prostacyclin administration: inhaled versus parenteral routes

involving larger animals.(28) Clinically, systemic hypotension has been reported to occur when inhaled PGI2 is used at a dose of 200-700 ng • kg−1 • min−1,(24) which corresponds to 20-80 µg of PGI2 administered over the course of 2 min to an adult weighing 60 kg.

Apparently, inhaled PGI2 does not interfere with respiratory mechanics (resistance and compliance) during lung extraction, as demonstrated by the similarities among our groups in terms of respiratory mechanics. Not interfering with respiratory mechanics is a desirable characteristic for lung preservation additives. The fact that PGI2 has this characteristic shows that its effects of are limited to the pulmonary vasculature and the cellular aspects of preservation.

In the present ex vivo lung perfusion study, functional performance was similar between the IPGI2 and PPGI2 groups, the former trending toward better lung compliance. Gas exchange was found to be worst in the IS group.

One characteristic of the ex vivo lung perfusion model used in the present study is an increase in mPAP over the course of perfusion, because the ex vivo lung perfusion system employs a nonpulsatile flow and an extracorporeal circuit.

Beginning at 40 min of perfusion, there was an increase in mPAP and in the wet/dry lung weight ratio, which is suggestive of the presence of edema, in the IS and PS group lungs. Those increases, together with the fact that some of the PS group lungs became unviable before the end of the perfusion period, indicate that those lungs were not as well-preserved as were those in the IPGI2 and PPGI2 groups.

Although the nominal values of the wet/dry lung weight ratio were higher in the IS and PS groups, there were no significant differences among the four groups under study in terms of that ratio. This reflects a bias related to the ex vivo model, in which all of the lungs develop edema.

This finding is possibly due to the combined effect of the increase in vascular permeability due to perfusion in an extracorporeal system and the 6-h duration of ischemia. Another group of authors used a similar system and found differences that were more pronounced among the groups; however, those authors limited the duration of hypothermic ischemia to 2-4 h.(10,29) An additional factor, which has recently come to our attention, is that Wistar rats can present

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with changes in vascular permeability due to an immune phenomenon related to allergy to dextran.(30) Because dextran is a compound that is found in the low potassium (Perfadex®) solution used in lung preservation, there will always be a possibility that that factor contributes to pulmonary edema. The use of a different breed, such as Sprague-Dawley, apparently reduces the likelihood of that type of allergic reaction.

In conclusion, the experimental model of PGI2 administration before lung extraction is feasible and reliable. During reperfusion, hemodynamics and gas exchange trended better with the use of PGI2 than with that of saline. The experimental model investigated in the present study can be used in future studies in order to evaluate other inhaled agents, such as perfluorocarbons.

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2. Quadri SM, Segall L, de Perrot M, Han B, Edwards V, Jones N, et al. Caspase inhibition improves ischemiareperfusion injury after lung transplantation. Am J Transplant. 2005;5(2):292-9.

3. Tremblay LN, Yamashiro T, DeCampos KN, Mestrinho BV, Slutsky AS, Todd TR, et al. Effect of hypotension preceding death on the function of lungs from donors with nonbeating hearts. J Heart Lung Transplant.

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5. Andrade CF, Martins LK, Tonietto TA, Koefender C, Anflor LC Jr, da Silva NB, et al. Partial liquid ventilation with perfluorodecalin following unilateral canine lung allotransplantation in non-heart-beating donors. J Heart Lung Transplant. 2004;23(2):242-51.

6. Ragaller M, Bleyl J, Tschö U, Winkler T, Regner M, Rasche S, et al. Effects of inhalation of perfluorocarbon aerosol on oxygenation and pulmonary function compared to PGI2 inhalation in a sheep model of oleic acid-induced lung injury. Intensive Care Med. 2001;27(5):889-97.

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About the authors Paulo Francisco Guerreiro Cardoso

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

Rogério Pazetti

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

Henrique Takachi Moriya

Assistant Professor. Engineering Department, Sector of Telecommunications and Control Systems, University of São Paulo Polytechnic Institute, São Paulo, Brazil.

Paulo Manuel Pêgo-Fernandes

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

Francine Maria de Almeida

Master’s Student. Department of Clinical Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.

Aristides Tadeu Correia

Research Technician. University of São Paulo School of Medicine, São Paulo, Brazil.

Karina Fechini

Biomedical Student, Universidade de Santo Amaro – UNISA, University of Santo Amaro – São Paulo, Brazil.

Fabio Biscegli Jatene

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

J Bras Pneumol. 2011;37(5):589-597

Original Article Hematopoietic stem cell transplantation: pulmonary function tests and post-transplant mortality* Testes de função pulmonar e mortalidade após o transplante de células-tronco hematopoiéticas*

Eliane Viana Mancuzo, Nilton Alves de Rezende

Abstract Objective: To determine whether the results of pulmonary function tests carried out in patients subsequently submitted to hematopoietic stem cell transplantation (HSCT) are associated with post-HSCT mortality. Methods: This was a prospective study involving patients older than 15 years of age who were submitted to allogenic HSCT between January of 2007 and March of 2008 at the Hospital das Clínicas da Universidade Federal de Minas Gerais, located in the city of Belo Horizonte, Brazil. Prior to HSCT, all of the patients underwent spirometry, determination of lung volumes, and determination of DLCO. Those same tests were repeated six months, one year, and two years after HSCT. Kaplan-Meier curves and two-tailed log-rank tests were used for survival analysis. The relative risk (RR) and 95% CI were calculated using the Cox proportional hazards model. The Cox regression model was used in the multivariate analysis. Results: The pre-HSCT pulmonary function results were normal in 40 (74.1%) of the 54 patients evaluated, 19 (35.2%) of whom died within the first 100 days after HSCT. By the end of the two-year follow-up period, 23 patients (42.6%) had died, the most common causes of death being septicemia, observed in 11 (47.8%), and septicemia-related respiratory insufficiency, observed in 10 (43.4%). The only variables significantly associated with post-HSCT mortality were alterations in spirometry results prior to HSCT (RR = 3.2; p = 0.016) and unrelated donor (RR = 9.0; p < 0.001). Conclusions: Performing spirometry prior to HSCT provides baseline values for future comparisons. Although alterations in spirometry results reveal a higher risk of post-HSCT mortality, such alterations do not contraindicate the procedure.

Keywords: Hematopoietic stem cell transplantation/mortality; Respiratory function tests; Donor selection.

Resumo Objetivo: Verificar se os resultados dos testes de função pulmonar realizados em pacientes submetidos a transplante de células-tronco hematopoiéticas (TCTH) estão associados com a mortalidade após o procedimento.

Métodos: Estudo prospectivo no qual foram incluídos pacientes maiores de 15 anos submetidos a TCTH alogênico, entre janeiro de 2007 e março de 2008, no Hospital das Clínicas da Universidade Federal de Minas Gerais, em Belo Horizonte (MG), e que realizaram espirometria, medida de volumes pulmonares e medida de DLCO antes do TCTH. Os testes foram repetidos seis meses, um ano e dois anos após TCTH. Para a análise de sobrevida, foram utilizados o método de Kaplan-Meier e testes de log-rank bicaudal. O risco relativo (RR) e IC95% foram calculados por meio do ajuste do modelo de riscos proporcionais de Cox. O modelo de regressão de Cox foi utilizado na análise multivariada. Resultados: Dos 54 pacientes incluídos, 40 (74,1%) apresentaram resultados normais de função pulmonar antes do TCTH. Ocorreram 23 óbitos (42,6%) em dois anos após o TCTH, sendo que 19 aconteceram antes de 100 dias. Dos 23 óbitos, 11 (47,8%) foram por septicemia e 10 (43,4%) por insuficiência respiratória aguda associada à septicemia. As únicas variáveis que mostraram associação significativa com mortalidade após TCTH foram alteração na espirometria antes do TCTH (RR = 3,2; p = 0,016) e doador não aparentado (RR = 9,0; p < 0,001). Conclusões: A realização da espirometria antes do TCTH fornece valores basais para comparações futuras. Alterações nesses resultados indicam um maior risco de mortalidade após o TCTH, embora esses não contraindicam o procedimento.

Descritores: Transplante de células-tronco hematopoéticas/mortalidade; Testes de função respiratória; Seleção do doador.

* Study carried out at the Federal University of Minas Gerais School of Medicine, Belo Horizonte, Brazil.

Correspondence to: Alves de Rezende. Rua Aimorés, 462/116, CEP 30140-070, Belo Horizonte, MG, Brasil.

Tel 55-31-3226-7738 E-mail: narezende@terra.com.br Financial support: Eliane Viana Mancuzo is the recipient of a fellowship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Office for the Advancement of Higher Education). Nilton Alves de Rezende is a researcher for the Instituto Nacional de Ciência e Tecnologia/ Instituto de Avaliação de Tecnologia em Saúde (INCT/IATS, National Institute of Science and Technology/Institute for Health Technology Assessment).

Submitted: 11 January 2011. Accepted, after review: 27 June 2011.

J Bras Pneumol. 2011;37(5):598-606

Hematopoietic stem cell transplantation: pulmonary function tests and post-transplant mortality

Introduction Hematopoietic stem cell transplantation (HSCT), whether allogenic, autologous, or syngeneic, is an important option in the treatment of hematological and oncological diseases, being available at more than 500 facilities distributed throughout 50 countries.

(1) Pulmonary complications, which occur in approximately 30-60% of recipients, constitute a major cause of post-HSCT morbidity and mortality. With the advances in prophylaxis and treatment of infectious conditions, the proportion of complications classified as noninfectious pulmonary complications (NIPCs) has increased significantly.(2) Early diagnosis and treatment of such complications can change the prognosis of HSCT recipients.(3-7) The pulmonary function tests (PFTs) used in the assessment and follow-up of patients submitted to HSCT include measurement of lung volumes, spirometry, and measurement of DLCO. (2,8-10) Although PFTs are internationally adopted for pre- and post-HSCT assessment, their true usefulness and the ideal interval between HSCT and PFTs remain debatable.(6,11) The current recommendation is that PFTs be performed prior to HSCT and one year after HSCT.(8) Some authors suggest that PFTs should be performed more frequently in the first two years after HSCT, especially in patients with chronic graftversus-host disease (GVHD).(9-11) It is believed that performing PFTs more frequently after HSCT would not only allow the identification of NIPCs but could enable early preventive and therapeutic interventions in at-risk patients.(8,12) The objective of the present study was to prospectively investigate whether the PFT results obtained prior to and after HSCT are associated with post-transplant mortality and post-transplant NIPCs, as well as to determine whether abnormal PFT results obtained prior to HSCT are associated with changes in the management of HSCT.

Methods The study sample included patients older than 15 years of age who underwent allogenic HSCT between January of 2007 and March of 2008 at the Hospital das Clínicas da Universidade Federal de Minas Gerais(HC-UFMG, Federal University of Minas Gerais Hospital das Clínicas),

599

located in the city of Belo Horizonte, Brazil.

Prior to HSCT, all of the patients underwent spirometry, measurement of lung volumes, and measurement of DLCO. Patients submitted to autologous transplantation were excluded, as were those aged 15 years or younger and those who, prior to HSCT, underwent spirometry only.

The variables studied were as follows: type of hemato-oncological disease that led to transplantation; chemotherapy received; sources of hematopoietic stem cells used; donor status (related or unrelated); pre-HSCT conditioning regimen; pharmacological prophylaxis used for GVHD; smoking status; lung diseases; and death. The occurrence of acute or chronic GVHD was established on the basis of the clinical, histological, and biochemical criteria devised

by Sullivan.(13) For the purpose of the present study, reports or descriptions of any kind of pulmonary infection, prior to or after HSCT, were not considered lung disease. The major NIPCs investigated after HSCT were as follows: bronchiolitis obliterans; bronchiolitis obliterans organizing pneumonia (BOOP); recent airflow obstruction; pulmonary fibrosis; and diffuse alveolar hemorrhage. Clinical, radiological, and functional criteria were applied in order to identify those complications.(2,14) None of the patients underwent lung biopsy for the diagnosis of such complications.

Through June of 2009, all PFTs were performed with the use of a Collins GSII system (Collins, Braintree, MA, USA). Between July of 2009 and February of 2010, a Collins CPL system was used in accordance with the Brazilian Thoracic Association guidelines.(15) The following variables were measured by spirometry: VC; FVC; FEV1; FEF25-75%; the FEV1/FVC ratio; and the FEF25-75%/FVC ratio. The predicted reference values used were those published by Pereira et al. for the Brazilian population aged between 25 and 78 years, for males, and between 20 and 74 years, for females.(15) The values devised by Mallozi were used for males between 15 and 24 years of age and for females between 15 and 19 years of age.(16) The multiple-breath helium dilution method was used for measuring absolute lung volumes, and the following variables were obtained: TLC; RV; and the RV/TLC ratio. The reference values were those devised by Crapo for patients younger than 20 years of age(17) and those devised by Neder et al. for patients J Bras Pneumol. 2011;37(5):598-606

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older than 20 years of age.(18) The single-breath hold technique (10-s breath hold) was used for the DLCO test. Values of DLCO were corrected for hemoglobin concentration. In accordance with Gaensler & Smith,(19) DLCO was considered reduced when it was below 75% of the predicted value.

On the basis of spirometry results, absolute lung volume values and DLCO values, abnormal pulmonary function was classified as follows(15): obstructive lung disease; restrictive lung disease; mixed obstructive and restrictive lung disease; increased RV and increased RV/TLC; and reduced DLCO. Subsequently, the patients were divided into two groups on the basis of abnormal results: those with abnormal spirometry results, abnormal absolute lung volumes, and abnormal DLCO; and those with abnormal spirometry results only.

Descriptive statistics are expressed as frequencies and percentages. The first step was to compare the different variables by univariate analysis, with the use of the Kaplan-Meier method and two-tailed log-rank tests.(20) The relative risk (RR) and 95% CI were quantified with the Cox proportional hazards model. The second step was to use the Cox regression model for determining which variables were independently associated with mortality.(21) Covariates with a p value < 0.25 (log-rank test) in the univariate analysis were included in the initial model. Covariates that, in isolation, had a p value p < 0.05 were retained for the next step.

The same criterion was used in several analyses until only variables with a p value p < 0.05 remained, indicating that those variables showed independent association and statistical significance. All analyses were performed with the programs R (R Development Core Team) and Epi Info, both of which are in the public domain.

The study was approved by the UFMG Research Ethics Committee (Ruling no. ETIC 244/06 of September 22, 2006), and all participating patients gave written informed consent.

Results Between January of 2007 and December of 2008, 91 patients were submitted to HSCT at the HC-UFMG. Of those 91 patients, 37 were excluded: 18 because the HSCT was autologous; 10 because they were younger than 15 years J Bras Pneumol. 2011;37(5):598-606

of age; and 9 because, prior to HSCT, they underwent spirometry only. Therefore, the initial sample consisted of 54 patients, whose clinical characteristics are summarized in Table 1. There was a high proportion of male patients (59%), of patients who had been previously diagnosed with chronic myeloid leukemia or had received other diagnoses (68%), and of nonsmokers (87%).

Only 1 patient was found to have pre-existing lung disease, and 7 (15%) developed an NIPC after HSCT. Of the 54 patients submitted to HSCT, 18 (33%) had acute GVHD. Among the 35 patients in whom it was possible to investigate chronic GVHD (19 of the 54 patients died within the first 100 days after HSCT), the condition was found to be present in 14 (40%).

The most commonly used conditioning regimen was busulfan + cyclophosphamide (in 72%), and the most commonly used GVHD prophylaxis was cyclosporine + methotrexate (in 65%). The most common source of stem cells for HSCT was the bone marrow (in 57%), and 91% of those cases involved unrelated donors. In the study sample, 4 patients developed an NIPC within the first six months after HSCT (2 had diffuse alveolar hemorrhage, 1 had BOOP, and 1 had recent airflow obstruction). Of those 4, only the patient who had developed recent airflow obstruction survived. At six months after HSCT, 3 patients (6%) developed airflow obstruction. However, by the end of the two-year follow-up period, no new events had occurred. Of the 4 patients who developed recent airflow obstruction, 2 improved during the follow-up period.

The mean age of the patients was 31.6 years, and the mean time from diagnosis to transplantation was 14.6 months. Table 2 lists the values for the functional parameters, expressed as means and standard deviations.

The baseline pulmonary function values were comparable to those of the general population.

Table 3 shows the most common lung diseases, as determined on the basis of spirometry results, lung volume values, and DLCO values. As can be seen, 22.2% of the patients had significantly abnormal pre-HSCT PFT results. Increased RV and an increased RV/ TLC ratio did not correlate with obstructive lung disease prior to or after HSCT. Only 1 patient with pre-HSCT airflow obstruction survived to the end of the two-year post-transplantation follow-up period. Of the 5 patients who were

Hematopoietic stem cell transplantation: pulmonary function tests and post-transplant mortality

601

Table 1 - Clinical and demographic characteristics of the patients submitted to hematopoietic stem cell transplantation.

Characteristic Patients n % Gender Male 32 59.3 Female 22 40.7 Hematological disease Chronic myeloid leukemia or other diagnosesa 37 68.5 Aplastic anemia 17 31.5 Recurrence Yes 4 7.4 No 50 92.6 Smoking Yes 7 13.0 No 47 87.0 Pre-existing lung disease Yes 1 1.9 No 53 98.1 Conditioning regimen Alemtuzumab 15 27.8 Busulfan + cyclophosphamide 39 72.2 Source of cells Bone marrow 31 57.4 Stem cells 22 40.7 Cord 1 1.9 Donor status Related 49 90.7 Unrelated 5 9.3 Chemotherapy Yes 29 53.7 No 25 46.3 GVHD prophylaxis Yes 35 64.8 No 19 35.2 Acute GVHD Yes 18 33.3 No 36 66.7 Chronic GVHDb Yes 14 40.0 No 21 60.0 Noninfectious pulmonary complications Yes 7 15.0 No 47 85.0 Onset of noninfectious pulmonary complications Within the first 100 days after transplantation (DAH) 2 4.3 At 100 days after transplantation (BOOP, AFO) 2 4.3 At six months after transplantation (AFO) 1 2.1 At one year after transplantation (AFO) 2 4.3 At two years after transplantation 0 0.0 No complications 47 85.0 Death Yes 23 42.6 No 31 57.4 GVHD: graft-versus-host disease; DAH: diffuse alveolar hemorrhage; BOOP: bronchiolitis obliterans organizing pneumonia; and AFO: airflow obstruction. aAcute lymphocytic leukemia, myelodysplasia, Hodgkinâ&#x20AC;&#x2122;s lymphoma, and non-Hodgkinâ&#x20AC;&#x2122;s lymphoma. bA total of 35 patients were assessed for this characteristic, since 19 died within the first 100 days after transplantation.

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Table 2 - Pulmonary function test results prior to hematopoietic stem cell transplantation (n = 54).a Parameter Results expressed as absolute values Results expressed as % of predicted VC, L 4.0 ± 1.0 99.1 ± 14.5 FVC, L 4.0 ± 1.0 98.6 ± 14.4 FEV1, L 3.4 ± 0.8 99.7 ± 14.5 FEF25-75%, L 4.0 ± 1.1 103.0 ± 30.9 FEV1/FVC 86.6 ± 6.4 99.6 ± 6.7 FEF25-75% /FVC 103.4 ± 32.7 104.9 ± 32.5 TLC, L 5.4 ± 1.4 96.4 ± 14.4 RV, L 1.4 ± 0.5 90.1 ± 24.6 DLCO, mL • min−1 • mmHg−1 90.7 ± 11.7 94.7 ± 11.7 Values expressed as mean ± SD.

a

found to have recent airflow obstruction, 3 were submitted to a specific therapeutic intervention.

Of those 3 patients, the one who had developed BOOP died, and the other 2 improved as a result of the treatment. All patients with reduced VC also had reduced TLC. Of the survivors, 7 did not undergo pulmonary function tests at the end of the two-year follow-up period.

Of the 54 patients evaluated, 23 (42.6%) died, the most common causes of death being septicemia, in 11 (47.8%), septicemia-related acute respiratory failure, in 10 (43.4%), and liver failure related to kidney failure, in 2 (8.8%). The 100-day survival rate was 65%, whereas the two-year survival rate was 57%.

Table 4 shows the result of the univariate analysis (log-rank test or Cox model) comparing variables between the patients who died and those who did not.

Table 5 shows the final multivariate regression model. The variable pre-existing lung disease was excluded from this analysis because of its low frequency in the sample (only in 1 patient).

In this model, the variables statistically related to death were unrelated donor (RR = 9.9; p < 0.001) and abnormal spirometry results (RR = 3.2; p = 0.016). In the final model, mortality was not found to be associated with the combination of abnormal spirometry results, abnormal lung volume values, and abnormal DLCO values.

Discussion The main results of the present study show that patients with impaired pulmonary function, as assessed by spirometry, and an unrelated donor were the most likely to die after HSCT. However, abnormal spirometry results do not contraindicate the procedure.

Table 3 - Lung diseases and abnormal DLCO in the patients submitted to hematopoietic stem cell transplantation, over time.

Type of lung Status Prior to At 100 At six At one At two disease/ transplantation days after months after year after years after abnormal transplantation transplantation transplantation transplantation DLCO n % n % n % n % n % Obstructive Yes 5 9.3 3 8.8 2 7.4 3 10.7 2 9.5 No 49 90.7 31 91.2 25 92.6 25 89.3 19 90.5 Restrictive Yes 5 9.3 3 8.8 3 11.1 2 7.1 2 9.5 No 49 90.7 31 91.2 24 88.9 26 92.9 19 90.5 Mixed Yes 0 0.0 0 0.0 1 3.7 1 3.6 1 4.8 obstructive No 54 100.0 34 100.0 26 96.3 27 96.4 20 95.2 and restrictive Yes 4 7.4 4 11.8 2 7.4 2 7.1 4 19.0 ↑RV and ↑RV/TLC No 50 92.6 30 88.2 25 92.6 26 92.9 17 81.0 Yes 2 3.7 5 14.7 2 7.4 0 0.0 2 9.5 ↓DLCO No 52 96.3 29 85.3 25 92.6 28 100.0 19 90.5 ↑: increased; ↓: reduced.

J Bras Pneumol. 2011;37(5):598-606

Hematopoietic stem cell transplantation: pulmonary function tests and post-transplant mortality

603

Table 4 - Results of the univariate analysis of the patients submitted to hematopoietic stem cell transplantation, by outcome (death vs. non-death).

Variable Patients, n Statistical p result Death Non-death Gender Male Female Hematological disease Chronic myeloid leukemia or other diagnosesa Aplastic anemia Preexisting lung disease Yes No Conditioning regimen With alemtuzumab Without alemtuzumab Source of cells Bone marrow Stem cells Donor status Related Unrelated Chemotherapy Yes No Prophylaxis Cyclosporine + methotrexate Cyclosporine Acute graft-versus-host disease Yes No Abnormal pulmonary function All tests Yes No Spirometry alone Yes No Age, years

15 8

17 14

1.1

0.285*

19 4

18 13

3.3

0.697*

1 22

0 31

2.4

0.126*

17 6

22 9

0.1

0.789*

11 11

20 11

1.1

0.291*

18 5

31 0

26.6

< 0.001*

9 14

16 15

0.5

0.467*

18 5

17 14

2.5

0.117*

9 14

9 22

0.1

0.772*

9 14

5 26

4.0

0.044*

8 15 31

2 29 23

9.6

0.001*

-

0.356**

Acute lymphocytic leukemia, myelodysplasia, Hodgkinâ&#x20AC;&#x2122;s lymphoma, and non-Hodgkinâ&#x20AC;&#x2122;s lymphoma. *Log-rank test. **Cox model. a

In the pre- and post-HSCT assessment, PFTs play an important role, being universally recommended. Although there are many studies on this subject in the literature, questions remain about the true usefulness of PFTs.(10) There has been only one retrospective study conducted in Brazil, undertaken at a major center for HSCT, in which spirometry alone was used in the pre- and post-HSCT assessment of pulmonary function.(5)

One relevant aspect of the present study was that spirometry results were evaluated together with lung volume values and DLCO values.

This was due to the fact that these variables represent different markers of the physiological status of such patients. Spirometry measures the volume of air inhaled and exhaled, as well as respiratory flows.(15) Although the causes of an obstructive pattern on PFTs are limited

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Table 5 - Results of the final model of the analysis of the patients submitted to hematopoietic stem cell transplantation, adjusted for mortality.

Variable Final model Relative risk 95% CI p Donor status Unrelated 9.9 2.9-33.5 < 0.001 Abnormal spirometry results Yes 3.2 1.2-7.3 0.016

to the airway, bronchiolitis obliterans being the pulmonary complication with the worst prognosis, a restrictive pattern can be secondary to parenchymal and nonparenchymal pulmonary involvement.(9) Thoracic irradiation, pulmonary toxicity of chemotherapy, infections, idiopathic pneumonitis, and GVHD are the factors most commonly associated with restrictive lung disease after HSCT.(9) The DLCO test measures the diffusion of gases from the alveoli into the interior of red blood cells; DLCO can be affected by a number of factors, such as alveolar-capillary membrane thickening, hemoglobin levels, and factors associated with restrictive lung disease.

(9,15)

The results of the present study show that most of our patients (78%) had normal pre-HSCT PFT results (absolute lung volumes, spirometry, and DLCO) prior to HSCT, and that even those who had abnormal pre-HSCT PFT results underwent the procedure.

Post-HSCT mortality showed significant associations with abnormal pre-HSCT spirometry results and with unrelated donor. It should be highlighted that there were 19 deaths within the first 100 days after HSCT, a fact that prevented the investigation of a possible association between abnormal PFT results after HSCT and mortality.

The investigation of the causes of death after HSCT revealed that mortality was associated with infection in 47.8% of cases, as well as with acute respiratory failure and infection in 43.4%.

It is known that mortality can range from 10-40% within the first 100 days after HSCT, and this rate is associated with receptor-related factors, such as age and underlying disease, as well as with the conditioning regimen, with procedure-related factors, such as GVHD, and with immunodeficiency and infection.(1,2) Despite the advances in prophylaxis and treatment of infectious complications, the incidence of infection remains high at our facility and contributed significantly to mortality, which, according to the literature, is close to 80% J Bras Pneumol. 2011;37(5):598-606

in patients who develop severe respiratory failure and require mechanical ventilation.(2) It is possible that, even without differentiating lung diseases, abnormal spirometry results reveal a higher risk of post-HSCT mortality, and this should be considered in the pre-operative assessment of patients with such results. Contrary to expectation, when evaluating abnormal spirometry results together with abnormal lung volume values and abnormal DLCO values, we found no significant association with mortality.

The pre-HSCT incidence of reduced DLCO was very low in the study population, and the sample size might have contributed to this result. The data obtained in the present study are in accordance with those obtained by Parimon et al., who also showed that pre-HSCT abnormal pulmonary function is significantly associated with post-HSCT risk of respiratory failure and of mortality. That study developed a risk score and found that lower FEV1 and DLCO values and respiratory failure are associated with higher post-HSCT mortality.(22) The higher mortality rate observed in recipients from unrelated donors was also reported by Patriarca et al.,(23) who found a significant association between mortality and unrelated donor (p = 0.04). The degree of relatedness and the HLA match between donor and receptor play an important role in immune reconstitution after transplantation.

Therefore, recipients of grafts from unrelated or HLA-unmatched donors, or a combination of the two, require stricter control of rejection mechanisms, which might be associated with immunodeficiency states and higher mortality.

(24)

The incidence of NIPCs in our study was 15% in two years, highlighting the fact that 15% of the patients died within the first 100 days after HSCT and therefore did not complete the PFTs. These data are in accordance with the 10-20% rates of NIPC incidence previously reported for patients submitted to HSCT.(23,25) In the present

Hematopoietic stem cell transplantation: pulmonary function tests and post-transplant mortality

study, it was not possible to investigate the association between NIPCs and abnormal PFT results because of the low occurrence of NIPCs at the time points assessed. In the literature, there are studies describing an association between NIPCs and abnormal pulmonary function. Two groups of authors retrospectively found that obstructive lung disease is associated with NIPCs after HSCT.(25,26) Chien et al., in a study of 915 patients, showed that a decrease of 5% in FEV1 at 100 days after transplantation is associated with airflow obstruction at one year after transplantation (RR = 2.6; 95% CI: 2.1-3.1) but not with mortality.(27) In the present study, unlike what is described in the literature, the PFTs were performed at relatively short time intervals, in the first year after HSCT, at an accredited laboratory, by a single professional, and in accordance with internationally accepted guidelines, thereby reducing the chance of methodological variations in the tests. In addition, we used the reference equations that best correlate with the different age groups and genders. These premises were emphasized by Chien et al. in their review of PFTs in HSCT.(10) Age and losses due to death within the first 100 days after transplantation significantly reduced the number of patients in our final sample. The increase in the number of autologous HSCTs, rather than in the number of allogenic HSCTs, in the two years when the patients were included also contributed to the smaller final sample size, in addition to complicating comparisons with most other studies, which were retrospective and included recipients of autologous or allogenic transplantation.

Despite the aforementioned restrictions, the results of the present study suggest that performing pre-HSCT spirometry is important because it provides baseline values for future comparisons. In addition, abnormal spirometry values reveal a higher risk of post-HSCT mortality, although such values do not contraindicate the procedure. Given that spirometry is inexpensive and relatively easy to perform, compared with measurement of absolute lung volumes and measurement of DLCO, which are not readily available at most health care facilities in Brazil, it seems reasonable that spirometry alone should be used in pre-HSCT PFTs, the more complex tests being reserved for selected cases. Ruling

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out NIPCs should be a priority in the assessment of patients with respiratory symptoms after HSCT.

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mortality after stem cell transplantation. Am J Respir Crit Care Med. 2005;172(3):384-90.

23. Patriarca F, Skert C, Bonifazi F, Sperotto A, Fili C, Stanzani M, et al. Effect on survival of the development of late-onset non-infectious pulmonary complications after stem cell transplantation. Haematologica.

2006;91(9):1268-72.

24. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med. 2004;351(22):2276-85.

25. Palmas A, Tefferi A, Myers JL, Scott JP, Swensen SJ, Chen MG, et al. Late-onset noninfectious pulmonary complications after allogeneic bone marrow transplantation. Br J Haematol. 1998;100(4):680-7.

26. Curtis DJ, Smale A, Thien F, Schwarer AP, Szer J. Chronic airflow obstruction in long-term survivors of allogeneic bone marrow transplantation. Bone Marrow Transplant.

1995;16(1):169-73.

27. Chien JW, Martin PJ, Flowers ME, Nichols WG, Clark JG. Implications of early airflow decline after myeloablative allogeneic stem cell transplantation. Bone Marrow Transplant. 2004;33(7):759-64.

About the authors Eliane Viana Mancuzo

Physician. Department of Pulmonology, Federal University of Minas Gerais School of Medicine Hospital das Clínicas, Belo Horizonte, Brazil.

Nilton Alves de Rezende

Associate Professor. Federal University of Minas Gerais School of Medicine, Belo Horizonte, Brazil.

J Bras Pneumol. 2011;37(5):598-606

Original Article Reference equations for the performance of healthy adults on field walking tests*, ** Equações de referência para os testes de caminhada de campo em adultos saudáveis

Victor Zuniga Dourado, Milena Carlos Vidotto, Ricardo Luís Fernandes Guerra

Abstract Objective: To develop regression equations for predicting six-minute and incremental shuttle walk distances (6MWD and ISWD, respectively), based on demographic characteristics, anthropometric variables, and grip strength. Methods: We evaluated 6MWD and ISWD in 98 healthy adults. Height, weight, and grip strength were also assessed. Using data from 90 of the participants (40 males; 60 ± 9 years of age), we devised linear equations adjusted for age, gender, height, and weight, and we developed alternate models that included grip strength.

We prospectively applied the equations in the 8 remaining participants (4 males; 59 ± 10 years), who had been randomly separated from the initial sample. Results: Age, gender, height, and weight collectively explained 54.5% and 64.9% of the variance in 6MWD and ISWD, respectively, whereas age, height, weight, and grip strength collectively explained 54.4% and 69.0% of the respective variances. There was no significant difference between the measured and predicted 6MWD using equations with and without grip strength (14 ± 57 vs. 13 ± 67 m). Similar results were observed for ISWD (25 ± 104 vs. 25 ± 93 m). Conclusions: Grip strength is a determinant of ISWD and 6MWD; however, it could not improve the power of equations adjusted by demographic and anthropometric variables. The validity of our models including grip strength should be further evaluated in patients with skeletal muscle dysfunction.

Keywords: Walking; Exercise; Reference Values; Exercise test.

Resumo Objetivo: Desenvolver equações de regressão para a previsão das distâncias caminhadas nos testes de caminhada de seis minutos e incremental shuttle walk test (DTC6 e ISWD) baseadas em atributos demográficos, antropométricos e força de preensão manual. Métodos: Avaliamos a DTC6 e ISWD em 98 adultos saudáveis. Estatura, peso e força de preensão manual foram também avaliados. Equações ajustadas para idade, gênero, estatura e peso e equações, incluindo também a força de preensão manual, foram desenvolvidas dos dados de 90 participantes (40 homens; 60 ± 9 anos). Aplicamos prospectivamente as equações em 8 participantes (4 homens; 59 ± 10 anos) randomicamente selecionados da amostra inicial. Resultados: Idade, gênero, altura e peso explicaram coletivamente 54,5% e 64,9% da variância da DTC6 e ISWD, respectivamente, ao passo que idade, altura, peso e força de preensão manual explicaram coletivamente 54,4% e 69.0% da variância da DTC6 e ISWD, respectivamente. A diferença entre a DTC6 prospectivamente avaliada e prevista não foi significativa usando equações com e sem força de preensão manual (14 ± 57 m vs. 13 ± 67 m). Resultados semelhantes foram observados para a ISWD (25 ± 104 m vs. 25 ± 93 m). Conclusões: A força de preensão manual é um determinante para DTC6 e ISWD; entretanto, não foi capaz de aumentar o poder das equações ajustadas por variáveis demográficas e antropométricas. A validade de nossos modelos incluindo a força de preensão manual deve ser avaliada em pacientes com disfunção muscular esquelética.

Descritores: Caminhada; Exercício; Valores de referência; Teste de esforço.

* Study carried out at the Universidade Federal de São Paulo – UNIFESP, Federal University of São Paulo – Baixada Santista Campus, Santos, Brazil.

Correspondence to: Victor Zuniga Dourado. Departamento de Ciências da Saúde, Avenida Ana Costa, 95, CEP 11060-001, Santos, SP, Brasil.

Tel./Fax: 55 13 3878-3763. E-mail: vzdourado@yahoo.com.br or victor.dourado@unifesp.br Financial support: This study received financial support in the form of a grant from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, São Paulo Research Foundation; Grant no. 2007/08673-3).

Submitted: 26 April 2011. Accepted, after review: 19 July 2011. ** A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

J Bras Pneumol. 2011;37(5):607-614

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Introduction Walking tests, such as the six-minute walk test (6MWT) and incremental shuttle walk test (ISWT),(1,2) are economically accessible and offer the advantage of operational simplicity. These tests are well established and have become widely used measures of exercise capacity in patients with any of a number of chronic diseases.

The 6MWT, which is of a fixed duration, is influenced by external factors, such as motivation and the amount of effort expended. Therefore, the instructions and level of encouragement given should be carefully standardized.(1) On the 6MWT, the pace is determined by the subject, and the distance covered therefore varies widely, even among healthy individuals.(3-6) However, on the ISWT, there is a controlled, progressive increase in pace every 60 s.(2) Both tests are safe when preformed appropriately and have been used, with no adverse effects, in thousands of patients with heart or lung disease.(1) Various demographic, anthropometric, and physiological factors can influence the total distance covered on field walking tests, such as the six-minute walk distance (6MWD) and the incremental shuttle walk distance (ISWD).

Shorter individuals and women have shorter strides and consequently cover less distance.

Elderly and obese individuals often have low lean body mass and therefore also cover shorter distances. The 6MWD has been reported to be below average in unmotivated individuals, those with cognitive deficits, and those with arthritis or other musculoskeletal disorders.(3,7) Other factors that can influence the 6MWD include symptoms of depression, impaired health-related quality of life, medication use, systemic inflammation, and impaired pulmonary function.(7) To our knowledge, only three studies have formulated reference equations to predict the 6MWD and ISWD in Brazilian individuals.(8-10) Iwama et al.,(9) who evaluated 6MWDs in 134 healthy Brazilians (73 women) ≥ 13 years of age, found that age and gender collectively explained 30.0% of the variance in 6MWD. Priesnitz et al.(8) evaluated a convenience sample of 188 healthy Brazilian children and adolescents (92 males) between 6 and 12 years of age, recruited from three elementary schools. The authors found that age, height, weight, and absolute difference between pre- and post-6MWT HR correlated significantly with 6MWD, collectively explaining J Bras Pneumol. 2011;37(5):607-614

36.6% of the 6MWD variance. Jürgensen et al.

(10) evaluated ISWD in 131 Brazilian individuals.

Using a predictive model, the authors showed that age, height, weight, and gender collectively explained 50.3% of the ISWD variance. In a recent multicenter study, the predictive equations varied widely across centers (adjusted R2 = 0.09-0.73) and explained < 30% of the 6MWD variance at four of the centers evaluated.

(11)

The assessment of grip strength (GS) has broad clinical applicability, because it is a low-cost, simple, rapid, and noninvasive method,(12,13) providing an indicator of general health and overall muscle function.(12) Various authors have found GC to correlate significantly and positively with 6MWD and ISWD, especially in patients with COPD.(7,14-16) In healthy elderly individuals, GS has been identified as a determinant of 6MWD.(7) The use of faulty reference equations can result in mistakes related to the interpretation of the level of physical fitness and the improvement in walking distance after interventions in patients with chronic diseases. Therefore, the purpose of this study was to develop regression equations for predicting the 6MWD and ISWD, based on demographic characteristics, anthropometric variables, and GS. We also attempted to determine whether GS correlates with ISWD and 6MWD.

Methods We evaluated 98 healthy subjects—all over 40 years of age—some recruited from among employees of the Federal University of São Paulo, located in the city of Santos, Brazil, and others recruited from among residents of the surrounding community, through newspaper advertisements. Subjects completed a questionnaire regarding physical activity, and those determined to engage in such activity for less than 30 min/day were classified as sedentary.

(17) On the basis of their BMI, the subjects were stratified into the following categories: underweight (< 18.5 kg/m2); normal weight (18.5-24.9 kg/m2); overweight (25-29.9 kg/m2); and obese (≥ 30 kg/m2). All of the subjects selected for study were healthy and ambulatory (having no cardiorespiratory, metabolic, neuromuscular, or musculoskeletal disease and requiring no walking aids). Subjects with abnormal post-

Reference equations for the performance of healthy adults on field walking tests

bronchodilator lung function were excluded,(18) as were those classified as obese. We randomly selected 8 individuals—one man and one woman from the 40-49, 50-59, 60-69, and ≥ 70 year age brackets, respectively—to serve as test subjects, and we developed reference equations based on data related to the remaining 90 participants. To verify the reliability of our reference equations, we applied them in the 8 test subjects. The study design was approved by the Human Research Ethics Committee of the Federal University of São Paulo, and all subjects gave written informed consent.

Weight and height were measured by standard techniques, with the subjects wearing light clothing and no shoes. Weight was measured to the nearest 0.1 kg with a calibrated scale, and height was determined to the nearest 0.5 cm with a stadiometer. The BMI was calculated as weight in kilograms divided by height in meters squared (kg/m2). Pulmonary function and bronchodilator reversibility tests were performed using a handheld spirometer (Spiropalm; COSMED, Rome, Italy), in accordance with American Thoracic Society criteria.(18) The 6MWT and ISWT were each administered twice, on alternate days. Before and after each test, we assessed HR, blood pressure, breathlessness, and leg fatigue. To minimize the learning effect, we allowed an interval of at least 30 min between tests.(1,19) The 6MWT was carried out in accordance with American Thoracic Society recommendations.(1) The test consisted of walking unaided, as fast as possible, for 6 min in a corridor 27-30 m in length. Every 60 s, raters provided standardized verbal encouragement, as follows: “You’re doing well” and “Keep up the good work”. The ISWT was carried out with the method described by Singh et al.(2) The test consisted of walking a 10-m course at a progressive pace. Walking speed was controlled by a series of sounds indicating the moment the subject should change directions around the cone. Every 60 s, another sound indicated the moment at which the subject should increase the pace. When the subject was unable to reach the closest cone (i.e. was > 0.5 m from the cone) by the time the signal sounded, the rater ended the test, which could also be terminated by the subject for any reason. Because the ISWT was developed to assess functional exercise capacity in patients with lung disease, the original

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protocol consists of 12 stages (total distance, 1,020 m). However, because we were applying the test in healthy subjects, we extended it to 15 stages (1,500 m), in order to avoid the ceiling effect.

The dominant hand was defined as that favored in carrying out daily activities. The participants were asked about hand preference for activities such as writing, eating, and carrying objects. We assessed the GS of the dominant hand with a Jamar dynamometer (TEC, Clifton, NJ, USA), using the method described by Mathiowetz et al.(12) Subjects were seated with one arm raised parallel to the trunk, shoulder in neutral rotation, elbow flexed 90°, and forearm in a neutral position. During the test, we allowed hyperextension of the wrist up to 30° and ulnar deviation up to 15°. We took three measurements, 30 s apart. The greatest of the three measurements was used in the data analysis.

The statistical analysis was performed with the Statistical Package for the Social Sciences, version 12 (SPSS Inc., Chicago, IL, USA). Data are presented as mean and standard deviation or as median and interquartile range. We employed the Kolmogorov-Smirnov test to evaluate normality of data distribution, Pearson’s or Spearman’s correlation coefficient to study correlations between variables, and unpaired t-test to determine intergroup differences in numerical data. We also used stepwise multiple linear regression analysis to identify the dependent variables that were the best predictors of 6MWD and ISWD. Age, gender, height, and weight were included in the regression models. Alternate models were constructed to include GS. Gender interaction terms were included for age, height, weight, and GS. Correlations between ISWD and GS and between 6MWD and GS were determined using the z statistic (MedCalc™, version 11.1.1; MedCalc Software, Mariakerke, Belgium). Sample size was estimated on the basis of the number of variables to be entered into the multiple regression analysis and the minimum number of observations required. The minimum sample size was calculated to be at least 50 subjects.

Multicollinearity in the models was avoided by excluding variables with variance inflation factors > 4. We evaluated the measured 6MWD and ISWD in comparison with the predicted J Bras Pneumol. 2011;37(5):607-614

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distances derived from our equations. The level of statistical significance was set at 5%.

Results The characteristics of the 90 subjects (40 males) are summarized in Table 1. All of the subjects had normal lung function. The age distribution of our sample was as follows: 40-49 years (n = 20); 50-59 years (n = 21); 60-69 years (n = 26); and ≥ 70 years (n = 23). Mean BMI was within the overweight range (28 ± 3 kg/ m2). Approximately 52% of the subjects were classified as sedentary. The GS, 6MWD, and ISWD values were greater in males than in females (43 ± 7 vs. 28 ± 5 kg, 641 ± 63 vs. 540 ± 72 m, and 600 ± 91 vs. 417 ± 103 m, respectively; p < 0.001 for all).

The univariate analysis showed that 6MWD correlated significantly with age (r = −0.35), height (r = 0.58), BMI (r = −0.47), and GS (Figure 1a), whereas ISWD correlated significantly with age, height, and BMI (r = −0.36, r = 0.66, and r = −0.48, respectively; p < 0.05 for all), as well as with GS (Figure 1b).

The correlation coefficient for ISWD and GS was significant higher than that obtained for 6MWD and GS (z statistic = 2.05; p = 0.03). Age, gender, height, and weight collectively explained 54.5% and 64.9% of the variance in 6MWD and ISWD, respectively (Table 2). In the alternate models, age, height, weight, and GS collectively explained 54.4% and 69% of the variance in 6MWD and ISWD, respectively (Table 3). No interactions with gender were detected.

Table 1 - General characteristics of the subjects.

Characteristic Mean ± SD (n = 90) Age, years 60 ± 9 Weight, kg 69 ± 12 Height, m 1.60 ± 0.09 BMI, kg/m2 26 ± 4 FEV1, %pred 111 ± 13 FVC, %pred 109 ± 11 FEV1/FVC, % 85 ± 6 GS, kg 33 ± 9 1st 6MWD, m 567 ± 75 2nd 6MWD, m 572 ± 83 1st ISWD, m 451 ± 133 2nd ISWD, m 474 ± 131 BMI: body mass index; GS: grip strength; 6MWD: six-minute walk distance; ISWD: incremental shuttle walk distance.

The validation sample comprised the 8 test subjects (means: age, 59 ± 10 years; height, 1.65 ± 0.08 m; weight, 74 ± 12 kg; and BMI, 27 ± 4 kg/m2). For those 8 subjects, the mean 6MWD was 588 ± 71 m, corresponding to 102 ± 9% and 102 ± 11% of the predicted values calculated with equations including and excluding GS, respectively. The difference between the measured and predicted 6MWD values was not significant, with or without GS (13 ± 67 m and 14 ± 57 m, respectively; p > 0.05). The mean ISWD was 515 ± 150 m, corresponding to 105 ± 15% and 105 ± 18% of the predicted values calculated by the equations with and without GS, respectively. The difference between the measured and predicted ISWD

Table 2 - Predictive model for incremental shuttle and six-minute walk distances in healthy subjects, using demographic and anthropometric attributes.

Variable Incremental shuttle walk distance Six-minute walk distance Partial R2 Coefficient SE p Partial R2 Coefficient SE p Constant 34.608 255.310 299.296 185.784 Age, years 0.041 −4.384 0.997 < 0.001 0.047 −2.728 0.725 < 0.001 Weight, kg 0.100 −2.949 0.788 < 0.001 0.112 −2.160 0.574 < 0.001 Height, m 0.443 553.336 157.264 < 0.001 0.346 361.731 114.438 0.002 Gender* 0.065 114.387 28.771 < 0.001 0.038 56.386 20.936 0.009 Total R2 = 0.649 Total R2 = 0.543 *Factor gender: men = 1; women = 0.

Reference equations employed in this model: Incremental shuttle walk distance = 34.608 − (4.384 vs. age) − (2.949 vs. weight) + (553.336 vs. height) + (114.387 vs. gender); standard error of the estimate = 79.4 m Six-minute walk distance = 299.296 − (2.728 vs. age) − (2.160 vs. weight) + (361.731 vs. height) + (56.386 vs. gender); standard error of the estimate = 57.7 m.

J Bras Pneumol. 2011;37(5):607-614

Reference equations for the performance of healthy adults on field walking tests

Figure 1 - Correlation of grip strength with six-minute walk distance (a) and incremental shuttle walk distance (b).

values was also not significant, with or without GS (25 ¹ 93 m and 25 ¹ 104 m, respectively; p > 0.05).

Discussion To our knowledge, the present study is the first to develop GS-based reference equations for predicting ISWD and 6MWD in healthy, fully ambulatory subjects. We found that GS played an important role in predicting 6MWD and ISWD in healthy older adults, explaining large proportions of the total variances in these variables. Although GS correlated strongly with 6MWD and ISWD, it correlated more significantly with ISWD. In our study, age, gender, weight, and height were identified as independent predictors of ISWD and 6MWD. These results are quite similar to those previously described for older Brazilians adults.(9,10) The influence of gender on walking distance might be attributable to the fact that men have greater absolute muscle strength,

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muscle mass, and height than do women. The negative influence of advanced age on ISWD might be explained by the gradual reduction in muscle mass, muscle strength, and maximal oxygen uptake that typically occurs in parallel with aging.(20) Height has a strong influence, which might be attributable to the greater stride length in taller individuals, stride length being a major predictor of gait speed.(21) However, findings related to the question of whether body weight correlates with 6MWD and ISWD have been inconsistent across studies.(5-7) Nevertheless, it is likely that, because of its curvilinear nature, this correlation has defied detection in linear regressions.(7,10,22) In the present study, the inclusion of GS did not improve the power of commonly used reference equations based on anthropometric and demographic attributes. This could be attributed to the great influence that age, weight, height, and gender has on GS. However, it is possible that the equations including GS would be more appropriate for the evaluation of patients with muscle depletion. In such cases, muscle strength would be considered, and the predicted performance on the 6MWT and ISWT might more accurately represent the functional capacity of the patients. Further studies are needed in order to assess the validity of these equations in patients who are more debilitated and have skeletal muscle dysfunction, such as those with lung diseases, especially COPD, cystic fibrosis, and bronchiectasis, in which there is typically pronounced muscle loss.

We found that GS correlated strongly with ISWD and 6MWD, more so with ISWD. Studies that have evaluated the validity of these walking tests in patients with chronic disease have found GS to be significantly correlated with 6MWD and ISWD.(14,16) Similar results have been described in healthy individuals.(4,7) The fact that muscle strength and body weight had a greater influence on the ISWD than on the 6MWD might be attributable to the incremental nature of the ISWT, in which the pace is progressively increased at each stage. It is likely that individuals walk with intensity above the lactate threshold during a large portion of the test, which results in greater recruitment of glycolytic muscle fibers.(23) One study assessed the ventilatory and HR variability thresholds in healthy subjects performing the ISWT and recognized indices J Bras Pneumol. 2011;37(5):607-614

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Table 3 - Predictive model for the incremental shuttle and six-minute walk distances in healthy subjects using demographic and anthropometric attributes and grip strength.

Variable Incremental shuttle walk distance (m) Six-minute walk distance (m) Partial R2 Coefficient SE p Partial R2 Coefficient SE p Constant −243.867 183.135 109.764 141.888 Age, years 0.038 −2.833 0.872 0.002 0.045 −1.794 0.675 0.004 Weight, kg 0.066 −3.259 0.716 < 0.001 0.088 −2.383 0.555 < 0.001 Height, m 0.047 575.101 126.924 < 0.001 0.062 423.110 98.337 < 0.001 Grip strength, kg 0.538 6.321 1.171 < 0.001 0.348 2.422 0.908 0.009 Total R2 = 0.690 Total R2 = 0.543 *Factor grip strength: men = 1; women = 0.

Reference equations employed in this model: Incremental shuttle walk distance = −243.867 − (2.833 vs. age) − (3.259 vs. weight) + (575.101 vs. height) + (6.321 vs. grip strength); standard error of the estimate = 74.6 m Six-minute walk distance = 109.764 − (1.794 vs. age) − (2.383 vs. weight) + (423.110 vs. height) + (2.422 vs. grip strength); standard error of the estimate = 57.8 m.

of transition between moderate and intense exercise.(24) However, on the 6MWT, the pace is controlled by the subject and an aerobic steady state is achieved.(25) This suggests that the exercise intensity is at or below the lactate threshold in most cases, which results in a lower demand for glycolytic muscle fiber recruitment.

(23) In agreement with this, Pelegrino et al.(26) found the 6MWD to be similar in COPD patients with and without lean body mass depletion, indicating that skeletal muscle has a limited influence on 6MWD. However, during the test, the patients with such depletion presented significantly greater HR and sensation of leg fatigue. Therefore, muscle mass and muscle function both seem to have a more consistent influence on ISWD than on 6MWD. Various chronic diseases have systemic manifestations. One major manifestation of such diseases is peripheral skeletal muscle dysfunction. Although reductions in muscle mass and strength occur in parallel, the correlation between these variables is not linear. Therefore, muscle depletion can occur even in patients with normal body mass and BMI. For example, patients of the same gender with the same anthropometric characteristics would be expected to cover the same distance on field walking tests, after adjustment for anthropometric and demographic attributes, based on reference equations. However, peripheral muscle strength (i.e., the degree of muscle depletion) can differ significantly between individuals. To predict performance on walking tests, muscle strength, widely J Bras Pneumol. 2011;37(5):607-614

recognized as a determinant of cardiorespiratory fitness, should be taken into account.

Our results have clinical implications.

Traditionally, GS has been used in evaluating the physical condition of the upper limbs. However, more recently, GS has been assessed in various clinical situations. For example, Ling et al.

(27) showed that GS was a major predictor of all-cause mortality in adults > 85 years of age.

Al Snih et al.(28) followed a population-based sample of 2,488 noninstitutionalized men and women ≥ 65 years of age, 507 of whom died within the first five years of the study. The authors found that GS was strongly correlated with mortality. Poorer performance on the timed walk test, as well as diabetes mellitus, hypertension, and cancer, were also found to be significant negative predictors of five-year survival. Previous studies have demonstrated a significant positive correlation between GS and body cell mass.

(29) Taekema et al.(30) found that lower GS was correlated with poorer scores for functional, psychological, and social health domains. The authors also showed that lower baseline GS was predictive of an accelerated decline in cognition and in the ability to perform activities of daily living. Therefore, the determination of GS could be useful for identifying elderly patients at risk for such a decline. As an index of general health and muscle strength, GS shows promise. Given the low cost of dynamometry, it is reasonable to include this variable in regression models designed to predict the distance covered on walking tests.

The main limitation of the present study was the use of a convenience sample, which might

Reference equations for the performance of healthy adults on field walking tests

have introduced a selection bias. However, this type of sample has often been used in studies evaluating reference values for the total distance walked on field walking tests.(3-7,10) The GS values, in combination with demographic and anthropometric attributes, did not increase the R2 values of the standard equations. This might be attributable to the fact that GS was consistently correlated with age, height, and weight, or there might have been multicollinearity among variables in the alternate models, which could also explain that finding. However, the variance inflation factor values were < 4, indicating that there was no such multicollinearity in the alternate models.

We conclude that GS is a determinant of the total distance covered on the 6MWT and ISWT. However, the inclusion of GS did not appreciably improve the power to predict 6MWD and ISWD in comparison with that of equations including only demographic and anthropometric attributes. Nevertheless, reference equations including muscle function could be useful for interpreting the walk performance of patients with skeletal muscle dysfunction.

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cardiopulmonary repercussions during the six-minute walk test in patients with COPD. J Bras Pneumol.

2009;35(1):20-6.

27. Ling CH, Taekema D, de Craen AJ, Gussekloo J, Westendorp RG, Maier AB. Handgrip strength and mortality in the oldest old population: the Leiden 85-plus study. CMAJ. 2010;182(5):429-35.

28. Al Snih S, Markides KS, Ray L, Ostir GV, Goodwin JS. Handgrip strength and mortality in older Mexican Americans. J Am Geriatr Soc. 2002;50(7):1250-6.

29. Norman K, Schütz T, Kemps M, Josef Lübke H, Lochs H, Pirlich M. The Subjective Global Assessment reliably identifies malnutrition-related muscle dysfunction. Clin Nutr. 2005;24(1):143-50.

30. Taekema DG, Gussekloo J, Maier AB, Westendorp RG, de Craen AJ. Handgrip strength as a predictor of functional, psychological and social health. A prospective population-based study among the oldest old. Age Ageing. 2010;39(3):331-7.

About the authors Victor Zuniga Dourado

Adjunct Professor. Universidade Federal de São Paulo – UNIFESP, Federal University of São Paulo – Baixada Santista Campus, Santos, Brazil.

Milena Carlos Vidotto

Adjunct Professor. Universidade Federal de São Paulo – UNIFESP, Federal University of São Paulo – Baixada Santista Campus, Santos, Brazil.

Ricardo Luís Fernandes Guerra

Adjunct Professor. Universidade Federal de São Paulo – UNIFESP, Federal University of São Paulo – Baixada Santista Campus, Santos, Brazil.

J Bras Pneumol. 2011;37(5):607-614

Original Article Spirometric reference values for healthy adults in the Mazandaran province of Iran*, ** Valores de referência para espirometria em adultos saudáveis na província de Mazandaran, Irã

Siavash Etemadinezhad, Ahmad Alizadeh

Abstract Objective: One of the major issues in the use of spirometry is the evaluation of the values obtained in comparison with standardized reference values. Such reference values should be determined by studying populations similar to the population in which they are intended to be used. Considering the anthropometric differences among races and the effect of regional issues, such as climate and air quality, it is recommended that these standards be set and used regionally. The objective of this study was to measure the spirometric values in residents of the Mazandaran province in Iran, as well as to determine which standardized reference values most closely correlate with the values obtained and to devise predictive equations for the target population. Methods: This was a cross-sectional study of 1,499 volunteers, from whom demographic and anthropometric data were collected. After having been instructed in the correct procedure, each volunteer underwent spirometry. From each volunteer, we obtained three spirometry curves that met the acceptability criteria established by the American Thoracic Society. The test with the highest values of FEV1 and FVC was employed in the analysis. Results: We observed significant correlations between the measured values and the reference values, for both genders. The strongest correlations were with the European Respiratory Society reference values and with the 18-20 year age bracket. The predictive equations devised were based on the regression coefficients obtained and the demographic data collected. Conclusions: Our results show that the European Respiratory Society standard is the most appropriate standard for use in the population studied.

Keywords: Spirometry/statistics & numerical data; Climate effects; Reference values; Iran.

Resumo Objetivo: Um dos maiores problemas no uso da espirometria é a avaliação dos valores obtidos em comparação a valores de referência padronizados. Tais valores de referência devem ser determinados pelo estudo de populações semelhantes àquelas que se deseja utilizar. Considerando as diferenças antropométricas entre raças e o efeito de variáveis regionais, como clima e qualidade do ar, recomenda-se que esses padrões sejam definidos e utilizados regionalmente. O objetivo deste estudo foi medir os valores espirométricos em residentes da província de Mazandaran, no Irã; determinar quais valores de referência padronizados se correlacionam de forma mais próxima aos valores obtidos; e produzir equações preditivas para a população alvo. Métodos: Estudo transversal com 1.499 voluntários, dos quais dados demográficos e antropométricos foram coletados. Após terem sido instruídos quanto ao procedimento adequado, cada voluntário foi submetido à espirometria, sendo obtidas três curvas espirométricas de acordo com os critérios de aceitabilidade da American Thoracic Society. O teste com os maiores valores de VEF1 e CVF foram utilizados na análise. Resultados: Houve correlações significativas entre os valores medidos e os valores de referência em ambos os gêneros. As correlações mais fortes ocorreram com os valores de referência da European Respiratory Society e com a faixa etária de 18-20 anos. As equações preditivas produzidas basearam-se nos coeficientes de regressão obtidos e nos dados demográficos coletados. Conclusões: Nossos resultados mostram que os valores de referência da European Respiratory Society são os mais apropriados para a população estudada.

Descritores: Espirometria/ estatística & dados numéricos; Efeitos do clima; Valores de referência; Irã (geográfico).

* Study carried out at the Mazandaran University of Medical Sciences, Sari, Iran.

Correspondence to: Siavash Etemadinezhad. Mazandaran University of Medical Sciences, Health Faculty and Health Research Center, School of Public Health, Km 18, Khazar Abad Road, Sari, Iran.

Tel. +98 151 354-3085. E-mail: dr.setemadi@yahoo.com Financial support: This study received financial support from the Research Deputy of the Mazandaran University of Medical Sciences.

Submitted: 28 April 2011. Accepted, after review: 15 August 2011. ** A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

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Introduction Spirometry is one of the best methods of assessing lung function. It is also used in the diagnosis and follow-up of many pulmonary diseases, as well as providing evidence for use in court cases regarding legal compensation for pulmonary impairment.(1-3) One of the foundations of the use of spirometry is the comparison between the values obtained from an individual and those that are considered the reference (predicted) values. Reference values are based on various factors, including age, gender, height, weight, and race.(1-3) It has been suggested that numerous other factors, such as the type of climate, influence these values and should therefore also be considered.(2,3) There are significant differences among reference values, depending on the formulas employed. To be generalizable, these values must be obtained by studying representative samples of the general population.(2) It has been recommended that these standards be set by governments.(1) It is currently accepted that referral centers should devise reference values by studying samples of healthy individuals within their region.(2) A study involving 41 male medical students between 23 and 26 years of age, conducted in 1994 in the city of Zanjan, Iran, showed that the mean FVC in the studied population was 90% of the predicted value.

(4) Another study, involving 423 children and adolescents, was conducted in 2000 in the city of Isfahan, Iran(5) The authors showed that there is difference between the most widely used reference values and those obtained for the general population of Iran.(5) A study conducted in Spain by Castellsagué et al. in 1998 demonstrated differences among ethnicities in terms of lung volumes.(6) Gore et al. found that the most widely used reference values were applicable to Whites in Australia.(7) In a study conducted by our group in 2006 in the city of Sari, Iran, we found that the spirometric values (FVC, FEV1, and FEF25-75%) for healthy adults (≥ 18 years of age) were more similar to the European Respiratory Society (ERS) standard than to other standards.(8) Common mathematical formulas used for calculating standard spirometric indices are typically based on values obtained for small samples of healthy individuals in Europe or the United States, and those values are then generalized to the population of the J Bras Pneumol. 2011;37(5):615-620

world at large, disregarding the fact there are anthropometric differences among races and environmental differences among regions.

In Iran, there is a lack of regional and even national spirometric standards, as well as a lack of comprehensive studies on the subject.

Therefore, the objective of this study was to determine whether the spirometric values in our population are similar to any of the standard reference values, as well as to use the values obtained in order to devise predictive equations specifically for use in the population of Iran.

Methods This was a cross-sectional study of healthy adults (≥ 18 years of age) residing in the Mazandaran province of Iran. Volunteers were randomly recruited from urban and rural health centers in every city in the province. The study was approved by the Institutional Review Board and Research Ethics Committee of the Mazandaran University of Medical Sciences. All volunteers gave written informed consent.

Assuming a sample composed of both genders and distributed throughout four age brackets, we calculated the appropriate sample size by using information obtained from previous studies of FVC and FEV1, together with the following formula:

N = 7 = 0/S α = 0.05 d = ./1 where S is the standard deviation, α is the probability threshold, and d is the effect size.

Using these calculations, we estimated the sample size required to be 1,500 individuals.

For the individuals selected, we collected demographic data (age and gender) using a questionnaire and anthropometric data (height and weight) through direct measurement with the appropriate tools (scale and stadiometer). Those data were entered into the computer program provided with the self-calibrating spirometer employed (Spirolab Π, Medical International Research, Rome, Italy). After each volunteer had been instructed in the correct procedure, the spirometry tests were conducted with the individual in a standing position. From each volunteer, we obtained three spirometry curves that met the acceptability criteria established by the American Thoracic Society. The test with the highest values of FVC and FEV1 was used in the analysis.(9,10)

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Table 1 - Demographic, anthropometric, and spirometric characteristics of adult residents of the Mazandaran province in Iran, by gender.

Characteristic Males Females Total Mean ± SD Mean ± SD Mean ± SD Age (years) 36.02 ± 10.49 35.44 ± 10.19 35.76 ± 10.35 Height (cm) 172.15 ± 7.09 158.78 ± 6.18 165.87 ± 9.44 Weight (kg) 77.72 ± 12.53 69.89 ± 12.78 74.05 ± 13.23 FVC (L) 4.59 ± 0.73 3.22 ± 0.54 3.94 ± 0.94 FEV1 (L) 3.90 ± 0.63 2.80 ± 0.49 3.38 ± 0.79 FEF25-75% (L) 4.46 ± 1.00 3.43 ± 0.86 3.98 ± 1.10

We applied the following exclusion criteria: having upper or lower respiratory symptoms; having dyspnea; being a smoker or former smoker; being a passive smoker; having been exposed to occupational hazards such as dust and irritating gases; using beta blockers; having heart disease, musculoskeletal disorders, or any other disabling chest disease; being unable or unwilling to participate in the study; and producing spirometry curves that did not meet the acceptability criteria. It is notable that 39 individuals were excluded because they were uncooperative or produced unacceptable spirometry curves.

The values obtained for our sample were compared with the reference values established by the ERS, the Intermountain Thoracic Society (ITS), the European Community for Coal and Steel (ECCS), Knudson, and Morris.(2) Using the values obtained, we also devised predictive equations specifically for use in the population of Iran.

The statistical analysis was performed with the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA). Differences between means were determined with paired t-tests, correlations were identified with Pearson’s correlation coefficient, and the prediction model was constructed by regression analysis.

Results We evaluated 1,499 individuals (795 males and 704 females), all between 18 and 60 years of

age. We found that the mean spirometric values were higher in males than in females (Table 1).

As expected, spirometric values showed a strong positive correlation with height (Table 2). The correlation between spirometric values and weight was weaker but still significant for certain parameters. As was also expected, there was an inverse correlation between age and spirometric values.

Table 3 shows the mean values of FVC, FEV1, and FEF25-75% obtained in our sample. As can be seen in Table 4, the values obtained correlated significantly with all of the established reference values, regardless of gender (p < 0.001 for all).

Among the male volunteers, the mean FVC did not differ significantly from the Knudson reference value (p = 0.193, T = −1.302); and the mean FEF25-75% did not differ significantly from the ERS reference value (p < 0.961, T = 0.049). Among the female volunteers, the mean FVC did not differ significantly from the ERS reference value (p = 0.783, T = 0.275); the mean FEV1 did not differ significantly from the ERS or Knudson reference values (p = 0.733, T = 0.341 and p = 0.169, T = 1.38, respectively); and the mean FEF25-75% did not differ significantly from the ITS or Morris reference values (p = 0.33, T = −2.138 and p = 0.431, T= −0.788, respectively).

We also found that the values obtained for FVC correlated significantly with the established reference values across all age brackets (Table 5).

On the basis of the regression coefficient values obtained and the demographic data

Table 2 - Correlation coefficients for the parameters measured in adult residents of the Mazandaran province in Iran, by age, height, weight, and gender.

Parameter FVC FEV1 FEF25-75% Male Female Male Female Male Female Age −0.553** −0.577** −0.588** −0.602** −0.356** −0.423** Height 0.665** 0.576** 0.595** 0.509** 0.253** 0.244** Weight 0.172** 0.047 0.153** 0.01 0.108** 0.007

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Table 3 - Values obtained for adult residents of the Mazandaran province in Iran, together with the corresponding international standards.

Parameter Measured ERS ITS Morris Knudson Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD FVC (L) 3.94 ± 0.94 3.96 ± 0.86 4.20 ± 0.87 3.98 ± 0.88 4.18 ± 0.84 FEV1 (L) 3.38 ± 0.79 3.36 ± 0.99 3.52 ± 0.68 3.35 ± 0.73 3.52 ± 0.67 FEF25-75% (L) 3.97 ± 1.10 4.09 ± 0.58 3.88 ± 0.63 3.72 ± 0.71 3.95 ± 0.62 ERS: European Respiratory Society; and ITS: Intermountain Thoracic Society.

collected, we devised the following predictive equations: For males FVC = 5.6H × 10−2 − 2.5A × 10−2 − W × 10−3 − 4.067 FEV1 = 3.9H × 10−2 − 2.6A × 10−2 − 1.94 FEF25-75% = 1.6H ×10−2 – 3.2A × 10−2 + 7W × 10−3 + 2.306

For females FVC = 3.7H × 10−2 − 2.5A × 10−2 + 3W × 10−3 − 2.034 FEV1 = 2.8H × 10−2 − 2.5A × 10−2 − 3W × 10−3 − 0.942 FEF25-75% = 1.6H × 10−2 − 3.5A ×10−2 − 6W × 10−3 + 1.774

where H is height (in cm), A is age (in years), and W is weight.

As can be seen in Table 5, the mean FVC was most similar to the ERS standard, for both genders. However, the mean FEV1 was most similar to the ERS standard in males and to the ITS standard in females. The mean FEF25-75% was most similar to the ERS standard in males and to the Knudson standard in females.

Discussion In our sample, the mean spirometric indices were higher in males than in females. This can be attributed, in part, to the influence that height has on these parameters.

A study conducted in 1997 by Pan et al.(11) showed that, in the local population of Taiwan, the mean FVC and FEV1, adjusted for age and height, were lower than the standard reference values established for White populations. The authors found that age and height both had a

significant influence on spirometric parameters.

The results of the present study also show that spirometric indices decrease in parallel with increasing age. We obtained the highest values for the 18-20 year age bracket, a finding that differs slightly from those of an earlier study conducted by our group,(8) in which the highest values were obtained for the 20-30 year age bracket.

In a study conducted in England and involving 6,053 healthy individuals (16-75 years of age), FVC, FEV1, and the FEV1/FVC ratio were found to be considerably higher than the ERS reference values.(12) However, in the present study, as well as in our earlier study,(8) the mean FVC was lower than the ERS reference value. In addition, we found that the mean FEV1, although higher than the ERS and Knudson reference values, was lower than the ITS and Morris reference values. Furthermore, in our sample, the mean FEF25-75% was lower than the ERS reference value but higher than other standards. A multicenter study involving 12,900 subjects (20-44 years of age) in 14 European countries compared the measured FVC and FEV1 with the ERS reference values and found that the ERS reference values were noticeably lower than the overall mean.(13) Nevertheless, the results of the present study show that the ERS reference values are noticeably higher than the mean values obtained among residents of the Mazandaran province in Iran.

Duarte et al.(14) evaluated FVC and FEV1 in a sample composed of 643 White individuals in Brazil. The authors evaluated the values obtained

Table 4 - Correlation coefficients of the values obtained for adult residents of the Mazandaran province in Iran, in comparison with international standards, by gender.

Parameter ERS ITS Knudson Morris Male Female Male Female Male Female Male Female FVC (L) 0.748 0.720 0.735 0.717 0.730 0.694 0.700 0.697 FEV1 (L) 0.723 0.683 0.711 0.696 0.706 0.683 0.684 0.616 FEF25-75% (L) 0.371 0.417 0.355 0.435 0.364 0.458 0.366 0.440 ERS: European Respiratory Society; and ITS: Intermountain Thoracic Society.

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Table 5 - Correlation coefficients of the FVC values obtained for adult residents of the Mazandaran province in Iran, in comparison with international standards, by age and gender.

Age ERS ITS Knudson Morris bracket Male Female Male Female Male Female Male Female <20 0.744** 0.395** 0.649** 0.377** 0.715** 0.416** 0.649** 0.315** 20-30 0.636** 0.568** 0.635** 0.509** 0.598** 0.484** 0.577** 0.484** 30-40 0.562** 0.585** 0.560** 0.610** 0.591** 0.546** 0.524** 0.585** >40 0.675** 0.616** 0.666** 0.647** 0.658** 0.635** 0.662** 0.641** ERS: European Respiratory Society; and ITS: Intermountain Thoracic Society.

in comparison with the current (2006) Brazilian standards, as well as in comparison with those established by Knudson and by the ECCS. They showed that the values obtained were most similar to the 2006 Brazilian standards, whereas they differed significantly from the Knudson and ECCS standards, which effectively invalidated the use of those standards in Brazil.(14) However, the values obtained in the present study did not differ significantly from the predicted values established by the ECCS. In another study conducted in Brazil in 2004,(15) the values of FEV1 and FVC were found to exceed those obtained 12 years prior (in 1992), a difference that could be attributable to technical factors.

In 2000, Golshan & Nematbakhsh conducted a study in the city of Isfahan.(16) The authors suggested that the lung volume reference values recommended for American and Europeans are appropriate for use in adults in Isfahan, despite the fact that estimated lung volumes were slightly higher in the last group. In an earlier study conducted in Brazil, spirometric values were obtained in 1,070 individuals.(17) The authors showed that the mean FVC obtained for females was 4% lower than the Knudson standard, leading to a higher rate of diagnosis of restrictive disorders in females, whereas there was no significant difference for males. They also found that mean FEV1 was higher than the Knudson standard for both genders, increasing the sensitivity of FEV1 for the diagnosis of obstructive lung disorders, although there was no significant difference in terms of the mean FEF25-75%.(17) The results of the present study show that all of the parameters measured correlated significantly with all of the standards evaluated, regardless of gender (p < 0.001 for all). A study of 41 male students (23-26 years of age) at Zanjan University showed that the mean FVC in the studied population was 90% of the predicted

value.(4) Sharifian et al.(18) evaluated 1,589 residents of the Kurdistan province in Iran and showed that the mean FVC obtained was lower than the reference value, whereas the mean FEV1 was comparable. In the present study, mean values were > 99% of the ERS reference values, > 93% of the Knudson reference values, and > 98% of the ITS reference values. The predictive equations we have devised make it clear that the values obtained for FVC were most similar to the ERS reference values, for both genders, whereas those obtained for FEV1 were most similar to the ERS reference values in males and to the ITS reference values in females. The mean FEF25-75% correlated most strongly with the ERS reference values in males and with the Knudson reference values in females.

On the basis of our results, taken together with those of previous studies, we can recommended the use of our predictive equations in all spirometry tests conducted in the region under study.

Acknowledgments We would like to express our appreciation to Mr. Golikani, Industrial Health Engineer at the Sari Health Faculty, for his cooperation and efforts.

References 1. Roy T, Edward P. Pulmonary function testing in industry.

In: Zenz C, editor. Occupational Medicine -- Principles and Practical Applications. 3rd ed. St. Louis: Mosby; 1994. p. 229-36.

2. Garay SM. Pulmonary function testing. In: Rom WN, Markowitz S. Environmental and Occupational Medicine. 4th ed. Philadelphia: Lippincott-Raven; 2007. p. 200-36.

3. Balmes JR, Scannell CH. Occupational lung diseases. In: LaDou J, editor. Occupational Environmental Medicine.

2nd ed., Hightstown: McGraw Hill Professional; 1997. p. 307.

4. Mortazavi N. Comparison of spirometric index function with standards in 23-26 year old male medical students

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of Zanjan University of Medical Sciences. J Zanjan Univ Med Sci. 2009;17(75):20-7.

5. Golshan M, Nemat Bakhsh M, Masjedi M. Determination of spirometric indices in 423 healthy non-smoking children and youngster in Isfahan. J Kerman Univ Med Sci. 1999;6(3):28-32.

6. Castellsagué J, Burgos F, Sunyer J, Barberà JA, Roca J. Prediction equations for forced spirometry from European origin populations. Barcelona Collaborative Group on Reference Values for Pulmonary Function Testing and the Spanish Group of the European Community Respiratory Health Survey. Respir Med. 1998;92(3):401-7.

7. Gore CJ, Crockett AJ, Pederson DG, Booth ML, Bauman A, Owen N. Spirometric standards for healthy adult lifetime nonsmokers in Australia. Eur Respir J. 1995;8(5):773-82.

8. Alizade A, Etemadinezhad S, Mohammadpor R. Comparison of measured spirometric values in healthy individuals over 18 years of Sari. J Mazandaran Univ Med Sci. 2006;55:65-7.

9. Bellia V, Pistelli R, Catalano F, Antonelli-Incalzi R, Grassi V, Melillo G, et al. Quality control of spirometry in the elderly. The SA.R.A. study. SAlute Respiration nell’Anziano = Respiratory Health in the Elderly. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1094-100.

10. Enright PL, Beck KC, Sherrill DL. Repeatability of spirometry in 18,000 adult patients. Am J Respir Crit Care Med. 2004;169(2):235-8.

11. Pan WH, Chen JY, Haung SL, Liou TL, Lee TK, Wang LY, et al. Reference spirometric values in healthy Chinese neversmokers in two townships of Taiwan. Chin J Physiol. 1997;40(3):165-74.

12. Falaschetti E, Laiho J, Primatesta P, Purdon S. Prediction equations for normal and low lung function from the Health Survey for England. Eur Respir J. 2004;23(3):456-63.

13. Roca J, Burgos F, Sunyer J, Saez M, Chinn S, Antó JM, et al. References values for forced spirometry. Group of the European Community Respiratory Health Survey.

Eur Respir J. 1998;11(6):1354-62.

14. Duarte AA, Pereira CA, Rodrigues SC. Validation of new Brazilian predicted values for forced spirometry in caucasians and comparison with predicted values obtained using other reference equations. J Bras Pneumol. 2007;33(5):527-35.

15. 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.

16. Golshan M, Nematbakhsh M. Prediction equations of ventilatory function in non-smoker adults in Isfahan, Iran. Iran J Med Sci. 2000;25(3-4):125-8.

17. Ladosky W, Andrade RT, Loureiro NG, Gandar JM, Botelho MM. Comparing reference spirometric values obtained from Knudson and Pereira equation adults [Article in Portuguese]. J Pneumologia. 2001;27(6):315-20.

18. Sharifian A, Sigary N, Rahimi A, Yazdanpanah K. Evaluation of normal pulmonary function test in people of Kurdistan Province. Sci J Kurdistan Univ Med Sci. 2007;12:15-20.

About the authors Siavash Etemadinezhad

Assistant Professor. Department of Occupational Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Ahmad Alizadeh

Assistant Professor. Department of Occupational Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

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Original Article Influenza A (H1N1)-associated pneumonia*, ** Pneumonia associada a influenza A (H1N1)

Antonello Nicolini, Simonassi Claudio, Fabrizio Rao, Lorenzo Ferrera, Michele Isetta, Monica Bonfiglio

Abstract Objective: To describe the characteristics of patients with influenza A (H1N1)-associated pneumonia treated at two hospitals in the region of Liguria, Italy, as well as to describe their treatment and outcomes. Methods: This was a prospective observational study including all patients older than 16 years of age with a confirmed diagnosis of influenza A (H1N1) who were admitted to Villa Scassi Hospital, in the city of Genoa, Italy, or to the Sestri Levante General Hospital, in the city of Sestri Levante, Italy, between September of 2009 and January of 2010. The primary outcome measure was mortality within 60 days after diagnosis. Secondary outcome measures were the need for mechanical ventilation and the length of hospital stay. Results: Of the 40 patients with a confirmed diagnosis of influenza A (H1N1), 27 presented pneumonia during the study period. The mean age of the 27 patients was 42.8 ± 14.8 years, and the mean length of hospital stay was 11.6 ± 8.2 days. Of the 27 patients, 20 had respiratory failure, 4 underwent invasive mechanical ventilation, and 5 underwent noninvasive ventilation. One patient had comorbidities, developed multiple organ failure, and died. Conclusions: During the influenza A (H1N1) pandemic, the associated mortality rate was lower in Italy than in other countries, and cases reported in the country typically had a milder course than did those reported elsewhere. Nevertheless, 9 of our cases (33%) rapidly evolved to respiratory failure, requiring mechanical ventilation.

Keywords: Pneumonia; Influenza A virus, H1N1 subtype; Respiratory insufficiency.

Resumo Objetivo: Descrever as características dos pacientes com pneumonia associada a influenza A (H1N1) tratados em dois hospitais na região da Ligúria, Itália, e descrever seu tratamento e desfechos. Métodos: Estudo prospectivo observacional que incluiu todos os pacientes com mais de 16 anos de idade e com diagnóstico confirmado de influenza A (H1N1) admitidos no Hospital Villa Scassi, em Gênova, ou no Hospital Geral de Sestri Levante, em Sestri Levante, Itália, entre setembro de 2009 e janeiro de 2010. O desfecho primário foi mortalidade em até 60 dias do diagnóstico, e os desfechos secundários foram necessidade de ventilação mecânica e tempo de hospitalização. Resultados: Durante o período do estudo, dos 40 pacientes com diagnóstico confirmado de influenza A (H1N1), 27 apresentaram pneumonia. A média de idade dos 27 pacientes foi de 42,8 ± 14,8 anos, e o tempo médio de hospitalização foi de 11,6 ± 8,2 dias. Dos 27 pacientes, 20 tiveram insuficiência respiratória, 4 necessitaram de ventilação mecânica invasiva e 5, de ventilação mecânica não invasiva. Somente 1 paciente com várias comorbidades teve falência múltipla de órgãos e faleceu. Conclusões: Embora a influenza A (H1N1) tenha sido mais branda e com menor incidência de mortalidade na Itália do que em outros países, 9 de nossos pacientes (33%) tiveram evolução rápida para falência respiratória e necessitaram de ventilação mecânica.

Descritores: Pneumonia; Vírus da influenza A subtipo H1N1; Insuficiência respiratória.

* Study carried out at the Villa Scassi Hospital, Genoa, Italy, and at the Sestri Levante General Hospital, Sestri Levante, Italy.

Correspondence to: Antonello Nicolini. Ospedale Civile Sestri Levante, Via Arnaldo Terzi, 43, 16039, Sestri Levante, GE, Itália.

Tel. 39 018541031. E-mail: antonello.nicolini@fastwebnet.it Financial support: None.

Submitted: 11 September 2010. Accepted, after review, 19 July 2011. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

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Nicolini A, Claudio S, Rao F, Ferrera L, Isetta M, Bonfiglio M

Introduction New diseases pose a challenge to clinicians.

When a novel infectious disease, influenza A (H1N1), became pandemic, it caused severe illness and resulted in significant increases in the utilization of health care services worldwide.

(1,2) The incubation period of the disease was similar to that of seasonal flu.(3) Approximately a quarter of all patients with this pandemic flu presented with gastrointestinal symptoms,(4,5) and approximately 40% of all hospitalized patients had findings consistent with pneumonia on initial chest X-rays. In addition, 10-30% of hospitalized patients required admission to ICUs and mechanical ventilation.(3,6,7) Radiographic findings were similar to those seen in cases of severe pneumonia.(4,8) Viral specimens from the lower respiratory tract (BAL fluid samples) are more reliable than are those of samples from the upper airway.(9) Rapid antigen tests have lower sensitivity and cannot exclude the diagnosis.

The preferred test is real-time PCR, which has a sensitivity of 98%, a positive predictive value of 100%, and a negative predictive value of 98%.(9,10) Antiviral drugs are recommended only for highrisk patients or severe cases. When secondary bacterial pneumonia is suspected, antibiotics must be used.(11) Other treatment modalities include ventilatory support and, in cases of severe pneumonia, corticosteroid therapy.(3) The major complications are respiratory failure and acute respiratory distress syndrome (ARDS).

(3,4,6) Autopsies of these patients have shown extensive diffuse alveolar damage, pulmonary hemorrhage, and necrotizing bronchiolitis.(12,13) Higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, lower PaO2/FiO2 ratio, shock, hemodialysis, and Streptococcus pneumoniae infection are independent factors predicting death.(6,7,10,14) From the beginning of the epidemic, influenza A (H1N1) infection seemed to have a more severe course and worse outcomes than did infection with seasonal influenza A. In addition, the demographic profile of influenza A (H1N1) infection was younger, and it affected individuals with fewer comorbidities. More severe respiratory involvement was noted, and a greater number of patients were admitted to ICUs with influenza A (H1N1)-associated pneumonia. The objective of the present study was to describe the characteristics of the patients with influenza J Bras Pneumol. 2011;37(5):621-627

A (H1N1)-associated pneumonia treated at two hospitals in the region of Liguria, Italy, between September of 2009 and January of 2010, as well as to describe their treatment and outcomes.

Methods Between September of 2009 (when the first case was diagnosed in the Italian region of Liguria) and January of 2010, a prospective observational study was conducted in Villa Scassi Hospital, Genoa, and in the General Hospital of Sestri Levante, Sestri Levante, Italy. The inclusion criteria were being at least 16 years of age, being diagnosed with influenza A (H1N1) infection, and presenting with radiological findings suggestive of pneumonia. The exclusion criteria were being hospitalized in the preceding 10 days and having concurrent lung cancer or tuberculosis. The primary outcome measure was mortality within 60 days after diagnosis. Secondary outcomes included the use of mechanical ventilation and ICU admission.

The study design was approved by the research ethics committees of the institutions.

During the study period, 40 patients diagnosed with influenza A (H1N1) were admitted to one of the hospitals. The diagnosis was confirmed by reverse transcriptase PCR (performed at the Institute for Public Health of the Medical University of Genoa, Genoa, Italy), and all tests were carried out using the guidelines recommended by the U.S. Centers for Disease Control and Prevention.(6) Nasopharyngeal swab specimens were collected from all of the patients at admission, and bronchial aspirate samples were obtained after tracheal intubation from the patients who required intubation. From a patient with suspected oseltamivir-resistant infection, BAL fluid was collected. In order to stratify the patients at admission, severity of illness was assessed using APACHE II score, the Simplified Acute Physiology Score II, and the PaO2/FiO2 ratio (during oxygen delivery with a high-flow face mask).(15) All patients were placed in negative-pressure isolation rooms.

Of the 40 patients, 27 presented with pneumonia. Any patient meeting the criteria for influenza A (H1N1) infection and evidence of recent pulmonary infiltrate on chest X-rays, without an alternative diagnosis, was classified as having pneumonia. Chest X-rays were independently evaluated by two investigators.

Influenza A (H1N1)-associated pneumonia

We also used an adapted score system (chest X-ray score) in order to grade the radiological severity of the pulmonary infiltrates.(15) Any patient meeting the criteria for influenza A (H1N1)-associated pneumonia with a positive culture for a bacterial pathogen from blood or BAL fluid samples was considered to have influenza (H1N1)-associated pneumonia and a bacterial co-infection. A chest CT scan was performed in the case of inconclusive chest X-ray findings or in order to evaluate the extent of pneumonia.

Statistical analysis was carried out dividing the patients into two groups: patients with mild disease and patients with severe disease.

The latter group comprised patients with sepsis, shock, acute lung injury, or ARDS, as well as patients who required intubation or noninvasive mechanical ventilation and patients admitted to the ICU or to the respiratory intermediate care unit.(16) Acute lung injury was defined as a PaO2/FiO2 ratio between 201 and 300, whereas ARDS was defined as a PaO2/FiO2 ratio ≤ 200.(17) Baseline clinical and laboratory characteristics of the two groups were compared using logistic regression analysis for categorical variables and analysis of covariance for continuous variables.

The level of statistical significance was set at p < 0.05.

Results Data related to the 27 patients with confirmed influenza A (H1N1)-associated pneumonia were analyzed. At admission, all patients were appropriately treated with oseltamivir (75 mg, twice a day) and received empirical treatment with antibiotics: 18 patients (66%) were treated with ceftriaxone, 3 (12%) received the ceftriaxone-clarithromycin combination, and 6 (22%) received additional broad-spectrum antibiotics.

Bacterial co-infection (with Staphylococcus aureus) was found in only 1 patient (in a BAL fluid sample). Clinical and laboratory characteristics of the 27 patients are reported in Table 1. Approximately 75% of the hospitalized patients were between 18 and 51 years of age. The male-to-female ratio was 1.25:1.00. The mean length of hospital stay was 11.6 ± 8.2 days; the number of days from the onset of influenza-like symptoms to hospital admission and initiation of antiviral therapy was 4.28 ± 1.72 days. During hospitalization,

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respiratory failure was documented in 19 of the 27 patients (70%), and ARDS was identified in 9 of those patients (33%). Of the 9 patients who required mechanical ventilation, 4 received invasive mechanical ventilation. One patient (3.7%), who suffered from dementia, developed multiple organ failure and died. That was the only patient who required extracorporeal membrane oxygenation. Fifteen patients had underlying medical conditions: bronchial asthma, in 4 (26.0%); COPD, in 3 (20.0%); diabetes, in 2 (13.5%); obesity, in 2 (13.5%); dementia, in 3 (20.0%); and hairy cell leukemia, in 1 (7%). Of the patients admitted to the ICU or to the respiratory intermediate care unit, 6 presented with comorbidities: dementia, in 2 (33.0%); COPD, in 2 (33.0%); diabetes, in 1 (16.5%); and obesity, in 1 (16.5%). The patients with dementia had the worst outcomes: 1 died, and another underwent intubation and had the longest stay in the ICU. The characteristics of the 9 patients admitted to the ICU or to the respiratory intermediate care unit are described in Table 2. In the comparison of the two groups (mild disease vs. severe disease), there were no significant differences regarding the mean age of the patients and the mean number of days from the onset of symptoms to the initiation of antiviral therapy. Higher levels of lactate dehydrogenase (LDH), higher PaO2, higher PaO2/ FiO2 ratio, higher chest X-ray scores, and greater number of lobes affected by the disease were independent variables that were associated with mechanical ventilation requirement and ICU admission, but not with 60-day mortality (Figure 1).

Discussion When the influenza A (H1N1) virus first appeared, it was evident that it could cause severe illness,(6) and this was confirmed in various studies.(6,9,12,14-28) Approximately 20-56% of the patients hospitalized with influenza A (H1N1) infection had respiratory failure and required mechanical ventilation.(6,18,19,25) The risk of developing respiratory failure has been significantly associated with scores, at admission, of ≥ 4 on the Sequential Organ Failure Assessment or ≥ 20 on the APACHE II, as well as with lymphocyte counts ≤ 800 mm3, interval between symptom onset and initiation J Bras Pneumol. 2011;37(5):621-627

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Table 1 - Clinical and laboratory characteristics of the 27 patients diagnosed with influenza A (H1N1)associated pneumonia, categorized by the severity of the disease.a Mild disease Severe disease Characteristic p n = 18 n=9 Age, years 46.15 ± 15.16 36.37 ± 13.23 0.33 Male gender, n 10 5 0.41 Fever, n 17 8 0.42 Shortness of breath, n 13 8 0.22 Cough, n 14 5 0.20 Myalgia, n 12 5 0.33 RR ≥ 30 breaths/min, n 12 8 0.15 Time from symptom onset to admission, days 4.62 ± 2.06 4.01 ± 0.81 0.08 PaO2, mmHg 71.88 ± 15.30 45.57 ± 7.91 0.007 PaO2/FiO2 317 ± 27 180 ± 89 < 0.001 Comorbidities, n 9 6 0.43 Number of lobar infiltrates 1.87 ± 1.02 3.87 ± 1.35 0.0012 White cells/mm3 8,900 ± 4,390 7,256 ± 3,965 0.41 Lymphocytes/mm3 1,960 ± 1,360 1,725 ± 823 0.21 Platelets/mm3 247,000 ± 96,000 231,000 ± 93,000 0.52 LDH, U/L 420 ± 172 759 ± 393 < 0.02 AST, U/L 20.07 ± 11.50 47.75 ± 26.03 0.10 ALT, U/L 52.25 ± 64.60 47.25 ± 37.75 0.20 Creatinine, mg/dL 0.59 ± 0.34 0.39 ± 0.36 0.41 Sodium, mEq/L 137.50 ± 3.30 137.80 ± 3.60 0.34 Hospital stay, days 9.62 ± 5.07 15.75 ± 12.51 0.06 APACHE II 5.25 ± 0.86 24.78 ± 9.79 0.001 SAPS II 16.41 ± 2.27 20.54 ± 31.00 0.001 Chest X-ray score 20.8 ± 2.1 12.5 ± 3.5 0.001 LDH: lactate dehydrogenase; AST: aspartate aminotransferase; ALT: alanine aminotransferase; APACHE II: Acute Physiology and Chronic Health Evaluation II; and SAPS II: Simplified Acute Physiology Score II. aValues expressed as mean ± SD, except where otherwise indicated.

of antiviral therapy > 48 h, chest X-ray scores ≥ 12,(21,25) and a body mass index > 40 kg/m2.(26) Influenza A (H1N1)-associated ARDS remains uncommon.(27) The most common diagnosis was pneumonia,(6,18,19) and the majority of pneumonia-related deaths occurred in young healthy adults with comorbidities.(9,26) In Europe (including Italy), influenza A (H1N1) infection had a milder course than in other countries.

(28) However, among the severe cases evaluated in the present study, we identified respiratory failure and the need for mechanical ventilation in 19 (70%) and 9 (33%), respectively, findings that are in agreement with those of other authors.(6,8,9,18,19) All of our patients were strictly monitored for the risk of rapid deterioration, especially for increased oxygen demand.(24) Although secondary outcomes, such as the frequency of mechanical ventilation requirement and length of hospital stay, were similar to

J Bras Pneumol. 2011;37(5):621-627

those reported for other countries, mortality was lower in our study than that in previous studies of the pandemic. In our study, age and gender distributions were similar to those previously reported.(9,28,29) Nearly 60% of the patients had pre-existing medical conditions, chronic lung diseases, diabetes, and hypertension being the most common, as has previously been reported.

(6,29) In our patients, symptoms included fever, cough, myalgia, and dyspnea, which have often been reported in other studies. However, the incidence of gastrointestinal symptoms, such as nausea, vomiting, and diarrhea, was much lower than in previous reports.(29) We observed elevated transaminase and LDH levels, which is also consistent with other reports.(6,29) Elevated LDH has been found to be significantly associated with the severity of the illness and admission to ICU.(29) In our sample, 33% of the patients were admitted to the ICU. There was

Influenza A (H1N1)-associated pneumonia

Table 2 - Characteristics of the 9 patients with severe disease admitted to ICUs or respiratory intermediate care units.a Characteristic Value APACHE II 24.78 ± 9.79 SAPS II 20.54 ± 31.00 Shock, n 2 ARDS, n 9 Invasive mechanical ventilation, n 4 Noninvasive mechanical ventilation, n 5 Days on mechanical ventilation 12.7 ± 15.9 Days in the ICU/RICU 19.5 ± 13.9 ECMO, n 1 Death, n 1 APACHE II: Acute Physiology and Chronic Health Evaluation II; SAPS II: Simplified Acute Physiology Score II; ARDS: acute respiratory distress syndrome; RICU: respiratory intermediate care unit; and ECMO: extracorporeal membrane oxygenation. aValues expressed as mean ± SD, except where otherwise indicated.

only one death. Although our data regarding ICU admission are similar to those collected in other countries,(29) mortality was lower in our study. Another study described patients with

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influenza A (H1N1) infection who were admitted to four infectious disease facilities in Liguria.(30) That study included 81 patients, of whom 50% had pneumonia, 12% were admitted to ICU, and 3% died. The authors found that respiratory and neurocognitive impairment was associated with severe disease and death. In our study, the only patient who died suffered from a neurocognitive disorder. To our knowledge, this association had not been previously described in the literature in English.

One limitation of our study is that the study samples represented less than 1% of all reported hospitalizations for influenza A (H1N1)associated pneumonia in Italy. Our hospitals are not referral centers for children and pregnant woman infected with influenza A (H1N1).

Therefore, no children or pregnant women were included in our study. This was an observational study, and participation was voluntary. It included only patients with confirmed influenza A (H1N1) infection. Therefore, our sample

Figure 1 - Regression analysis showing the independent variables that were associated with mechanical ventilation requirement and ICU admission, by disease severity. LDH: lactate dehydrogenase; and CXR: Chest X-ray.

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might not be representative of all hospitalized patients. Finally, the low mortality rate in our sample makes it impossible to compare our study with other studies or countries in terms of this outcome (mortality).

In conclusion, patients with suspected influenza A (H1N1) infection should be moved to negative-pressure isolation rooms as soon as possible to avoid transmission of the infection. They should receive continuous oxygen monitoring. Antiviral treatment should not be delayed. This infection requires proactive management.

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2. Satpathy HK, Lindsay M, Kawwass JF. Novel H1N1 virus infection and pregnancy. Postgrad Med. 2009;121(6):106-12.

3. Marjani M, Parvaneh B, Tabarsi P, Mansouri SD. Update on 2009 pandemic Influenza A (H1N1) virus. Tanaffos.

2010;9(1):8-14.

4. Gordon SM. Update on 2009 pandemic influenza A (H1N1) virus. Cleve Clin J Med. 2009;76(10):577-82.

5. Zimmer SM, Burke DS. Historical perspective-Emergence of influenza A (H1N1) viruses. N Engl J Med. 2009;361(3):279-85.

6. Perez-Padilla R, de la Rosa-Zamboni D, Ponce de Leon S, Hernandez M, Quiñones-Falconi F, Bautista E, et al. Pneumonia and respiratory failure from swineorigin influenza A (H1N1) in Mexico. N Engl J Med. 2009;361(7):680-9.

7. Bewick T, Myles P, Greenwood S, Nguyen-Van-Tam JS, Brett SJ, Semple MG, et al. Clinical and laboratory features distinguishing pandemic H1N1 influenza-related pneumonia from interpandemic community-acquired pneumonia in adults. Thorax. 2011;66(3):247-52.

8. Marchiori E, Zanetti G, Hochhegger B, Rodrigues RS, Fontes CA, Nobre LF, et al. High-resolution computed tomography findings from adult patients with Influenza A (H1N1) virus-associated pneumonia. Eur J Radiol.

2010;74(1):93-8.

9. Blyth CC, Iredell JR, Dwyer DE. Rapid-test sensitivity for novel swine-origin influenza A (H1N1) virus in humans.

N Engl J Med. 2009;361(25):2493.

10. Cunha BA. Swine Influenza (H1N1) pneumonia: clinical considerations. Infect Dis Clin North Am. 2010;24(1):203-28.

11. Barlow GD; BSAC Council. Swine flu and antibiotics. J Antimicrob Chemother. 2009;64(5):889-94.

12. Mauad T, Hajjar LA, Callegari GD, da Silva LF, Schout D, Galas FR, et al. Lung pathology in fatal novel human influenza A (H1N1) infection. Am J Respir Crit Care Med. 2010;181(1):72-9.

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13. Mukhopadhyay S, Philip AT, Stoppacher R. Pathologic findings in novel influenza A (H1N1) virus (“Swine Flu”) infection: contrasting clinical manifestations and lung pathology in two fatal cases. Am J Clin Pathol.

2010;133(3):380-7.

14. Chien YS, Su CP, Tsai HT, Huang AS, Lien CE, Hung MN, et al. Predictors and outcomes of respiratory failure among hospitalized pneumonia patients with 2009 H1N1 influenza in Taiwan. J Infect. 2010;60(2):168-74.

15. Kute VB, Godara SM, Goplani KR, Gumber MR, Shah PR, Vanikar AV, et al. High mortality in critically ill patients infected with 2009 pandemic influenza A (H1N1) with pneumonia and acute kidney injury. Saudi J Kidney Dis Transpl. 2011;22(1):83-9.

16. Zarychanski R, Stuart TL, Kumar A, Doucette S, Elliott L, Kettner J, et al. Correlates of severe disease in patients with 2009 pandemic influenza (H1N1) virus infection.

CMAJ. 2010;182(3):257-64.

17. Gómez-Gómez A, Magaña-Aquino M, Garcia-Sepúlveda C, Ochoa-Pérez UR, Falcón-Escobedo R, Comas-García A, et al. Severe pneumonia associated with pandemic (H1N1) 2009 outbreak, San Luis Potosí, Mexico. Emerg Infect Dis. 2010;16(1):27-34.

18. Riquelme R, Riquelme M, Rioseco ML, Inzunza C, Gomez Y, Contreras C, et al. Characteristics of hospitalised patients with 2009 H1N1 influenza in Chile. Eur Respir J. 2010;36(4):864-9.

19. Estenssoro E, Ríos FG, Apezteguía C, Reina R, Neira J, Ceraso DH, et al. Pandemic 2009 influenza A in Argentina: a study of 337 patients on mechanical ventilation. Am J Respir Crit Care Med. 2010;182(1):41-8.

20. Xiao H, Lu SH, Ou Q, Chen YY, Huang SP. Hospitalized patients with novel influenza A (H1N1) virus infection: Shanghai, June - July 2009. Chin Med J (Engl).

2010;123(4):401-5.

21. Koegelenberg CF, Irusen EM, Cooper R, Diacon AH, Taljaard JJ, Mowlana A, et al. High mortality from respiratory failure secondary to swine-origin influenza A (H1N1) in South Africa. QJM. 2010;103(5):319-25.

22. Choi WJ, Kim WY, Kim SH, Oh BJ, Kim W, Lim KS, et al.

Clinical characteristics of pneumonia in hospitalized patients with novel influenza A (H1N1) in Korea. Scand J Infect Dis. 2010;42(4):311-4.

23. Louie JK, Acosta M, Winter K, Jean C, Gavali S, Schechter R, et al. Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California. JAMA. 2009;302(17):1896-902.

24. Rello J, Rodríguez A, Ibañez P, Socias L, Cebrian J, Marques A, et al. Intensive care adult patients with severe respiratory failure caused by Influenza A (H1N1)v in Spain. Crit Care. 2009;13(5):R148.

25. Chien YS, Su CP, Tsai HT, Huang AS, Lien CE, Hung MN, et al. Predictors and outcomes of respiratory failure among hospitalized pneumonia patients with 2009 H1N1 influenza in Taiwan. J Infect. 2010;60(2):168-74.

26. Gill JR, Sheng ZM, Ely SF, Guinee DG, Beasley MB, Suh J, et al. Pulmonary pathologic findings of fatal 2009 pandemic influenza A/H1N1 viral infections. Arch Pathol Lab Med. 2010;134(2):235-43.

27. Lai AR, Keet K, Yong CM, Diaz JV. Severe H1N1Associated acute respiratory distress syndrome: A case series. Am J Med. 2010;123(3):282-285.

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28. Cantero Caballero M, Touma Fernández A, Granda Martín MJ, Castuera Gil A, Zegarra Salas P, Cuenca Carvajal C, et al. Hospital care of patients with A/ H1N1 influenza: evaluation of the first 1000 reported cases in Spain [Article in Spanish]. Med Clin (Barc).

2010;135(1):1-7.

29. Cui W, Zhao H, Lu X, Wen Y, Zhou Y, Deng B, et al.

Factors associated with death in hospitalized pneumonia

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patients with 2009 H1N1 influenza in Shenyang, China.

BMC Infect Dis. 2010;10:145.

30. Bassetti M, Parisini A, Calzi A, Pallavicini FM, Cassola G, Artioli S, et al. Risk factors for severe complications of the novel influenza A (H1N1): analysis of patients hospitalized in Italy. Clin Microbiol Infect.

2011;17(2):247-50.

About the authors Antonello Nicolini

Physician. Division of Respiratory Diseases, General Hospital of Sestri Levante, Sestri Levante, Italy.

Simonassi Claudio

Physician. Division of Respiratory Diseases, Villa Scassi Hospital, Genoa, Italy.

Fabrizio Rao

Physician. Division of Respiratory Diseases, Villa Scassi Hospital, Genoa, Italy.

Lorenzo Ferrera

Physician. Division of Respiratory Diseases, Villa Scassi Hospital, Genoa, Italy.

Michele Isetta

Physician. Division of Respiratory Diseases, Villa Scassi Hospital, Genoa, Italy.

Monica Bonfiglio

Physician. Intensive Care Unit, Lavagna Hospital, Lavagna, Italy.

J Bras Pneumol. 2011;37(5):621-627

Original Article Restriction enzyme analysis of the hsp65 gene in clinical isolates from patients suspected of having pulmonary tuberculosis in Teresina, Brazil*, ** Análise de restrição enzimática do gene hsp65 de isolados clínicos de pacientes com suspeita de tuberculose pulmonar em Teresina, Piauí

Maria das Graças Motta e Bona, Maria José Soares Leal, Liline Maria Soares Martins, Raimundo Nonato da Silva, José Adail Fonseca de Castro, Semiramis Jamil Hadad do Monte

Abstract Objective: To identify mycobacterial species in the sputum of patients suspected of having pulmonary tuberculosis and to determine the impact that the acquisition of this knowledge has on the therapeutic approach. Methods: We evaluated 106 patients suspected of having pulmonary tuberculosis and referred to the pulmonology department of a public hospital in the city of Teresina, Brazil. Morning sputum specimens were evaluated for the presence of mycobacteria by sputum smear microscopy and culture. We used PCR and restriction enzyme analysis of the hsp65 gene (PRA-hsp65) to identify the strains of mycobacteria isolated in culture. Results: A total of 206 sputum samples were analyzed. Patient ages ranged from 15 to 87 years, and 67% were male. There was cough in 100% of the cases. The predominant radiographic pattern was moderate disease, observed in 70%. Smear positivity was 76%, and isolation in culture occurred in 91% of the cultures. Traditional tests identified nontuberculous mycobacteria (NTM) in 9% of the isolates. The PRA-hsp65 method confirmed these data, showing seven band patterns that were able to identify the isolated species of NTM: Mycobacterium kansasii; M. abscessus 1; M. abscessus 2; M. smegmatis; M. flavescens 1; M. gordonae 5; and M. gordonae 7. All of the patients with NTM were over 60 years of age, and bronchiectasis was seen in 88% of the X-rays. There were two cases of reinfection, initially attributed to M. abscessus and M. kansasii. Conclusions: In immunocompetent patients, NTM can infect the lungs. It is important to identify the specific NTM in order to establish the correct diagnosis and choose the most appropriate therapeutic regimen. The PRA-hsp65 method is useful in identifying NTM species and can be implemented in molecular biology laboratories that do not specialize in the identification of mycobacteria.

Keywords: Tuberculosis; Mycobacteria, atypical; Polymerase chain reaction; Brazil.

Resumo Objetivo: Identificar as espécies de micobactérias encontradas no escarro de pacientes com suspeita de tuberculose pulmonar e analisar o impacto dessas identificações na abordagem terapêutica. Métodos: Foram avaliados 106 pacientes com suspeita de tuberculose pulmonar encaminhados para o serviço de pneumologia de um hospital público em Teresina, Piauí. Espécimes de escarro matinal foram avaliados quanto à presença de micobactérias por baciloscopia e cultura. Foram utilizadas PCR e análise de restrição enzimática do gene hsp65 (PRA-hsp65) para a identificação das cepas de micobactérias isoladas em cultura. Resultados: Foram analisadas 206 amostras de escarro. A idade dos pacientes variou de 15 a 87 anos, sendo 67% do gênero masculino. Tosse ocorreu em 100% dos casos. O padrão radiográfico predominante foi de lesão moderada, observada em 70%. A positividade no esfregaço foi de 76%, e isolamento em cultura ocorreu em 91% das culturas executadas. Testes tradicionais identificaram micobactérias não tuberculosas (MNT) em 9% dos isolados. O método PRA-hsp65 confirmou esses dados, mostrando sete padrões de bandas capazes de identificar as espécies de MNT isoladas: Mycobacterium kansasii; M. abscessus 1; M. abscessus 2; M. smegmatis; M. flavescens 1; M. gordonae 5 e M. gordonae 7. Todos os pacientes com MNT tinham mais de 60 anos, e observaram-se bronquiectasias em 88% das radiografias. Houve dois casos de reinfecção, identificados inicialmente como infecção por M. abscessus e M. kansasii. Conclusões: As MNT causam infecção pulmonar em pacientes imunocompetentes, e a identificação das MNT é importante para estabelecer o diagnóstico correto e a decisão terapêutica mais adequada. O método PRA-hsp65 é útil para identificar espécies de MNT e pode ser implantado em laboratórios de biologia molecular não especializados em micobactérias.

Descritores: Tuberculose; Micobactérias atípicas; Reação em cadeia da polimerase; Brasil. * Study carried out at the Universidade Federal do Piauí – UFPI, Federal University of Piauí – Teresina, Brazil.

Correspondence to: Semiramis Jamil Hadad do Monte. Campus Ministro Petrônio Portela, Bloco 16, Bairro Ininga, CEP 64048-232, Teresina, PI, Brasil.

Tel. 55 86 32155691. Fax: 55 86 32155690. E-mail: libpi@ufpi.br Financial support: This study received financial support from the Federal University of Piauí Immunogenetics and Molecular Biology Laboratory.

Submitted: 6 October 2010. Accepted, after review: 29 April 2011. ** A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

J Bras Pneumol. 2011;37(5):628-635

Restriction enzyme analysis of the hsp65 gene in clinical isolates from patients suspected of having pulmonary tuberculosis in Teresina, Brazil

Introduction Tuberculosis (TB) remains one of the main public health problems in most countries. It is estimated that one third of the world population is infected with Mycobacterium tuberculosis.

Brazil ranks 14th among the 22 countries with the highest incidence of TB, at 48 cases/100,000 population in 2007.(1) The increase in the number of TB cases is mostly caused by poverty, extreme malnutrition, HIV infection, migration of infected people, inadequate control measures, inaccessibility to effective pharmacological treatment, and difficulty in monitoring the pharmacological treatment.(2) Those factors have collectively prompted the spread of drug-resistant strains, including the multidrug-resistant forms.(2) The presence of comorbidities, including HIV infection,(3) and the delay in diagnosis are important concerns and should be targets of TB control strategies in Brazil because undiagnosed cases of TB are a major source of TB transmission.(4) Since the advent of effective treatment for TB in the 1950s, the isolation of M. tuberculosis has become routine. Some of the cases initially described as TB infection were subsequently recognized as cases of infection with nontuberculous mycobacteria (NTM).

(5) Because these organisms are ubiquitous, exposure to them is universal. There is as yet no evidence of animal-to-human transmission of NTM. In humans, NTM disease is assumed to be acquired through exposure to environmental factors, although a specific source has yet to be identified.(6,7) Among immunocompetent patients, the incidence of pulmonary disease caused by NTM has been increasing worldwide.

(5,6) Prior to the AIDS pandemic, most cases of lung disease in individuals with bronchiectasis, COPD, sequelae of TB, or pneumoconiosis were attributable to species belonging to the M. avium-intracellulare complex.(8) The clinical profile and radiological features of NTM infections are often indistinguishable from those seen in pulmonary disease caused

by M. tuberculosis, making it essential that the diagnosis, be based on the identification of the species involved. Accurate diagnosis to the species level can have a direct impact on clinical management because of the different patterns of drug susceptibility. Therefore, timely, precise identification of the causative agent is

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essential to improving management and clinical outcomes.(9) Microbiology is currently the gold standard for diagnosing mycobacterial infections.

Identification of AFB in sputum smears is a simple, fast, low-cost technique; however, its sensitivity ranges from 30% to 80% depending on the isolation in culture, the local prevalence, and the methodology adopted.(10) In contrast, sputum culture is a highly sensitive and specific method, albeit laborious and time-consuming (28-60 days to obtain a result).(11) Various studies have suggested that molecular techniques are useful for the etiological diagnosis of TB. In 1993, one group of authors proposed a molecular method(12) based on PCR and restriction enzyme analysis of the hsp65 gene (PRA-hsp65), a gene found in all mycobacterial species with species-specific nucleotide sequences. An effective, widely used, and easily reproducible method that does not require viable microorganisms, PRA-hsp65 allows the identification of various species of NTM in a single reaction.(9,12-14) The accurate etiological diagnosis of mycobacterial infection at the species level is essential for the appropriate management of mycobacterial infections. Based on the hypothesis that PRA-hsp65 is able to differentiate between M. tuberculosis and NTM for clinical and therapeutic purposes, the objective of the present study was to identify the mycobacterial species isolated from the sputum of patients suspected of having pulmonary TB (PTB). We also attempted to determine the impact that the acquisition of this knowledge has on the therapeutic approach taken.

Methods Between January and June of 2007, 106 patients suspected of having PTB were referred to the pulmonology department of a public hospital in the city of Teresina, located in the state of PiauĂ­, Brazil. The inclusion criterion was being able to produce sputum spontaneously. The exclusion criteria were being under treatment with antituberculosis drugs at the time of sputum collection and having been diagnosed with extrapulmonary TB. The study project was approved by the Research Ethics Committee of the Federal University of PiauĂ­ (Protocol no. CAAE 0124.0.045.000-06), J Bras Pneumol. 2011;37(5):628-635

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Bona MGM, Leal MJS, Martins LMS, Silva RN, Castro JAF, Monte SJH

in accordance with Brazilian National Health Council Resolution 196/1996. All of the patients gave written informed consent.

After performing clinical and radiographic evaluations, we collected spontaneous morning sputum samples (two from each patient).

The samples were sent to the Maria José Leal Laboratory for Microbiological Diagnosis.

Laboratory techniques (sputum smear microscopy and culture) were standardized in accordance with the norms and guidelines described in the Guidebook for Tuberculosis Bacteriology published by the Brazilian National Ministry of Health.(15) Ziehl-Neelsen-stained smears were examined under microscopy for the semi-quantitative AFB counts and cord factor detection.(12,15) For the isolation of mycobacteria, culture was performed on Löwenstein-Jensen medium.(15) When two cultures were positive, the one with the most abundant growth of mycobacterial strains was selected for macroscopic, microscopic, and biochemical analyses, as well as for genotyping. Phenotyping of strains, for presumptive identification, included macroscopic screening (colony morphology and pigmentation), microscopic analysis (cord factor detection and identification of contaminating microorganisms), and biochemical analysis, the last performed with an M. tuberculosis identification kit (MTBAC; Probac do Brasil Produtos Bacteriológicos Ltda., São Paulo, Brazil). Strains with pigmented or smooth, fastgrowing, nonphotochromogenic colonies that showed no cord factor under microscopy were presumptively classified as NTM. Genotyping was performed by PRA-hsp65, as previously described,(12) in the Molecular Biology and Immunogenetics Laboratory of the Federal University of Piauí.

Samples were prepared as follows: a loop of mycobacteria grown on Löwenstein-Jensen medium was suspended in 1 mL of Tris-EDTA buffer (10 mM Tris and 1 mM EDTA; pH = 8) and was heat-inactivated for 10 min at 80°C. After inactivation, the bacteria were centrifuged for 15 min. The pellet was resuspended in 100 µL of Tris-EDTA and transferred to a tube containing glass beads (Precellys®24; Bertin Technologies, Montigny-le-Bretonneux, France).

The suspended cells were mechanically disintegrated for 2 min in a Precellys®24 apparatus (Bertin Technologies). After a 10-min centrifugation J Bras Pneumol. 2011;37(5):628-635

step, the supernatant was transferred to a new tube. All centrifugation steps were carried out at 13,000 rpm in microcentrifuge tubes (Eppendorf, Hamburg, Germany).

A total of 5 µL of lysate were added to each reaction tube. The composition of the PCR mixture (50 µL) was 50 mM KCl, 10mM Tris-HCl (pH = 8.3), 1.5 mM MgCl2, 10% glycerol, 200 mM (each) deoxynucleoside triphosphate, 0.5 µM (each) primer, and 1.25 U of Taq polymerase (HotStarTaq Plus DNA Polymerase; QIAGEN, Düsseldorf, Germany). The reaction was subjected to 45 cycles of amplification (1 min at 94°C, 1 min at 60°C, and 1 min at 72°C); this was followed by 10 min of extension at 72°C. The primers Tb11 (5’-ACCAACGATGGTGTGTCCAT) and Tb12 (5’-CTTGTCGAACCGCATACCCT) amplified a 439-bp fragment between nucleotide positions 398 and 836 of the published gene sequence.(16) Restriction analysis was performed using 15 µL of PCR products digested separately with 5 U of the restriction enzymes BstEII and HaeIII, in accordance with the manufacturer instructions (Promega Corporation, Madison, WI, USA). BstEII was digested by incubation at 60°C for 1.5 h, and HaeIII was digested by incubation at 37°C for 1.5 h.

Digestion products were mixed with 4 µL of gel loading buffer (0.25% bromophenol blue and 40% sucrose in water) and loaded onto gels prepared with 4% agarose in Trisborate-EDTA buffer (89 mM Tris, 89 mM boric acid, and 2 mM EDTA; pH = 8.0). DNA size markers (50- and 25-bp DNA ladders) were applied in three lanes (two 50-bp lanes at the extremities of the gel and one 25-bp lane in the center). After electrophoresis, the gels were stained with ethidium bromide, visualized on a UV transilluminator, and photographed. The PRA-hsp65 patterns were interpreted with the aid of previously published tables.(17) Negative and positive controls—water and M. tuberculosis H37Rv DNA (ATCC 27294; American Type Culture Collection, Manassas, VA, USA), respectively—were included in each experiment.

The medical charts of the patients were reviewed in order to obtain information regarding previous diagnoses of TB, positive AFB results, and previous isolations of M. tuberculosis, NTM, or both.

Restriction enzyme analysis of the hsp65 gene in clinical isolates from patients suspected of having pulmonary tuberculosis in Teresina, Brazil

For data analysis, we compared the fragments obtained after enzyme treatment of amplicons with the restriction patterns stored in a PRA electronic database,(17) as well as with the HaeIII and BstEII patterns, thus creating an algorithm for differentiating among NTM strains at the species level. After obtaining the clinical, radiographic, microbiological, and molecular results, we analyzed the data using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA).

Results Of the 106 patients evaluated, 3 were excluded: 2 because the sputum samples were insufficient for analysis and 1 because of culture contamination. Of the 103 remaining patients, 94 were diagnosed with PTB on the basis of isolation of M. tuberculosis from sputum samples. Strains of NTM were isolated from the sputum samples of the remaining 9 patients.

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Only 2 patients were classified as cases of reinfection. The mean age was 46.8 years (range, 15-87 years), and males predominated (67%).

The two most common symptoms were cough and purulent sputum. Table 1 shows the clinical, radiographic, and microbiological features of the patients.

The biochemical tests employed proved capable of identifying M. tuberculosis and NTM. Mean age was significantly higher among the patients in whom NTM were identified than among those in whom M. tuberculosis was identified (64.1 vs. 46.8 years; p < 0.05). There were no significant differences between the patients with M. tuberculosis and those with NTM regarding clinical symptoms or gender.

However, all of the patients who presented with NTM also presented with radiological findings of bronchiectasis, AFB-positive smear, and isolation in culture. Of the isolates submitted to PRA-hsp65, 91.0% showed a BstEII or HaeIII

Table 1 - Clinical, radiographic, and microbiological features of patients who were clinically suspected of having pulmonary infection with Mycobacterium tuberculosis or nontuberculous mycobacteria and were treated at a pulmonology referral center in Teresina, Brazil, from January to June of 2007.

Variables Mycobacterium tuberculosis Nontuberculous mycobacteria (%) (%) Demographic characteristics Gender Male 64 (62.13) 5 (4.85) Female 30 (29.12) 4 (3.88) Age, years < 25 22 (23.4) 25-50 42 (44.7) > 50 30 (31.9) 9 (100) Clinical symptoms Cough 94 (100) 9 (100) Weight loss 66 (70.21) 4 (44.4) Purulent sputum 85 (90.42) 9 (100) Evening fever 74 (78.72) 6 (66.6) Malaise 55 (58.51) 5 (55.5) Dyspnea 55 (58.51) 4 (44.4) Chest pain 55 (58.51) 3 (33.3) Night sweats 46 (48.93) 2 (22.2) Radiographic features Disease Minimal 25 (26.59) 8 (88.89) Moderate 66 (70.21) 1 (11.11) Severe 3 (3.20) Microbiological features Smear results Positive 157(76) 18 (100) Negative 46 (22) Isolation in culture Positive 188 (91) 18 (100) Negative 2 (1) -

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pattern for M. tuberculosis. The PRA-hsp65 identified seven NTM strains: M. kansasii; M. abscessus 1; M. abscessus 2; M. smegmatis; M. flavescens 1; M. gordonae 5; and M. gordonae 7.(17) The band patterns are shown in Table 2. As in the cases of primary infection, M. abscessus 1 and M. kansasii were identified in the sputum samples from the 2 patients with reinfection. All of the NTM strains identified by PRA-hsp65 were also identified as NTM by the p-nitrobenzoic acid test and the thiophene-2-carboxylic acid hydrazide test.

The standard treatment regimen (the rifampin-isoniazid-pyrazinamide combination) failed in 2 of the 103 patients under study.

Those 2 patients had previously experienced treatment failure with ethionamide, pyrazinamide, ethambutol, and streptomycin.

M. kansasii and M. abscessus 1 were isolated from the sputum samples collected from those patients. In addition, both species had been isolated from earlier sputum samples from those patients, supporting the diagnosis. The patient in whom M. kansasii was isolated in culture was treated with clarithromycin (500 mg p.o. every 12 h) and ethambutol for 12 months.

Follow-up evaluation showed complete clinical remission. The patient became asymptomatic 1 year after treatment initiation and remained so after clarithromycin discontinuation. The patient in whom M. abscessus 1 was isolated showed no clinical response to any of the various therapeutic regimens that were initiated on the basis of susceptibility test results. The patient remained symptomatic until death, which occurred 5 years after the diagnosis of pulmonary disease caused by NTM. M. abscessus 2 was isolated from 1 patient.

Although the patient was not hospitalized, empirical treatment with the rifampin-isoniazidpyrazinamide combination was administered for 2 months while we awaited the results of the molecular identification. Because the patient remained symptomatic, the rifampin-isoniazidpyrazinamide combination was replaced by clarithromycin (500 mg/12 h for 18 months) and amikacin (15 mg • kg−1 • day−1 administered intravenously every 12 h for 15 days), followed by the same doses of clarithromycin and amikacin administered on Mondays, Wednesdays, and Fridays for 2 months. After 18 months, the patient was asymptomatic and the culture results were negative. Therefore, the treatment was discontinued. Because of socioeconomic factors, the remaining 7 patients suspected of having TB were hospitalized and treated with the rifampinisoniazid-pyrazinamide combination while we awaited the results of the sputum culture.

Those patients also remained symptomatic.

The results of molecular identification by the PRA-hsp65 method were as follows: M. gordonae, in 3 patients; M. flavescens, in 1; M. smegmatis, in 1; M. kansasii, in 1; and M. abscessus 2, in 1. Because of operational problems, it was impossible to carry out a sensitivity test; nevertheless, the therapeutic regimen was changed. For the 3 patients in whom M. gordonae was isolated in culture, the antibiotic regimen was changed to clarithromycin (500 mg/12 h). In the first month, the patients showed significant clinical improvement. Culture results were negative by the sixth month. The treatment lasted 12 months, after which the patients were completely asymptomatic. The patient in whom M. flavescens was isolated in culture showed no improvement during the first

Table 2 - Molecular identification, by PCR and restriction enzyme analysis of the hsp65 gene, of species of mycobacteria isolated in culture of clinical samples collected from patients with pulmonary tuberculosis treated at a pulmonology referral center in Teresina, Brazil, from January to June of 2007.

Mycobacterial (n/N) Band profiles species BstEII HaeIII Mycobacterium tuberculosis (94/103) 235-115-85 150-125-70 M. kansasii 1 (2/103) 235-210 130-105-80 M. abscessus 1 (1/103) 235-210 145-70-60-55 M. abscessus 2 (1/103) 235-210 200-70-60-50 M. smegmatis (1/103) 235-130/85 145-125-60 M. flavescens 1 (1/103) 440 140-60-55 M. gordonae 5 (1/103) 235-210 125-110 M. gordonae 7 (2/103) 235-115-100 155-110-60

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Restriction enzyme analysis of the hsp65 gene in clinical isolates from patients suspected of having pulmonary tuberculosis in Teresina, Brazil

2 months of therapy. When PRA-hsp65 revealed the presence of M. flavescens, the standard therapy was discontinued, and clarithromycin (500 mg p.o. every 12 h) was administered for 1 year. The patient achieved complete clinical remission within 1 month after treatment initiation and remained asymptomatic after the discontinuation of clarithromycin. The patients in whom M. smegmatis and M. kansasii were isolated in culture were treated with clarithromycin (500Â mg p.o. every 12Â h) and ethambutol (1,000 mg/day p.o.) for 12Â months. All 7 patients achieved complete clinical remission within 1 year after treatment initiation. We can therefore affirm that all of the patients were infected, rather than colonized, given that they satisfactorily responded to the changes in the therapeutic regimen.

Discussion In the present study, NTM accounted for 9% of the isolates, M. gordonae and M. kansasii being the most common strains. The maximum time elapsed between isolation in culture and species identification by PRA-hsp65 was 24 h, which is impossible when growth and chemical tests are used. The time required for those tests to provide definitive species identification ranges from several weeks to as long as 2 months, given that several of those tests require macroscopic growth of colonies in culture in order to be read.(9-11,13-15) In order to discriminate between M. tuberculosis complex and NTM, we used the conventional methods (i.e., the p-nitrobenzoic acid test and the thiophene-2-carboxylic acid hydrazide test). The time required in order to obtain the results was 4 weeks.

Studies have identified new species of NTM, and more than 140 species are currently known, the identification of species by conventional techniques being therefore an arduous, timeconsuming task that requires several laboratory tests and highly qualified human resources.(9,13) Although PRA-hsp65 and classical methods consume the same amount of time in their initial steps, PRA-hsp65 has a major advantage over classical methods in later steps. In fact, PRA-hsp65 can identify mycobacteria as early as 24 h after isolation in culture. In contrast, the time required for classical methods to identify mycobacteria after isolation in culture can be as long as 60 days.(9,10,12)

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The actual prevalence of NTM in Brazil has yet to be determined.(18-20) It is known that NTM can be isolated from environmental sources, can colonize the mucosal surfaces of immunocompetent individuals, and can cause infection.(20) Consequently, isolating NTM only once might not indicate infection. Therefore, it is mandatory to use criteria in order to differentiate between colonization and infection.(21) A substantial increase in the occurrence of NTM as etiological agents of both pulmonary and cutaneous infections is expected, mainly among elderly individuals with COPD(7,22) and cross infection. Studies have shown that NTM not only colonize but also pervade tissues, eventually causing infection.(23-25) However, it is not easy to make this differentiation. The criteria for making this distinction have been standardized by the American Thoracic Society.

(7,26)

In our study, species that had previously been identified in the same patients (M. abscessus 1 and M. kansasii) were identified in only 2 cases, which were therefore characterized as cases of reinfection. It is of note that those patients were female, had not undergone any endoscopic procedure, and presented with bronchiectasis.

Good epidemiological control requires rapid and precise identification of the etiological agent. Therefore, in order to complement the conventional methods, it is crucial to develop new biochemical strategies for the identification of mycobacteria. In this context, PRA-hsp65 is an attractive option because it is fast, accurate, and reproducible. In addition, it can be performed in laboratories set up for microbiology and molecular biology. These features hasten test results and allow better management. Therefore, PRA-hsp65 can be a valuable addition to the array of diagnostic tests for mycobacterial infections. In this scenario, the incorporation of a molecular biology method to be performed in clinical diagnostic laboratories becomes increasingly relevant. The choice of therapeutic regimen for the treatment of TB should not be based exclusively on AFB smear results, because TB treatment is long and requires microorganism eradication in order to avoid the development and dissemination of multidrug-resistant forms deriving from an inappropriate initial treatment.

In Brazil and other developing countries, in which the incidence of TB is higher, it is common J Bras Pneumol. 2011;37(5):628-635

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practice to start patients on antituberculosis drugs before the identification of mycobacteria, particularly in cases of positive sputum smear.

However, physicians should be alert to the possibility that there might be no clinical response, given that NTM are common, as shown in the present study. The correct identification of NTM species is crucial, because other, specific antimicrobials will have to be chosen on the basis of identification and susceptibility test results.(19,27) In this context, PRA-hsp65 is the most appropriate method because it can identify the NTM species within 24 h after their isolation in culture. In contrast, the time required for the conventional method of identifying the NTM species (which is based on growth and chemical properties) is over 30 days. Because PRA-hsp65 yields results more rapidly, the appropriate therapeutic regimen can be started more rapidly.

In conclusion, the present study showed that the implementation of PRA-hsp65 for the identification of mycobacteria in a nonspecialized molecular biology laboratory is feasible.

Although it is recognized that PRA-hsp65 should not be considered a replacement for other tests that are used in order to diagnose TB, PRA-hsp65 constitutes an additional diagnostic tool to investigate the etiology of the disease, especially in individuals with no clinical response to antituberculosis drugs. The method can contribute to a faster identification of mycobacteria in public laboratories, thus optimizing management.

Acknowledgments We would like to thank the patients, the Brazilian National Pulmonology Health Care Council; and the Getúlio Vargas Hospital. We are also grateful to Miguel Pires de Moura for allowing us to conduct the study at the institution; Dr. Karla Valéria Batista Lima for her assistance in implementing the PRA-hsp65 method; Dr. Maria José Soares Leal for allowing us to execute the microbiological methods for isolation and identification of mycobacteria in her laboratory; and the Federal University of Piauí for approving the implementation of the PRA-hsp65 method in the Immunogenetics and Molecular Biology Laboratory.

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References 1. World Health Organization. Global Tuberculosis Control: Epidemiology, Strategy, Financing: WHO Report 2009.

Geneva: World Health Organization; 2009.

2. Maher D, Raviglione M. Global epidemiology of tuberculosis. Clin Chest Med. 2005;26(2):167-82, v.

3. Rao VK, Iademarco EP, Fraser VJ, Kollef MH. The impact of comorbidity on mortality following in-hospital diagnosis of tuberculosis. Chest. 1998;114(5):1244-52.

4. Belo MT, Luiz RR, Hanson C, Selig L, Teixeira EG, Chalfoun T, et al. Tuberculosis and gender in a priority city in the state of Rio de Janeiro, Brazil. J Bras Pneumol.

2010;36(5):621-5.

5. Runyon EH. Anonymous mycobacteria in pulmonary disease. Med Clin North Am. 1959;43(1):273-90.

6. Falkinham JO 3rd. Nontuberculous mycobacteria in the environment. Clin Chest Med. 2002;23(3):529-51.

7. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175(4):367-416. Erratum in: Am J Respir Crit Care Med. 2007;175(7):744-5.

8. Hadad DJ, Palhares MC, Placco AL, Domingues CS, Castelo Filho A, Ferrazoli L, et al. Mycobacterium avium complex (MAC) isolated from AIDS patients and the criteria required for its implication in disease. Rev Inst Med Trop Sao Paulo. 1995;37(5):375-83.

9. Tortoli E. Impact of genotypic studies on mycobacterial taxonomy: the new mycobacteria of the 1990s. Clin Microbiol Rev. 2003;16(2):319-54.

10. Sommers HM, McClatchy JK. Laboratory Diagnosis of the Mycobacterioses. Washington, D.C.: American Society for Microbiology, 1983.

11. Kent PT, Kubica GP. 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.

12. Telenti A, Marchesi F, Balz M, Bally F, Böttger EC, Bodmer T. Rapid identification of mycobacteria to the species level by polymerase chain reaction and restriction enzyme analysis. J Clin Microbiol. 1993;31(2):175-8.

13. Leão SC, Bernardelli A, Cataldi A, Zumarraga M, Robledo J, Realpe T, et al. Multicenter evaluation of mycobacteria identification by PCR restriction enzyme analysis in laboratories from Latin America and the Caribbean. J Microbiol Methods. 2005;61(2):193-9.

14. Devallois A, Goh KS, Rastogi N. Rapid identification of mycobacteria to species level by PCR-restriction fragment length polymorphism analysis of the hsp65 gene and proposition of an algorithm to differentiate 34 mycobacterial species. J Clin Microbiol.

1997;35(11):2969-73.

15. Brasil. Ministério da Saúde. Centro de Vigilância em Saúde. Centro de Referência Prof. Hélio Fraga. Manual de Bacteriologia da Tuberculose. Rio de Janeiro: Ministério da Saúde, Centro de Vigilância em Saúde, Centro de Referência Prof. Hélio Fraga, Departamento de Vigilância Epidemiológica, Coordenação Geral de Laboratórios de Saúde Pública; 2005.

16. Shinnick TM. The 65-kilodalton antigen of Mycobacterium tuberculosis.

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17. Prasite [homepage on the Internet]. Lausanne: Hospices Cantonaux; c1999 [updated 2007 Sep 15; cited 2010 Aug 12]. Available from: http://app.chuv.ch/prasite/ index.html.

18. Matos ED, Santana MA, de Santana MC, Mamede P, de Lira Bezerra B, Panão ED, et al. Nontuberculosis mycobacteria at a multiresistant tuberculosis reference center in Bahia: clinical epidemiological aspects. Braz J Infect Dis. 2004;8(4):296-304.

19. Pedro HS, Pereira MI, Goloni MR, Ueki SY, Chimara E. Nontuberculous mycobacteria isolated in São José do Rio Preto, Brazil between 1996 and 2005. J Bras Pneumol. 2008; 34(11):950-5.

20. Zamarioli LA, Coelho AG, Pereira CM, Nascimento AC, Ueki SY, Chimara E. Descriptive study of the frequency of nontuberculous mycobacteria in the Baixada Santista region of the state of São Paulo, Brazil. J Bras Pneumol.

2008;34(8):590-4.

21. Centro de Vigilância Epidemiológica “Alexandre Vranjac” [homepage on the Internet]. São Paulo: Secretaria da Saúde do Estado de São Paulo. [cited 2006 Jul 15].

Micobacterioses: recomendações para o diagnóstico e tratamento. [Adobe Acrobat document, 29p.] Available

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from: ftp://ftp.cve.saude.sp.gov.br/doc_tec/tb/MNT_ Final_9-12-05a.pdf 22. Guide SV, Holland SM. Host susceptibility factors in mycobacterial infection. Genetics and body morphotype.

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23. Tanaka E, Amitani R, Niimi A, Suzuki K, Murayama T, Kuze F. Yield of computed tomography and bronchoscopy for the diagnosis of Mycobacterium avium complex pulmonary disease. Am J Respir Crit Care Med. 1997;155(6):2041-6.

24. Moore EH. Atypical mycobacterial infection in the lung: CT appearance. Radiology. 1993;187(3):777-82.

25. Jeong YJ, Lee KS, Koh WJ, Han J, Kim TS, Kwon OJ. Nontuberculous mycobacterial pulmonary infection in immunocompetent patients: comparison of thinsection CT and histopathologic findings. Radiology.

2004;231(3):880-6.

26. Ueki SY, Martins MC, Telles MA, Virgilio MC, Giampaglia CM, Chimara E, et al. Micobactérias não-tuberculosas: diversidade das espécies no estado de São Paulo. J Bras Patol Med Lab. 2005;41(1):1-8.

27. Koh WJ, Kwon OJ, Lee KS. Nontuberculous mycobacterial pulmonary diseases in immunocompetent patients.

Korean J Radiol. 2002;3(3):145-57.

About the authors Maria das Graças Motta e Bona

Adjunct Professor. Universidade Federal do Piauí – UFPI, Federal University of Piauí – Teresina, Brazil.

Maria José Soares Leal

Professor. Universidade Federal do Piauí – UFPI, Federal University of Piauí – Teresina, Brazil.

Liline Maria Soares Martins

Assistant Professor. Universidade Estadual do Piauí – UESPI, Piauí State University – Teresina, Brazil.

Raimundo Nonato da Silva

Molecular Biologist. Immunogenetics and Molecular Biology Laboratory, Universidade Federal do Piauí – UFPI, Federal University of Piauí – Teresina, Brazil.

José Adail Fonseca de Castro

Researcher, Immunogenetics and Molecular Biology Laboratory, Universidade Federal do Piauí – UFPI, Federal University of Piauí – and Adjunct Professor II, Universidade Estadual do Piauí – UESPI, Piauí State University – Teresina, Brazil.

Semiramis Jamil Hadad do Monte

Associate Professor III. Universidade Federal do Piauí – UFPI, Federal University of Piauí – Teresina, Brazil.

J Bras Pneumol. 2011;37(5):628-635

Original Article Active tuberculosis among health care workers in Portugal*, ** Tuberculose ativa entre profissionais de saúde em Portugal

José Castela Torres da Costa, Rui Silva, José Ferreira, Albert Nienhaus

Abstract Objective: To determine the incidence of active tuberculosis (TB) in a cohort of health care workers (HCWs).

Methods: Descriptive study of active TB cases identified in an occupational health screening of 6,112 HCWs between 2005 and 2010. Cases of active TB were defined as those in which Mycobacterium tuberculosis was identified by direct microscopy or culture; those in which there were symptoms or clinical signs of TB and necrotizing granuloma, as detected by histology; and those in which the radiological findings were consistent with active TB. Results: Among the 6,112 HCWs evaluated, we identified 62 cases of active TB: pulmonary TB (n = 43); pleural TB (n = 15); lymph node TB (n = 2); pericardial TB (n = 1); and cutaneous TB (n = 1). Seven HCWs were asymptomatic at the time of diagnosis. Of the 62 cases of active TB, 48 developed within the first 10 years of occupational exposure in the workplace, 36 of those occurring within the first 5 years. Physicians and nurses accounted for the highest numbers of cases (22 and 21, respectively). Conclusions: In HCWs employed in Portugal, the TB burden is high. Physicians and nurses are the HCWs who are at the highest risk of developing active TB. We found the risk of developing this disease to be highest in the first years of exposure, as has been reported in previous studies. In high-incidence countries, TB screening of HCWs is important for controlling the transmission of this disease.

Keywords: Tuberculosis/diagnosis; Occupational health; Health personnel.

Resumo Objetivo: Determinar a incidência de tuberculose (TB) ativa em uma coorte de profissionais de saúde (PS).

Métodos: Estudo descritivo dos casos de TB ativa identificados entre 2005 e 2010 no rastreio de medicina do trabalho efetuado em 6.112 PS. Casos de TB ativa foram definidos como aqueles com identificação de Mycobacterium tuberculosis por microscopia direta ou cultura; aqueles com sintomas ou sinais clínicos de TB e granuloma necrotizante, detectado por histologia; e aqueles com achados radiológicos consistentes com TB ativa.

Resultados: Dos 6.112 PS avaliados, houve 62 casos de TB ativa (TB pulmonar, em 43; TB pleural, em 15; TB ganglionar, em 2; TB do pericárdio, em 1; TB cutânea, em 1). Sete PS estavam assintomáticos no momento do diagnóstico. Dos 62 casos de TB ativa, a doença ocorreu nos primeiros 10 anos de exposição ocupacional em 48 e nos primeiros 5 anos em 36. A maioria dos casos verificou-se em médicos e enfermeiros (22 e 21, respectivamente).

Conclusões: O impacto da TB em PS em Portugal é elevado. Os médicos e enfermeiros são os PS com o maior risco de desenvolver TB ativa. Tal como relatado em estudos prévios, parece haver um risco mais elevado de desenvolver essa doença nos primeiros anos de exposição. Em países de elevada incidência, o rastreio de TB nos PS é importante no controle da transmissão dessa doença.

Descritores: Tuberculose/diagnóstico; Saúde do trabalhador; Pessoal de saúde.

* Study carried out at the São João Hospital, Porto, Portugal.

Correspondence to: José Castela Torres da Costa. Estrada de Santa Luzia, 269, 4900-408, Viana do Castelo, Portugal.

Tel. 351 22 551-2100. E-mail: zecatoco@sapo.pt Financial support: None.

Submitted: 14 February 2011. Accepted, after review: 26 April 2011. ** A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

J Bras Pneumol. 2011;37(5):636-645

Active tuberculosis among health care workers in Portugal

Introduction According to the World Health Organization (WHO), the year 2008 brought 9.4 million new cases of tuberculosis (TB) and 1.8 million TB-related deaths, approximately 500,000 of which were in patients infected with HIV. It is estimated that multidrug-resistant TB cases accounted for another 500,000 cases. The number of affected individuals has led the WHO to categorize the disease as a global emergency.

(1) In Portugal, the incidence of TB was 24 new cases/100,000 population in 2009.(2) Despite a reduction observed in recent years, Portugal still has one of the highest TB incidence rates among European Union countries.(2) Health care workers (HCWs) are at an increased risk of infection with Mycobacterium tuberculosis because they are exposed to patients with active disease in settings that favor transmission, especially when working in inadequately ventilated spaces and when performing procedures involving contaminated aerosols.(3-5) Given this increased risk of contracting the disease in the workplace, TB is considered an occupational disease in Portugal.

(6) In any given geographic area, the incidence of TB in HCWs is related to the incidence in the general population of that area,(7) added to the profession-specific risk.(8-10) In Portugal, despite the mandatory reporting of active TB cases, there are no official records of the numbers of affected HCWs. The goal of this study was to determine the incidence of active TB cases among HCWs at a general hospital in Portugal.

Methods In this descriptive study, the occupational risk of M. tuberculosis infection was assessed in 6,112 HCWs (Table 1), all of whom were working or training at the São João Hospital, located in the city of Porto, Portugal, between 2005 and 2010. On the basis of the 2005 Centers for Disease Control and Prevention (CDC) guidelines and taking into consideration the number of beds, together with the mean annual number of patients diagnosed with TB (258 patients, with an HCW to TB patient ratio of 17.2 to 1), the TB risk at the facility has been classified as “moderate”.(10) The HCWs were examined at hiring and thereafter on a regular annual basis.

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Occasional examinations were performed in symptomatic HCWs and in cases of ongoing TB contact. Using a questionnaire, we collected data related to age, gender, work sector, length of employment as an HCW, BCG vaccination status, symptoms, and history of TB. For each HCW, the risk of TB transmission was classified on the basis of the CDC classification,(10) as follows: low—for HCWs who will never be exposed to persons with known or suspected TB or to clinical specimens that might contain M. tuberculosis; moderate—for HCWs who might be exposed to persons with TB or to clinical specimens that might contain M. tuberculosis; or high/ongoing—for HCWs working in a sector in which there is a risk of person-to-person transmission of M. tuberculosis or evidence of such transmission (among patients or HCWs) within the last year.

The data analyzed in this study were collected as part of a screening program aimed at identifying HCWs with latent TB infection (LTBI) or active TB. The screening consisted of the following: evaluation of respiratory symptoms (cough, sputum, hemoptysis, and chest pain) and constitutional symptoms (fatigue, anorexia, fever, and hyperhidrosis); chest X-ray at hiring, in the presence of symptoms, and in HCWs meeting the criteria for LTBI; and tuberculin skin test (TST) with 2 tuberculin units of PPD in 0.1 mL (RT23; Statens Serum Institut, Copenhagen, Denmark), unless contraindicated (previous TST induration ≥ 10 mm, previous diagnosis of TB with appropriate treatment, severe viral infection/immunization with a livevirus vaccine within the past month, extensive burns, or eczema). Since 2007, in vitro ELISA, based on IFN-gamma (IFN-γ) release assay (IGRA, QuantiFERON-TB Gold In-tube; Cellestis, Carnegie, Australia), has been performed simultaneously with TSTs. Individuals with a TST induration ≥ 10 mm and an IFN-γ response ≥ 0.35 IU/mL were considered positive for infection. Those in whom M. tuberculosis was identified by direct microscopy or by culture (on Löwenstein-Jensen medium) were classified as having active TB, as were those with symptoms or clinical signs of TB and presenting with necrotizing granuloma detected by histology. A diagnosis of active TB was also made in cases of radiological abnormalities consistent with the disease in the pleura or lung J Bras Pneumol. 2011;37(5):636-645

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Table 1 - Characteristics of health care workers screened for tuberculosis, São João Hospital, Porto, Portugal, 2005-2010.

Characteristic n = 6,112 Gender, n (%) Male 1,669 (27.3) Female 4,443 (72.7) Job description, n (%) Aide 905 (14.8) Administrative Assistant 373 (6.1) Nurse 2,045 (33.5) Physicians 1,714 (28.0) Technician 513 (8.4) Other 562 (9.2) Length of employment, n (%) 0-5 years 2,364 (38.7) 6-10 years 1,003 (16.4) 11-15 years 776 (12.7) ≥ 16 years 1,969 (32.2) Ratio of HCWs to TB inpatientsa 17.2:1 BCG vaccination, n (%) Yes 3,721 (60.9) No 2,391 (39.1) > 3 times 436 (7.1) Symptomatic, n (%) 207 (3.4) Alterations on chest X-rays, n (%) 108 (3.3%)b HCW: health care worker. aMean annual number of TB inpatients, 258. bChest X-rays performed in only 3,276 of the 6,112 HCWs.

parenchyma (apical fibrosis). We defined LTBI as infection with M. tuberculosis, without any clinical manifestation, and presenting with a TST induration ≥ 10 mm or an IFN-γ response ≥ 0.35 IU/mL, assuming that active TB had been ruled out. All HCWs diagnosed with active TB were also screened for HIV-1 and -2 antibodies

by ELISA. Cases of LTBI and suspected cases of active TB were referred to the pulmonology department of our hospital.

The screening program was conducted in accordance with the objectives of the São João Hospital Commission for the Prevention and Control of Tuberculosis. The anonymity of the participating HCWs was guaranteed.

Results Infection with M. tuberculosis was evaluated in 6,112 HCWs (4,443 females and 1,669 males) who were working or training at São João Hospital between 2005 and 2010. Using the CDC criteria,(10) we determined that, in the J Bras Pneumol. 2011;37(5):636-645

most recent evaluation, the risk of exposure to TB was low in 687 (11.2%) of the HCWs evaluated, whereas it was moderate in 4,008 (65.6%) and high/ongoing in 1,417 (23.2%).

The mean age was 38 ± 11 years, and the mean length of employment was 12 ± 11 years. Of the 6,112 HCWs evaluated, 3,721 (60.9%) had been vaccinated with BCG, as confirmed by their vaccination record or by the presence of a vaccination scar (Table 1). On the symptoms portion of the questionnaire, 207 (3.4%) of the HCWs reported respiratory or general symptoms.

Of the 3,276 chest X-rays taken, 108 (3.3%) revealed abnormalities (Table 1).

Over the course of the study period, there were a total of 62 cases of active TB (Table 2), the incidence peaking in the years 2005 to 2007 (Figure 1). Among those 62 cases, there were 43 cases of pulmonary TB (multidrug-resistant in 2), 15 cases of pleural TB, 2 cases of TB in the cervical lymph nodes, 1 case of pericardial TB, and 1 case of cutaneous TB. Among those with pulmonary involvement, M. tuberculosis was identified by direct microscopy or culture in 34. Seven HCWs were asymptomatic at the time of diagnosis (made on the basis of a positive culture in 4 and on the basis of highly suggestive radiological images in 3). In all 62 HCWs diagnosed with active TB, the serology was negative for HIV-1 and -2. Of the 62 cases of active TB evaluated in the present study, 48 (77%) developed within the first 10 years of occupational exposure in the workplace, 36 (58%) occurring within the first 5 years (Figure 2).

The distribution of the 62 HCWs with active TB by work sector, stratified by the level of risk, was as follows: 4 (6.5%) worked in low-risk sectors; 40 (64.5%) worked in moderate-risk sectors; and 18 (29.0%) worked in high-risk sectors. Similarly, the distribution by professional group was as follows: 22 (35.5%) were physicians; 21 (33.9%) were nurses; 9 (14.5%) were aides; 5 (8.1%) were technicians; and 5 (8.1%) held other positions.

Among the cases of active TB, the results of the TST and IGRA performed at the time of diagnosis were available in 53 and 28 cases, respectively, and were positive in 50 and 26.

These data are reported in greater detail in Table 3. Of the 2 cases in which the IGRA results were negative at the time of diagnosis, one

IFN-γ (IU/mL) nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd

TST (mm) 20 (p) 13 (p) nd 0 (n) nd 20 (p) nd 16 (p) 20 (p) 19 (p) 12 (p) nd 16 (p) 15 (p) nd 12 (p) 18 (p) 18 (p) nd nd 18 (p) 17 (p) 20 (p) nd 16 (p) 14 (p) 15 (p) 18 (p) 18 (p) 19 (p) 16 (p)

HCW: health care worker; TST: tuberculin skin test; nd: no data; (p): positive; (n): negative; PP: Pleuro-pulmonary; PM: Pulmonary-mediastinal; MDR-P: Multidrug-resistant pulmonary; and Ad. Assist.: Administrative Assistant. aIdentified by direct microscopy or culture. bNo data at this writing; presumably normal at diagnosis (in 2005). cNo data at the time of diagnosis; 0.14 IU/ mL one month after beginning TB treatment.

Table 2 - Description of active tuberculosis cases among health care workers, São João Hospital, Porto, Portugal, 2005-2010.

Case Sex Age Position Risk in Year Years Presentation Symptoms Chest Mycobacterium sector of as an at X-ray tuberculosisa diagnosis HCW diagnosis 1 F 23 Nurse Moderate 2005 1 Pulmonary Yes Abnormal Positive 2 F 32 Physician Moderate 2005 4 Pleural Yes Abnormal Negative 3 F 22 Nurse High 2005 <1 Pulmonary Yes Abnormal Negative 4 F 48 Nurse High 2005 10 Pulmonary Yes Abnormal Positive 5 M 26 Physician Moderate 2005 1 Pleural Yes Abnormal Negative 6 F 53 Nurse Moderate 2005 32 Pleural Yes Abnormal Negative 7 F 61 Aide Moderate 2005 18 Pulmonary Yes Abnormal Positive 8 F 29 Physician Moderate 2005 2 Pulmonary Yes Abnormal Positive 9 F 36 Technician Moderate 2005 10 Pulmonary Yes Abnormal Positive 10 M 43 Aide Moderate 2005 17 Pulmonary Yes Abnormal Positive 11 F 26 Nurse Moderate 2005 3 Pleural Yes Abnormal Negative 12 F 51 Aide High 2005 7 Lymph node Yes ndb Negative 13 F 28 Nurse High 2005 3 Pleural Yes Abnormal Negative 14 F 31 Nurse Moderate 2005 8 Pulmonary Yes Abnormal Positive 15 M 50 Other Low 2005 22 PP Yes Abnormal Positive 16 F 27 Nurse Moderate 2005 5 Pleural Yes Abnormal Negative 17 F 28 Nurse Moderate 2005 5 PM Yes Abnormal Positive 18 F 40 Nurse Moderate 2005 16 Pulmonary No Abnormal Positive 19 F 29 Physician High 2005 4 Pleural Yes Abnormal Negative 20 M 26 Physician Moderate 2006 2 Pleural Yes Abnormal Negative 21 F 23 Nurse Moderate 2006 1 MDR-P No Abnormal Positive 22 F 35 Other Moderate 2006 4 Pleural Yes Abnormal Positive 23 F 32 Physician High 2006 2 PP Yes Abnormal Negative 24 F 37 Physician High 2006 3 MDR-P Yes Abnormal Positive 25 F 56 Nurse High 2006 32 Pulmonary Yes Abnormal Positive 26 F 38 Aide High 2006 14 Pulmonary Yes Abnormal Negative 27 F 33 Nurse Moderate 2006 11 Pulmonary Yes Abnormal Negative 28 F 36 Physician High 2006 2 Pulmonary Yes Normal Positive 29 F 38 Aide High 2006 8 Pulmonary Yes Abnormal Positive 30 F 26 Nurse High 2006 4 Pulmonary Yes Abnormal Positive 31 F 31 Technician Moderate 2006 5 Pulmonary No Abnormal Negative

Active tuberculosis among health care workers in Portugal 639

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J Bras Pneumol. 2011;37(5):636-645

M M F F M F F M F F M F M F M F F F F F F F M F F F F F M F F

32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

29 25 28 27 32 49 26 30 30 29 30 30 33 30 45 39 25 26 34 50 25 27 25 29 61 26 38 31 55 30 25

Age

Physician Nurse Nurse Physician Physician Technician Ad. Assist.

Physician Aide Physician Physician Technician Physician Physician Physician Physician Nurse Physician Nurse Other Physician Nurse Other Nurse Aide Physician Aide Technician Aide Nurse Physician

Position

High Moderate Moderate High Moderate Moderate Low Moderate Moderate Moderate Moderate High High High Moderate High High Moderate High Moderate Moderate High Low High Low Moderate Moderate Moderate High Moderate High

Risk in sector

Year of diagnosis 2006 2007 2007 2007 2007 2007 2007 2007 2007 2007 2007 2007 2007 2007 2007 2008 2008 2008 2008 2008 2008 2009 2009 2009 2009 2009 2010 2010 2010 2010 2010 Years as an HCW 4 3 6 1 1 19 5 3 10 4 4 8 2 6 19 3 3 1 12 11 <1 3 4 3 33 <1 7 6 36 9 1 Pulmonary Pleural Pulmonary Pleural Pulmonary Pulmonary Pleural Pleural Pulmonary Pleural Pulmonary Pulmonary Pericardium Pulmonary Pulmonary Pulmonary Pulmonary Pulmonary Pulmonary Cutaneous Pulmonary Pulmonary Pulmonary Pleural Lymph node Pulmonary Pulmonary Pulmonary Pulmonary Pulmonary Pulmonary

Presentation

Symptoms at diagnosis Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes No Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal Normal Abnormal Abnormal Abnormal Abnormal Normal Abnormal Abnormal Abnormal Abnormal Abnormal Abnormal

Chest X-ray Positive Negative Positive Negative Positive Negative Negative Negative Positive Negative Positive Positive Negative Negative Positive Positive Positive Positive Positive Positive Positive Positive Positive Negative Negative Positive Positive Positive Positive Negative Negative

Mycobacterium tuberculosisa nd 20 (p) 17 (p) 17 (p) nd 25 (p) 13 (p) 14 (p) 18 (p) 13 (p) 18 (p) 22 (p) 12 (p) 16 (p) Na 18 (p) 16 (p) 15 (p) 12 (p) 21 (p) 13 (p) 17 (p) 8 (n) 13 (p) 19 (p) 14 (p) 19 (p) 10 (p) 6 (n) 23 (p) 20 (p)

TST (mm) nd 0.42 (p) 2.11 (p) nd 0.65 (p) 19.76 (p) 4.25 (p) 8.87 (p) ndc 0.65 (p) 3.17 (p) 0.92 (p) 0.40 (p) 2.13 (p) 2.11 (p) 3.97 (p) 6.32 (p) 0.17 (n) 3.50 (p) 49.09 (p) 1.30 (p) 1.96 (p) 1.83 (p) 2.10 (p) 0.28 (p) 3.57 (p) 1.40 (p) 4.59 (p) 13.75 (p) 18.61 (p) 8.53 (p)

IFN-Îł (IU/mL)

HCW: health care worker; TST: tuberculin skin test; nd: no data; (p): positive; (n): negative; PP: Pleuro-pulmonary; PM: Pulmonary-mediastinal; MDR-P: Multidrug-resistant pulmonary; and Ad. Assist.: Administrative Assistant. aIdentified by direct microscopy or culture. bNo data at this writing; presumably normal at diagnosis (in 2005). cNo data at the time of diagnosis; 0.14 IU/ mL one month after beginning TB treatment.

Sex

Case

Table 2 - Continued...

640 Costa JCT, Silva R, Ferreira J, Nienhaus A

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Figure 1 - Annual incidence of active tuberculosis (TB, per 100,000 population) among health care workers, São João Hospital, Porto, Portugal, 2005-2010.

was a case of pulmonary TB, M. tuberculosis being identified in a sputum sample, and one was a case of TB of the cervical lymph nodes, granulomas being found in a biopsy sample. In both of those cases, IGRA was repeated after 6 months, and the results remained negative.

Discussion At the hospital under study, the prevalence of LTBI was 55.2% when the diagnostic criterion was a TST ≥ 10 mm, compared with 25.9% when an IFN-γ response ≥ 0.35 IU/mL was used as the criterion, and these results have been published elsewhere.(11) Prophylactic treatment with isoniazid was prescribed for HCWs in whom the infection had occurred within the last two years or who were considered to be at high risk for developing active TB. None of those who completed the treatment developed active TB, which underscores the importance of screening for and treating LTBI as a means of preventing active TB.

Figure 2 - Analysis of the 62 cases of active tuberculosis (TB) identified between 2005 and 2010 among health care workers (HCW) at São João Hospital, Porto, Portugal, stratified by the number of years employed as an HCW (years of potential exposure to TB) prior to diagnosis.

Studies based on DNA analysis have shown that TB transmission occurs in the working environment.(12,13) Despite this evidence, other authors do not recognize an increased risk of TB in HCWs. This is because some studies conducted in developed countries with higher incomes have found the incidence of TB to be lower in HCWs than in the general population.(9) Some authors suggest that, in countries with a higher mean income, where TB is more common in HCWs who are first-generation immigrants, TB is acquired in the community and is unrelated to occupational risk.(14) Therefore, there could be differences between low- and high-income countries in terms of the recognition of TB as an occupational disease. De Vries et al.(12) evaluated 67 HCWs with TB and found that 42% of the infections had been acquired in the hospital, compared with 28% that had been acquired in the community and 30% that had been acquired abroad.

For persons employed as HCWs in Portugal, TB is considered an occupational disease,(6) which entitles affected individuals to significant compensation, up to several tens of thousands of Euros. In the absence of a clear distinction between TB cases that are truly work-related and those that are acquired in the community, the expenditures related to such compensation are considerable. Therefore, epidemiological tools (e.g., DNA fingerprinting) should be used as a means of documenting TB as an occupational disease. The fact that we did not employ such tools represents a major limitation of the present study.

Although there is a clear relationship between the number of hospitalized TB patients and TB incidence in HCWs, the risk J Bras Pneumol. 2011;37(5):636-645

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Table 3 - Cases of active tuberculosis, by year, among health care workers, São João Hospital, Porto, Portugal, 2005-2010.

Year n TST n TST conversion n IGRA n 2005 19 ≥ 15 mm 9 Conversion 3 No data ≥ 10 and < 15 mm 3 No conversion 9 < 10 mm 1 No data 7 No data 6 2006 13 ≥ 15 mm 9 Conversion 7 No data ≥ 10 and < 15 mm 1 No conversion 3 < 10 mm 0 No data 3 No data 3 2007 14 ≥ 15 mm 8 Conversion 6 Conversion 12 ≥ 10 and < 15 mm 4 No conversion 4 < 10 mm 0 No data 4 No data 2 No data 2 2008 6 ≥ 15 mm 4 Conversion 1 Conversion 5 ≥ 10 and < 15 mm 2 No conversion 3 < 10 mm 0 No data 2 No conversion 1 2009 5 ≥ 15 mm 2 Conversion 2 Conversion 4 ≥ 10 and < 15 mm 2 No conversion 2 < 10 mm 1 No data 1 No conversion 1 2010 5 ≥ 15 mm 3 Conversion 1 Conversion 5 ≥ 10 and < 15 mm 1 No conversion 3 < 10 mm 1 No data 1 No conversion 0 Total 62 ≥ 15 mm 35 Conversion 20 Conversion 26 ≥ 10 and < 15 mm 13 No conversion 24 < 10 mm 3 No data 18 No conversion 2 No data 11 TST: tuberculin skin test; and IGRA: IFN-gamma release assay.

is more closely related to the infrastructure and maintenance of the facility than to the number of TB admissions per HCW.(15) Factors related to the increased risk for HCWs include delayed diagnosis,(16) misdiagnosis in the initial evaluation, advanced age, absence of suspicious clinical signs (e.g., coughing), lack or inadequacy of personal protective equipment and preventive measures, and inadequate ventilation, especially in polyvalent hospital wards.(16,17) The control of TB as a nosocomial disease requires, above all, the adoption of collective measures, such as the rapid identification of suspected or confirmed cases of active TB, the rapid implementation of airborne precautions, and the use of surgical masks or N95 respirators by the HCWs.(18) Although BCG vaccination has proven effective in reducing the most severe forms of TB, its efficacy in preventing pulmonary TB is variable.(19,20) Given the limited effectiveness of BCG vaccination,(19,20) strategies for preventing TB should be based on the identification and J Bras Pneumol. 2011;37(5):636-645

treatment of LTBI as a means of reducing the number of infected individuals and the risk of progression to active TB.(21) It is generally accepted that treating LTBI reduces the risk of developing active TB by more than 50%.(18,21-24) In the present study, we observed an apparent relationship between duration of exposure and risk of TB, the risk of developing active TB being higher in the first years of exposure.

This temporal relationship, as previously reported,(25) is similar to that found for recent TST conversions, the time to which is directly proportional to risk, i.e., when the conversion is more recent, the risk of progression to active TB is greater.(26) The small number of active TB cases in our sample precluded appropriate statistical confirmation of the influence of age and years of exposure as risk factors for active TB development. If future results support our data, additional efforts should be made to provide HCWs with adequate education about infectious

Active tuberculosis among health care workers in Portugal

diseases and preventive strategies, from the hire date onward.

In our study, the distribution of active TB cases was not uniform across years, the number of cases peaking at 19 (equivalent to 351/100,000 population) in 2005, whereas the incidence in the general population of the city of Porto was only 45.4/100,000 population in 2006.(27) After the implementation of the screening program at the hospital under study, there was a significant reduction in the number of new cases of active TB among HCWs. In 2009, as well as in 2010, there were only 5 such cases (equivalent to 93/100,000 population), less than a third of the incidence in 2005, although still three times higher than that reported for the general population of the area (33.7/100,000 population) in 2009.(2) The reduction in the number of cases of active TB in HCWs between 2005 and 2010 probably reflects the efforts made to identify at-risk populations and to treat recently infected HCWs with LTBI who were considered to be at high risk of developing active TB, as well as the implementation of effective personal protection and educational programs for HCWs. Seven of the active TB cases evaluated were diagnosed in asymptomatic HCWs who were screened because of ongoing exposure and the risk of person-to-person transmission of M. tuberculosis or evidence of such transmission (among patients or HCWs). Four of those cases were AFB-positive, and chest X-ray findings were abnormal in all 7. Such cases underscore the need for a planned screening program, especially when there is exposure to individuals (patients or co-workers) with contagious forms of TB and the appropriate preventive measures are not in place.

Most of the cases of active TB diagnosed during the study period were cases of pulmonary TB, which was multidrug-resistant in 2 of those cases. Among the cases of extrapulmonary TB, a case of cutaneous TB, attributed to an occupational accident in a microbiology laboratory, is noteworthy for its rarity.

Most of the active TB cases occurred in HCWs assigned to moderate- or high-risk sectors (less than 7% of such cases occurred in sectors classified as low risk), which lends credence to the idea that there is a relationship between occupational exposure and active TB.

643

The cases that occurred in low-risk sectors might represent a community-acquired form of the disease, or a nosocomial form acquired in “common” areas. As previously mentioned, this distinction could have been made through the use of DNA fingerprinting. In addition, we found the incidence of active TB to be similar among physicians and nurses (1.28% and 1.03%, respectively), who routinely have closer contact with patients and constitute the largest occupational groups among HCWs. The sensitivity of IGRA in patients with TB has been reported to be between 81% and 89%.

(28,29) In a recent study conducted by Diel et al., IGRA had a 100% negative predictive value for progression to active TB in close contacts with a high pre-test likelihood of disease.(30) In our study, IGRA came into use in 2007 and was performed at the time of diagnosis in 28 of the cases of active TB reported since that time. In 26 of those 28 cases, the IGRA results were positive (sensitivity of 93%). Among the 51 active TB cases for which TST results are available, the results were positive in 48 (sensitivity of 94%), although there was a high number of false positives. Of the 2 cases in which the IGRA results were negative, 1 was a case of AFB-positive pulmonary TB and the other was a case of TB in the cervical lymph nodes. The TST results were positive in both of those cases.

In conclusion, in HCWs employed in Portugal, the TB burden is high. There seems to be a relationship between the duration of exposure and the risk of developing TB, that risk being higher in the first years of exposure.

The incidence of TB in physicians is similar to that observed for nurses. The sensitivity of IGRA at the time of diagnosis is greater than 90% in patients with active TB. In high-incidence countries, TB screening is particularly important because it can identify asymptomatic HCWs with LTBI or active TB.

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About the authors José Castela Torres da Costa

Physician. Occupational Health Division & Allergy Division, São João Hospital, Porto, Portugal.

Rui Silva

Physician. Occupational Health Division & Allergy Division, São João Hospital, Porto, Portugal.

José Ferreira

Physician. Occupational Health Division, São João Hospital, Porto, Portugal.

Albert Nienhaus

Head. Department of Occupational Health Research, University of Hamburg, Hamburg, Germany.

J Bras Pneumol. 2011;37(5):636-645

Original Article Tuberculin skin test: operational research in the state of Mato Grosso do Sul, Brazil* Teste tuberculínico: pesquisa operacional no Mato Grosso do Sul

Sandra Maria do Valle Leone de Oliveira, Antônio Ruffino-Netto, Anamaria Mello Miranda Paniago, Olcinei Alves de Oliveira, Marli Marques, Rivaldo Venâncio da Cunha, Renato Andreotti

Abstract Objective: To investigate operational aspects of tuberculin skin test (TST) use in tuberculosis control programs and at specialized Brazilian National Sexually Transmitted Diseases/AIDS and Viral Hepatitis Program health care clinics in priority municipalities for tuberculosis control in the state of Mato Grosso do Sul, Brazil. Methods: This was a descriptive, cross-sectional, epidemiological survey. Data on qualifications/training of professionals administering TSTs, timing of the TST, procedures in cases of loss to follow-up (reading), material availability, and material storage were collected through interviews and technical visits. For the 2008-2009 period, we determined the numbers of screenings in vulnerable populations, of TSTs performed, and of patients treated for latent tuberculosis.

Results: We interviewed 12 program managers in six municipalities. Some programs/clinics did not perform TSTs. Nursing teams administered the TSTs, results were read by non-specialists, and specialization/refresher courses were scarce. The PPD RT23 was stored in 5-mL flasks under appropriate conditions. Insulin syringes were commonly used. Testing was available during business hours, three times a week. In cases of loss to follow-up, telephone calls or home visits were made. Of the 2,305 TSTs evaluated, 1,053 (46%) were performed in indigenous populations; 831 (36%) were screenings in prisons, performed for training; and only 421 (18%) involved contacts of tuberculosis patients or vulnerable populations. Four vulnerable patients and 126 indigenous subjects were treated for latent tuberculosis. Conclusions: These priority municipalities showed operational difficulties regarding human resources, materials, and data records.

Keywords: Tuberculin test; Health services research; HIV; Latent tuberculosis; Chemoprevention.

Resumo Objetivo: Investigar a operacionalização da utilização do teste tuberculínico (TT) em programas de controle de tuberculose e em serviços de assistência especializada do Programa Nacional de Doenças Sexualmente Transmissíveis/AIDS e Hepatites Virais em municípios prioritários para o controle da tuberculose no estado de Mato Grosso do Sul. Métodos: Estudo epidemiológico descritivo, transversal, do tipo inquérito. A formação profissional dos responsáveis pela realização do TT, existência de treinamentos, período de realização dos TTs, conduta em caso de perda de leitura, insumos disponíveis e sua conservação foram levantados por meio de entrevistas e visitas técnicas. O número de inquéritos em populações vulneráveis, número de TTs realizados e número de pacientes em tratamento de tuberculose latente entre 2008 e 2009 foram também levantados. Resultados: Foram entrevistados 12 gestores de seis municípios. Alguns programas/serviços não realizavam o TT. A equipe de enfermagem realizava os TTs, não havia leitores especialistas, e treinamentos eram raros. A conservação dos frascos de PPD RT23 (5 mL) era adequada. Frequentemente utilizava-se a seringa de insulina. A realização de TT ocorria no horário comercial, três vezes na semana. Em caso de perda de leitura em alguns locais, realizava-se contato telefônico ou visita domiciliar. O total de TT realizados foi de 2.305, dos quais 1.053 (46%) foram realizados em populações indígenas, 831 (36%) foram realizados em ambientes prisionais para fins de treinamento (inquéritos), e apenas 421 (18%) foram realizados em contatos de pacientes com tuberculose e em populações vulneráveis. O tratamento de tuberculose latente foi realizado em 4 pacientes vulneráveis e em 126 indígenas. Conclusões: Os municípios prioritários demonstraram dificuldades operacionais em relação a recursos humanos, insumos e registros de informação.

Descritores: Teste tuberculínico; Pesquisa sobre serviços de saúde; HIV; Tuberculose latente; Quimioprevenção. * Study carried out at the Professora Esterina Corsini Day Hospital, Federal University of Mato Grosso do Sul, Campo Grande, Brazil.

Correspondence to: Sandra Maria do Valle Leone de Oliveira. Hospital-Dia Prof. Esterina Corsini, NHU/UFMS, Rua Senador Filinto Muller, s/n, CEP 79080-190, Campo Grande, MS, Brasil.

Fax: 55 67 3345-3651. E-mail: sandrinhaleone@gmail.com or sandra.leone@ufms.br Financial support: This study received financial support from the International Clinical Operational and Health Services Research and Training Award (ICOHRTA) Mandate (AIDS/TB Grant no. 2 U2R TW006883-06).

Submitted: 9 April 2011. Accepted, after review: 20 June 2011.

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Introduction Latent tuberculosis affects approximately one third of the world population, and it has been estimated that the annual risk of progression to active tuberculosis among HIV-infected individuals is as high as 10%, tuberculosis therefore being the most common opportunistic disease and the leading cause of death among HIV-infected individuals worldwide.(1) The tuberculin skin test (TST) is one of the tools for the identification of latent tuberculosis and is an ancillary test for the diagnosis of active tuberculosis. The results of the TST guide the therapeutic approach to latent tuberculosis.(2-6) The TST is performed by the Mantoux method, which consists of the administration of 0.1 mL (2 TU) of PPD RT23 on the volar aspect of the forearm. The results of the test are read within 48-72 h after PPD RT23 administration.

(4,7,8) Individuals with an induration ≥ 10 mm are considered infected.

However, in immunocompromised individuals, the cut-off induration value has been set at 5 mm.(7) Strategies to reduce the incidence of tuberculosis in HIV-infected individuals include the preventive use of isoniazid in patients with latent tuberculosis, the initiation of antiretroviral therapy, and measures aimed at preventing the transmission of the disease in the community by detecting active cases as early as possible.(1,8) The preventive approach prioritizes individuals who are immunocompromised or are receiving immunosuppressive therapy, children younger than two years of age, and the elderly, as well as health care workers and medical students, who are at a higher risk of becoming infected because of occupational exposure.(9-13) Latent tuberculosis treatment with isoniazid plays a fundamental role in tuberculosis control and can prevent active tuberculosis in 60-90% of the cases.(13,14) Operational difficulties in identifying latent tuberculosis constitute major obstacles to the implementation of preventive therapy with isoniazid.(15) The objective of the present study was to investigate operational aspects of TST use in tuberculosis control programs (TCPs) and at primary care clinics (PCCs) affiliated with the

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Brazilian National Sexually Transmitted Disease (STD)/AIDS and Viral Hepatitis Program in priority municipalities for tuberculosis control in the state of Mato Grosso do Sul, Brazil.

Methods This was a descriptive, cross-sectional, epidemiological survey. On the basis of tuberculosis control data and epidemiological markers, we chose six priority municipalities in the state of Mato Grosso do Sul. The survey was conducted between May and June of 2010.

We interviewed six municipal coordinators of TCPs; four managers of specialized TCP-affiliated PCCs in five priority municipalities, including a specialized PCC that provides treatment to patients in two priority municipalities; one state coordinator of a TCP; and one state coordinator of the Brazilian National STD/AIDS and Viral Hepatitis Program. One of the investigators made a technical visit to each of the facilities.

For each municipality, we collected data regarding the principal operational aspects of TST use, including the organization of the facility (human resources, materials, and patient access to the test) and TST administration indicators (screenings, number of TSTs performed, and number of patients treated for latent tuberculosis). When there were no records or information regarding certain operational aspects of TST use, we asked why the test had not been performed.

The interviews covered the following: qualifications/training of professionals administering TSTs and reading TST results; availability of materials; days of the week on which TSTs were performed; and procedures in cases of loss to follow-up (reading). For the 2008-2009 period, we determined the numbers of screenings in vulnerable populations, of TSTs performed, and of patients treated for latent tuberculosis.

Secondary information sources were TST registries (if available), patient registries, and registries of the follow-up treatment of tuberculosis cases, as well as TST results registered in medical charts or in the Brazilian Case Registry Database (for tuberculosis and AIDS cases).

The study was approved by the Human Research Ethics Committee of the Federal J Bras Pneumol. 2011;37(5):646-654

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University of Mato Grosso do Sul (Protocol no.

1722).

Results The six municipalities under study shared one characteristic: the TCP and immunization program nursing teams were responsible for administering the TST. In general, the TST was administered by nurse technicians or by TCP managers (nearly all of whom were nurses), as can be seen in Chart 1. In all of the priority municipalities evaluated, all of the TSTs performed were provided by TCPs. Of the four managers of the specialized PCCs in the priority municipalities under study, one declined to participate in the study. Of the three specialized PCCs under study, only two offered TSTs. In the capital of the state, the decentralization of the TCP to the health districts resulted in the TST being administered by the nursing staff of PCCs affiliated with the Family Health Program.

The Campo Grande TCP manager reported that, including the screenings in prisons and the tests performed in two specialized PCCs, 169 TSTs were performed. All of the health care workers stated that they learned how to administer the TST through professional experience. Health care workers had reportedly received training in how to administer the TST during BCG vaccination training courses. Our survey revealed that there were no training courses for the health care workers at the specialized PCCs under study;

however, in the 2008-2009 period, there was, via four of the TCPs, at least one training course for the health care workers who administered the TST to prison or penitentiary inmates.

It was reported that, via the Mato Grosso do Sul State TCP, two training courses were held at prisons in the state capital in 2009.

The courses provided training to 26 health care workers in two priority municipalities. The principal objectives of the training courses were to improve the TST administration technique and to standardize the reading of TST results.

Neither of the municipalities had health care workers that specialized in reading TST results.

Tuberculin syringes were used by all but one TCP. In that case, the procedure was performed with insulin syringes, available via the immunization program. At the specialized PCCs, the syringes that were most commonly used were insulin syringes. Tuberculin syringes were used at only one specialized PCC. In all of the municipalities under study, PPD RT23 was stored in 5-mL flasks under appropriate, temperature-controlled conditions, i.e., in refrigerators, which were also used to store the vaccines administered via the local immunization program. In one of the municipalities, we found flasks that had remained open for more than 30 days and were past their expiration date.

Testing was available during business hours (from 7:00-11:00 a.m. and from 1:005:00 p.m.), three times a week. There was no repressed demand for TSTs. At the specialized

Chart 1 - Operational aspects evaluated and results obtained in the priority municipalities for tuberculosis control in the state of Mato Grosso do Sul, 2008-2009.

Operational aspects evaluated Professionals responsible for administering TSTs Training TST hours available Procedures in cases of loss to follow-up PPD RT23 storage container (5 mL-flask) Records of TST results Type of syringe used in order to perform the test Screenings in health care students/workers

Results Nursing staff No specialists in reading TST results Business hours on weekdays (no repressed demand) Home visits, via four of the TCPs; telephone calls, via five of the TCPs; and no strategies to counter loss to follow-up at the specialized PCCs Appropriately stored in refrigerators that were also used to store vaccines No specific registries of TST results Tuberculin syringes at 1 specialized PCC and insulin syringes at 5 specialized PCCs Tuberculin syringes via 5 TCPs None

TST: tuberculin skin test; TCP: tuberculosis control program; and PCC: primary care clinic.

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PCCs, no specific protocol was followed when patients failed to return for the reading of the TST results. However, our survey revealed that, if tested via the TCPs of five of the municipalities under study, such patients were contacted by telephone, whereas those tested via the TCPs of four of the municipalities under study were visited at home.

None of the specialized PCCs had any record of the number of TSTs performed. For the tests performed via the TCPs, we counted all of the tests that had been recorded in the patient registries, as well as those that had been recorded in the registries of the follow-up treatment of tuberculosis cases. Information sources such as TST registries were nonexistent; the results were available exclusively in the medical charts of the patients.

A survey conducted at a referral center for the outpatient treatment of HIV-infected individuals in Campo Grande revealed that 113 (80.7%) of the 140 patients followed in the 2008-2009 period had never had a TST. Among those patients, the median duration of outpatient follow-up was 8 years. At the time, the facility had no professionals who were trained in administering TSTs, stored none of the materials required in order to perform TSTs, and had no isoniazid on hand. According to the facility records, as of 2009, no patients had been treated for latent tuberculosis.

Four of the TCPs had no records of patients treated for latent tuberculosis during the study period (2008-2009). According to the records, the specialized PCCs affiliated with those TCPs had treated only two cases of latent tuberculosis during that same period. Among all of the PCCs affiliated with those TCPs, a total of 4 patients were treated for latent tuberculosis during the study period.

In the priority municipalities for tuberculosis control, 421 TSTs were reported to have been performed, collectively, via the TCPs and at the specialized PCCs. Of the 2,305 TSTs performed, 1,053 (46%) were performed in indigenous populations; 831 (36%) were screenings in prisons, performed for training; and only 421 (18%) involved contacts of tuberculosis patients or priority populations, such as HIV-infected individuals.(16) In the indigenous populations, the TSTs resulted in 124 patients being treated for latent tuberculosis, a figure that is noteworthy

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among those observed for all of the priority municipalities that had TCPs and specialized PCCs.(16) Five screenings were performed in prisons, and one was performed at a military barracks. Those screenings were performed either in an attempt to identify contacts of tuberculosis patients or in order to provide technical training. There were no records of screenings in other vulnerable populations, such as health care students/workers, rheumatology patients, and transplant recipients. The reasons given/observed for not performing TSTs more often were the lack of a TST protocol, the low credibility of the TST, failure to request the annual TST recommended for HIV-infected individuals, and a lack of awareness that patients with latent tuberculosis should be treated.

Discussion Although the municipalities under study are priority municipalities for tuberculosis control measures, the TCPs had operational difficulties regarding human resources, materials, and record keeping. The operational difficulties of the TCPs and STD/AIDS Programs were the underuse of TSTs, the insufficient number of professionals trained in TST administration, the lack of specialists qualified to read TST results, the lack of standardization of the syringes used, the lack of recording of the number of tests performed, and the lack of information regarding the treatment for latent tuberculosis. In numerous countries, those same operational difficulties have been reported, not only for the performance of the TST but also for pharmacological treatment.(15,17) It is estimated that, worldwide, only 1.3% of the vulnerable population received prophylaxis against tuberculosis in 2009. However, between 2002 and 2009, the number of countries providing such prophylaxis gradually increasedâ&#x20AC;&#x201D; from 8 to 102.(1) In 2009, the specialized Brazilian National STD/AIDS and Viral Hepatitis Program PCCs were surveyed with the Sistema de Controle LogĂ­stico de Medicamentos (SICLOM, Logistic Medication Monitoring System), with the objective of monitoring the number of patients being treated for latent tuberculosis. To the antiretroviral therapy request form, a field was added in which TST results and the therapeutic approach can be registered. Although 21 Brazilian states reported (to the Brazilian National Ministry of Health) J Bras Pneumol. 2011;37(5):646-654

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that TSTs had been performed at the specialized PCCs during the study period, only 7,972 TSTs were reportedly performed, and those tests resulted in only 539 patients being treated for latent tuberculosis (Chart 2). In the state of Mato Grosso do Sul, 148 TSTs were reported to have been administered to individuals registered in the SICLOM, resulting in 21 patients being treated for latent tuberculosis. The lack of records, the failure to send information to state managers on a regular basis, and the low number of TSTs performed in vulnerable populations are evident nationwide.

It was estimated that there were 592,914 HIV-infected individuals in Brazil in 2010.(18) Of those, at least 80% (474,331 individuals) should have been tested annually. Given that the expected rate of TST positivity is 20%, 94,866 of those individuals could be candidates for latent tuberculosis treatment. However, according to

the records, only 7,972 (1.68%) of those 474,331 individuals were tested and only 573 (0.12% of the target population; 7.19% of those tested) were treated for latent tuberculosis.

Our analysis of TST use reveals a disconnect between guidelines and practice. Although scientific evidence of the importance of the TST and preventive treatment for latent tuberculosis has been collected for 18 years, this does not seem to be reflected in the number of TSTs performed in the various at-risk populations, in which the test should be administered on an annual basis, or in the number of individuals treated for latent tuberculosis.(15) The international recommendations for TST use in vulnerable populations date from 1965, and, in 1993, the Union Against Tuberculosis and Lung Disease, together with the World Health Organization, strongly recommended that the TST be performed in such populations and that

Chart 2 - Number of tuberculin skin tests performed and number of patients treated for latent tuberculosis among HIV-infected individuals at specialized primary care clinics, by state. State of Mato Grosso do Sul, Brazil, 2009.

States Tuberculin HIV-infected population Individuals treated for skin tests latent tuberculosis n n n Rio de Janeiro 1,296 81,606 236 São Paulo 2,563 212,071 139 Paraná 2,019 28,376 44 Minas Gerais 490 41,791 37 Rio Grande do Sul 492 58,495 30 Mato Grosso do Sul 148 6,700 29 Santa Catarina 616 28,727 24 Espírito Santo 84 8,682 10 Alagoas 15 3,842 6 Tocantins 88 1,303 6 Mato Grosso 37 7,615 4 Federal District of Brasília 13 7,824 2 Acre 1 570 1 Bahia 67 17,886 1 Pará 8 10,763 1 Paraíba 1 4,773 1 Piauí 9 3,660 1 Rondônia 17 2,734 1 Amapá 1 979 0 Ceará 3 12,062 0 Maranhão 1 7,867 0 Total 7,972 548,326 573 Data registered in the Logistic Medication Monitoring System, the Brazilian National Mortality Database, and the Brazilian National CD4+/CD8+ T Lymphocyte Count and Viral Load Network Laboratory Test Control System (Brazilian Ministry of Health. Department of Health Surveillance. Department of Sexually Transmitted Diseases/AIDS and Viral Hepatitis, unpublished data, 2011).(18)

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individuals with latent tuberculosis be treated.(1) That recommendation was reiterated in 1998 and 2004.(1,8,15,16) Since 1997, the Centers for Disease Control and Prevention have recommended that HIV-infected individuals undergo the TST and receive preventive treatment with isoniazid.(19) Operational studies conducted in various Brazilian states revealed that the lack of organization at PCCs can have a negative effect on access to diagnosis and time to diagnosis, as well as on adherence to treatment and continuity of enrollment in TCPs.(20,21) The lack of standardization of syringes for the TST impedes the proper administration of the test, because the dose administered is not precisely the recommended dose, and this can increase the number of false-negative test results.(22) It is estimated that 50% of PPD is lost because it goes out of date while still in the flask or spoils after the flask is opened; however, this loss can be reduced by the use of tuberculin syringes and by the correct handling of the product by trained professionals. The fact that few TSTs are requested contributes to PPD loss due to expiration, contamination, or flasks that remain open for more than 30 days, all of which result in loss of potency and, consequently, increase the number of false-negative results. It is known that the size of the PPD flask influences TST results because of PPD adsorption to the flask wall as a result of the ratio between PPD volume and the inner surface of the flask; therefore, flasks of lower volume might cause lower induration than that obtained when PPD is stored in larger flasks, as demonstrated in a study comparing 1.5-mL and 5-mL flasks.(23) In 2009, the Brazilian National Ministry of Health began to distribute PPD in 1.5-mL flasks.

The operational difficulties involved in performing TSTs on weekends and the lack of a strategy to counter loss to follow-up (reading) at the specialized PCCs might be factors that reduce the efficacy of TST use. The ratio between the number of patients with latent tuberculosis infection and the number of patients treated for latent tuberculosis should be calculated and used as an indicator, which might lead to a reorganization of the PCCs in an attempt to increase TST use.(6) Our survey revealed two successful experiences during the study period: one at a specialized PCC; and the other related to a

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TCP through which an indigenous population was treated—that of the Mato Grosso do Sul State Distritos Sanitários Especiais Indígenas da Secretaria Especial de Saúde Indígena (DSEI/ SESAI, Health Districts of the Special Department of Indigenous Health). At the specialized PCC, the proportion of TSTs requested was low in 2008 (19.27%). However, 109 HIV-infected individuals underwent TSTs at that PCC in 2009. On the day of sample collection for viral load determination and CD4/CD8 cell counts, those individuals also underwent the TST. Among those patients, the prevalence of latent tuberculosis was found to be 13.9%.(11) In the DSEI/SESAI, the TST coverage was high, as was that of latent tuberculosis treatment, both of which were provided at a rate far greater than that observed in the general population. In the TCP of the DSEI/SESAI, the operational aspects were well managed, as they were at the abovementioned PCC. There were strategies to counter loss to follow-up (reading), and the availability of drugs for preventive treatment was guaranteed. The information was systematized in specifically designed registries.

It is of note that, in the state capital, the decentralization of services to PCCs did not seem to increase TST use and might have resulted in disorganization at the referral centers. The TSTs performed via the TCPs should be decentralized first to referral centers (where HIV-infected individuals, transplant recipients, patients with chronic kidney disease, and patients with rheumatic diseases are treated) and subsequently to PCCs, where the demand tends to be lower.

In order to change the focus of the existing policies and develop new ones, with the objective of reducing costs, improving compliance with the operational strategies, and reducing the duplication of efforts, the definition of priority municipalities for tuberculosis control should also include cases of HIV infection or AIDS. (6) Otherwise, there is a risk that the situation observed in the present study will persist.

It takes time, formal training, and experience for professionals administering and reading TSTs to do it properly. These requirements, together with the low number of TSTs performed at PCCs, can explain why most professionals are not qualified to perform TSTs. The expansion of the public health care system led to an increase in the number of professionals hired, a reduction in the number of training courses offered, and a J Bras Pneumol. 2011;37(5):646-654

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substantial reduction in the number of trained professionals employed by the public health care system. Training courses should be offered annually, with the objective of developing human resources that are qualified to read TST results.(18,22,24-26) Although studies conducted in Brazil and abroad found considerable evidence to support the recommendation that health care students and workers be screened for latent tuberculosis (at admission/hiring and annually), our survey found that this screening has not been performed, which makes it impossible to treat this at-risk population prophylactically.(11,14,27) Health care workers in the state of Mato Grosso do Sul were screened by the TST only once, in 2004, and the prevalence of latent tuberculosis was found to be 37.8%. However, the screening did not result in annual follow-up evaluations or in preventive treatment in cases of TST conversion.(10) The integration between the STD/AIDS programs and the TCPs is limited, which constitutes an operational barrier.(15) It is recommended that TCPs be promptly integrated with other referral centers at which TSTs are performed in order to identify latent tuberculosis in adult contacts of tuberculosis patients, in individuals using TNF-α inhibitors, and in transplant recipients under immunosuppressive therapy or using corticosteroids.(7) In the literature,(1,16,20) the reasons described for not screening individuals by the TST, as well as those described for not treating individuals with latent tuberculosis, are similar to those found in the present study: minimal physician experience in the management of preventive therapy; the fact that the benefits of preventive therapy are not made clear; the lack of credibility of the TST; and the low number of trained professionals, which is due to high staff turnover. Other factors that can be considered operational barriers are the difficulty that patients have in understanding the use of preventive treatment and the low socioeconomic status of patients, both of which result in treatment noncompliance.(16,20) Few TSTs are performed via the TCPs and specialized PCCs that provide treatment to individuals with tuberculosis and HIV-infected individuals, and few individuals belonging to other priority groups for tuberculosis control receive treatment for latent tuberculosis. Joint activities of the Brazilian National Tuberculosis J Bras Pneumol. 2011;37(5):646-654

Control Program and the Brazilian National STD/ AIDS and Viral Hepatitis Program can effectively reduce the number of tuberculosis cases in the long term. The public health care system should be reorganized in order to guarantee the efficient flow of information within its hierarchy.

This will increase the number of TSTs performed and the number of patients treated for latent tuberculosis.

The TST remains a valuable method for controlling tuberculosis. Operational studies should be conducted in all Brazilian states in order evaluate the obstacles to TST use in the diagnosis and treatment of tuberculosis.

Acknowledgments We would like to thank the STD/AIDS and Viral Hepatitis Division of the Department of Health Surveillance, the Mato Grosso do Sul State STD/AIDS and Viral Hepatitis Coordinators, the Mato Grosso do Sul State Tuberculosis Control Program Coordinators, and the Mato Grosso do Sul State Distritos Sanitários Especiais Indígenas da Secretaria Especial de Saúde Indígena (DSEI/ SESAI, Health Districts of the Special Department of Indigenous Health) for kindly providing the information requested.

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24. Ruffino-Netto A, Teruel, JR; Duarte, GG Análise dos erros nas leituras de provas tuberculínica I. Rev Serv Nac Tub. 1967;11:350-64.

25. Teruel JR, Netto AR, Duarte GG. Standardization of tuberculin test readers. Tubercle. 1969;50(4):350-5.

26. Almeida MC,Vinha VP, Ruffino-Netto A. Padronização de técnica de aplicação e leitura no teste tuberculínico.

Medicina (Ribeirão Preto). 1973;6:23-30.

27. Lopes LK, Teles SA, Souza AC, Rabahi MF, Tipple AF. Tuberculosis risk among nursing professionals from Central Brazil. Am J Infect Control. 2008;36(2):148-51.

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About the authors Sandra Maria do Valle Leone de Oliveira

Doctoral Student. Graduate Program in Infectious and Parasitic Diseases, Federal University of Mato Grosso do Sul, Campo Grande, Brazil.

Antônio Ruffino-Netto

Full Professor of Social Medicine. University of São Paulo at Ribeirão Preto School of Medicine, Ribeirão Preto, Brazil.

Anamaria Mello Miranda Paniago

Adjunct Professor. Federal University of Mato Grosso do Sul Prof. Hélio Mandetta School of Medicine, Campo Grande, Brazil.

Olcinei Alves de Oliveira

Nurse. University Hospital Center, Federal University of Mato Grosso do Sul, Campo Grande, Brazil.

Marli Marques

State Coordinator. Tuberculosis Control Program, Mato Grosso do Sul State Health Department, Campo Grande, Brazil.

Rivaldo Venâncio da Cunha

Associate Professor. Federal University of Mato Grosso do Sul Prof. Hélio Mandetta School of Medicine, Campo Grande, Brazil.

Renato Andreotti

Researcher. Empresa Brasileira de Pesquisa Agropecuária – Embrapa, Brazilian Agency for Agricultural Research – Beef Cattle Division, Campo Grande, Brazil.

J Bras Pneumol. 2011;37(5):646-654

Brief Communication Occurrence of influenza among patients hospitalized for suspicion of influenza A (H1N1) infection in 2010 at a sentinel hospital in São Paulo, Brazil*, ** Ocorrência de influenza em pacientes hospitalizados com suspeita de infecção por influenza A (H1N1) em 2010 em um hospital sentinela na cidade de São Paulo

Thaís Boim Melchior, Sandra Baltazar Guatura, Clarice Neves Camargo, Aripuanã Sakurada Aranha Watanabe, Celso Granato, Nancy Bellei

Abstract In 2010, 96 patients suspected of being infected with the influenza A (H1N1) virus were hospitalized at the Hospital São Paulo, located in the city of São Paulo, Brazil. Of those 96 patients, 4 (4.2%) were found to be infected with influenza A virus—3 with influenza A (H1N1) and 1 with seasonal influenza A—and 2 patients (2.1%) were found to be infected with influenza B virus. Most (63.5%) of the suspected cases occurred in children, as did half of the positive cases. The second wave of influenza A (H1N1) infection was weaker in São Paulo. The decrease in the number of hospitalizations for H1N1 infection in 2010 might be attributable to vaccination.

Keywords: Influenza A virus, H1N1 subtype; Influenza, human; Pneumonia; Pandemics.

Resumo Em 2010, 96 pacientes com suspeita de infecção por influenza A (H1N1) foram hospitalizados no Hospital São Paulo, na cidade de São Paulo (SP). Desses, 4 pacientes (4,2%) foram diagnosticados com influenza A — 3 com influenza A (H1N1) e 1 com influenza sazonal — e 2 pacientes (2,1%) foram diagnosticados com influenza B. A maioria dos casos suspeitos (63,5%) e metade dos casos positivos ocorreram em crianças. A segunda onda de influenza A (H1N1) foi mais fraca em São Paulo. A vacinação pode ter contribuído para a redução das internações devido a essa infecção em 2010.

Descritores: Vírus da influenza A subtipo H1N1; Influenza humana; Pneumonia; Pandemias.

Influenza virus infections are a major cause of respiratory disease worldwide. In early 2009, a new subtype of influenza A virus emerged and spread rapidly around the world. In May of 2009, the first case of the novel influenza A (H1N1) virus was confirmed in Brazil, and the virus affected thousands of people during the first pandemic wave, mostly in the south and southeast of the country.(1) Presentations varied from mild flu to severe pneumonia and death, and the first wave of the influenza A (H1N1) outbreak led to a great number of hospitalizations for suspected infection.(2) At the Hospital São Paulo, a sentinel

hospital located in the city of São Paulo, Brazil, over 4,000 patients with influenza-like symptoms were treated in 2009, during the first wave of influenza A (H1N1) infection,(3) and 159 of those patients were hospitalized. Among the 159 hospitalized patients, infection with the influenza A (H1N1) virus was confirmed in 31 (19.5%).(4) Between March and June of 2010, a national H1N1 immunization program was implemented for various risk groups.(5) The objective of the present study was to describe the types of influenza viruses affecting patients who were hospitalized at the Hospital São Paulo

* Study carried out in the Virology Laboratory, Infections Diseases Branch, Medicine Department, Federal University of São Paulo, São Paulo, Brazil.

Correspondence to: Nancy Cristina Junqueira Bellei. Rua Pedro de Toledo, 781, 15º andar frente, Vila Clementino, CEP 04039-032, São Paulo, SP, Brasil.

Tel./Fax: 55 11 5081-5394. E-mail: nbellei@uol.com.br Financial support: None.

Submitted: 22 March 2011. Accepted, after review: 6 June 2011. ** A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

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Melchior TB, Guatura SB, Camargo CN, Watanabe ASA, Granato C, Bellei N

Figure 1 - Hospitalization rate for suspected and confirmed cases of influenza in 2010, by age group. d: days; m: months; and y: years.

with the influenza A/California/04/2009 (H1N1) virus—and one had been collected during epidemiological week 45 (November 7-13), being confirmed as infected with the seasonal influenza virus. The samples testing positive for influenza B had been collected during epidemiological weeks 23 and 33 (June 6-12 and August 8-14, respectively).

The first three patients with confirmed influenza A (H1N1) infection, all of whom were male, were 9 months, 54 years, and 3 months of age, respectively. The two patients with influenza B infection, both of whom were female, were 5 and 19 years of age, respectively, and another, 62-year-old, female patient was infected with the seasonal influenza A (H3N2) virus.

All six patients infected with the influenza virus required oxygen therapy, three (50%)

Epidemiological weeks (2010) Influenza A

Influenza B

Negative

Figure 2 - Influenza infection in hospitalized patients in 2010, by epidemiological week.

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45 (07-13/11)

33 (15-21/08)

31 (01-07/08)

29 (18-24/27)

27 (04-10/07)

25 (20-26/06)

23 (06/12/06)

19 (09-15/05)

17 (25/04-01/05)

15 (11-17/04)

13 (28/03-03/04)

8 (21-27/02)

12 10 8 6 4 2 0 3 (17-23/01)

Patients

for suspected influenza A (H1N1) infection in 2010.

Nasal swabs were collected from 96 patients (median age, 3.0 years; range, 0-85 years) hospitalized between January and December of 2010. The study was approved by the local research ethics committee, and all participating patients gave written informed consent.

From the samples collected, viral genomic RNA was extracted using an extraction kit (QIAamp Viral RNA; QIAGEN, Hilden, Germany).

Influenza A and B tests were performed by RT-PCR,(6) and the products were submitted to electrophoresis on 1.5% agarose gels. The diagnosis of influenza A (H1N1) was based on real-time RT-PCR results.(7) Of the 96 admissions evaluated, 11 (11.5%) occurred during epidemiological week 23 (June 6-12), more than in any other epidemiological week. Most of the patients (55.2%) were hospitalized before the end of the H1N1 influenza vaccination program. Of the samples collected, only 4 (4.2%) tested positive for influenza A, and 2 (2.1%) tested positive for influenza B. Among the hospitalized patients studied, the male/female ratio was 1.34. Of the suspected cases, 61 (63.5%) were in children under 12 years of age (median age, 2.0 years; range, 0-7 years), as were 3 (50.0%) of the 6 positive cases (Figure 1).

As can be seen in Figure 2, the samples testing positive for influenza A had been collected during epidemiological weeks 16, 17, and 18 (April 18-24, April 25-May 1, and May 2-8, respectively)—all being confirmed as infected

21 (23-29/05)

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Occurrence of influenza among patients hospitalized for suspicion of influenza A (H1N1) infection in 2010 at a sentinel hospital in São Paulo, Brazil

requiring mechanical ventilation. Two (33.3%) of the six patients had an underlying disease.

The 9-month-old male infant had received one dose of the vaccine less than 14 days before symptom onset and was co-infected with adenovirus, as confirmed during hospitalization.

That child required mechanical ventilation and developed nosocomial bacterial pneumonia.

The 54-year-old male patient had chronic kidney disease and had been unaware of the immunization program. The 3-month-old child, who was admitted with wheezing and cyanosis, required oxygen therapy. That child was found to have no bacterial infection and was discharged after a few days. The 62-year-old female patient had chronic heart failure and had not been vaccinated against influenza. She presented with bacterial pneumonia due to Staphylococcus aureus and required mechanical ventilation. The 5-year-old girl infected with the influenza B virus had not been vaccinated against influenza and showed no signs of underlying disease but required oxygen therapy. In the 19-year-old female patient infected with the influenza B virus, with no preexisting risk factors, the outcome was unfavorable, the patient being admitted to the ICU and requiring mechanical ventilation. Antiviral drugs were administered to all six patients. Although antiviral therapy was started more than 48 hours after the onset of illness, all six of those patients survived.

In 2009 and 2010, the prevalence of confirmed infection with influenza A (H1N1) virus among patients hospitalized at our sentinel hospital was 19.5% (31/159)(4) and 4.2% (4/96), respectively. In 2010, the Brazilian National Pandemic Influenza A (H1N1) Immunization Program exceeded the goal of vaccinating 80% of the target population, vaccinating over 87 million people, mainly those with chronic diseases, children under 2 years of age, pregnant women, adults in the 20-39 age bracket, health care workers, and indigenous people.(8) Over 45% of the national population was vaccinated, making this program the largest campaign of its kind in the world. The United States, for example, vaccinated 24% of its population, whereas Mexico, France, and Germany vaccinated 20%, 8%, and 6%, respectively.(9) Influenza A (H1N1) vaccination programs might be credited with the decrease in the number of hospitalizations at our hospital in 2010, although the levels of

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influenza A (H1N1) circulating in the population cannot be estimated.

Worldwide, the rate of influenza A (H1N1) infection decreased in 2010, even in European countries, where the coverage of vaccination programs has been low.(10) Possible explanations for this decrease include the use of preventive measures, such as frequent hand washing with soap, water, and alcohol, by the population,(11) as well as the fact that the seroprevalence rates for individuals previously infected with the influenza A (H1N1) virus remain unknown.

The influenza vaccination strategy developed by the Brazilian National Ministry of Health targets people with chronic comorbidities, such as patients with heart disease or renal disease.

Unfortunately, two of our adult patients with influenza had not been immunized. One of those patients had also forgone the seasonal vaccine recommended for the elderly in late April.(12) On August 10, 2010, the World Health Organization announced that H1N1 was in the post-pandemic phase.(13) The influenza A (H1N1) virus is still circulating in the city of São Paulo, albeit at lower levels. By epidemiological week 35 of 2010, only 9.2% of the cases reported to the Department of Health Surveillance of the Brazilian National Ministry of Health had been confirmed as cases of infection with the influenza A (H1N1) virus.(14) The great number of negative suspected cases might suggest the circulation of other respiratory viruses and of bacterial infections in the same period. One limitation of the present study was that negative samples were not tested for other viruses.

The future of influenza A (H1N1) as a seasonal virus is uncertain. However, a considerable number of cases have recently been reported, during winter in the northern hemisphere.(15) Surveillance for influenza remains essential due to the diversity of influenza strains circulating worldwide.

References 1. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde [cited 2010 Apr 13]. Boletim Eletrônico Epidemiológico. Influenza Pandêmica (H1N1) 2009 - Análise da situação epidemiológica e da resposta no ano de 2009. [Adobe Acrobat document, 21p.] Available from: http://portal.saude.gov.br/portal/ arquivos/pdf/ano10_n01_influenza_pandh1n1_br.pdf 2. Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team, Dawood FS, Jain S, Finelli L, Shaw

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MW, Lindstrom S, et al. Emergence of a novel swineorigin influenza A (H1N1) virus in humans. N Engl J Med. 2009;360(25):2605-15. Erratum in: N Engl J Med. 2009;361(1):102.

3. Cabeca TK, Carraro E, Goto JM, Cuba GT, Hidalgo S, Granato CF, et al. Clinical characteristics of 2009 H1N1 patients at a tertiary hospital in Sao Paulo, Brazil. 7th Congresso Paulista de Infectologia; 2010 Jun 3-6; São Paulo, Brazil. São Paulo: Elsevier; 2010.

4. Watanabe AS, Carraro E, Moreira L, Camargo C, Sinohara J, Puerari D, et al. Respiratory virus infections among hospitalized patients with suspected influenza A H1N1 2009 virus during the first pandemic wave in Brazil.

Braz J Infect Dis. 2011;15(3):220-4.

5. Prefeitura de São Paulo [homepage on the internet].

São Paulo: Prefeitura de São Paulo. [updated 2010 Jun 02; cited 2010 Oct 05]. Secretaria Municipal da Saúde - Vacinação Influenza A/H1N1. Available from: http://www.prefeitura.sp.gov.br/cidade/secretarias/ saude/vigilancia_em_saude/doencas_e_agravos/index. php?p=16476 6. Carraro E, Neto DF, Benfica D, SittaPerosa AH, Granato CF, Bellei NC. Applications of a duplex reverse transcription polymerase chain reaction and direct immunofluorescence assay in comparison with virus isolation for detection of influenza A and B. Diagn Microbiol Infect Dis. 2007;57(1):53-7.

7. World Health Organization [homepage on the internet].

Geneva: World Health Organization. [updated 2009 Oct 06; cited 2010 Apr 13]. CDC protocol of realtime RTPCR for influenza A (H1N1). [Adobe Acrobat document, 8p.] Available from: http://www.who.int/csr/ resources/publications/swineflu/CDCRealtimeRTPCR_ SwineH1Assay-2009_20090430.pdf 8. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde [cited 2010 Apr 13]. Informe Técnico Quinzenal de Influenza. Influenza Pandêmica (H1N1) 2009 - Monitoramento da Síndrome Respiratória Aguda Grave (SRAG) em Hospitalizados. [Adobe Acrobat document, 7p.] Available from: http://portal.saude. gov.br/portal/arquivos/pdf/informe_influenza_8_ agosto19_8_10.pdf

9. Portal da Saúde [homepage on the internet]. Brasília: Ministério da Saúde. [updated 2010 Jun 02; cited 2010 Dec 17]. Notícias - Mobilização nacional chega ao fim, mas vacinação contra H1N1 em municípios continua. Available from: http://portal. saude.gov.br/portal/aplicacoes/noticias/default. cfm?pg=dspDetalheNoticia&id_area=124&CO_ NOTICIA=11359 10. Centers for Disease Control and Preventions. [homepage on the internet]. Atlanta: Centers for Disease Control and Preventions. [updated 2011 Apr 1; cited 2011 Apr 1]. Seasonal Flu: International Situation Update. Global Flu Activity Update. Available from: http://www.cdc. gov/flu/international/activity.htm.

11. Machado AA. How to prevent, recognize and diagnose infection with the swine-origin Influenza A (H1N1) virus in humans. J Bras Pneumol. 2009;35(5):464-9.

12. Ministério da saúde. Secretaria de vigilância em saúde.

Departamento de vigilância epidemiológica. Programa nacional de imunizações. Informe Técnico Operacional - Estratégia Nacional de Vacinação Contra o Vírus Influenza Pandêmico (H1N1) 2009. Brasília: Ministério da Saúde; 2010.

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

Geneva: World Health Organization. [updated 2010 Aug 10; cited 2010 Nov 26]. H1N1 in post-pandemic period.

Available from: http://www.who.int/mediacentre/news/ statements/2010/h1n1_vpc_20100810/en/index.html 14. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde [cited 2010 Apr 13]. Informe Técnico Quinzenal de Influenza. Influenza Pandêmica (H1N1) 2009 - Monitoramento da Síndrome Respiratória Aguda Grave (SRAG) em Hospitalizados. [Adobe Acrobat document, 6p.] Available from: http://portal. saude.gov.br/portal/arquivos/pdf/informe_influenza_ setembro_2010.pdf 15. Centers for Disease Control and Preventions. [homepage on the internet]. Atlanta: Centers for Disease Control and Preventions. [updated 2011 Feb 19; cited 2011 Feb 22]. FluView: 2010-2011 Influenza Season - Week 7 ending February 19, 2011. Available from: http://www. cdc.gov/flu/weekly

About the authors Thaís Boim Melchior

Master’s Student in Biological Science. Federal University of São Paulo, São Paulo, Brazil.

Sandra Baltazar Guatura

Laboratory Supervisor. Virology Laboratory, Infections Diseases Branch, Medicine Department, Federal University of São Paulo, São Paulo, Brazil.

Clarice Neves Camargo

Doctoral Student. Federal University of São Paulo, São Paulo, Brazil.

Aripuanã Sakurada Aranha Watanabe

Postdoctoral Student. Federal University of São Paulo, São Paulo, Brazil.

Celso Granato

Head. Virology Laboratory, Infections Diseases Branch, Medicine Department, Federal University of São Paulo, São Paulo, Brazil.

Nancy Bellei

Head. Virology Laboratory, Infections Diseases Branch, Medicine Department, Federal University of São Paulo, São Paulo, Brazil.

J Bras Pneumol. 2011;37(5):655-658

Brief Communication Negative expiratory pressure test: a new, simple method to identify patients at risk for obstructive sleep apnea*, ** Teste de pressão negativa expiratória: um novo método simples para identificar pacientes com risco para apneia obstrutiva do sono

Luis Vicente Franco de Oliveira, Salvatore Romano, Raquel Pastréllo Hirata, Newton Santos de Faria Júnior, Lílian Chrystiane Giannasi, Sergio Roberto Nacif, Fernando Sergio Studart Leitão Filho, Giuseppe Insalaco

Abstract The objective of this article was to describe a new method for assessing expiratory flow limitation during spontaneous breathing, using the negative expiratory pressure test to identify patients at risk for obstructive sleep apnea. Upper airway collapsibility is evaluated by measuring decreases in flow and in expired volume in the first 0.2 seconds after negative expiratory pressure application at 10 cmH2O. The negative expiratory pressure test is easily applied and could be adopted for the evaluation of expiratory flow limitation caused by upper airway obstruction in patients with obstructive sleep apnea.

Keywords: Sleep apnea, obstructive/diagnosis; Sleep apnea, obstructive/prevention and control; Airway resistance.

Resumo O objetivo deste artigo foi descrever um novo método para avaliar a limitação ao fluxo expiratório durante a respiração espontânea, possibilitando a identificação do risco para apneia obstrutiva do sono através do teste de pressão negativa expiratória. A colapsabilidade da via aérea superior é avaliada pela medida da queda de fluxo e de volume expirado a 0,2 segundos imediatamente após a aplicação de pressão negativa expiratória de 10 cmH2O. O teste de pressão negativa expiratória é de fácil aplicação e poderia ser utilizado na avaliação da limitação ao fluxo expiratório causada por obstrução da via aérea superior em sujeitos portadores de apneia obstrutiva do sono.

Descritores: Apneia do Sono Tipo Obstrutiva/diagnóstico; Apneia do Sono Tipo Obstrutiva/prevenção & controle; Resistência das Vias Respiratórias.

In recent years, there has been growing interest in the role that the upper airways play in breathing, especially during sleep. In large part, this interest has come from the increased recognition of the diagnosis of obstructive sleep apnea (OSA), which is characterized by pharyngeal collapse and occlusion during sleep, causing intermittent hypoxia, sudden reduction of intrathoracic pressure, and frequent awakenings with consequent sleep fragmentation.(1) It has been reported that OSA affects 2-5% of the middle-aged population,(2) and the syndrome is associated with significant morbidity and mortality. In a study of the

epidemiology of sleep apnea, involving adults in the city of São Paulo, Brazil, the reported prevalence of OSA was even higher (24.8% and 9.6% in males and females, respectively).(3) In addition, OSA has significant social implications related to accidents,(4) cardiovascular risk,(5) neuropsychological impairment,(6) impaired quality of life,(7) and increased health care utilization.(8) Therefore, the underdiagnosis of OSA can have relevant consequences.

Approximately 50% of individuals with OSA are also hypertensive.(9) In patients with OSA, the relative odds of having a stroke are increased by 58% and those of developing coronary artery

* Study carried out under the auspices of the Graduate Program in Rehabilitation Sciences, Nove de Julho University, São Paulo, Brazil.

Correspondence to: Luis Vicente Franco de Oliveira. Graduate Program in Rehabilitation Sciences, Nove de Julho University, Avenida Francisco Matarazzo, 612, Água Branca, CEP 05001-100, São Paulo, SP, Brazil.

Tel./Fax: 55 11 3665-9890. E-mail: oliveira.lvf@pq.cnpq.br Financial support: This study received financial support from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazilian National Council for Scientific and Technological Development; Research Productivity Grant no. 307618/2010-2).

Submitted: 12 April 2011. Accepted, after review: 4 August 2011. ** A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

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disease are increased by 27%.(10) The mechanism responsible for pharyngeal collapse during sleep remains uncertain. Investigators have implicated anatomic factors(11) and neuromuscular control factors,(12) as well as fluid accumulations and fat deposits,(13) as factors that can increase pharyngeal collapsibility during sleep in OSA patients.

Despite the abundance of scientific evidence, OSA is still underdiagnosed in the general population. This is due to multiple causes, such as lack of knowledge on the part of physicians and the limited access that patients have to diagnosis and treatment of OSA.(14) In addition, the diagnostic procedures are expensive, and predictive criteria are still unsatisfactory. Obesity parameters are important predictors, although not all OSA patients are obese and not all obese subjects have OSA. The identification of new markers of OSA would be useful. Because increased upper airway collapsibility is one of the main determinants of OSA,(15) the response to the application of negative expiratory pressure (NEP) could be a predictor of this disorder.

The NEP test involves applying negative pressure at the mouth during expiration.

It is performed during waking and requires minimal subject cooperation. It is based on the principle that, in the absence of expiratory flow limitation (EFL), the increase in the pressure gradient between the alveoli and the airway opening caused by NEP should result in increased expiratory flow. Subjects in whom NEP application does not elicit an increase in flow during the terminal portion of the tidal expiration compared with the previous flowvolume loop are classified as flow-limited. More recently, NEP has also been used in studies of upper airway characteristics in obese subjects and subjects with OSA. It has been suggested that, in the absence of intrathoracic airway obstruction, the response to NEP application reflects the degree of upper airway collapsibility.

(16-20)

In obese subjects and subjects with OSA, EFL has to date been quantified by the proportion of tidal expiration over which NEP does not induce any appreciable increase in flow with respect to the control expired tidal volume. However, this method does not always make it possible to discern between EFL of extrathoracic origin and EFL of intrathoracic origin.(19) Alternative J Bras Pneumol. 2011;37(5):659-663

assessments of the capacity of NEP application to detect upper airway obstruction could be useful. The application of NEP elicits a flow spike, mainly because of dynamic airway compression downstream from the compliant oral and neck structures, and, to a small extent, because of the common-mode rejection ratio of the differential pressure transducer used to measure flow,(17) followed by a decrease in flow of variable degrees among subjects. The sudden decrease in flow is caused by an increase in resistance of the oropharyngeal structures,(16) which reflects upper airway collapsibility (extrathoracic EFL).

During the test, NEP is generated by a circular Venturi device (AeroMech Devices; Almonte, ON, Canada) attached to a tank of compressed air. The Venturi device includes a solenoid valve. The solenoid valve has an opening time of 50 ms; it is automatically activated in early expiration and remains open for 2 s by software control (DirecWin version 2.18a; Raytech Instruments Inc., Vancouver, BC, Canada).

A pneumotachograph (model 3830; Hans Rudolph, Kansas City, MO, USA) is connected to the mouthpiece. As shown in Figure 1, flow and mouth pressure are also measured (DirecNEP model 200A; Raytech Instruments Inc.). An NEP value of 10 cmH2O was assessed by occluding the mouthpiece with a stopper and adjusting the compressed air flow.

The application of NEP during early expiration produces an immediate peak flow, followed by a sudden decrease of a variable degree. Upper airway collapsibility is evaluated by measuring flow limitation as Δflow, expressed as a percentage of the peak flow immediately after NEP application. The minimum flow is identified in the first 200 ms of NEP application to avoid reflex and voluntary reactions to the NEP stimulus.(16) Values of ∆flow% are calculated considering the highest of seven measurements.

Upper airway collapsibility is also evaluated by measuring expired volume in the first 0.2 s (V0.2) after NEP application (Figure 2). These values are expressed as a percentage of the mean inspiratory volume of the three breaths preceding NEP application. Measured volumes are accepted only when differences between inspiration and expiration for each of the three previous breaths were less than 10%. Values of V0.2 are calculated as the mean of seven measurements.

Negative expiratory pressure test: a new, simple method to identify patients at risk for obstructive sleep apnea

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Figure 1 - Experimental setup used in the negative expiratory pressure (NEP) test. The mouth pressure and flow were simultaneously registered during spontaneous breathing and during NEP application. A/D: analog/ digital.

2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 –0.2 –0.4 –0.6

to evaluate upper airway obstruction by flow interruption technique, i.e., extrathoracic EFL measured as Δflow expressed as a percentage of the peak flow immediately after NEP application.(16) In a validation study,(20) 37 subjects underwent the NEP test in a sitting position at 10 cmH2O. The analysis performed with Δflow% showed a strong correlation with the apneahypopnea index. We also assessed EFL induced

by NEP as flow, in the flow-volume loop, during NEP application, which was equal to or lower than the corresponding flow in any part of the control flow-volume loop (EFL), expressed as a percentage of control tidal volume (%VT) and Δflow%, based on the mean of four measurements.(16) A controlled study involving 48 subjects tested this new measure as described above (with ∆flow% and V0.2 measurements),

Peak flow NEP application

0

1

2

3

4

5

6

∆V

Flow (L/s)

In the present study, care was taken to keep the neck in a neutral position during the test.

The subjects performed the test while awake, during quiet breathing with a nose clip, in the sitting and supine positions. At least four regular breaths were allowed between NEP applications.

The flow and mouth pressure signals were filtered through a low-pass filter and sampled at 200 Hz. Both digital signals were displayed in real time on the computer screen and stored on the computer for subsequent analysis. Data analysis was performed using software developed by the Italian National Research Council, Institute of Biomedicine and Molecular Immunology A. Monroy, Palermo, Italy, written in MATLAB 6.5 (The MathWorks, Natick, MA, USA).

This method was initially used to assess intrathoracic EFL in patients with COPD.(17) In another study, the authors have proposed

V0.2

7

8

9

10

Time (s)

Figure 2 - Measurement techniques of upper airway collapsibility: expiratory volume within 0.2 s (V0.2), expressed as a percentage of the mean inspiratory volume of the three breaths preceding negative expiratory pressure (NEP) application, and the decrease in flow (ΔV), expressed as a percentage of the peak flow.

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in order to investigate the usefulness of this technique as a screening test for severe OSA (apnea-hypopnea index > 30 events/h). In both analyses, significant differences were found between normal subjects and those with apnea, indicating that this might be a useful parameter for identifying subjects with severe OSA.(20) In conclusion, the NEP test is easily applied and could facilitate the evaluation of EFL caused by upper airway obstruction in individuals with OSA.

References 1. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force.

Sleep. 1999;22(5):667-89.

2. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230-5.

3. Tufik S, Santos-Silva R, Taddei JA, Bittencourt LR. Obstructive sleep apnea syndrome in the Sao Paulo Epidemiologic Sleep Study. Sleep Med. 2010;11(5):441-6.

4. Sassani A, Findley LJ, Kryger M, Goldlust E, George C, Davidson TM. Reducing motor-vehicle collisions, costs, and fatalities by treating obstructive sleep apnea syndrome. Sleep. 2004;27(3):453-8.

5. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study.

JAMA. 2000;283(14):1829-36.

6. Kim HC, Young T, Matthews CG, Weber SM, Woodward AR, Palta M. Sleep-disordered breathing and neuropsychological deficits. A population-based study.

Am J Respir Crit Care Med. 1997;156(6):1813-9.

7. Flemons WW, Tsai W. Quality of life consequences of sleep-disordered breathing. J Allergy Clin Immunol.

1997;99(2):S750-6.

8. Otake K, Delaive K, Walld R, Manfreda J, Kryger MH. Cardiovascular medication use in patients with undiagnosed obstructive sleep apnoea. Thorax.

2002;57(5):417-22.

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9. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000;342(19):1378-84.

10. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier Nieto F, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med. 2001;163(1):19-25.

11. Schwab RJ, Gefter WB, Hoffman EA, Gupta KB, Pack AI. Dynamic upper airway imaging during awake respiration in normal subjects and patients with sleep disordered breathing. Am Rev Respir Dis. 1993;148(5):1385-400.

12. Jeffries B, Brouillette RT, Hunt CE. Electromyographic study of some accessory muscles of respiration in children with obstructive sleep apnea. Am Rev Respir Dis. 1984;129(5):696-702.

13. Brennick MJ, Pack AI, Ko K, Kim E, Pickup S, Maislin G, et al. Altered upper airway and soft tissue structures in the New Zealand Obese mouse. Am J Respir Crit Care Med. 2009;179(2):158-69.

14. Logan AG, Perlikowski SM, Mente A, Tisler A, Tkacova R, Niroumand M, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens. 2001;19(12):2271-7.

15. Fogel RB, Malhotra A, White DP. Sleep. 2: pathophysiology of obstructive sleep apnoea/hypopnoea syndrome. Thorax. 2004;59(2):159-63.

16. Insalaco G, Romano S, Marrone O, Salvaggio A, Bonsignore G. A new method of negative expiratory pressure test analysis detecting upper airway flow limitation to reveal obstructive sleep apnea. Chest.

2005;128(4):2159-65.

17. Koulouris NG, Valta P, Lavoie A, Corbeil C, Chassé M, Braidy J, et al. A simple method to detect expiratory flow limitation during spontaneous breathing. Eur Respir J. 1995;8(2):306-13.

18. Tantucci C, Duguet A, Ferretti A, Mehiri S, Arnulf I, Zelter M, et al. Effect of negative expiratory pressure on respiratory system flow resistance in awake snorers and nonsnorers. J Appl Physiol. 1999;87(3):969-76.

19. Van Meerhaeghe A, Delpire P, Stenuit P, Kerkhofs M. Operating characteristics of the negative expiratory pressure technique in predicting obstructive sleep apnoea syndrome in snoring patients. Thorax.

2004;59(10):883-8.

20. Romano S, Salvaggio A, Hirata RP, Lo Bue A, Picciolo S, Oliveira LV, et al. Upper airway collapsibility evaluated by a negative expiratory pressure test in severe obstructive sleep apnea. Clinics (Sao Paulo). 2011;66(4):567-72.

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About the authors Luis Vicente Franco de Oliveira

Professor. Graduate Program in Rehabilitation Sciences, Nove de Julho University, São Paulo, Brazil.

Salvatore Romano

Researcher. Respiratory Pathophysiology Section, Italian National Research Council “A. Monroy” Institute of Biomedicine and Molecular Immunology, Palermo, Italy.

Raquel Pastréllo Hirata

Master’s Student. Graduate Program in Rehabilitation Sciences, Nove de Julho University, São Paulo, Brazil.

Newton Santos de Faria Júnior

Master’s Student. Graduate Program in Rehabilitation Sciences, Nove de Julho University, São Paulo, Brazil.

Lílian Chrystiane Giannasi

Associate Researcher. Sleep Laboratory, Nove de Julho University, São Paulo, Brazil.

Sergio Roberto Nacif

Associate Researcher. Sleep Laboratory, Nove de Julho University, São Paulo, Brazil.

Fernando Sergio Studart Leitão Filho

Professor. University of Fortaleza – UNIFOR – School of Medicine, Fortaleza, Brazil.

Giuseppe Insalaco

Senior Researcher. Respiratory Pathophysiology Section, Italian National Research Council “A. Monroy” Institute of Biomedicine and Molecular Immunology, Palermo, Italy.

J Bras Pneumol. 2011;37(5):659-663

Brief Communication Identification of Mycobacterium bovis among mycobacterial isolates from human clinical specimens at a university hospital in Rio de Janeiro, Brazil*, ** Identificação de Mycobacterium bovis em cepas micobacterianas isoladas de espécimes clínicos humanos em um complexo hospitalar na cidade do Rio de Janeiro

Luciana Fonseca Sobral, Rafael Silva Duarte, Gisele Betzler de Oliveira Vieira, Marlei Gomes da Silva, Neio Boechat, Leila de Souza Fonseca

Abstract In 2005 and 2006, 8,121 clinical specimens submitted to the Mycobacteriology Laboratory of the Clementino Fraga Filho University Hospital/Thoracic Diseases Institute, in the city of Rio de Janeiro, Brazil, were inoculated on Löwenstein-Jensen medium containing glycerol and pyruvate. There were 79 mycobacteria isolates that presented growth only on pyruvate-containing medium, and those isolates were selected for the presumptive identification of Mycobacterium bovis. The selected isolates were screened with biochemical tests, PCR amplification (with the specific primers Rv0577 and Rv1510), and pyrazinamide susceptibility tests. All of the strains isolated showed specific phenotypical and genotypical patterns characteristic of M. tuberculosis, and no M. bovis strains were detected.

Keywords: Tuberculosis; Mycobacterium bovis; Polymerase chain reaction.

Resumo Entre 2005 e 2006, 8.121 espécimes clínicos enviados ao Laboratório de Micobactérias do Hospital Universitário Clementino Fraga Filho/Instituto de Doenças do Tórax, no Rio de Janeiro, RJ, foram inoculados em meio LöwensteinJensen contendo glicerol e piruvato. Desses espécimes, 79 isolados de micobactérias tiveram crescimento somente em meio com piruvato, sendo selecionados para a identificação presuntiva de Mycobacterium bovis. Esses isolados foram submetidos à identificação por testes bioquímicos, amplificação por PCR com primers específicos (Rv0577 e Rv1510) e teste de suscetibilidade à pirazinamida. Todas as cepas apresentaram padrões fenotípicos e genotípicos de M. tuberculosis, não sendo detectado M. bovis.

Descritores: Tuberculose; Mycobacterium bovis; Reação em cadeia da polimerase.

Historically, Mycobacterium bovis has been associated with extrapulmonary tuberculosis in children, usually due to the consumption of raw milk from infected cows.(1) This framework is still in place in developing countries, especially in Africa, where there are reports that M. bovis has been isolated in 10-20% of children with cervical lymphadenitis.(2) In addition, in middleand high-income countries, the pattern of M. bovis infection has changed, causing disease

in hunters,(3) as well as in immunosuppressed individuals, such as alcoholics and HIV-infected patients.(4) In the United States, M. bovis infection has been identified in immigrant communities, particularly in those with a history of consuming unpasteurized dairy products.(5) Although bovine tuberculosis has been identified in Brazil,(6) there are no data available on human tuberculosis caused by M. bovis in the country.

The lack of reporting might be due to the fact

* Study carried out in the Mycobacteriology Laboratory of the Hospital Universitário Clementino Fraga Filho/Instituto de Doenças do Tórax da Universidade Federal do Rio de Janeiro – HUCFF/IDT-UFRJ, Clementino Fraga Filho University Hospital/Thoracic Diseases Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil – and at Professor Paulo de Góes Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Correspondence to: Luciana Fonseca Sobral. Laboratório de Bacteriologia Veterinária, Universidade Federal Fluminense, CEP 24210‑130, Niterói, RJ, Brazil.

Tel. 55 21 2629-2435. Fax: 55 21 2629-2432. E-mail: lucianafonsecas@gmail.com Financial support: This study received financial support from the Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development), Institutos Nacionais de Ciência e Tecnologia (INCT, National Institutes of Science and Technology), and the International Clinical Operational and Health Services Research and Training Award (ICOHRTA) Mandate (AIDS/TB Grant no. 5 U2R TW006883-03). Luciana F. Sobral is the recipient of a grant from Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ, Rio de Janeiro Research Foundation).

Submitted: 8 December 2010. Accepted, after review: 2 May 2011. ** A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

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Identification of Mycobacterium bovis among mycobacterial isolates from human clinical specimens at a university hospital in Rio de Janeiro, Brazil

that few mycobacteriology laboratories routinely use culture media containing pyruvate. However, there is considerable epidemiological interest on the prevalence of zoonotic tuberculosis in Brazil.

In addition, the fact that M. bovis is naturally resistant to pyrazinamide, one of the three drugs used in the treatment of tuberculosis, gives the isolation and identification of M. bovis in human clinical specimens a practical purpose in that this knowledge can inform decisions regarding treatment. The Mycobacteriology Laboratory of the Hospital Universitário Clementino Fraga Filho/Instituto de Doenças

do Tórax da Universidade Federal do Rio de Janeiro (HUCFF/IDT-UFRJ, Clementino Fraga Filho University Hospital/Thoracic Diseases Institute, Federal University of Rio de Janeiro) receives approximately 5,500 samples annually.

The hospital is a referral center for the diagnosis and treatment of severe forms of chronic and acute diseases, as well as of tuberculosis/HIV co-infection, in the state of Rio de Janeiro, Brazil. The objective of the present study was to investigate the prevalence of M. bovis in patients at the hospital.

Between 2005 and 2006, all clinical specimens referred to the Laboratory of Mycobacteriology of the HUCFF/IDT-UFRJ were decontaminated with the Kubica method,(7) and 0.2 mL were inoculated into two tubes of glycerol-containing Löwenstein-Jensen (LJ) culture medium and into one tube of pyruvatecontaining LJ medium. The tubes were incubated at 37°C for up to 90 days.(7) The phenotypic identification of the M. tuberculosis complex was performed by means of biochemical tests (for niacin production, nitrate reduction, and thermal inactivation of catalase).(7,8) Specimens were also submitted to the pyrazinamide susceptibility test, as described by Canetti et al.(9): culture medium (pH = 5.0-5.2) + 100 mg/mL of pyrazinamide. In that test, the critical proportion of pyrazinamide is 10%.(7) For the molecular identification, DNA extraction was carried out in accordance with national guidelines.

(10) Amplification was performed according to Huard et al.(11) with modifications. In brief, two PCR mixes were prepared, each containing 1.25 mL of DMSO, 2.5 mL of 10× buffer, 0.75 mL of 50 mM magnesium chloride, 0.5 mL of 10 mM dNTP (A, T, C, and G), 13.8 mL of purified water, 0.2 mL of platinum Taq

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polymerase (Invitrogen, Karlsruhe, Germany), and 5 mL of bacterial DNA, in a final volume of 25 mL. To each of the mixes, 0.5 mL of one of the primers used (Rv1510 and Rv0577) were added.(11) The PCR amplification was performed as follows: 35 cycles of denaturation at 94°C for 1 min, annealing at 60°C for 1 min, extension at 72°C for 1 min; and a final extension step at 72°C for 10 min. The PCR product was run on a 1% agarose gel containing 0.5% ethidium bromide solution and observed under UV light.

During the study period, our laboratory received 10,861 clinical samples for the routine diagnosis of mycobacterial infection, of which 8,121 were inoculated into tubes containing LJ medium + sodium pyruvate, yielding 1,793 positive cultures. Of those, 79 mycobacteria strains recovered from the clinical specimens presented growth only on LJ medium containing sodium pyruvate, and those isolates were selected for the presumptive identification of M. bovis. The screening using three biochemical tests—niacin production, nitrate reduction, and catalase inactivation—showed that 57 isolates belonged to the M. tuberculosis complex, 14 were nontuberculous mycobacteria, and 8 strains did not grow in a second culture in a new tube with LJ (Table 1).

All M. tuberculosis complex isolates showed the standard M. tuberculosis biochemical pattern: niacin production, nitrate reduction, and negativity for catalase. In order to confirm these data, a few isolates were randomly selected and submitted to the pyrazinamide susceptibility test. Scorpio et al.(12) cloned the pyrazinamidase gene (pncA) from M. tuberculosis and M. bovis and found that a mutation was only observed in strains of M. bovis and of several subspecies of BCG. This mutation makes M. bovis and BCG intrinsically resistant to pyrazinamide.

Table 1 - Origins of the clinical specimens giving rise to isolates identified as belonging to the Mycobacterium tuberculosis complex or as nontuberculous mycobacteria.

Source of clinical M. tuberculosis NTM specimen complex Pulmonary 45 14 Extrapulmonary 10 0 Unknown 2 0 Total 57 14 NTM: Nontuberculous mycobacteria.

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Jong et al.(13) used the pyrazinamide test to identify M. bovis among 1,526 isolates and found that all 11 M. bovis isolates were resistant to pyrazinamide, compared with only 1.3% of the M. tuberculosis isolates. Of the 28 isolates identified as M. tuberculosis in the present study, only 3 were found to be resistant to pyrazinamide.

In making the differential diagnosis between M. tuberculosis and M. bovis, it is advisable to use not only phenotypic tests but also genotypic markers,(14) and various molecular biology techniques have been used successfully in the characterization of M. tuberculosis isolates.

Huard et al.(11) developed a PCR panel based on the deletions found in the complex in order to identify these species, using seven primers that amplified regions within the 16S rRNA loci. In the present study, we chose to perform PCR with two pairs of primers (Rv1510 and Rv0577) for better identification of M. tuberculosis isolates.

The gene Rv0577 is present in all species of the M. tuberculosis complex, albeit absent in most nontuberculous mycobacteria, whereas the Rv1510 gene is known to be found in M. tuberculosis, M. africanum types I and II, and M. canettii, albeit absent in M. bovis and BCG. The 42 isolates that grew only on pyruvate and had a biochemical pattern consistent with M. tuberculosis were submitted to PCR, and all showed positive amplification for Rv1510, which is not found in M. bovis strains. Of the 42 isolates tested for Rv0577, 33 showed positive amplification, indicating that the isolates belonged to the M. tuberculosis complex (Table 2).

The results of the phenotypic and genotypic identification carried out in our study indicate that, during the study period, no M. bovis isolates were obtained. This result seems surprising because bovine tuberculosis is still prevalent in our country. In 2004, a study involving 454,108 animals showed a prevalence ranging from 0.37% in the southeast to 3.62% in the north.

(6) In a study conducted in the state of Rio de

Janeiro,(15) 12.7% of the dairy calves tested were found to be reactive to the skin prick test.

The present study was conducted at a tertiary hospital that serves as a referral center for transplant assessment, as well as for AIDS, cancer, and other diseases, which would facilitate the externalization of the M. bovis tuberculosis.

Kantor et al.(16) extensively reviewed the international literature on zoonotic tuberculosis in Latin America, finding a prevalence ranging from 0.0% to 2.5%. According to the authors, human tuberculosis caused by M. bovis has been reported only in Argentina, Brazil, Ecuador, and Venezuela. The same authors showed that, during a 20-year period (1987-2006), the Professor Hélio Fraga Referral Center, located in the city of Rio de Janeiro and operating under the auspices of the Brazilian National Ministry of Health, identified only one case of tuberculosis caused by M. bovis, and that strain was isolated from the blood of an HIV-positive patient. From 2001 to 2005, the referral laboratories of the Adolfo Lutz Institute, located in the city of São Paulo, tested approximately 355,000 cultures using a pyruvate medium and isolated only two M. bovis strains, one from a lymph node sample and one from a liquor sample. In Rio Grande do Sul, a state with a tradition of animal husbandry, M. bovis was not identified among the 5,000 M. tuberculosis isolates tested. We were unable to identify any strain with an M. bovis profile among 1,793 mycobacteria isolates recovered during the study period.

One limitation of the present study is that the HUCFF/IDT-UFRJ primarily serves patients from urban areas. Although our data and those obtained by the other authors cited above showed no isolation of M. bovis, the presence of M. bovis in raw milk was demonstrated by two groups of authors in São Paulo.(17,18) Given that there is significant consumption of raw milk among the Brazilian population, these studies demonstrated that there is a potential risk of contamination by M. bovis that might lead

Table 2 - Results of additional tests for the identification of Mycobacterium bovis in the isolates tested.

Pyrazinamide PCR primer Rv0677 PCR primer Rv1510 Total susceptibility test result Positive Negative Positive Susceptible 19 6 25 25 Resistant 2 1 3 3 Not performed 12 2 14 14 Total 33 9 42 42

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Identification of Mycobacterium bovis among mycobacterial isolates from human clinical specimens at a university hospital in Rio de Janeiro, Brazil

to infection and illness. However, there have been very few reports of tuberculosis caused by M. bovis in the country. Zoonotic tuberculosis in Brazil is definitely underreported. Cultures for mycobacteria are performed, in regional and national laboratories, only in special cases or for drug resistance surveys and only on glycerol-containing media, on which M. bovis grows poorly. It is also possible that the lack of isolation of M. bovis is the result of improved control activities of bovine tuberculosis.

Supporting this hypothesis is the fact that, in 2001, the Brazilian National Program for the Control and Eradication of Brucellosis and Animal Tuberculosis made it mandatory to carry out skin prick tests in animals owned by milk production cooperatives.

References 1. Thoen CO, Lobue PA, Enarson DA, Kaneene JB, de Kantor IN. Tuberculosis: a re-emerging disease in animals and humans. Vet Ital. 2009;45(1):135-81.

2. Oloya J, Opuda-Asibo J, Kazwala R, Demelash AB, Skjerve E, Lund A, et al. Mycobacteria causing human cervical lymphadenitis in pastoral communities in the Karamoja region of Uganda. Epidemiol Infect.

2008;136(5):636-43.

3. Wilkins MJ, Meyerson J, Bartlett PC, Spieldenner SL, Berry DE, Mosher LB, et al. Human Mycobacterium bovis infection and bovine tuberculosis outbreak, Michigan, 1994-2007. Emerg Infect Dis. 2008;14(4):657-60.

4. Evans JT, Smith EG, Banerjee A, Smith RM, Dale J, Innes JA, et al. Cluster of human tuberculosis caused

by Mycobacterium bovis: evidence for person-to-person transmission in the UK. Lancet. 2007;369(9569):1270-6.

5. Rodwell TC, Moore M, Moser KS, Brodine SK, Strathdee SA. Tuberculosis from Mycobacterium bovis in binational communities, United States. Emerg Infect Dis. 2008;14(6):909-16.

6. Roxo E. Situação atual da tuberculose bovina no Brasil. In: Secretaria de Defesa Agropecuária. Programa Nacional de Controle e Erradicação de Brucelose e Tuberculose Animal, PNCEBT DDD2005. São Paulo: SDA; 2005. p. 1-5.

7. Brasil. Ministério da Saúde. Centro de Vigilância em Saúde. Centro de Referência Prof. Hélio Fraga. Manual

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de Bacteriologia da Tuberculose. Rio de Janeiro: Ministério da Saúde, Centro de Vigilância em Saúde, Centro de Referência Prof. Hélio Fraga, Departamento de Vigilância Epidemiológica, Coordenação Geral de Laboratórios de Saúde Pública; 1994.

8. Kent, PT, Kubica, GP. Public health mycobacteriology: A guide for the level III laboratory. Atlanta: U. S. Department of Health and Human Services; 1985.

9. 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.

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

Manual nacional de vigilância laboratorial da tuberculose e outras micobactérias. Brasília: Ministério da Saúde; 2008.

11. Huard RC, Lazzarini LC, Butler WR, van Soolingen D, Ho JL. PCR-based method to differentiate the subspecies of the Mycobacterium tuberculosis complex on the basis of genomic deletions. J Clin Microbiol.

2003;41(4):1637-50.

12. Scorpio A, Collins D, Whipple D, Cave D, Bates J, Zhang Y. Rapid differentiation of bovine and human tubercle bacilli based on a characteristic mutation in the bovine pyrazinamidase gene. J Clin Microbiol.

1997;35(1):106-10.

13. de Jong BC, Onipede A, Pym AS, Gagneux S, Aga RS, DeRiemer K, et al. Does resistance to pyrazinamide accurately indicate the presence of Mycobacterium bovis? J Clin Microbiol. 2005;43(7):3530-2.

14. Viana-Niero C, Leão SC. Limitations of the use of the mtp40 fragment as a marker of differentiation between Mycobacterium tuberculosis and M. bovis. J Bras Pneumol. 2004;30(4):498-500.

15. Lilenbaum W, Schettini J, Ribeiro ER, Souza GN, Moreira EC, Fonseca LS. Tuberculose bovina: prevalência e estudo epidemiológico em treze propriedades de diferentes sistemas de produção na Região dos Lagos do Estado do Rio de Janeiro. Rev Bras Med Vet. 1998;20:120-3.

16. de Kantor IN, Ambroggi M, Poggi S, Morcillo N, Da Silva Telles MA, Osório Ribeiro M, et al. Human Mycobacterium bovis infection in ten Latin American countries. Tuberculosis (Edinb). 2008;88(4):358-65.

17. Pardo RB, Langoni H, Mendonça LJ, Chi KD. Isolamento de Mycobacterium spp. do leite de vacas suspeitas e positivas para tuberculose. Braz J Vet Res Anim Sci. 2001;38(6):284-7.

18. Leite CQ, Anno IS, Leite SR, Roxo E, Morlock GP, Cooksey RC. Isolation and identification of mycobacteria from livestock specimens and milk obtained in Brazil. Mem Inst Oswaldo Cruz. 2003;98(3):319-23.

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About the authors Luciana Fonseca Sobral

Biologist. Universidade Federal Fluminense, Niterói, Brazil.

Rafael Silva Duarte

Associate Professor. Prof. Paulo de Góes Institute of Microbiology, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Gisele Betzler de Oliveira Vieira

Pharmacist. Mycobacteriology Laboratory of Hospital Universitário Clementino Fraga Filho/Instituto de Doenças do Tórax da Universidade Federal do Rio de Janeiro – HUCFF/IDT-UFRJ, Clementino Fraga Filho University Hospital/Thoracic Diseases Institute, Federal University of Rio de Janeiro – Rio de Janeiro, Brazil.

Marlei Gomes da Silva

Biologist. Professor Paulo de Góes Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Neio Boechat

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

Leila de Souza Fonseca

Full Professor. Professor Paulo de Góes Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

J Bras Pneumol. 2011;37(5):664-668

Review Article Predictive parameters for weaning from mechanical ventilation* Parâmetros preditivos para o desmame da ventilação mecânica

Sérgio Nogueira Nemer, Carmen Sílvia Valente Barbas

Abstract The use of predictive parameters for weaning from mechanical ventilation is a rather polemic topic, and the results of studies on this topic are divergent. Regardless of the use of these predictive parameters, the spontaneous breathing trial (SBT) is recommended. The objective of the present study was to review the utility of predictive parameters for weaning in adults. To that end, we searched the Medline, LILACS, and PubMed databases in order to review articles published between 1991 and 2009, in English or in Portuguese, using the following search terms: weaning/desmame, extubation/extubação, and weaning indexes/indices de desmame. The use of clinical impression is an inexact means of predicting weaning outcomes. The most widely used weaning parameter is the RR/tidal volume (VT) ratio, although this parameter presents heterogeneous results in terms of accuracy. Other relevant parameters are MIP, airway occlusion pressure (P0.1), the P0.1/MIP ratio, RR, VT, minute volume, and the index based on compliance, RR, oxygenation, and MIP. An index created in Brazil, the integrative weaning index, has shown high accuracy. Although recommended, the SBT is inaccurate, approximately 15% of extubation failures going unidentified in SBTs. The main limitations of the weaning indexes are related to their use in specific populations, the cut-off points selected, and variations in the types of measurement. Since the SBT and the clinical impression are not 100% accurate, the weaning parameters can be useful, especially in situations in which the decision as to weaning is difficult.

Keywords: Weaning; Intensive care units; Ventilators, mechanical; Respiration, artificial.

Resumo A utilização de parâmetros preditivos para o desmame da ventilação mecânica é um tema de grande polêmica, com estudos divergindo sobre esse assunto. Independentemente da utilização desses parâmetros preditivos, o teste de respiração espontânea (TRE) é recomendado. O objetivo do presente estudo foi revisar a utilidade dos parâmetros preditivos para o desmame em adultos. Para tanto, foram pesquisadas as bases de dados Medline, LILACS e PubMed e foram selecionados artigos publicados entre 1991 e 2009, em língua inglesa ou portuguesa, utilizando-se os seguintes termos: weaning/desmame; extubation/extubação e weaning indexes/índices de desmame. A utilização da impressão clínica é uma forma inexata para predizer o desfecho do desmame. O parâmetro mais utilizado é a relação FR/volume corrente (VT), embora essa apresente resultados heterogêneos em termos de acurácia. Outros parâmetros relevantes são PImáx, pressão de oclusão nas vias aéreas (P0,1), relação P0,1/PImáx, FR, VT, volume minuto e o índice composto por complacência, FR, oxigenação e PImáx. Criado no Brasil, o índice integrativo de desmame tem mostrado alta acurácia. Embora recomendado, o TRE não é acurado, não identificando aproximadamente 15% das falhas de extubação. As principais limitações dos índices de desmame são devidas ao seu uso em populações específicas, aos pontos de cortes selecionados e a variações nas formas de mensuração. Como o TRE e a impressão clínica não têm 100% de acurácia, os parâmetros de desmame podem ser úteis, principalmente em situações nas quais o processo de decisão para o desmame é difícil.

Descritores: Desmame; Unidades de terapia intensiva; Ventiladores mecânicos; Respiração artificial.

* Study carried out at the Niterói Hospital de Clínicas, Niterói, Brazil, and at the University of São Paulo School of Medicine Hospital de Clínicas, São Paulo, Brazil.

Correspondence to: Sérgio Nogueira Nemer. Rua Miguel de Frias, 95, bloco B, apto. 101, Icaraí, CEP 24220-001, Niterói, RJ, Brasil.

Tel 55 21 2729-1070. E-mail: snnemer@gmail.com.br Financial support: None.

Submitted: 4 February 2010. Accepted, after review: 31 August 2010.

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Introduction Although weaning from mechanical ventilation (MV) is successful in most cases, the first attempt fails in 20% of patients.(1) In addition, weaning accounts for over 40% of the total MV time,(1) the proportion varying in function of the etiology of respiratory failure. Prolonged MV is associated with various complications, such as ventilatorassociated pneumonia,(2) ventilator-induced diaphragmatic dysfunction,(3,4) and critical illness polyneuropathy.(5) Therefore, in order to avoid these and other complications, patients should be weaned from MV as soon as possible. There are various weaning indices, all having the objective of establishing the prognosis for this process, which, contrary to what many think, cannot be established by clinical impression and the spontaneous breathing trial (SBT) alone.(6) Therefore, clinical impression in combination with an evaluation of the weaning indices and the SBT might provide a more precise prognosis for weaning from MV. The weaning indices are used in many ICUs, and various review articles have either recommended or have not ruled out the use of these indices.(1,6-11) Some of the most well-known weaning indices, such as the RR/tidal volume (VT) ratio and MIP, have been incorporated into the routine of many ICUs and are measured prior to extubation. However, few of these indices have high accuracy,(12) and one study recommended that they not be used.(13) The objective of the present study was to review the utility of the weaning indices in adults being treated in a general ICU, with a focus on the most widely used and most accurate indices.

Research strategy The present review was carried out by searching the Medline, LILACS, and PubMed databases in order to review articles published between 1991 and 2009, in English or in Portuguese, using the following search terms: weaning/desmame, extubation/extubação, and weaning indexes/índices de desmame (in intubated adults). We selected the reviews that were based on evidence or consensuses and those of greatest relevance, as well as the original articles of greatest impact, which had been cited in the reviews selected. We rejected articles that J Bras Pneumol. 2011;37(5):669-679

focused more on comparing modalities of MV weaning than on the weaning indices per se.

Essential definitions Prolonged MV is defined as MV for more than 21 days and for more than 6 h/day.(10) The process of release from ventilatory support is defined as weaning from MV.(6) The SBT is the evaluation of tolerance to spontaneous breathing, for a period of 30 min to 2 h, on pressure support ventilation (PSV) at 7 cmH2O, on continuous positive airway pressure (CPAP), or unassisted through a T-tube.

(6) It is recommended that the SBT be performed prior to extubation.(7,8) Successful weaning from MV is defined as spontaneous breathing (not requiring reintubation/MV) for at least the first 48 h after extubation.(8) A distinction is made between weaning failure (intolerance to the SBT without ventilatory support) and extubation failure (intolerance to extubation).(14) A weaning index or predictive parameter for weaning is a criterion that evaluates a given physiological aspect of respiratory function, with the objective of distinguishing between patients who might tolerate the SBT and those who might not.(15) The weaning indices should be evaluated before the SBT, which functions as a diagnostic test to determine the probability of successful extubation.(8) Integrative parameters are those that evaluate more than one physiological aspect of respiratory function.

How can the accuracy of the predictive parameters for MV weaning be evaluated?

The diagnostic tests that are most widely used to evaluate the accuracy of the parameters for weaning from MV are as follows: sensitivity; specificity; positive predictive value (PPV); negative predictive value (NPV); positive likelihood ratio (PLR); negative likelihood ratio (NLR); post-test probability of weaning success or failure, determined by application of Bayes’ theorem(13,16-18); and calculation of the area under the curve (AUC) of the ROC curve, which is the test that is most widely used.(2,13,17-19) In the context of MV weaning, the sensitivity of a measure is defined as its ability to accurately identify, from among the patients who present with a positive index (e.g., a RR/VT ratio < 105

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Chart 1 - Diagnostic tests available to evaluate the accuracy of the predictive parameters for weaning from mechanical ventilation.

Test Formula Sensitivity TP/(TP + FN) = frequency of TP = [1 − frequency of FN] Specificity TN/(TN + FP) = frequency of TN = [1 − frequency of FP] PPV TP/(TP + FP) NPV TN/(TN + FN) PLR Frequency of TP/frequency of FP = sensitivity/(1 − specificity) NLR Frequency of FN/frequency of TN = (1 − sensitivity)/specificity TP: true-positive; TN: true-negative; FP: false-positive; FN: false-negative; PLR: positive likelihood ratio; and NLR: negative likelihood ratio. Adapted from various sources.(13,15-19)

breaths • min−1 • L−1), the proportion of those in whom weaning will be successful.(16) Conversely, the specificity of a measure is defined as its ability to identify, from among the patients who present with a negative index (e.g., a RR/VT ratio > 105 breaths • min−1 • L−1), the proportion of those in whom weaning will fail.(16) The PPV indicates the proportion of patients who present with a positive results for a given index and are successfully weaned from MV, whereas the NPV indicates the proportion of patients who present with negative results for a given index and fail in being weaned from MV.(16) A true-positive test result correctly predicts successful MV weaning.(13,16) A true-negative test result correctly predicts unsuccessful MV weaning.(13,16) A false-positive test result predicts successful MV weaning, but the patient is not weaned from MV.(13,16) A false-negative test result predicts unsuccessful MV weaning, but the patient is weaned from MV.(13,16) The PLR indicates the probability of a positive index resulting in successful weaning from MV, divided by the probability of the same index resulting in weaning failure.(16) In other words, the PLR expresses how many times it is more likely to obtain a positive result for a given index in patients who have been weaned from MV compared with those who have not.(16) The NLR indicates the probability of a negative index resulting in successful weaning from MV divided by the probability of the same index resulting in weaning failure.(16) In other words, the NLR expresses how many times it is more likely to obtain a negative result for a given index in patients who have not been weaned from MV compared with those who have.(16) An LR of 0.5-2.0 indicates that a parameter is mildly associated with the post-test probability

of weaning success or failure. Values of LR of 2.0-5.0 and 0.3-0.5 are weakly but significantly associated with changes in the probability of weaning success or failure, respectively. Values of LR of 5.0-10.0 and 0.1-0.3 are more significantly associated with changes in the probability of weaning success or failure, respectively. Values of LR above 10 and below 0.1 are strongly associated with changes in the probability of weaning success or failure, respectively.(13) Chart 1 shows the diagnostic tests available, together with their respective formulas.

Bayes’ theorem describes the relationship between pre- and post-test probability.(13,16) Therefore, Bayes’ theorem evaluates the ability of an index to predict MV weaning outcome.

(13,16)

The analysis of the ROC curve allows the ability of an index to discriminate between two groups of patients (those who have been weaned and those who have not) to be evaluated, with the advantage of not depending on the cut-off value selected.(13,16) According to one author,(20) based on the AUC, a test can be classified as follows: AUC < 0.50, uninformative; AUC of 0.50-0.69, inaccurate; AUC of 0.70-0.89, moderately accurate; AUC of 0.90-0.99, highly accurate; and AUC of 1.00, perfect.

Initiation of weaning from MV: clinical evaluation and predictive parameters Patients can be weaned from MV if they meet at the following minimal criteria: resolution or stabilization of the underlying disease; adequate gas exchange; hemodynamic stability; and capacity to breathe spontaneously.(21) If these criteria are met, the SBT should be performed.

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If the clinical evaluation is unfavorable, the weaning indices are useless.(22) There is no sense in measuring the predictive parameters for weaning from MV if the condition that prompted the initiation of MV has not improved. However, when the clinical evaluation is favorable and the indices indicate a positive prognosis, the chances of success are greater.

(22) Clinical evaluation in isolation does not accurately predict the outcome of weaning from MV,(6,10) the PPV and NPV of such evaluation being only 50% and 67%, respectively.(6,23) Clinical evaluation does not include the analysis of the respiratory mechanics, ventilatory demand, or respiratory muscle strength, which are important criteria, especially when evaluated in combination. The weaning indices inform decisions regarding MV weaning in patients at high risk for weaning failure.(7) Although a given index might not be very accurate overall, it is, in general, highly accurate when its values are extremely unfavorable (e.g., MIP > −15 or −10 cmH2O). The indices are also useful in guiding the evaluation and treatment of patients in whom weaning from MV failed, identifying the causes of intolerance.(7) Even if the completion of the SBT is able to predict 85% of the chance of weaning success,(6) approximately 15% of patients do not tolerate the 48 h following extubation. In one study,(24) extubation failed in 121 (13.4%) of the 900 patients who completed (1,7,8)

Chart 2 - Clinical criteria that patients should meet in order to be considered ready for weaning from mechanical ventilation.

Clinical criteria for weaning from mechanical ventilation Resolution or improvement of the condition that led to mechanical ventilation initiation Patient without hypersecretion (defined as the need for aspiration > 2 h) Effective cough (PEF > 160 L/min) Hemoglobin > 8-10 g/dL Adequate oxygenation (PaO2/FiO2 > 150 mmHg or SaO2 > 90% and FiO2 < 0.5) Body temperature < 38.5-39.0°C Without dependence on sedatives Without dependence on vasopressor agents (e.g., dopamine < 5 µg • kg−1 • min−1) No acidosis (pH ranging from 7.35 and 7.45) No electrolyte disturbances Adequate fluid balance

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the SBT. The clinical criteria to determine whether patients are ready to be weaned from MV are described in Chart 2.

Predictive parameters for MV weaning Among the various indices, the most wellknown and most widely used is the rapid shallow breathing index, also known as the RR/VT ratio.

(25,26) The RR/VT ratio has been evaluated in more than 22 studies,(26) having been mentioned and recommended in large-scale review articles on MV weaning.(1,8,9) There have been few original or review articles on MV weaning that did not consider the RR/VT ratio. The RR/VT ratio identifies the development of rapid shallow breathing. Although some studies have found the RR/VT ratio to be inaccurate,(13,27,28) high RR/VT ratios (> 100-105 breaths • min−1 • L−1) are associated with unsuccessful weaning from MV.(1,8,9,16,25) The RR/VT ratio was originally devised to be measured during spontaneous breathing, through the use of a spirometer connected to the artificial airway.(25) However, there have been studies evaluating the RR/VT ratio on PSV and during CPAP.(16,27) The measurement of the RR/ VT ratio during CPAP at 5 cmH2O yielded a result that was 28-38% lower than was that obtained during spirometry.(16) The measurement of the RR/VT ratio on PSV at 10 cmH2O yielded a result that was 46-82% lower than was that obtained through spirometry.(16) Therefore, the RR/VT ratio should be measured during spontaneous breathing, through a spirometer, in order to maintain its cut-off value, typically between 100 and 105 breaths • min−1 • L−1. If the RR/ VT ratio is measured during CPAP or on PSV, a different cut-off value should be validated, which has yet to be done.

According to review articles published as of 2009,(7,8,10) the principal parameters are as follows: the RR/VT ratio; MIP; the airway occlusion pressure at 0.1 s (P0.1)/MIP ratio; RR; VT; minute volume; and an integrated evaluation of dynamic compliance, RR, oxygenation, and MIP, known as the compliance, rate, oxygenation, and pressure (CROP) index. Other important parameters include P0.1,(11,17,19) P0.1 × the RR/VT ratio,(17) static respiratory system compliance (Cst,rs),(25,29) the PaO2/FiO2 ratio,(30,31) and VC.(13) One group of authors recently devised a new index, designated the integrative weaning index

Predictive parameters for weaning from mechanical ventilation

(IWI), which is calculated with the following formula(18):

IWI = (Cst,rs × SaO2) ÷ RR/VT ratio The IWI is used in order to evaluate, in an integrative manner, respiratory mechanics, oxygenation, and breathing pattern. Since Cst,rs and SaO2 are directly proportional to one another and indirectly proportional to the RR/VT ratio, a higher IWI translates to a better prognosis. The measurement of Cst,rs during weaning was considered to be one of the limitations of that study.(18) Values of IWI ≥ 25 are predictive of successful weaning from MV.(18)

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On the basis of the scale proposed by Swets,(20) the IWI was shown to be highly accurate.(18) In the most recent analysis of the IWI, Nemer et al. prospectively evaluated 216 patients and found that the AUC for the IWI was greater than was that obtained for the RR/VT ratio (0.96 vs. 0.85; p = 0.003), as well as being greater than the AUCs obtained for the other indices evaluated (p < 0.002).(18) Among the 216 patients, MV weaning failed in 33. Extubation failure occurred in 6 (18%) of the 33 patients who completed the SBT. The IWI was accurate in establishing a prognosis for 5 of the 6 patients. As in the study conducted by Frutos-Vivar et al.,(24) Nemer et al.

Chart 3 - Weaning indices, with the respective cut-off values, evaluated in the literature.

Indices Author, year of publication LR RR/VT < 105 breaths • min−1 • L−1 NR Yang & Tobin, 1991(25) RR/VT < 60 breaths • min−1 • L−1 Capdevilla et al., 1995(19) NR −1 −1 RR/VT < 100 breaths • min • L NR Sassoon & Mahutte, 1993(17) RR/VT < 100 breaths • min−1 • L−1 Conti et al., 2004(13) 0.69 RR/VT < 105 breaths • min−1 • L−1 Nemer et al., 2009(18) 2.99 (17) P0.1 < 5.5 cmH2O NR Sassoon & Mahutte, 1993 (19 P0.1 < 5.0 cmH2O Capdevilla et al., 1995 NR P0.1 < 4.0 cmH2O Conti et al., 2004(13) 1.17 P0.1 < 3.1 cmH2O Nemer et al., 2009(18) 2.52 MIP < −15 cmH2O NR Yang & Tobin, 1991(25) MIP < −50 cmH2O Capdevilla et al., 1995(19 NR MIP < −16 cmH2O Conti et al., 2004(13) 0.87 MIP < −25 cmH2O Nemer et al., 2009(22) NR P0.1/MIP < 0.09 cmH2O Capdevilla et al., 1995(19 NR P0.1/MIP < 0.15 cmH2O Conti et al., 2004(13) 1.87 P0.1/MIP < 0.14 cmH2O Nemer et al., 2009(22) NR −1 −1 P0.1 × RR/VT < 300 cmH2O/breaths • min • L Conti et al., 2004(13) 0.61 P0.1 × RR/VT < 270 cmH2O/breaths • min−1 • L−1 Nemer et al., 2009(18) 2.81 −1 −1 P0.1 × RR/VT < 450 cmH2O/breaths • min • L NR Sassoon & Mahutte, 1993(17) Cst,rs > 33 mL/cmH2O NR Yang & Tobin, 1991(25) Cst,rs > 30 mL/cmH2O Nemer et al., 2009(18) 3.40 RR < 38 breaths/min NR Yang & Tobin, 1991(25) RR < 35 breaths/min Conti et al., 2004(13) 1.17 RR < 30 breaths/min Nemer et al., 2009(18) 1.87 Minute volume < 12 L Conti et al., 2004(13) 1.0 Minute volume < 15 L NR Yang & Tobin, 1991(25) PaO2/FiO2 Nemer et al., 2009(18) 1.79 IWI > 25 mL • cmH2O−1 • breaths−1 • min−1 • L−1 Nemer et al., 2009(18) 16.05 (25) CROP > 13 mL • breaths−1 • min−1 NR Yang & Tobin, 1991 (13) VC > 11 mL/kg Conti et al., 2004 1.3 VT > 5 mL/kg Conti et al., 2004(13) 1.54 VT > 315 mL Nemer et al., 2009(18) 2.81

AUC 0.89 0.72 0.78 0.70 0.85 0.64 0.93 0.47 0.73 0.61 0.71 0.57 0.52 0.99 0.71 0.78 0.67 0.81 0.80 0.68 0.83 0.76 0.52 0.76 0.54 0.76 0.65 0.96 0.78 0.71 0.67 0.81

VT: tidal volume; P0.1: airway occlusion pressure; Cst,rs: static respiratory system compliance; IWI: integrative weaning index; CROP: compliance, rate, oxygenation, and pressure ([index] of dynamic compliance, respiratory rate, oxygenation, and MIP); LR: likelihood ratio; AUC: area under the (ROC) curve; and NR: not reported.

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showed that the SBT is not always sufficient to evaluate the prognosis of weaning from MV and that the evaluation of certain weaning indices is therefore necessary.(18) Although the IWI has yielded promising results, the index must be tested in other studies in order to confirm its accuracy. Chart 3 shows the cut-off values that indicate successful weaning from MV, as well as the AUCs and the probabilities, for the IWI and other major international parameters.

Although it is widely used, MIP generally presents an inaccurate or moderately accurate AUC,(13,19,25) the values of which range from 0.57 to 0.71. Good respiratory muscle strength alone is not sufficient for patients to be weaned from MV, since the respiratory muscles are predominantly resistant muscles. However, MIP remains a valuable parameter, because patients who present with extreme inspiratory muscle weakness (MIP > −15 cmH2O) will probably be unable to breathe spontaneously.

Another problem related to MIP is the wide range of methods for its measurement.(32) An analogical or digital vacuum manometer can be used in order to measure MIP. In addition, MIP can be measured with the software that accompanies artificial ventilators. Such software generally measures MIP without exhalation, a measurement that is consistent with that made by using a vacuum manometer without a unidirectional valve. When a unidirectional valve is used, patients can inhale and exhale deeply, reaching the inspiratory and expiratory reserve volumes, thereby generating greater force due to increased diaphragmatic mobility.

When a unidirectional valve is not used, MIP is measured during VT breathing, which generates less force due to decreased diaphragmatic mobility. Although MIP was originally intended to be measured with a unidirectional valve for 20 s,(16) there have been studies showing no differences between MIP measurements obtained with and without a unidirectional valve,(22) and measurement periods of longer than 20 s have been used.(32) The period during which MIP is measured varies greatly, ranging from 1 s to over 20 s.(32) Despite its name, MIP is, in some hospitals, still considered to be the mean of the values obtained with three or more measurements.(32) Although the most widely used method for measuring MIP is with a vacuum manometer coupled to a unidirectional J Bras Pneumol. 2011;37(5):669-679

valve, there is no consensus regarding the ideal method. In normal individuals, MIP is generally < −80 cmH2O.(33) Values of MIP < −20 cmH2O are predictive of successful weaning from MV.(16) One important parameter for MV weaning from MV is P0.1, which indicates central respiratory activity; however, in order to determine P0.1, an esophageal balloon or ventilators should be introduced (tracheal P0.1 is also considered to be an accurate MV weaning parameter).(33) Among the parameters that evaluate central respiratory activity, tracheal P0.1 determination is probably the method that is most widely available in ICUs. The physiological values of P0.1 range from 0.5 to 1.5 cmH2O,(33) and P0.1 values lower than 4.0(13) or 4.2 cmH2O(16) generally predict successful weaning from MV. The AUC for P0.1 generally ranges from 0.47(13) to 0.93.(19) In patients with certain conditions, including lung hyperinflation and reduced inspiratory muscle strength of various etiologies, it is rare to see an elevated P0.1.(33) Therefore, although patients with neurological and neuromuscular diseases, as well as those with COPD, might present with increased central respiratory activity, their P0.1 values might not be high. In addition, P0.1 correlates with respiratory effort (a criterion that is also used to evaluate the prognosis for MV weaning): a P0.1 value = 3.5 cmH2O corresponds to a respiratory effort of approximately 0.75 J/L. Respiratory effort values lower than 0.75 J/L are considered predictive of successful weaning from MV.(33) Respiratory effort is automatically calculated and monitored by certain modern ventilators (those with microprocessors).

The P0.1/MIP ratio is an integrative index that aims at increasing the accuracy of its two components. In one study,(19) the AUC for the P0.1/MIP ratio (0.99 ± 0.01) was greater than was that that obtained for any of the other weaning indices evaluated. However, these results differ from those of other studies, in which the AUC for the P0.1/MIP ratio ranged from 0.71(13) to 0.78.(22) In another study,(22) no significant differences were found between the AUC for P0.1 and that for the P0.1/MIP ratio (0.76 ± 0.06 vs.

0.78 ± 0.06; p = 0.69). However, the AUC for P0.1 and that for the P0.1/MIP ratio were both greater than was that for MIP in isolation (0.76 ± 0.06 vs. 0.52 ± 0.08; p = 0.004; and 0.78 ± 0.06 vs.

0.52 ± 0.08; p = 0.0006, respectively).(22) These results showed that only MIP was potentiated by

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the integration between P0.1 and MIP, given that the AUC for P0.1 and that for the P0.1/MIP ratio were similar.(22) The PaO2/FiO2 ratio, which is the reference for the evaluation of oxygenation in patients with acute lung injury and acute respiratory distress syndrome,(34) is not highly accurate for weaning from MV,(30,35) and the PaO2/FiO2 ratio cut-off values that predict successful weaning from MV vary greatly (from 150 to 200).(9) In one study,(30) 89% of the patients with a PaO2/FiO2 ratio of 120-200 were successfully extubated.

In another,(35) a PaO2/FiO2 ratio of 238 showed a PPV of 90% but a NPV of 10%. Therefore, although the PaO2/FiO2 ratio is greatly valued, there are no justifiable reasons for its routine use as a parameter for MV weaning.

Although the PaO2/FiO2 ratio should remain as a reference for the evaluation of patients with acute respiratory distress syndrome and acute lung injury, it is not always an appropriate parameter for weaning from MV. Of the more than 66 weaning indices proposed, only 5-7(7,10) are associated with significant clinical changes in the probability of the MV weaning outcome(7) or present a significant LR for the evaluation of MV weaning outcome.

(10) Therefore, as of 2009, only the following weaning indices had been recommended for routine use: the RR/VT ratio; MIP; the P0.1/MIP ratio; RR; VT; minute volume; and the CROP index. There is a wide divergence of opinion regarding the recommendations for routine use of the weaning indices. According to the leading specialist in this topic, Martin Tobin,(15,16,25,26) at least some of the indices, particularly the RR/ VT ratio, should be used routinely. However, according to another specialist, Scott Epstein, there have been two consensuses in which the routine use of weaning indices was not recommended.(36) Epstein recently questioned whether those recommendations might change if the accuracy of the IWI is confirmed.(36)

Pathophysiology of weaning failure and of extubation failure Although weaning from MV depends on various factors, the principal factors are respiratory muscle strength, respiratory muscle load, and the intensity of the respiratory drive.

(1) Generally, weaning from MV fails due to an imbalance between respiratory muscle function

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and the respiratory muscle load.(1,37) The causes of reduced respiratory muscle efficiency include central inhibition, bone marrow diseases, phrenic nerve injury, neuropathies, neuromuscular junction impairment, and muscle weakness of various etiologies.(8,37) The causes of increased ventilatory demand include increased central respiratory drive, sepsis, fever, pain, increased dead space ventilation, and decreased elastic recoil (of the lung and chest wall).(8,37) The principal causes of MV dependence include neurological causes (due to respiratory system involvement or cardiovascular involvement) and psychological factors.(1,8,10) Other causes include metabolic disorders, endocrine dysfunction, electrolyte disturbances, malnutrition, obesity, and anemia.(8) It is essential to identify the cause of MV weaning failure, in order to adopt a new approach that focuses on the triggering factor.

Chart 4 shows the criteria for defining weaning failure.

Because weaning failure has various causes, integrative indices are generally more accurate.

(10,18,25) The evaluation of the weaning indices aids in identifying the causative factor of MV weaning failure, which can then be treated.(7) The etiology of extubation failure differs from that of weaning failure and is associated with upper airway impairment, including laryngospasm, abundant secretion, and ineffective cough.(1,11,14,30) Therefore, the accuracy of weaning indices in predicting extubation failure is limited.(14) Tests to evaluate extubation, such as the cuff leak test (which evaluates Chart 4 - Criteria to define weaning failure.

Signs of intolerance to spontaneous breathing (weaning failure) PaO2 < 50-60 mmHg and FiO2 > 0.5 SaO2 < 88-90% and FiO2 > 0.5 PaCO2 > 50 mmHg or increased by more than 8 mmHg pH < 7.32 or reduced by more than 0.07 RR > 35 breaths/min or increased by more than 50% HR > 140 bpm or increased by more than 20% SBP > 180 mmHg or < 90 mmHg Uncontrollable psychomotor agitation Reduced level of consciousness Excessive sweating and cyanosis Evidence of increased respiratory muscle effort SBP: systolic blood pressure. Adapted from Boles et al.(8)

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air leak after cuff deflation) are generally not recommended for routine use.(10,11) Extubation failure is associated with prolonged MV, with prolonged hospital stay, and with greater mortality, especially if reintubation is delayed.

(1,14)

As previously mentioned, weaning failure is defined as intolerance to the SBT in the absence of ventilatory support, whereas extubation failure is defined as intolerance to extubation.

(14) However, a diagnosis of extubation failure requires evidence of upper airway involvement (revealing orotracheal tube dependence).(10,14) In this aspect, this definition might not be precise, given that approximately 15% of patients tolerate the SBT but need to be reintubated,(6) not necessarily due to orotracheal tube dependence. Patients who require reintubation for reasons unrelated to the upper airways should not be classified as cases of extubation failure.

Some patients tolerate the SBT for 2 h and are extubated without complications, only to subsequently develop respiratory failure without any type of impairment related to orotracheal tube dependence. Such patients should not be classified as cases of extubation failure, since the etiology is unrelated to orotracheal tube dependence. If the definition of extubation failure were applied to all reintubated patients, such patients would have to be classified as cases of extubation failure rather than weaning failure, as they are commonly diagnosed. We hope that the definition of extubation failure will one day be applied exclusively to cases of orotracheal tube dependence rather than to all reintubated patients.

Applications and limitations of the weaning indices in different populations The weaning indices have some limitations, and it seems that the greatest of all is the wide variety of methods for their measurement. Such methods vary from hospital to hospital, as well as from professional to professional within the same hospital.(32) This variation can lead to great differences among the results obtained.

There are over ten different types of MIP measurements, which depend on various factors, including the equipment used, the duration of occlusion, and the value used (the mean, the J Bras Pneumol. 2011;37(5):669-679

most negative value, or the most reproducible value).(32) The RR/VT ratio should be measured during spontaneous breathing.(25) However, studies have measured the RR/VT ratio during CPAP and even on PSV(16,27) without necessarily changing the cut-off value used, a fact that completely changes the results and prognoses of the parameter.(16) Another major limitation is the fact that different cut-off values are used for different populations or even for similar populations.

Although the original cut-off value for the RR/ VT ratio is 100-105 breaths • min−1 • L−1, studies using cut-off values of 60 and 76 breaths • min−1 • L−1 have achieved greater accuracy than that achieved with the original cut-off value.

(19,38)

The use of predictive indices in neurological patients does not seem to predict extubation outcome accurately.(39) In a retrospective analysis of 62 neurological patients,(39) traditional indices, such as the RR/VT ratio, MIP, and the PaO2/ FiO2 ratio, were found to have low sensitivity, low specificity, or both. In that study,(39) the RR/VT ratio showed high specificity but low sensitivity (0.88 and 0.18, respectively). Not even the SBT was shown to be accurate in the study population, showing high sensitivity but low specificity (0.90 and 0.20, respectively).(39) In neurological patients, a Glasgow coma scale score ≥ 8 seems to be more accurate than are the traditional indices in predicting the outcome of weaning from MV.(40,41) Studies evaluating weaning indices in patients with COPD have shown that the RR/ VT ratio(42) and P0.1(43) are capable of identify weaning failure. Regarding the cut-off values used, one group of authors(44) showed that the cut-off values for COPD patients are generally different from (10% higher than) those used for heterogeneous populations. That study(44) revealed that the AUCs for the indices evaluated (MIP, RR/VT ratio, Cst,rs, RR, the CROP index, and P0.1/MIP ratio) were greater than the 0.9 only for the CROP index and for P0.1. One group of authors(45) recently evaluated 64 patients with COPD and reported that the RR/VT ratio was inaccurate in predicting MV weaning outcome, despite the fact that two cut-off values were used: the traditional cut-off value of 105 breaths • min−1 • L−1 and a higher cut-off value, of 130 breaths • min−1 • L−1. For the

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cut-off value of 105 breaths • min−1 • L−1, the specificity and sensitivity of the RR/VT ratio were only 0.38 and 0.63, respectively, compared with 0.66 and 0.54, respectively, for the cut-off value of 130 breaths • min−1 • L−1. The evaluation of the weaning indices in patients with COPD has been shown to be only moderately accurate,(12) and there seems to be no gold standard index for that population.(44) Weaning indices have also been evaluated in patients on MV for prolonged periods.

(31,46,47) One group of authors(31) retrospectively evaluated clinical criteria and certain weaning indices in 1,307 patients in whom MV was prolonged. Of the weaning indices evaluated (the PaO2/FiO2 ratio, the RR/VT ratio, and MIP), only the RR/VT ratio identified no statistically significant differences between patients who had been weaned from MV and those who had not (146.4 ± 91.4 vs. 154.5 ± 106.2 breaths • min−1 • L−1; p = 0.262).(31) Another group of authors(47) evaluated various weaning indices in 30 patients in whom MV was prolonged. Of the traditional weaning indices/criteria evaluated (VT, the RR/VT ratio, dynamic compliance of the respiratory system, and MIP), only the RR/VT ratio and MIP identified statistically significant differences between patients who had been weaned from MV and those who had not (74.1 ± 44.0 vs. 148.2 ± 121.4 breaths • min−1 • L−1; p = 0.03; and 57.3 ± 18.2 vs. 38.6 ± 13.5 cmH2O; p = 0.001, respectively). Because controlled MV directly affects the diameter of diaphragm muscle fibers types I and II, reducing it by more than 50% over periods longer than 18 h of continuous MV, weaning indices that evaluate diaphragm strength, such as MIP, might be successfully applied to that population.(4,48) There is evidence that the use of weaning protocols are associated with decreases in duration of MV, length of hospital stay, and weaning time.(49) The predictive parameters for weaning are included in weaning protocols,(8-10,49) which greatly improve the results of these protocols.

Final considerations The weaning indices have limitations, which are principally related to the study population, the cut-off values used, and the means of measurement. Although the weaning indices can be used in homogeneous populations,

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the accuracy of the indices might be lower in such populations than in heterogeneous populations. The evaluation of weaning indices in neurological patients seems to be the least indicated among those related to homogeneous populations.

Although integrative indices are generally more accurate, their accuracy in predicting the outcome of extubation might be limited.

Since the accuracy of the SBT in evaluating the prognosis of weaning from MV is approximately 85% and clinical evaluation alone is not sufficient, accurate indices, such as the RR/VT ratio and the recently devised IWI, might be needed in order to make the outcome of weaning from MV safer.

The weaning indices are useful in identifying patients who will probably be unable to tolerate weaning from MV. The weaning indices are also useful in identifying reversible causes of weaning failure, serving as references for subsequent attempts.

Although few of the weaning indices are accurate, we are of the opinion that at least 5 of these indices should be recommended for routine use. Because the clinical impression and SBT are not 100% accurate, the MV weaning parameters can be useful, especially in situations in which the decision to wean from MV is problematic.

References 1. Eskandar N, Apostolakos MJ. Weaning from mechanical ventilation. Crit Care Clin. 2007;23(2):263-74, x.

2. Ntoumenopoulos G, Presneill JJ, McElholum M, Cade JF. Chest physiotherapy for the prevention of ventilator-associated pneumonia. Intensive Care Med. 2002;28(7):850-6.

3. Vassilakopoulos T, Petrof BJ. Ventilator-induced diaphragmatic dysfunction. Am J Respir Crit Care Med. 2004;169(3):336-41.

4. Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;358(13):1327-35.

5. Frutos-Vivar F, Esteban A. Critical illness polyneuropathy: a new (or old?) reason for weaning failure. Crit Care Med. 2005;33(2):452-3.

6. Ely EW, Baker AM, Dunagan DP, Burke HL, Smith AC, Kelly PT, et al. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med. 1996;335(25):1864-9.

7. Epstein SK. Weaning from ventilatory support. Curr Opin Crit Care. 2009;15(1):36-43.

8. Boles JM, Bion J, Connors A, Herridge M, Marsh B, Melot C, et al. Weaning from mechanical ventilation.

Eur Respir J. 2007;29(5):1033-56.

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9. Koch RL. Therapist driven protocols: a look back and moving into the future. Crit Care Clin. 2007;23(2):14959, vii-viii.

10. MacIntyre NR, Cook DJ, Ely EW Jr, Epstein SK, Fink JB, Heffner JE, et al. Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine.

Chest. 2001;120(6 Suppl):375S-95S. 11. Goldwasser R, Farias A, Freitas EE, Saddy F, Amado V, Okamoto V. Desmame e interrupção da ventilação mecânica. In: Carvalho CR, coordinator. III Congresso Brasileiro de Ventilação Mecânica. J Bras Pneumol.

2007;33(Suppl 2S):S128-S136.

12. Meade M, Guyatt G, Cook D, Griffith L, Sinuff T, Kergl C, et al. Predicting success in weaning from mechanical ventilation. Chest. 2001;120(6 Suppl):400S-24S. 13. Conti G, Montini L, Pennisi MA, Cavaliere F, Arcangeli A, Bocci MG, et al. A prospective, blinded evaluation of indexes proposed to predict weaning from mechanical ventilation. Intensive Care Med. 2004;30(5):830-6.

14. Epstein SK. Decision to extubate. Intensive Care Med. 2002;28(5):535-46.

15. Tobin MJ, Alex CG. Discontinuation of mechanical ventilation. In: Tobin MJ, editor. Principles and practice of mechanical ventilation. New York: McGraw Hill; 1994. p. 1177-206.

16. Tobin MJ, Jubran A. Weaning from mechanical ventilation. In: Tobin MJ, editor. Principles and practice of mechanical ventilation. New York: McGraw Hill; 2006. p. 1185-220.

17. Sassoon CS, Mahutte CK. Airway occlusion pressure and breathing pattern as predictors of weaning outcome.

Am Rev Respir Dis. 1993;148(4 Pt 1):860-6.

18. Nemer SN, Barbas CS, Caldeira JB, Cárias TC, Santos RG, Almeida LC, et al. A new integrative weaning index of discontinuation from mechanical ventilation. Crit Care.

2009;13(5):R152.

19. Capdevila XJ, Perrigault PF, Perey PJ, Roustan JP, d’Athis F. Occlusion pressure and its ratio to maximum inspiratory pressure are useful predictors for successful extubation following T-piece weaning trial. Chest.

1995;108(2):482-9.

20. Swets JA. Measuring the accuracy of diagnostic systems.

Science. 1988;240(4857):1285-93.

21. MacIntyre N. Discontinuing mechanical ventilatory support. Chest. 2007;132(3):1049-56.

22. Nemer SN, Barbas CS, Caldeira JB, Guimarães B, Azeredo LM, Gago R, et al. Evaluation of maximal inspiratory pressure, tracheal airway occlusion pressure, and its ratio in the weaning outcome. J Crit Care. 2009;24(3):441-6.

23. Stroetz RW, Hubmayr RD. Tidal volume maintenance during weaning with pressure support. Am J Respir Crit Care Med. 1995;152(3):1034-40.

24. Frutos-Vivar F, Ferguson ND, Esteban A, Epstein SK, Arabi Y, Apezteguía C, et al. Risk factors for extubation failure in patients following a successful spontaneous breathing trial. Chest. 2006;130(6):1664-71.

25. Yang KL, Tobin MJ. A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. N Engl J Med. 1991;324(21):1445-50.

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26. Tobin MJ, Jubran A. Meta-analysis under the spotlight: focused on a meta-analysis of ventilator weaning. Crit Care Med. 2008;36(1):1-7.

27. Shikora SA, Benotti PN, Johannigman JA. The oxygen cost of breathing may predict weaning from mechanical ventilation better than the respiratory rate to tidal volume ratio. Arch Surg. 1994;129(3):269-74.

28. Lee KH, Hui KP, Chan TB, Tan WC, Lim TK. Rapid shallow breathing (frequency-tidal volume ratio) did not predict extubation outcome. Chest. 1994;105(2):540-3.

29. Aboussouan LS, Lattin CD, Anne VV. Determinants of time-to-weaning in a specialized respiratory care unit.

Chest. 2005;128(5):3117-26.

30. Khamiees M, Raju P, DeGirolamo A, Amoateng-Adjepong Y, Manthous CA. Predictors of extubation outcome in patients who have successfully completed a spontaneous breathing trial. Chest. 2001;120(4):1262-70.

31. Wu YK, Kao KC, Hsu KH, Hsieh MJ, Tsai YH. Predictors of successful weaning from prolonged mechanical ventilation in Taiwan. Respir Med. 2009;103(8):1189-95.

32. Soo Hoo GW, Park L. Variations in the measurement of weaning parameters: a survey of respiratory therapists.

Chest. 2002;121(6):1947-55.

33. Laghi F. Assessment of respiratory output in mechanically ventilated patients. Respir Care Clin N Am. 2005;11(2):173-99.

34. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149(3 Pt 1):818-24.

35. Krieger BP, Ershowsky PF, Becker DA, Gazeroglu HB. Evaluation of conventional criteria for predicting successful weaning from mechanical ventilatory support in elderly patients. Crit Care Med. 1989;17(9):858-61.

36. Epstein SK. Routine use of weaning predictors: not so fast. Crit Care. 2009;13(5):197.

37. Gosselink R, Bott J, Johnson M, Dean E, Nava S, Norrenberg M, et al. Physiotherapy for adult patients with critical illness: recommendations of the European Respiratory Society and European Society of Intensive Care Medicine Task Force on Physiotherapy for Critically Ill Patients. Intensive Care Med. 2008;34(7):1188-99.

38. Danaga AR, Gut AL, Antunes LC, Ferreira AL, Yamaguti FA, Christovan JC, et al. Evaluation of the diagnostic performance and cut-off value for the rapid shallow breathing index in predicting extubation failure. J Bras Pneumol. 2009;35(6):541-7.

39. Ko R, Ramos L, Chalela JA. Conventional weaning parameters do not predict extubation failure in neurocritical care patients. Neurocrit Care.

2009;10(3):269-73.

40. Navalesi P, Frigerio P, Moretti MP, Sommariva M, Vesconi S, Baiardi P, et al. Rate of reintubation in mechanically ventilated neurosurgical and neurologic patients: evaluation of a systematic approach to weaning and extubation. Crit Care Med. 2008;36(11):2986-92.

41. Namen AM, Ely EW, Tatter SB, Case LD, Lucia MA, Smith A, et al. Predictors of successful extubation in neurosurgical patients. Am J Respir Crit Care Med. 2001;163(3 Pt 1):658-64.

42. Jubran A, Tobin MJ. Pathophysiologic basis of acute respiratory distress in patients who fail a trial of weaning from mechanical ventilation. Am J Respir Crit Care Med. 1997;155(3):906-15.

Predictive parameters for weaning from mechanical ventilation

43. Hilbert G, Gruson D, Portel L, Vargas F, GbikpiBenissan G, Cardinaud JP. Airway occlusion pressure at 0.1 s (P0.1) after extubation: an early indicator of postextubation hypercapnic respiratory insufficiency.

Intensive Care Med. 1998;24(12):1277-82.

44. Alvisi R, Volta CA, Righini ER, Capuzzo M, Ragazzi R, Verri M, et al. Predictors of weaning outcome in chronic obstructive pulmonary disease patients. Eur Respir J. 2000;15(4):656-62.

45. Boutou AK, Abatzidou F, Tryfon S, Nakou C, Pitsiou G, Argyropoulou P, et al. Diagnostic accuracy of the rapid shallow breathing index to predict a successful spontaneous breathing trial outcome in mechanically ventilated patients with chronic obstructive pulmonary disease. Heart Lung. 2010 [Epub ahead of print].

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46. Scheinhorn DJ, Hassenpflug M, Artinian BM, LaBree L, Catlin JL. Predictors of weaning after 6 weeks of mechanical ventilation. Chest. 1995;107(2):500-5.

47. Carlucci A, Ceriana P, Prinianakis G, Fanfulla F, Colombo R, Nava S. Determinants of weaning success in patients with prolonged mechanical ventilation. Crit Care. 2009;13(3):R97.

48. Powers SK, Kavazis AN, Levine S. Prolonged mechanical ventilation alters diaphragmatic structure and function.

Crit Care Med. 2009;37(10 Suppl):S347-53.

49. Blackwood B, Alderdice F, Burns K, Cardwell C, Lavery G, O’Halloran P. Use of weaning protocols for reducing duration of mechanical ventilation in critically ill adult patients: Cochrane systematic review and meta-analysis.

BMJ. 2011;342:c7237. doi: 10.1136/bmj.c7237.

About the authors Sérgio Nogueira Nemer

Scientific Coordinator. Niterói Hospital de Clínicas, Niterói, Brazil.

Carmen Sílvia Valente Barbas

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

J Bras Pneumol. 2011;37(5):669-679

Review Article Gastroesophageal reflux disease and airway hyperresponsiveness: concomitance beyond the realm of chance?* Doença do refluxo gastroesofágico e hiperresponsividade das vias aéreas: coexistência além da chance?

Jaqueline Cavalcanti de Albuquerque Ratier, Emilio Pizzichini, Marcia Pizzichini

Abstract Gastroesophageal reflux disease and asthma are both quite common the world over, and they can coexist. However, the nature of the relationship between these two diseases remains unclear. In this study, we review controversial aspects of the relationships among asthma, airway hyperresponsiveness, and gastroesophageal reflux disease in adults and in children.

Keywords: Asthma; Bronchial hyperreactivity; Gastroesophageal reflux.

Resumo A doença do refluxo gastroesofágico e a asma são duas condições mundialmente comuns e podem coexistir.

Contudo, a natureza da relação entre essas duas doenças ainda não é bem compreendida. Neste artigo, revisamos alguns aspectos controversos da relação entre asma, hiperresponsividade das vias aéreas e refluxo gastroesofágico, tanto em adultos, quanto em crianças.

Descritores: Asma; Hiper-reatividade brônquica; Refluxo gastroesofágico.

Introduction In every country, gastroesophageal reflux disease (GERD) and asthma, both of which have significant effects on health, are quite common and can coexist. There is no consensus definition for epidemiological studies of asthma or GERD, and, depending on the age group, both conditions pose diagnostic difficulties. In addition, the worldwide prevalence of these two conditions has been increasing in recent years.

(1,2)

There have been few population-based studies of the prevalence of GERD, either in adults or in children.(3) In adults, the estimated prevalence of GERD, when defined as at least one episode of heartburn per week, ranges from 10% to 20% in Western countries, whereas it is less than 5% in Asia.(4) The prevalence of GERD symptoms in children treated at pediatric

clinics is less than 10%.(5) However, specific populations of children, such as those with neurological problems, esophageal atresia, or chronic respiratory diseases, those who are obese, and those who were born prematurely, are at increased risk for GERD.(1) Asthma is a common condition that affects virtually all age groups, being the most common chronic disease in children and being particularly prevalent in developed countries.

The International Study of Asthma and Allergies in Childhood (ISAAC), in an evaluation of 13,604 schoolchildren (6-7 years of age) and 20,554 adolescents (13-14 years of age), showed a high prevalence of asthma in Brazil.(6) In addition, the prevalence of wheezing 12 months prior to the medical visit in Brazil was found to be 27.2% among children and adolescents in the city of

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

Correspondence to: Márcia M. M. Pizzichini. Departamento de Clínica Médica, Universidade Federal de Santa Catarina, Hospital Universitário, Campus Universitário, Trindade, CEP 88040-970, Florianópolis, SC, Brasil.

Tel. 55 47 3234-7711. E-mail: mpizzich@matrix.com.br Financial support: None.

Submitted: 28 February 2011. Accepted, after review: 23 May 2011.

J Bras Pneumol. 2011;37(5):680-688

Gastroesophageal reflux disease and airway hyperresponsiveness: concomitance beyond the realm of chance?

Porto Alegre, whereas, among adolescents only, the prevalence ranged from 9.6% (in the city of Itabira) to 27.1% (in the city of Salvador).(7-10) Studies investigating the relationship between asthma and GERD continue to produce conflicting results.(11) In the present review, we discuss some controversial aspects of the relationships among asthma, airway hyperresponsiveness (AHR), and GERDâ&#x20AC;&#x201D;in adults and in children.

Gastroesophageal reflux and GERD: definition and mechanisms Gastroesophageal reflux (GER), defined as the involuntary passage of gastric contents into the esophagus, is a normal physiological process that occurs several times throughout the day in healthy children and adults. Most reflux episodes are brief and asymptomatic, occurring postprandially in the distal esophagus.(1) Various structures at the esophagogastric junction are important in maintaining an antireflux barrier: the lower esophageal sphincter (LES); the crural diaphragm (CD); and the phrenoesophageal ligament. The LES is the intrinsic sphincter, and the CD is the extrinsic sphincter. The two sphincters are anatomically superimposed and anchored to each other by the phrenoesophageal ligament. The intrinsic basal tone of the LES increases when the CD contracts; through this and other mechanisms, the LES prevents the reflux of gastric contents into the lower esophagus.(12)The pathophysiology of GERD is multifactorial and is associated with three potential abnormalities in LES motility: incompetence of the LES; inadequate gastric emptying; and delayed gastric emptying. The loss of the resting tone of the LES or the increase in its relaxation frequency favors the return of gastric contents. Likewise, if esophageal peristalsis is not sufficient to eliminate reflux, there will be greater contact between the gastric acid and the mucosa, and this factor (insufficient clearance) alone can cause esophagitis.(12) Other determinants of reflux include anatomical changes in the region, such as the mere separation of the pillars of the diaphragmatic hiatus, with or without hiatal hernia, resulting in the loss of the angle of Hiss and shortening of the esophagus.(12,13) Whereas GER is a physiological condition, GERD refers to GER accompanied by digestive

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symptoms, extradigestive symptoms, or a combination of the two, together with complications that do not resolve spontaneously.

(1,14) In children, gastrointestinal symptoms of GERD vary according to age, although, in general, they include retrosternal burning, epigastric pain, and regurgitation.(1,3,5) In children and adults, respiratory symptoms associated with GERD include wheezing, persistent cough, and dyspnea.(11,14) However, these symptoms are nonspecific.(1,3,14) In addition, children frequently have difficulty in characterizing the intensity of each symptom, and retrosternal burning can be reported as pain. In some cases, GERD symptoms are minimal or absent.(1,3,5) In general, the diagnosis of GERD is made on the basis of the signs, symptoms, and complications of reflux, if any of those are significant enough to require medical attention.

The diagnosis of GERD can be confirmed by esophageal biopsy via upper gastrointestinal tract endoscopy, esophageal manometry, intraluminal impedance monitoring, 24-h esophageal pH monitoring, or intraluminal impedance monitoring combined with 24-h esophageal pH monitoring.(1,14,15) None of these methods has all the characteristics needed in order to be considered the gold standard.

Upper gastrointestinal tract endoscopy is the most reliable method to detect GERDrelated esophagitis.(16) However, the absence of esophagitis does not exclude the diagnosis of GERD. Manometry evaluates esophageal motility and is indicated in cases of symptoms suggestive of esophageal dysmotility; however, manometry findings are not sensitive or specific enough to confirm the diagnosis of GERD.(1) Intraluminal impedance monitoring is a noninvasive method that detects the retrograde flow of fluids and air into the esophagus.(16) However, normal values for the various pediatric age groups have yet to be defined.(1) Despite being a valid method for measuring the frequency and duration of GER, 24-h esophageal pH monitoring is insensitive to GER that is slightly acid or alkaline.(16,17) By convention, a drop in esophageal pH to below 4.0 is considered an episode of GER. For the investigation of GER, esophageal pH monitoring has good sensitivity and specificity (87-93% and 93-97%, respectively),(14,17) although there is no J Bras Pneumol. 2011;37(5):680-688

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consistent evidence that the severity of exposure to GER is correlated with the symptoms and complications of GERD. According to the recently issued North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the management of GERD, esophageal pH monitoring is useful for evaluating the efficacy of antisecretory therapy, for correlating symptoms (cough and chest pain) with GERD episodes, and for identifying children in whom GER can aggravate extradigestive symptoms.(1) More recently, intraluminal impedance monitoring combined with 24-h esophageal pH monitoring has been used for the diagnosis of GERD. Intraluminal impedance monitoring has the additional advantage of detecting episodes of GER that is slightly acid or alkaline. However, its usefulness has yet to be fully established.

Other diagnostic tests, such as ultrasound of the esophagus and stomach, are not recommended for children, because they do not differentiate between pathological and physiological GER.(1)

AHR: definition and mechanisms Asthma is a chronic disease, defined by episodic respiratory symptoms, variable airflow limitation, AHR, and airway inflammation.

(18) Respiratory symptoms, variable airflow limitation, and AHR are often associated with eosinophilic airway inflammation, which is considered characteristic of asthma.(19) Defined as excessive constriction of the airways in response to various stimuli, AHR is a seen in virtually all patients with asthma.(19,20) In general, AHR is measured by bronchial challenge with bronchoconstrictors, of which the most commonly used are methacholine, histamine, cAMP, and hypertonic saline.(20) In asthma patients, the intensity of AHR is proportional to the severity of the asthma, AHR intensity increasing after exposure to asthma triggers (such as viral infections, allergens, and occupational agents) and decreasing after treatment with anti-inflammatory drugs.(20) In addition, it has been shown that AHR can occur in patients with airflow limitation caused by other diseases, such as COPD.(21) In such diseases, AHR is intimately associated with airway caliber.

Therefore, AHR is believed to have a fixed component and a variable component. The fixed component would be predominantly the result J Bras Pneumol. 2011;37(5):680-688

of geometric changes in airway caliber, whereas the variable component would be associated with exposure to provoking agents or with asthma treatment.(20) It is thought that AHR is the cause of asthma symptoms and of the variability in airflow limitation.(22) Although AHR is intimately associated with current asthma, this is an imperfect association because of the heterogeneity of airway responsiveness in the general population.

(20) Recent epidemiological studies have reported the presence of asymptomatic AHR (without symptoms or a history suggestive of asthma) in 6-17% of the subjects studied.(23) In children between 8 and 12 years of age, the reported prevalence of AHR, measured by hypertonic saline challenge testing, varies widely among countries, the lowest and highest prevalence rates identified in the ISAAC phase II being 2.1% in Albania and 47.8% in India, respectively.(24) However, the ISAAC phase II did not report the proportion of individuals with asymptomatic AHR. In a study conducted in Canada(25) and involving a random sample of non-atopic asymptomatic children without allergic rhinitis (mean age, 8 years), the prevalence of hyperresponsiveness to methacholine was found to be 50%. In children, asymptomatic AHR has been associated with atopy, allergic rhinitis, and small airway caliber, as well as with a variety of respiratory symptoms.(23) Although the significance and course of asymptomatic AHR remain unclear, it is a recognized risk factor for asthma and COPD.(20,25) Various studies have identified a positive association between childhood AHR and the risk of developing asthma later in life.(26-28) Rasmussen et al.(27) evaluated 547 children in Australia and identified asymptomatic AHR in 7.5%. Subsequent assessments of that subgroup revealed that 44%, 27%, and 10% continued to have asymptomatic AHR after 3, 6, and 9 years, respectively. The subsequent development of asthma was more common among the children with asymptomatic AHR, especially among those who continued to have asymptomatic AHR over time, than among those without. In another study, Stern et al.(28) reported that, when present at the age of 6 years, atopy and cold air-induced AHR were independent predictors of persistent asthma at the age of 22.

Gastroesophageal reflux disease and airway hyperresponsiveness: concomitance beyond the realm of chance?

There has been only one study investigating the presence of airway inflammation in children with asymptomatic AHR.(29) In that study, induced sputum samples from 13 children with asymptomatic AHR were tested and the results were compared with those obtained in children with and without asthma. The authors found that children with asymptomatic AHR do not have eosinophilic airway inflammation. The same authors suggested that, in such children, AHR is caused by inflammatory mediators or by structural changes in the airways, changes for which testing for sputum cellularity would have low sensitivity.(29)

GERD, asthma, and AHR There has long been interest in the relationship between asthma and GERD. For many years, it was thought that GERD could certainly trigger or worsen asthma. This belief originated from the observation that subjects with asthma often have GERD and that esophageal acidification increases airway resistance, as well as from the interpretation of the results of small, and not always controlled, studies showing that antireflux medication controlled asthma.(30-32) Recent studies and systematic reviews have cast doubt on this belief and have renewed discussions of the significance of the relationship between asthma and GERD. However, there are still major difficulties that preclude a conclusive interpretation of this relationship.

The major difficulties of studies investigating the relationship between asthma and reflux include the following: the poor characterization of asthma and the absence of objective measures for the diagnosis of asthma and the classification of asthma severity; imprecise definitions of GER; the lack of a gold standard method for diagnosing GER; the inability of current methods to identify not only the different types of GER (acid, slightly acid, and alkaline) but also their magnitude; and the lack of well-established criteria for determining the value of a diagnosis of asymptomatic GER. Despite the aforementioned difficulties, there is no doubt that GERD is common in subjects with asthma, and this has been shown in numerous prevalence studies. Two recent systematic reviews indicated that the prevalence of GERD symptoms is substantially higher in adults and children with asthma than in those

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without.(11,33) In a review of 28 studies of adults with asthma, the mean prevalence of GERD symptoms was 59.2% in the asthma group, compared with 38.1% in the control group. The prevalence of GER diagnosed by pH monitoring was 51%.(33) In another review, which included 20 studies of children with asthma, the mean age-adjusted prevalence of GERD was 22.8% (Figure 1).(11) Prevalence studies employing 24-h pH monitoring have also shown that asymptomatic GER is common in adults and children with asthma. In fact, it is estimated that only 5% of all subjects with GER are symptomatic.(34) It is also estimated that 10-62% of all individuals with asthma have asymptomatic GER, the broad variability being attributed to differences in asthma severity and in the methodology used for assessing GER symptoms.(34) Similar findings have been reported in studies involving children.

While compiling the literature upon which to base the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition evidence-based guidelines for the management of GERD, Vandenplas et al.(1) reviewed 16 studies, involving a total of 683 children with persistent asthma and with abnormal 24-h esophageal pH monitoring results. Approximately half of those children were asymptomatic or had few GER symptoms. These results are in line with those of a study of 69 children with asthma (1-5 years of age) in which the prevalence of asymptomatic GER was reported to be 31.8%.(35)

Figure 1- Prevalence of reflux symptoms, abnormal pH monitoring results, and esophagitis detected by endoscopy in children and adults with asthma.a aData taken from Takkar et al.(11) and Havemann et al.(33)

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Despite the aforementioned findings, prevalence studies have not produced sufficient evidence to determine whether the relationship between asthma and GERD is incidental or causal.(36) Even longitudinal studies have been unable to answer this question. For instance, Ruigómez et al.(37) investigated the association between asthma and GERD in two cohorts of patients treated at primary care facilities in the United Kingdom. Their results showed that, in that population, the risk of being diagnosed with GERD in the first three years of follow-up was significantly higher for the patients who were diagnosed with asthma than for those who were not so diagnosed, especially in the first year. In this aspect, the conclusion of these authors(37) was similar to that of the authors of the two aforementioned systematic reviews.(11,33) Nevertheless, patients with GERD do not seem to be at increased risk of developing asthma.

(11,33,37)

The reported association between reflux and asymptomatic AHR (hyperresponsiveness without asthma symptoms) is also intriguing and raises other questions about the cause-andeffect relationship between asthma and GER. One group of authors(38) found that 36% of adult patients with GERD and without respiratory symptoms had asymptomatic AHR. The authors suggested that GER was associated with the increase in asymptomatic AHR. Those results were confirmed by another group of authors,(39) who found that the prevalence of AHR was 50% in adults with GERD, compared with 27% in the control subjects.

Finally, is difficult to demonstrate the relationship between asthma and GERD in treatment studies, because there is no standard outcome measure for the longitudinal determination of the effect that GER has on the symptoms and functional manifestations of asthma.(40) The principal reasons given to explain the lack of consistency in the results of studies of GER treatment in asthma patients include those mentioned above, plus the following: the lack of appropriate characterization of asthma patients; the lack of objective measures for the diagnosis of asthma and classification of asthma severity; the varying criteria used for diagnosing GERD; the lack of objective, or at least welldefined, criteria for quantifying improvement; and the lack of distinctions among the types of J Bras Pneumol. 2011;37(5):680-688

GER and the levels of GER severity. Therefore, it is not surprising that pharmacological intervention studies continue to produce conflicting results. Although some longitudinal studies of the asthma-GERD combination in children(41,42) and adults(43) have demonstrated symptomatic or functional improvement of asthma after long-term GER treatment, others have failed to show such benefits.(44-46) There is still insufficient evidence to determine whether asthma predisposes to GER or vice-versa.(36,40) Figure 2 shows the pathophysiological mechanisms by which GER can worsen asthma and vice-versa (Figure 2), which are also still under debate. There are two mechanisms by which GER can precipitate asthma symptoms: via the vagal reflex, which is triggered by the mere presence of acid in the esophagus; and via microaspiration of gastric contents into the trachea. Conversely, it is believed that asthma itself can cause GER for two reasons: because asthma alters intrathoracic pressure during breathing, thereby triggering the vagal reflex; and because asthma patients are treated with drugs that change the LES pressure.(47-49)

Effects of GER on asthma From a theoretical standpoint, GER affects asthma primarily through two mechanisms, which can occur in isolation or in combination: esophageal acidification; and tracheal microaspiration of refluxed material.

The theory of esophageal acidification (the reflex theory) suggests that the mere presence of gastric contents in the esophagus results in vagal stimulation, with consequent bronchospasm, given that the esophagus and the airways have the same embryonic origin and share the same autonomic innervation through the vagus.(49)

Figure 2 - Possible mechanisms to explain the high prevalence of gastroesophageal reflux and gastroesophageal reflux disease (GERD) in asthma.a a Adapted from Harding et al.(49)

Gastroesophageal reflux disease and airway hyperresponsiveness: concomitance beyond the realm of chance?

Recent studies(50,51) involving the measurement of airway responsiveness after esophageal infusion of acid in asthma patients with and without GERD have not confirmed the results of previous studies,(52) which had shown increases in airway responsiveness and bronchoconstriction after such infusion. Differences in the infusion rate, in the volume of acid infused, and in how AHR was measured could explain these discrepancies.

Experimental studies in animal models have also produced contradictory results, for the same reasons as those applicable to studies in humans, plus the fact that some studies used higher concentrations of hydrochloric acid than those found in non-experimental conditions.

(53-56) Nevertheless, studies involving esophageal acidification in animals have shown that there is an increase in airway resistance,(54) an increase in tracheal pressure,(54) and extravasation of fluid.

(55)

The theory of microaspiration holds that microaspiration of gastric contents into the trachea increases airway resistance. One group of authors(53) studied the effects of esophageal administration of hydrochloric acid in guinea pigs with and without allergic airway inflammation. Esophageal administration of hydrochloric acid, even in large volumes, did not significantly change airway resistance in either group. In contrast, intratracheal administration of small volumes of hydrochloric acid caused a substantial increase in airway resistance, even in the control group. Those authors concluded that tracheal microaspiration was the most likely mechanism to explain the effects of GER on asthma. In line with these results, a more recent study in rats(56) showed that tracheal aspiration of acids can cause the onset of acute AHR by disrupting the integrity of the airway epithelial barrier.

Effects of asthma on GER From a pathophysiological standpoint, asthma can predispose to GER by a variety of mechanisms that can coexist: increased intrathoracic pressure; vagal dysfunction; altered CD function; and decreased LES pressure due to asthma treatment.(49) The roles that these mechanisms play in the onset of GER are still under debate. In individuals with asthma, the pressure gradient between the chest and the abdominal cavity can be increased. At the end

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of exhalation, the pressure gradient between the esophagus and the stomach is 4-5 mmHg. (57) Normal LES pressure (10-35 mmHg) is sufficient to endure this gradient. In asthma, in the presence of bronchoconstriction, especially in severe cases, the increased pressure gradient between the esophagus and the stomach can surpass LES pressure, resulting in GER.(58) Conversely, it is well known that subjects with asthma have increased vagal responsiveness.

Therefore, asthma could also affect GER by autonomic dysregulation, which would result in a lower LES pressure gradient, favoring GER episodes.(59)Altered CD function has also been considered a mechanism by which asthma can affect GER.(12) The CD is known to contribute to the LES pressure gradient, particularly during inhalation. Hyperinflation associated with bronchoconstriction in asthma can affect the function of the CD by changing its geometry.

(56) Finally, although it is believed that GER can be triggered or potentiated by the asthma treatment itself, particularly by the use of β2-adrenergic agonists, theophylline, or high doses of oral corticosteroids, which are known to affect LES pressure, the results of studies testing the increase in GER due to these drugs are also controversial.(60)

Final considerations In summary, because of the paucity of wellconducted studies, there is still no concrete evidence of any causal relationships among GERD, asthma, and AHR. This is partially due to methodological difficulties, which include difficulties in confirming the diagnosis and difficulties in quantifying the severity of these conditions. After these difficulties have been overcome, well-designed longitudinal studies will be able to explain the nature of the relationship between asthma and GERD, as well as the implications of therapeutic interventions for the natural history of these conditions.

Therefore, this is a field of research that is open to further investigation.

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15. Francavilla R, Magistà AM, Bucci N, Villirillo A, Boscarelli G, Mappa L, et al. Comparison of esophageal pH and multichannel intraluminal impedance testing in pediatric patients with suspected gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2010;50(2):154-60.

16. Modlin IM, Hunt RH, Malfertheiner P, Moayyedi P, Quigley EM, Tytgat GN, et al. Diagnosis and management of non-erosive reflux disease--the Vevey NERD Consensus Group. Digestion. 2009;80(2):74-88.

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24. Büchele G, Genuneit J, Weinmayr G, Björkstén B, Gehring U, von Mutius E, et al. International variations in bronchial responsiveness in children: findings from ISAAC phase two. Pediatr Pulmonol.

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26. Ownby DR, Peterson EL, Johnson CC. Factors related to methacholine airway responsiveness in children. Am J Respir Crit Care Med. 2000;161(5):1578-83.

27. Rasmussen F, Taylor DR, Flannery EM, Cowan JO, Greene JM, Herbison GP, et al. Outcome in adulthood of asymptomatic airway hyperresponsiveness in childhood: a longitudinal population study. Pediatr Pulmonol.

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28. Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study.

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29. Pin I, Radford S, Kolendowicz R, Jennings B, Denburg JA, Hargreave FE, et al. Airway inflammation in symptomatic and asymptomatic children with methacholine hyperresponsiveness. Eur Respir J. 1993;6(9):1249-56.

30. Kiljander TO, Laitinen JO. The prevalence of gastroesophageal reflux disease in adult asthmatics.

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31. Harding SM, Guzzo MR, Richter JE. 24-h esophageal pH testing in asthmatics: respiratory symptom correlation with esophageal acid events. Chest. 1999;115(3):654-9.

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34. Fass R, Dickman R. Clinical consequences of silent gastroesophageal reflux disease. Curr Gastroenterol Rep. 2006;8(3):195-201.

35. Teixeira BC, Norton RC, Penna FJ, Camargos PA, Lasmar LM, Macedo AV. Gastroesophageal reflux and asthma in childhood: a study on their relationship using esophageal PH monitoring. J Pediatr (Rio J). 2007;83(6):535-40.

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38. Bagnato GF, Gulli S, Giacobbe O, De Pasquale R, Purello D’Ambrosio F. Bronchial hyperresponsiveness in subjects with gastroesophageal reflux. Respiration.

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39. Lapa MS, Rodrigues Jr RR, Fiss E. Bronchial hyperreactivity in patients with gastroesophageal reflux disease. J Bras Pneumol. 2005;31(4):286-91.

40. Asano K, Suzuki H. Silent acid reflux and asthma control. N Engl J Med. 2009;360(15):1551-3.

41. Khoshoo V, Mohnot S, Haydel R Jr, Saturno E, Edell D, Kobernick A. Bronchial hyperreactivity in non-atopic children with asthma and reflux: effect of anti-reflux treatment. Pediatr Pulmonol. 2009;44(11):1070-4.

42. dos Santos LH, Ribeiro IO, Sánchez PG, Hetzel JL, Felicetti JC, Cardoso PF. Evaluation of pantoprazol treatment response of patients with asthma and gastroesophageal reflux: a randomized prospective double-blind placebo-controlled study. J Bras Pneumol.

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43. Kiljander TO, Harding SM, Field SK, Stein MR, Nelson HS, Ekelund J, et al. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med. 2006;173(10):1091-7.

44. American Lung Association Asthma Clinical Research Centers, Mastronarde JG, Anthonisen NR, Castro M, Holbrook JT, Leone FT, et al. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med. 2009;360(15):1487-99.

45. Kiljander TO, Junghard O, Beckman O, Lind T. Effect of esomeprazole 40 mg once or twice daily on asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2010;181(10):1042-8.

46. Sopo SM, Radzik D, Calvani M. Does treatment with proton pump inhibitors for gastroesophageal reflux disease (GERD) improve asthma symptoms in children

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47. Stein MR. Possible mechanisms of influence of esophageal acid on airway hyperresponsiveness. Am J Med. 2003;115 Suppl 3A:55S-59S. 48. Martins MA. Asthma and gastroesophageal reflux disease. J Bras Pneumol. 2007;33(2):XI-XII. 49. Harding SM. Gastroesophageal reflux: a potential asthma trigger. Immunol Allergy Clin North Am. 2005;25(1):131-48.

50. Araujo AC, Aprile LR, Dantas RO, Terra-Filho J, Vianna EO. Bronchial responsiveness during esophageal acid infusion. Lung. 2008;186(2):123-8.

51. Araujo AC, Aprile RL, Dantas RO, Terra-Filho J, Martins MA, Vianna EO. The effect of esophageal acidification on bronchial obstruction in individuals with asthma with gastroesophageal reflux. J Bras. Pneumol.

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52. Wu DN, Tanifuji Y, Kobayashi H, Yamauchi K, Kato C, Suzuki K, et al. Effects of esophageal acid perfusion on airway hyperresponsiveness in patients with bronchial asthma. Chest. 2000;118(6):1553-6.

53. Lopes FD, Alvarenga GS, Quiles R, Dorna MB, Vieira JE, Dolhnikoff M, et al. Pulmonary responses to tracheal or esophageal acidification in guinea pigs with airway inflammation. J Appl Physiol. 2002;93(3):842-7.

54. Lang IM, Haworth ST, Medda BK, Roerig DL, Forster HV, Shaker R. Airway responses to esophageal acidification. Am J Physiol Regul Integr Comp Physiol.

2008;294(1):R211-9.

55. Hamamoto J, Kohrogi H, Kawano O, Iwagoe H, Fujii K, Hirata N, et al. Esophageal stimulation by hydrochloric acid causes neurogenic inflammation in the airways in guinea pigs. J Appl Physiol. 1997;82(3):738-45.

56. Allen GB, Leclair TR, von Reyn J, Larrabee YC, Cloutier ME, Irvin CG, et al. Acid aspiration-induced airways hyperresponsiveness in mice. J Appl Physiol.

2009;107(6):1763-70.

57. Mittal RK, Balaban DH. The esophagogastric junction. N Engl J Med. 1997;336(13):924-32.

58. Zerbib F, Guisset O, Lamouliatte H, Quinton A, Galmiche JP, Tunon-De-Lara JM. Effects of bronchial obstruction on lower esophageal sphincter motility and gastroesophageal reflux in patients with asthma. Am J Respir Crit Care Med. 2002;166(9):1206-11.

59. Lodi U, Harding SM, Coghlan HC, Guzzo MR, Walker LH. Autonomic regulation in asthmatics with gastroesophageal reflux. Chest. 1997;111(1):65-70.

60. Field SK. Gastroesophageal reflux and asthma: can the paradox be explained? Can Respir J. 2000;7(2):167-76.

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About the authors Jaqueline Cavalcanti de Albuquerque Ratier

Master’s Student. Graduate Program in Medical Sciences, Federal University of Santa Catarina, Florianópolis, Brazil.

Emilio Pizzichini

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

Marcia Pizzichini

Coordinator. Graduate Program in Medical Sciences, Federal University of Santa Catarina, Florianópolis, Brazil.

J Bras Pneumol. 2011;37(5):680-688

Case Report Pulmonary actinomycosis as a pseudotumor: A rare presentation* Actinomicose pulmonar na forma pseudotumoral: Uma apresentação rara

Hylas Paiva da Costa Ferreira, Carlos Alberto Almeida de Araújo, Jeancarlo Fernandes Cavalcanti, Roberta Lacerda Almeida de Miranda, Rachel de Alcântara Oliveira Ramalho

Abstract Some lung diseases are true diagnostic challenges due to their various clinical presentations. Actinomycosis is one such disease, potentially affecting various organs and systems. We report the case of a patient with pulmonary actinomycosis as a pseudotumor, which is usually only diagnosed by thoracotomy or thoracoscopy.

Keywords: Actinomycosis; Thoracic neoplasms; Bacterial infections and mycoses.

Resumo Algumas patologias pulmonares apresentam-se como verdadeiros desafios diagnósticos devido às suas diversas formas de apresentação. A actinomicose é uma dessas patologias, podendo atingir diversos órgãos e sistemas.

Relatamos o caso de uma paciente com a forma pseudotumoral pulmonar da doença, cujo seu diagnóstico geralmente só é realizado através de toracotomia ou toracoscopia.

Descritores: Actinomicose; Neoplasias torácicas; Infecções bacterianas e micoses.

Introduction Actinomycosis is a rare, chronic disease, and there is thoracic involvement in 15-50% of cases.(1) Actinomycosis is characterized by the formation of abscesses and by tissue fibrosis.(2) The disease is caused by facultative anaerobic gram-positive bacteria that normally colonizes the mouth, colon, and urogenital tract.(1,3-5) The bacterium was first isolated from human autopsy material by Israel in 1878,(2,3) and the first case of pulmonary actinomycosis was described by Ponfick in 1882.(3) The pathogenic species of Actinomyces do not exist in nature; they are natural inhabitants and commensals of the oropharynx, gastrointestinal tract, and female genital tract in humans; consequently, humans are a natural reservoir of Actinomyces spp.,(2) and there have been no reports of person-to-person transmission.(1,2,5) Because the microorganism involved is not virulent, the adjacent tissues will become infected only if there is a loss of

mucosal integrity.(4,5) The cervicofacial, thoracic, abdominal, and pelvic areas, as well as the central nervous system, are the areas that are most commonly affected,(1,2) and the treatment of choice is long-term penicillin therapy.(1)

Case report A 26-year-old female patient was hospitalized for the investigation of a tumor mass in the left upper lobe, with invasion of the mediastinum and chest wall. The patient presented with a 60-day history of chest pain that did not radiate and did not improve with the use of analgesics.

The pain was accompanied by daily fever, dyspnea, worsening of overall health status, and productive cough with mucoid expectoration.

She reported no weight loss or hemoptysis; nor did she report headache or other neurological symptoms.

* Study carried out at the Onofre Lopes University Hospital, Universidade Federal do Rio Grande do Norte – UFRN, Federal University of Rio Grande do Norte – Natal, Brazil.

Correspondence to: Hylas Paiva da Costa Ferreira. Rua Auris Coelho, 235, Lagoa Nova, CEP 59075-050, Natal, RN, Brasil.

Tel 55 84 9623-0910. E-mail: endotorax@hotmail.com Financial support: None.

Submitted: 12 May 2010. Accepted, after review: 25 August 2010.

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The patient was referred to the thoracic surgery department of our hospital for diagnostic investigation. Contrast-enhanced magnetic resonance imaging showed a mass with irregular borders, measuring 9.2 × 7.2 × 6.0 cm. The mass occupied the entire left upper lobe, invading the mediastinum and chest wall and involving the left common carotid artery, the left subclavian artery, and part of the aortic arch (Figure 1). A CT scan of the chest revealed invasion of the abovementioned structures and of the vertebral bodies, as well as the left supraclavicular fossa (Figures 2 and 3).

Two CT-guided transthoracic needle biopsies were performed, but the results were inconclusive (chronic inflammatory process). Because the results were inconclusive, we decided to perform exploratory thoracotomy, which revealed intense hepatization in the left upper lung lobe and a hardened mass that bled when cut. Frozen section analysis was negative for neoplasia.

The Grocott-Gomori methenamine-silver stain technique revealed filamentous structures and foreign body giant cell reaction, which facilitated the diagnosis of pulmonary actinomycosis.

Treatment with crystalline penicillin was initiated, and, on postoperative day 7, the patient presented with progressive clinical worsening, accompanied by psychomotor agitation and progressive respiratory failure. Mechanical ventilation and vasoactive drugs were required.

On post-admission day 30, the patient presented with convulsions, which responded well to the use of anticonvulsants. Treatment with crystalline penicillin was continued. The patient showed progressive improvement and was discharged with a prescription for 6 months of continuous treatment with amoxicillin. Complete remission was achieved. At this writing, the patient presented with fibrosis of the left lower lobe and was under follow-up treatment.

Figure 1 - Magnetic resonance imaging of the chest revealing a pulmonary mass without cleavage planes and with mediastinal structures.

A. meyeri, and A. gerencseriae,(3,5) which are the species that are pathogenic for humans.(2) Although the genus Actinomyces was once classified as a fungus because of its hyphal branching, it is currently classified as a bacterium,(2,5,7) which presents endemically and is universally distributed, with no predominance of gender, age, race, occupation, or time of year.

Although colonization with Actinomyces sp. is not considered an opportunistic infection, it is most common in patients with some degree of immunodeficiency.(5) Pulmonary actinomycosis generally results from the aspiration of oropharyngeal or gastrointestinal secretions into the respiratory tract.(8) Alcoholism, poor oral hygiene, and dental caries can also contribute to the development of the disease.(8) This type of infection generally involves the cervicofacial region in approximately 55% of the cases,(3,6,7,9,10) the thoracic region in approximately 15% of the cases,(1,3,6,7,9,10) and

Discussion Actinomycosis is a chronic granulomatous infectious disease,(6) caused by a filamentous, anaerobic gram-positive microorganism of the genus Actinomyces,(2,3,6) a microorganism that is part of the microbiota of the oral cavity, gastrointestinal tract, and urogenital tract.(1,4-6) Approximately 30 Actinomyces spp. have been isolated, and the most common are A. israelii,

A. naeslundii, A. odontolyticus, A. viscosus, J Bras Pneumol. 2011;37(5):689-693

Figure 2 - Chest CT scan revealing a mass invading the chest wall, without cleavage planes and with mediastinal structures.

Pulmonary actinomycosis as a pseudotumor: A rare presentation

Figure 3 - Chest CT scan (lung window).

the abdominal/pelvic region in 20% of the patients,(3,6,7,9,10) as well as the central nervous system, in a lower proportion of cases.(3,9,10) The incidence of pulmonary actinomycosis has decreased because of the widespread use of antibiotics.(5) Because of the uncommon presentationâ&#x20AC;&#x201D;large masses and invasion of adjacent structuresâ&#x20AC;&#x201D;it is difficult to make a diagnosis of pulmonary actinomycosis, and the infection is easily mistaken for neoplasia. In general, pulmonary actinomycosis is diagnosed only by histopathological examination.(1,3,5,11,12) The diagnosis is typically delayed because of the indolent natural history of the disease and the absence of inflammatory signs.(3) Because pulmonary actinomycosis can coexist with lung cancer, nocardiosis, and tuberculosis,(1,2) the diagnosis can be established by isolating Actinomyces sp. from tissue samples collected by thoracotomy.(4,7-9) Therefore, tissue culture is required, and colonies appear after 3-7 days of incubation(2); however, in order to confirm the diagnosis, the culture should remain under observation for 21 days.(2) Thoracic actinomycosis is uncommon and, when it does occur, can be erroneously diagnosed as bronchopneumonia or lung cancer.

(7) Thoracic actinomycosis is far more common in adults than in children, as well as being far more common in males than in females.(3,8,12) Thoracic actinomycosis can involve the lungs and pleura, as well as invading the mediastinum and chest wall.(2,5,7) The expansion of a chronic pulmonary focus can lead to the development of empyema and invasion/destruction of the ribs, scapular girdle, and sternum.(2) The involvement of mediastinal structures rarely results in

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superior vena cava syndrome, tracheoesophageal fistula, or pericarditis/myocarditis.(2) The onset of pulmonary actinomycosis is insidious (with cough, expectoration, fever, and weight loss), and hemoptysis or pleuritic pain can occur.

(1) Inflammatory tissue can form within and obstruct the bronchus.(1) Hemoptysis is common and has been reported in up to 50% of the cases evaluated in case series.(12) The incidence of pulmonary actinomycosis is higher in male patients because, among males, the number of cases of facial trauma is higher and oral hygiene is poorer.(3,8) Pulmonary actinomycosis accounts for approximately 15-45% of all reported cases of actinomycosis, and cardiac involvement is rarer, accounting for only 2% of the cases.(5) The species that is most commonly isolated in the thoracic form of the disease is A. israelii.(7) The routes of Actinomyces infection include aspiration of oropharyngeal secretions or gastric contents; direct extension of cervicofacial infection to the mediastinum through the deep fascia of the neck; transdiaphragmatic or retroperitoneal infection from the abdomen; and, more rarely, hematogenous dissemination.(2,7) The signs and symptoms are nonspecific and highly variable,(4) the most common being chest pain, dyspnea, fever, weight loss, and cough,(2,4,5,8,9,12) which are sometimes mistaken for symptoms of tuberculosis or neoplasia.(2) Patients can also present with leukocytosis, accompanied by neutrophilia and moderate anemia.(1,9) There are no radiological signs that are indicative of thoracic actinomycosis,(4) and chest X-ray findings can mimic a wide variety of diseases, including pulmonary infiltrate (suggestive of mild pneumonia) and micronodular infiltrate accompanied by pulmonary cavitation or large masses (suggestive of neoplasia), pleural effusion being common.(1,2,4,8,9) In advanced cases, a CT scan of the chest can reveal involvement of the chest wall, mediastinal involvement, and pleural involvement.(1,4,9) An image of diffuse involvement that crosses anatomical boundaries is highly suggestive of pulmonary actinomycosis.

(4)

The differential diagnosis of pulmonary actinomycosis includes recurrent pneumonia, pulmonary infarction, lung cancer, Wegenerâ&#x20AC;&#x2122;s granulomatosis, nocardiosis, pulmonary sequestration, and bronchogenic cyst.(12) J Bras Pneumol. 2011;37(5):689-693

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The prognosis of infections is excellent if treatment is given in a timely manner.

Hematogenous dissemination is a relatively common complication of the thoracic and advanced forms of the disease.(1,4,5) Less common complications, such as pleural empyema, hemoptysis, and chronic sinusitis, can also occur.(4) The lack of diagnostic suspicion of actinomycosis can worsen the prognosis or treatment results, as well as leading patients to undergo unnecessary extensive surgery.(4) The genus Actinomyces is susceptible to a wide variety of antibiotics in vitro, and penicillin G is the drug of choice for the treatment of actinomycosis, therapy consisting of high doses (18-24 million IU/day) for 2-6 weeks, followed by oral amoxicillin for 6-12 months.(1-4,6-10,12) Patients who are allergic to penicillin can be treated with doxycycline, erythromycin, or cephalosporins, all of which have been shown to be effective.(2,3,5,8,12) However, most strains are resistant to ciprofloxacin.(3) There are reports of satisfactory results with the use of levofloxacin,(1) and some authors have suggested that patients with pulmonary actinomycosis can be individual candidates for shorter courses of antibiotics.

(11) Surgical treatment of actinomycosis is controversial and should be restricted to abscess drainage, debridement of necrotic tissue, curettage of bone, and drainage of empyema.(2,5) Mortality is relatively low, depending on the site of infection and on early diagnosis. However, there have been case series in which the reported mortality was as high as 28%.(4,5) In conclusion, actinomycosis is a disease of insidious onset with nonspecific symptoms and therefore poses a diagnostic challenge. The disease should be included in the differential diagnosis when patients with poor oral hygiene present with chronic pneumonia or a

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pulmonary mass suggestive of lung cancer but accompanied by air bronchogram and an area of low attenuation on CT scans of the chest.

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8. Santos JW, Nascimento DZ, Guerra VA, Vassoler RM, Simon TT, Machado FP, et al. Pulmonary Actinomycosis: An old disease that is still diagnosed late. Clin Pulm Med. 2008;15(3):173-6.

9. Taştepe AI, Ulaşan NG, Liman ST, Demircan S, Uzar A. Thoracic actinomycosis. Eur J Cardiothorac Surg.

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10. Filipović B, Milinić N, Nikolić G, Ranthelović T. Primary actinomycosis of the anterior abdominal wall: case report and review of the literature. J Gastroenterol Hepatol. 2005;20(4):517-20.

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Optimal duration of IV and oral antibiotics in the treatment of thoracic actinomycosis. Chest.

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About the authors Hylas Paiva da Costa Ferreira

Professor of Thoracic Surgery. Universidade Federal do Rio Grande do Norte – UFRN, Federal University of Rio Grande do Norte – Natal, Brazil.

Carlos Alberto Almeida de Araújo

Professor of Thoracic Surgery. Universidade Federal do Rio Grande do Norte – UFRN, Federal University of Rio Grande do Norte – Natal, Brazil.

Jeancarlo Fernandes Cavalcanti

Professor of Emergency Medicine. Universidade Federal do Rio Grande do Norte – UFRN, Federal University of Rio Grande do Norte – Natal, Brazil.

Roberta Lacerda Almeida de Miranda

General Practitioner. Onofre Lopes University Hospital, Universidade Federal do Rio Grande do Norte – UFRN, Federal University of Rio Grande do Norte – Natal, Brazil.

Rachel de Alcântara Oliveira Ramalho

Doctoral Student in Medicine. Universidade Federal do Rio Grande do Norte – UFRN, Federal University of Rio Grande do Norte – Natal, Brazil.

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Letter to the Editor Robotic thymectomy for myasthenia gravis Timectomia robótica para miastenia gravis

Rodrigo Afonso da Silva Sardenberg, Ricardo Zugaib Abadalla, Igor Renato Louro Bruno Abreu, Eli Faria Evaristo, Riad Naim Younes

To the Editor: A 20-year old woman was referred to the Department of Thoracic Surgery of Hospital Sírio Libanês as a candidate for thymectomy.

She had a two-year history of myasthenia gravis, presenting with diplopia, ptosis, and mild generalized weakness (stage IIA according to the Osserman classification).

The physical examination was unremarkable.

Preoperative procedures included chest radiograph, CT of the chest, pulmonary function tests, and a complete neurological work-up.

Blood tests were positive for acetylcholine receptor antibodies. The CT findings excluded the possibility of thymoma. The patient was deemed a good candidate for thymectomy by thoracoscopic robot-assisted surgery.

The patient was submitted to general and epidural anesthesia, a double-lumen endotracheal tube was placed, and she was positioned in a left-sided 30° elevated lateral decubitus. The camera port was placed in the fourth intercostal space at the anterior axillary line, and the instrument ports were placed in the third intercostal space at the mid-axillary line and in the fifth intercostal space at the midclavicular line (Figure 1). A three-dimensional 0° camera was introduced for the complete visualization of the pleural space, and the two arms of the robotic surgical system (da Vinci®; Intuitive Surgical, Inc., Menlo Park, CA, USA) were attached. For the left arm, an EndoWrist® instrument (Intuitive Surgical, Inc.) was used, whereas an electrocautery unit was used for the right arm. The left arm was mainly used to grasp the thymus, and the dissection was performed with the right arm.

The dissection began inferiorly at the left cardiophrenic angle along the left phrenic nerve (Figure 2). The thymus gland was separated from the retrosternal area, and the left inferior horn of the thymus was isolated and dissected from the pericardium.

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As the dissection proceeded, the innominate vein was identified, and the thymic veins were clipped and divided. The cardiophrenic angle was then dissected on the right side, and both upper thymic poles were isolated. The dissection finished at the lower right side, with identification of the right phrenic nerve and subsequent exploration of the pleura.

The thymus gland and the anterior mediastinal/cervical fat tissue were resected radically and removed through the trocar port.

After hemostasis had been achieved, a 28F drainage chest tube was inserted into the pleural cavity through the port of the fifth intercostal space, the lung was reinflated, and the other wounds were closed in a standard fashion. The total operative time was 120 min, including the robotic docking, thymus resection, and skin closure.

The postoperative period was uneventful, the chest tube was removed 48 h after surgery, and the patient was discharged 72 h after surgery.

The final histology revealed thymic hyperplasia, with no ectopic foci in the resected surrounding tissue.

After a three-month follow-up period, the patient was clinically well, and a reduction in the prednisone dose was possible, although the cholinesterase inhibitors were kept at the same dosage. Although she had pain at the incision site for approximately one month, she returned to work 15 days after surgery and was able to resume light sports one month after hospital discharge.

The first thymectomy by robot-assisted surgery for the treatment of a small thymoma was performed in 2001,(1) and, throughout that decade, many reports confirmed the advantages of this new technique for thymus resection.

Myasthenia gravis is an autoimmune disease that affects neuromuscular transmission and results in chronic weakness and various levels of fatigue in striated muscles. The pathophysiology is related to the presence of acetylcholine receptors

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generated in the thymus, which ultimately lead to the symptoms.

Thymectomy is a widely accepted therapeutic option as an adjunct to clinical treatment, yielding positive results in terms of improvement and remission of symptoms. In this setting, numerous thymectomy techniques, of varying degrees of invasiveness, have been proposed, generating controversy regarding the best surgical approach for myasthenia gravis.(2-5) The optimal timing for thymectomy has yet to be established; however, it is probably best performed when patients still have minimal bulbar and respiratory symptoms.

If the clinical status allows, it is also helpful to lower the dosage of corticoids. Some authors have suggested that the response is better if thymectomy is performed as soon as the disease is diagnosed.

Analyzing the literature, we have found that transcervical thymectomy is limited to the removal of the intracapsular portion of the lobes. Therefore, this is associated with a higher amount of residual thymus and, as a consequence, with a higher operation rate without the remission of symptoms due to ectopic foci.(1) One means of overcoming this problem is to perform extended transcervical thymectomy using a sternal retractor under the manubrium, although that does not allow the surgeon to remove the layers of the pleura.(2) Therefore, combined transsternal and cervical thymectomy consists of the en-bloc removal of all thymus in the neck and mediastinum. It is the benchmark operation, which other approaches are to be compared with.(2) Recent advances in video-assisted thoracoscopic surgery (VATS) and minimally invasive surgical techniques have made thymectomy possible. These approaches have reduced morbidity, mortality, infection rates, postoperative hospital stays, and the use of pain medication.(3) The da VinciÂŽ surgical system consists of an input device (surgeon console) and an output device (patient-side manipulator) with two or three instrument arms and one camera arm. The surgeon operates the console, which translates the position and the motion of the hands over highly sensitive motion sensors to the end of the instruments at a remote location. The instrument arms have seven degrees of freedom, promoting motion scaling and tremor filtering. In addition,

Figure 1 - Port placement on the left hemithorax.

the EndoWristŽ surgical instrument has a 360° range of motion, improving maneuverability around anatomic structures.(4) The disadvantages of this technique include loss of tactile sense, limited instrumentation compared with the VATS technique, and higher costs. The outcomes are comparable to those obtained with VATS, such as shorter hospital stays and less pain.(5) We could safely visualize and dissect the upper lobes of the thymus, with a radical and complete resection, including all of the fat from the pericardium down to the diaphragm. We opted for a left-side approach, because it allows easier access to the aortopulmonary window, which is a common location of ectopic thymic tissue.(6) In addition, a left-side approach makes it easier to identify the phrenic nerve, which is mandatory in this population of patients.

We believe that, with the robotic approach, radical thymectomy can be performed safely, and

Figure 2 - Thymus dissection at the left cardiophrenic angle.

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this might lower the threshold for neurologists to recommend surgery for their patients with myasthenia gravis.

Rodrigo Afonso da Silva Sardenberg Thoracic Surgeon, Hospital Sírio Libanês and Hospital Albert Einstein, São Paulo, Brazil Ricardo Zugaib Abadalla General Surgeon, Hospital Sírio Libanês, São Paulo, Brazil Igor Renato Louro Bruno Abreu Thoracic Surgeon, Hospital Sírio Libanês, São Paulo, Brazil Eli Faria Evaristo Neurologist, Hospital Sírio Libanês and Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil Riad Naim Younes Associate Professor, Department of Surgery, University of São Paulo School of Medicine, São Paulo, Brazil.

Director of the Advanced Center for Thoracic Diseases, Hospital Sírio Libanês, São Paulo, Brazil

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References 1. Jaretzki A 3rd. Thymectomy for myasthenia gravis: analysis of controversies--patient management.

Neurologist. 2003;9(2):77-92.

2. Cooper JD, Al-Jilaihawa AN, Pearson FG, Humphrey JG, Humphrey HE. An improved technique to facilitate transcervical thymectomy for myasthenia gravis. Ann Thorac Surg. 1988;45(3):242-7.

3. Mack MJ, Landreneau RJ, Yim AP, Hazelrigg SR, Scruggs GR. Results of video-assisted thymectomy in patients with myasthenia gravis. J Thorac Cardiovasc Surg.

1996;112(5):1352-9; discussion 1359-60.

4. Hashizume M, Konishi K, Tsutsumi N, Yamaguchi S, Shimabukuro R. A new era of robotic surgery assisted by a computer-enhanced surgical system. Surgery.

2002;131(1 Suppl):S330-3.

5. Demmy TL, James TA, Swanson SJ, McKenna RJ Jr, D’Amico TA. Troubleshooting video-assisted thoracic surgery lobectomy. Ann Thorac Surg. 2005;79(5):174452; discussion 1753.

6. Rückert JC, Czyzewski D, Pest S, Müller JM. Radicality of thoracoscopic thymectomy--an anatomical study. Eur J Cardiothorac Surg. 2000;18(6):735-6.

Letter to the Editor Diaphragmatic pacing: unusual indication with successful application Marca-passo diafragmático: indicação incomum, aplicação bem-sucedida

Rodrigo Afonso da Silva Sardenberg, Liliana Bahia Pereira Secaf, Adriana Cordeiro Pinotti, Mário Augusto Taricco, Roger Schmidt Brock, Riad Naim Younes

To the Editor: Syringomyelia is the development of a fluidfilled cavity or syrinx within the spinal cord.

Hydromyelia is a dilatation of the central canal by cerebrospinal fluid and can be included within the definition of syringomyelia.(1) A 20-year-old male patient was referred to the Department of Thoracic Surgery of the Hospital Sírio Libanês as a candidate for diaphragmatic pacing (DP) with phrenic nerve stimulation, because he had chronic apnea due to syringomyelia and had been dependent on mechanical ventilation for the last 5 years, with repeated pulmonary infections and prolonged hospitalizations. At referral, his clinical condition was good, and his phrenic nerve conduction, as evaluated by electromyography, was normal.

The patient underwent a bilateral anterior third-space mini-thoracotomy, with doublelumen intubation. The electrodes were placed underneath the phrenic nerves (direct contact between the nerves and the exposed metal) and fixed to the pericardium using a 4-0 nonabsorbable suture.

A subcutaneous pocket was created for receiver placement near the lower costal margin, where the electrode leads entered the thorax through an intercostal space. Two identical devices were implanted, one on each side, during the same procedure. After the receivers had been connected to the electrodes, the whole system was tested, with the help of an engineer who was present in the operating room. The incisions were closed in layers and a 14F chest tube (with Heimlich valve) was placed in position.

The postoperative recovery period was uneventful, and diaphragm conditioning was initiated two weeks after implantation.

Radiofrequency signals, generated by a battery-powered transmitter (Figure 1a), were sent from an external antenna (Figure 1a), fixed to the implanted receivers (Figure 1b), which

convert the radio signals in electrical impulses, causing diaphragmatic contraction.

To avoid fatigue, DP was initiated at a frequency of 15 Hz for 15 min during each waking hour in the first week, with increases of 15 min/week, as tolerated by the patient. After 30 days of DP, the patient was discharged in good clinical condition, being submitted to 60 min of continuous DP every day.

At this writing, after 90 days of DP, the patient had been submitted to continuous pacing for approximately 10 h every day, requiring mechanical ventilation especially when sleeping. No muscle fatigue had been reported.

The quality of speech had improved, and the tracheal stoma had been maintained in place with a 6.0-mm diameter cannula.

In 1972, Glenn et al.(2) introduced DP with phrenic nerve stimulation for quadriplegic patients on ventilatory support. Although the procedure was successful, increasing experience identified a more physiological method of DP in quadriplegic patients using simultaneous and continuous pacing of both hemidiaphragms.

In 1984, the experience of ventilation in five quadriplegic patients who had been submitted to pacing for 11 to 33 months after diaphragm conditioning was reported.(3) The authors obtained promising results, demonstrating that 24-h bilateral pacing of the conditioned diaphragm was feasible.

In quadriplegic patients and in those with congenital central hypoventilation syndrome (CCHS), DP with phrenic nerve stimulation can improve quality of life by eliminating the dependence on a ventilator. The damage to the central nervous system must be above the second or third cervical level, since DP is possible only if the nerve-cell bodies are viable (located in the anterior horns at C3-C5).(3,4) In contrast, trauma to the mid-cervical spine (at C3, C4, or C5) usually precludes the use of DP. Diseases of the lower motor neurons or of the

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Figure 1 - Device for phrenic nerve stimulation: external parts (in a) and internal parts (in b).

anterior horn cells, such as polio or amyotrophic lateral sclerosis, have been considered contraindications to DP for the same reason.

(4) Patients with CCHS are excellent candidates.

Some of them hypoventilate only during sleep and can therefore utilize DP at night, rendering them ventilator-free. The ideal candidates for DP with phrenic nerve stimulation are those with complete upper cervical spine injuries (at C1 or C2) that lead to apnea, those with certain types of central sleep apnea or CCHS, and those with brainstem tumors, infarction, or strokes associated with CCHS.(5,6) The electrodes used in DP can be placed adjacent to the phrenic nerve, either in the neck or in the chest. The cervical approach is easier, although some problems might occur, such as local infections due to previous tracheostomy adjacent to the incision, loss of conduction because of the phrenic branch at the cervical level, and rhythmic motions of upper extremities by functioning portions of the brachial plexus.

Thoracic approaches include thoracotomy, thoracoscopy, or robotics. In our patient, we performed a bilateral mini-thoracotomy, because he presented with recurrent pneumonias, and decortication was necessary for phrenic nerve dissection. In this setting, the phrenic nerve is located along the mediastinum, lying on both sides laterally to the pericardium. It is important to keep a 2-3 mm margin of intact perineural tissue surrounding the nerve to preserve its blood supply.(7) J Bras Pneumol. 2011;37(5):697-699

Conditioning of the diaphragm requires a gradually increasing duration of pacing, and the patient should be carefully monitored during conditioning.(7-9) Fluoroscopy can be used to determine the maximal diaphragm excursion.

(4,6,7)

The selection of the appropriate DP parameters is dependent on the underlying reason for requiring ventilatory support. Patients with quadriplegia usually have significant disuse atrophy of the diaphragm, and the duration of DP should therefore be increased by only 3-5 min per day, in order to avoid fatigue.(10) In one study, 12 patients with quadriplegia and spinal cord injury were submitted to DP electrode implantation, and 6 of those patients continued DP over the long-term, with a mean duration of 13.7 years.(6) The use of DP can provide various advantages to patients with respiratory insufficiency. Such advantages include a significant reduction in the number of upper airway infections and episodes of pneumonia; lower individual costs for airway management equipment; improvement in quality of life and speech capability; avoidance of tracheostomy decannulation, and ventilator weaning; and improved educational and employment opportunities.

The long-term success of DP depends on good selection criteria, based on pre-operative evaluations, as well as on the education of family members/caregivers and careful monitoring by the medical team.

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We conclude that, in carefully selected patients, DP is clinically feasible with no apparent clinical or physiological detriment.

Patients in whom long-term DP is successful demonstrate social independence and better survival. Although the potential patient pool is limited, DP offers numerous advantages when compared with ventilator systems, primarily better quality of life.

Rodrigo Afonso da Silva Sardenberg Thoracic Surgeon, Hospital Sírio Libanês and Hospital Albert Einstein, São Paulo, Brazil Liliana Bahia Pereira Secaf General Clinician, Hospital Sírio Libanês, São Paulo, Brazil Adriana Cordeiro Pinotti General Surgeon, Hospital Sírio Libanês, São Paulo, Brazil Mário Augusto Taricco Associate Professor, Department of Neurosurgery, University of São Paulo School of Medicine, São Paulo, Brazil

References 1. Henriques Filho PS, Pratesi R. Sleep disorder: a possible cause of attention deficit in children and adolescents with Chiari malformation type II. Arq Neuropsiquiatr.

2009;67(1):29-34.

2. Glenn WW, Holcomb WG, McLaughlin AJ, O’Hare JM, Hogan JF, Yasuda R. Total ventilatory support in a quadriplegic patient with radiofrequency electrophrenic respiration. N Engl J Med. 1972;286(10):513-6.

3. Glenn WW, Hogan JF, Loke JS, Ciesielski TE, Phelps ML, Rowedder R. Ventilatory support by pacing of the conditioned diaphragm in quadriplegia. N Engl J Med. 1984;310(18):1150-5.

4. Adler D, Gonzalez-Bermejo J, Duguet A, Demoule A, Le Pimpec-Barthes F, Hurbault A, et al. Diaphragm pacing restores olfaction in tetraplegia. Eur Respir J. 2009;34(2):365-70.

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

6. Elefteriades JA, Quin JA. Diaphragm pacing. Ann Thorac Surg. 2002;73(2):691-2.

7. Miller JI, Farmer JA, Stuart W, Apple D. Phrenic nerve pacing of the quadriplegic patient. J Thorac Cardiovasc Surg. 1990;99(1):35-9; discussion 39-40.

8. Chervin RD, Guilleminault C. Diaphragm pacing for respiratory insufficiency. J Clin Neurophysiol.

1997;14(5):369-77.

9. Wetstein L. Technique for implantation of phrenic nerve electrodes. Ann Thorac Surg. 1987;43(3):335-6.

10. Murray C, Seton C, Prelog K, Fitzgerald DA. Arnold Chiari type 1 malformation presenting with sleep disordered breathing in well children. Arch Dis Child.

2006;91(4):342-3.

Roger Schmidt Brock Assistant Neurosurgeon, Hospital Sírio Libanês, São Paulo, Brazil Riad Naim Younes Associate Professor, Department of Surgery, University of São Paulo School of Medicine, São Paulo, Brazil Director of the Advanced Center for Thoracic Diseases, Hospital Sírio Libanês, São Paulo, Brazil

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Letter to the Editor Nonfunctional middle mediastinal paraganglioma: diagnostic and surgical management Paraganglioma não funcional de mediastino médio: diagnóstico e manejo cirúrgico

Marcelo Cunha Fatureto, João Paulo Vieira dos Santos, Evelyne Gabriela Schmaltz Chaves Marques, Tarcísio Barcelos Evangelista, Wilson Alves Marques da Costa

To the Editor: Pheochromocytomas are tumors derived from chromaffin cells of the sympathetic nervous system. When arising from extraadrenal chromaffin cells, these tumors are called paragangliomas or chemodectomas.

(1-3) Mediastinal paragangliomas are rare, only approximately 150 cases having been reported in the literature, and two-thirds of these tumors are located in the anterior or middle mediastinum.

(4) Mediastinal paragangliomas are derived from the para-aortic and paravertebral ganglion chain.(3) Multicentric tumors are observed in 23% of cases, and there seems to be no specific distribution in the remaining cases.(5) Similar to pheochromocytomas, paragangliomas can secrete catecholamines, although most are nonfunctional.(3,6) Functional mediastinal paragangliomas are discovered as a result of the effects of catecholamine hypersecretion(1-3) or of compression, which leads to hoarseness, dysphagia, dyspnea, and chest pain.(7) The diagnosis is incidental in more than 50% of all cases.(8) Mediastinal paragangliomas are highly vascularized tumors that adhere to adjacent mediastinal structures, such as the heart, large blood vessels, trachea, and spine, and surgical management is therefore difficult.(1,2) The differential diagnosis includes Castleman’s disease, neuroendocrine tumors, lymphomas, and hemangiomas.

We report the case of a patient with a middle mediastinal tumor diagnosed after resection as nonfunctional paraganglioma. This is a very rare tumor, and it is uncommon for such a tumor to be identified preoperatively.

A 60-year-old White female sought treatment in the Thoracic Surgery Department of the

Hospital de Clínicas da Universidade Federal do Triângulo Mineiro (Triângulo Mineiro Federal J Bras Pneumol. 2011;37(5):700-702

University Hospital de Clínicas) with a 2-year history of moderate, constant pain in the left hemithorax. The patient reported no weight loss and classified herself as a nonsmoker. She had arterial hypertension, fibromyalgia, depression, and Chagas disease, all of which were controlled.

Physical examination, laboratory test results, and chest X-ray findings were normal. An echocardiogram showed a solid, heterogeneous opacity between the right pulmonary artery and the aortic arch. Chest CT revealed a well-defined mass in the middle mediastinum, measuring 5.5 × 5.2 × 4.7 cm, which was markedly enhanced after intravenous contrast administration. There were no signs of invasion, although the mass was exerting mild compression on the adjacent vascular structures (Figure 1).

Considering the diagnoses of a neuroendocrine tumor, Castleman’s disease, and lymphoma, we first submitted the patient to diagnostic mediastinoscopy. During the procedure, there was massive bleeding from the tumor and we were unable to obtain biopsy material for freezing. It therefore became necessary to perform right lateral thoracotomy.

Through careful dissection and the application of numerous metal hemostatic clips, we successfully resected the tumor, which was a solid, elastic, highly vascularized mass, measuring 5 × 5 cm, located adjacent to the pulmonary artery, aortic arch, pericardium, and esophagus.

The postoperative evolution was favorable, and the patient was discharged on postoperative day 10 with mild dysphonia, which subsided within a few weeks. At this writing, the patient had been asymptomatic for 2 years and showed no signs of recurrence.

The diagnosis of mediastinal paraganglioma was confirmed by histopathological analysis and immunohistochemistry. The tumor tested positive for synaptophysin, chromogranin A, and S-100 protein but negative for cytokeratin

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Figure 1 - Contrast-enhanced CT scans of the chest.

In a, coronal section; in b, axial section; and in c, sagittal section. Note the well-delineated mass in the middle mediastinum in close contact with the right pulmonary artery and the aortic arch.

(Figure 2). The resected subcarinal lymph nodes showed no signs of metastasis.

The diagnosis of paraganglioma is based on clinical symptoms, imaging exams, and biochemical tests.(3,8) The biochemical diagnosis of functional paragangliomas is made by measuring catecholamines and their metabolites in urine.(3,6) The main imaging methods used for the diagnosis of paragangliomas are CT and nuclear magnetic resonance imaging, both of which have

Figure 2 - Photomicrograph of an H&E-stained slide, showing a well-delineated and partially encapsulated benign tumor, consisting of oval or (rare) cylindrical cells. Note the slightly hyperchromatic, pleomorphic nuclei, the eosinophilic cytoplasms, and the finely granular chromatin.

a sensitivity of nearly 98%.(9) Some investigators have suggested that magnetic resonance angiography is the most effective method.(4) Metaiodobenzylguanidine scintigraphy is useful for the localization of extra-adrenal tumors and for the detection of multiple tumors.(4,6) The malignancy rate is higher for paragangliomas than for pheochromocytomas (29-40% vs. 10-15%). Distant metastases are typically to the lung and bones.(2) The treatment of choice is complete surgical resection,(2,3,8) which is difficult because of tumor hypervascularization and anatomical juxtaposition.

Combined incision and extracorporeal circulation are often necessary.

(2,3) We believe that right thoracotomy provides the best access to tumors at this site. Due to the large number of small vessels in this area, which contains various major structures, hemostatic clips or a harmonic scalpel should be used in order to guarantee efficient hemostatic control.

The difficulties encountered in the resection of mediastinal paragangliomas include intraoperative bleeding and secretion of catecholamines in patients with metabolically active tumors.(2,3) Hormonal crises, although uncommon, have been associated with significant morbidity and mortality.(8) A meticulous surgical technique and rigorous hemodynamic control (before and during the procedure) are the cornerstones of the prevention and management of these complications.(3) After complete resection of the tumor, the prognosis is favorable.

(2,3,7,8) Postoperative follow-up is fundamental for the early detection of metastatic disease, tumor recurrence, or late onset of multiple primary tumors.

At this writing, our patient was in good health, and the initial postoperative dysphonia had improved. Chest X-ray findings and urinary catecholamine metabolites were within normal ranges. Because the diagnosis was unexpected, these metabolites were not measured during the preoperative period.

Some investigators recommend preoperative embolization of paragangliomas at sites of difficult access (e.g., the neck) and the use of radiotherapy rather than resection when surgery is contraindicated or in complex situations, such as tumors involving the base of the skull.

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included in the differential diagnosis of mediastinal tumors. Because paragangliomas are highly vascularized, they represent a challenge for the thoracic surgeon in terms of diagnosis and surgical strategy for complete resection. Nevertheless, in patients submitted to paraganglioma resection, postoperative morbidity and mortality rates are low.

Marcelo Cunha Fatureto Adjunct Professor, Department of Thoracic Surgery, Hospital de Clínicas, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil João Paulo Vieira dos Santos Attending Physician, Department of Thoracic Surgery, Hospital de Clínicas, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil Evelyne Gabriela Schmaltz Chaves Marques Resident in Surgery, Department of Surgery, Hospital de Clínicas, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil Tarcísio Barcelos Evangelista Resident in Surgery, Department of Surgery, Hospital de Clínicas, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil Wilson Alves Marques da Costa Physician, Hospital de Clínicas, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil

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References 1. Francis IR, Korobkin M. Pheochromocytoma. Radiol Clin North Am. 1996;34(6):1101-12.

2. Lin MW, Chang YL, Lee YC, Huang PM. Non-functional paraganglioma of the posterior mediastinum. Interact Cardiovasc Thorac Surg. 2009;9(3):540-2.

3. Wald O, Shapira OM, Murar A, Izhar U. Paraganglioma of the mediastinum: challenges in diagnosis and surgical management. J Cardiothorac Surg. 2010;5:19.

4. Ximenes Netto M, Paniágua PR, Piauilino MA, Oliveira HA, Ishii L. Mediastinal paraganglioma with lung metastases. J Bras Pneumol. 2005;31(1):76-9.

5. Herrera MF, van Heerden JA, Puga FJ, Hogan MJ, Carney JA. Mediastinal paraganglioma: a surgical experience.

Ann Thorac Surg. 1993;56(5):1096-100.

6. Soteras Roura C, Bustos García de Castro A, Cabeza Martínez B, Ferreirós Domínguez J. Mediastinal paragangliomas: a report of 2 cases [Article in Spanish].

Radiologia. 2009;51(4):420-3.

7. Brown ML, Zayas GE, Abel MD, Young WF Jr, Schaff HV. Mediastinal paragangliomas: the mayo clinic experience.

Ann Thorac Surg. 2008;86(3):946-51.

8. Young WF Jr. Paragangliomas: clinical overview. Ann N Y Acad Sci. 2006;1073:21-9.

9. Bouloux PG, Fakeeh M. Investigation of phaeochromocytoma.

Clin Endocrinol (Oxf).

1995;43(6):657-64.

Notícias Pós-Doutorado em pneumologia com Bolsa da FAPESP A FAPESP oferece uma oportunidade de Bolsa de Pós-Doutorado com duração de 24 meses para o projeto “Avaliação da musculatura ventilatória ins e expiratória nas doenças respiratórias”. O candidato deve ter: doutoramento concluído há menos de sete anos; experiência com medidas de mecânica ventilatória e fisiologia respiratória; experiência com avaliações das respostas fisiológicas pulmonares ao esforço; experiência de pelo menos um ano em um centro internacional.

O candidato interessado e que preencha os requisitos em questão deverá enviar currículo atualizado para o professor Carlos Carvalho (crrcarvalho@uol.com.br), no Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, até o dia 15 de outubro de 2011. Maiores informações, favor acessar o link: http://agencia.fapesp.br/14395

DAxAS® roflumilaste - USO ORAL, ADULTO. INDICAÇÕES: tratamento de manutenção de pacientes com doença pulmonar obstrutiva crônica (DPOC) grave (VEF1 pós-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 nesses 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. 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 observaram interações clinicamente relevantes com: salbutamol inalado, formoterol, budesonida, montelucaste, digoxina, varfarina, sildenafila, 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, malestar, astenia, fadiga, dor muscular, lombalgia. Reações raras (> 1/10.000 e < 1/1.000): depressão e distúrbios do humor, ginecomastia, disgeusia, hematoquezia, 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. 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. *Marca depositada.

Referências bibliográficas: 1- Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011 Jan 14. doi: 10.1111/j.1476-5381.2011.01218.x. 2- Diamant Z, Spina D. PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease. Pulm Pharmacol Ther. 2011; 1-8. 3- Gross NJ, Giembycz MA, Rennard SI. Treatment of chronic obstructive pulmonary disease with roflumilast, a new phosphodiesterase 4 inhibitor. CPOD. 2010 Apr; 7(2):141-53. 4- Sanford M. Roflumilast: in chronic obstructive pulmonary disease. Drugs. 2010;70(12):1615-27. 5- Daxas® [Bula]. São Paulo: Nycomed Pharma. 6- Calverley PM et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374(9691):685-694. 7- Fabbri LM, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long acting bronchodilators: two randomised clinical trials. Lancet. 2009;374(9691):695-703. 8- Rennard SI, et al. Reduction of exacerbations by the PDE4 inhibitor roflumilast - the importance of defining different subsets of patients with COPD. Respir Res. 2011;12(1):18. 9- European Medicines Agency. Daxas EPAR. [online] 2010 [citado em 2011 fev 21]. Disponível em: URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/001179/WC500095211.pdf 10- Miravitlles M. Cough and sputum production as risk factors for poor outcomes in patients with COPD. Respiratory Medicine. 2011; xx, 1e11 11- GOLD Executive Committee. Global Initiative for Chronic Obstructive Lung Disease strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: updated 2010. [online] 2010 [citado em 2011 mar 14]. Disponível em: URL: http://www.goldcopd.org/Guidelineitem.asp?l1=2&l2=1&intId=989 12- Hurst JR, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010 Sep 16;363(12):1128-38. 13- Hatzelmann A, et al. The preclinical pharmacology of roflumilast – A selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2010; 23(4):235-56. 14- McIvor RA. Future options for disease intervention: important advances in phosphodiesterase 4 inhibitors. Eur Respir Rev 2007; 16(05):105-112. 15- Garcia-Aymerich J, et al. Risk factors of readmission to hospital for a COPD exacerbation: a prospective study. Thorax. 2003;58(2):100-5. 16- Burgel PR, et al. Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects. Chest.

2009;135(4):975-82. 17- Saetta M, et al. CD8+ve cells in the lungs of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;160(2):711-7.

PRODUTO DE TITULARIDADE DA NYCOMED PHARMA LTDA. E COPROMOVIDO PELA MSD.

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

roflumilaste 500mcg INDO ALÉM DOS SINTOMAS.1

APRESENTANDO DAxAS®

TERAPIA QUE VAI Além DOS SINTOmAS1,2 Agindo sobre a inflamação crônica latente na DPOC.1,3 Exclusivo

modo de ação anti-inflamatória. 1,3-5

Reduz

a taxa de exacerbação. 1,2,4,6,7

melhora

a função pulmonar. 1,3,13,19,22

Beneficia pacientes1,13 com risco de exacerbação:1,5,11,12,16 - tosse e expectoração crônicas - histórico de exacerbação.

1 comprimido ao dia

DAxAS® ESTá DISPONíVEl Em cAIxAS DE 30 cOmPRImIDOS12

Associado ao tratamento de manutenção12

Contraindicações: alergia aos componentes da fórmula e pacientes com insuficiência hepática moderada ou grave.

Interações medicamentosas: a administração de indutores enzimáticos do citocromo P450, como rifampicina e anticonvulsionantes, 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.

EM CASO DE DÚVIDAS LIGUE GRATUITAMENTE

SAC: 0800-7710345

www.nycomed.com.br Nycomed Pharma Ltda. Rua do Estilo Barroco, 721 - 04709-011 - São Paulo - SP

roflumilaste 500mcg INDO ALÉM DOS SINTOMAS.1

Controle e adesão para o tratamento da asma1-9 OXIMAX® (furoato de mometasona). INDICAÇÕES: indicado para o controle e na profilaxia da asma de qualquer intensidade, inclusive no tratamento dos pacientes asmáticos dependentes de corticosteróides inalatórios ou sistêmicos, e de pacientes asmáticos não-dependentes de corticosteróides, porém inadequadamente controlados com outros esquemas de tratamento.

CONTRAINDICAÇÕES: contra-indicado em pacientes com hipersensibilidade conhecida ao furoato de mometasona ou à lactose. PRECAUÇÕES E ADVERTÊNCIAS: Durante os estudos clínicos, ocorreu o desenvolvimento de infecções localizadas de boca e faringe com Candida albicans. Poderá haver o desencadeamento de um episódio de broncoespasmo com aumento imediato de sibilos após a dose. É necessário cuidado especial com pacientes em processo de transição de corticosteróides sistemicamente ativos para OXIMAX. OXIMAX não é um broncodilatador e não é indicado para o alívio rápido do broncoespasmo ou de outros episódios agudos de asma. Durante esses episódios, os pacientes poderão precisar de terapia com corticosteróides orais. OXIMAX não deve ser utilizado durante a gravidez, nem por mães que estejam amamentando, a menos que o benefício justifique o risco potencial à mãe, ao feto ou ao bebê. INTERAÇÕES MEDICAMENTOSAS: A co-administração de OXIMAX com o cetoconazol, um potente inibidor da enzima CYP3A4, pode aumentar os níveis plasmáticos de furoato de mometasona durante administração concomitante. REAÇÕES ADVERSAS: As reações adversas mais comuns são cefaléia, rinite alérgica, faringite, infecção do trato respiratório superior, sinusite, candidíase oral, dismenorréia, dor músculo esquelética, dor lombar e dispepsia.

POSOLOGIA: OXIMAX destina-se ao uso em adultos e em crianças a partir de 12 anos. A dose inicial recomendada na terapia com OXIMAX para a maioria dos pacientes, independentemente de terem sido anteriormente tratados apenas com broncodilatadores ou corticosteróides inalatórios, é de 400 μg uma vez por dia, aplicados com o dispositivo. Alguns pacientes podem ser mais adequadamente controlados com 400 μg administrados em duas doses diárias (200 μg duas vezes por dia). A redução da dose para 200 μg uma vez por dia pode ser uma alternativa para a manutenção eficiente em alguns pacientes. MS 1.0093.0211.

VENDA SOB PRESCRIÇÃO MÉDICA. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. Mais informações à disposição da classe médica no departamento científico da Mantecorp. Distribuição exclusiva à classe médica.

(MB-OXI5). Referências bilbiográficas: 1. D’Urzo A. Mometasone furoate dry-powder inhaler for the control of persistent asthma Expert Opin Pharmacother. 2007;8(16):2871-84. 2. Sabatini F, et al. Concentration-dependent effects of mometasone furoate and dexamethasone on foetal lung fibroblast functions involved in airway inflammation and remodeling. Pulm Pharmacol Ther.

2003;16(5):287-97. 3. Hauri H P. Glucocorticoid receptor activation by long acting steroids and its modification by inflammation.

Thesis. Philosophisch-Naturwissenschaftlichen Fakultät, Basel, 2007. 4. Tayab ZR, et al. Pharmacokinetic/pharmacodynamic evaluation of urinary cortisol suppression after inhalation of fluticasone propionate and mometasone furoate. Br J Clin Pharmacol.

2007;64(5):698-705. 5. Sharpe M, Jarvis B. Inhaled mometasone furoate: a review of its use in adults and adolescents with persistent asthma. Drugs. 2001;61(9):1325-50. 6. Corren J, et al. Comparison of once-daily mometasone furoate versus oncedaily budesonide in patients with moderate persistent asthma. Int J Clin Pract. 2003 ;57(7):567-72. 7. Price D, et al. Improved adherence with once-daily versus twice-daily dosing of mometasone furoate administered via a dry powder inhaler: a randomized open-label study. BMC Pulm Med. 2010;10:1. 8. Bula do produto. 9. Palmqvist M, et al. Inhaled dry-powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect and potency. Eur Respir J 1997; 10: 2484-9.

CONTRAINDICAÇÕES: contraindicado em pacientes com hipersensibilidade conhecida ao furoato de mometasona ou à lactose. INTERAÇÕES MEDICAMENTOSAS: a coadministração de OXIMAX com o cetoconazol, um potente inibidor da enzima CYP3A4, pode aumentar os níveis plasmáticos de furoato de mometasona durante administração concomitante.

Controle e adesão para o tratamento da asma1-9

AMPM

Ação anti-inflamatória máxima 1-3 mais potente que a fluticasona 4 Feedback

Max

Dispositivo amigável.

O paciente percebe que usou o medicamento.

Menos que 1% de

biodisponibilidade sistêmica 5

Potencializa a capacidade pulmonar

1,2,6

Máxima adesão: apenas 1 vez ao dia

7,8

redução dos mecanismos de remodelamento 2

Eventos 2011 NACIONAL XIV Congresso Paulista de Pneumologia e Tisiologia 17 a 20 de novembro Local: Centro Fecomércio de Eventos São Paulo - SP

INTERNACIONAIS ERS 2011 24 a 28 de setembro Local: Amsterdam - Holanda CHEST 2011 22 a 27 de outubro Local: Honolulu - Hawaii - EUA

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.

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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 de Carvalho Editor-Chefe do Jornal Brasileiro de Pneumologia SEPS 714/914, Bloco E, Asa Sul, salas 20/223.

CEP 70390-145 - Brasília - DF, Brasil.

Telefones/Fax: 0xx61-3245-1030, 0xx61‑3245-6218

Email do Jornal Brasileiro de Pneumologia: jpneumo@jornaldepneumologia.com.br (Secretária Luana Campos)

VAN.11.C.122 - Produzido em Julho/2011.

Escolha alcançar e manter o controle 1

Spray HFA com contador DOSE A DOSE2

• Controle rápido e sustentado da asma em pacientes não controlados.2,4,5 • Utiliza HFA como propelente. 3

6/200 mcg

6/100 mcg

Referências bibliográficas: 1. Kairos: publicação dirigida aos médicos, farmacêuticos, odontólogos, e outros profissionais de saúde. 2011; Jan/Março,266: pag 187. 2. Hampel FC, Martin P, Mezzanotte WS. Early bronchodilatory effects of budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI and albuterol pMDI: 2 randomized controlled trials in adults with persistent asthma previously treated with inhaled corticosteroids. J Asthma. 2008 May;45(4):265-72. 3. Bula do produto. 4.Kaiser H, Parasuraman B, Boggs R, Miller CJ, Leidy NK, O’Dowd L. Onset of effect of budesonide and formoterol administered via one pressurized metered-dose inhaler in patients with asthma previously treated with inhaled corticosteroids. Ann Allergy Asthma Immunol. 2008;101(3):295-303. 5. Kaiser H, Miller CJ, O´Dowd L. Measured onset of bronchodilation with budesonide and formoterol administered via one pressurized metered-dose inhaler (pMDI) in patients with asthma previously receiving inhaled corticosteroids (Abstract no. 974). J Allergy Clin Immunol 2007;119:S249.

• Reduz em 57% as exacerbações em comparação

Vannair® 6/100 mcg/inalação e Vannair® 6/200 mcg/inalação (fumarato de formoterol diidratado/budesonida) é composto por substâncias que possuem diferentes modos de ação e que apresentam efeitos aditivos em termos de redução da asma do que outros produtos isoladamente. A budesonida é um glicocorticosteroide que tem uma rápida (dentro de horas) e dose-dependente ação anti-inflamatória nas vias aéreas e o formoterol é um agonista beta-2-adrenérgico seletivo de início de ação rápido (1-3 minutos) e de longa duração (pelo menos 12 horas). Contraindicações: hipersensibilidade a budesonida, ao formoterol ou a outros componentes da fórmula.Interações medicamentosas: o metabolismo da budesonida é mediado principalmente pela CYP3A4, uma subfamília do citocromo P450. Portanto, inibidores desta enzima, como o cetoconazol ou suco de grapefruit (pomelo), podem aumentar a exposição sistêmica à budesonida. A cimetidina apresenta um leve efeito inibidor sobre o metabolismo hepático da budesonida. Fármacos como a procainamida, fenotiazina, agentes anti-histamínicos (terfenadina), inibidor da monoaminooxidase (MAO) e antidepressivos tricíclicos foram relacionados com um intervalo QTc prolongado e um aumento do risco de arritmia ventricular. Os bloqueadores beta-adrenérgicos (incluindo os colírios oftálmicos) podem atenuar ou inibir o efeito do formoterol (para maiores informações vide bula completa do produto). Indicações: Vannair® está indicado no tratamento da asma nos casos em que o uso de uma associação (corticosteroide inalatório com um beta-2 agonista de ação prolongada) é apropriado. Cuidados e Advertências: é recomendado que a dose seja titulada quando o tratamento de longo prazo é descontinuado e este não deve ser interrompido abruptamente. Para minimizar o risco de candidíase orofaríngea, o paciente deve ser instruído a lavar a boca com água após administrar as inalações de Vannair®. Uma deterioração súbita e progressiva do controle da asma é um risco potencial e o paciente deve procurar suporte médico. Pacientes que necessitaram de terapia corticosteroide de alta dose emergencial ou tratamento prolongado de altas doses recomendadas de corticosteroides inalatórios podem exibir sinais e sintomas de insuficiência adrenal quando expostos a situações de estresse grave. Administração de corticosteroide sistêmico adicional deve ser considerada durante situações de estresse ou cirurgia eletiva. Vannair® deve ser administrado com cautela em pacientes com graves alterações cardiovasculares (incluindo anomalias do ritmo cardíaco), diabetes mellitus, hipocalemia não tratada ou tireotoxicose. Pacientes com prolongamento do intervalo QTc devem ser cuidadosamente observados (para maiores informações vide bula completa do produto). Uso durante a gravidez e a lactação: categoria C de risco de gravidez. Este medicamento não deve ser utilizado por mulheres grávidas sem orientação médica ou do cirurgião dentista. A administração de Vannair® em mulheres lactantes deve ser apenas considerada se os benefícios esperados para a mãe superarem qualquer possível risco para a criança (para maiores informações vide bula completa do produto). Reações adversas: as reações adversas que foram associadas à budesonida ou ao formoterol são apresentadas a seguir. Comum: palpitações, candidíase na orofaringe, cefaleia, tremor, leve irritação na garganta, tosse, rouquidão. Incomum: taquicardia, náusea, cãibras musculares, tontura, agitação, ansiedade, nervosismo e perturbações do sono (para outras reações adversas, vide bula completa do produto). Posologia: a dose de Vannair® deve ser individualizada conforme a gravidade da doença. Quando for obtido o controle da asma, a dose deve ser titulada para a menor dose que permita manter um controle eficaz dos sintomas. Vannair® 6/100 mcg/ inalação: Adultos (a partir de 18 anos de idade): 2 inalações uma ou duas vezes ao dia. Em alguns casos, uma dose máxima de 4 inalações duas vezes ao dia pode ser requerida como dose temporária de manutenção durante a piora da asma. Adolescentes (12-17 anos): 2 inalações uma ou duas vezes ao dia. Durante a piora da asma a dose pode temporariamente ser aumentada para o máximo de 4 inalações duas vezes ao dia.

Crianças (6-11 anos): 2 inalações duas vezes ao dia. Dose máxima diária: 4 inalações. Vannair® 6/200 mcg/inalação: Adultos (a partir de 18 anos de idade): 2 inalações uma ou duas vezes ao dia. Em alguns casos, uma dose máxima de 4 inalações duas vezes ao dia pode ser requerida como dose temporária de manutenção durante a piora da asma. Adolescentes (12-17 anos): 2 inalações uma ou duas vezes ao dia.

Durante a piora da asma a dose pode temporariamente ser aumentada para o máximo de 4 inalações duas vezes ao dia. Instruções de Uso: vide bula completa do produto. Superdose: a superdosagem de formoterol irá provavelmente provocar efeitos típicos dos agonistas beta-2-adrenérgicos: tremor, cefaleia, palpitações e taquicardia. Poderá igualmente ocorrer hipotensão, acidose metabólica, hipocalemia e hiperglicemia. Pode ser indicado um tratamento de suporte e sintomático. A administração de uma dose de 90 mcg durante três horas em pacientes com obstrução brônquica aguda e quando administrada três vezes ao dia como um total de 54 mcg/dia por 3 dias para a estabilidade asmática não suscitou quaisquer problemas de segurança. Não é esperado que uma superdosagem aguda da budesonida, mesmo em doses excessivas, constitua um problema clínico. Quando utilizado cronicamente em doses excessivas, podem ocorrer efeitos glicocorticosteroides sistêmicos (para informações de superdosagem grave vide bula completa do produto). Apresentações: Vannair® 6/100 mcg/inalação: Aerossol bucal 6/100 mcg/inalação em embalagem com 1 tubo contendo 120 doses. USO ADULTO E PEDIÁTRICO. Vannair® 6/200 mcg/inalação: Aerossol bucal 6/200 mcg/inalação em embalagem com 1 tubo contendo 120 doses. USO ADULTO. USO POR INALAÇÃO ORAL. VENDA SOB PRESCRIÇÃO MÉDICA. Para maiores informações, consulte a bula completa do produto. (VAN6_100_002a / VAN6_200_002a). AstraZeneca do Brasil Ltda., Rod. Raposo Tavares, Km 26,9 - Cotia - SP - CEP 06707-000 Tel.: 0800-0145578. www.astrazeneca.com.br. Vannair®. MS – 1.1618.0234.

• A opção terapêutica segura, inclusive para crianças

CONTRAINDICAÇÃO: HIPERSENSIBILIDADE A BUDESONIDA E/OU AO FORMOTEROL E AOS OUTROS COMPONENTES DA FORMULAÇÃO. INTERAÇÃO MEDICAMENTOSA: DA BUDESONIDA COM O CETOCONAZOL. A PERSISTIREM OS SINTOMAS O MÉDICO DEVERÁ SER CONSULTADO. Material destinado à classe médica.

com formoterol+budesonida4

Spray:2 25/50 mcg 25/125 mcg 25/250 mcg

Diskus:3 50/100 mcg 50/250 mcg 50/500 mcg

de 4 a 11 anos5 • É a terapia combinada que provou alcançar e manter o controle da asma definido pelo GINA1

Com Seretide, a asma não detém seu paciente.

Referências bibliográficas: 1 - BATEMAN, ED. et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med, 170(8): 836-44, 2004. 2 - Seretide® Spray (xinafoato de salmeterol/propionato de fluticasona). Bula do produto. 3 - Seretide® Diskus (xinafoato de salmeterol/propionato de fluticasona).

Bula do produto. 4 - DAHL, R. et al. EXCEL: A randomised trial comparing salmeterol/fluticasone propionate and formoterol/budesonide combinations in adults with persistent asthma.

Respir Med, 100(7): 1152-62, 2006. 5 - KRAMER, JM. Balancing the benefits and risks of inhaled long-acting beta-agonists — the influence of values. N Engl J Med, 360(16): 1592-5, 2009.

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).

A minibula encontra-se no interior desta edição.

Material de divulgação 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 ao Serviço de Informação Médica (DDG 0800 701 22 33 ou http://www.sim-gsk.com.br).

REPENSE SER182009 – JAN/10 www.gsk.com.br Estrada dos Bandeirantes, 8.464 • Jacarepaguá Rio de Janeiro • RJ • CEp 22783-110 CNpJ 33247 743/0001-10

Material Produzido em maio/2011

Jornal Brasileiro de Pneumologia

Disponível nas doses de 150 mg e 300 mg

O único Ultra-LABA com rápido início de ação em 5 minutos com 24 horas de Broncodilatação

J Bras Pneumol. v.37, number 5, p. 571-702 September/October 2011

PUBLICAÇÃO OFICIAL DA SOCIEDADE BRASILEIRA DE PNEUMOLOGIA E TISIOLOGIA

Highlight

ASTHMA Acute asthma management in children: knowledge of the topic among health professionals at teaching hospitals in the city of Recife, Brazil

Weaning from MV Editorial Martin J. Tobin

EXPERIMENTAL An experimental rat model of ex vivo lung perfusion for the assessment of lungs after prostacyclin administration: inhaled versus parenteral routes

PULMONARY FUNCTION

Hematopoietic stem cell transplantation: pulmonary function tests and post-transplant mortality Reference equations for the performance of healthy adults on field walking tests Spirometric reference values for healthy adults in the Mazandaran province of Iran

INFECTION

Robotic Thymectomy

Occurrence of influenza among patients hospitalized for suspicion of influenza A (H1N1) infection in 2010 at a sentinel hospital in São Paulo, Brazil September/October 2011 volume 37 number 5

Pneumonia associada a influenza A (H1N1)

SLEEP Negative expiratory pressure test: a new, simple method to identify patients at risk for obstructive sleep apnea

TUBERCULOSIS Restriction enzyme analysis of the hsp65 gene in clinical isolates from patients suspected of having pulmonary tuberculosis in Teresina, Brazil Active tuberculosis among health care workers in Portugal Tuberculin skin test: operational research in the state of Mato Grosso do Sul, Brazil Identification of Mycobacterium bovis among mycobacterial isolates from human clinical specimens at a university hospital in Rio de Janeiro, Brazil

REVIEW Weaning from mechanical ventilation Gastroesophageal reflux disease and the airways

p.571-702

ONBRIZETM 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: ONBRIZETM 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% do valor normal previsto e um VEF1/CVF pós-broncodilatador inferior a 70%. Posologia: Adultos – A dose recomendada de ONBRIZETM é uma inalação uma vez ao dia do conteúdo de uma cápsula de ONBRIZETM 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. Método de administração: As cápsulas de ONBRIZETM devem ser administradas apenas por via inalatória oral e apenas usando o inalador. As cápsulas de ONBRIZE™ não devem ser engolidas. ONBRIZETM 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 armazenadas no blíster, e apenas removidas imediatamente antes do uso. Contraindicações: Hipersensibilidade ao princípio ativo ou a qualquer um dos excipientes. ONBRIZETM é contraindicado para pacientes asmáticos. Precauções e Advertências: Asma – ONBRIZETM 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, ONBRIZETM 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 ONBRIZETM 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 fertilidade com 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 ONBRIZETM. Lactação – o uso de ONBRIZETM 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 beta2-adrenérgicos. 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. • Referência bibliográfica: (1) Battram C, Charlton SJ et al. In vitroan in Vivo Pharmacological Characterization of 5-[(5,6-Diethyl-indan-2ylamino)-1-hydroxy-ethyl]-8-hydroxy-1Hquinolin-2-one(Indacaterol), a Novel Inhaled Beta 2 Adrenoceptor Agonist with a 24 h Duration of Action.

The Journal of Pharamacology and Experimental Therapeutics 2006; Vol 317:762-770. Material destinado exclusivamente à classe médica. A figura do leão é meramente ilustrativa, não refletindo o mecanismo de ação do medicamento. www.portal.novartis.com.br/onbrize.

Publicação Bimestral

Six-minute walk test: reference values for healthy adults in Brazil

1

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 hipocalemicos.

ISSN 1806-3713

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

Six-minute walk test Editorial Celso R. F. de Carvalho